H trs tipos principais de alcalides:

A colchicina exemplo de um proto-alcalide. Os Pseudo-alcalides podem

ser derivados de;
Terpenoids ou
Purines
ALCALIDES VERDADEIROS
A unidade sica na io!enesis dos alcalides verdadeiros um
aminocido. Os nitro!nios n"o heteroc#clicos anis ou $ue est"o em cadeias
laterais s"o derivados do A%&TATO e'ou do T&(P&)O* $uando o
+&TH,O),)& -or responsvel pela a adi."o de !rupos met#licos aos
tomos do nitro!nio.
Os alcalides s"o sust/ncias altamente reativas com atividade
iol!ica em doses aixos.
0&1,),23O
4. %ontem o nitro!nio - derivado !eralmente de um aminocido.
5. 6osto amar!o* slidos !eralmente rancos 7exce."o - a nicotina um
l#$uido marrom8.
9. 0"o precipitados com iodetos de metal pesado.

A maioria de alcalides s"o precipitados em pH neutro ou de
solu."o li!eiramente ac#dica pelo rea!ente de +a:er 7solu."o
iodo mercuriato de potssio8. Precipitate de cor creme.
O rea!ente de 0ra!endor-- 7solu."o do iodo ismutato de
potassio8 d precipitado colorido de laran;a com alcalides.
A ca-e#na* um derivado da purine* n"o precipita como a maioria
de alcalides.
<. Os alcalides s"o sicos - -ormam sais sol=veis em !ua. A maioria
de alcalides s"o sust/ncias cristalinas em de-inidas $ue se unem
com os cidos -ormando sais. )as plantas* podem existir
no estado livre*
como sais ou
como )-xidos.
>. Ocorre em um n=mero limitado das plantas. O cido nuclico existe
em todas as plantas* ; a mor-ina existe em somente uma espcie da
planta.
Os alcalides podem ser classi-icados;

nos termos de sua atividade ?,O@A6,%A*
&strutura BCD+,%A 7n=cleo $ue contem o nitro!nio8*
caminho ?,OEF)TH&T,% 7a maneira como s"o produGidos na
planta8.
Perguntas Freqentemente Feitas Sobre A Cafena
4. A $u#mica da ca-e#na e de produtos relacionados
4. Buanto ca-e#na h dentro H drinI'-ood'pill JK
5. Buanto ca-e#na l est no ca- de LK
9. Buimicamente -alando* $ue ca-e#naK
<. M verdadeiro $ue o ch n"o tem nenhum ca--eine'Nhat
theine* theoromine* etc.K
>. Onde posso eu encontrar um 6,1 da molcula da ca-e#naK
O. M verdadeiro $ue o espresso tem menos ca-e#na do $ue o ca-
re!ularK
P. %omo a ca-e#na provaK
Q. Buanto theoromine'theoph:lline h...K
R. O ca- escuro dos roast tem menos ca-e#na do $ue roast clarosK
4S.%omo eu me.o o #ndice da ca-e#na no repousoK
44. H um limite le!al para o #ndice da ca-e#naK
5. %a-e#na e sua sa=de
4. (etirada 0a %a-e#na
5. Bue acontecer $uando voc overdoseK
9. &-eitos da ca-e#na em mulheres !rvidas.
<. %a-e#na e Osteoporosis 7perda do clcio8
>. &studos nos side-e--ects da ca-e#na...
O. %a-e#na e seu metaolism.
9. Tariado
4. %omo voc pronuncia o mateK
<. (eceitas
4. O chocolate coriu -ei;Ues do espresso
5. %omo -aGer seu prprio chocolate
9. )OTA: para ver se h o ca- as receitas veri-icam o 1AB do
ca-
>. (ecursos &letrVnicos
O. Administrivia
4. %omo eu come.o a cpia a mais nova deste 1ABK
5. @ista dos contriuinte
9. %op:ri!ht
1 A qumi!a "a !afena e "e #ro"utos re$a!iona"os
1 %uanto !afena &' "entro ( "rin)*foo"*#i$$ +,
0e acordo com a associa."o nacional de eidas ;eves* o se!uinte o
#ndice da ca-e#na em m! por a lata de 45 on.as de soda:
Sr. sugar-Free Pibb 58,8
Pepsi um da sacudida 71,2
RedBull 80 da Afri-Cla 100,0 !"# !pr 250
ml# 55,5 bebida da e$ergia da ba%eria da aba &',8
d surge 51,0 d amarel 52,8 de (ell d ci%ri$
5& d p$%ap) d r*al+ 55,0 da m$%a$+a da die%a
d r*al+ 55,0 da m$%a$+a !$e$+uma cafe,$a em
Ca$ad-# !.'mg pr a la%a 8/, a cafe,$a d guara$a#
-- 1&0mg0l 1 &'.7mg0ca$ de Bar2 sec gra$de da cla
.0,0 da die%a RC .',0 Ca$ad- da cla .',0 de Pepsi
.5,& RC da die%a de Aspe$ .',0 da cla .7,2 de
Pepsi d *ermel+ .8 da %empes%ade .8 d 3r.
Pime$%a .4,' da lara$5a &0 de Su$6is% da sda &0,5
da APR78A9:7 d Sr. Pibb &0,8 da cla &&,& da die%a
de S+as%a da cla &&,& da cere5a de S+as%a da cla
&&,& de S+as%a da Cca-Cla &5,' cla seca 1,2 da
die%a de Ca$ad- da cer*e5a 2. da rai/ 7 Acima 3e 0
Bar2 3a 3ie%a 3a Cer*e5a 0 3a Rai/ 3a Ca$eca 3e
Ri%e 3a 3ie%a Clas ;ara$5a (i$ucisa 0 3a
<mpregada dm)s%ica 3a ;ara$5a 0 3e Su$drp 3a
Cer*e5a 0 3a Rai/ 3e 0 Spri%e 0 = >ma Cer*e5a 0 3a
Rai/ 3e ?
;abra%@ri 101.'mg0500ml da ams%ra
47.7mg0500ml 2 da ams%ra 1 de Ara$6BC
;abra%@ris 3e Ameri%ec+, Faculdade
Pi$%a, DEF %es%ad se%embr 0., 4'
;abra%@ri 4'.&mg0500ml m)di de Ara$6BC
;abra%@ris de Ameri%ec+, %es%ads ags%
24, 4'
Por meio da compara."o* um copo de P on.as do ca- tem as
se!uintes $uantidades da ca-e#na 7ma!nsio8* de acordo com o unIer e o
+cNilliams na dieta do W. Am.. P<:5Q-95* 4RPR:
G%e5e 115-175 <spress 100mg da cafe,$a 1
ser*i$g !1.5-B/#
80-1.5 i$s%a$%e breHed '5-100 3ecaf,
breHed .-& 3ecaf, c+- d i$s%a$%e 2-.,
c$gelad !12 $Ias.# 70 c+-, c+- '0
breHed, impr%ad, breHed, <. >.. &0 c+-,
ma%e 25-150mg d i$s%a$%e .0
A variailidade na $uantidade de ca-e#na em um copo do ca- ou de
ch relativamente !rande mesmo se preparado pela mesma pessoa usando
o mesmo dia do e$uipamento e dos in!redientes aps o dia.
(e-erence Variability in caffeine consumption from coffee and tea: Possible
significance for epidemiological studies by B. Stavric, R. Klassen, B.
Watkinson, K. Karpinski, R. Stapley, and P. ried in !oundations of
"#emical $o%icology !, Volume &', number &, pp. ((()((*, (+** e um -cil
de ler a vista !eral* ,ooking for t#e Perfect Bre- by S. .isenberg, !Science
/e-s !, Volume (00, 1pril (', (+**, pp. &2&)&20.
%ite do manual de laoratrio:
1 cafe3na est4 atual no c#4 sae e no caf5 6 e%tens7o de
apro%imadamente 89. : c#4 contem tamb5m outros dois
alcal;ides, t#eobromine e t#eop#ylline. .stes <ltimos dois
rela%am os m<sculos lisos onde a cafe3na estimula o
cora=7o e os sistemas respiratory.
Os e-eitos do theoromine s"o* comparado X ca-e#na e ao
theoph:lline* relativamente moderados. &ntretanto* a cacau contem oito
veGes mais theoph:lline do $ue a ca-e#na. Tamm* a ca-e#na -oi mostrada X
li!a com outras sust/ncias para o potenc: adicionado. Assim os e-eitos do
theoromine puderam ser real.ados pela ca-e#na no chocolate.
O theoromine altamente txico aos c"es e mata muitos canids':ear
atravs do envenenamento do chocolate . 1aG exame completamente de um
dose aos n#veis -atais do alcance 7um od:Yei!ht de mais de 5SS m!'I!8
mas al!uns c"es tm um hito mau de comer -ora das latas do lixo e al!uns
proprietrios tm um hito mau de c"es de alimenta."o doce. Al!uns oreos
n"o -erir"o um c"o* mas uma lira do chocolate pode -aGer os danos
considerveis.
Os sinais cl#nicos do toxicit: do theoromine nos canids !eralmente
mani-estam Q horas aps o in!estion e podem incluir: thirst* vomitin!*
diarrhea* incontinence urinar:* nervousness* spasms clonic do m=sculo*
apreensUes e coma. Todo o pensamento do c"o para in!ested uma
$uantidade !rande do chocolate deve ser traGido a uma cl#nica da
emer!ncia o mais cedo poss#vel* onde o tratamento inclui !eralmente o uso
do emetics e do carv"o de lenha ativado. O c"o necessitar assim ser
monitorado para manter o contrapeso apropriado do l#$uido e do eletrlito.
Patho!enesis do toxicit: do theoromine: evidente as $uantidades
!randes do theoromine tm um e-eito diuretic* relaxam os m=sculos lisos* e
estimulam o cora."o e o cns.
(e-erncia:
1raser* +. de %larence* et al* eds. O manual veterinrio de +ercI* Po ed.
(ahYa:* )W: +ercI Z %o.* ,nc. 4RR4. pp. 4O<9-<<.
&m atos da ca-e#na dos seres humanos particularmente no crero e
nos m=sculos es$ueletais $uando o theoph:lline alve;ar o cora."o* o
ronchia* e os Iidne:s.
Outros dados na ca-e#na:
7 cp da barra .0mg d c+cla%e da cla .0-
&5mg d ma%e 25-150mg d c+- .0-70mg d caf)
imedia% '0-80mg d caf) 40-150mg Perma$eI-acrda a
%abule%a fria .0mg d rele* d pill 100mg 8i*ari$
200mg
A se!uinte in-orma."o de Bo-es and "#urc#>s ood values of
portions commonly used, by 1nna ?e Planter Bo-es.
,ippincott, P#ila. (+*+. Pages &'()&: "affeine.
3ceC
C+c d ba6i$g da cafe,$a d mag$)si d
c+cla%e, u$sHee%e$ed, padeirs -- 1 dce
alemJ de /!28 g# 25, padeirs -- 1 $Ia
!28 g# 8 semi-sHee%, padeirs -- 1 $Ia
!28 g# 1.
C+c lasca padeirs -- 10& de cp !&. g#
1. dce alemJ, padeirs -- 10& de cp
!&. g# 15
Barra d c+cla%e, CadburK -- 1 $Ia !28
g# 15 barra de 1,& $Ias d c+c d lei%e.
.-10 barra de 1,& $Ias d c+c bra$c 2-&
barra de 1,& $Ias d lei%e de c+cla%e
escur d lei%e de c+cla%e 8/ d c+c
28 8 *idr 2-7 de 8 $Ias
3esser%sC PDF d pudim de Lell, C+c !&7
g# 2 musse de C+c da mis%ura de Lell-7
!45 g# ' musse d fudge d c+c de Lell
!8' g# 12 c+cla%e cbriram fei5J d
espress .-5
Bebidas
. %easp$s +eapi$g da mis%ura 8 d p@ d
c+c 2 cl+eres d sKrup 5 d c+c 1
mis%ura 2ue$%e 5 da cacau d e$*elpe
As f@rmulas die%)%icas asseguram-se, si$al
de adiIJ, c+c, labra%@ris de Rss -- 8
$Ias !254 g# 10 barra d c+cla%e de
lei%e de CadburK
(ais ma%erialC
7 pder M m-gic de Guara$a M
!cmple%ame$%e cmum em Germa$K#, 15 ml de
-lcl cm 5g Guara$a semeia 250,0
c-psulas d mag$)si Guara$a cm 500
mag$)si das seme$%es 25,0 d mag$)si
G.0c-psula
!cafe,$a sup$d de 5N $as seme$%es cm
i$dicad $a li%era%ura#
O P)1 da soda de 6uarana est ui$uitous em ?rasil e
-re$uentemente dispon#vel no mantimento tropical a$ui. M
realmente tast: e emala um Yallop. 6uarana acorda-o acima
como louco* mas n"o causa tremores do ca-.
M poss#vel $ue alm X ca-e#na* h al!uma outra sust/ncia no
!uarana $ue produG tamm um e-eito* desde $ue [ sentiu
di-erente do $ue o ca-. +esmo vai para o mate.
(etorne ao #ndice
- %uanto !afena $' est' no !af. "e /,
Dndice da ca-e#na nos -ei;Ues e nas misturas
7-onte: ?oletim de not#cias -- +ountanos ?ros. %a- %o.* Ean
1rancisco8
Burb$s 1,20N Celebes Aalssi de
8ARO<PA;S0SPRAOGQPS Brasil ClRmbia 1,22
<Scels ClRmbia 1,.7 Suprem 1,.7 Qarrar-
(6a <%+ipia$ G 1,1.
TTT PRADS;APO7D <D3S Q<R< TTTua%emala
A$%igua 1..2
O$dia$ (Ksre 1..7
Lamaica$ Blue (%$0?alle$sfrd <s%a%e 1.2&
La*a <s%a%e AuKumas 1.20
Ae$Ka AA 1..'
A$a <S%ra Prime 1..2
(eSic Pluma Al%ura 1.17
(c+a (a%%ari !Eeme$# 1.01
DeH Gui$ea 1..0
Pa$ama 7rga$ic 1..&
Suma%ra (a$d+eli$g-;i$%$g 1..0
Pa$/a$ia PeaberrK 1.&2
UimbabHe 1.10
B;<D3S = 3ARA R7ASPS
Clmbia Suprem 3ar6 1..7N
<spress Ras% 1..2
Fre$c+ Ras% 1.22
8ie$$a Ras% 1.27
(c+a-La*a 1.17
3<CAFS--all V .02N Hi%+ SHiss ?a%er
Prcess
Re%ur$ % O$deS
0 C&emi!a$$1 s#ea)ing2 3&at is !affeine,
%a--eine is an alIaloid. There are numerous compounds called
alIaloids* amon! them Ye have the meth:lxanthines* Yith three
distin!uished compounds: ca--eine* theoph:lline* and
theoromine* -ound in cola nuts* co--ee* tea* cacao eans* mate
and other plants. These compounds have di--erent iochemical
e--ects* and are present in di--erent ratios in the di--erent plant
sources. These compounds are ver: similar and di--er onl: :
the presence o- meth:l !roups in tYo positions o- the chemical
structure. The: are easil: oxidiGed to uric acid and other
meth:luric acids Yhich are also similar in chemical structure.
%a--eine:
Eources: %o--ee* tea* cola nuts* mate* !uarana.
&--ects: Etimulant o- central nervous s:stem* cardiac muscle*
and
respirator: s:stem* diuretic 0ela:s -ati!ue.
Theoph:lline:
Eources: Tea
&--ects: %ariac stimulant* smooth muscle relaxant* diuretic*
vasodilator
Theoromine:
Eources: Principle alIaloid o- the cocoa ean 74.>-9\8 %ola
nuts and tea
&--ects: 0iuretic* smooth muscle relaxant* cardiac stimulant*
vasodilator.
7,n-o -rom +ercI ,ndex8
The presence o- the other alIaloids in colas and tea ma: explain
Yh: these sometimes have a stron!er IicI than co--ee. %olas*
Yhich have loYer ca--eine contents than co--ee are* reportedl:*
sometimes more active. Tea seems the stron!est -or some.
%o--ee seems more lastin! -or mental alertness and o--ers -eYer
;itters than the others.
A search in %AE and produced these names and s:non:ms:
RD 58-08-2 R<GOSPRE
CD 1Q-Puri$e-2,'-di$e, .,7-di+Kdr-
1,.,7-%rime%+Kl- !4CO# !CA OD3<W DA(<#
7PQ<R CA OD3<W DA(<SC
CD Caffei$e !8CO#
7PQ<R DA(<SC
CD 1,.,7-Prime%+Kl-2,'-diSpuri$e
CD 1,.,7-Prime%+KlSa$%+i$e
CD 7-(e%+Kl%+ep+Klli$e
CD Aler%-Pep
CD Cafei$a
CD Caffei$
CD Cafipel
CD Guara$i$e
CD Affei$
CD (a%ei$a
CD (e%+Kl%+ebrmi$e
CD D-3/
CD Refres+X$
CD S%im
CD P+ei$
CD P+ei$e
CD Pri-A2ua
(F C8 Q10 D& 72
The !orre!t name is the -irst one* 4H-Purine-5*O-dione* 9*P-
dih:dro-4*9*P-trimeth:l- 7This is the ]inverted name ]8 The
]uninverted name ] is 9*P-0ih:dro-4*9*P-trimeth:l-4H-purine-
5*O-dione
+ercI ,ndex excerpt...
"affeine: 0,@)di#ydro) (,0,@)trimet#yl) (A)
purine) &,')dioneB (,0,@)trimet#yl%ant#ineB
(,0,@)trimet#yl) &,')dio%opurineB coffeineB
t#einB guaranineB met#ylt#eobromineB /o)
?oC.
"*A(D/8:&B mol -t (+8.(+. " 8+.8*9, A
2.(+9, / &*.*29, : ('.8*9.
:ccurs in tea, coffee, mate leavesB also in
guarana paste and cola nuts: S#uman, E.S.
pat. &,2D*,282 F(+2D to General oodsH.
:btained as a by)product from t#e manuf of
caffeine)free coffee: Barc#, E.S. pat.
&,*(@,2** F(+2@ to Standard BrandsHB
/utting, E.S. pat. &,*D&,@0+ F(+2@ to Aill
Bros. "offeeHB 1dler, .arle, E.S. pat.
&,+00,0+2 F(+'D to General oodsH.
"rystal structure: Sutor, 1cta "ryst. ((, 820,
F(+2*H. Synt#esis: isc#er, 1c#, Ber. &*,
&8@0, 0(02 F(*+2HB Gepner, Kreps, I. Gen.
"#em. ESSR (', (@+ F(+8'HB Bredereck et
al., Ber. *0, &D( F(+2DHB "rippa, "rippa,
armaco .d. Sci. (D, '(' F(+22HB
S-idinsky, BaiCer, E.S. pats. &,@*2,('& and
&,@*2,('0 F(+2@ to Juinine "#em. WorksHB
Bredereck, Gotsmann, Ber. +2, (+D& F(+'&H.
Ae%agonal prisms by sublimation, mp &0*
". Sublimes (@* ". ast sublimation is
obtained at ('D)('2 " under (mm press. at
2 mm distance. d (.&0. Kb at (+ ": D.@ %
(DKF)(8H. Ka at &2 ": L(.D % (DKF)(8H. pA
of (9 soln '.+. 1M solns of caffeine salts
dissociate Muickly. 1bsorption spectrum:
Aartley, I. "#em. Soc. *@, (*D& F(+D2H. :ne
gram dissolves in 8' ml -ater, 2.2 ml -ater
at *D ", (.2 ml boiling -ater, '' ml alco#ol,
&& ml alco#ol at 'D ", 2D ml acetone, 2.2 ml
c#loroform, 20D ml et#er, (DD ml benCene,
&& ml boiling benCene. reely sol in pyrroleB
in tetra#ydrofuran contg about 89 -aterB
also sol in et#yl acetateB slig#tly in petr
et#er. Soly in -ater is increased by alkali
benCoates, cinnamates, citrates, or
salicylates.
Nono#ydrate, felted needles, contg *.29
A&:. .fflorescent in airB complete
de#ydration takes place at *D ". ,?2D
orally in rats: &DD mgOkg.
1cetate, "*A(D/8:&.F"A0"::AH&,
granules or po-derB acetic acid odorB acid
reaction. ,oses acetic acid on e%posure to
air. Soluble in -ater or alco#ol -it#
#ydrolysis into caffeine and acetic acid.
Keep -ell stoppered.
Aydroc#loride di#ydrate,
"*A(D/8:&.A"l.&A&:, crystals, dec *D)
(DD " -it# loss of -ater and A"l. Sol in
-ater and in alco#ol -it# dec.
$#erap "at: "entral stimulant.
$#erap "at FVetH: Aas been used as a
cardiac and respiratory stimulant and as a
diuretic.
Return to Pnde%
4 Is it true t&at tea &as no !affeine*5&at is t&eine2
t&eobromine2 et!,
1rom ]Principles o- iochemistr: ]* Horton and al* 4RR9.
"affeine is sometimes called !t#eine ! -#en
it>s in tea. $#is is probably due to an ancient
misconception t#at t#e active constituent is
different. $#eop#ylline is present only in
trace amounts. Pt is more diuretic, more
to%ic and less speedy.
"affeine
(,0,@)trimet#yl%ant#ine
$#eop#ylline
(,0)dimet#yl%ant#ine
$#eobromine
0,@)dimet#yl%ant#ine
"offee and tea contain caffeine and
t#eop#ylline, respectively, -#ic# are
met#ylated purine derivatives t#at in#ibit
c1NP p#osp#odiesterase. Pn t#e presence of
t#ese in#ibitors, t#e effects of c1NP, and
t#us t#e stimulatory effects of t#e #ormones
t#at lead to its production, are prolonged
and intensified.
Theoromine and theoph:lline are tYo dimeth:lxanthines that
have tYo rather than three meth:l !roups. Theoromine is
consideral: YeaIer than ca--eine and theoph:lline* havin!
aout one tenth the stimulatin! e--ect o- either.
Theoromine is -ound in cocoa products* tea 7onl: in ver:
small amounts8 and Iola nuts* ut is not -ound in co--ee. ,n
cocoa* its concentration is !enerall: aout P times as !reat as
ca--eine. Althou!h* ca--eine is relativel: scarce in cocoa* its
mainl: ecause o- theoromine that cocoa is ]stimulatin! ].
Theoph:lline is -ound in ver: small amounts in tea* ut has a
stron!er e--ect on the heart and reathin! than ca--eine. 1or this
reason it is o-ten the dru! o- choice in home remedies -or
treatin! asthma ronchitis and emph:sema. The theoph:lline
-ound in medicine is made -rom extracts -rom co--ee or tea.
(eturn to ,ndex
6 5&ere !an I fin" a gif of t&e !affeine mo$e!u$e,
%a--eine ^ 4*9*P-Trimeth:lxanthine
A di--erent vieY o- the ca--eine molecule.
The 0epartment o- %hemistr: at Wamaica o- the Cniversit: o-
Nestern ,ndies has made availale an avi and an mpe! o- a
rotation o- the ca--eine molecule* amon! other molecules and
chemical processes. The index pa!e contains more in-ormation
and the linIs to the clips.
CQ.
Y
D
0 Z
D----C C117
YY YY Y
YY YY Y
CQ C D--CQ.
Z 0 Z 0
D C
Y YY
CQ. 7
There is a !i- picture at the Yuarchive.Yustl.edu -tp site or an:
o- its mirror sites under
mul%imedia0images0gif0c
caffei$e
Theoromine is also a common component o- co--ee* tea*
chocolate* and mate 7particularl: in these last tYo8.

P+ebrmi$e
CQ.
Y
D
0 Z
D----C C117
YY YY Y
YY YY Y
CQ C D--Q
Z 0 Z 0
D C
Y YY
CQ. 7
Theoph:lline Yas once thou!ht to e a ma;or component o- tea.
This is not correct. Tea contains si!ni-icantl: more amounts o-
ca--eine than o- theoph:lline.
P+ep+Klli$e
CQ.
Y
D
0 Z
D----C C117
YY YY Y
YY YY Y
CQ C D--CQ.
Z 0 Z 0
D C
Y YY
Q 7
(eturn to ,ndex
7 Is it true t&at es#resso &as $ess !affeine t&an regu$ar !offee,
Fes and no. An espresso cup has aout as much ca--eine as a
cup o- darI reY. ?ut servin!s -or espresso are much smaller.
Nhich means that the content o- ca--eine per milliliter are
much hi!her than Yith a re!ular reY. +oreover* ca--eine is
more $uicIl: assimilated Yhen taIen in concentrated dosa!es*
such as an espresso cup.
The m:th o- loYer ca--eine espresso comes comes -rom the -act
that the darIer roast eans used -or espresso do have less
ca--eine than re!ularl: roasted eans as roastin! is supposed to
reaI up or sulimate the ca--eine in the eans 7, have read this
$uote on research articles* ut -ound no scienti-ic studies
supportin! it. An:od: out thereK8. ?ut espresso is prepared
usin! pressuriGed Yater throu!h si!ni-icantl: more !round
7tYice as muchK8 than re!ular drip co--ee* resultin! in a hi!her
percenta!e o- ca--eine per milliliter. Please re-er also to 0oes
darI roast co--ee have less ca--eine than li!ht roastK
Here[s the ca--eine content o- 0rip'&spresso'?reYed %o--ee:
3rip 115-175
<spress 100 1 ser*i$g !1-
2/#
BreHed 80-1.5
(eturn to ,ndex
8 9o3 "oes !affeine taste,
%a--eine is ver: itter. ?ar$[s (oot ?eer contains ca--eine and
the compan: sa:s that it has ]45.PQm! per OoG ] and that the:
]add it as a -lavorin! a!ent -or the sharp itterness ]
(eturn to ,ndex
: 9o3 mu!& t&eobromine*t&eo#&1$$ine t&ere is in ,
Eources: Ph:sicians 0esI (e-erence and ,nstitute o- 1ood
Technolo!ies -rom Pa-ai and WanIieYicG 74RR48 0(C6E A)0
HC+A) ?&HAT,OC(
cca 250mg
%+ebrmi$e
bi%%ersHee% c+c. bar 1.0mg
%+ebrmi$e
5 / cup breHed cffee $ %+ebrmi$e
%ea 5/ cup breHed .mi$
Hi%+ %eabag .-& mg
%+ep+Klli$e
3ie% C6e $ %+ebrmi$e
r %+ep+Klli$e
(eturn to ,ndex
; Does "ar) roast !offee &a<e $ess !affeine t&an $ig&t roast,
,t reall: depends on hoY :ou measure the ca--eine. ,- :ou
measure : Yei!ht :ou actuall: have more ca--eine in darI
roast ecause the Yater loss i- -aster than the ca--eine loss. ,-
:ou measure : volume :ou have less ca--eine ecause the
eans expand as the: roast.
(eturn to ,ndex
1=9o3 "o I measure !affeine !ontent at &ome,
To the est o- m: InoYled!e this can not e accomplished
Yithout sophisticated e$uipment. The 0epartment o- &ner!:[s
Ye pa!e rie-l: explains Yhat is involved.
(eturn to ,ndex
11 Is t&ere a $ega$ $imit for !affeine !ontent,
The ansYer to that is it depends on the countr:. A -eY examples
o- laYs related to ca--eine content -or -ood and drinIs include
the -olloYin!:
,n the Cnited Etates there is a limit o- Om! o- ca--eine per
li$uid ounce in evera!es. There is also a limit o- 5SSm! in
pills such as Tivrin.
Australia has a limit o- Australia 4<>m! o- ca--eine per liter.
,n parts o- )orthern Thailand it is completel: ille!al. ,t Yas
outlaYed as a precursor to meth.
(eturn to ,ndex
Caffeine an" 1our 9ea$t&
Im#ortant> ?&is information 3as e@!er#te" from se<era$ sour!es2
no !$aims are ma"e to its a!!ura!1 ?&e FA% mantainer is not a
medical doctor an" !annot <ou!& for t&e a!!ura!1 of t&is
information
1 Caffeine 5it&"ra3a$> Pro!e"ures an" S1m#toms
9o3 to !ut !affeine inta)e,
+ost people report a ver: !ood success ratio : cuttin! doYn
ca--eine intaIe at the rate o- 4'5 cup o- co--ee a da:. This is
InoYn as Caffeine Fa"ing . Alternativel: :ou mi!ht tr:
reducin! co--ee intaIe in discrete steps o- tYo--ive cups o-
co--ee less per YeeI 7dependin! on hoY hi!h is :our initial
intaIe8. ,- :ou are drinIin! more than 4S cups o- co--ee a da:*
:ou should seriousl: consider cuttin! doYn.
The est Ya: to proceed is to consume ca--eine re!ularl: -or a
YeeI* Yhile Ieepin! a precise lo! o- the times and amounts o-
ca--eine intaIe 7rememer that chocolate* tea* soda evera!es
and man: headache pills contain ca--eine as Yell as co--ee8. At
the end o- the YeeI proceed to reduce :our co--ee intaIe at the
rate recommended aove. (ememer to have sustitutes
availale -or drinIin!: i- :ou are not !oin! to have a hot cup o-
co--ee at :our 4S minute reaI* :ou mi!ht consider havin! hot
chocolate or heral tea* ut )OT deca--* since deca-- has also
een shoYn to e addictive. This should taIe :ou throu!h the
YorIs Yithout much prolem.
Eome other people $uit cold turIe:. NithdraYal s:mptoms are
$uite nast: this Ya: 7see section eloY8 ut the: can usuall: e
countered Yith lots o- sleep and exercise. +an: people report
ein! ale to stop drinIin! ca--eine almost cold-turIe: Yhile
on holida:s on the each. ,- $uittin! cold turIe: is provin! too
hard even in the each* drinIin! a coIe mi!ht help.
5&at are t&e s1m#toms of !affeine 3it&"ra3a$,
(e!ular ca--eine consumption reduces sensitivit: to ca--eine.
Nhen ca--eine intaIe is reduced* the od: ecomes
oversensitive to adenosine. ,n response to this
oversensitiveness* lood pressure drops dramaticall:* causin!
an excess o- lood in the head 7thou!h not necessaril: on the
rain8* leadin! to a headache.
This headache* Yell InoYn amon! co--ee drinIers* usuall: lasts
-rom one to -ive da:s* and can e alleviated Yith anal!esics
such as aspirin. ,t is also alleviated Yith ca--eine intaIe 7in -act
several anal!esics contain ca--eine dosa!es8.
O-ten* people Yho are reducin! ca--eine intaIe report ein!
irritale* unale to YorI* nervous* restless* and -eelin! sleep:*
as Yell as havin! a headache. ,n extreme cases* nausea and
vomitin! has also een reported.
(e-erences.
%a--eine and Health. W. &. Wames* Academic Press* 4RR4.
Pro!ress in %linical and ?iolo!ical (esearch Tolume 4>Q. 6. A.
Epiller* &d. Alan (. @iss ,nc* 4RQ<.
(eturn to ,ndex
- 5&at &a##ens 3&en 1ou o<er"ose,
1rom 0esI (e-erence to the 0ia!nostic %riteria -rom 0E+-9-(
7American Ps:chiatric Association* 4RQP8:
"affeine)Pnduced :rganic Nental ?isorder
0D2.+D "affeine Pnto%ication
(. Recent consumption of caffeine,
usually in e%cess of &2D mg.
&. 1t least five of t#e follo-ing signs:
(. restlessness
&. nervousness
0. e%citement
8. insomnia
2. flus#ed face
'. diuresis
@. gastrointestinal disturbance
*. muscle t-itc#ing
+. rambling flo- of t#oug#t and
speec#
(D.tac#ycardia or cardiac
arr#yt#mia
((. periods of ine%#austibility
(&.psyc#omotor agitation
0. /ot due to any p#ysical or ot#er
mental disorder, suc# as an 1n%iety
?isorder.
?asicall:* overdosin! on ca--eine Yill proal: e ver: ver:
unpleasant ut not Iill or deliver permanent dama!e. 9o3e<er2
Peo#$e "o "ie from it
Toxic dose
The @0_>S o- ca--eine 7that is the lethal dosa!e reported to
Iill >S\ o- the population8 is estimated at 4S !rams -or oral
administration. As it is usuall: the case* lethal dosa!e varies
-rom individual to individual accordin! to Yei!ht. ,n!estion
o- 4>Sm!'I! o- ca--eine seems to e the @0_>S -or all
people. That is* people Yei!htin! >S Iilos have an @0_>S o-
approx. P.> !rams* people Yei!htin! QS Iilos have an
@0_>S o- aout 45 !rams.
,n cups o- co--ee the @0_>S varies -rom >S to 5SS cups o-
co--ee or aout >S vivarins 75SSm! each8.
One exceptional case documents survival a-ter in!estin! 5<
!rams. The minimum lethal dose ever reported Yas 9.5
!rams intravenously * this does not represent the oral +@0
7minimum lethal dose8.
,n small children in!estion o- 9> m!'I! can lead to
moderate toxicit:. The amount o- ca--eine in an avera!e cup
o- co--ee is >S - 5SS m!. ,n-ants metaoliGe ca--eine ver:
sloYl:.
E:mptoms
A!ute ca--eine poisonin! !ives earl: s:mptoms o-
anorexia* tremor* and restlessness. 1olloYed :
nausea* vomitin!* tach:cardia* and con-usion. Eerious
intoxication ma: cause delirium* seiGures*
supraventricular and ventricular tach:arrh:thmias*
h:poIalemia* and h:per!l:cemia.
C&roni! hi!h-dose ca--eine intaIe can lead to
nervousness* irritailit:* anxiet:* tremulousness*
muscle tYitchin!* insomnia* palpitations and
h:perre-lexia. 1or lood testin!* cross-reaction Yith
theoph:lline assa:s Yill detect toxic amounts.
7+ethod ,A8 ?lood concentration o- 4-4S m!'@ is
normal in co--ee drinIers* Yhile QS m!'@ has een
associated Yith death.
Treatment
Emergen!1 Aeasures
+aintain the airYa: and assist ventilation. 7Eee
Appendix A8
Treat seiGures Z h:potension i- the: occur.
H:poIalemia usuall: !oes aYa: : itsel-.
+onitor Tital Ei!ns.
S#e!ifi! "rugs B anti"otes ?eta locIers e--ectivel:
reverse cardiotoxic e--ects mediated : excessive
eta-adrener!ic stimulation. Treat h:potension or
tach:arrh:thmias Yith intravenous propanolol* .S4 - .
S5 m!'I!. * or esmolol* .S> m!'I! * care-ull: titrated
Yith loY doses. &smolol is pre-erred ecause o- its
short hal- li-e and loY cardioselectivit:.
De!ontamination
,nduce vomitin! or per-orm !astric lava!e.
Administer activated charcoal and cathartic.
6ut empt:in! is proal: not needed i- 4 5 are
per-ormed promptl:.
Appendix A
Per-ormin! airYa: assistance.
<. ,- no necI in;ur: is suspected* place in the ]Eni--in! ]
position : tiltin! the head acI and extendin! the
-ront o- the necI.
>. Appl: the ]WaY Thrust ] to move the ton!ue out o- the
Ya: Yithout -lexin! the necI: Place thum -in!ers
-rom oth hands under the acI o- the ;aY and thrust
the ;aY -orYard so that the chin sticIs out. This
should also hurt the patient* alloYin! :ou to ;ud!e
depth o- coma. :8
O. Tilt the head to the side to alloY vomit and snot to
drain out.
1rom conversations on alt.dru!s.ca--eine:
The toxic dose is !oin! to var: -rom person to person*
dependin! primaril: on uilt-up tolerance. A couple people
report sYalloYin! 4S to 49 vivarin and endin! up in the
hospital Yith their stomaches pumped* Yhile a -eY sa: the:[ve
taIen that man: and arel: sta:ed aYaIe.
A s:mptom lacIin! in the clinical manual ut reported : at
least tYo people on the net is a loss o- motor ailit:: inailit: to
move* speaI* or even linI. The experience is consistentl:
descried as ver: unpleasant and not -un at all* even : those
ver: -amiliar Yith ca--eine nausea and headaches.
(eturn to ,ndex
0 Effe!ts of !affeine on #regnant 3omen
%a--eine has lon! een suspect o- causin! mal--ormations in
-etus* and that it ma: reduce -ertilit: rates.
These reports have proved controversial. Nhat is InoYn is that
ca--eine "oes causes mal-ormations in rats* Yhen in!ested at
rates comparale to PS cups a da: -or humans. +an: other
species respond e$uall: to such lar!e amounts o- ca--eine.
0ata is scant* as experimentation on humans is not -easile. ,n
an: case moderation in ca--eine in!estion seems to e a prudent
course -or pre!nant Yomen. (ecent re-erences are Pastore and
EavitG* %ase-control stud: o- ca--einated evera!es and preterm
deliver:. American Wournal o- &pidemiolo!:* Wan 4RR>.
A recent stud: -ound a YeaI linI etYeen Eudden-,n-ant-
0eath-E:ndrome 7E,0E8 and ca--eine consumption : the
mother* Yhich rein-orces the recommendation -or moderation
-possil: even astinence- aove.
On men* it has een shoYn that ca--eine reduces rates o- sperm
motilit: Yhich ma: account -or some -indin!s o- reduced
-ertilit:.
(eturn to ,ndex
4 Caffeine an" Osteo#orosis CCa$!ium $ossD
1rom the Wournal o- A+A: 7WA+A* 5O Wan. 4RR<* p. 5QS-9.8
]There Yas a si!ni-icant association etYeen 7drinIin! more8
ca--einated co--ee and decreasin! one mineral densit: at oth
the hip and the spine* independent o- a!e* oesit:* :ears since
menopause* and the use o- toacco* estro!en* alcohol* thiaGides*
and calcium supplements Hin YomenJ. ]
&xcept Yhen:
]?one densit: did not var: H...J in Yomen Yho reported
drinIin! at least one !lass o- milI per da: durin! most o- their
adult lives. ]
That is* i- :ou drinI a !lass o- milI a da:* there is no need to
Yorr: aout the ca--eine related loss o- calcium.
(eturn to ,ndex
6 Stu"ies on t&e si"eEeffe!ts of !affeine
7AA;AD3, Califr$ia !>PO# -- Cffee maK be
gd fr life. A ma5r s%udK +as fu$d
feHer suicides am$g cffee dri$6ers %+a$
%+se H+ abs%ai$ed frm %+e +% blac6
breH.
P+e s%udK f $earlK 1.0,000 Dr%+er$
Califr$ia reside$%s a$d %+e recrds f
&,500 H+ +a*e died l6ed a% %+e effec%s
f cffee a$d %ea $ mr%ali%K.
Cardilgis% Ar%+ur Ala%s6K said f %+e
surprisi$g resul%s, [[P+is is $% a flu6e
fi$di$g because ur s%udK Has *erK large,
i$*l*ed a mul%iracial ppula%i$, me$,
Hme$, a$d eSami$ed clselK $umerus
fac%rs rela%ed % mr%ali%K suc+ as
alc+l c$sump%i$ a$d sm6i$g.XX
P+e u$i2ue sur*eK als fu$d $ li$6
be%Hee$ cffee c$sump%i$ a$d dea%+ ris6.
A$d i% c$firmed a [[Hea6XX c$$ec%i$ f
cffee r %ea % +ear% a%%ac6 ris6 -- bu%
$% % %+er cardi*ascular c$di%i$s
suc+ as s%r6e.
P+e s%udK Has c$duc%ed bK %+e +eal%+
mai$%e$a$ce rga$i/a%i$ Aaiser Perma$e$%e
a$d Has repr%ed ?ed$esdaK i$ %+e A$$als
f <pidemilgK.
(eturn to ,ndex
7 Caffeine an" 1our metabo$ism
%a--eine increases the level o- circulatin! -att: acids. This has
een shoYn to increase the oxidation o- these -uels* hence
enhancin! -at oxidation. %a--eine has een used -or :ears :
runners and endurance people to enhance -att: acid
metaolism. ,t[s particularl: e--ective in those Yho are not
haitual users.
%a--eine is not an appetite suppressant. ,t does a--ect
metaolism* thou!h it is a !ood $uestion Yhether its use trul:
maIes an: di--erence durin! a diet. The $uestionale rationale
-or its ori!inal inclusion in diet pills Yas to maIe a poor man[s
amphetamine-liIe preparation -rom the non-stimulant
s:mpathomimetic phen:lpropanolamine and the stimulant
ca--eine. 7That :ou end up Yith somethin! ver: non-
amphetamine liIe is neither here nor there.8 The comination
dru!s Yere called ]0exatrim ] or 0exa-Yhosis 7as in
0exedrine8 -or a reason* namel:* to assert its similarit: in the
minds o- prospective u:ers. HoYever* ca--eine has not een in
OT% diet pills -or man: :ears per order o- the 10A* Yhich
stated that there Yas no evidence o- e--icac: -or such a
comination.
1rom 6oodman and 6ilman[s The Pharmacolo!ical ?asis o-
Therapeutics:
"affeine in combination -it# an analgesic,
suc# as aspirin, is -idely used in t#e
treatment of ordinary types of #eadac#e.
$#ere are fe- data to substantiate its
efficacy for t#is purpose. "affeine is also
used in combination -it# an ergot alkaloid
in t#e treatment of migrane F"#apter 0+H.
.rgotamine is usually administered orally
Fin combination -it# caffeineH or
sublingually Q...R Pf a patient cannot tolerate
ergotamine orally, rectal administration of a
mi%ture of caffeine and ergotamine tartarate
may be attempted.
$#e bioavailability Qof ergotamineR after
sublingual administration is also poor and
is often inadeMuate for t#erapeutic purposes
Q...R t#e concurrent administration of
caffeine F2D)(DD mg per mg of ergotamineH
improves bot# t#e rate and e%tent of
absorption Q...R Ao-ever, t#ere is little
correspondence bet-een t#e concentration
of ergotamine in plasma and t#e intensity or
duration of t#erapeutic or to%ic effects.
"affeine en#ances t#e action of t#e ergot
alkaloids in t#e treatment of migrane, a
discovery t#at must be credited to t#e
sufferers from t#e disease -#o observed t#at
strong coffee gave symptomatic relief,
especially -#en combined -it# t#e ergot
alkaloids. 1s mentioned, caffeine increases
t#e oral and rectal absorption of
ergotamine, and it is -idely believed t#at
t#is accounts for its en#ancement of
t#erapeutic effects.
)oYada:s most o- researchers elieve that the stimulator:
actions are attriutale to the anta!onism o- the adenosine.
A!onists at the adenosine receptors produce sedation Yhile
anta!onists at these sites* liIe ca--eine and theoph:lline induce
stimulation* and Yhat is even more important* the latter
sustance also reverse a!onists-induced s:mptoms o- sedation*
thus indicatin! that this e--ects !o throu!h these receptors.
Another possiilit:* hoYever* is that meth:lxanthines enhance
release o- excitator: aminoacids* liIe !lutamate and aspartate*
Yhich are the main stimulator: neurotransmitters in the rain.
As to the side e--ects: meth:lxanthines inhiit protective
activit: o- common antiepileptic dru!s in exptl. animals in
doses comparale to those used in humans Yhen correction to
the sur-ace area is made. ,t should e underlined* that althou!h
tolerance develop to the stimulator: e--ects o- theo or ca--eine
Yhen administered on a chronic ase* Ye -ound no tolerance to
the aove e--ects . This haGardous in-luence Yas even enhanced
over time. There-ore* it should e emphasiGed that individuals
su--erin! -rom epileps: should avoid* or at least reduce
consumption o- co--ee and other ca--eine-containin! evera!es.
(eturn to ,ndex
Ais!e$$aneous
1 9o3 "o 1ou #ronoun!e mate,
+AH-teh. +AH liIe in malt* and -teh liIe in 6ral. Patten.
(eturn to ,ndex
Re!i#es
1 C&o!o$ate !o<ere" es#resso beans
Fou Yon[t !et sin!le* !loss: eans* ut the taste is there`
4. Put darI roast co--ee eans on a Yaxpaper-covered
aIin! sheet.
5. +elt some chocolate : putin! a container Yith the
chocolate in a pan o- oilin! Yater* stir the chocolate
Yhen it is !ettin! hot. Eome experimentation re!ardin!
Yhat chocolate to use is in place. , used chocolate chips
o- -rom 6irardelli. One should proal: aim -or darI and
not too sYeet chocolate.
9. Pour the chocolate over the eans and smear it so that
each ean is covered - :ou should have a sin!le la:er o-
covered eans not too -ar apart.
<. Nhen the eans have cooled o-- a little it* put the sheet
in the -rid!e'-reeGer.
>. Nhen solid* reaI o-- a piece and en;o:.
- 9o3 to ma)e 1our o3n !&o!o$ate
Here[s the recipe -or maIin! a real chocolate evera!e.
,mportant steps are in bo$"fa!e .
Ingre"ients
4-5I! 75-<pounds8 o- cocoa eans.
A manuall: operated !rinder.
Instru!tions
Ei-t throu!h the eans removin! an: impurities 7pieces o-
!rass* leaves* etc8.
Place the eans in a pan 7no te-lon8 and roast them. Etir
-re$uentl:. As the eans roast the: start maIin! ]pop ]
sounds liIe popcorn. ?eans are read: Yhen :ou estimate
that approx >S-P>\ o- the eans have popped. 0o not let
the eans urn* thou!h a it o- lacI on each ean is oI.
Peel the eans. Peelin! roasted cocoa eans is liIe
peelin! aIed potatoes: The hotter the: are the easier it is
to peel the darn thin!s* at the expense o- third de!ree
urns on :our -in!ers. 7Tip: Cse Iitchen mittens and
rush the eans in :our hands8. ,- the eans are too hard
to peel roast them a it lon!er.
6rind the eans into a pan. The: produce a darI oil:
paste called ]cocoa paste ].
The oil in the cocoa has a itter taste that :ou have to !et
used to. , liIe it this Ya:* ut not all people do. Here are
the alternatives:
5it& oi$ * Yhich !ives :ou a richer -lavour:
Epread aluminum -oil on a tale and maIe small pies o-
chocolate* aout 4'< o- an inch hi!h* and O inches in
diameter. @et them rest overni!ht. The mornin! a-ter the:
are hard talets. (emove them -rom the aluminum -oil
and rap them in it. Etore in the -reeGer.
5it&out oi$ * some -lavour is !one* less itter* YeaIer
7Yhimper8 chocolate:
Put the paste inside a thin cloth 7liIe linen8* close the
cloth and s$ueeGe until the oil comes out. ,- :ou mana!e
to !et most o- the oil out* Yhat is le-t is hi!h $ualit:
cocoa poYder* liIe 0roste[s.
Nhat is le-t noY is either itter talets or itter cocoa
poYder.
Fou can noY maIe a nice evera!e as -olloYs:
?oil a liter o- milI 7or Yater* liIe in ancient +exican
st:le. @iIe Yater -or chocolate* ]%omo a!ua para
chocolate ]: :ou InoY8.
Nhen the milI is Yarm 7not hot8 add a chocolate pie in
pieces. Etir Yith a lender 7ut e care-ul` the lender[s
electric cord should )OT touch the pot or an: other hot
thin! around it8.
Nhen the chocolate has dissolved add 4'5-9'< cups o-
su!ar 7dependin! hoY sYeet :ou liIe :our chocolate8
and lend in -ast. Aa)e sure t&e sugar is !om#$ete$1
"isso$<e" in t&e !&o!o$ate ot&er3ise it 3ou$" be bitter
no matter &o3 mu!& sugar 1ou ma1 a"" after3ar"s .
Add a teaspoon o- cinnamon or natura$ vanilla -lavour
7arti-icial vanilla -lavour Yith chocolate results in an
aY-ul medicine liIe -lavour8 i- :ou liIe* and lend a!ain.
@et the mixture oil* Yhen it starts to !et ul: $uicIl:
remove the pan -rom the stove top* and rest the ottom
a!ainst a soaIed cloth. Put a!ain on stove top* it should
!et ul: almost immediatel:* remove once a!ain and
repeat one last time. This aerates the chocolate Yhich
enhances -lavour.
,n a mu!* put aout 4'5-9'< o- the chocolate mixture* and
add cold milI* until the temperature and'or the
concentration o- the -lavour is ri!ht -or :our tastes.
Accompan: Yith 1rench Pastries. Fum Fum``
&n;o:`
(eturn to ,ndex
E$e!troni! Resour!es
(eturn to ,ndex
A"ministri<ia
9o3 "o I get t&e ne3est !o#1 of t&is FA%,
HoY do , !et the neYest cop: o- this 1ABK
+: pa!e at http:''co--ee-a$.com'
or via e-mail send a messa!e to
ca--eine-a$aco--ee-a$.com
or -or the co--ee -a$:
+: pa!e at http:''co--ee-a$.com'
or via e-mail send a messa!e to
co--ee-a$aco--ee-a$.com
List of Contributors
This 1AB is a collective e--ort. Here[s a list o- most 7allK8
o- the contriutors.
OIta: AhisIa
+arc Aurel
Ecott Austin
Tom ?en;amin
Wenni-er ?e:er
Eteve ?liss
0avid Alan ?oGaI
(a;iv
Trevor P. ?u!era
WacI %arter
(ichard 0rapeau
W:m 0:er
Eteve 0:er
Ete-an &n!strom
@emieux 1rancois
Ecott 1isher
0ave Huddle
+att Humphre:
Tom 1 barlsson
?o bummer-eld
0r. (oert @ancashire
Wohn @evine
Alex @opeG-OrtiG
Alec +u--ett
0ana +:ers
Tim )emec
+iIe Oliver
Wim Pailin
0ave Palmer
Etuart Phillips
Eiohan Purcell
%ar: A. Eandvi!
Wesse T EheidloYer
Etepahine da Eilva
+ichael A Emith
+ari W. Etoddard
Thom
0eanna b. Toin T.&.
)icI TsouIas
Adam Turo--
6anesh Cttam
0avid (. ?. NalIer
Orion Nilson
Piotr NlaG
Ted Foun!
Eteven ciIopoulos
Eusan Emith
bevin +acIie
Co#1rig&t
This 1AB is %op:ri!ht 7%8 4RR<*4RR> : Alex @opeG-
OrtiG.
This 1AB is %op:ri!ht d 4RRQ*5SS4 : 0aniel OYen.
This text* in Yhole or in part* ma: not e sold in an:
medium* includin!* ut not limited to* electronic* %0-
(O+* or pulished in print* Yithout the explicit* Yritten
permission o- 0aniel OYen.
(eturn to ,ndex
%op:ri!ht 7%8 4RR<*4RR> Alex @peG-OrtiG.
%op:ri!ht d 4RRQ*5SS4 0aniel OYen.
Home Pa!e
Please send comments to 0aniel OYen.
FA% Dos Porta"ores Do ?r1#tamine
Por Petrus Pennanen
com a;uda de Nic#ael de Nelbourne .
H:pertexture e es-or.o dontinuin! da ilustra."o atravs de http:''deox:.or!
POST en_pt http://babelfish.al done en
TraduGa de
DeBabelize!
GET en_pt
A!radecimentos a muitos indiv#duos para a a;uda em unir isto.
Ee voc souer as -ontes dos tr:ptamines $ue n"o s"o mencionados
a$ui satis-aGem enviam-nos.
GET en_pt
F$tima bus!a "e Gu$&o 1;;; "o u#"ate "o "eo@1
este FA% #ara
GET en_pt
,niidores e tr:ptamines de +AO
E#ntese de derivatives de 0+T
Eapos 0e Ps:chedelic
Os 1un!os
As Plantas
(e-erncias
Ora$ e #arentera$$1 "eri<ati<es #s1!&otro#i! ati<os "o tr1#tamine
?aseado em +cbenna Z em torres 4RQ<
0ados compilados de bantor* et al. 4RQS ; Ehul!in 4RPO * 4RQ5 ;
Ehul!in Z %arter 4RQS
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S sintomas ( autonomicB pouca atividade central.
S & os esters do p#osp#ate s7o psilocybin e "ey)(+, respectivamenteB
ambos s7o stoic#iometrically eMuivalente aos isomers 8)#ydro%y.
S 0 cardiovascular e sintomas autonomicB pouca atividade central.
S amine pressor de 8 1 mel#or Mue um #allucinogen no #omem.
S 2 um antidepressivo mel#or Mue um #allucinogen no #omem.
S ' basearam em relat;rios anonymous na imprensa da configura=7o.
/en#um estudo cl3nico foi publicado.
S @ nen#uma atividade oral com doses at5 magn5sio &D, podem ser
parenterally ativos.
Outros tr:ptamines potencial ps:chedelic incluem:
O--luoro-al-a-meth:ltr:ptamine* P-meth:ltr:ptamine* >-
meth:ltr:ptamine
>--luorotr:ptamine* O--luorotr:ptamine e >- e O--luorotr:ptophans.
GET en_pt
Pro!urare este FA% #or
n"i!e
GET en_pt
Inibi"ores e tr1#tamines "e AAO
O oxidase de +onoamine 7+AO8 o pathYa: preliminar do
inactivation de a maioria de tr:ptamines. Por causa disto* os
iniidores do enG:me de +AO 7+AO,s8 podem ser usados potentiate
os e-eitos dos tr:ptamines e -aGer oral 0+T e >-+eO-0+T ativos.
Os iniidores de +AO caem em duas classes: +AO,s irreversile e
revers#vel. Alm podem iniir $ual$uer um ou amos os dois tipos do
enG:me* de +ao-a e de +ao- de +AO $ue s"o associados com os
neurVnios serotoner!ic e dopaminer!ic respectivamente. @i!amento
irreversile de +AO,s 7por exemplo o iproniaGid e o phenelGine dos
h:draGides8 permanentemente ao enG:me e X inii."o da causa +AO
$ue duram 4-5 semanas aps o in!estion. E"o usados clfnica tratar o
depression. +AO,s revers#vel* tal como o mocloemide* $ue usado
como um antidepressivo* e o harmine e o harmaline eta-carolines-
carolines* e-icaG por um tempo muito mais curto* talveG at 5<
horas. Os usurios recreacionais da dro!a em torno do mundo est"o
usando principalmente o harmine e o harmaline apesar da -alta de
estudos cient#-icos em seus e-eitos em seres humanos.
Os nativos de AmaGon cominaram tradicional a videira do caapi de
?anisteriopsis* $ue contem o harmine* o harmaline e eta-carolines-
carolines relacionado* com as plantas 0+T-contendo para -aGer um
oral ativo reY o a:ahuasca chamado . Outras plantas $ue contm o
harmine e'ou o harmaline podem ser sustitu#das para o caapi do ?.. [
o a:ahuasca norte-americano usual [ consiste em raiGes das sementes
do harmala de Pe!anum e do illinoensis de 0esmanthus* e [ no
acaciahuasca australian [ sae do complanata do acacia s"o cominados
com o material dos acacias 0+T-contendo 7o e--ectivit: desta mistura
n"o -oi con-irmado8. +AO,s -oi usado tamm potentiate os e-eitos
dos co!umelos $ue contm o psiloc:in. Terence +cbenna
mencionou o chocolate $ue um +AO, -raco* $ue poderia ser uma
raG"o para o hito popular de in!estin! co!umelos com cacau.
As sementes do harmala de Pe!anum 7rue s:rian8 s"o a -onte natural a
mais concentrada do harmine e harmaline - aproximadamente 9\ de
seu peso consiste nestes alcalides. O caapi de ?anisteriopsis -oi
encontrado para conter S*4Q\ a 4*9O\ eta-carolines-carolines*
com a concentra."o do harmine $ue S*S>P\ a S*O9>\ 7 +cbenna et
al. 4RQ< 8. 0e acordo com relatrios anecdotal um !rama das
sementes do harmala do P. in!ested inie +AO astante para -aGer
oral 0+T ativo.
Harmine e o harmaline s"o hallucino!enic no seus prprios com os
doses $ue partem de ma!nsio ao redor 9SS 7 )aran;o 4ROP 8* mas
causam -re$uentemente side-e--ects -#sicos tais como o nausea e os
tremors neste dose variam. Tm e-eitos emocionais ou [ ps:chedelic [
pouco* mas produGem hallucinations visuais -ortes. Por causa desta os
nativos de AmaGon adicionam -re$uentemente as $uantidades maiores
7P>-4SS cm da haste por o dose8 de caapi do ?. ao a:ahuasca reY do
$ue needed para a inii."o de +AO 7 @una 4RQ< 8.
H uns peri!os si!ni-icativos em usar iniidores de +AO. A maioria
de +AO,s potentiate os e-eitos cardiovascular do t:ramine e dos
outros monoamines encontrados nos alimentos. O in!estion do $uei;o
envelhecido* cerve;a* vinho* picIled herrin!* -#!ado de !alinha*
-ermento* $uantidades !randes de ca-* -rutas de citrino* -i!s
enlatados* -ei;Ues lar!os* chocolate ou o creme $uando +AO -or
iniido pode causar uma crise h:pertensive includin! uma ascens"o
peri!osa na press"o de san!ue. Os e-eitos dos amphetamines* de
anestsicos !erais* de sedatives* de anti-histamines* de lcool* de
anal!esics potent e de a!entes anticholiner!ic e do antidepressivo s"o
prolon!ados e intensi-ied. O overdosa!e de +AO,s por se tamm
poss#vel com e-eitos includin! a hiper-re-lexia e os convulsions.
GET en_pt
Pro!urare este FA% #or
GET en_pt
n"i!e
Sntese "e "eri<ati<es "e DA?
Os derivatives do tr:ptamine e eta-%arolines-%arolines -oram
detectados como metaolites endo!enous nos mam#-eros* includin!
seres humanos. Os trans-erases meth:l $ue catal:Ge a s#ntese dos
tr:ptamines* includin! 0+T* >-+eO-0+T e u-otenine* s"o
encontrados no pulm"o humano* no crero* no l#$uido cererospinal*
no -#!ado e no cora."o 7 +cbenna Z torres 4RQ< 8. )a !l/ndula
pineal +AO o pathYa: preliminar do serotonin* um
neurotransmitter do inactivation s:nthesiGed do tr:ptophan do amino-
cido. Ee +AO -or ostru#do pelo harmine* o harmaline ou o outro
serotonin dos iniidores de +AO podem ser convertidos pelos
enG:mes H,O+T e ,)+T do meth:ltrans-erase em tr:ptamines
ps:chedelic 7serotonin -- --g >-+eO-tr:pt do 7hiomt8. -- 75einmt8 --g
>-+eO-0+T8.
Assim* in!estin! o l-l-tr:ptophan para aumentar n#veis do serotonin*
uma arra do doce para aumentar a $uantidade de tr:ptophan $ue
come.a a seus crero e material de planta natural $ue contm 5>->S
ma!nsio harmine'harmaline ao loco +AO* tudo ao mesmo tempo*
pVde causar sua !l/ndula pineal s:nthesiGe $uantidades sustanciais
de >-+eO-0+T 7 a maioria 4RQO 8. ,sto extremamente peri!oso
para pessoas com dese$uil#rio ou es$uiGo-renia existente do amine.
Para conse$hncias poss#veis dos povos normais* saudveis se;a mau
HIO ?EH?E IS?O
Cm iniidor potent de ,)+T* $ue um enG:me necessrio para a
s#ntese de 0+T e de >-+eO-0+T* encontrado em concentra.Ues
particularmente elevadas na !l/ndula pineal. %ontornear ou uma
inii."o da s#ntese deste iniidor puderam ser responsvel para
trances e outros estados ps:chedelic conse!uiram ]sem dro!as]
7 Etrassman 4RRS 8. Te;a o arti!o de Etrassman para mais in-o e
speculation sore a !l/ndula pineal.
GET en_pt
Pro!urare este FA% #or
GET en_pt
n"i!e
Sa#os De Ps1!&e"e$i!
ADVER?IHDO estes sapos s"o VENENOSOS. Ee
voc comesse o venom voc poderia MORRER.
0iversos suspecies deste tipo de sapo s"o meramente
venenosos. )"o pense mesmo sore -aGer isto a menos
$ue voc puder absolutamente identi-icar a espcie* e
saia todas as conse$hncias de -um-la venom. &u
sei todas estas coisas e decidi-me n"o -umar o venom
secado do sapo* e a$uela minha recomenda."o a voc.
AHO?E o sapo mencionado esta se."o* alvarius de
Bufo, uma espcie rara e posta em peri!o - dimitri
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http
\9A\51\51YYY.deox:.or!\51audio\51-ro!s.au
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http
\9A\51\51YYY.deox:.or!\51audio\51-ro!s.au?u-otenine e >-
h:drox:-indoleth:lamines relacionados s"o constituents comuns dos
venoms dos !enera H:la* @eptodact:lus* (ana e ?u-o. ?u-otenine n"o
ps:chedelic em doses raGoveis 7com doses maiores h uns e-eitos
laterais ph:siolo!ical peri!osos8* mas a pele de uma espcie* alvarius
de ?u-o* contem >S-4OS ma!nsio >-+eO-0+T'! da pele 7 0al: Z
NitIop 4RP4 8. M a =nica espcie de ?u-o saida para conter um
tr:ptamine hallucino!enic 7 +cbenna Z torres 4RQ< 8. A maioria
74RQ<8 d instru.Ues para coletar e secar o venom:
O venom -resco pode -Xcilmente ser coletado sem dano ao sapo. Cse
uma placa de vidro lisa ou todo o outro $uadrado 45-inches liso*
nonporous da super-#cie ao menos. Prenda o sapo na -rente da placa*
$ue reparada em uma posi."o vertical. )esta maneira* o venom
pode ser coletado na placa de vidro* livre da su;eira e do l#$uido
lierados $uando o sapo se!urado.
Buando voc est pronto para come.ar* prenda o sapo -irmemente
com uma m"o e* com o pole!ar e o -ore-in!er de sua outra m"o*
esprema-o perto da ase da !l/ndula at $ue o venom es!uinche -ora
dos pores e na placa de vidro. Cse este mtodo coletar
sistematicamente o venom de cada uma das !l/ndulas !ranular do
sapo: a$ueles no -orearm* a$ueles no tiia e no -emur do p hind* e*
naturalmente* os parotids na !ar!anta . %ada !l/ndula pode ser
espremida uma se!unda veG para um rendimento adicional do venom
se voc permitir ao sapo um preiod one-hour do descanso. 0epois $ue
isto as !l/ndulas est vaGio e re$uer $uatro a seis semanas para a
re!enera."o.
O venom viscous e leitoso-ranco na cor $uando espremido
primeiramente das !l/ndulas. %ome.a a secar dentro dos minutos e
ad$uire a cor e a textura do cimento de orracha. (aspe o venom da
placa de vidro* se$ue-o completamente* e armaGene-o em um
recipiente hermtico at $ue voc este;a pronto para o -umar.
0avis e Neil 74RR58 -umaram o venom e descreveram o $ue
aconteceu:
)a compara."o com os compostos puros o venom do sapo
parece mais por muito tempo durando e* por$ue um n"o perde
completamente o contato com realidade* um sensual distante
mais a!radvel* mais uni-orme. @o!o aps o inhalation ,
experimentaram sensations nivelando mornos* um sentido da
maravilha e o em estar* os hallucinations auditor: -ortes* $ue
inclu#ram um som da inseto-ci!arra $ue -uncionasse atravs de
minha mente e parecesse li!ar meu corpo X terra. &mora eu
estava dentro* havia um sentido da sensa."o da terra* o pa seco
do solo do deserto eee T(A)E@AT,O) &)0E H&(&
eeessin! throu!h m: -in!ers* the stars at midda:* the scent o-
cactus and sa!e* the -eel o- dr: leaves throu!h hands. Etron!
visual hallucinations in orliIe rilliance* diamond patterns that
undulated across m: visual -ield. The experience Yas in ever:
sense pleasant* Yith no disturin! ph:sical s:mptoms* no
nausea* perhaps a sli!ht sense o- increased heart rate. Narm
Yaves coursed up and doYn m: od:. The e--ects lasted onl: a
-eY minutes ut a pleasant a-ter!loY continued -or almost an
hour. 7Nade 0avis* personal oservation* Wanuar: 45* 4RR48
Pro-ound alteration o- consciousness Yithin a -eY seconds o-
exhalin!. , relax into a deep* peace-ul interior aYareness. There
is nothin! scar: aout the e--ects and no sense o- toxicit:. , tr:
to descrie m: -eelin!s ut am unale to talI -or the -irst -ive
minutes and then onl: Yith some di--icult:. This is a poYer-ul
ps:choactive dru!* one that , thinI Yould appeal to most people
Yho liIe the e--ects o- hallucino!ens. 1or the next hour , -eel
sloY and velvet:* Yith a sli!ht pressure in m: head. )o lon!-
lastin! e--ects to report. 7AndreY T. Neil* personal oservation*
Wanuar: 45* 4RR48.
Other animals contain 0+T such as the !or!onian Paramuricea
chamaeleon 7 %imino Z 0e Ete-ano* 4RPQ 8.
GET en_pt
Sear!& t&is FA% for
GET en_pt
tab$e of !ontents
F J H K I
L E A J S 9 R M M A E D
1amil:: ?olitiaceae
6enus: A!roc:e
Epecies: -arinacea
%ontains psiloc:in 7 boiIe et al. 4RQ4 8.
6enus: %onoc:e
Epecies: c:anopus* Iuehneriana* sili!ineoides* smithii
%. c:anopus 7 ?enedict et al. 4RO5 8 and %. smithii 7 ?enedict et al.
4ROP 8 contain psiloc:in and psilocin Yhile %. Iuehneriana contains
psilocin onl: 7 Oheno;a et al. 4RQP 8. %. sili!ineoides ma: also contain
these alIaloids 7 Echultes Z Ho-mann 4RPR p. <S8.
1amil:: %oprinaceae
6enus: %opelandia
Epecies: anomala* ispora* camod!iniensis* chloroc:stis*
c:anescens* tropicalis
All species contain psilocin and psiloc:in* -or %. c:anescens 7
Echultes Z Ho-mann 4RPR p. <S8 and -or %. camod!iniensis as Yell as
%. tropicalis 7 Arora* 4RQO 8* and -or %. anomala as Yell as %. ispora 7
+erlin Z Allen* 4RR9 8.
6enus: Panaeolina*
Epecies: castanei-olius* -oenisecii
P. -oenisecii contains psiloc:in 7 (oers et al. 4ROR 8.
6enus: Panaeolus
Epecies: a-ricanus* antillarum* ater* campanulatus* -irmicola*
microsporus* olivacens* retiru!is* separatus* sphinctrinus*
sualteatus
Eeveral Panaeolus species contain psiloc:in. 1or P. antillarum re-er to
Allen et al. 74RR48* -or P. ater re-er to ?resinsI: et al. 74RRS8 * -or P.
papilionaceus 7 6urevich et al. 4RR5 8* -or P. retiru!is 7 1iussello et al.
4RP4'P5 8* -or P. separatus 77 +iller Wr. 4RP5 8* -or P. sphinctrinus 7 Hein
Z Nasson* 4R>Q p. 9558 and -or P. olivacens 7 Oheno;a et al. 4RQP 8. P.
sualteatus contains oth psilocin and psiloc:in 7 Oheno;a et al. 4RQP
8 ut Yas InoYn to e hallucino!enic since 4R>R 7 Etein* 4R>R 8. P.
-irmicola is also descried as hallucino!enic and proal: contains the
same alIaloids 7 Echultes* 4RPR 8.
6enus: Psath:rella
Epecies: candollenana
%ontains psiloc:in 7 boiIe et al. 4RQ4 8 and psilocin 7 Oheno;a et al.
4RQP 8.
1amil:: %ortinariaceae
6enus: 6alerina
Epecies: ste!lichii
%ontains psiloc:in and psilocin 7 ?esl* 4RR9 8.
6enus: 6:mnopilus
Epecies: aeru!inosus* li$uiritiae* luteus* purpuratus* spectailis*
validipes* viridans
+an: 6:mnopilus contain psiloc:in* -or 6. aeru!inosus* 6. luteus* 6.
spectailis* 6. validipes and 6.viridans re-er to Hat-ield et al. 74RPQ8 .
1or 6. li$uiritiae 7 boiIe* 4RQ4 8 and -or 6. purpuratus 7 6artG 4RR4 8.
6enus: ,noc:e
Epecies: aeru!inascens* calamistrata* coelestium* cor:dalna*
haemacta* tricolor
These contain psilocin and psiloc:in* -or P. aeru!inascens re-er to
Haeselarth et al. 74RQ>8 and -or the others Eti;ve et al. 74RQ>8 .
1amil:: @epiotaceae
6enus: @epiota
Epecies: humei +urrill also InoYn as peele ]Peele[s @epiota]
This mushrooms Yas claimed : Peele o- 1lorida +:colo!: (esearch
%enter 7PO ?ox Q4S< Pensacola 1lorida 95>S>8 to contain a le!al
tr:ptamine* Yhich produces a trip Yith less ph:sical s:mptoms and
etter ailit: o- lo!ical thinIin! than psilocin or psiloc:in. ?ioassa:
results didn[t -ind ps:choactivit: 7 AIers 4RR5 8.
1amil:: Pluteaceae
6enus: Pluteus
Epecies: atricapillus* c:anopus* ni!roviridis* salicinus
P. atricapillus contains psiloc:in 7 Oheno;a et al. 4RQP 8 Yhile oth P.
salicinus 7 Eaupe 4RQ4 8 and P. ni!roviridis 7 %hristiansen et al. 4RQ< 8
contain psilocin and psiloc:in.
1amil:: Pol:poraceae
6enus: 6erronema
Epecies: -iula* sYartGii
These contain psiloc:in.
6enus: H:!roc:e
Epecies: psittacina
This contains psiloc:in.
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http\9A
\51\51YYY.deox:.or!
\51mushYord.htm http:''ael-ish.altavista.com'ael-ish'urltrurlK
lp^en_ptZurl^http\9A\51\51YYY.deox:.or!\51mushYord.htm
1amil:: Etrophariaceae
6enus: Psiloc:e
Epecies: P> bnoYn hallucino!enic species i antio$uensis*
aucIlandii* eliconiae* coprophila* croulus* cuensis 7pictured8 *
!uatapensis* samuiensis* suacutipilea*
There are at least P> mushroom species in this !enera that contain
psilocin and psiloc:in in 6uGman 4RQ9 * and there are several more
recentl: discovered species such as P. aucIlandii 7 6uGman et al. 4RR9
8* P. samuiensis 7 6uGman et al. 4RR4 8 and P. antio$uensis* P.
eliconiae* P. !uatapensis and P. suacutipilea 7 6uGman et al. 4RR< 8.
Also P. coprophila* Yhile lacIin! psilocin 7maIin! it a non-luein!
psiloc:e8 is InoYn to contain psiloc:in 7 Arora* 4RQO 8. P. croulus is
also InoYn to e hallucino!enic 7 Phillips* 4RQ4 8.
,ma!es o- Psiloc:e c:anescens* c:ano-irillosa* aGurescens*
semilanceata* pelliculosa* silvatica can e seen at A 6aller: o-
Psiloc:e +ushrooms * H:perreal Teonanacatl
GET en_pt
Sear!& t&is FA% for
GET en_pt
tab$e of !ontents
P L A H ? S
PLAH2 PLAH?2 PLAHE?
1amil:: Acanthaceae
6enus: Wusticia
Epecies: pectoralis 7var. stenoph:lla8
NaiIas o- Orinoco headYaters in TeneGuela add dried and pulveriGed
leaves o- this her to their Tirola-snu--. ,ntensel: aromatic smellin!
leaves proal: contain tr:ptamines 7 Echultes 4RPP 8. Plants are
availale -rom -rom Hoti Products or ..O- the ;un!le .
1amil:: AiGoaceae
6enus: 0elosperma
%ontains 0+T and )-meth:ltr:ptamine 7 (ivier Z Pilet* 4RP4 8.
1amil:: Alariaceae
6enus: &cIlonia
Epecies: maxima
%rouch et al. 74RR58 reported -indin! 0+T in roYn seaYeed extract
sold as belpaI and intended to e used as a plant -ertiliGer. HoYever*
suse$uent anal:sis : W. 6artG su!!ests none is present.
1amil:: Apoc:naceae
6enus: Prestonia
Epecies: amaGonicaK
+a: contain 0+T ut the specimen used ma: have een misidenti-ied
7 Emith 4RPP 8.
1amil:: %actaceae
6enus: &chinocereus
Epecies: salm-d:cIianus* tri!lochidiatus
These cacti !roYin! in +exico are InoYn to Tarahumare ,ndians as
pe:ote or hiIuli and used in their -estivals. &. tri!lochidiatus contains a
tr:ptamine derivative* possil: >-+eO-0+T 7 ?:e 4RPR 8. &. salm-
d:cIianus is also supposed to contain tr:ptamines accordin! to Horus
?otanicals catalo! 4RR5.
6enus: Trichocereus
Epecies: terschecIii ]%ardon !rande]
0+T has een isolated -rom this species !roYin! in )orth-Nestern
Ar!entina 7 Echultes Z Ho-mann 4RPR p. >Q8.
1amil:: %aesalpininaceae
6enus: Petalost:lis
Epecies: cassiodies
@eaves and stem contain S.<-S.>\ tr:ptamine* 0+T and other
alIaloids 7 Wohns et al. 4ROO 8.
1amil:: 1aaceae
6enus: 0esmodium
Epecies: !an!etium* !:rans* tiliae-olium* tri-lorum*
@eaves* root* stem and seeds contain 0+T and S.SO\ >-+eO-0+T o-
Yet Yei!ht 7 ?aner;ee Z 6hosal 4ROR 8.
6enus: @espedeGa
Epecies: icolor
@eaves and root contain 0+T and >-+eO-0+T 7 Emith 4RPP 8. Eeeds
o- this hard: perennial shru are availale -rom ..O- the ;un!le -or j>.
6enus: +ucuna
Epecies: pruriens
@eaves* stem and -ruit o- this ;un!le vine contains 0+T and >-+eO-
0+T 7 6hosal et al.* 4RP4 8. Eeeds are availale -rom ..O- the ;un!le
-or j>.
6enus: Ph:llodium
Epecies: pulchellum
0ried plant material produced S.5\ >-+eO-0+T and small amounts
o- 0+T 7 6hosal Z +uIher;ee 4ROO 8.
1amil:: +imosaceae
6enus: Anadenanthera 7Piptandenia8
Epecies: colurina* contorta* excelsa* macrocarpa* pere!rina
?lacI eans -rom these trees are toasted* pulveriGed and mixed Yith
ashes or calcined shells to maIe ps:chedelic snu-- called :opo :
,ndians in Orinoco asin in %olomia* TeneGuela and possil: in
southern part o- ?rasilian AmaGon. Fopo is loYn into the nostrils
throu!h amoo tues or snu--ed : irdone tues. The trees !roY in
open plain areas* and leaves* arI and seeds contain 0+T* >-+eO-
0+T and related compounds 7Echultes 4RPO * 4RPP ; Pachter et al.
4R>R ; Ph:tochem 44* P9P8.
6enus: Acacia
Epecies: con-usa H0+T*stJ* ;urema* maidenni H0+T*J niopo*
nuica H0+T* lJ* phleoph:lla H0+T*lJ* pol:acantha H0+T*lJ
susp. camp:lacantha* sene!al H0+T*lJ* simplici-olia
H0+T**l*stJ* simplex* tortilis.
The letters -olloYin! the tr:ptamine 70+T in all o- these
cases8 re-er to Yhere the tr:ptamine is -ound in the plant:
]st] is stems* ]] is arI* and ]l] is leaves.
0ried A. con-usa stems contain S.S<\ )-meth:ltr:ptamine and S.S5\
0+T 7 Arthur et al. 4ROP 8. The dried leaves o- A. phleoph:lla contain
S.9\ 0+T 7 (ovelli Z Tau!han 4ROP 8. The arI o- A. maidenii
contains S.O\ o- )-meth:ltr:ptamine and 0+T in the proportions
approx. 5:9 7 1itG!erald Z Eioumis 4RO> 8. A. simplex also contains
0+T 7 Poupat et al. 4RPO 8. Eeveral Eudanese species have 0+T 7
Naha Z &lIheir* 4RP> 8. Eeeds o- several acacia species are availale
-rom ..O- the ;un!le.
6enus: 0esmanthus
Epecies: illinoensis ],llinois ?undle-loYer]
Thompson et al. report that the root arI o- this )orth American
perennial shru contains S.9<\ 0+T and S.44\ )-meth:ltr:ptamine.
The arI accounts -or aout a hal- o- the total Yei!ht o- the roots. The
plant should e resistant to cold and drau!ht and eas: to !roY. ..O- the
Wun!le sells 0. illinoensis seeds and dried roots 7seed pacIet j9* P
!rams j4S* oG j5>; roots < oG j4>* pound j>S8. Eeeds are also availale
-rom more main-stream mail-order houses.
6enus: +imosa
Epecies: scarella* tenui-lora 7^^ hostilis8 ]tepescohuite]*
verrucosa
The roots o- +. hostilis* Yhich is not the common houseplant +.
pudica 7]sensitive plant]8* contain S.>P\ 0+T and are used : ,ndians
o- Pernamuso Etate in ?raGil as part o- their Furema cult 7 Pachter et
al. 4R>R * Echultes 4RPP * 7 +ecIes-@oGo:a et al. 4RRS 8. +. scarella
contains 0+T and )-meth:ltr:ptamine 7 0e +oraes et al.* 4RRS 8.
?arI o- +. verrucosa also contains 0+T 7 Emith 4RPP 8.
6enus: Testulea
Epecies: !aonensis
%ontains 0+T 7 @eoeu- et al.* 4RPP 8.
1amil:: +alpi!hiaceae
6enus: ?anisteriopsis
Epecies: muricata 7^ar!entea8* rus:ana 7see 0iplopter:s
carerana8
?oth contain 0+T 7 Emith 4RPP 8.
6enus: 0iplopter:s
Epecies: carerana
)atives o- Yestern AmaGon add 0+T- and )-meth:ltr:ptamine
containin! leaves o- the vine 0. carerana to a drinI made -rom
?anisteriopsis caapi* Yhich contains eta-carolines harmine and
harmaline* to hei!hten and len!then the visions 7 Echultes 4RPP * Emith
4RPP 8. 0. carerana is also InoYn as ?anisteriopsis rus:ana.
1amil:: +:risticaceae
6enus: Hors-ieldia
Epecies: supera
%ontains >-+eO-0+T as Yell as a eta-caroline 7 Wossan! et al. 4RR4
8.
6enus: ,r:anthera
Epecies: macroph:lla
The arI contains >-+eO-0+T 7 Holmstedt et al. 4RQS 8.
6enus: Tirola
Epecies: caloph:lla* caloph:lloidea* ru-ula* sei-era* theiodora
The arI resin o- these trees is used to prepare hallucino!enic snu--s in
northYestern ?raGil : oilin!* dr:in! and pulveriGin! it. Eometimes
leaves o- a Wusticia are added. The snu-- acts rapidl: and violentl:*
]e--ects include excitement* numness o- the lims* tYitchin! o- -acial
muscles* nausea* hallucinations* and -inall: a deep sleep; macroscopia
is -re$uent and enters into NaiIa elie-s aout the spirits resident in the
dru!.] Enu--s made -rom T. theiodora arI contain up to 44\ >-+eO-
0+T and 0+T. Also leaves* roots and -loYers contain 0+T.
AmaGonian %olomia natives roll small pellets o- oiled resin in a
evaporated -iltrate o- arI ashes o- 6ustavia Poeppi!iana and in!est
them to rin! on a rapid intoxication 7 Emith 4RPP * Echultes 4RPP 8.
1amil:: Pandanaceae
6enus: Pandanus ]EcreY pine]
0+T has een isolated -rom Pandanus nuts !roYin! in )eY 6uinea 7
?arrau 4R>Q* 4RO5 8.
1amil:: Poaceae
6enus: Arundo
Epecies: donax
@eaves* -loYers and rhiGomes contain 0+T* u-otenine and related
compounds 7 6hosal et al. 4RP5 8.
6enus: Phalaris
Epecies: a$uatica 7tuerosa8* arundinacea
@eaves o- P. arundinacea and leaves and seedlin!s o- P. a$uatica
contain 0+T* >-+eO-0+T and related compounds 7 Emith 4RPP 8. P.
arundinacea plants are availale -rom ..O- the ;un!le -or j4>.
6enus: Phra!mites
Epecies: australis
(hiGomes contain 0+T 7 Nassel et al. 4RQ> 8.
1amil:: (uiaceae
6enus: Ps:chotria
Epecies: cartha!inensis* viridis 7ps:chotriae-olia8
Ps:chotria leaves are added to a hallucino!enic drinI prepared -rom
?anisteriopsis caapi and ?. rus:ana 7Yhich contain eta-carolines8 to
stren!then and len!then the e--ects in Yestern AmaGon. P.
cartha!inensis and P. viridis oth contain 0+T 7 (ivier* 4RP5 8. > seeds
o- P. viridis cost j4S -rom ..O- the ;un!le.
1amil:: (utaceae
6enus: 0ict:oloma
Epecies: incanescens
?arI contains S.S<\ >-+eO-0+T 7 Pachter et al. 4R>R 8.
6enus: @imonia
Epecies: acidissima
%ontains 0+T 7 Au car!a* 4RQO 8.
6enus: +elicope
Epecies: leptococca
%ontains >-+eO-0+T as Yell as >-+eO-0+T-Oxide and a eta-
caroline 7 EIaltsounis et al. 4RQ9 8.
6enus: Tepris
Epecies: ampod:
The leaves and ranches contains up to S.5\ 0+T 7 ban-1an 4RPS 8.
6enus: canthox:lum
Epecies: aorescens
%ontains 0+T 7 6rina et al.* 4RQ5 8.
tale o- contents
Referen!es
Au car!a* +.H. 4RQO. Three neY simple indole alIaloids -rom
@imonia acidissima. @lo:dia <R7>8* RS4-RS<.
AIers* ?.P. 4RR5. Peele[s @epiota: An identi-ication and a
clari-ication. +:cotaxon <97S8* <O4-<OR.
Arora* 0. 4RQO. +ushrooms 0em:sti-ied: A %omprehensive 6uide to
the 1lesh: 1un!i. Ten Epeed Press* ?erIle:.
Arthur* H.(.* @oo* E.). Z @amerton* W.A. 4ROP. )-meth:lated
tr:ptamines and other constituents o- Acacia con-usa +err. o- Hon!
bon!. Aust. W %hem. 5S* Q44.
?aner;ee* P.b. Z 6hosal* E. 4ROR. Eimple indole ases o- 0esmodium
!an!eticum. Aust. W %hem. 55* 5P>-5PP.
?arrau* W. 4R>Q.
)ouvelles oservations au su;et des plantes hallucino!enes d[usa!e
autochtone en )ouvelle-6uinee. W A!ric. Trop. ?ot. Appl. >* 9PP-9PQ.
?arrau* W. 4RO5.
Oservations et travaux recents sur les ve!etaux hallucino!enes de la
)ouvelle-6uinee. W A!ric. Trop. ?ot. Appl. R* 5<>-5<R.
?enedict* (.6.* ?rad:* @.(.* Emith* A.H. Z T:ler* T.&. 4RO5.
Occurrence o- psiloc:in and psilocin in certain %onoc:e and
Psiloc:e species. @lo:dia 5>* 4>O-4>R.
?enedict* (.6.* T:ler* T.&. Z Natlin!* (. 4ROP.
?luein! in %onoc:e* Psiloc:e and a Etropharia Epecies and the
0ectection o- Psiloc:in. @lo:dia 9S758* 4>S-4>P.
?esl* H. 4RR9.
6alerina ste!lichii spec. nov.* a hallucino!enic 6alerina. ceitschri-t
-uer +:Iolo!ie >R758* 54>-54Q.
?resinsI:* A. Z ?esl* H. 4RRS.
A %olour Atlas o- Poisonous 1un!i. Nol-e Pulishin! @td* @ondon.
?:e* (.A. 4RPR.
Hallucino!enic plants o- the Tarahumara. W. &thnopharmacolo!: 4*
59-<Q.
%hristiansen* A.@.* (asmussen* b.&. Z Hoeiland* b. 4RQ<.
0etection o- psiloc:in and psilocin in )orYe!ian species o- Pluteus
and %onoc:e. Planta +ed. >S* 9<4-9<9.
%imino* 6. Z 0e Ete-ano* E. 4RPQ.
%hemistr: o- +editerranean 6or!onians. Eimple indole derivatives
-rom Paramuricea chamaeleon. %omptes (endus ?iochem. Ph:siol.
Eer. %. O4* 9O4-9O5.
%rouch* ,.W.* Emith +.T.* Tan Etaden W.* @eYis* +.W. Z Hoad* 6.T.
4RR5.
,denti-ication o- auxins in a commercial seaYeed concentrate. W Plant
Ph:siolo!: 49R7>8* >RS->R<.
0al:* W.N. Z NitIop* ?. 4RP4.
%hemistr: and pharmacolo!: o- -ro! venoms. ,n: Tenomous animals
and their venoms. Tol ,,. )eY ForI: Academic Press.
0avis* N. Z Neil* A.T. 4RR5.
,dentit: o- a )eY Norld Ps:choactive Toad. Ancient +esoamerica 9
74RR58 >* >4->R.
0e +oraes* &.H.1.* Alvaren!a* c.+.A.* 1erreira* c.+.6.E. Z Alisue*
6. 4RRS.
Buim. )ova 49* 9SQ.
1itG!erald* W.E. Z Eioumis* A.A. 4RO>.
AlIaloids o- Australian @e!uminosae T. Aust. W %hem. 4Q* <99.
1iussello* ). Z %eruti-Ecarti* W. 4RP4'P5.
PresenGa di psilociina edi >-idrossi-indolderivati in Panaeolus
retiru!is. Atti Acc. Eci. Torino 4SO* P5>-P9>.
6artG* W. 4RR4.
,n-luence o- phosphate on -ruitin! and secondar: metaolism o-
m:celia o- Psiloc:e cuensis* Psiloc:e semilanceata and
6:mnopilus purpuratus. ceitschri-t -uer +:Iolo!ie >P748* 4<R-4><.
6hosal* E.* %haudhuri* (.b.* 0utta* E.b. Z ?hattachar:a* E.b. 4RP5.
Occurrence o- curaromimetic indoles in the -loYers o- Arundo donax.
Planta +ed. 54* 55.
6hosal* E. Z +uIher;ee* ?. 4ROO.
,ndole-9-alI:lamine ?ases o- 0esmodium pulchellum. W* Or!. %hem.
94* 55Q<.
6hosal* E.* Ein!h* E. Z ?hattachar:a* E.b. 4RP4.
AlIaloids o- +ucuna pruriens* %hemistr: and Pharmacolo!:. Planta
+ed. 4R* 5PR
6rina* W.A. et al. 4RQ5.
%onstituents o- canthox:lum aorescens. Part P. Old Z neY alIaloids
-rom canthox:lum aorescens. W. Or!anic %hemistr: <P* 5O<Q-5O>4.
6urevich* @.E. 4RR9.
,ndole derivatives in certain Panaeolus species -rom &ast &urope Z
Eieria. +:colo!ical (esearch RP758* 5>4-5><.
6urevich* @.E. Z AstapenIo* T.T. 4RR5.
%hromato!raphic stud: o- some indole metaolites in Panaeolus
asidiom:cetes. +iIolo!i:a , 1itopatholo!i!a 5O798* 4QR-4R<.
6uGman* 6. 4RQ9.
The 6enus Psiloc:e. ?eihe-te cur )ova HedYin!ia P<* 4-<9R.
6uGman* 6.* ?andala* T.+. Z Allen* W.N. 4RR9.
A )eY ?luin! Psiloc:e -rom Thailand. +:cotaxon 5O* 4>>-4OS.
6uGman* 6.* ?andala* T.+. Z bin!* %. 4RR4.
A )eY Epecies o- Psiloc:e o- Eection capotecorum -rom )eY
cealand. +:colo!ical (esearch R>* >SP->SQ.
6uGman* 6.* Ealdarria!a* F.* Pineda* 1.* 6arcia* 6. Z TelaG$ueG* @.1.
4RR<.
)eY Epecies o- Psiloc:e -rom %olomia and 0iscussion on the
InoYn species. +:cotaxon * 55>.
Haeselarth* 6.* +ichaelis* H. Z EalniIoY* W. 4RQ>.
)achYeis von Psiloc:in in ,noc:e aeru!inescens. +:Iol. +itt. l.
5Q748* >R-O5.
Hat-ield* 6.+.* Taldes* @.W. Z Emith* A.H. 4RPQ.
The occurrence o- psiloc:in in 6:mnopilus species. @lo:dia <4*
4<S-4<<.
Hein* (. Z Nasson* (.6. 4R>Q.
@es champi!nons hallucino!enes du +exi$ue. +useum )ational
d[Histoire )aturelle* Paris.
Holmstedt* ?.* @ind!ren* W.&.* et al. 4RQS.
,ndole alIaloids in AmaGonian +:risticaceae: 1ield and laorator:
research. ?ot. +us. @ea-l.* Harvard Cniv. 5Q* 54>-59<.
Wohns* E.(.* @amerton* W.A. Z Eioumis* A.A. 4ROO.
AlIaloids o- the Australian @e!uminosae T,. Aust. W %hem. 4R* QR9.
Wossan!* A.* Wossan!* %.* Hadi* H.A.* Eevenet* T. Z ?odo* ?. 4RR4.
Hors-iline* an oxindole alIaloid -rom Hors-ieldia supera. W. Or!anic
%hem. >O7598* O>5P-O>9S.
ban 1an* %. et al. 4RPS.
Alcaloides de Tepris ampod: 7(utacees8. Ph:tochem. R* 45Q9-45R4.
bantor* (.&.* 0udlettes* E.0. Z Ehul!in* A.T. 4RQS.
>-+ethox:-al-a-meth:l- tr:ptamine 7al-a*O-dimeth:lserotonin8* a
hallucino!enic homolo! o- serotonin. ?iolo!ical Ps:chiatr: Tol 4>*
9<R-9>5.
boiIe* F.* Nada* b.* busano* 6.* )oGoe* E.* Z FoIo:ama* b. 4RQ4.
,solation o- Psiloc:in -rom Psiloc:e ar!entipes and its
0etermination in Epecimens o- some +ushrooms. @lo:dia <<798* 9O5-
9O>.
@eoeu-* +. et al.* 4RPP.
AlIaloids and triterpenes o- Testulea !aonensis. Plant +edicine
Ph:totherap: 44* 59S.
@una* @.&. 4RQ<.
The Healin! Practices o- a Peruvian Ehaman. W. &thnopharmacolo!:
44* 459-499.
+cbenna* 0.W.* ToYers* 6.H.).* Z Aott* 1. 74RQ<8.
+onoamine oxidase inhiitors in Eouth American hallucino!enic
plants: Tr:ptamines and ?eta-caroline constituents o- a:ahuasca. W
&thnopharmacolo!: 4S* 4R>-559.
+cIenna* 0.W. Z ToYers* 6.H.). 4RQ<.
?iochemistr: and Pharmacolo!: o- Tr:ptamines and eta-%arolines:
A +inirevieY. W Ps:choactive 0ru!s 4O7<8.
+ecIes-@oGo:a* +.* @oGo:a* L.* +arles* (.W.* Eouc:-?reau* %.* Een*
A. Z Arnason* W.T. 4RRS.
)*)-dimeth:ltr:ptamine alIaloid in +imosa tenui-lora arI
7tepescohuite8. Arch. ,nvest. +ed. +ex. 54758* 4P>-P.
+erlin* +.0. Z Allen* W.N. 4RR9.
Epecies identi-ication and chemical anal:sis o- ps:choactive -un!i in
the HaYaiian islands. Wournal o- &thnopharmacolo!: <S748* 54-<S.
+iller Wr.* O.b. 4RP5.
+ushrooms o- )orth America. 0utton Z %o.* Eprin!-ield.
+ost* Alert. 4RQ<.
?u-o Alvarius: the Ps:chedelic Toad o- the Eonoran 0esert . Tenom
Press ?ox 5QO9 0enton TL PO5S5.
+ost* Alert. 4RQO.
&ros and the Pineal: the la:man[s !uide to cereral solitaire . Tenom
Press* 0enton* TL.
)aran;o* %. 4ROR.
Ps:chotropic Properties o- the Harmala AlIaloids. ,n: &-ron 7&d.8 The
&thnopharmacolo!ic Eearch -or Ps:choactive 0ru!s.
Oheno;a* &.* WoIiranta* W.* +aIinen* T.* baiIIonen* A. Z AiraIsinen*
+.+. 4RQP. The Occurrence o- Psiloc:in and Psilocin in 1innish
1un!i. @lo:dia >S7<8* P<4-P<<.
Pachter* ,.W* cacharias* 0.& Z (ieir* O. 4R>R.
,ndole AlIaloids o- Acer saccharinum 7the Eilever +aple8*
0ict:oloma incanescens* Piptadenia colurina* and +imosa hostilis. W
Or! %hem 5<* 45Q>-P.
Phillips* (. 4RQ4.
+ushrooms and other -un!i o- 6reat ?ritain and &urope. Pan ?ooIs*
@ondon.
Poupat* %.* Ahond* A. Z Eevenet* T. 4RPO.
Alcaloides 0e Acaia simplici-olia. Ph:tochemistr: 4>* 5S4R-545S.
(ivier* @. Z @ind!ren* W-&. 4RP5.
]A:ahuasca*] the Eouth American Hallucino!enic 0rinI: an
&thnootanical and %hemical ,nvesti!ation. &conomic ?otan: 5O*
4S4-45R.
(ivier* @. Z Pilet* P.&. 4RP4.
Annee ?iolo!i$ue 4S* 45R.
(oers* W.&.* T:ler* T.&. Z Ola[h* 6.+. 4ROR.
Additional evidence supportin! the occurrence o- psiloc:in in
Panaeolus -oenisecii. @lo:dia 95* 9RR-<SS.
(ovelli* ?. Z Tau!han* 6.). 4ROP.
AlIaloids o- Acacia ,. 0imeth:ltr:ptamine in Acacia phleoph:lla.
Aust. W %hem. 5S* 45RR-49SS.
Eaupe* E.6. 4RQ4.
Occurence o- Psiloc:in'Psilocin in Pluteus salicinus 7Pluteaceae8.
+:colo!ia P9* PQ4-PQ<.
Echultes* (.&. 4RPO.
,ndole AlIaloids in Plant Hallucino!ens. W o- Ps:chedelic 0ru!s Tol
Q748* P-5>.
Echultes* (.&. 4RPP.
The ?otanical and %hemical 0istriution o- Hallucino!ens. W o-
Ps:chedelic 0ru!s Tol R798* 5<P-5O9.
Echultes* (.&. 4RPR.
Hallucino!enic Plants: Their &arliest ?otanical 0escriptions. W o-
Ps:chedelic 0ru!s Tol 4474-58* 49-5<.
Echultes* (.&. Z Ho-mann* A. 4RPR.
Plants o- the 6ods. +c6raY-Hill. (eprint availale -rom Healin! Arts
Press* (ochester* TT.
Echultes* (.&. Z Ho-mann* A. 4RQS.
The ?otan: and %hemistr: o- Hallucino!ens. Eprin!-ield* ,ll:
Thomas.
Ehul!in* A.T. 4RPO.
Ps:chotomimetic a!ents. ,n: 6ordon* +. 7&d.8
Ps:chopharmacolo!ical A!ents* Tol ,T. )eY ForI: Academic Press.
Ehul!in* A.T. 4RQ5.
%hemistr: o- Ps:chotomimetics. ,n: Ho--meister* 1. Z Etille* 6. 7&ds.8
HandooI o- &xperimental Pharmacolo!:* Tol >>: Alcohol and
Ps:chotomimetics* Ps:chotropic &--ects o- %entral-Actin! 0ru!s.
)eY ForI: Eprin!er-Terla!.
EIaltsounis* A.@.* Tille$uin* 1. Z boch* +. 4RQ9.
Plantes des )ouvelle- %aledonie @LLL,,,: Alcaloides des ti!es
-euillees de +elicope leptococca. @lo:dia <O7>8* P95.
Emith* T.A. 4RPP.
(evieY: Tr:ptamine and (elated %ompounds in Plants.
Ph:tochemistr: 4O 4P4-4P>.
Etein* E.,. 4R>R.
%linical Oservations on the &--ects o- Panaeolus venenosus Tersus
Psiloc:e caerulescens +ushrooms. +:colo!ica >4* <R.
Eti;ve* T.* blan* W. Z bu!per* N. 4RQ>.
Occurrence o- psiloc:in and aeoc:stin in the !enus ,noc:e.
Persoonia 45* <OR-<P5.
Etrassman* (.W. 4RRS.
The Pineal 6land: %urrent &vidence 1or ,ts (ole ,n %onsciousness.
,n: @:ttle* T. 7&d.8 Ps:chedelic +ono!raphs and &ssa:s Tol >.
Thompson* A.%.* )icollier* 6.1. Z Pope* 0.1 4RQP.
,ndolealI:lamines o- 0esmanthus illinoensis and Their 6roYth
,nhiition Activit:. W A!ric. 1ood %hem. 9>* 9O4-9O>.
Naha* E.b. Z &lIheir* F.+. 4RP>.
0imeth:lt:rptamine -rom the leaves o- certain Acacia species o-
northern Eudan. @lo:dia 9Q* 4PO-4PP.
Nassel* 6.+. et al. 4RQ>.
AlIaloids -rom the rhiGomes o- Phra!mites australis %av. Ecientia
Pharmaceutica >9* 4OR-4PS.
Petrus.PennanenahelsinIi.-i e &ver:thin! is per-ect -orever
+ichael -rom +elourne e 0itto
RELA?ED SPACES
0+T
)*)-0,+&THF@T(FPTA+,)&
http:''ael-
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com'ael-i
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Ehamanism
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ErroO O nome "e arqui<o nPo foi es#e!ifi!a"o
FA% Dos Porta"ores Do ?r1#tamine
por Petrus Pennanen
com a;uda de Nic#ael de Nelbourne .
H:pertexture e es-or.o dontinuin! da ilustra."o atravs de http:''deox:.or!

en_pt http://babelf ish.al done en
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GET en_pt
A!radecimentos a muitos indiv#duos para a a;uda em unir isto.
Ee voc souer as -ontes dos tr:ptamines $ue n"o s"o mencionados
a$ui satis-aGem enviam-nos.
GET en_pt
F$tima bus!a "e Gu$&o 1;;; "o u#"ate "o "eo@1
este FA% #ara
GET en_pt
,niidores e tr:ptamines de +AO
E#ntese de derivatives de 0+T
Eapos 0e Ps:chedelic
Os 1un!os
As Plantas
(e-erncias
Ora$ e #arentera$$1 "eri<ati<es #s1!&otro#i! ati<os "o tr1#tamine
?aseado em +cbenna Z em torres 4RQ<
0ados compilados de bantor* et al. 4RQS ; Ehul!in 4RPO * 4RQ5 ;
Ehul!in Z %arter 4RQS
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S sintomas ( autonomicB pouca atividade central.
S & os esters do p#osp#ate s7o psilocybin e "ey)(+, respectivamenteB
ambos s7o stoic#iometrically eMuivalente aos isomers 8)#ydro%y.
S 0 cardiovascular e sintomas autonomicB pouca atividade central.
S amine pressor de 8 1 mel#or Mue um #allucinogen no #omem.
S 2 um antidepressivo mel#or Mue um #allucinogen no #omem.
S ' basearam em relat;rios anonymous na imprensa da configura=7o.
/en#um estudo cl3nico foi publicado.
S @ nen#uma atividade oral com doses at5 magn5sio &D, podem ser
parenterally ativos.
Outros tr:ptamines potencial ps:chedelic incluem:
O--luoro-al-a-meth:ltr:ptamine* P-meth:ltr:ptamine* >-
meth:ltr:ptamine
>--luorotr:ptamine* O--luorotr:ptamine e >- e O--luorotr:ptophans.
GET en_pt
Pro!urare este FA% #or
GET en_pt
n"i!e
Inibi"ores e tr1#tamines "e AAO
O oxidase de +onoamine 7+AO8 o pathYa: preliminar do
inactivation de a maioria de tr:ptamines. Por causa disto* os
iniidores do enG:me de +AO 7+AO,s8 podem ser usados potentiate
os e-eitos dos tr:ptamines e -aGer oral 0+T e >-+eO-0+T ativos.
Os iniidores de +AO caem em duas classes: +AO,s irreversile e
revers#vel. Alm podem iniir $ual$uer um ou amos os dois tipos do
enG:me* de +ao-a e de +ao- de +AO $ue s"o associados com os
neurVnios serotoner!ic e dopaminer!ic respectivamente. @i!amento
irreversile de +AO,s 7por exemplo o iproniaGid e o phenelGine dos
h:draGides8 permanentemente ao enG:me e X inii."o da causa +AO
$ue duram 4-5 semanas aps o in!estion. E"o usados clfnica tratar o
depression. +AO,s revers#vel* tal como o mocloemide* $ue usado
como um antidepressivo* e o harmine e o harmaline eta-carolines-
carolines* e-icaG por um tempo muito mais curto* talveG at 5<
horas. Os usurios recreacionais da dro!a em torno do mundo est"o
usando principalmente o harmine e o harmaline apesar da -alta de
estudos cient#-icos em seus e-eitos em seres humanos.
Os nativos de AmaGon cominaram tradicional a videira do caapi de
?anisteriopsis* $ue contem o harmine* o harmaline e eta-carolines-
carolines relacionado* com as plantas 0+T-contendo para -aGer um
oral ativo reY o a:ahuasca chamado . Outras plantas $ue contm o
harmine e'ou o harmaline podem ser sustitu#das para o caapi do ?.. [
o a:ahuasca norte-americano usual [ consiste em raiGes das sementes
do harmala de Pe!anum e do illinoensis de 0esmanthus* e [ no
acaciahuasca australian [ sae do complanata do acacia s"o cominados
com o material dos acacias 0+T-contendo 7o e--ectivit: desta mistura
n"o -oi con-irmado8. +AO,s -oi usado tamm potentiate os e-eitos
dos co!umelos $ue contm o psiloc:in. Terence +cbenna
mencionou o chocolate $ue um +AO, -raco* $ue poderia ser uma
raG"o para o hito popular de in!estin! co!umelos com cacau.
As sementes do harmala de Pe!anum 7rue s:rian8 s"o a -onte natural a
mais concentrada do harmine e harmaline - aproximadamente 9\ de
seu peso consiste nestes alcalides. O caapi de ?anisteriopsis -oi
encontrado para conter S*4Q\ a 4*9O\ eta-carolines-carolines*
com a concentra."o do harmine $ue S*S>P\ a S*O9>\ 7 +cbenna et
al. 4RQ< 8. 0e acordo com relatrios anecdotal um !rama das
sementes do harmala do P. in!ested inie +AO astante para -aGer
oral 0+T ativo.
Harmine e o harmaline s"o hallucino!enic no seus prprios com os
doses $ue partem de ma!nsio ao redor 9SS 7 )aran;o 4ROP 8* mas
causam -re$uentemente side-e--ects -#sicos tais como o nausea e os
tremors neste dose variam. Tm e-eitos emocionais ou [ ps:chedelic [
pouco* mas produGem hallucinations visuais -ortes. Por causa desta os
nativos de AmaGon adicionam -re$uentemente as $uantidades maiores
7P>-4SS cm da haste por o dose8 de caapi do ?. ao a:ahuasca reY do
$ue needed para a inii."o de +AO 7 @una 4RQ< 8.
H uns peri!os si!ni-icativos em usar iniidores de +AO. A maioria
de +AO,s potentiate os e-eitos cardiovascular do t:ramine e dos
outros monoamines encontrados nos alimentos. O in!estion do $uei;o
envelhecido* cerve;a* vinho* picIled herrin!* -#!ado de !alinha*
-ermento* $uantidades !randes de ca-* -rutas de citrino* -i!s
enlatados* -ei;Ues lar!os* chocolate ou o creme $uando +AO -or
iniido pode causar uma crise h:pertensive includin! uma ascens"o
peri!osa na press"o de san!ue. Os e-eitos dos amphetamines* de
anestsicos !erais* de sedatives* de anti-histamines* de lcool* de
anal!esics potent e de a!entes anticholiner!ic e do antidepressivo s"o
prolon!ados e intensi-ied. O overdosa!e de +AO,s por se tamm
poss#vel com e-eitos includin! a hiper-re-lexia e os convulsions.
GET en_pt
Pro!urare este FA% #or
GET en_pt
n"i!e
Sntese "e "eri<ati<es "e DA?
Os derivatives do tr:ptamine e eta-%arolines-%arolines -oram
detectados como metaolites endo!enous nos mam#-eros* includin!
seres humanos. Os trans-erases meth:l $ue catal:Ge a s#ntese dos
tr:ptamines* includin! 0+T* >-+eO-0+T e u-otenine* s"o
encontrados no pulm"o humano* no crero* no l#$uido cererospinal*
no -#!ado e no cora."o 7 +cbenna Z torres 4RQ< 8. )a !l/ndula
pineal +AO o pathYa: preliminar do serotonin* um
neurotransmitter do inactivation s:nthesiGed do tr:ptophan do amino-
cido. Ee +AO -or ostru#do pelo harmine* o harmaline ou o outro
serotonin dos iniidores de +AO podem ser convertidos pelos
enG:mes H,O+T e ,)+T do meth:ltrans-erase em tr:ptamines
ps:chedelic 7serotonin -- --g >-+eO-tr:pt do 7hiomt8. -- 75einmt8 --g
>-+eO-0+T8.
Assim* in!estin! o l-l-tr:ptophan para aumentar n#veis do serotonin*
uma arra do doce para aumentar a $uantidade de tr:ptophan $ue
come.a a seus crero e material de planta natural $ue contm 5>->S
ma!nsio harmine'harmaline ao loco +AO* tudo ao mesmo tempo*
pVde causar sua !l/ndula pineal s:nthesiGe $uantidades sustanciais
de >-+eO-0+T 7 a maioria 4RQO 8. ,sto extremamente peri!oso
para pessoas com dese$uil#rio ou es$uiGo-renia existente do amine.
Para conse$hncias poss#veis dos povos normais* saudveis se;a mau
HIO ?EH?E IS?O
Cm iniidor potent de ,)+T* $ue um enG:me necessrio para a
s#ntese de 0+T e de >-+eO-0+T* encontrado em concentra.Ues
particularmente elevadas na !l/ndula pineal. %ontornear ou uma
inii."o da s#ntese deste iniidor puderam ser responsvel para
trances e outros estados ps:chedelic conse!uiram ]sem dro!as]
7 Etrassman 4RRS 8. Te;a o arti!o de Etrassman para mais in-o e
speculation sore a !l/ndula pineal.
GET en_pt
Pro!urare este FA% #or
GET en_pt
n"i!e
Sa#os De Ps1!&e"e$i!
ADVER?IHDO estes sapos s"o VENENOSOS. Ee
voc comesse o venom voc poderia MORRER.
0iversos suspecies deste tipo de sapo s"o meramente
venenosos. )"o pense mesmo sore -aGer isto a menos
$ue voc puder absolutamente identi-icar a espcie* e
saia todas as conse$hncias de -um-la venom. &u
sei todas estas coisas e decidi-me n"o -umar o venom
secado do sapo* e a$uela minha recomenda."o a voc.
AHO?E o sapo mencionado esta se."o* alvarius de
Bufo, uma espcie rara e posta em peri!o - dimitri
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http
\9A\51\51YYY.deox:.or!\51audio\51-ro!s.au
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http
\9A\51\51YYY.deox:.or!\51audio\51-ro!s.au?u-otenine e >-
h:drox:-indoleth:lamines relacionados s"o constituents comuns dos
venoms dos !enera H:la* @eptodact:lus* (ana e ?u-o. ?u-otenine n"o
ps:chedelic em doses raGoveis 7com doses maiores h uns e-eitos
laterais ph:siolo!ical peri!osos8* mas a pele de uma espcie* alvarius
de ?u-o* contem >S-4OS ma!nsio >-+eO-0+T'! da pele 7 0al: Z
NitIop 4RP4 8. M a =nica espcie de ?u-o saida para conter um
tr:ptamine hallucino!enic 7 +cbenna Z torres 4RQ< 8. A maioria
74RQ<8 d instru.Ues para coletar e secar o venom:
O venom -resco pode -Xcilmente ser coletado sem dano ao sapo. Cse
uma placa de vidro lisa ou todo o outro $uadrado 45-inches liso*
nonporous da super-#cie ao menos. Prenda o sapo na -rente da placa*
$ue reparada em uma posi."o vertical. )esta maneira* o venom
pode ser coletado na placa de vidro* livre da su;eira e do l#$uido
lierados $uando o sapo se!urado.
Buando voc est pronto para come.ar* prenda o sapo -irmemente
com uma m"o e* com o pole!ar e o -ore-in!er de sua outra m"o*
esprema-o perto da ase da !l/ndula at $ue o venom es!uinche -ora
dos pores e na placa de vidro. Cse este mtodo coletar
sistematicamente o venom de cada uma das !l/ndulas !ranular do
sapo: a$ueles no -orearm* a$ueles no tiia e no -emur do p hind* e*
naturalmente* os parotids na !ar!anta . %ada !l/ndula pode ser
espremida uma se!unda veG para um rendimento adicional do venom
se voc permitir ao sapo um preiod one-hour do descanso. 0epois $ue
isto as !l/ndulas est vaGio e re$uer $uatro a seis semanas para a
re!enera."o.
O venom viscous e leitoso-ranco na cor $uando espremido
primeiramente das !l/ndulas. %ome.a a secar dentro dos minutos e
ad$uire a cor e a textura do cimento de orracha. (aspe o venom da
placa de vidro* se$ue-o completamente* e armaGene-o em um
recipiente hermtico at $ue voc este;a pronto para o -umar.
0avis e Neil 74RR58 -umaram o venom e descreveram o $ue
aconteceu:
)a compara."o com os compostos puros o venom do sapo
parece mais por muito tempo durando e* por$ue um n"o perde
completamente o contato com realidade* um sensual distante
mais a!radvel* mais uni-orme. @o!o aps o inhalation ,
experimentaram sensations nivelando mornos* um sentido da
maravilha e o em estar* os hallucinations auditor: -ortes* $ue
inclu#ram um som da inseto-ci!arra $ue -uncionasse atravs de
minha mente e parecesse li!ar meu corpo X terra. &mora eu
estava dentro* havia um sentido da sensa."o da terra* o pa seco
do solo do deserto eee T(A)E@AT,O) &)0E H&(&
eeessin! throu!h m: -in!ers* the stars at midda:* the scent o-
cactus and sa!e* the -eel o- dr: leaves throu!h hands. Etron!
visual hallucinations in orliIe rilliance* diamond patterns that
undulated across m: visual -ield. The experience Yas in ever:
sense pleasant* Yith no disturin! ph:sical s:mptoms* no
nausea* perhaps a sli!ht sense o- increased heart rate. Narm
Yaves coursed up and doYn m: od:. The e--ects lasted onl: a
-eY minutes ut a pleasant a-ter!loY continued -or almost an
hour. 7Nade 0avis* personal oservation* Wanuar: 45* 4RR48
Pro-ound alteration o- consciousness Yithin a -eY seconds o-
exhalin!. , relax into a deep* peace-ul interior aYareness. There
is nothin! scar: aout the e--ects and no sense o- toxicit:. , tr:
to descrie m: -eelin!s ut am unale to talI -or the -irst -ive
minutes and then onl: Yith some di--icult:. This is a poYer-ul
ps:choactive dru!* one that , thinI Yould appeal to most people
Yho liIe the e--ects o- hallucino!ens. 1or the next hour , -eel
sloY and velvet:* Yith a sli!ht pressure in m: head. )o lon!-
lastin! e--ects to report. 7AndreY T. Neil* personal oservation*
Wanuar: 45* 4RR48.
Other animals contain 0+T such as the !or!onian Paramuricea
chamaeleon 7 %imino Z 0e Ete-ano* 4RPQ 8.
GET en_pt
Sear!& t&is FA% for
GET en_pt
tab$e of !ontents
F J H K I
L E A J S 9 R M M A E D
1amil:: ?olitiaceae
6enus: A!roc:e
Epecies: -arinacea
%ontains psiloc:in 7 boiIe et al. 4RQ4 8.
6enus: %onoc:e
Epecies: c:anopus* Iuehneriana* sili!ineoides* smithii
%. c:anopus 7 ?enedict et al. 4RO5 8 and %. smithii 7 ?enedict et al.
4ROP 8 contain psiloc:in and psilocin Yhile %. Iuehneriana contains
psilocin onl: 7 Oheno;a et al. 4RQP 8. %. sili!ineoides ma: also contain
these alIaloids 7 Echultes Z Ho-mann 4RPR p. <S8.
1amil:: %oprinaceae
6enus: %opelandia
Epecies: anomala* ispora* camod!iniensis* chloroc:stis*
c:anescens* tropicalis
All species contain psilocin and psiloc:in* -or %. c:anescens 7
Echultes Z Ho-mann 4RPR p. <S8 and -or %. camod!iniensis as Yell as
%. tropicalis 7 Arora* 4RQO 8* and -or %. anomala as Yell as %. ispora 7
+erlin Z Allen* 4RR9 8.
6enus: Panaeolina*
Epecies: castanei-olius* -oenisecii
P. -oenisecii contains psiloc:in 7 (oers et al. 4ROR 8.
6enus: Panaeolus
Epecies: a-ricanus* antillarum* ater* campanulatus* -irmicola*
microsporus* olivacens* retiru!is* separatus* sphinctrinus*
sualteatus
Eeveral Panaeolus species contain psiloc:in. 1or P. antillarum re-er to
Allen et al. 74RR48* -or P. ater re-er to ?resinsI: et al. 74RRS8 * -or P.
papilionaceus 7 6urevich et al. 4RR5 8* -or P. retiru!is 7 1iussello et al.
4RP4'P5 8* -or P. separatus 77 +iller Wr. 4RP5 8* -or P. sphinctrinus 7 Hein
Z Nasson* 4R>Q p. 9558 and -or P. olivacens 7 Oheno;a et al. 4RQP 8. P.
sualteatus contains oth psilocin and psiloc:in 7 Oheno;a et al. 4RQP
8 ut Yas InoYn to e hallucino!enic since 4R>R 7 Etein* 4R>R 8. P.
-irmicola is also descried as hallucino!enic and proal: contains the
same alIaloids 7 Echultes* 4RPR 8.
6enus: Psath:rella
Epecies: candollenana
%ontains psiloc:in 7 boiIe et al. 4RQ4 8 and psilocin 7 Oheno;a et al.
4RQP 8.
1amil:: %ortinariaceae
6enus: 6alerina
Epecies: ste!lichii
%ontains psiloc:in and psilocin 7 ?esl* 4RR9 8.
6enus: 6:mnopilus
Epecies: aeru!inosus* li$uiritiae* luteus* purpuratus* spectailis*
validipes* viridans
+an: 6:mnopilus contain psiloc:in* -or 6. aeru!inosus* 6. luteus* 6.
spectailis* 6. validipes and 6.viridans re-er to Hat-ield et al. 74RPQ8 .
1or 6. li$uiritiae 7 boiIe* 4RQ4 8 and -or 6. purpuratus 7 6artG 4RR4 8.
6enus: ,noc:e
Epecies: aeru!inascens* calamistrata* coelestium* cor:dalna*
haemacta* tricolor
These contain psilocin and psiloc:in* -or P. aeru!inascens re-er to
Haeselarth et al. 74RQ>8 and -or the others Eti;ve et al. 74RQ>8 .
1amil:: @epiotaceae
6enus: @epiota
Epecies: humei +urrill also InoYn as peele ]Peele[s @epiota]
This mushrooms Yas claimed : Peele o- 1lorida +:colo!: (esearch
%enter 7PO ?ox Q4S< Pensacola 1lorida 95>S>8 to contain a le!al
tr:ptamine* Yhich produces a trip Yith less ph:sical s:mptoms and
etter ailit: o- lo!ical thinIin! than psilocin or psiloc:in. ?ioassa:
results didn[t -ind ps:choactivit: 7 AIers 4RR5 8.
1amil:: Pluteaceae
6enus: Pluteus
Epecies: atricapillus* c:anopus* ni!roviridis* salicinus
P. atricapillus contains psiloc:in 7 Oheno;a et al. 4RQP 8 Yhile oth P.
salicinus 7 Eaupe 4RQ4 8 and P. ni!roviridis 7 %hristiansen et al. 4RQ< 8
contain psilocin and psiloc:in.
1amil:: Pol:poraceae
6enus: 6erronema
Epecies: -iula* sYartGii
These contain psiloc:in.
6enus: H:!roc:e
Epecies: psittacina
This contains psiloc:in.
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1amil:: Etrophariaceae
6enus: Psiloc:e
Epecies: P> bnoYn hallucino!enic species i antio$uensis*
aucIlandii* eliconiae* coprophila* croulus* cuensis 7pictured8 *
!uatapensis* samuiensis* suacutipilea*
There are at least P> mushroom species in this !enera that contain
psilocin and psiloc:in in 6uGman 4RQ9 * and there are several more
recentl: discovered species such as P. aucIlandii 7 6uGman et al. 4RR9
8* P. samuiensis 7 6uGman et al. 4RR4 8 and P. antio$uensis* P.
eliconiae* P. !uatapensis and P. suacutipilea 7 6uGman et al. 4RR< 8.
Also P. coprophila* Yhile lacIin! psilocin 7maIin! it a non-luein!
psiloc:e8 is InoYn to contain psiloc:in 7 Arora* 4RQO 8. P. croulus is
also InoYn to e hallucino!enic 7 Phillips* 4RQ4 8.
,ma!es o- Psiloc:e c:anescens* c:ano-irillosa* aGurescens*
semilanceata* pelliculosa* silvatica can e seen at A 6aller: o-
Psiloc:e +ushrooms * H:perreal Teonanacatl
GET en_pt
Sear!& t&is FA% for
GET en_pt
tab$e of !ontents
P L A H ? S
PLAH2 PLAH?2 PLAHE?
1amil:: Acanthaceae
6enus: Wusticia
Epecies: pectoralis 7var. stenoph:lla8
NaiIas o- Orinoco headYaters in TeneGuela add dried and pulveriGed
leaves o- this her to their Tirola-snu--. ,ntensel: aromatic smellin!
leaves proal: contain tr:ptamines 7 Echultes 4RPP 8. Plants are
availale -rom -rom Hoti Products or ..O- the ;un!le .
1amil:: AiGoaceae
6enus: 0elosperma
%ontains 0+T and )-meth:ltr:ptamine 7 (ivier Z Pilet* 4RP4 8.
1amil:: Alariaceae
6enus: &cIlonia
Epecies: maxima
%rouch et al. 74RR58 reported -indin! 0+T in roYn seaYeed extract
sold as belpaI and intended to e used as a plant -ertiliGer. HoYever*
suse$uent anal:sis : W. 6artG su!!ests none is present.
1amil:: Apoc:naceae
6enus: Prestonia
Epecies: amaGonicaK
+a: contain 0+T ut the specimen used ma: have een misidenti-ied
7 Emith 4RPP 8.
1amil:: %actaceae
6enus: &chinocereus
Epecies: salm-d:cIianus* tri!lochidiatus
These cacti !roYin! in +exico are InoYn to Tarahumare ,ndians as
pe:ote or hiIuli and used in their -estivals. &. tri!lochidiatus contains a
tr:ptamine derivative* possil: >-+eO-0+T 7 ?:e 4RPR 8. &. salm-
d:cIianus is also supposed to contain tr:ptamines accordin! to Horus
?otanicals catalo! 4RR5.
6enus: Trichocereus
Epecies: terschecIii ]%ardon !rande]
0+T has een isolated -rom this species !roYin! in )orth-Nestern
Ar!entina 7 Echultes Z Ho-mann 4RPR p. >Q8.
1amil:: %aesalpininaceae
6enus: Petalost:lis
Epecies: cassiodies
@eaves and stem contain S.<-S.>\ tr:ptamine* 0+T and other
alIaloids 7 Wohns et al. 4ROO 8.
1amil:: 1aaceae
6enus: 0esmodium
Epecies: !an!etium* !:rans* tiliae-olium* tri-lorum*
@eaves* root* stem and seeds contain 0+T and S.SO\ >-+eO-0+T o-
Yet Yei!ht 7 ?aner;ee Z 6hosal 4ROR 8.
6enus: @espedeGa
Epecies: icolor
@eaves and root contain 0+T and >-+eO-0+T 7 Emith 4RPP 8. Eeeds
o- this hard: perennial shru are availale -rom ..O- the ;un!le -or j>.
6enus: +ucuna
Epecies: pruriens
@eaves* stem and -ruit o- this ;un!le vine contains 0+T and >-+eO-
0+T 7 6hosal et al.* 4RP4 8. Eeeds are availale -rom ..O- the ;un!le
-or j>.
6enus: Ph:llodium
Epecies: pulchellum
0ried plant material produced S.5\ >-+eO-0+T and small amounts
o- 0+T 7 6hosal Z +uIher;ee 4ROO 8.
1amil:: +imosaceae
6enus: Anadenanthera 7Piptandenia8
Epecies: colurina* contorta* excelsa* macrocarpa* pere!rina
?lacI eans -rom these trees are toasted* pulveriGed and mixed Yith
ashes or calcined shells to maIe ps:chedelic snu-- called :opo :
,ndians in Orinoco asin in %olomia* TeneGuela and possil: in
southern part o- ?rasilian AmaGon. Fopo is loYn into the nostrils
throu!h amoo tues or snu--ed : irdone tues. The trees !roY in
open plain areas* and leaves* arI and seeds contain 0+T* >-+eO-
0+T and related compounds 7Echultes 4RPO * 4RPP ; Pachter et al.
4R>R ; Ph:tochem 44* P9P8.
6enus: Acacia
Epecies: con-usa H0+T*stJ* ;urema* maidenni H0+T*J niopo*
nuica H0+T* lJ* phleoph:lla H0+T*lJ* pol:acantha H0+T*lJ
susp. camp:lacantha* sene!al H0+T*lJ* simplici-olia
H0+T**l*stJ* simplex* tortilis.
The letters -olloYin! the tr:ptamine 70+T in all o- these
cases8 re-er to Yhere the tr:ptamine is -ound in the plant:
]st] is stems* ]] is arI* and ]l] is leaves.
0ried A. con-usa stems contain S.S<\ )-meth:ltr:ptamine and S.S5\
0+T 7 Arthur et al. 4ROP 8. The dried leaves o- A. phleoph:lla contain
S.9\ 0+T 7 (ovelli Z Tau!han 4ROP 8. The arI o- A. maidenii
contains S.O\ o- )-meth:ltr:ptamine and 0+T in the proportions
approx. 5:9 7 1itG!erald Z Eioumis 4RO> 8. A. simplex also contains
0+T 7 Poupat et al. 4RPO 8. Eeveral Eudanese species have 0+T 7
Naha Z &lIheir* 4RP> 8. Eeeds o- several acacia species are availale
-rom ..O- the ;un!le.
6enus: 0esmanthus
Epecies: illinoensis ],llinois ?undle-loYer]
Thompson et al. report that the root arI o- this )orth American
perennial shru contains S.9<\ 0+T and S.44\ )-meth:ltr:ptamine.
The arI accounts -or aout a hal- o- the total Yei!ht o- the roots. The
plant should e resistant to cold and drau!ht and eas: to !roY. ..O- the
Wun!le sells 0. illinoensis seeds and dried roots 7seed pacIet j9* P
!rams j4S* oG j5>; roots < oG j4>* pound j>S8. Eeeds are also availale
-rom more main-stream mail-order houses.
6enus: +imosa
Epecies: scarella* tenui-lora 7^^ hostilis8 ]tepescohuite]*
verrucosa
The roots o- +. hostilis* Yhich is not the common houseplant +.
pudica 7]sensitive plant]8* contain S.>P\ 0+T and are used : ,ndians
o- Pernamuso Etate in ?raGil as part o- their Furema cult 7 Pachter et
al. 4R>R * Echultes 4RPP * 7 +ecIes-@oGo:a et al. 4RRS 8. +. scarella
contains 0+T and )-meth:ltr:ptamine 7 0e +oraes et al.* 4RRS 8.
?arI o- +. verrucosa also contains 0+T 7 Emith 4RPP 8.
6enus: Testulea
Epecies: !aonensis
%ontains 0+T 7 @eoeu- et al.* 4RPP 8.
1amil:: +alpi!hiaceae
6enus: ?anisteriopsis
Epecies: muricata 7^ar!entea8* rus:ana 7see 0iplopter:s
carerana8
?oth contain 0+T 7 Emith 4RPP 8.
6enus: 0iplopter:s
Epecies: carerana
)atives o- Yestern AmaGon add 0+T- and )-meth:ltr:ptamine
containin! leaves o- the vine 0. carerana to a drinI made -rom
?anisteriopsis caapi* Yhich contains eta-carolines harmine and
harmaline* to hei!hten and len!then the visions 7 Echultes 4RPP * Emith
4RPP 8. 0. carerana is also InoYn as ?anisteriopsis rus:ana.
1amil:: +:risticaceae
6enus: Hors-ieldia
Epecies: supera
%ontains >-+eO-0+T as Yell as a eta-caroline 7 Wossan! et al. 4RR4
8.
6enus: ,r:anthera
Epecies: macroph:lla
The arI contains >-+eO-0+T 7 Holmstedt et al. 4RQS 8.
6enus: Tirola
Epecies: caloph:lla* caloph:lloidea* ru-ula* sei-era* theiodora
The arI resin o- these trees is used to prepare hallucino!enic snu--s in
northYestern ?raGil : oilin!* dr:in! and pulveriGin! it. Eometimes
leaves o- a Wusticia are added. The snu-- acts rapidl: and violentl:*
]e--ects include excitement* numness o- the lims* tYitchin! o- -acial
muscles* nausea* hallucinations* and -inall: a deep sleep; macroscopia
is -re$uent and enters into NaiIa elie-s aout the spirits resident in the
dru!.] Enu--s made -rom T. theiodora arI contain up to 44\ >-+eO-
0+T and 0+T. Also leaves* roots and -loYers contain 0+T.
AmaGonian %olomia natives roll small pellets o- oiled resin in a
evaporated -iltrate o- arI ashes o- 6ustavia Poeppi!iana and in!est
them to rin! on a rapid intoxication 7 Emith 4RPP * Echultes 4RPP 8.
1amil:: Pandanaceae
6enus: Pandanus ]EcreY pine]
0+T has een isolated -rom Pandanus nuts !roYin! in )eY 6uinea 7
?arrau 4R>Q* 4RO5 8.
1amil:: Poaceae
6enus: Arundo
Epecies: donax
@eaves* -loYers and rhiGomes contain 0+T* u-otenine and related
compounds 7 6hosal et al. 4RP5 8.
6enus: Phalaris
Epecies: a$uatica 7tuerosa8* arundinacea
@eaves o- P. arundinacea and leaves and seedlin!s o- P. a$uatica
contain 0+T* >-+eO-0+T and related compounds 7 Emith 4RPP 8. P.
arundinacea plants are availale -rom ..O- the ;un!le -or j4>.
6enus: Phra!mites
Epecies: australis
(hiGomes contain 0+T 7 Nassel et al. 4RQ> 8.
1amil:: (uiaceae
6enus: Ps:chotria
Epecies: cartha!inensis* viridis 7ps:chotriae-olia8
Ps:chotria leaves are added to a hallucino!enic drinI prepared -rom
?anisteriopsis caapi and ?. rus:ana 7Yhich contain eta-carolines8 to
stren!then and len!then the e--ects in Yestern AmaGon. P.
cartha!inensis and P. viridis oth contain 0+T 7 (ivier* 4RP5 8. > seeds
o- P. viridis cost j4S -rom ..O- the ;un!le.
1amil:: (utaceae
6enus: 0ict:oloma
Epecies: incanescens
?arI contains S.S<\ >-+eO-0+T 7 Pachter et al. 4R>R 8.
6enus: @imonia
Epecies: acidissima
%ontains 0+T 7 Au car!a* 4RQO 8.
6enus: +elicope
Epecies: leptococca
%ontains >-+eO-0+T as Yell as >-+eO-0+T-Oxide and a eta-
caroline 7 EIaltsounis et al. 4RQ9 8.
6enus: Tepris
Epecies: ampod:
The leaves and ranches contains up to S.5\ 0+T 7 ban-1an 4RPS 8.
6enus: canthox:lum
Epecies: aorescens
%ontains 0+T 7 6rina et al.* 4RQ5 8.
tale o- contents
Referen!es
Au car!a* +.H. 4RQO. Three neY simple indole alIaloids -rom
@imonia acidissima. @lo:dia <R7>8* RS4-RS<.
AIers* ?.P. 4RR5. Peele[s @epiota: An identi-ication and a
clari-ication. +:cotaxon <97S8* <O4-<OR.
Arora* 0. 4RQO. +ushrooms 0em:sti-ied: A %omprehensive 6uide to
the 1lesh: 1un!i. Ten Epeed Press* ?erIle:.
Arthur* H.(.* @oo* E.). Z @amerton* W.A. 4ROP. )-meth:lated
tr:ptamines and other constituents o- Acacia con-usa +err. o- Hon!
bon!. Aust. W %hem. 5S* Q44.
?aner;ee* P.b. Z 6hosal* E. 4ROR. Eimple indole ases o- 0esmodium
!an!eticum. Aust. W %hem. 55* 5P>-5PP.
?arrau* W. 4R>Q.
)ouvelles oservations au su;et des plantes hallucino!enes d[usa!e
autochtone en )ouvelle-6uinee. W A!ric. Trop. ?ot. Appl. >* 9PP-9PQ.
?arrau* W. 4RO5.
Oservations et travaux recents sur les ve!etaux hallucino!enes de la
)ouvelle-6uinee. W A!ric. Trop. ?ot. Appl. R* 5<>-5<R.
?enedict* (.6.* ?rad:* @.(.* Emith* A.H. Z T:ler* T.&. 4RO5.
Occurrence o- psiloc:in and psilocin in certain %onoc:e and
Psiloc:e species. @lo:dia 5>* 4>O-4>R.
?enedict* (.6.* T:ler* T.&. Z Natlin!* (. 4ROP.
?luein! in %onoc:e* Psiloc:e and a Etropharia Epecies and the
0ectection o- Psiloc:in. @lo:dia 9S758* 4>S-4>P.
?esl* H. 4RR9.
6alerina ste!lichii spec. nov.* a hallucino!enic 6alerina. ceitschri-t
-uer +:Iolo!ie >R758* 54>-54Q.
?resinsI:* A. Z ?esl* H. 4RRS.
A %olour Atlas o- Poisonous 1un!i. Nol-e Pulishin! @td* @ondon.
?:e* (.A. 4RPR.
Hallucino!enic plants o- the Tarahumara. W. &thnopharmacolo!: 4*
59-<Q.
%hristiansen* A.@.* (asmussen* b.&. Z Hoeiland* b. 4RQ<.
0etection o- psiloc:in and psilocin in )orYe!ian species o- Pluteus
and %onoc:e. Planta +ed. >S* 9<4-9<9.
%imino* 6. Z 0e Ete-ano* E. 4RPQ.
%hemistr: o- +editerranean 6or!onians. Eimple indole derivatives
-rom Paramuricea chamaeleon. %omptes (endus ?iochem. Ph:siol.
Eer. %. O4* 9O4-9O5.
%rouch* ,.W.* Emith +.T.* Tan Etaden W.* @eYis* +.W. Z Hoad* 6.T.
4RR5.
,denti-ication o- auxins in a commercial seaYeed concentrate. W Plant
Ph:siolo!: 49R7>8* >RS->R<.
0al:* W.N. Z NitIop* ?. 4RP4.
%hemistr: and pharmacolo!: o- -ro! venoms. ,n: Tenomous animals
and their venoms. Tol ,,. )eY ForI: Academic Press.
0avis* N. Z Neil* A.T. 4RR5.
,dentit: o- a )eY Norld Ps:choactive Toad. Ancient +esoamerica 9
74RR58 >* >4->R.
0e +oraes* &.H.1.* Alvaren!a* c.+.A.* 1erreira* c.+.6.E. Z Alisue*
6. 4RRS.
Buim. )ova 49* 9SQ.
1itG!erald* W.E. Z Eioumis* A.A. 4RO>.
AlIaloids o- Australian @e!uminosae T. Aust. W %hem. 4Q* <99.
1iussello* ). Z %eruti-Ecarti* W. 4RP4'P5.
PresenGa di psilociina edi >-idrossi-indolderivati in Panaeolus
retiru!is. Atti Acc. Eci. Torino 4SO* P5>-P9>.
6artG* W. 4RR4.
,n-luence o- phosphate on -ruitin! and secondar: metaolism o-
m:celia o- Psiloc:e cuensis* Psiloc:e semilanceata and
6:mnopilus purpuratus. ceitschri-t -uer +:Iolo!ie >P748* 4<R-4><.
6hosal* E.* %haudhuri* (.b.* 0utta* E.b. Z ?hattachar:a* E.b. 4RP5.
Occurrence o- curaromimetic indoles in the -loYers o- Arundo donax.
Planta +ed. 54* 55.
6hosal* E. Z +uIher;ee* ?. 4ROO.
,ndole-9-alI:lamine ?ases o- 0esmodium pulchellum. W* Or!. %hem.
94* 55Q<.
6hosal* E.* Ein!h* E. Z ?hattachar:a* E.b. 4RP4.
AlIaloids o- +ucuna pruriens* %hemistr: and Pharmacolo!:. Planta
+ed. 4R* 5PR
6rina* W.A. et al. 4RQ5.
%onstituents o- canthox:lum aorescens. Part P. Old Z neY alIaloids
-rom canthox:lum aorescens. W. Or!anic %hemistr: <P* 5O<Q-5O>4.
6urevich* @.E. 4RR9.
,ndole derivatives in certain Panaeolus species -rom &ast &urope Z
Eieria. +:colo!ical (esearch RP758* 5>4-5><.
6urevich* @.E. Z AstapenIo* T.T. 4RR5.
%hromato!raphic stud: o- some indole metaolites in Panaeolus
asidiom:cetes. +iIolo!i:a , 1itopatholo!i!a 5O798* 4QR-4R<.
6uGman* 6. 4RQ9.
The 6enus Psiloc:e. ?eihe-te cur )ova HedYin!ia P<* 4-<9R.
6uGman* 6.* ?andala* T.+. Z Allen* W.N. 4RR9.
A )eY ?luin! Psiloc:e -rom Thailand. +:cotaxon 5O* 4>>-4OS.
6uGman* 6.* ?andala* T.+. Z bin!* %. 4RR4.
A )eY Epecies o- Psiloc:e o- Eection capotecorum -rom )eY
cealand. +:colo!ical (esearch R>* >SP->SQ.
6uGman* 6.* Ealdarria!a* F.* Pineda* 1.* 6arcia* 6. Z TelaG$ueG* @.1.
4RR<.
)eY Epecies o- Psiloc:e -rom %olomia and 0iscussion on the
InoYn species. +:cotaxon * 55>.
Haeselarth* 6.* +ichaelis* H. Z EalniIoY* W. 4RQ>.
)achYeis von Psiloc:in in ,noc:e aeru!inescens. +:Iol. +itt. l.
5Q748* >R-O5.
Hat-ield* 6.+.* Taldes* @.W. Z Emith* A.H. 4RPQ.
The occurrence o- psiloc:in in 6:mnopilus species. @lo:dia <4*
4<S-4<<.
Hein* (. Z Nasson* (.6. 4R>Q.
@es champi!nons hallucino!enes du +exi$ue. +useum )ational
d[Histoire )aturelle* Paris.
Holmstedt* ?.* @ind!ren* W.&.* et al. 4RQS.
,ndole alIaloids in AmaGonian +:risticaceae: 1ield and laorator:
research. ?ot. +us. @ea-l.* Harvard Cniv. 5Q* 54>-59<.
Wohns* E.(.* @amerton* W.A. Z Eioumis* A.A. 4ROO.
AlIaloids o- the Australian @e!uminosae T,. Aust. W %hem. 4R* QR9.
Wossan!* A.* Wossan!* %.* Hadi* H.A.* Eevenet* T. Z ?odo* ?. 4RR4.
Hors-iline* an oxindole alIaloid -rom Hors-ieldia supera. W. Or!anic
%hem. >O7598* O>5P-O>9S.
ban 1an* %. et al. 4RPS.
Alcaloides de Tepris ampod: 7(utacees8. Ph:tochem. R* 45Q9-45R4.
bantor* (.&.* 0udlettes* E.0. Z Ehul!in* A.T. 4RQS.
>-+ethox:-al-a-meth:l- tr:ptamine 7al-a*O-dimeth:lserotonin8* a
hallucino!enic homolo! o- serotonin. ?iolo!ical Ps:chiatr: Tol 4>*
9<R-9>5.
boiIe* F.* Nada* b.* busano* 6.* )oGoe* E.* Z FoIo:ama* b. 4RQ4.
,solation o- Psiloc:in -rom Psiloc:e ar!entipes and its
0etermination in Epecimens o- some +ushrooms. @lo:dia <<798* 9O5-
9O>.
@eoeu-* +. et al.* 4RPP.
AlIaloids and triterpenes o- Testulea !aonensis. Plant +edicine
Ph:totherap: 44* 59S.
@una* @.&. 4RQ<.
The Healin! Practices o- a Peruvian Ehaman. W. &thnopharmacolo!:
44* 459-499.
+cbenna* 0.W.* ToYers* 6.H.).* Z Aott* 1. 74RQ<8.
+onoamine oxidase inhiitors in Eouth American hallucino!enic
plants: Tr:ptamines and ?eta-caroline constituents o- a:ahuasca. W
&thnopharmacolo!: 4S* 4R>-559.
+cIenna* 0.W. Z ToYers* 6.H.). 4RQ<.
?iochemistr: and Pharmacolo!: o- Tr:ptamines and eta-%arolines:
A +inirevieY. W Ps:choactive 0ru!s 4O7<8.
+ecIes-@oGo:a* +.* @oGo:a* L.* +arles* (.W.* Eouc:-?reau* %.* Een*
A. Z Arnason* W.T. 4RRS.
)*)-dimeth:ltr:ptamine alIaloid in +imosa tenui-lora arI
7tepescohuite8. Arch. ,nvest. +ed. +ex. 54758* 4P>-P.
+erlin* +.0. Z Allen* W.N. 4RR9.
Epecies identi-ication and chemical anal:sis o- ps:choactive -un!i in
the HaYaiian islands. Wournal o- &thnopharmacolo!: <S748* 54-<S.
+iller Wr.* O.b. 4RP5.
+ushrooms o- )orth America. 0utton Z %o.* Eprin!-ield.
+ost* Alert. 4RQ<.
?u-o Alvarius: the Ps:chedelic Toad o- the Eonoran 0esert . Tenom
Press ?ox 5QO9 0enton TL PO5S5.
+ost* Alert. 4RQO.
&ros and the Pineal: the la:man[s !uide to cereral solitaire . Tenom
Press* 0enton* TL.
)aran;o* %. 4ROR.
Ps:chotropic Properties o- the Harmala AlIaloids. ,n: &-ron 7&d.8 The
&thnopharmacolo!ic Eearch -or Ps:choactive 0ru!s.
Oheno;a* &.* WoIiranta* W.* +aIinen* T.* baiIIonen* A. Z AiraIsinen*
+.+. 4RQP. The Occurrence o- Psiloc:in and Psilocin in 1innish
1un!i. @lo:dia >S7<8* P<4-P<<.
Pachter* ,.W* cacharias* 0.& Z (ieir* O. 4R>R.
,ndole AlIaloids o- Acer saccharinum 7the Eilever +aple8*
0ict:oloma incanescens* Piptadenia colurina* and +imosa hostilis. W
Or! %hem 5<* 45Q>-P.
Phillips* (. 4RQ4.
+ushrooms and other -un!i o- 6reat ?ritain and &urope. Pan ?ooIs*
@ondon.
Poupat* %.* Ahond* A. Z Eevenet* T. 4RPO.
Alcaloides 0e Acaia simplici-olia. Ph:tochemistr: 4>* 5S4R-545S.
(ivier* @. Z @ind!ren* W-&. 4RP5.
]A:ahuasca*] the Eouth American Hallucino!enic 0rinI: an
&thnootanical and %hemical ,nvesti!ation. &conomic ?otan: 5O*
4S4-45R.
(ivier* @. Z Pilet* P.&. 4RP4.
Annee ?iolo!i$ue 4S* 45R.
(oers* W.&.* T:ler* T.&. Z Ola[h* 6.+. 4ROR.
Additional evidence supportin! the occurrence o- psiloc:in in
Panaeolus -oenisecii. @lo:dia 95* 9RR-<SS.
(ovelli* ?. Z Tau!han* 6.). 4ROP.
AlIaloids o- Acacia ,. 0imeth:ltr:ptamine in Acacia phleoph:lla.
Aust. W %hem. 5S* 45RR-49SS.
Eaupe* E.6. 4RQ4.
Occurence o- Psiloc:in'Psilocin in Pluteus salicinus 7Pluteaceae8.
+:colo!ia P9* PQ4-PQ<.
Echultes* (.&. 4RPO.
,ndole AlIaloids in Plant Hallucino!ens. W o- Ps:chedelic 0ru!s Tol
Q748* P-5>.
Echultes* (.&. 4RPP.
The ?otanical and %hemical 0istriution o- Hallucino!ens. W o-
Ps:chedelic 0ru!s Tol R798* 5<P-5O9.
Echultes* (.&. 4RPR.
Hallucino!enic Plants: Their &arliest ?otanical 0escriptions. W o-
Ps:chedelic 0ru!s Tol 4474-58* 49-5<.
Echultes* (.&. Z Ho-mann* A. 4RPR.
Plants o- the 6ods. +c6raY-Hill. (eprint availale -rom Healin! Arts
Press* (ochester* TT.
Echultes* (.&. Z Ho-mann* A. 4RQS.
The ?otan: and %hemistr: o- Hallucino!ens. Eprin!-ield* ,ll:
Thomas.
Ehul!in* A.T. 4RPO.
Ps:chotomimetic a!ents. ,n: 6ordon* +. 7&d.8
Ps:chopharmacolo!ical A!ents* Tol ,T. )eY ForI: Academic Press.
Ehul!in* A.T. 4RQ5.
%hemistr: o- Ps:chotomimetics. ,n: Ho--meister* 1. Z Etille* 6. 7&ds.8
HandooI o- &xperimental Pharmacolo!:* Tol >>: Alcohol and
Ps:chotomimetics* Ps:chotropic &--ects o- %entral-Actin! 0ru!s.
)eY ForI: Eprin!er-Terla!.
EIaltsounis* A.@.* Tille$uin* 1. Z boch* +. 4RQ9.
Plantes des )ouvelle- %aledonie @LLL,,,: Alcaloides des ti!es
-euillees de +elicope leptococca. @lo:dia <O7>8* P95.
Emith* T.A. 4RPP.
(evieY: Tr:ptamine and (elated %ompounds in Plants.
Ph:tochemistr: 4O 4P4-4P>.
Etein* E.,. 4R>R.
%linical Oservations on the &--ects o- Panaeolus venenosus Tersus
Psiloc:e caerulescens +ushrooms. +:colo!ica >4* <R.
Eti;ve* T.* blan* W. Z bu!per* N. 4RQ>.
Occurrence o- psiloc:in and aeoc:stin in the !enus ,noc:e.
Persoonia 45* <OR-<P5.
Etrassman* (.W. 4RRS.
The Pineal 6land: %urrent &vidence 1or ,ts (ole ,n %onsciousness.
,n: @:ttle* T. 7&d.8 Ps:chedelic +ono!raphs and &ssa:s Tol >.
Thompson* A.%.* )icollier* 6.1. Z Pope* 0.1 4RQP.
,ndolealI:lamines o- 0esmanthus illinoensis and Their 6roYth
,nhiition Activit:. W A!ric. 1ood %hem. 9>* 9O4-9O>.
Naha* E.b. Z &lIheir* F.+. 4RP>.
0imeth:lt:rptamine -rom the leaves o- certain Acacia species o-
northern Eudan. @lo:dia 9Q* 4PO-4PP.
Nassel* 6.+. et al. 4RQ>.
AlIaloids -rom the rhiGomes o- Phra!mites australis %av. Ecientia
Pharmaceutica >9* 4OR-4PS.
Petrus.PennanenahelsinIi.-i e &ver:thin! is per-ect -orever
+ichael -rom +elourne e 0itto
RELA?ED SPACES
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2. Alcalides
Muitos dos copostos pu!os o ais cedo isolados co ati"idade
biol#$ica e!a alcal#ides. %sto e!a de"ido & facilidade da isola'(o. O
nit!o$)nio faz $e!alente o b*sico coposto e o coposto e+iste na
planta coo u sal. ,ssi- os alcal#ides s(o e+t!a.dos
f!e/uenteente co *$ua ou *cido sua"e e !ecupe!ados ent(o
coo o ate!ial c!istalino pelo t!ataento co a base.
,ntes de ap!o+iadaente 011 anos h*- a al*!ia e!a o scou!$e de
Eu!opa- p!o"a"elente sendo int!oduzido at!a"2s de o O!iente
M2dio. , al*!ia 2 causada pelos p!otozoa do $enus Plasmodium -
contidos coo spo!es no $ut dos mosquitos dos an#feles- /ue
espalha ent(o os spo!es aos se!es huanos /uando o!de.
En/uanto os e+plo!ado!es do espanhol e do Po!tu$ese coe'a!a
a colonize ,2!ica sul- descob!i!a ua cu!a pa!a a al*!ia sabida
aos indians nati"os. Este e!a o ba!3 das rvores da chinchona. O uso
do bark da chinchona t!ata! a al*!ia foi !elatado p!iei!aente e
Eu!opa e 4500- e o p!iei!o ba!3 alcan'ou 6oa
ap!o+iadaente 47 anos ais ta!de. Os ch*s feitos do ba!3
cu!a!a os po"os /ue sof!e da al*!ia- u dos scou!$es
p!incipais e Eu!opa na/uele tepo- e o ba!3 to!nou8se sabido
coo o ba!3 de 9esuit. Po! causa das dife!en'as filos#ficas ent!e
P!otestants e catholics- uitos P!otestants !ecusou se! t!atado co o
ba!3. : do P!otestants o ais p!oeinente do tepo- Oli"e!
;!o<ell- o!!ido !epo!tedl= da al*!ia po! causa deste
stubbo!nness.
%solado o!i$inalente do succirubra da chinchona - o /uinine 2 u
de 04 alcal#ides co est!utu!as !elacionadas- e o coposto
antiala!ial p!incipal- na planta. >os alcal#ides fo!a definidos e
"*!ias anei!as- as ua defini'(o "e !azoa"elente pe!to da
!ealidade. : alcal#ide 2 u coposto planta8de!i"ado /ue se?a
t#+ico ou ph=siolo$icall= ati"o- contenha u nit!o$)nio e u anel
hete!oc=clic- se?a b*sico- tenha ua est!utu!a cople+a- e se?a de
dist!ibui'(o liitada no !eino de planta.@ , al*!ia 2 ainda u
p!oblea p!incipal du!ante todo o undo- e- ebo!a as d!o$as
antiala!ial sint2ticas suplante pela aio! pa!te o /uinine coo o
t!ataento pa!a a al*!ia du!ante a $ue!!a de undo %%- o /uinine 2
f!e/uenteente ua "ez out!a "ez a d!o$a da escolha po!/ue as
tensAes da al*!ia se to!na!a !esistentes &s d!o$as sint2ticas.
Ent!etanto- a busca pa!a out!as d!o$as antiala!ial das fontes
natu!ais continuou tab2. :a das d!o$as no"as as ais
p!oetedo!as 2 /in$haosu- isolado do annua do artemisia - u
ses/uite!pene >"e?a abai+o@ /ue contenha ua est!utu!a o!i$inal do
t!io+ane.
Ent!e o ais faoso dos alcal#ides s(o os alcal#ides de Solanaceae
ou de t!opane . ,s plantas /ue cont) estes alcal#ides fo!a
usadas du!ante todo o histo!= $!a"ado coo "enenos- as uitos
dos alcal#ides t) p!op!iedades pha!aceutical "aliosas. , at!opina-
o fo!ul*!io !aceic do h=osc=aine- "e do belladonna do atropa
>ni$htshade o!tal@ e 2 usada dilate as pupilas do olho. , at!opina 2
tab2 u stiulant do ;BS e 2 usada coo u t!ataento pa!a o
en"enenaento do $*s de ne!"o. Scopolaine- u out!o eb!o
desta classe 2 usado coo u t!ataento pa!a a doen'a de
o"iento. , coca.na- da coca de Erythroxylum - 2 !elacionada
p!C+ia na est!utu!a- 2 tab2 u stiulant do ;BS- e foi usada
coo u anest2sico t#pico no opthaolo$=. D tab2 ua d!o$a
do abuso. , coca.na foi encont!ada e /uantidades uito pe/uenas
na f#!ula o!i$inal da ;oca8;ola- as n(o e!a o inte!esse p!incipal
do :SD, na/uele tepo. , cafe.na foi conside!ada se! o p!oblea
p!incipal co a bebida. O stramonium do datura >9ison<eed@- ua
planta encont!ada e Ei!$.nia conte copostos siila!es.
Os alcal#ides do e!$ot ") de u fun$o- o purpurea de Claviceps -
/ue 2 u pa!asite no centeio e no t!i$o. Os alcal#ides do e!$ot s(o
!espons*"eis pa!a o e!$otiso >fo$o do St. ,nthon=@- /ue se
anifesta coo o e!$otiso $an$!enous- tendo po! !esultado a
pe!da dos eb!os- ou o e!$otiso con"ulsi"e- tendo po! !esultado
hallucinations. E abos os casos- a o!te se$ue $e!alente e os
outb!ea3s do e!$otiso causa!a 44.111 o!tes e 6Fssia t(o
ta!de /uanto 4G75. Ho?e o p!oblea 2 !econhecido e cont!olado.
,l$uns dos alcal#ides do e!$ot fo!a usados t!ata! headaches do
i$!aine e diso!de!s se+ual e aplica'Aes cl.nicas. O ais faoso
destes alcal#ides 2 o dieth=laide *cido l=se!$ic- ISD- u
hallucino$en pode!oso /ue se?a u de!i"ati"e sint2tico dos p!odutos
natu!ais. Os alcal#ides siila!es- pa!ticula!ente e!$ine- s(o
encont!ados tab2 e $lo!ies e+icanos da anh(- tais coo
Ipomeoa tricolor .
Os alcal#ides do o!phine - de!i"ados do popp= de opiu-
somniferum do papaver - s(o apazi$uado!es da do! e na!cotics
pode!osos. , ati"idade na!cotic do somniferum do P. foi anotada e
tabuletas sue!ian e 0J11 B.;.- fazendo lhe u das d!o$as as
ais "elhas conhecido. O opiu 2 o late+ secado das cabe'as da
seente do somniferum do P. - e foi usado coo u anal$esic
>eliina ou ali"ia a do!@ e na!cotic >induz o sono ou o d!o<siness@
nas p!epa!a'Aes tais coo o laudanu e pa!e$o!ic. O o!phine 2 o
alcal#ide p!incipal e foi isolado p!iei!aente ent!e 4K10 e 4K15. Loi
usado e+tensaente pa!a o !ele"o da do! /ue coe'a nos 4K01Ms-
as !econhecido tab2 coo sendo addicti"e. E ua tentati"a
de faze! o o!phine ais enos addicti"e- os /u.icos de Ba=e!
acet=lated os $!upos do h=d!o+=l pa!a p!oduzi! o diacet=lo!phine.
%sto foi int!oduz.do no e!cado coo u apazi$uado! non8non8
addicti"e da do! sob o he!oin do noe de co2!cio po!
ap!o+iadaente dois anos no 4G11Ns adiantado- at2 /ue se est)"e
!econhecido pa!a esta! ais addicti"e do /ue o o!phine. Out!os
de!i"ati"es do o!phine fo!a desen"ol"idos e encont!a!a o uso
coo anta$onistas do opiate ou coo os t!an/uilize!s aniais.
Einc!istine - ua das d!o$as antileu3eic as ais potent no uso
ho?e- foi isolado e ua busca pa!a t!ataentos do diabetes do
rosea de Vinca >a$o!a roseus de Catharanthus @ nos 4GJ1 ?unto co
o "inblastine- u hoolo$ue e /ue o $!upo n8eth=l 2 o+idado a
u oiet= do alde.do. Esta 2 ua est!utu!a t(o cople+a /ue est*
isolado ainda da planta >o pe!i<in3le de Mada$ascan@ ho?e elho!
/ue p!epa!ado pela s.ntese. , udan'a pe/uena na est!utu!a-
ent!etanto- causa ua udan'a si$nificati"a no efficac=
pha!oacolo$ical. Einc!istine >leu!oc!istine- E;6@ 2 o ais eficaz e
leu3eias da infOncia e nos l=phoas de t!ataento dos non8
Hod$3inNs- onde o "inblastine >"incaleu3oblastine- EIB@ 2 usado
t!ata! a doen'a de Hod$3inNs.
Pa!a t!*s & int!odu'(o
,os Te!penes
,o *cido e ao Pol=3etide de Shi3iic p!odutos natu!ais de!i"ados
Hoe
The Quinine Alkaloids
The Cinchona al3aloids a!e anothe! "e!= ipo!tant sub$!oup of the
pol=c=clic 8ca!boline al3aloids.P!io! to about 011 =ea!s a$o- ala!ia
<as the scou!$e of the Peste!n <o!ld. Mala!ia <as p!obabl= the
ost coon disease in 6oe and Iondon at the tie. E"en toda=-
illions of people die each =ea! f!o ala!ia- and hund!eds of
illions of people suffe! f!o the disease. The disease is caused b=
a p!otozoa of the $enus Plasmodium sp!ead as spo!es contained in
the nopheles os/uito <hich sp!eads the into the bloodst!ea of
huan "ictis. The a?o! cu!e fo! this d!ead disease is /uinine- the
p!incipal al3aloid of the Cinchona t!ee <hich is indi$enous to the
t!opical ,ndes ountains. The!e a!e an= tales of ho< the
antiala!ial p!ope!ties of Cinchona ba!3 <as fi!st disco"e!ed- but the
fi!st <!itten !epo!t of its efficac= <as b= Lathe! ;alancha in the
Chronicle of !t. u"ustine in 4500. %t <as at least t<el"e o!e =ea!s
befo!e a Lathe! Tafu! b!ou$ht soe of the ba!3 bac3 to 6oe. The
cu!es <hich <e!e accoplished b= d!in3in$ a Qbe"e!a$eQ ade f!o
the po<de!ed ba!3 <e!e nothin$ sho!t of aazin$.
Ho<e"e!- the fact that it <as coin$ f!o the ;atholic chu!ch ade
the cu!e suspect to P!otestants- and Oli"e! ;!o<ell died in 45JK
f!o ala!ia- e"en thou$h the cu!e <as a"ailable. The actual
Cinchona o! fe"e! t!ee <as not disco"e!ed until 4R0R. Befo!e that
tie- the 9esuits <ho disco"e!ed the cu!e had to a3e due <ith
t!adin$ <ith the %ndians fo! the ba!3. Supposedl=- the %ndians hid the
t!ee f!o the Eu!opeans as a eans of d!i"in$ the f!o South
,e!ica. Supplies of the t!ee <e!e !apidl= depleted in South ,e!ica-
and 9a"a- unde! the Dutch- becae the ain supplie! of Cinchona
al3aloids until Po!ld Pa! %% <hen s=nthetic antiala!ial a$ents
becae <idel= a"ailable. %n !ecent =ea!s- st!ains of ala!ia <hich a!e
!esistant to the s=nthetic antiala!ials ha"e be$un to a3e thei!
appea!ance- and the "alue of /uinine as an antiala!ial a$ent is once
a$ain on the !ise.
64 67 >S@8isoe! >8@8isoe! 8;HT;H7 8H cinchonine cinchonidine
8;HT;H7 8O;H0 /uinidine /uinine 8;H7;H0 8H dih=d!ocinchonine
dih=d!ocinchonidine 8;H7;H0 8O;H0 dih=d!o/uinidine
dih=d!o/uinine Uuinine <as fi!st isolated in 4K71 b= 9oseph Pelletie!
and 9oseph ;a"entou- but the st!uctu!e dete!ination too3 o"e! 411
=ea!s. B= 4KKV- 7J additional al3aloids !elated to /uinine had been
isolated- and an additional 5 <e!e added bet<een 4KKV and 4GV4.
,pp!o+iatel= 40 out of the 04 still ha"e un3no<n st!uctu!es. The!e
a!e ei$ht a?o! al3aloids <hich occu! as fou! pai!s of enantioe!s- as
sho<n abo"e. The >S@8isoe!s ha"e the 76-0S confi$u!ation- and the
>8@8isoe!s ha"e the 7S-06 confi$u!ation.
Uuinine has t=picall= been the ost used of the al3aloids fo!
pha!acolo$ical pu!poses- sipl= because it <as the fi!st isolated.
Uuinine- in addition to its antiala!ial p!ope!ties- is a bacte!iocide-
local anesthetic- ca!dios"ascula! stiulant- and anal$esic. Uuinidine-
in addition to its antiala!ial p!ope!ties- has been used to p!e"ent
ce!tain t=pes of ca!diac a!!=thias.
The Tropane Alkaloids
The t!opane al3aloids- <hich ha"e the K8azabic=cloW0.7.4Xoctane
nucleus- a!e coonl= found in plants of th!ee failies- the
Solanaceae- E!=th!o+=laceae- and ;on"ol"ulaceae failies. The
al3aloids isolated f!o plants of these failies- <hile ha"in$ se"e!al
le$itiate edicinal uses- a!e p!obabl= best 3no<n fo! thei! to+ic
p!ope!ties. This can be a a?o! p!oble since the plants p!oduce
"e!= att!acti"e be!!ies <hich a!e teptin$ to sall child!en. ,s fe< as
th!ee be!!ies of henbane >#yoscyamus ni"er@ o! deadl= ni$htshade
>tropa belladonna@ can cause death in infants. Man= of the plants in
the Solanaceae fail= contain t!opane al3aloids- <hich a!e
!esponsible fo! the to+ic effects of the plants. ;leopat!a is !eputed to
ha"e tested the effects of henbane and deadl= ni$htshade on he!
sla"es to in"esti$ate the possibilit= of usin$ these e+t!acts to coit
suicide >she found the to+ic effects too painful@. The <i"es of the
6oan epe!o!s- ,u$ustus and ;laudius- used deadl= ni$htshade to
u!de! la!$e nube!s of 6oans. The and!a3e >$andra"ora
officinarum@ <as !eputed to possess aph!odisiac p!ope!ties and <as
p!ized fo! these p!ope!ties. Ho<e"e!- the !oots also contain la!$e
/uantities of the t!opane al3aloid h=oscine >scopolaine@- a3in$ the
plant hi$hl= to+ic. %atura stramonium& a plant coon to Ei!$inia-
and othe! %atura species a!e <idel= dist!ibuted th!ou$hout the <o!ld.
These plants ha"e a lon$ histo!= of bein$ used as both sedati"es and
as poisons.
E+t!acts of %atura metel- soeties called Hindu Datu!a- <e!e used
as 3noc3out d!ops to lu!e "i!$ins into p!ostitution and then b= the
p!ostitutes to sedate thei! clients. The 6oan a!= led b= Ma!3
,nton= in ,sia Mino! <as se"e!el= c!ippled b= deaths caused b=
eatin$ a %atura species. %ndians in ;olobia used anothe! %atura
species fo! infanticide. %nfants died afte! nu!sin$ <hen an e+t!act of
%atura <as sea!ed on the nipples of the othe!. %atura
stramonium is also 3no<n as ?ison<eed and- afte! nea!l= ta3in$ the
li"es of soe of the 9aesto<n settle!s- <as <idel= used fo!
edicinal pu!poses- p!ia!il= as a sedati"e.
%n the 4G51Ys and 4GR1Ys- thei! <e!e a nube! of cases of poisonin$
due to ?ison<eed <hen people in$ested the plant to t!= to induce a
hi$h siila! to cocaine. The Solanaceae al3aloids de!i"ed f!o these
plants- <hile "e!= to+ic- a!e often ipo!tant edicinal a$ents.
,t!opine- the !aceic fo! of >8@8h=osc=aine- <as fi!st isolated f!o
tropa belladonna in 4K00. >8@8H=osc=aine <as also isolated in
4K00 f!o #yoscyamus ni"er. This t!opane al3aloid is a usca!inic
!ecepto! anta$onist. Musca!inic !ecepto!s a!e in"ol"ed in const!iction
of the pupil- "asodilation- ode!atin$ the hea!tbeat- and stiulatin$
sec!etions. The ost failia! use of at!opine- as the sulfate salt- is as
a =d!iatic to dilate the pupil of the e=e du!in$ an opthaolo$ical
e+aination. %n fact- the ?uice of the be!!ies of . belladonna <as
used du!in$ the 6enaissance b= ladies of the %talian cou!ts to
e+a$$e!ate the size of thei! e=es b= dilatin$ the pupils. >The !ou$h
t!anslation of belladonna f!o %talian is beautiful lad=.@ ,t!opine has
also found use as a ;BS stiulant and is useful in t!eatin$ poisonin$
cases- pa!ticula!l= anticholineste!ase poisonin$ induced b=
o!$anophospho!ous insecticides and ne!"e $as and poisonin$
induced b= the to+ic p!inciples of the ush!oo manita muscaria.
Scopolaine- >8@8h=oscine- <hich <as fi!st isolated in 4KK4 f!o
#yoscyamus muticus and !copolia atropides is a ;BS dep!essant at
hi$h doses- and has been used in cobination <ith o!phine to
induce Qt<ili$ht sleepQ befo!e and du!in$ labo!- and in salle! doses-
to p!e"ent otion sic3ness.
%n !ecent =ea!s- a t!opane al3aloid isolated f!o se"e!al
E!=th!o+=laceae species has becoe o!e noto!ious. This- of
cou!se- is cocaine- <hich <as fi!st isolated f!o coca- the d!ied
lea"es of Erythroxylum coca >Boli"ian coca@ o! Erythroxylum
truxillense >Pe!u"ian coca@- in 4K57 b= Pohle!. The anesthetic
p!ope!ties of cocaine ha"e been 3no<n since the 4KK1Ms.
The h=d!ochlo!ide of cocaine is used as a topical anesthetic in
opthaolo$= as 4Z solution >a+iu@. ;ocaine is to+ic in la!$e
enou$h doses <hen ta3en inte!nall=- pa!ticula!l= <hen ta3en b=
in?ection- but is also a potent ;BS stiulant <hich has led to its
abuse. %t is addicti"e but <ithd!a<al effects a!e !eputed to be ild.
>These effects ha"e also been 3no<n since the late 4Gth >8@8
h=osc=aine at!opine BH0;OO H;- 5HJOH OH- ;5HJH OOBH0;.
>8@8scopolaine BH0;OO H;5HJOH-Oec$onine
cocaineBH0;;O7;H0 ;O7HBH0;O7;;5HJ OH centu!=.
6eebe! that She!loc3 Holes- Si! ,!thu! ;onan Do=leMs
le$enda!= detecti"e- <as a habitual use! of cocaine.@
;oca has been of econoic ipo!tance in Peste!n cultu!es since the
4J11Ys. But coca <as also
ipo!tant to the %ndian cultu!es of South ,e!ica- pa!ticula!l= the
%ncas in Pe!u- fo! at least 4111 =ea!s
befo!e the Spanish a!!i"ed in the Be< Po!ld. ;he<in$ coca lea"es
p!o"ided a stiulato!= effect fo!
he!dsen and othe! <o!3e!s in the %nca cultu!e- but it <as not in
coon usa$e b= e"e!= %ndian. Once
the Spanish a!!i"ed- coca lea"es becae an ipo!tant coodit=-
and fo! a <hile <as used in place of
one= in South ,e!ica. ;oca che<in$ inc!eased aon$ both
nati"es and Eu!opeans- but an=
chu!chen and issiona!ies <e!e opposed to its use- pa!ticula!l=
aon$ the nati"es ><ho needed to be
con"e!ted to ;atholicis@. Since the al3aloid content of the coca
lea"es de$!aded upon lon$ sto!a$e- it
<asnYt until the 4K11Ys that coca ade la!$e! in!oads into Eu!ope. %n
the late 4K11Ys- a nube! of
be"e!a$es based on coca be$an to appea!- includin$ se"e!al coca
<ines- fo! use as ild stiulants. %n
4KK5- 9ohn St=th Pebe!ton !efo!ulated his coca <ine into a
nonalcoholic be"e!a$e- <hich he naed
;oca8;ola- to $et a!ound a de"elopin$ tepe!ance o"eent. The
o!i$inal fo!ulation of ;oca8;ola
used coca leaf f!o South ,e!ica <hich contains "e!= lo< aounts
of cocaine. One estiate is that the
o!i$inal fo!ulation contained- at ost- 4.J $ of cocaine pe! ounce
of ;oca8;ola- not enou$h to p!o"ide
an= stiulation o! cause addiction. >The stiulato!= effect of ;oca8
;ola o!e li3el= coes f!o the
caffeine content.@ B= 4G15- all cocaine had been eliinated f!o the
fo!ula of ;oca8;ola- and in 4G44-
in a st!an$e tu!n of e"ents- the a3e!s <e!e sued b= the $o"e!nent
fo! false ad"e!tisin$ because the
be"e!a$e did not contain cocaine!
Ec$onine is the pa!ent al3aloid of cocaine- and can be easil=
p!oduced f!o cocaine and othe! este!s
isolated f!o the plant b= acid h=d!ol=sis. ;ocaine can then be
p!epa!ed f!o ec$onine b= t!eatent <ith
ethanol follo<ed b= benzoic acid. This is the basic p!ocedu!e used
in the clandestine d!u$ labs.
The Ergot Alkaloids
One of the pha!acolo$icall= ost ipo!tant $!oups of indole
al3aloids is the e!$oline- o! e!$ot-
al3aloids. These al3aloids a!e isolated f!o the d!ied scle!otiu of
the fun$us Claviceps purpurea
>H=poc!eaceae@ >e!$ot@. This fun$us is a pa!asite on !=e and <heat
and othe! $!ains. %n$estion of
containated $!ain- ost often afte! the $!ain has been ade into
b!ead- causes e!$otis- also 3no<n
as the QDe"ilMs cu!seQ o! QSt. ,nthon=Ms fi!e-Q and has been a p!oble
fo! centu!ies. %t has been noted in
<!itin$s f!o ;hina as ea!l= as 4411 B.;. and in ,ss=!ia in 511 B.;.-
and 9ulius ;aesa!Ms le$ions suffe!ed
an epideic of e!$otis du!in$ one of the capai$ns in Gaul. %n GGV
,.D.- an epideic in L!ance 3illed
bet<een 71-111 and J1-111 people- and in 4G75- at least 44-111
cases of e!$otis occu!!ed in 6ussia.
E!$otis can cause con"ulsions- nausea- and dia!!hea in ild fo!s-
and the!e is soe thou$ht that an
outb!ea3 of e!$otis a= ha"e been the cause of the Qbe<itchin$sQ
<hich led to the Sale <itch t!ials in
the :nited States in 45G4. E!$otis a= also ha"e caused soe of
the e+t!ee dest!uction associated
<ith the L!ench 6e"olution. %n the Middle ,$es- e!$otis <as
desc!ibed as causin$ "ictis to dies
Qise!abl=- thei! libs eaten up b= the hol= fi!e that blac3ed li3e
cha!coal.Q People tu!ned to the chu!ch
fo! help- assuin$ that the disease <as !et!ibution fo! thei! sins. %n
pa!ticula!- the= p!a=ed to St. ,nthon=
fo! deli"e!ance- $i"in$ !ise to the nae fo! the disease. E!$otis
ta3es t<o fo!s- $an$!enous e!$otis-
in <hich tin$lin$ effects <e!e felt in fin$e!s and toes follo<ed in an=
cases b= d!= $an$!ene of the libs
and finall= loss of the libs- and con"ulsi"e e!$otis- in <hich the
tin$lin$ <as follo<ed b= hallucinations
and dele!iu and epileptic8t=pe seizu!es. %n both cases- death <as
slo< and painful. E!$otis has no<
been !eco$nized as a !esult of infection b= a =coto+in- and the
e!$otis pla$ues ha"e been eliinated.
Ho<e"e!- the al3aloids de!i"ed f!o e!$ot ha"e assued ne<
ipo!tance fo! thei! pha!acolo$ical
p!ope!ties- and e!$ot is p!oduced coe!ciall= fo! the p!epa!ation of
these al3aloids.
The!e a!e th!ee ain $!oups of e!$ot al3aloids- the cla"ine t=pe- the
<ate!8soluble l=se!$ic acid t=pe-
and the <ate!8insoluble l=se!$ic acid t=pe o! peptide e!$ot al3aloids.
The cla"ine t=pe of al3aloids- such
as a$!ocla"ine and el=ocla"ine- a!e $ene!all=
!e$a!ded as p!ecu!so!s to the othe! $!oups of e!$ot
al3aloids in the bio$enetic path<a=. These al3aloids a!e
aon$ se"e!al of the e!$ot al3aloids also isolated f!o
hi$he! plants- pa!ticula!l= the seeds of Ipomoea violacea
and 'ivea corymbosa >Mololiu/ui-Q the Me+ican o!nin$
$lo!=@- both ebe!s of the ;on"ol"ulaceae fail=.
These al3aloids a!e not used pha!acolo$icall=- but
a$!ocla"ine is a po<e!ful ute!ine stiulant- and an= of
the e!$ot al3aloids a!e p!olactin !elease inhibito!s.
The <ate!8soluble l=se!$ic acid de!i"ati"es a!e ost often
aide de!i"ati"es. ,on$ the ost ipo!tant of these a!e
e!$ono"ine and eth=se!$ide. E!$ono"ine has potent ute!ine
cont!action acti"it= and is used in t!eatin$ postpa!tu heo!!ha$es.
%t has lo< "asoconst!icto! action. Meth=se!$ide is used as a c!anial
"asodilato! in the t!eatent of i$!aine headaches.
Pe!haps the ost infaous of the sei8s=nthetic de!i"ati"es of
the e!$ot al3aloids is l=se!$ic acid dieth=l aide >ISD@. %t <as fi!st
s=nthesized b= ,lbe!t Hofann of Sandoz ,G in 4G0K- but its
hallucino$enic p!ope!ties <e!e not 3no<n until 4GV0. Phile <o!3in$
<ith a saple of ISD in his labo!ato!=- Hoffann accidentall=
in$ested soe. He desc!ibed ho< QOn a L!ida= afte!noon- ,p!il 45-
4GV0- <hile <o!3in$ in the labo!ato!=- % <as seized b= a peculia!
sensation of
"e!ti$o and !estlessness. Ob?ects- as <ell as the shape of =
associates in
the labo!ato!ies- appea!ed to unde!$o optical chan$es. % <as unable
to
concent!ate on = <o!3. %n a d!eali3e state- % left fo! hoe- <he!e
an
i!!esistable u!$e to lie do<n and sleep o"e!cae e. Ii$ht <as so
intense as
to be unpleasant. % d!e< the cu!tains and iediatel= fell into a
peculia! state
of Md!un3ennessM- cha!acte!ized b= an e+a$$e!ated ia$ination. Pith
=
e=es closed- fantastic pictu!es of e+t!ao!dina!= plasticit= and
intensi"e colo!
seeed to su!$e to<a!ds e. ,fte! t<o hou!s- this state $!aduall=
subsided
eth=se!$ide e!$ono"ine
HB
OH
HB
OH
O O
B
H
B
;H0
H H
B
;H0
B
;H0
l=se!$ic acid dieth=laide
H
B ;H0
B
H
O
B
l=se!$ic acid a$!ocla"ine el=ocla"ine
B
H
B
;H0
HO7;
H
B
H
B
;H0
H
H H
H
B
;H0
B
H
OH
and % <as able to eat dinne! <ith a $ood appetite.Q The follo<in$
Monda=- to confi! that he had indeed
in$ested soe of the ISD- Hoffann p!epa!ed a solution containin$
7J1 [$ of ISD and delibe!atel=
in$ested it. ,fte! V1 inutes- he found he had Q difficult= in
concent!ation- "isual distu!bances- a!3ed
desi!e to lau$hQ and left fo! hoe. On the !ide hoe Q% had $!eat
difficult= in spea3in$ cohe!entl=- = field
of "ision s<a=ed befo!e e....% had the ip!ession of bein$ unable to
o"e f!o the spot.Q The s=ptos
continued fo! si+ hou!s afte! Hoffann !eached his hoe and he
desc!ibed ho< Qall ob?ects appea!ed in
unpleasant- constantl= chan$in$ colo!s- the p!edoinant shades
bein$ sic3l= $!een and blue...,
!ea!3able featu!e <as the anne! in <hich all acoustic pe!ceptions
<e!e t!ansfo!ed into optical
effects.Q Hoffann had ta3en app!o+iatel= fi"e ties the Qno!alQ
dose of ISD and had e+pe!ienced
the fi!st Qbad t!ip.Q
Lo! a <hile follo<in$ the disco"e!= of the pha!acolo$ical effects of
ISD- it <as used in ps=chiat!=-
pa!ticula!l= in the t!eatent of alcoholic schizoph!enia. %n !ecent
=ea!s- e"idence has coe out that it <as
used in the 4GJ1s on ilita!= Q"oluntee!sQ to stud= its effect-
p!esuabl= as a cheical <a!fa!e <eapon.
%n the ea!l= 4G51s- p!oponents of its use as a <a= to achie"e a state
of ni!"ana- such as D!. Tioth=
Iea!=- be$an usin$ it hea"il= and dist!ibutin$ it th!ou$hout the hi$h
school and colle$e a$e population-
often adso!bed into a su$a! cube. This attitude that ISD <as a Q$ood
d!u$Q <as foste!ed b= popula!
son$s- li3e the 9effe!son ,i!planeMs QPhite 6abbitQ and the BeatlesM
QIuc= %n The S3= Pith DiaondsQ-
<hich supposedl= desc!ibed the effects of Q$oodQ ISD t!ips.
:nfo!tunatel=- an= ISD t!ips tu!ned out to
be bad t!ips- and an= hea"= use!s of ISD e+pe!ienced bad
flashbac3 t!ips at a late! tie. >One sideli$ht
to the hallucino$enic effects of ISD is the !esult of findin$ e!$ot
al3aloids in Me+ican o!nin$ $lo!= seeds.
Soe see3e!s of ni!"ana th!ou$h hallucino$ens be$an in$estin$
la!$e /uantities of o!nin$ $lo!= seeds.
6athe! than hallucino$enic acti"it=- these foolish people e+pe!ienced
p!ia!il= to+ic !eactions thus
obtainin$ ni!"ana in an unintended <a=.@ ,fte! a !elati"el= b!ief tie-
the popula!it= of ISD as a
hallucino$en diinished- and it becae soe<hat of a histo!ical
!elic. Ho<e"e!- it has sta!ted to a3e a
coebac3 in the d!u$ unde!$!ound in !ecent =ea!s. This tie- the
ta!$et sees to be $!ade school a$e
child!en- and the pushin$ of ISD to these child!en a= be "ie<ed b=
soe as a eans of hoo3in$ the
on ha!d d!u$s li3e cocaine and he!oin as the= $!o< olde!.
The <ate!8insoluble l=se!$ic acid de!i"ati"es a!e
p!ia!il= peptide e!$ot al3aloids li3e e!$otaine.
This copound <as fi!st isolated in 4G4K- but its
st!uctu!e <as not dete!ined until 4GJ4. E!$otaine-
as its ta!t!ate salt- is a anal$esic specificall= used fo!
t!eatent of se"e!e i$!aine headaches. %t is often
used in con?unction <ith caffeine- <hich const!icts
ce!eb!al blood "essels- and a dose of 7 $ ta3en
o!all= often !esults in /uic3 !elief. 78B!oo88
e!$oc!=ptine- a seis=nthetic de!i"ati"e- has !educed
to+icit= and is no< coe!ciall= a"ailable to be used
in the !eduction of lactation in <oen. %t has also
been used in t!eatent of se+ual diso!de!s- and has
been sho<n to enhance se+ual libidos in both en
and <oen.
78b!oo88e!$o3!=ptine e!$otaine
H
B ;H0
B
H
O
B
B
HB
O
OH
O
O
;5HJ
HB O
O
OH
B
B
O
O
B
H
B
;H0
H
Morphine and Related Alkaloids
The na!cotic acti"it= of Papaver somniferum <as !eco!ded on
Sue!ian tablets datin$ bac3 to 0J11
B.;. The Ebe!s pap=!us also cites its use in t!eatin$ Qcolic.Q The fi!st
desc!iption of the collection of c!ude
opiu appea! in the <!itin$s of Diosco!ides. The G!ee3s p!esc!ibed
opiu fo! a "a!iet= of illnesses- and it
<as pa!ticula!l= useful as a sedati"e. The opiu popp= <as fi!st
culti"ated in the Medite!!anean a!ea-
then int!oduced into %ndia in the 4Jth centu!=- and then soe<hat
late! into ;hina. %t is no< $!o<n
th!ou$hout the !e$ion f!o the Middle East to the La! East as
a Qcash c!op.Q Opiu is the ai!8d!ied late+ of the head >o!
seed case@ of P. somniferum- and contains p!ia!il= the
al3aloids o!phine >V874Z@ and codeine >1.K87.JZ@- alon$
<ith othe! al3aloids. ;odeine appea!s to be the p!ecu!so! to
o!phine. The seeds do not contain an= of the o!phine
al3aloids. 6a< opiu is usuall= containated <ith
adulte!ants such as f!a$ents of the heads- pulp f!o fi$s
and othe! f!uits- t!a$acanth- bees<a+- cuin seed- sta!ch-
and ino!$anic substances such as cla=- sand- stone- and lead f!o
pipe o! bullets. Opiu acts on the
;BS- fi!st stiulatin$ then dep!essin$ ne!"e !esponse. %t has
anal$esic- na!cotic- and antipe!istaltic
effects. Tinctu!es of opiu ha"e been used fo! an= =ea!s.
Iaudanu- <hich is a deodo!ized tinctu!e of
opiu- <as used e+tensi"el= as an antipe!istaltic t!eatent o!
sedati"e- pa!ticula!l= in Eu!ope. Pa!e$o!ic-
<hich is a tinctu!e of opiu <ith added capho!- <as used <idel= in
Eu!ope and the :.S. to t!eat
dia!!hea. %t <as often used in cobination <ith a i+tu!e of
belladona- 3aolin- and pectin fo! this pu!pose.
Mo!phine- the p!incipal al3aloid of P. somniferum- <as fi!st isolated in
eithe! 4K10 o! 4K15 b=
Se!tu!ne!. The st!uctu!e <as fi!st p!oposed in 4G7J b= Si! 6obe!t
6obinson- and late! confi!ed b= the
total s=nthesis of Gates and Ma!shall. Pu!e o!phine <as used-
be$innin$ in the 4K01s- fo! pain !elief-
pa!ticula!l= afte! the ad"ent of the h=pode!ic s=!in$e in 4KJ0- and
<as /uic3l= !eco$nized to be
addicti"e. Ho<e"e!- it <as <idel= used- pa!ticula!l= in ilita!=
edicine- due
to its "e!= potent anal$esic p!ope!ties. Othe! side effects include
nausea-
"oitin$- d!o<siness- ood chan$es- a dec!ease in ental accuit=-
!espi!ato!= a!!est- and constipation. The constipation is caused b=
dec!eased
H;l sec!etion in the stoach <hich in tu!n inc!eases the tone of the
fi!st pa!t
of the duodenu and dela=s passa$e of the $ast!ic contents. Since
o!phine
<as the best a?o! anal$esic a"ailable- pha!aceutical copanies
be$an to
sea!ch fo! a nonaddicti"e substitute. %n 4KRV- diacet=lo!phine <as
s=nthesized b= ,lde! P!i$ht of St. Ma!=Ms Hospital Medical School-
and Ba=e!
a!3eted this de!i"ati"e f!o 4KGK th!ou$h 4G41 as QHe!oin-Q a
nonaddicti"e
o!phine substitute and cou$h edicine. The nae he!oin cae
f!o its
!eputation as a Qhe!oicQ d!u$. Othe! pha!aceutical copanies- such
as Eli Iill=- also sold he!oin o"e! the
counte! in the :.S. %n 4G11- he!oin <as touted
as Q...the pe!fect d!u$- o!e potent =et less
ha!ful....Habituation has been noted in a sall
pe!centa$e of cases-....none of the patients
suffe! f!o this habituation.Q %n 4G1J- it <as
noted in a classic case of unde!stateent that
Qalthou$h he!oin is stated not to $i"e !ise to
habituation- a o!e e+tended 3no<led$e of the
d!u$ <ould see to indicate that this is not
enti!el= co!!ect.Q B= 4G41- it <as uni"e!sall=
!eco$nized that he!oin <as o!e addicti"e than
o!phine and it <as !eo"ed f!o the a!3et.
%t has becoe appa!ent o"e! the =ea!s as
!esea!che!s ha"e sea!ched fo! a o!phine
substitute that sall st!uctu!al chan$es to the
o!phine nucleus can ha"e a?o! effects on the
acti"it=. Lo! instance- codeine is one tenth as
po<e!ful a na!cotic as o!phine- and its effect
diacet=lo!phine
Qhe!oinQ
B ;H0
O
;H0;O7
;H0;O7
eto!phine
nalo+one 6
nalo!phine
B ;H0
O
;H0O
HO
B 6
O
HO
HO HO
O
O
B
OH
HO
codeine o!phine
B ;H0
O
HO
;H0O HO
HO
O
B ;H0
on the !espi!ato!= cente! is about one fou!th that of o!phine. %n
addition to bein$ less to+ic- it is less
addicti"e >althou$h it is still "e!= addicti"e@. The B8all=l- B8p!op=l- and
B8c=clop!op=leth=l hoolo$ues of
o!phine a!e all o!phine >opiate@ anta$onists. The= copete fo! the
o!phine !ecepto! site and
eliinate the !espi!ato!= dep!ession effect of o!phine. Balo+one is a
pu!e anta$onist. %t is acti"e at a
lo<e! dose than the a$onist and has been used to t!eat o!phine o!
he!oin o"e!doses. Eto!phine- <hich
is p!epa!ed "ia a Diels8,lde! !eaction of eth=l "in"=l 3etone <ith
thebaine follo<ed b= fu!the!
odification- is uch o!e po<e!ful >J111841111 ties as po<e!ful@
than o!phine as an anal$esic. %t is
also a hallucino$en <ith potenc= e/ui"alent to that of ISD. The
p!incipal use of eto!phine has been as a
t!an/uilize! fo! the captu!e of la!$e <ild anials.
P&arma!o$og1 "e Vinb$astine2 "e Vin!ristine2 "e Vin"esine e "e
Vinore$bine
H Taela Bu#mica 0a %ompara."o k P!ina 0o PeriYinIle J
O inb$astine V e o <in!ristine s"o alcalides encontrados no periYinIle de
+ada!ascar * roseus de "at#arant#us 7classi-icado anteriormente como o
rosea de Vinca * $ue conduGiu a estes alcalides chamados se tornando "e
Vin!a "os !om#ostos 8.
& o <in"esine e o <inore$bine * derivatives semis:nthetic do vinlastine*
todos traalham iniindo o mitosis 7divis"o da pilha8 no meta#&ase .
&stes alcalides li!am ao tubu$in * assim impedindo $ue a pilha -a.a os
ei@os que necessita poder mover ao redor seus chromosomes en$uanto se
divide 7esta similar X a."o do colchicine * mas om di-erente do -ranco
a a."o do paclitaxel * $ue inter-ere com a divis"o da pilha mantendo os
eixos de ser $uerado para aixo8. &stes alcalides parecem tamm
inter-erir com a ailidade das pilhas s:nthesiGe o DHA e o RHA . Todos
s"o administrados intravenousl: em seu -ormulrio do sul-ate uma veG
uma semana; estas solu.Ues s"o -atais se -orem administradas $ual$uer
outra maneira* e podem causar muitos da irrita."o do tecido se escaparem
-ora da veia. &mora estes trs compostos se;am muito similares na
estrutura e tenham a mesma a."o sica* tm distintamente e-eitos
di-erentes no corpo.
Tinlastine administrado tipicamente em um dose de O milli!rams por
o medidor $uadrado da super-#cie do corpo. M introduG#do no mercado
como Telan por &li @ill: e tem um hal--li-e no loodstream de 5< horas.
Tinlastine principalmente =til para tratar a doen.a de Hod!Iin* o
l:mphoma l:mphoc:tic* o l:mphoma histioc:tic* cancer testicular
avan.ado* cancer de peito avan.ado* sarcoma de baposi* e doen.a de
@etterer-EiYe. Parece tamm lutar o cancer inter-erindo com o
metaolism do cido !lutamic 7especi-icamente* os pathYa:s $ue
conduGem do cido !lutamic ao ciclo de bres e X -orma."o do urea8. Os
povos com in-ec.Ues acterianas n"o devem ser dados esta dro!a* nem
devem mulheres !rvidas* desde $ue causou de-eitos severos do
nascimento nos estudos animais. Os e-eitos laterais incluem a perda do
caelo* o nausea* conta!ens aaixadas da pilha do san!ue* headache* dor
do estVma!o* numness* constipation e sores da oca. Os danos do
marroY de osso s"o o -ator dose-limitando t#pico.
Tincristine* $ue introduG#do no mercado como Oncovin por &li @ill:*
tem um hal--li-e do serum de aproximadamente Q> horas. M usado
principalmente tratar o leuIemia a!udo* o rhadom:osarcoma* o
neurolastoma* a doen.a de Hod!Iin e os outros l:mphomas. O dose
t#pico em 4*< milli!rams por o medidor $uadrado da super-#cie do corpo
uma veG $ue uma semana* e o neurotoxicit: s"o o dose $ue limita o -ator
7ele pode causar os danos ao sistema nervoso peri-rico8. Por causa deste*
os povos com disorders neuromuscular devem diri!ir claramente desta
dro!a se poss#vel. 0o mesmo modo* os povos com al!uns -ormulrios do
s:ndrome do %harcot-+arie-0ente devem evitar o vincristine. As
mulheres !rvidas n"o devem de-initivamente -aGer exame d* por$ue
causa de-eitos severos do nascimento nos testes animais. Os e-eitos
laterais incluem a$ueles encontrados com vinlastine* mais prolemas
nervosos do sistema tais como o impairment sensor:; al!uns povos
podem tamm desenvolver prolemas ou spasms respirando do pulm"o
lo!o depois $ue a dro!a administrada. Os povos desenvolvem
ocasionalmente cancers secundrios se receerem a dro!a ;unto com
outras dro!as anticancer $ue est"o saidas para ser carcino!ens.
Tindesine tem um hal--li-e do serum de aproximadamente 5< horas e
administrado em um dose de 9 milli!rams por o medidor $uadrado da
super-#cie do corpo. Eeus toxicit: e e-eitos laterais s"o similares X$ueles
do vinlastine. Tindesine* $ue introduG#do no mercado so os nomes
&ldisine e 1ildesin* usado principalmente tratar cancers do melanoma e
de pulm"o 7carcinomas8 e* com outras dro!as* tratar cancers uterine.
Tinoreline est atualmente em experimenta.Ues cl#nicas da -ase ,, como
um tratamento para o cancer ovarian. &star introduG#do no mercado
como )aveline por 6laxo Nellcome* ,nc.* se as experimenta.Ues -orem
em sucedidas e o 10A aprovar a dro!a. Assim distante* o vinoreline
parece ter uma escala mais lar!a da atividade antitumor do $ue os outros
alcalides do vinca. &m experimenta.Ues preclinical* mostrou a promessa
em tratar pacientes com os cancers ovarian epithelial e* em comina."o
com o cisplatin da dro!a do chemotherap:* em tratar pacientes com os
cancers de pulm"o da non-pe$ueno-pilha. Os e-eitos laterais desta dro!a
incluem o diarrhea* o nausea* e a perda do caelo; parece ser menos de
um veneno do nervo do $ue o vindesine.
Para mais in-orma."o* visita:
%aderno Ovarian 0a Pes$uisa 0e %ancer: Tinoreline 7)aveline8
1olha do -ato de Tincristine do instituto nacional do cancer
O Pro;eto 0o Acesso: Tinlastine
O Pro;eto 0o Acesso: Tincristine
Tindesine %ompreensivo: Csos e e-eitos laterais
ReferQn!ias>
?udavari* Eusan* ed. 4RQR. : Tndice ?e Nerck: Ema enciclop5dia dos
produtos Mu3micos, das drogas e do Biologicals . (ahYa:* )W* +ercI Z
%o.
6oodman* @ouis Ean-ord* Al-red 6ilman* e Al-red 6oodman 6ilman*
eds. 4RRS. 1 base p#armacological do t#erapeutics * l edi."o. &lms-ord*
)F* ,mprensa 0e Per!amon.
+utschler* &rnst* e Hartmut 0erendor-. 4RR>. 1=Ues ?a ?roga:
Princ3pios b4sicos e aspectos t#erapeutic. &stu!arda* 6erman:*
pulishers cient#-icos do medpharm.
referVncia (++2 W c;pia da mesa do m5dico . +ontvale* )W* +dico
&conomia 0ados Produ."o %ompanhia.
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http\9A
\51\51iotech.icm.utexas.edu
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%A(TA 0O PHFTO%H&+,ET(F
&nvenenamento 0a Planta* Alcalides - Tropane
mltimo Cpdated: )ovemro 5R* 5SS4 Avalie este arti!o
&mail a um cole!a

E:non:ms e Ie:Yords relacionados: elladonna* erva daninha do ;imson*
erva daninha do loco* datura sacred* trometa do an!el* mandraIe* henane
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0os (etratos


Autor: (ichard um Na!ner* +0* Ph0 * e$uipe de -uncionrios consultando*
departamento da medicina da emer!ncia* hospital do &@ 0orado de Tucson;
%onsultante* dro!a do ariGona e centro de in-orma."o do veneno
%oauthor7s8: Eamuel + beim* +0 * diretor do pro!rama* pro-essor do
associado* departamento da cirur!ia* divis"o da medicina da emer!ncia*
universidade do centro das cincias da sa=de do ariGona

(ichard um Na!ner* +0* Ph0* um memro das se!uintes sociedades
mdicas: 1aculdade americana de mdicos da emer!ncia * e associa."o
mdica americana

&ditor7s8: +ichael E ?eeson* +0* +?A * diretor do pro!rama*
departamento da medicina da emer!ncia* sistema da sa=de de Eumma;
Pro-essor do associado da medicina cl#nica da emer!ncia* -aculdade do
nordeste das universidades de Ohio; Wohn T Tan0eToort* Pharm0* 0A?AT *
6erente* Pro-essor Assistente %l#nico* 0epartamento 0o Pharmac:* Hospital
0as (e!iUes; +ichael Hod!man* +0 * pro-essor cl#nico assistente da
medicina* departamento da medicina da emer!ncia* ?assett Healthcare;
Wohn HalamIa* +0 * o-icial de in-orma."o principal* sistema de %are6roup
Healthcare* pro-essor assistente da medicina* departamento da medicina da
emer!ncia* centro mdico de ?eth ,srael 0eaconess; Pro-essor assistente da
medicina* escola mdica de Harvard; e (a:mond W (oer!e* +0* +PH*
1AA&+* 1A%+T * pro-essor cl#nico do associado da medicina da
emer!ncia* universidade da escola de Pittsur!h da medicina; Atendendo X
e$uipe de -uncionrios* departamento da medicina da emer!ncia* hospital
das +a!ee-+ulheres da universidade do centro mdico de Pittsur!h
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0os (etratos


1undo: Os alcalides s"o os metaolites da planta $ue tm uma estrutura
$u#mica nitro!en-containin! do anel* alcalide-como o reactivit: $u#mico* e
a atividade pharmacolo!ic. Os amines do alcalide do stimulant* os amines
hallucino!enic do alcalide* e os alcalides altamente anticholiner!ic do
tropane 7ou os alcalides do elladonna8 compreendem os 9 !rupos
pharmacolo!ic principais de amines do alcalide.
As plantas $ue contm alcalides do tropane 7ou o ic:clic8* atropina*
scopolamine* e h:osc:amine incluem o se!uinte:
&spcie do datura 7erva daninha do ;imson* trometa do an!el* ma." do
espinho8
H:osc:amus ni!er 7henane8
?elladonna do atropa 7ni!htshade mortal8
O--icinarum de +andra!ora 7mandraIe8
Todas estas plantas tm histories lon!os do uso hallucino!enic e -oram
conectadas com o sorcer:* o Yitchcra-t* a medicina nativa* e os rites ma!ico-
reli!iosos $ue datam para trs a 4>SS ?% e a od:sse: de Homer . 7uso de
Homer da planta mol: como um antidote Xs dro!as anticholiner!ic
venenosas de %irce pode ter sido o uso primeiramente !ravado de uma
anticolinesterase inverter o intoxication anticholiner!ic central.8
As medicinas heral chinesas $ue contm alcalides do tropane -oram
usadas tratar o asthma* o ronchitis crVnico* a dor* e os sintomas do -lu. &m
+xico* o datura -eito exame por mulheres de Fa$ui para diminuir a dor
do parto. &m n-rica* um uso comum deve -umar sae do datura para aliviar o
asthma e prolemas pulmonar:. +uitas culturas YorldYide adicionam
plantas com alcalides do tropane 7particularmente espcie do datura8 Xs
eidas alcolicas ao intoxication do aumento.
(ecentemente* o datura -oi usado como um hallucino!en recreacional nos &.
C.* tendo por resultado casos espordicos do envenenamento e da morte
anticholiner!ic. Os casos numerosos do envenenamento anticholiner!ic
tamm resultaram dos contaminadores do alcalide do elladonna nos
alimentos* includin! o ch de Para!uai comercialmente compra 7um ch
heral derivado do para!uariensis de ,lex 8* no hamur!er* no mel* no
porrid!e duro -eito do millet contaminado* e da ]no vinho homemade da -lor
lua]. Outros in!estions acidentais incluem o empre!o errado como um
ve!etal e um inclusion selva!ens edile no toothpaste homemade.
Pathoph:siolo!:: O toxicit: das plantas $ue contm alcalides do tropane
mani-esta-se como o envenenamento anticholiner!ic clssico. Os sintomas
ocorrem !eralmente 9S-OS minutos depois $ue in!estion e podem continuar
por 5<-<Q horas por$ue os alcalides do tropane atrasam esvaGiar e
asorption !astric.
Ecopolamine* a!indo como um anta!onista em receptors muscarinic
peri-ricos e centrais* pensado para ser o composto preliminar responsvel
para os e-eitos txicos destas plantas. Os alcalides de Tropane s"o
encontrados em todas as partes das plantas* com concentra.Ues as mais
elevadas nas raiGes e nas sementes.
A atropina um arti-act do puri-ication* produGido pelo racemiGation do l-
h:osc:amine. A propor."o de cada presente do alcalide varia entre a
espcie* a poca do ano* a posi."o* e a parte de planta. T"o pouco $uanto um
meio de teaspoon da semente do datura* e$uivalente a S*4 ma!nsio da
atropina por a semente* causou a morte da apreens"o cardiopulmonar:. A
rota usual do in!estion como um ch* emora in!estin! sementes ou a
outra planta parte e -umar secado sae tamm comum.
1re$hncia:
)os &. C.: A incidncia espordica* com os con;untos de casos do
envenenamento* na maior parte entre adolescents usando plantas para seus
e-eitos hallucino!enic. &m 4RR<* um aumento 4S--old no n=mero dos casos
-oi relatado em 1lorida. O acesso di-undido X in-orma."o em plantas
hallucino!enic atravs do ,nternet pode conduGir a um aumento mais
adicional na incidncia.
,nternacional: A incidncia YorldYide desconhecida. &ntretanto* os casos
-oram relatados em Austrlia* ?rasil* Hon! bon!* +xico* TanG/nia*
1ormosa* e TeneGuela* atestando X distriui."o !eo!r-ica lar!a da espcie
do datura.
+ortalit:'+oridit:: Os casos de )on-atal s"o underreported
provavelmente.
&m 4RR9* 94Q casos do envenenamento do datura -oram relatados X
associa."o americana de centros de controle do veneno; os centros para o
controle da doen.a 7%0%8 relataram 5 mortes.
&m 4RR<* o %0% relatou P casos do envenenamento anticholiner!ic em 9
-am#lias $ue consumiram o ch de Para!uai comercial contaminado.
Os relatrios de caixas ou de con;untos espordicos dos casos $ue envolvem
o uso intencional como um hallucino!en s"o -re$hentes; a maioria de
pacientes recuperam unevent-ull:.
As mortes relacionadas de a-o!ar-se* de exposi."o* e de -alta do cuidado de
suporte -oram relatadas.
Eexo: )enhum predilection sexual existe.
,dade: )enhum predilection da idade existe* emora o uso do datura como
uma dro!a recreacional se;a mais comum entre adolescents. Z nsp
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Histor::
%omo em al!um paciente $ue apresenta-se com uma mudan.a a!uda no
status mental ou no envenenamento suspeitado* tentativa de oter a se!uinte
in-orma."o:
Termine aps o histor: mdico
Histor: do medication
0escri."o precisa ou amostra do toxicant7s8 suspeitado
(ota de administra."o* de $uantidade in!ested* de tempo desde o in!estion*
e de raG"o para o in!estion
%o-in!estants-in!estants e uso do lcool ou das outras dro!as da rua
Os sinais e os sintomas iniciais podem incluir o se!uinte:
+emranas mucous e pele secas
0is-a!ia e d:sarthria
Photophoia
Tis"o orrada
Tach:cardia
(eten."o urinar:
Os sinais e os sintomas iniciais podem ser se!uidos pelo h:perthermia* pela
con-us"o* pelo a!itation* pelo comativeness* pelas apreensUes* pelo coma* e
pela morte.
O amnesia a respeito dos eventos $ue se!uem o in!estion de alcalides do
tropane comum.
A identi-ica."o de plantas in!ested pode ser dia!nostic do envenenamento
do alcalide do tropane.
As espcies do datura* as plantas o mais !eralmente encontradas $ue contm
alcalides do tropane* s"o anurios de 9-> ps com !rosseiro-coarse-toothed
saem.
as -lores Trometa-dadas -orma s"o 9-> pole!adas no comprimento* com as
ptalas coloridas ranco-plido-violetas 7ve;a o retrato 4 * retrato 58.
Os mais importantes para a identi-ica."o taxonomic s"o os pods spin:*
redondos* chamered da semente 7ve;a o retrato 98.
&xame: O ]vermelho mnemVnico como uma eterraa* seca como um osso*
cortina por$ue um ast"o* louco como um hatter* e por mais $uente $ue um
hare] este;a =til recordar o toxidrome anticholiner!ic.
Einais vitais
Tach:cardia e tach:pnea
Hiperpirexia 7em aproximadamente 5S\ dos casos8
H:pertension e h:potension inconsistent* depression respirator: 7raro8
Pele seca morna 7pode ser nivelado8
%ae.a* orelhas* olhos* nariG* e !ar!anta
+:driasis e ciclople!ia 7$uase sempre ocorra e possa persistir por dias8
Ee$ue as memranas mucous
AdVmen
Eons diminu#dos do oYel
0istention da exi!a urinar:
)eurolo!ic
A!itation* con-us"o* e hallucinations
ApreensUes* coordena."o diminu#da do m=sculo* paral:sis* depression
respirator:* e coma 7raro8
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0os (etratos


0elirium* dementia* e amnesia
,n-ec."o de H,T e A,0E
H h:perth:roidism* tempestade do th:roid e doen.a das sepulturas J
H:po!l:cemia
+enin!itis
&nvenenamento 0a Planta* 6l:cosides - %ardiac
&nvenenamento 0a Planta* Hers
&nvenenamento 0a Planta* H:po!l:cemics
&s$uiGo-renia
Etatus &pilepticus
Toxicit:* Amphetamine
Toxicit:* Anticholiner!ic
Toxicit:* Antidepressivo
Toxicit:* Antid:srh:thmic
Toxicit:* Antihistamine
Toxicit:* %oca#na
Toxicit:* Hallucino!en
Toxicit:* %o!umelo - Hallucino!ens
E:ndromes 0a (etirada eee T(A)E@AT,O) &)0E H&(& eee
BuicI 1ind
Author ,n-ormation
,ntroduction
%linical
0i--erentials
NorIup
Treatment
+edication
1olloY-up
+iscellaneous
Pictures
?ilio!raph:
%licI -or related ima!es.
(elated Articles
0elirium* 0ementia* and Amnesia
H,T ,n-ection and A,0E
HH:perth:roidism* Th:roid Etorm and 6raves 0iseaseJ
H:po!l:cemia
+enin!itis
Plant Poisonin!* 6l:cosides - %ardiac
Plant Poisonin!* Hers
Plant Poisonin!* H:po!l:cemics
EchiGophrenia
Etatus &pilepticus
Toxicit:* Amphetamine
Toxicit:* Anticholiner!ic
Toxicit:* Antidepressant
Toxicit:* Antid:srh:thmic
Toxicit:* Antihistamine
Toxicit:* %ocaine
Toxicit:* Hallucino!en
Toxicit:* +ushroom - Hallucino!ens
NithdraYal E:ndromes

%ontinuin! &ducation
%+& availale -or this topic. %licI here to taIe this %+&.

Patient &ducation
%licI here -or patient education.


Z nsp NO(bCP Eection > o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


@a Etudies:
)o speci-ic dia!nostic studies -or tropane alIaloid poisonin!s exist.
Tropane alIaloids are not included in standard dru!s o- ause or
comprehensive toxicolo!: panels; serum dru! concentrations are neither
help-ul nor readil: availale to aid in initial mana!ement.
Eince acetaminophen and salic:late are common co-in!estants in man:
poisonin!s* consider assa:s -or acetaminophen and salic:late levels.
,n -erile patients* consider lood and urine cultures.
Eerum electrol:te levels ma: provide insi!ht into other intoxicatin! a!ents
and co-in!estants.
%onsider a pre!nanc: test -or all patients capale o- earin! children.
,ma!in! Etudies:
%onsider %T scan o- the head -or patients Yith altered mental status that is
inade$uatel: explained : toxicit: -rom in!ested a!ent or is unresponsive to
appropriate intervention.
Other Tests:
Otain an electrocardio!ram 7&%68 at presentation -or all patients Yith
suspected toxic in!estions.
Procedures:
%onsider lumar puncture 7@P8 -or patients Yith -ever and altered mental
status.
%onsider invasive monitorin! -or hemod:namicall: unstale patients.
Z nsp T(&AT+&)T Eection O o- 44
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+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


Prehospital %are: Transport patient to nearest emer!enc: -acilit: Yith
capailities -or advanced li-e support 7A@E8* at minimum. Primar:
assessment should -ocus on airYa: and respirator:* circulator:* and
neurolo!ic s:stems.
Cnless patient is extremel: a!itated* otain ,T access and monitor vital
si!ns -re$uentl:.
%onsider administration o- naloxone and thiamine.
0o not use ipecac and de-er administration o- activated charcoal* unless a
prolon!ed transport time is anticipated.
Assess -or h:po!l:cemia and other causes o- altered mental status. +ana!e
seiGures Yith enGodiaGepines.
Ph:sosti!mine is not recommended in prehospital settin!.
&mer!enc: 0epartment %are: As in all cases o- suspected poisonin!* -olloY
the A?%0&s o- emer!enc: medicine 7airYa:* reathin!* circulation*
disailit:* exposure8* then the A?%0&s o- toxicolo!: 7antidotes* asics*
chan!e asorption* chan!e distriution* chan!e elimination8.
Provide ox:!en and intuate i- si!ni-icant %)E or respirator: depression
exists and no !a! re-lex is present. Assess circulation and initiate cardiac and
pulse oximetr: monitorin!. Otain a 45-lead &%6 and evaluate -or B(E
prolon!ation* ischemia* and evidence o- arrh:thmia.
Einus tach:cardia is common and does not re$uire treatment -or a stale
patient. Otain lood -or laorator: anal:sis and edside !lucose
measurement Yhile otainin! ,T access. ,nspection a-ter -ull-od: exposure
should e per-ormed to assess si!ns o- trauma or seiGure.
A!itated or hallucinatin! patients o-ten respond to reassurance and a
darIened room. ,- chemical restraint is re$uired* enGodiaGepines are the
dru!s o- choice. &arl: consultation Yith a poison control center is -re$uentl:
help-ul.
%onsider 6, decontamination -oremost. ,pecac is contraindicated ecause o-
the potential -or seiGures. 6astric lava!e is controversial; Yhile it is
commonl: per-ormed* no reliale data on outcomes exist to support its use*
and the risI o- aspiration and other complications is increased. Administer
activated charcoal 74-5 !'I!8 orall: or per naso!astric or oro!astric tue.
One or 5 additional doses ma: e !iven at 4- or 5-hour intervals to ensure
ade$uate !ut decontamination.
An ileus Yithout distension is not a contraindication to a sin!le dose o-
charcoal* and charcoal !iven alone ma: e as e--ective or more e--ective
than emesis and lava!e procedures. Cse o- cathartics to hasten elimination
-rom 6, tract remains controversial. Eoritol ma: e used Yith -irst dose o-
charcoal; -urther use ma: cause serious -luid shi-ts to the intestine* diarrhea*
deh:dration* and h:pernatremia.
Tropane alIaloids are lipophilic and cross the lood-rain arrier;
hemodial:sis and hemoper-usion are !enerall: ine--ective. )o e--ective
methods o- chan!in! distriution or elimination o- tropane alIaloids exist.
Epeci-ic antidote -or tropane alIaloid toxicit: is ph:sosti!mine salic:late* a
reversile acet:lcholinesterase inhiitor capale o- directl: anta!oniGin!
%)E mani-estations o- anticholiner!ic toxicit:.
Ph:sosti!mine 7at doses loYer than those producin! peripheral side e--ects
o- salivation* lacrimation* urination* de-ecation* emesis8 can reverse central
e--ects o- the -olloYin! conditions:
%oma
EeiGures
Hallucinations
A!itation
Eevere d:sIinesias
(espirator: depression
HoYever* unless asolute certaint: can e estalished that the toxicit:
present is due to tropane alIaloid poisonin! and not to co-in!estants or other
sustances* con-irmator: peripheral mani-estations o- anticholiner!ic
toxicit: should coexist prior to administration o- ph:sosti!mine.
Ph:sosti!mine can induce a li-e-threatenin! choliner!ic crisis 7e!* seiGures*
respirator: depression* as:stole8. Eince most patients can e sa-el: treated
Yithout this antidote* ph:sosti!mine pre-eral: should e used in
consultation Yith a poison control center and !enerall: should e used onl:
-or patients in the -olloYin! states:
Cnresponsive to supportive measures
Tach:d:srh:thmias and suse$uent hemod:namic compromise
,ntractale seiGures unresponsive to enGodiaGepines
&xtremel: severe a!itation or ps:chosis
Ph:sosti!mine is contraindicated in patients receivin! tric:clic
antidepressants* disop:ramide* $uinidine* procainamide* cocaine* or other
a!ents producin! cardiac conduction anormalities. (elative
contraindications include reactive airYa: disease* intestinal ostruction* and
administration o- depolariGin! paral:tic a!ents.
1olloYin! 6, decontamination* most patients rarel: re$uire more than
ph:siolo!ic monitorin! and ps:cholo!ic support.
Patients experiencin! a!itation and hallucinations usuall: respond to
reassurance and enGodiaGepines.
+ost phenothiaGines are contraindicated ecause o- their anticholiner!ic
properties.
,- si!ns or s:mptoms o- urinar: retention exist* 1ole: catheteriGation should
e per-ormed -or ladder decompression.
%onsultations:
&arl: consultation Yith a toxicolo!ist or poison control center is -re$uentl:
use-ul -or toxic exposures or in!estions to help in decision-maIin! Yith
re!ard to decontamination and therapeutic interventions; this is particularl:
true Yith the use o- ph:sosti!mine in cases o- tropane alIaloid poisonin!.
Ps:chiatric consultation is important -or all intentional in!estions.
%ontact Yith primar: care provider is optimal -or all hospital admissions or
cases o- serious illness.
Z nsp +&0,%AT,O) Eection P o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


Activated charcoal is indicated -or all tropane alIaloid poisonin!s* Yith the
possile exception o- poisonin! -rom smoIin! leaves. ?enGodiaGepines are
-irst-line a!ents -or a!itation and seiGures. Ph:sosti!mine should e used
onl: -or li-e-threatenin! complications.
0ru! %ate!or:: 6, decontaminant -- Activated charcoal is used a-ter a dru!
or plant in!estion to limit adsorption o- toxins. Traditionall: !iven a-ter the
stomach has een emptied : emesis or lava!e* recent evidence indicates
that it ma: e used alone* Yithout lava!e. 0ru! )ame
Activated charcoal 7@i$ui-%har8 -- &mer!enc: treatment in poisonin!
caused : dru!s and chemicals. )etYorI o- pores present in activated
charcoal adsors 4SS-4SSS m! o- dru! per !ram o- charcoal. An extremel:
important component o- tropane alIaloid poisonin!. +a: decrease severit:
and duration o- poisonin!. 0oes not dissolve in Yater.
1or maximum e--ect* administer Yithin 9S min a-ter in!estin! poison.
Adult 0ose 4 !'I! PO or : !astric tue; repeat dose o- S.5>-S.> !'I! ma:
e !iven in 5 h; -irst dose ma: e !iven Yith cathartic 7e!* soritol8
Pediatric 0ose o5 :ears: )ot recommended
g5 :ears: S.>-4 !'I! PO or : !astric tue
%ontraindications 0ocumented h:persensitivit:; poisonin! or overdosa!e
o- mineral acids and alIalies; 6, ostruction
,nteractions +a: inactivate ipecac s:rup i- used concomitantl:;
e--ectiveness o- other medications decrease Yith coadministration; do not
mix charcoal Yith sheret* milI* or ice cream 7decreases adsorptive
properties o- activated charcoal8
Pre!nanc: % - Ea-et: -or use durin! pre!nanc: has not een estalished.
Precautions Protect airYa: in patients Yith asent !a! re-lex; not ver:
e--ective in poisonin!s o- ethanol* methanol* and iron salts; induce emesis
e-ore !ivin! activated charcoal; a-ter emesis Yith ipecac* patient ma: not
tolerate activated charcoal -or 4-5 h; can administer in earl: sta!es o- !astric
lava!e; Yithout soritol* !astric lava!e returns are lacI
0ru! %ate!or:: ?enGodiaGepines -- 1irst-line a!ents -or treatment o-
tropane-alIaloid-induced seiGures. @oraGepam is thou!ht to e most
e--ective and has a lon!er seiGure hal--li-e than diaGepam. 0ru! )ame
@oraGepam 7Ativan8 -- Eedative h:pnotic Yith short onset o- e--ects and
relativel: lon! hal--li-e. 0O% i- ,T access is availale.
,ncreasin! the action o- !amma-aminout:ric acid 76A?A8* Yhich is a
ma;or inhiitor: neurotransmitter in the rain* ma: depress all levels o-
%)E* includin! limic and reticular -ormation.
+onitorin! patient[s lood pressure a-ter administerin! dose is important.
Ad;ust prn.
Adult 0ose S.4 m!'I! ,T; rate o- 5 m!'min; commonl: administered 4-<
m! initiall:* Yith doses up to 4S m! prn
Pediatric 0ose S.4 m!'I! ,T initial dose 7S.4>-S.5 m!'I! P(8
%ontraindications 0ocumented h:persensitivit:; preexistin! %)E
depression; h:potension; narroY-an!le !laucoma
,nteractions Toxicit: o- enGodiaGepines in %)E increases Yhen used
concurrentl: Yith alcohol* phenothiaGines* ariturates* and +AO,s
Pre!nanc: 0 - Cnsa-e in pre!nanc:
Precautions %aution Yith renal or hepatic impairment* m:asthenia !ravis*
or!anic rain s:ndrome* or ParIinson disease
0ru! )ame
+idaGolam 7Tersed8 -- Csed as alternative in termination o- re-ractor:
status epilepticus. ?ecause midaGolam is Yater solule* it taIes
approximatel: 9 times lon!er than diaGepam to peaI &&6 e--ects. Thus
clinician must Yait 5-9 min to -ull: evaluate sedative e--ects e-ore
initiatin! procedure or repeatin! dose. Pulished reports o- ,+ and anecdotal
reports o- nasal use exist 7Yhen ,T access is not possile8.
Adult 0ose 4S m! ,+ 7Yhen ,T'P( is impossile8
(e-ractor: status: S.5 m!'I! ,T then in-usion S.4-S.< m!'I!'h; intuation
and pressor support are necessar:
Pediatric 0ose S.5 m!'I! ,+* then otain ,T access
%ontraindications 0ocumented h:persensitivit:; preexistin! h:potension;
narroY-an!le !laucoma; sensitivit: to prop:lene !l:col 7the diluent8
,nteractions Eedative e--ects o- midaGolam ma: e anta!oniGed :
theoph:llines; narcotics and er:throm:cin ma: accentuate sedative e--ects
o- midaGolam ecause o- decreased clearance
Pre!nanc: 0 - Cnsa-e in pre!nanc:
Precautions %aution Yith con!estive heart -ailure* pulmonar: disease* renal
impairment* and hepatic -ailure
0ru! )ame
0iaGepam 7Talium8 -- 0epresses all levels o- %)E 7e!* limic and reticular
-ormation8* possil: : increasin! activit: o- 6A?A. 1re$uentl: used in
prehospital s:stems since re-ri!eration is not re$uired.
Adult 0ose S.4> m!'I! ,T; not to exceed 5S m!
Pediatric 0ose Administer as in adults ,T; S.9-S.> m!'I! P(
%ontraindications 0ocumented h:persensitivit:; narroY-an!le !laucoma
,nteractions ,ncreases toxicit: o- enGodiaGepines in %)E Yith
coadministration o- phenothiaGines* ariturates* alcohols* and +AO,s
Pre!nanc: 0 - Cnsa-e in pre!nanc:
Precautions %aution Yith other %)E depressants* loY alumin levels* or
hepatic disease 7ma: increase toxicit:8
0ru! %ate!or:: %holiner!ic a!ents -- Ph:sosti!mine is indicated onl: -or
reversal o- li-e-threatenin! complications o- tropane alIaloid poisonin! 7e!*
tach:d:srh:thmias Yith hemod:namic compromise* seiGures re-ractor: to
other therapeutic interventions* and severe a!itation or hallucinations
unresponsive to other therap:8. The decision to use ph:sosti!mine ideall:
should e made in consultation Yith a toxicolo!ist or poison control center.
0ru! )ame
Ph:sosti!mine 7Antilirium8 -- (eversile anticholinsterase inhiitor that
increases the concentration o- acet:lcholine at choliner!ic s:napses. The
onl: reversile anticholinesterase inhiitor that readil: crosses the lood-
rain arrier to produce the desired %)E e--ects.
Eome recommend repeated sloY ,T pushes o- S.4-S.9 m! $9min to a
maximum o- 5 m! to decrease potential -or li-e-threatenin! cardiovascular
adverse e--ects.
Adult 0ose 5 m! sloY ,TP; ma: e repeated as indicated; clinical e--ects
last 5S-OS min
Pediatric 0ose S.S5-S.SO m! ,TP; not to exceed S.> m!'min or 5 m! as a
sin!le dose; clinical e--ects last 5S-OS min; ma: repeat prn
%ontraindications 0ocumented h:persensitivit:; asthma; cardiovascular
disease; diaetes; !an!rene; intestinal ostruction; uro!enital ostruction;
patients receivin! choline esters or depolariGin! neuromuscular locIers
,nteractions +a: inhiit or reverse e--ects o- nondepolariGin!
neuromuscular locIers 7e!* vecuronium or pancuronium8
Pre!nanc: % - Ea-et: -or use durin! pre!nanc: has not een estalished.
Precautions Patients should e on a cardiac monitor; ma: precipitate a
choliner!ic crisis 7e!* seiGures* respirator: depression* as:stole8; atropine
should e at edside; ma: precipitate ronchorrhea and ronchospasm; ma:
induce -asciculations and muscle YeaIness; administer S.> m! o- atropine
,T'm! o- ph:sosti!mine to reverse choliner!ic crisis induced :
ph:sosti!mine
Z nsp 1O@@ON-CP Eection Q o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


1urther ,npatient %are:
?ase admission decisions on patient[s si!ns and s:mptoms.
As:mptomatic patients Yithout si!ns o- anticholiner!ic toxicit: or altered
mental status ma: e dischar!ed a-ter O hours o- oservation.
Admit s:mptomatic patients to an ,%C settin! -or monitorin! and treatment.
The: ma: e dischar!ed a-ter a s:mptom--ree period o- O hours Yithout use
o- supportive therap: or antidotes and a-ter appropriate consultations and
-olloY-up have een arran!ed.
Z nsp +,E%&@@A)&OCE Eection R o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


+edical'@e!al Pit-alls:
1ailure to maIe the dia!nosis
1ailure to otain a toxicolo!: consult in a criticall: ill patient Yith
pol:sustance toxicit:.
Z nsp P,%TC(&E Eection 4S o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


%aption: Picture 4. 0atura stramonium 7;imson Yeed8. )ote <-> inch lon!
Yhite -loYers. p 5SSS (ichard Na!ner
TieY 1ull EiGe ,ma!e
e+edicine coom TieY 7,nteractive`8
Picture T:pe: Photo
%aption: Picture 5. 0atura stramonium -loYer. )ote the trumpetliIe shape. p
5SSS (ichard Na!ner
TieY 1ull EiGe ,ma!e
e+edicine coom TieY 7,nteractive`8
Picture T:pe: Photo
%aption: Picture 9. 0atura stramonium 7close-up o- unripe seed pods8. )ote
spin: appearance o- pods. p 5SSS (ichard Na!ner
TieY 1ull EiGe ,ma!e
e+edicine coom TieY 7,nteractive`8
Picture T:pe: Photo
Z nsp ?,?@,O6(APHF Eection 44 o- 44
Author ,n-ormation ,ntroduction %linical 0i--erentials NorIup Treatment
+edication 1olloY-up +iscellaneous Pictures ?ilio!raph:


Anon:mous: Anticholiner!ic poisonin! associated Yith an heral tea--)eY
ForI %it:* 4RR<. ++N( +or +ortal NIl: (ep 4RR> +ar 5<; <<7448:
4R9-> H+edlineJ .
Anon:mous: Wimson Yeed poisonin!--Texas* )eY ForI* and %ali-ornia*
4RR<. ++N( +or +ortal NIl: (ep 4RR> Wan 5P; <<798: <4-< H+edlineJ .
%han TF: Anticholiner!ic poisonin! due to %hinese heral medicines. Tet
Hum Toxicol 4RR> Apr; 9P758: 4>O-P H+edlineJ .
%han! EE* Nu +@* 0en! W1: Poisonin! : 0atura leaves used as edile
Yild ve!etales. Tet Hum Toxicol 4RRR Au!; <47<8: 5<5-> H+edlineJ .
0eYitt +E* EYain (* 6ison @? Wr: The dan!ers o- ;imson Yeed and its
ause : teena!ers in the banaYha Talle: o- Nest Tir!inia. N T +ed W
4RRP Wul-Au!; R97<8: 4Q5-> H+edlineJ .
1rancis P0* %larIe %1* A@,A: An!el trumpet lil: poisonin! in -ive
adolescents: clinical -indin!s and mana!ement. W Paediatr %hild Health 4RRR
1e; 9>748: R9-> H+edlineJ .
6reene 6E* Patterson E6* Narner &: ,n!estion o- an!el[s trumpet: an
increasin!l: common source o- toxicit:. Eouth +ed W 4RRO Apr; QR7<8: 9O>-
R H+edlineJ .
Ha:man W* A@,A: 0atura poisonin!--the An!el[s Trumpet. Patholo!: 4RQ>
Wul; 4P798: <O>-O H+edlineJ .
Hun! O@* @eYin )A* HoYland +A: Heral preparations. ,n: 6old-ranI[s
Toxicolo!ic &mer!encies. Oth ed. 4RRQ.
Huxtale (W: The toxicit: o- alIaloids in -oods and hers. ,n: 1ood
Poisonin!: HandooI o- )atural Toxins. Tol P. +arcel 0eIIer; 4RR5: 59P-
O5.
+icIe ++: The case o- hallucino!enic plants and the ,nternet. W Ech Health
4RRO Oct; OO7Q8: 5PP-QS H+edlineJ .
Olson b(: Poisonin! and 0ru! Overdose. 9rd ed. Eimon Z Echuster Trade;
4RRQ.
Pereira %A* )ishioIa E de 0: Poisonin! : the use o- 0atura leaves in a
homemade toothpaste. W Toxicol %lin Toxicol 4RR<; 95798: 95R-94 H+edlineJ
.
PlaitaIis A* 0uvoisin (%: Homer[s mol: identi-ied as 6alanthus nivalis @.:
ph:siolo!ic antidote to stramonium poisonin!. %lin )europharmacol 4RQ9
+ar; O748: 4-> H+edlineJ .
(amireG +* (ivera &* &reu %: 1i-teen cases o- atropine poisonin! a-ter
hone: in!estion. Tet Hum Toxicol 4RRR 1e; <4748: 4R-5S H+edlineJ .
(od!ers 6% Wr* Ton banel (@: %onservative treatment o- ;imsonYeed
in!estion. Tet Hum Toxicol 4RR9 1e; 9>748: 95-9 H+edlineJ .
(YiGa HT: Wimson Yeed -ood poisonin!. An epidemic at Csan!i rural
!overnment hospital. Trop 6eo!r +ed 4RR4 Wan-Apr; <974-58: Q>-RS
H+edlineJ .
Echultes (&* Ho--mann A: Hol: -loYer o- the )orth Etar: 0atura. ,n: Plants
o- the 6ods: Their Eacred* Healin!* and Hallucino!enic PoYers. 4RR5: 4SO-
44.
Emith &A* +eloan %&* PicIell WA: Ecopolamine poisonin! -rom homemade
[moon -loYer[ Yine. W Anal Toxicol 4RR4 Wul-Au!; 4>7<8: 54O-R H+edlineJ .
Tion!son W* Ealen P: +ass in!estion o- Wimson Need : eleven teena!ers.
0el +ed W 4RRQ )ov; PS7448: <P4-O H+edlineJ .
Crich (N* ?oYerman 0@* @evisI: WA: 0atura stramonium: a -atal
poisonin!. W 1orensic Eci 4RQ5 Oct; 5P7<8: R<Q->< H+edlineJ .
Tanderho-- ?T* +osser bH: Wimson Yeed toxicit:: mana!ement o-
anticholiner!ic plant in!estion. Am 1am Ph:sician 4RR5 Au!; <O758: >5O-9S
H+edlineJ .
)OT&:
+edicine is a constantl: chan!in! science and not all therapies are clearl:
estalished. )eY research chan!es dru! and treatment therapies dail:. The
authors* editors* and pulisher o- this ;ournal have used their est e--orts to
provide in-ormation that is up-to-date and accurate and is !enerall: accepted
Yithin medical standards at the time o- pulication. HoYever* as medical
science is constantl: chan!in! and human error is alYa:s possile * the
authors* editors* and pulisher or an: other part: involved Yith the
pulication o- this article do not Yarrant the in-ormation in this article is
accurate or complete* nor are the: responsile -or omissions or errors in the
article or -or the results o- usin! this in-ormation. The reader should con-irm
the in-ormation in this article -rom other sources prior to use. ,n particular*
all dru! doses* indications* and contraindications should e con-irmed in the
pacIa!e insert. 1C@@ 0,E%@A,+&(
Plant Poisonin!* AlIaloids - Tropane excerpt
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PR7GRA(A ODP<RDACO7DA; DA S<G>RAD9A \>](OCA
OS CRI?RRIOS "e SAFDE AALIEH?AIS :=
ALCALIDES "o PNRROLISIDIHE
este relatrio contm as opiniUes coletivas um !rupo internacional dos
peritos e n"o representam necessariamente as decisUes ou a pol#tica indicada
da or!aniGa."o da sa=de do mundo ou do pro!rama unido do amiente das
na.Ues
Pulicado so o sponsorship comum do pro!rama unido do amiente das
na.Ues e da or!aniGa."o da sa=de do mundo
Or!aniGa."o 6enera 4RQQ 0a Ea=de 0o +undo
,E?) R5 < 4><5QS 5
7c8 Or!aniGa."o 4RQQ 0a Ea=de 0o +undo
As pulica.Ues da or!aniGa."o da sa=de do mundo aprec#am a prote."o do
cop:ri!ht de acordo com as provisUes do protocolo 5 da conven."o
universal do cop:ri!ht. Para direitas da reprodu."o ou da tradu."o de
pulica.Ues do NHO* na parte ou no toto, a aplica."o deve ser -eita ao
escritrio de pulica.Ues* or!aniGa."o da sa=de do mundo* 6enera*
EYitGerland. A or!aniGa."o da sa=de do mundo d oas-vindas a tais
aplica.Ues.
As desi!na.Ues empre!adas e a apresenta."o do material nesta pulica."o
n"o implicam a express"o de nenhuma opini"o $ual$uer na parte do
secretariat da or!aniGa."o da sa=de do mundo a respeito do status le!al de
al!uma pa#s* territrio* cidade ou rea ou de suas autoridades* ou de
concernir o delimitation de seus -ronteiras ou limites.
O mention de companhias espec#-icas ou de produtos de determinados
-aricantes n"o implica $ue est"o endossados ou recomendados pela
or!aniGa."o da sa=de do mundo na pre-erncia a outra de uma natureGa
similar $ue n"o mencionada. Os erros e as omissUes excetuadas* os nomes
de produtos proprietrios s"o distin!uidos por letras importantas iniciais.
%(,TM(,OE
0& EAm0& A+?,&)TA,E 0OE D)0,%&E PA(A A@%A@A,0&E 0O
PF((O@,c,0,)&
P(&1n%,O
,)T(O0C23O - A@%A@A,0&E 0O PF((O@,c,0,)& & EAm0&
HC+A)A
4. EC+n(,O & (&%O+&)0A2q&E
4*4. Eumrio
4*5. 1ontes e estrutura $u#mica
4*9. +ecanismos e caracter#sticas do toxicit:
4*<. &-eitos no homem
4*<*4. )atureGa e extens"o dos riscos de sa=de
4*>. +todos para a preven."o
4*O. (ecomenda.Ues
4*O*4. (ecomenda.Ues !erais
4*O*5. (ecomenda.Ues para a pes$uisa
5. P(OP(,&0A0&E & +MTO0OE A)A@DT,%OE
5*4. &strutura $u#mica e propriedades
5*5. +todos anal#ticos
5*5*4. @#$uidos
do tecido de planta 5*5*4*5 da extra."o 5*5*4*4 e tecidos
iol!icos 5*5*5. Anlise para o chromato!raph: thin-la:er
dos alcalides 5*5*5*4 do p:rroliGidine 7T@%8 5*5*5*5
chromato!raph: de !s hi!h-per-ormance do chromato!raph: l#$uido
7HP@%8 5*5*5*9 76%8 e do resonance 5*5*5*< ma!ntico nuclear de
spectrometr: maci.o 7+E8 spectrometr: 7)+(8 5*5*5*> as tinturas do
indicador da rea."o 5*5*5*O de &hrlich 5*5*5*P 5*9 pesando diretos.
0etermina."o dos metaolites nos tecidos animais
9. 1O)T&E & PATHNAFE 0A &LPOE,23O
9*4. Alcalides hepatotxicos do p:rroliGidine e suas -ontes
9*5. Pneumotoxic e outros alcalides txicos 9*9
do p:rroliGidine. PathYa:s da exposi."o
9*9*4. %ontamina."o das colheitas de alimento 9*9*5
do !rampo. ,n-usions heral
9*9*9. Cso de PA-conter plantas como o alimento
9*9*<. +el contaminado
9*9*>. @eite
9*9*O. %arne
9*9*P. Cso de PAs como a!entes chemotherapeutic para o cancer
<. +&TA?O@,E+
<*4. Asorption* excretion* e distriui."o <*4*4
do tecido. Asorption
<*4*5. &xcretion e distriui."o
<*5. (otas metaolic
<*5*4. H:drol:sis
<*5*5. / - oxida."o
<*5*9. %onvers"o aos metaolites p:rrolic
<*9. &-eitos dos tratamentos $ue a-etam o metaolism
<*<. Outros -atores $ue a-etam o metaolism
<*>. Outras rotas metaolic
<*O. +etaolism do p:rroliGidine / - xidos
<*P. +etaolism no homem
>. +&%A),E+OE 0O TOL,%,TF & 0& OCT(AE A2q&E
?,O@A6,%AE
>*4. +etaolites responsveis para o toxicit:
>*4*4. ?ase metaolic do toxicit:
>*4*5. ,sola."o dos metaolites p:rrolic
>*4*9. Os aspectos $u#micos do chemistr: p:rrolic
da prepara."o >*4*9*5 dos metaolites >*4*9*4 associaram com
as a.Ues txicas >*4*<. +etaolites mais adicionais poss#veis
>*5. A.Ues txicas dos metaolites p:rrolic
>*5*4. Animais
>*5*4*4 esters de P:rrolic 7deh:dro-alcalides8 >*5*4*5 lcoois
de P:rrolic 7deh:dro-necines8 >*5*5. %ulturas de pilha
>*5*9. Participa."o poss#vel do peroxidation >*9
do lipid da memrana. 1atores $u#micos e metaolic $ue
a-etam o toxicit:
>*9*4. %aracter#sticas estruturais de um alcalide txico
>*9*5. Ativa."o e detoxication
>*9*9. 1atores $ue a-etam o toxicit: do reactivit:
ativo dos metaolites >*9*9*4 do metaolite >*9*9*5 o n=mero
dos !rupos reactive >*<. Os metaolites associaram com as a.Ues
iol!icas
dos alcalides >*<*4 do p:rroliGidine. Hepatotoxicit: a!udo
>*<*5. Hepatotoxicit: crVnico
>*<*9. Pneumotoxicit:
>*<*<. Toxicit: em outros tecidos
>*<*>. %arcino!enicit:
>*<*O. Atividade antitumour
>*>. Preven."o e tratamento do p:rroliGidine $ue envenena
>*>*4. 0ietas modi-icadas
>*>*5. Pre-treatment para real.ar o detoxication dos metaolites
ativos >*>*9. Outros tratamentos
O. &1&,TOE )OE A),+A,E
O*4. Testes padrUes da doen.a causados por !enera di-erentes da planta
e
da participa."o do r!"o na espcie di-erente O*5. Oserva.Ues do
campo - outreaIs nos animais de -aGenda
O*9. &studos nos animais de -aGenda
O*<. &studos animais experimentais
O*<*4. &-eitos no hepatotoxicit:
do parente do -#!ado O*<*4*4 de PAs di-erente e de seu / -
xidos O*<*4*5 -atores $ue a-etam o mecanismo a!udo dos e-eitos O*<*4*< do
hepatotoxicit: O*<*4*9 dos e-eitos crVnicos O*<*5 da a."o O*<*4*> txicos.
&-eitos nos pulmUes
O*<*5*4 e-eitos a!udos O*<*5*5 e-eitos crVnicos O*<*5*9
mecanismos da a."o txica O*<*9. &-eitos no sistema nervoso central
O*<*<. &-eitos em outros r!"os
O*<*>. Terato!enicit:
O*<*O. 1etotoxicit:
O*<*P. Os danos
O*<*Q do chromosome do muta!enicit: O*<*P*4. O
carcino!enesis
O*<*Q*4 puri-ied alcalides O*<*Q*5 materiais de planta O*<*Q*9
metaolites do alcalide do p:rroliGidine e o s:nthetic analo!ous comina a
estrutura O*<*Q*< molecular e a atividade carcino!enic O*<*R. Atividade
antimitotic
O*<*4S. ,mmunosuppression
O*<*44. &-eitos no metaolism mineral
O*<*45. +todos para a avalia."o do hepatotoxicit:
e do pneumotoxicit: crVnicos O*>. &-eitos nos animais
selva!ens
O*>*4. %ervos
O*>*5. Peixes
O*>*9. ,nsetos
P. &1&,TOE )O HO+&+
P*4. %aracter#sticas cl#nicas da doen.a veno-veno-occlusive 7TO08
P*5. %aracter#sticas patholo!ical salient da doen.a veno-veno-
occlusive
P*9. (elatrios humanos do caso da doen.a veno-veno-occlusive
P*<. TO0 e cirrhosis do -#!ado
P*>. 0i-eren.as entre TO0 e o cirrhosis indian da in-/ncia
7,%%8 P*O. 0oen.a de pulm"o crVnica
P*P. $ric#odesma $ue envenena
P*Q. (elacionamento entre o n#vel de dose e os e-eitos txicos
P*R. Alcalides do p:rroliGidine como um a!ente chemotherapeutic
para
o cancer P*4S. Preven."o de envenenar no homem
Q. %O)T(O@& ?,O@A6,%O
R. ATA@,A23O 0& (,E%OE & 0& &1&,TOE 0& EAm0& HC+A)A
)O A+?,&)T&
R*4. %ondi.Ues humanas R*4*4
da exposi."o. 1ontes relatadas da exposi."o humana
R*4*5. A espcie da planta envolveu
R*4*9. +odalidades e pathYa:s da contamina."o
da exposi."o R*4*9*4 de colheitas da !r"o R*4*9*5 medicinas
heral R*4*9*9 plantas PA-contendo usadas como o alimento e as eidas
R*4*9*< o outro alimento contaminado por PAs R*4*<. )#veis da entrada
R*5. &-eitos a!udos da exposi."o
R*5*4. 0oen.a de -#!ado a!uda
R*9. &-eitos crVnicos da exposi."o
R*9*4. %irrhosis do -#!ado
R*9*5. +uta!enicit: e terato!enicit:
R*9*9. %ancer do -#!ado
R*9*<. &-eitos em outros r!"os
R*<. &-eitos no amiente
R*<*4. A!ricultura
R*<*5. Animais selva!ens
R*<*9. ,nsetos
R*<*<. (&1&(r)%,AE do solo e
da !ua
APr)0,%& ,. A@%A@A,0&E 0O PF((O@,c,0,)& & ECAE 1O)T&E
0A P@A)TA
APr)0,%& ,,.
)OTA AOE @&,TO(&E 0OE O(,6,)A,E 0OE %(,TM(,OE
%ada es-or.o -oi -eito apresentar t"o exatamente a in-orma."o nos ori!inais
dos critrios como poss#vel sem impropriamente retardado sua pulica."o.
)o interesse de todos os usurios dos ori!inais amientais dos critrios de
sa=de* os leitores s"o pedidos amavelmente comunicar todos os erros $ue
puderem ter ocorrido ao !erente do pro!rama internacional na se!uran.a
$u#mica* or!aniGa."o da sa=de do mundo* 6enera* EYitGerland* a -im de
$ue possam ser inclu#dos nos corri!enda* $ue aparecer"o em volumes
suse$hentes.
e e e
%(,TM(,OE 0& EAm0& A+?,&)TA,E PA(A A@%A@A,0&E 0O
PF((O@,c,0,)&
Cm !rupo de tare-a do NHO em critrios de sa=de amientais para
alcalides do p:rroliGidine encontrou-se com em TashIent* C(EE* em 4 - >
deGemro 4RQO. O 0r. +. 6ounar ariu a reuni"o em nome das trs
or!aniGa.Ues co-patrocinando do ,P%E 7C)&P',@O'NHO8. O !rupo de
tare-a reviu e revisou o ori!inal dos critrios do eso.o e -G uma avalia."o
dos riscos de sa=de da exposi."o aos alcalides do p:rroliGidine.
O acesso aos papis ori!inais no assunto pulicado na C(EE -oi -eito
poss#vel pelo P(O1&EEO( +. A?0C@@AHO0WA&TA. 0(. A.(. Os
+ATTO%bE escreveram os primeiros eso.os das se.Ues em propriedades
e em mtodos anal#ticos* em metaolism* e em mecanismos do toxicit: e de
outras a.Ues iol!icas. 0r. %.%.W. %C@T&)O(* P(O1&EEO( a;udado
H.0. TA)0O) no -inaliGation do ori!inal aps a reuni"o de !rupo da tare-a.
O 0r. W. PariGeI* $ue era ori!inalmente o memro da e$uipe de -uncionrios
de ,P%E responsvel para a prepara."o do ori!inal* e devia ser secretria do
!rupo de tare-a* n"o poderia assistir X reuni"o por causa da doen.a repentina*
e o !rupo de tare-a -oi a;udado em seu lu!ar pelo 0r. +. 6ounar* memro
anterior da e$uipe de -uncionrios de ,P%E. O 0r. A. Prost era responsvel
para a vers"o -inal do ori!inal.
O secretariat reconhece a a;uda do ot
eee T(A)E@AT,O) &)0E H&(& eeeh Pro-essor H.0.
Tandon and 0r %.%.W. %ulvenor. The TasI 6roup meetin! in TashIent
Yas or!aniGed : the %entre o- ,nternational Pro;ects* CEE( Etate
%ommittee -or Ecience and Technolo!:.
The e--orts o- all Yho helped in the preparation and
-inaliGation o- the document are !rate-ull: acInoYled!ed.
e e e
Partial -inancial support -or the pulication o- this criteria
document Yas Iindl: provided : the Cnited Etates 0epartment o-
Health and Human Eervices* throu!h a contract -rom the )ational
,nstitute o- &nvironmental Health Eciences* (esearch Trian!le ParI*
)orth %arolina* CEA - a NHO %ollaoratin! %entre -or &nvironmental
Health &--ects.
e e e
A comprehensive data ase on p:rroliGidine alIaloids has een
made availale : %E,(O 0ivision o- Animal Health* Private ?a!
)o. 4* ParIville* Tic. 9S>5* Australia. The data ase consists o-
alIaloid occurrence tales and Ie:Yorded ilio!raph: readale :
E%,-+AT& so-tYare s:stem 7?ilio!raphic +ana!er* ,nstitute -or
Ecienti-ic ,n-ormation8* ut adaptale to other s:stems. ,t is
availale -rom %E,(O on ,?+ - P% disIettes; price on application to
@.N. Emith.
P(&1A%&
A disease caused : the consumption o- plants containin!
p:rroliGidine alIaloids 7PAs8 has een reco!niGed independentl: as
an endemic disease in certain parts o- the Nest ,ndies and in
CGeIistan in the CEE(. OutreaIs o- the disease have a--ected
si!ni-icant se!ments o- populations or lar!e numers o- people in
!eo!raphicall: con-ined areas in A-!hanistan* ,ndia* and
CGeIistan. The outreaIs have een caused throu!h contamination
o- the staple -ood crops Yith the seeds o- plants containin! PAs*
!roYin! amon! the crops; such plants are liIel: to thrive -olloYin!
periods o- drou!ht.
,t is notale that the same -amil: o- plants that caused
endemic disease and lar!e-scale outreaIs in CGeIistan also caused
another outreaI o- the disease in ad;acent A-!hanistan* lon! a-ter
the chemical etiolo!: o- the disease 7throu!h consumption o- toxic
seeds in the -ood8 had een identi-ied in the CEE(. This happened
ecause there Yas a lacI o- !eneral aYareness o- the causal
relationship etYeen the chemical present in the plant and the
disease. Eporadic cases continue to occur in di--erent parts o-
the Yorld throu!h the consumption o- seeds or plant parts
containin! toxic PAs* as home remedies* evera!es* or -ood.
The ,P%E reco!niGed that this Yas a health prolem that mi!ht
e lethal* and that it Yas entirel: preventale* provided that it
Yas reco!niGed in time. ,t Yas also reco!niGed that the
dissemination o- InoYled!e* aout oth the disease and the sources
o- the chemicals involved* Yould e a critical step in its
prevention.
Accordin!l:* the ,P%E invited Pro-essor H.0. Tandon* Yho Yas
responsile -or estalishin! such a causal relationship in the
outreaIs in A-!hanistan and ,ndia* to prepare a dra-t criteria
document and to assist in its -urther development and -inaliGation
a-ter the TasI 6roup meetin!* Yhich Yas held in TashIent* CEE(* on
4 - > 0ecemer* 4RQO.
,n most episodes o- toxic human disease caused : PAs* the
liver has een the principal tar!et or!an* except -or an outreaI
in the CEE( caused :
$ric#odesma
alIaloids* in Yhich the s:mptoms
Yere mostl: extra-hepatic. The &nvironmental Health %riteria
document provides comprehensive covera!e o- the hepatotoxic PAE*
ut lacI o- relevant documentation prevented the TasI 6roup -rom
anal:sin! the role o-
$ric#odesma
alIaloids in detail.

,)T(O0C%T,O) - PF((O@,c,0,)& A@bA@O,0E A)0 HC+A)
H&A@TH
P:rroliGidine alIaloids 7PAs8 are -ound in plants !roYin! in
most environments and all parts o- the Yorld. The main sources are
the -amilies ?ora!inaceae 7all !enera8* %ompositae 7tries

Senecionae
and
.upatoriae
8* and @e!uminosae 7!enus
"rotalaria
8* and
the potential numer o- alIaloid-containin! species is as hi!h as
OSSS* or 9\ o- the Yorld[s -loYerin! plants 7%ulvenor* 4RQS8. The:
have lon! een InoYn to e a health haGard -or livestocI* at least
since 4RS5 7Echoental* 4RO98* and loss o- livestocI in various
parts o- the Yorld has een traced to their !raGin! on certain
plants !roYin! in pastures* especiall: -olloYin! periods o- drou!ht
or in arid climates. The: have een -ound to e toxic -or all
species o- animals tested 7Echoental* 4RO98* thou!h some species*
notal: the !uinea-pi!* are resistant 7%hesne:
Z
Allen* 4RP9a;
Nhite et al.* 4RP98. Human disease caused : PA toxicit: has een
InoYn to e endemic in the central Asian repulics o- the CEE(* at
least since the earl: thirties 7,smailov* 4R<Qa*; +nushIin* 4R<R8
Yhen several outreaIs occurred* and the cause Yas discovered to e
the seeds o- plants o-
Aeliotropium
species 70urovinsIii* 4R<P*
4R>5; bhanin* 4R<Q8* Yhich contaminated the staple -ood crops. A
spate o- reports -olloYed* mostl: -rom the Nest ,ndies* o- acute
and chronic liver disease 7?ras et al.* 4R><* 4RO4; ?ras
Z
Hill*
4R>O; Etirlin! et al.* 4RO58* associated Yith the in!estion :
people o- heral in-usions -or the treatment o- certain ailments.
Echoental 74RO48 and 0avidson 74RO98 su!!ested that* in vieY o- the
evidence o- the hepatotoxicit: o- PAs* consumption o- plants
containin! them could e o- etiolo!ical si!ni-icance in human liver
disease* especiall: in developin! countries Yhere the: are consumed
as -ood or heral medicines. ,n spite o- this* and the -act that
such an ui$uitous source o- toxic material is capale o- producin!
animal and human disease and that there have een more recent
reports* the PAs have not attracted much attention in the Yorld as
a health haGard. ,n -act* a recent handooI on naturall: occurrin!
toxic a!ents in -ood 7(echici!l* Wr* 4RQ98 re-ers to them onl: in
passin! and maIes no mention o- human disease caused : them.
Teno-occlusive disease 7TO08 7?ras
Z
Hill* 4R>O8* Yhich is
characteriGed : the dominant occlusive lesion o- the centriloular
veins o- the liver loule and is caused : these alIaloids* has
since een reported -rom all parts o- the Yorld* in oth man and
animals 7Hill* 4ROS; ?ras* 4RP98. ,t has een attriuted to the
accidental contamination o- -ood : toxic plant products or the
in!estion o- heral in-usions. There have een reports o- stra:
cases and o- small outreaIs -rom oth developin! and developed
countries. HoYever* in the most recent studies -rom A-!hanistan
7Tandon
Z
Tandon* 4RP>; +ohaat et al.* 4RPO; Tandon* ?.). et al.*
4RPQ; Tandon* H.0. et al.* 4RPQ8 and ,ndia 7Tandon* ?.). et al.*
4RPO; Tandon* (.b. et al.* 4RPO; brishnamachari et al.* 4RPP;
Tandon* H.0. et al.* 4RPP; Tandon* ?.). et al.* 4RPQ8* the disease
has een reported to a--ect lar!e masses o- the population*
resultin! in hi!h mortalit:* and has een attriuted to the
accidental contamination o- their staple -ood crops : PA-
containin! seeds o- plants* -olloYin! periods o- drou!ht.
There is conclusive evidence -rom studies on experimental
animals that the e--ects o- a sin!le exposure to PAs ma: pro!ress
relentlessl: to advanced chronic liver disease and cirrhosis
7Echoental
Z
+a!ee* 4R>P* 4R>R; )olan et al.* 4ROO8* -olloYin! a
lon! interval o- apparent Yell-ein!* and Yithout an: other latent
or provocative -actor 7Echoental
Z
+a!ee* 4R>R8. The loYest levels
o- such alIaloids administered thus -ar to experimental animals*
e.!.* 4 - < m!'I! diet* have produced chronic liver disease and
tumours 7Hooper
Z
Ecanlan* 4RPP; %ulvenor
Z
Wa!o* 4RPR8.
P:rroliGidine alIaloids have also een shoYn to act s:ner!isticall:
Yith a-latoxin* another environmental toxin present in a!ricultural
products* in causin! cirrhosis and hepatoma in primates 7@in et
al.* 4RP<8. Thou!h there is no conclusive evidence :et o- a
carcino!enic role o- PAs in man* such a possiilit: has een
suspected on the asis o- experimental data 7Hill* 4ROS; Nilliams
et al.* 4ROP; ,A(%* 4RPO* 4RQ9; Huxtale* 4RQS; %ulvenor* 4RQ98*
and experimental studies have demonstrated carcino!enicit: in rats
!iven dosa!es e$uivalent to those reported to have een in!ested in
human cases 7%ooI et al.* 4R>S; %ulvenor* 4RQ98.
AlIaloids'toxic metaolites have een shoYn to e secreted in
the milI o- lactatin! dair: cattle 70icIinson et al.* 4RPO8 and
rats* and the :oun! o- oth sexes have een shoYn to su--er toxic
dama!e* even Yhen sucIled : mothers treated Yith retrosine* Yho
apparentl: are not a--ected themselves 7Echoental* 4R>R8. Euch
sucIlin! animals ma: also e in apparent !ood health Yhile the
livers shoY toxic e--ects. Protein-de-icient and :oun! sucIlin!
animals are particularl: vulnerale 7Echoental* 4R>R8.
%hromosomal aerrations have een demonstrated in rats and
humans Yith veno-occlusive disease 7+artin et al.* 4RP58.
AlIaloids have een -ound in the hone: secreted : ees -eedin!
on the toxic plants 70einGer et al.* 4RPP8. Accordin! to %ulvenor
and his co-YorIers* populations in some countries are exposed to
loY levels o- alIaloids in commonl: used -oodstu--s* e.!.* hone: in
Australia 7%ulvenor et al.* 4RQ4; %ulvenor* 4RQ9* 4RQ>8 and com-re:
in man: countries 7%ulvenor et al.* 4RQSa; %ulvenor* 4RQ>8.
Human cases o- acute disease -olloYin! the rie- in!estion o-
the alIaloids have een InoYn to pro!ress to cirrhosis 7Etuart
Z

?ras* 4R>P; ?ra!insIii
Z
?ooIhadGaev* 4RO>; Etillman et al.* 4RPP;
Tandon* ?.). et al.* 4RPP; Tandon* H.0. et al.* 4RPP8 in as short a
period as 9 months -rom the acute phase 7Etuart
Z
?ras* 4R>P8. The
initial disease ma: e cr:ptic 7?ra!insIii
Z
?ooIhadGaev* 4RO>8
and ma: not e ascried to heral consumption* and :et ma: pro!ress
to cirrhosis 7Huxtale* 4RQS8. Teno-occlusive disease Yas stated
to e the most common cause o- cirrhosis in in-ants in Wamaica
7?ras et al.* 4RO48 and has een elieved to e a si!ni-icant
etiolo!ical -actor -or adult cirrhosis* especiall: in developin!
countries 76upta et al.* 4RO98.
Plants InoYn or suspected to contain toxic alIaloids are Yidel:
used -or medicinal purposes as home remedies all over the Yorld*
Yithout s:stematic testin! -or sa-et: 7Echoental* 4RO9; Emith
Z

%ulvenor* 4RQ48 and some are even used as -ood 7Echoental
Z
%oad:*
4ROQ; %ulvenor* 4RQS8. There are several reports o- the continued
use o- such hers -or medicinal purposes in technicall: advanced
countries 7%ulvenor* 4RQS8.
Senecio Xacobaea
continues to e sold
at heralists shops in the Cnited bin!dom 7Echoental* 4RO9; ?urns*
4RP58* and
Symp#ytum
spp. 7com-re:8 are still used as a ve!etales*
evera!es* or remedies 7+attocIs* 4RQS8. ?oth these hers are
InoYn to e carcino!enic 7,A(%* 4RPO; Hirono et al.* 4RPQ8. Foun!
-loYer stalIs o-
Petasites Xaponicus
+axim* the pre-loom -loYer
o- colts-oot*
$ussilago farfara,
the lea- and root o- com-re:*

Symp#ytum officinale,
and the :oun! leaves and stalIs o-
arfugium
Xaponicum
and
Senecio cannabifolius,
Yhich are all used in Wapan
as human -ood or heral remedies* are InoYn to e carcino!enic -or
rats 7Hirono et al.* 4RQ98.
Symp#ytum % uplandicum
):man 7(ussian
com-re:8* Yhich contains several toxic PAs 7%ulvenor et al.* 4RQS8
echimidine and P acet:l:copsamine ein! the main constituents* is
used as a salad plant* !reen drinI* and medicinal her. ,t has
een estimated that the rate o- in!estion o- alIaloids -rom this
her ma:* over a period o- time* exceed the levels reported to have
een taIen durin! the A-!han outreaI. There is a report o- at
least one patient Yho developed toxic e--ects as a result o-
consumin! a com-re: preparation 7%ulvenor et al.* 4RQSa; (idIer et
al.* 4RQ>8. Arseculeratne et al. 74RQ48 -ound that 9 o- the >S
medicinal hers commonl: used in Eri @anIa contained PAs that had
een proved to e hepatotoxic -or animals. The: su!!ested that
consumption o- such hers mi!ht contriute to the hi!h incidence o-
chronic liver disease* includin! primar: liver cancer* in Asian and
A-rican countries* especiall: as the: ma: act s:ner!isticall: Yith
a-latoxin and hepatitis ? virus. The risI o- toxic e--ects due to
these alIaloids ma: e particularl: hi!h in children 7Echoental*
4R>R; Wa!o* 4RPS8 and protein malnutrition* Yhich exists in some
countries* ma: potentiate them 7Echoental
Z
+a!ee* 4R>P8. (ecent
studies -rom Hon! bon! 7bumana et al.* 4RQ>; %ulvenor et al.*
4RQO8* the Cnited bin!dom 7+c6ee et. al* 4RPO; (idIer et al.*
4RQ>8* and the CEA 7Etillman et al.* 4RPP; 1ox et al.* 4RPQ; (idIer
et al.* 4RQ>8 report instances o- human disease that have een
caused : the use o- such hers* resultin! in -atalit: or the
development o- cirrhosis* even in countries Yith Yell-developed
health services and amon! the hi!her economic and educated strata
o- societ:. ,ndeed* Etillman et al. 74RPP8* -rom the CEA* called PA
toxicosis the ]iceer! disease]* impl:in! that cases o- this
disease mi!ht e more -re$uent than reported in the CEA* especiall:
amon! populations o- +exican-American ori!in. ,n !eneral* the use
o- heral remedies is not elicited in the clinical histor: and
patients do not volunteer this in-ormation themselves.
1urthermore* the alIaloids are eliminated Yithin 5< h 7Huxtale*
4RQS8 and* even thou!h methods are availale -or their detection in
iolo!ical tissues and -luids* the suspicion cannot e con-irmed*
as the s:mptoms ma: taIe several da:s or months to appear.
%ontamination o- -ood crops is particularl: liIel: to occur in
parts o- the Yorld Yith arid climates* poor or uncertain rain-all*
poor irri!ation -acilities* and -olloYin! periods o- drou!ht* all
o- Yhich promote the !roYth o- the PA-containin! plants that !roY
as Yeeds amon! cultivated crops* as has een -ound in studies on
the outreaIs in A-!hanistan* ,ndia* and the CEE( 7TereIhov* 4R9R;
0urovinsIii* 4R<P; ,smailov* 4R<Qa*; Tandon
Z
Tandon* 4RP>;
+ohaat et al.* 4RPO; Tandon* ?.). et al.* 4RPO; Tandon* (.b. et
al.* 4RPO; Tandon* H.0. et al.* 4RPQ8 and in !raGin! pastures. The
use o- traditional medicines is common in these countries and there
is insu--icient aYareness o- this haGard* the disease condition*
and its dia!nostic patholo!ical picture. 1urthermore* health
services are poorl: developed. Thus* man: o- the cases or even
outreaIs ma: !o unnoticed or unrecorded and ma: even e ascried
to malnutrition 7@ancet* 4RQ<8. Also* man: o- the reported cases
o- so-called ]?udd-%hiari s:ndrome]* a condition associated Yith
ostruction o- ma;or hepatic veins and'or in-erior vena cava* ma:
actuall: e cases o- veno-occlusive disease 7EherlocI* 4ROQ8* in
Yhich onl: the central veins o- the liver loule or suloular
veins are occluded.
Another t:pe o- PAs*
$ric#odesma
alIaloids* has een InoYn to
cause a human outreaI o- disease in the CEE(* throu!h
contamination o- the staple cereal Yith the seeds containin! these
PAs; in this outreaI* the s:mptoms Yere principall: extra-hepatic
7,smailov et al.* 4RPS8.
This document is aimed at -ocusin! on a health menace that is
insu--icientl: reco!niGed* in order to evaluate the health risIs on
the asis o- pulished data* and to dra-t a set o- recommendations
that Yould help in its reco!nition* prevention* and control.

4. EC++A(F A)0 (&%O++&)0AT,O)E
4.4. Eummar:
The in!estion o- p:rroliGidine alIaloids 7PAs8 in -oods and
medicinal hers results in acute and chronic e--ects in man*
a--ectin! mainl: the liver. 0ata -rom experimental animal studies
indicate that PAs represent a potential cause o- cancer in man.
The alIaloids are produced : numerous plant species and occur
throu!hout the Yorld. ,n the present document* the alIaloids and
their properties are descried to!ether Yith the sources o- human
exposure and the diseases that the: produce in man and animals.
The risIs -or human health are evaluated and recommendations are
made -or reducin! such risIs.

4.5. Eources and %hemical Etructure
The InoYn p:rroliGidine alIaloids* most o- Yhich are
hepatotoxic* are produced : plant species Yithin the -olloYin!
-amilies: ?ora!inaceae 7
Aeliotropium, $ric#odesma, Symp#ytum,
and
most other !enera8* %ompositae 7
Senecio, .upatorium,
and other
!enera o- the tries
Senecioneae
and
.upatoriaeH, ,eguminosae
7!enus
"rotalaria
8* and Ecrophul-ariaceae 7!enus
"astilleXa
8.
These !enera are mainl: heraceous and ver: Yidel: distriuted*
some species ein! -ound in most re!ions o- the Yorld. The
ma;orit: o- the species Yithin these !enera have not :et een
investi!ated* ut are expected to contain p:rroliGidine alIaloids.
The hepatotoxic alIaloids have a 4*5-doule ond in the
p:rroliGidine rin! and ranched chain acids* esteri-:in! a
R-h:drox:l and pre-eral: also the P-h:drox:l sustituent. +odi-ied
seco-p:rroliGidine alIaloids* in Yhich the central ond etYeen the
) and %Q atoms is roIen* are also hepatotoxic. Eome
Senecio

species contain non-asic derivatives that are >-oxop:rroles. The
toxicit: o- these derivatives ma: e similar to that o- the
alIaloids* ut this aspect has not een investi!ated. The
alIaloids occur as -ree ases and
/
-oxides. The latter are
reduced to the -ree ases in the !astrointestinal tract o- animals
and have a similar toxicit: Yhen in!ested orall:.
Euitale anal:tical procedures are availale -or screenin!
plant species* includin! a simple -ield test -or toxic alIaloids.
Thin-la:er chromato!raph: 7T@%8* hi!h-per-ormance li$uid 7HP@%8*
!as chromato!raph: 76%8* and !as chromato-!raph:-mass spectrometr:
76%-+E8 have een applied -or separatin!* characteriGin!* and
$uanti-:in! the alIaloids present. &--ective use o- these
procedures re$uires authentic alIaloids -or standards* -eY o- Yhich
are availale. ,mproved anal:tical methods are re$uired -or the
determination o- ver: loY levels o- alIaloids in some -oodstu--s.

4.9. +echanisms and 1eatures o- Toxicit:
The toxic e--ects o- p:rroliGidine alIaloids are due to
activation in the liver. +etaolism o- the alIaloids : mixed-
-unction oxidases leads to p:rrolic deh:dro-alIaloids* Yhich are
reactive alI:latin! a!ents. (eaction o- initial metaolites Yith
constituents o- the liver cell in Yhich the: are -ormed are
proal: the main cause o- liver cell necrosis. +etaolites are
released into the circulation and are elieved to pass e:ond the
liver to the lun! causin! vascular lesions characteristic o-
primar: pulmonar: h:pertension* especiall: Yhen alIaloids* such as
monocrotaline* are administered to animals.
,n experimental animals* PAs are $uicIl: metaoliGed and are
almost completel: excreted in 5< h* so that no residual products
are detectale in the iolo!ical -luids or od: tissues a-ter this
period.
The rate o- -ormation o- p:rrolic metaolites is in-luenced :
the induction or inhiition o- the mixed--unction oxidases in the
liver* ut the relationship etYeen the rate o- metaolism and
expression o- toxicit: is uncertain.
Eeveral p:rroliGidine alIaloid-derivatives and related
compounds are InoYn to cause chromosome aerrations in plants*
leuIoc:te cell cultures o- the marsupial
FPotorus tridactylusH,

and in hamster cell lines. Eome p:rroliGidine alIaloids induce
micronuclei -ormation in er:throc:tes in the one marroY and -etal
liver in mice* sister chromatid exchan!es in a %hinese hamster cell
line and human l:mphoc:tes
in vitro,
and repair 0)A s:nthesis in
rodent hepatoc:te cell cultures. %hromosome aerrations have een
reported in the lood cells o- children su--erin! -rom veno-
occlusive disease TO0* presumal: caused : -ulvine.
A numer o- p:rroliGidine alIaloids have een shoYn to e
muta!enic in the
Salmonella typ#imurium
assa:* a-ter metaolic
activation. The carcino!enic activit: o- p:rroliGidine alIaloids
appears to parallel their muta!enic ehaviour* ut not their
hepatotoxicit:.
Heliotrine at doses o- >S m!'I! od: Yei!ht or more*
administered to rats durin! the second YeeI o- !estation* has een
shoYn to induce several anormalities in the -etus. 0oses o-
5SS m!'I! od: Yei!ht resulted in intrauterine deaths or resorption
o- -etuses. 0eh:droheliotridine* the metaolic p:rrole derivative o-
heliotrine* Yas 5.> times more e--ective on a molar asis than its
parent PA in inducin! terato!enic e--ects.
The ailit: o- PAs to cross the placental arrier in the rat
and to induce premature deliver: or death o- litters has een
demonstrated. The emr:o
in utero
appears to e more resistant to
the toxic e--ects o- p:rroliGidine alIaloids than the neonate. PAs
are InoYn to have passed throu!h the mother[s milI to the
sucIlin!s.
+e!aloc:tosis* the presence o- enlar!ed hepatoc:tes containin!
lar!e* h:per-chromatic nuclei* is a characteristic -eature o-
p:rroliGidine alIaloid-induced chronic hepatotoxicit: in
experimental animals. The enlar!ed hepatoc:tes arise throu!h the
poYer-ul antimitotic action o- the p:rrole metaolites o-
p:rroliGidine alIaloids. This chan!e has not een oserved in the
human liver* thou!h human -etal liver cells
in vitro
culture
ecome enlar!ed Yhen exposed to PAs* indicatin! susceptiilit: to
the antimitotic e--ect o- the alIaloids.
,n experimental animals* protein-rich and sucrose-onl: diets
have !iven some measure o- protection a!ainst the e--ects o- the
alIaloids* as has pre-treatment o- animals Yith thiols* anti-
oxidants* or Ginc chloride.
PAs are noted mainl: -or the poisonin! o- livestocI due to the
animals !raGin! on PA-containin! toxic Yeeds* and lar!e-scale
outreaIs have een recorded. Euch episodes have een reported
-rom most parts o- the Yorld* includin! those Yith temperate or
cold climates. Etudies carried out on a Yide variet: o- -arm and
laorator: animals have revealed !enerall: common -eatures o-
toxicit: Yith some species variations. The liver is the principal
tar!et or!an. ,n small laorator: animals* doses approachin! a
lethal dose produce a con-luent* strictl: Gonal haemorrha!ic
necrosis in the liver loule* Yithin 45 - <Q h o- administration o-
PAs. Eimultaneousl: in non-human primates* or a-ter a short time in
the rat* chicIen* and sYine* chan!es e!in to occur* and later
ecome or!aniGed* in the suintima o- the central or suloular
veins in the liver resultin! in their occlusion. The reticulin
-rameYorI in the central Gone o- the loule collapses -olloYin!
necrosis leadin! to scarrin!. (epeated administration o- suitale
doses leads to chronic liver lesion characteriGed : me!aloc:tosis*
and increasin! -irosis* Yhich ma: result in cirrhosis. %hronic
liver disease includin! cirrhosis has een shoYn to develop in the
rat -olloYin! administration o- a sin!le dose o- a PA. ,n a numer
o- animal species* the lun!s develop vascular lesions
characteristic o- primar: pulmonar: h:pertension Yith secondar:
h:pertroph: o- the ri!ht ventricle o- the heart. ,n rats*
appropriatel: loY repeated doses o- several alIaloids have een
shoYn to induce tumours* mainl: in the liver. ,n some studies* a
sin!le dose has een carcino!enic.
The central nervous s:stem is the tar!et or!an o- the toxic PAs
contained in Trichodesma* Yhich produce spon!: de!eneration o- the
rain.

4.<. &--ects on +an
,n man* PA poisonin! is usuall: mani-ested as acute veno-
occlusive disease characteriGed : a dull dra!!in! ache in the
ri!ht upper adomen* rapidl: -illin! ascites resultin! in marIed
distension o- the adomen* and sometimes associated Yith oli!uria*
and massive pleural e--usion. ,t can also mani-est as suacute
disease Yith va!ue s:mptoms and persistent hepatome!al:. %hildren
are particularl: vulnerale. +an: cases pro!ress to cirrhosis and*
in some cases* a sin!le episode o- acute disease has een
demonstrated to pro!ress to cirrhosis* in spite o- the -act that
the patient has een removed -rom the source o- toxic exposure and
has een !iven s:mptomatic treatment. +ortalit: can e hi!h Yith
death due to hepatic -ailure in the acute phase or due to
hematemesis resultin! -rom ruptured oesopha!eal varices caused :
cirrhosis. @ess severel: a--ected cases ma: shoY clinical* or even
apparentl: complete* recover:. The TasI 6roup Yas not aYare o- an:
sustantiated report o- primar: pulmonar: h:pertension resultin!
-rom PA toxicit:. HoYever* in vieY o- the evidence in experimental
animals and circumstantial evidence in one case report* the
possiilit: o- the development o- toxic pulmonar: disease in man
cannot e ruled out. There is a report o- an outreaI o-

$ric#odesma
poisonin! in the CEE( in Yhich the s:mptoms Yere mainl:
neurolo!ical.

4.<.4. )ature and extent o- health risIs
The tYo main sources o- p:rroliGidine alIaloid poisonin!
reported in human ein!s are the consumption o- cereal !rain
contaminated : Yeeds containin! the alIaloids and the use o-
alIaloid-containin! hers -or medicinal and dietar: purposes. A
third -orm o- exposure* Yith the potential to a--ect lar!e
populations is the possile loY-level contamination o- some
-oodstu--s* such as hone: and milI* ut the TasI 6roup Yas not
aYare o- an: cases o- human toxicit: havin! een caused throu!h the
contamination o- these -oods.
@iver disease caused : the contamination o- cereal !rains has
een reported in rural populations in A-!hanistan* ,ndia* Eouth
A-rica* and the CEE(. A contriutin! -actor appears to e
anormall: dr: Yeather* resultin! in the !roYth o- an exceptionall:
hi!h proportion o- the alIaloid-containin! Yeeds in the crops* the
seeds o- Yhich contaminate the cereal !rain on harvestin!. The
Yeeds responsile -or InoYn outreaIs have een
Aeliotropium,
$ric#odesma, Senecio,
and
"rotalaria
species. +ortalit: in such
outreaIs has een reported to e hi!h. ,n the lar!est reported
outreaI in northYestern A-!hanistan* an estimated QSSS people Yere
a--ected in a total population o- 9> SSS Yith 4OSS - 5SSS deaths.
Human poisonin! throu!h the medicinal use o- hers containin!
p:rroliGidine alIaloids has een reported -rom all parts o- the
Yorld. PAs Yere responsile -or a common liver disease in children
in Wamaica* and individual cases in &cuador* Hon! bon!* ,ndia* the
Cnited bin!dom* and the CEA. The plants involved Yere species o-
%rotalaria* Heliotropium*
Senecio, Symp#ytum,
and
Gynura.
Symp#ytum
-containin! preparations present a particular haGard
ecause o- their Yidespread use and the !enerall: hi!h levels o-
individual exposures. The use o- hers is almost universal in
traditional -olI medicine and is increasin! in developed countries.
Eome o- the hers used contain p:rroliGidine alIaloids and have a
lon!-term toxicit: that is unsuspected : the people taIin! them.
bnoYled!e o- the species used in heral medicine and the -re$uenc:
o- such use is ver: limited in the scienti-ic literature. Aout <S
such species are listed in this report* aout one-third o- Yhich
are in use in developed countries. The: are o-ten prescried :
heralists* naturopaths* and other non-orthodox practitioners. The
extent o- the contriution to acute and chronic liver disease
cannot e accuratel: assessed. ,t ma: also constitute an
etiolo!ical -actor in cirrhosis o- the liver and* once this sta!e
is reached* it ma: not e possile to identi-: the cause as a PA.
PAs are InoYn to e transmitted -rom the -eed o- dair: animals
into milI and to cause toxic dama!e in the sucIlin! :oun!. One
instance o- lar!e-scale contamination o- hone: is InoYn to have
een caused : a common Yeed rich in PAs* Yhich Yas the source o-
nectar and pollen -or the hone:-secretin! ees. )o reports o-
cases o- acute toxicit: caused : consumption o- contaminated dair:
products or hone: Yere availale to the TasI 6roup. 1urthermore*
no in-ormation is availale on the possile presence o- PAs or
their metaolites in the meat o- animals -ed toxic Yeeds e-ore
slau!hter; hoYever* the possiilit: o- toxic disease ein! caused
throu!h this medium is considered to e loY.
There are no sustantial* lon!-term -olloY-up data to assess
Yhether exposure to PAs results in increased incidence o- chronic
liver disease or cancer in man. Availale clinical and
experimental data su!!est that a sin!le episode o- PA toxicit: and
possil: also a lon!-term loY level exposure ma: lead to cirrhosis
o- the liver. PAs could also e possile carcino!ens in man* since
a numer o- them have een demonstrated to induce cancer in
experimental animals* the main tar!et or!an ein! the liver. These
include some Yhich have caused episodes o- human toxicit:* and some
others Yhich are -ound in hers traditionall: used as items o-
-ood. Also* in several instances o- human toxicit:* the reported
dail: rates o- intaIe o- such PAs Yere in close ran!e o- those
InoYn to induce tumours in rats. HoYever* these risIs cannot e
ade$uatel: assessed on a $uantitative asis. There are indications
that PA intoxications leadin! to liver disease are more prevalent
than the reported -re$uenc: o- cases Yould seem to indicate.
?ecause o- their InoYn involvement in human poisonin! and their
possile carcino!enicit:* exposure to p:rroliGidine alIaloids
should e Iept as loY as practicall: achievale. The settin! o-
re!ulator: tolerance levels -or certain -ood products ma: e
re$uired in some situations.

4.>. +ethods -or Prevention
The onl: InoYn method o- prevention is to avoid consumption o-
the alIaloids. ,n the CEE(* a set o- a!ricultural 7or
a!rotechnical8 le!islative* ph:to-sanitar: and educational measures
has prevented neY outreaIs o- poisonin! due to
Aeliotropium
and

$ric#odesma,
since 4R<P.

4.O. (ecommendations
4.O.4. 6eneral recommendations
4. %ereal crops should e assessed throu!hout the Yorld -or
possile contamination : Yeeds liIel: to contain p:rroliGidine
alIaloids. Appropriate !rain inspection s:stems are desirale
in order to achieve near-Gero levels o- contamination : such
Yeeds.
5. There is a need to create aYareness* amon! the !eneral
population and those responsile -or the deliver: o- health
services* Yith re!ard to the haGards o- consumin! such plants
as contaminants in -ood or as -ood* or -or medicinal purposes.
Advice on haGards should include mention o- possile increased
risIs* i- the alIaloid intaIe is associated Yith dru!
treatment* 7e.!. phenoaritone8 or -oods Yhich increase the
level o- liver metaoliGin! enG:mes.
9. &thnootanical and taxonomic studies are re$uired in man:
countries to provide speci-ic in-ormation on the use o- plant
species containin! p:rroliGidine alIaloids -or medicinal and
dietar: purposes. There ma: e a need to control the sale o-
some species* and their prescription : heralists and other
practitioners o- traditional s:stems o- medicine.
<. Hone: and dair: products* oth local and ulI supplies* should
e assa:ed -or p:rroliGidine alIaloids in all re!ions Yhere a
risI o- contamination o- these -oodstu--s has een identi-ied.

4.O.5 (ecommendations -or research
4. @on!-term -olloY-up studies o- the survivors o- oth alIaloid
poisonin! in human ein!s and animal outreaIs are re$uired* in
order to determine the possile development o- chronic liver
disease or cancer. Eimilar studies are also desirale on
individuals Yho re!ularl: consume com-re: or other PA-
containin! hers over a sustantial period o- time.
5. &pidemiolo!ical studies should e carried out in countries Yith
a hi!h incidence o- primar: liver cancer* in order to determine
Yhether there is an association Yith the intaIe o- hers
containin! p:rroliGidine alIaloids.
9. A netYorI o- re-erence laoratories is needed to assist memer
states in identi-:in! plants and their seeds suspected o-
producin! toxic e--ects and -or the assa: and identi-ication o-
PAs. Provisions ma: e made -or the eas: availailit: o- pure
alIaloids -or use as re-erence standards -or assa:s.
<. ,t is necessar: to develop improved assa: procedures* suitale
-or the purposes o- recommendation 7<8 in section 4.O.4*
particularl: usin! -luorescence and immunochemical methods.
>. There is a need -or -urther toxicolo!ical studies* such as
studies on the carcino!enicit: o- echimidine and the toxicit:
o- the >-oxop:rrole constituents o-
Senecio
species* and -or
studies that Yould provide more $uantitative in-ormation on the
various adverse iolo!ical e--ects o- PAs. A stud: o- the
carcino!enicit: o- the alIaloids in the pi! is also indicated*
since the pi! exhiits a hi!h sensitivit: to acute and suacute
toxicit: similar to that seen in man.
O. Etud: is re$uired o- the possile alIaloid content o- the meat*
or!ans* and -at o- animals that have recentl: consumed plants
containin! p:rroliGidine alIaloids.
P. &xperimental studies are needed on the in-luence o- nutritional
status on the metaolism* and acute and chronic e--ects o- PAs.
Q. 1urther metaolic studies are re$uired to de-ine more
speci-icall: the enG:mes involved in the microsomal activation
and detoxi-ication o- PAs* to determine Yhether or!anelles
other than microsomes are involved* and to explore -urther*
$uantitative relationships etYeen di--erent routes o-
metaolism.
R. The maximum no-oserved-adverse-e--ect dose levels -or repeated
lon!-term administration in the rat and the pi! need to e
determined.
4S. &xperimental studies should e conducted to determine:
7a8 Yhether p:rroliGidine alIaloid
/
-oxides ma: e
metaoliGed directl: into the p:rrolic deh:droalIaloid
in mitochondria* especiall: in tumour cells; and
78 Yhich P<>S enG:mes are involved in the activation and

/
-oxidation o- PAs and thence in the selective
induction o-
/
-oxidation enG:mes.
44. A stud: mi!ht e conducted o- human variailit: and its !enetic
aspects in relation to -actors that in-luence susceptiilit: to
PAs; -or example* the stud: o- mixed--unction oxidase levels
in the liver : metaolism o- appropriate test sustances
reco!niGed as harmless.

5. P(OP&(T,&E A)0 A)A@FT,%A@ +&THO0E
5.4 %hemical Etructure and Properties
The chemical structure o- PAs in relation to their toxic
e--ects has een revieYed recentl: : +attocIs 74RQO8. The
p:rroliGidine alIaloids Yith Yhich this document is concerned are
those that have previousl: een called ]hepatotoxic] or
]nucleotoxic]. Here it is proposed to re-er to them as ]toxic]
PAs* ecause o- the Yei!ht o- evidence noY availale that the:
produce dama!e in other or!ans as Yell as the liver* and the need
to avoid a restrictive term. There are other t:pes o-
p:rroliGidine alIaloids* such as those that occur in the plant
-amil: Orchidaceae* Yhich are not toxic and are not discussed here.
The toxic PAs are esters o- the amino-alcohols derived -rom the
heteroc:clic nucleus. The p:rroliGidine molecule is made up o- tYo
>-memered rin!s inclined to each other as shoYn in 1i!. 4 so that
!eometric isomerism is possile* and Yhich share a common nitro!en
at position <.

+ost hepatotoxic alIaloids are esters o- molecules similar to
that shoYn in 1i!. 478 74-h:drox:meth:l-4:5-deh:dro-
p:rroliGidine8. HoYever* a -eY hepatotoxic alIaloids are esters o-
the amino-alcohol otonecine* e.!.* petasitenine 71i!. 5* )o.P8.
The unsaturated p:rroliGidine nucleus itsel- is not toxic* ut
esters o- ranched-chain acids are. &ster linIa!es ma: e at
positions R* P* or 7rarel:8 O. Eome esters have an ]open]
molecule* e.!.* heliotrine* Yhereas others are macroc:clic
diesters* e.!.* monocrotaline and retrosine. &xamples o- some
p:rroliGidine alIaloid structures are shoYn in 1i!. 5.
The rin! nucleus contains a doule ond at the 4:5 position*
Yhich is essential -or the toxic e--ects o- the alIaloid* ut not
-or unrelated e--ects.
4.
.c#imidine
%hemical structure:

%hemical -ormula: %5
SH
94
)O
P
(elative molecular mass: 9RP
%AE re!istr: numer: >5S-OQ-9
5.
Aeliotrine
%hemical structure:

%hemical -ormula: %
4O
H
5P
)O
>
(elative molecular mass: 949
%AE re!istr: numer: 9S9-99-9
9.
Pndicine)
)
)o%ide
%hemical structure:

%hemical -ormula: %
4>
H
5>
)O
O
(elative molecular mass: 94>
%AE re!istr: numer: <4PSQ-PO-9
<.
Iacobine
%hemical structure:

%hemical -ormula: %
4Q
H
5>
)O
O
(elative molecular mass: 9>4
%AE re!istr: numer: OQPS-OP-9
>.
,asiocarpine

%hemical structure:
%hemical -ormula: %
54
H
99
)O
P
(elative molecular mass: <44
%AE re!istr: numer: 9S9-9<-<
O.
Nonocrotaline

%hemical structure:
%hemical -ormula: %
4O
H
59
)O
O
(elative molecular mass: 95>
%AE re!istr: numer: 94>-55-S
P.
Petasitenine

%hemical structure:
%hemical -ormula: %
4R
H
5P
)O
P
(elative molecular mass: 9Q4
%AE re!istr: numer: OS495-4R-O
Q.
Retrorsine
7retrosine
/
-oxide ^ isatidine8

%hemical structure:
%hemical -ormula: %
4Q
H
5>
)O
O
(elative molecular mass: 9>4
%AE re!istr: numer: <QS-><-O
R.
Senecionine

%hemical structure:
%hemical -ormula: %
4Q
H
5>
)O
>
(elative molecular mass: 99>
%AE re!istr: numer: 49S-S4-Q
4S.
Symp#ytine

%hemical structure:
hemical -ormula: %
5S
H
94
)O
O
(elative molecular mass: 9Q4
%AE re!istr: numer: 55>P4-R>->
44.
$ric#odesmine

%hemical structure:
%hemical -ormula: %
4Q
H
5P
)O
O
(elative molecular mass: 9>9
%AE re!istr: numer: ><Q-RS-9
45.
Pncanine

%hemical structure:
%hemical -ormula: %
4Q
H
5P
)O
>
(elative molecular mass: 99P
%AE re!istr: numer: <QS-PP-9
As the TasI 6roup met in TashIent* it is o- historical interest
to recall that the structures o- heliotrine and lasiocarpine* the
main alIaloids o-
Aeliotropium lasiocarpum,
Yere YorIed out :
0r 6.P. +en[shiIov and associates in +oscoY in the 4R9Ss. This
YorI included determinin! the structure o- heliotridine* the parent
compound o- the amino-alcohol* heliotridane. 0r +en[shiIov[s
studies Yere carried out at essentiall: the same time* ut
independentl: o- studies : &n!lish and American authors on
retronecine-ased alIaloids.
The alIaloids in plants are o-ten -ound to!ether Yith their

/
-oxides* Yhich are also toxic* Yhen in!ested orall:. The
p:rroliGidine alIaloids ac$uire their toxic properties onl: throu!h
the toxic p:rrolic intermediates 7the !eneral structure o- Yhich is
shoYn in 1i!. 98 -ormed : the mixed--unction oxidases o- the
hepatoc:tes. To -orm these p:rrolic derivatives* the alIaloid
molecule should have:
7a8 a doule ond at the 4:5 position o- the rin! nucleus;
78 esteri-ied h:drox:l !roups in the nucleus at the % R
and'or % P positions; and
7c8 a ranched caron chain in at least one o- the ester side-
chains 7+c@ean* 4RP<8.

Eustitution at the a position o- the acid and esteri-ication o-
the %-P h:drox: !roup oth enhance the toxicit: o- the alIaloid
7(oins* 4RQ58.
A !roup o- related alIaloids* isolated -rom
Senecio
species :
?ohlmann et al. 74RPR8* have non-asic p:rrolic structures similar
to those o- toxic p:rroliGidine alIaloid metaolites* ut the: are
chemicall: deactivated : the presence o- a caron:l !roup at
position 9 o- the p:rroliGidine nucleus* e.!.* senaetnine 71i!. <8.
Eenaetnine does not possess the acute hepatotoxic characteristics
o- asic p:rroliGidine alIaloids. HoYever* it had a direct
irritant action on tissues near the site o- intraperitoneal
administration and caused dama!e to pulmonar: vascular tissue Yhen
!iven intraveinous to rats 7+attocIs
Z
0river* 4RQP8.

The alIaloids are -airl: stale chemicall:* ut the ester
!roups ma: under!o h:drol:sis under alIaline conditions. Eome
alIaloids in plant material ma: decompose durin! dr:in! 7?ull et
al.* 4ROQ8* ut others appear to e stale under similar conditions
7Pedersen* 4RP>; ?irecIa et al.* 4RQS8. The
/
-oxides o-
unsaturated p:rroliGidines are more readil: decomposed : heat than
the asic alIaloids* especiall: Yhen dr:. HoYever* the stailit:
o- the alIaloids and
/
-oxides in hot Yater as* -or example* in
cooIin!* is not InoYn.
Eome p:rroliGidine alIaloids have a limited Yater soluilit:*
unless neutraliGed Yith acid; ut others 7e.!.* indicine8* and all
the
/
-oxides* are readil: solule.

5.5 Anal:tical +ethods
Nhen anal:sin! -or PAs* it is important to reco!niGe that this
!roup consists o- man: di--erent compounds 7section 5.48 and that
these o-ten occur as mixtures in plants or in materials o- plant
ori!in. The: ma: var: in structure* relative molecular mass*
response to anal:tical procedures* and toxicit:. ?oth asic
alIaloids and correspondin!
/
-oxides ma: e present at the same
time. Thus* Yhere such mixtures are present* anal:ses Yill
inevital: e approximate* unless the individual components are
separated and identi-ied.
)evertheless* such estimates can e use-ul. ,n particular* all
hepatotoxic PAs are unsaturated in the sense that the: possess a
4:5-doule ond in the p:rroliGidine nucleus* and anal:tical
methods that are speci-ic -or this structure can e o- value in
screenin! -or potential toxicit:. A simple $ualitative -ield test
-or screenin! plant materials -or the presence o- such alIaloids
and their
/
-oxides* Yithout the need o- hi!h technolo!: e$uipment*
is descried in section 5.5.5.>.

5.5.4 &xtraction
5.5.4.4 Plant tissue
P:rroliGidine alIaloids are usuall: extracted -rom dried*
milled plant material Yith hot or cold alcohol. The alcohol is
evaporated* the ases taIen up in dilute acid* and -ats extracted
Yith ether or petroleum. ,t is usual* at this sta!e* to reduce an:

/
-oxides present to the correspondin! asic alIaloids Yith Ginc*
e-ore maIin! the solution alIaline and extractin! the alIaloids
Yith chloro-orm 7boeIemoer
Z
Narren* 4R>48. Alternativel:* alcohol
can e continuousl: circulated throu!h the plant material and then
cation exchan!e resin* and the alIaloids suse$uentl: eluted -rom
the resin 7+attocIs* 4RO4; 0ea!en
Z
0einGer* 4RPP8. PAs can also
e extracted : soaIin! plant material in dilute a$ueous acid
7?ri!!s et al.* 4RO>; %rai! et al.* 4RQ<8.
5.5.4.5 ?iolo!ical -luids and tissues
P:rroliGidine alIaloids have een extracted -or anal:tical
purposes -rom hone: 70einGer et al.* 4RPP8* milI 70icIinson et al.*
4RPO8* lood-plasma 7Ames
Z
PoYis* 4RPQ; +c%omish et al.* 4RQS8*
urine 7+attocIs* 4ROPa; Wa!o et al.* 4ROR; &vans et al.* 4RPR8* and
ile 7Wa!o et al.* 4ROR; @a-ranconi et al.* 4RQ>8.
Nhen attemptin! to isolate PAs -rom animal tissues* it must e
appreciated that the toxic alIaloids are o-ten metaoliGed ver:
rapidl: in animals* so that the amounts that are recoverale
7except -rom urine8* onl: a -eY hours a-ter alIaloid in!estion* ma:
e extremel: small. Tarious methods have een used to separate
PAs* ut some mixtures are extremel: di--icult to separate. On the
anal:tical scale* the most use-ul methods are thin-la:er
chromato!raph: 7T@%8* hi!h-per-ormance li$uid chromato!raph:
7HP@%8* and !as chromato!raph: 76%8 7section 5.5.58.

5.5.5 Anal:sis -or p:rroliGidine alIaloids
5.5.5.4 Thin-la:er chromato!raph: 7T@%8
1or T@%* silica plates are usuall: used* eluted Yith chloro-orm:
methanol:a$ueous ammonia mixtures 7Eharma et al.* 4RO>; %halmers
et al.* 4RO>8; solvents suitale -or the
/
-oxides* Yhich
are more Yater-solule* have een descried : +attocIs 74ROP8
and Na!ner et al. 74RQ48. The most sensitive methods -or
detectin! PAs on T@% are those usin! &hrlich rea!ent
7<-dimeth:laminoenGaldeh:de8 7+attocIs* 4ROP8. The unsaturated
alIaloids are est visualiGed : spra:in! the plates -irst Yith a
solution o- orthochloranil* then Yith &hrlich rea!ent* heatin!
a-ter each spra: 7+ol:neux
Z
(oitman* 4RQS8. The
/
-oxides o-
unsaturated p:rroliGidines are detected : spra:in! a solution o-
acetic anh:dride* heatin! the plate* and then spra:in! &hrlich
rea!ent 7+attocIs* 4ROP8.
P:rroliGidine alIaloids Yith a saturated ase moiet: must e
detected in other Ya:s 7Yhich are not speci-ic -or p:rroliGidines8*
e.!.* : exposin! the dried plates to iodine vapour* or : spra:in!
Yith an iodoismuth 70ra!endor--8 rea!ent 7+unier* 4R>98.
5.5.5.5 Hi!h-per-ormance li$uid chromato!raph: 7HP@%8
Anal:tical or preparative scale HP@% separation o-
p:rroliGidine alIaloids has een descried : Ee!all 74RPRa*8 and
0imenna et al. 74RQS8* and an improved method has een reported :
(amsdell
Z
?uhler 74RQ48. AlIaloids -rom
Symp#ytum officinale

7com-re:8 have een separated on an anal:tical scale : Tittel et
al. 74RPR8* and partiall: separated on a preparative scale :
HuiGin! et al. 74RQ48. CT detectors are usuall: used -or the HP@%
o- p:rroliGidine compounds 7+attocIs* 4RQO8.
5.5.5.9 6as chromato!raph: 76%8 and mass spectrometr: 7+E8
The 6% characteriGation o- PAs usin! pacIed columns has een
descried : %halmers et al. 74RO>8 and Nieden-eld et al. 74RQ48.
+ixtures o- alIaloids -rom com-re: 7
Symp#ytum
sp.8* normall: hard
to separate* Yere resolved : %ulvenor et al. 74RQSa8 and 1rahn et
al. 74RQS8 : 6% o- the meth:loronate derivatives.
6as chromato!raph: comined Yith mass spectrometr: 76%-+E8 has
ecome a valuale and hi!hl: sensitive means -or oth the
identi-ication and the $uantitative determination o- p:rroliGidine
alIaloids. Thus* alIaloids extracted -rom hone: Yere separated and
identi-ied : 0einGer et al. 74RPP8 and 7as ut:loronate
derivatives8 : %ulvenor et al. 74RQ48. 0einGer et al. 74RPQ8
descried a method -or the reco!nition 7ut not the individual
identi-ication8 o- retronecine-ased p:rroliGidine alIaloids* :
h:drol:sin! them to retronecine 7the amino alcohol moiet:8 -olloYed
: 6%-+E o- its is-tri-luoroacetate. The use o- capillar: 6% has
!reatl: improved the sensitivit: o- p:rroliGidine alIaloid
anal:sis* especiall: Yhen used Yith +E 7@uth: et al.* 4RQ48. The
+E o- p:rroliGidine compounds has een revieYed 7?ull et al.* 4ROQ;
+attocIs* 4RQO8.
P:rroliGidine
/
-oxides !enerall: under!o thermal decomposition*
Yhen su;ected to 6%* ut the: can -irst e reduced to the
correspondin! asic alIaloids 7boeIemoer
Z
Narren* 4R>48.
Alternativel: the: ma: e derivatised. Thus* trimeth:lsil:lation
o- indicine
/
-oxide or heliotrine
/
-oxide can lead either to the
trimeth:lsil:l 7T+E8 derivative o- the parent alIaloid or to the
T+E derivative o- the deh:dro-alIaloid 7p:rrolic derivative8*
dependin! on the rea!ents used* and these products Yill run
success-ull: on 6%-+E 7&vans et al.* 4RPR* 4RQS8.
5.5.5.< )uclear ma!netic resonance 7)+(8 spectrometr:
A convenient* ut relativel: insensitive* method* speci-icall:
-or the determination o- unsaturated PAs* has een descried :
+ol:neux et al. 74RPR8. The asic alIaloids are extracted* then
su;ected to )+( spectrometr: alon! Yith an internal standard
7
p
-dinitroenGene8. This enales $uantitative measurements to e
made o- the si!nal7s8 representin! the H5 proton7s8 in unsaturated
p:rroliGidines* and thus the alIaloid7s8 can e determined.
Buantitative )+( anal:sis o- p:rroliGidine alIaloid mixtures -rom

Senecio vulgaris
has een descried : Pieters
Z
TlietincI 74RQ>8
and compared Yith an HP@% method : the same authors 74RQO8.
Bualitative aspects o- the )+( spectrometr: o- p:rroliGidine
alIaloids have een revieYed : ?ull et al. 74ROQ8 and +attocIs
74RQO8.
5.5.5.> The &hrlich reaction
This method 7+attocIs* 4ROPa* 4ROQ8 is speci-ic -or
unsaturated p:rroliGidine alIaloids and is not suitale -or other
alIaloids. Thus* it is the most use-ul colorimetric method -or
potentiall: hepatotoxic p:rroliGidine compounds. The procedure
converts the alIaloid into its
/
-oxide* usin! h:dro!en peroxide.
The product reacts Yith acetic anh:dride to -orm a p:rrolic
derivative 7deh:dro-alIaloid8 that !ives a ma!enta colour Yith a
speciall: modi-ied &hrlich rea!ent. The latter contains oron
tri-luoride to !ive maximum sensitivit:. As little as > s! o- most
unsaturated p:rroliGidines can e measured : this method. ,- the
oxidation sta!e is omitted* onl: the unsaturated p:rroliGidine

/
-oxides can e determined. The determination o- p:rroliGidine

/
-oxides has also een discussed : +attocIs 74RP48.
A simpli-ication o- the aove colorimetric procedure Yas
descried : +attocIs 74RP4d8 to provide a $ualitative test that
could e used to screen lar!e numers o- plant samples -or the
presence o- unsaturated p:rroliGidine alIaloid
/
-oxides. An
improved version o- this -ield test is noY availale 7+attocIs
Z

WuIes* 4RQP8. ,t is suitale -or an: plant parts* such as leaves*
stems* -loYers* seeds* or roots* or materials o- plant ori!in* such
as cereals or heral teas* ut has not :et een applied to cooIed
-ood.
The plant material 7S.5 - 4 !8 is extracted : !rindin! it Yith
a$ueous ascoric acid 7>\8 and a small amount o- sand. The
solution is -iltered and divided into tYo e$ual portions 7]test]
and ]lanI]8. An a$ueous solution 7S.5 ml8 o- sodium nitroprusside
7>\8 containin! sodium h:droxide 74S
-9
mol8 is added to the ]test]
sample. ?oth portions are heated -or approximatel: 4 min at PS -
QS t%; then &hrlich rea!ent is added and heatin! is continued -or
4 min. The &hrlich rea!ent contains <-dimeth:laminoenGaldeh:de
7> !8 dissolved in a mixture o- acetic acid 7OS ml8* Yater 79S ml8*
and OS\ perchloric acid 74S ml8. A ma!enta colour in the ]test]
compared Yith the ]lanI] indicates the presence o- an unsaturated
PA
/
-oxide. The ]lanI] ma: shoY a colour i- the plant contains
compounds* such as indoles or p:rroles* Yhich can themselves !ive a
colour Yith &hrlich rea!ent. The intensit: o- colour in the
]sample] compared Yith the ]lanI] can !ive a rou!h idea o- the
amount o- alIaloids present* and indicate Yhether -urther chemical
or toxicolo!ical testin! o- the plant material is adviseale.
,n practice* the ma;orit: o- PA-containin! plants contain
enou!h alIaloid in the
/
-oxide -orm 7o-ten a lar!e proportion8 to
react positivel: in this test. The main exceptions are some seeds

F"rotalariaH
* Yhich ma: contain much alIaloid ase* ut little or
no
/
-oxide. These 7and an: other sample not containin!
chloroph:ll8 can e tested -or asic PAs : !rindin! them Yith
chloro-orm* heatin! the -iltered extract Yith a solution 7S.4 ml8
o- orthochloranil 7S.>\8 in acetonitrile* and then heatin! it Yith
&hrlich rea!ent. A ma!enta colour indicates the presence o- an
unsaturated PA. )on-toxic p:rroliGidine alIaloids havin! a
saturated p:rroliGidine nucleus* and p:rroliGidine alIaloids that
are otonecine esters* such as petasitenine* Yill not respond to
this test.
5.5.5.O ,ndicator d:es
A method !enerall: applicale to tertiar: ases has een
adapted -or p:rroliGidine alIaloids : ?irecIa et al. 74RQ48. ,t
is sensitive* ut is not speci-ic -or this !roup o- alIaloids* and
it does not distin!uish etYeen the saturated and unsaturated
alIaloids. A chloro-orm solution o- the alIaloid is shaIen Yith
acidi-ied a$ueous meth:l oran!e. The :elloY alIaloid:d:e complex
is suse$uentl: released -rom the chloro-orm phase* usin! ethanolic
sul-uric acid* and measured spectrophotometricall:.
5.5.5.P 0irect Yei!hin!
An insensitive Ya: to determine the alIaloids in* -or example*
a plant sample* providin! enou!h is availale* is to extract the
alIaloids 7section 5.5.48 and Yei!h them. This Yill provide a
rou!h measure o- the total ases present in the sample; hoYever*
these ma: not necessaril: e PAs. )evertheless* the sample can
then e su;ected to -urther tests* e.!.* 6%-+%* nuclear ma!netic
resonance 7)+(8* or colorimetric anal:sis. 1urthermore*
p:rroliGidine
/
-oxides are !enerall: too Yater solule to e
apprecial: extractale -rom a$ueous solution : chloro-orm. Thus*
i- tYo portions o- the sample are extracted* and one o- them is
reduced to convert
/
-oxides to ases* the Yei!ht di--erence etYeen
the tYo products Yill represent the alIaloid existin! in the -orm
o-
/
-oxide in the ori!inal sample.

5.9 0etermination o- +etaolites in Animal Tissues
,mportant metaolites o- toxic p:rroliGidine alIaloids in
animals include ]p:rrolic] derivatives 7deh:dro-alIaloids8 and

/
-oxides. A procedure -or measurin! p:rrolic metaolites in tissue
samples 7such as liver or lun!8 has een descried : +attocIs
Z

Nhite 74RPS8. The sample 7usuall: S.> !8 is homo!eniGed in an
ethanolic solution o- mercuric chloride; the solids are separated
: centri-u!ation and heated Yith &hrlich rea!ent to !ive a solule
colour that can e measured spectrophotometricall:.
The measurement o- p:rrolic and
/
-oxide metaolites* -ormed :
the action o- hepatic microsomal preparations on PAs
in vitro
* is
an improvement descried : +attocIs
Z
?ird 74RQ98.

9. EOC(%&E A)0 PATHNAFE O1 &LPOEC(&
9.4 Hepatotoxic P:rroliGidine AlIaloids and Their Eources
Plants constitute the onl: natural source o- p:rroliGidine
alIaloids 7PAs8 that cause toxic reactions in man and animals. PAs
occur in a numer o- species in the -amilies ?ora!inaceae*
%ompositae* @e!uminosae 7!enus
"rotalaria
8* (anunculaceae 7!enus

"alt#a
8* and Ecrophulariaceae 7!enus
"astilleXa
8 7Tale 48. The
most important !enera o- PA-containin! toxic plants are
"rotalaria

7@e!uminosae8*
Senecio
7%ompositae8*
Aeliotropium, $ric#odesma,
1msinckia, .c#ium
* and
Symp#ytum
7?ora!inaceae8 7Hooper* 4RPQ8.
The recorded cases o- human toxicit: have mainl: een caused : at
least 45 di--erent p:rroliGidine alIaloids* mostl: derived -rom

Aeliotropium, Senecio,
and
"rotalaria
!enera. The
Senecio
spp.
!roY throu!hout the Yorld; the
"rotalaria
spp. are mainl: -ound in
the tropics and sutropics 7%ulvenor* 4RQS8.
Tale 4. @ist o- plant !enera containin! toxic p:rroliGidine alIaloids
7Yith numer o- species investi!ated8
-------------------------------------------------------------------------------------
1amil: 6enera
-------------------------------------------------------------------------------------
Apoc:naceae
ernaldia
748*
Parsonsia
7<8*
?ora!inaceae
1lkanna
748*
1msinckia
7<8*
1nc#usa
758*
1sperugo
748*
Borago
748*

"accinia
748*
"ynoglossum
7R8*
.c#ium
798*
Aackelia
748*

Aeliotropium
75>8*
,appula
758*
,indelofia
7P8*
,it#osperum
748*

Nacrotomia
748*
Nessersc#midtia
748*
Nyosotis
758*
Paracaryum
748*

Paracynoglossum
748*
Rindera
7>8*
Solenant#us
7<8*
Symp#ytum
7P8*

$ournefortia
758*
$rac#elant#us
758*
$ric#odesma
758*
Elugbekia
748
%ompositae
1denostyles
798*
Brac#yglottis
748*
"acalia
7<8*
"onoclinium
748*

"rassocep#alum
748*
?oronicum
758*
.c#inacea
758*
.milia
758*

.rec#tites
748*
.upatorium
7Q8*
arfugium
748*
Gynura
758*

,igularia
7>8*
Petasites
7<8*
Senecio
74<58*
Syneilesis
748*

$ussilago
748
@e!uminosae
"rotalaria
7OS8
(anunculaceae
"alt#a
758
Ecrophulariaceae %astille;a 748
-------------------------------------------------------------------------------------
An alphaetical list o- p:rroliGidine alIaloids Yith their
plant sources has een pulished : Emith
Z
%ulvenor 74RQ48 and
+attocIs 74RQO8. An updated version is attached as Appendix ,.
The plant !enera containin! toxic PAs are listed in Tale 4
indicatin! the numer o- species investi!ated -or PAs. A
comprehensive list o- species o- plants elon!in! to each o- these
!enera* the alIaloids isolated -rom each* and the part o- the plant
containin! the alIaloid are presented in Appendix ,,. Tale 4 in
Appendix ,, includes species InoYn to contain alIaloids o- proved
hepatotoxicit:* or o- a molecular structure that Yould maIe them
ver: proal: hepatotoxic. Tale 5 in Appendix ,, includes species
containin! p:rroliGidine amino-alcohols or esters* Yhich* Yhile not
havin! all the -eatures o- hepatotoxicit:* Yould need onl: minor
structural modi-ications to render them hepatotoxic. Plants o- the
same taxonomic !roups as the plants o- proven hepatotoxicit: are
listed in part 7a8 o- the tale. There is a possiilit: that* on
-urther examination* hepatotoxic alIaloids ma: e -ound* as minor
constituents* in strains or parts o- these plants not :et
investi!ated or under speci-ic conditions o- !roYth. ,t should e
noted that the species that have een investi!ated and are listed
are onl: -eY compared Yith the total numer o- species in each
!enera. ,t has een recommended : Emith
Z
%ulvenor 74RQ48 that it
Yould e prudent to re!ard all species in the -amil: ?ora!inaceae
and the !enera
"rotalaria, Senecio,
and
.upatorium as potentially
hepatotoxic.
,t is pertinent to note that the alIaloid content in di--erent
parts o- the plant 7e.!.* roots* leaves* stalIs* -loYers* and uds8
varies and is su;ect to -luctuations accordin! to the climate*
soil conditions* and time o- harvestin! 70annin!er et al.* 4RQ9;
Hartmann
Z
cimmer* 4RQO8. +attocIs 74RQS8 demonstrated that the
alIaloid content o- the leaves o-
Symp#ytum
spp. 7(ussian
com-re:8* Yhich are used as an item o- -ood* varies Yith their
maturit:. The toxic PA content is hi!hest at the e!innin! o- the
ve!etative period and declines as the leaves mature. The PA
content o- the roots is much hi!her than that o- the leaves* and
dried leaves contain a hi!her concentration than -resh leaves
7+attocIs* 4RQO8. Accordin! to 0annin!er et al. 74RQ98* in some
species
FSymp#ytum asperumH,
relativel: lon! stora!e ma: lead to a
reduction in the alIaloid content* presumal: ecause enG:mes are
released durin! dr:in!. %andrian et al. 74RQ<8 studied the
stailit: o- PAs in ha: and sila!e containin! various amounts o-

Senecio alpinus.
The PA content o- ha: remained constant -or
several months* ut the PAs in sila!e Yere mainl: de!raded.
HoYever* the de!radation o- PAs Yas much less complete in the loYer
concentration ran!e. A $uantitativel: si!ni-icant PA-de!radation
product in sila!e Yas identi-ied as retronecine. Eila!e Yith an

S. alpinus
percenta!e o- 9.> - 59 still contained macroc:clic PAs at
a concentration o- aout 5S m!'I! Yet Yei!ht. Euch sila!e Yas not
considered sa-e -or cattle earin! in mind that a OSS-I! cal- eats
aout 9S I! sila!e'da:* amountin! approximatel: to a dail: intaIe
o- aout 4 m! PAs'I! od: Yei!ht. ,n -eedin! trials Yith
Senecio
Xacobaea,
Wohnson 74RPR8 -ound that the minimum lethal dose -or
cattle Yas etYeen 4 and 5 m! PAs'I! od: Yei!ht per da:.
PAs InoYn to have een associated Yith instances o- human toxic
liver disease in di--erent parts o- the Yorld are listed in Tale
5. TYo !roups o- alIaloids that* accordin! to %ulvenor 74RQ98* are
consumed in si!ni-icant amounts : people in di--erent parts o- the
Yorld include:
7a8
.c#imidine, acetyllycopsamine, and related alkaloids
Fmany countriesH
@eaves o- plants o- the
Symp#ytum
sp. 7
Symp#ytum officinale

7com-re:8 and
Symp#ytum % uplandicum
8 are used traditionall: as a
salad and as a medicinal her in Australia* man: countries o-
&urope* and the CEA.
S. officinale
has een shoYn to e
carcino!enic -or rats 7Hirono et al.* 4RPQ8. @eaves o- (ussian
com-re: contain a concentration o- alIaloids 7mainl: echimidine8 o-
S.4 - 4.> !'I!. The hi!hest level o- dail: consumption o- the
alIaloids has een estimated to e > - O m! 7%ulvenor* 4RQ98.
78
.c#imidine and related alkaloids F1ustraliaH
PAs derived -rom
.c#ium plantagineum,
Yith echimidine as the
ma;or component* have een -ound in hone: secreted : ees -eedin!
on the plant 7%ulvenor et al.* 4RQ48. The plant is a ma;or source
o- hone: 7section 9.9.<8.

9.5 Pneumotoxic and Other Toxic P:rroliGidine AlIaloids
)ot all hepatotoxic alIaloids are pneumotoxic. The commonest
ones used to produce experimental lun! in;ur: are -ulvine 7?arnes
et al.* 4RO<; ba: et al.* 4RP4a; Na!envoort et al.* 4RP<a*8 and
monocrotaline 7@alich
Z
&hrhart* 4RO5; %hesne:
Z
Allen* 4RP9;
Huxtale et al.* 4RPP8. These are also the most active 7+attocIs*
4RQO8. The seeds o-
"rotalaria spectabilis,
Yhich contain
monocrotaline* have also een used to stud: pneumotoxic e--ects on
experimental animals 7Turner
Z
@alich* 4RO>; ba:
Z
Heath* 4ROO; ba:
et al.* 4ROPa8 and
". spectabilis
has een called the pulmonar:
h:pertension plant 7ba:
Z
Heath* 4ROR8* ecause o- the pulmonar:
h:pertensiono!enic properties o- the PAs it contains. %ulvenor et
al. 74RPOa8 screened O5 PAs -or hepatotoxicit: and pneumotoxicit:.
%hronic lun! lesions Yere produced : most compounds that induced
chronic liver lesions* thou!h hi!h doses Yere re$uired in some
instances. ,t is possile that chronic lun! lesions ma: not occur
in experimental animals ecause o- earl: death due to acute
toxicit:. HoYever* the authors identi-ied a numer o- PAs that
Yere particularl: prone to produce chronic lun! dama!e in rats
includin! crispatine* senecionine* seneciph:lline* and usaramine
745-memered macroc:clic* retronecine diesters8* anacrotine and
madurensine 7crotonecine esters8* and the heliotridine esters*
heliosupine* lasiocarpine* and rinderine.
The molecular structure-activit: re$uirements -or
pneumotoxicit: are the same as those -or hepatotoxicit:. This is
consistent Yith their oth ein! caused : the same toxic
metaolites and : the metaolic activation o- the alIaloids in the
liver cells to -orm a reactive p:rrolic deh:dro-alIaloid 7%ulvenor
et al.* 4RPOa8.
Trichodesmine and incanine* -ound in the seeds o-
$ric#odesma
incanum
7Funusov
Z
PleIhanova* 4R>R8* are elieved to have een
the causative -actors o- the ]OGhalan!ar encephalitis] that Yas
endemic in CGeIistan* CEE( 74R<5 - >48* in Yhich the s:mptoms and
si!ns Yere related primaril: to the central nervous s:stem
7Ehtener!
Z
Orlova* 4R>>8 7section P.P8.
Tale 5. ,nstances o- human toxicit: caused : p:rroliGidine alIaloidsa


Principal Plant %ountr:' %ause o- intaIe
(e-erence
alIaloid (e!ion


Heliotrine and Heliotropium A-!hanistan contamination
Tandon
Z
Tandon
other alIaloids popovii 74RP>8;
Tandon*
similar to ?.). et al.
lasiocarpine 74RPQ8; Tandon*
H.0. et al.
74RPQ8;
+ohaat et al.
74RPO8
Eenecionine Eenecio Eouth contamination
Nilmot
Z
illici-ormis; A-rica (oertson
Eenecio-urchelli 74R5S8
Eenecio spp. Eouth contamination EelGer
Z
A-rica ParIer 74R>48
AlIaloids o- %rotalaria &cuador medicine @:-ord
et al.
trichodesmine ;uncea 74RPO8
and senecionine
t:pe
Heliotrine and Heliotropium Hon! bon! medicine
bumana et al.
lasiocarpine lasiocarpum 74RQ>8;
%ulvenor et al.
74RQO8


Tale 5. 7cont[d8


Principal Plant %ountr:' %ause o- intaIe
(e-erence
alIaloid (e!ion


%rotananine and %rotalaria ,ndia contamination
Tandon* (.b.
cronaurmine nana et al. 74RPO8;
brishnamachari
et al. 74RPP8;
Eiddi$ui et al.
74RPQa*8
Heliotrine Heliotropium ,ndia medicine 0atta et
al.
)-oxide eichYaldii 74RPQa*8
+onocrotaline %rotalaria Nest ,ndies medicine ?ras
et al.
-ulvine retusa; 74R><* 4R>P8
%rotalaria
-ulva Etuart
Z
?ras
74R>P8
,lex sp. Cnited medicine +c6ee et al.
bin!dom 74RPO8
(iddelline Eenecio CEA medicine Etillman
et al.
retrorsine lon!ilous 74RPP8; 1ox et
)-oxide al. 74RPQ8;
7Yith others8 Huxtale 74RQS8
,ndicine )-oxide puri-ied CEA medicine
@etendre et al.
chemical 74RQ<8
E:mph:tine* E:mph:tum sp. CEA medicine
(idIer et al.
s:m!landine* and 74RQ>8;
other s:mph:tum Huxtale
alIaloids et al 74RQO8


Tale 5. 7cont[d8


Principal Plant %ountr:' %ause o- intaIe
(e-erence
alIaloid (e!ion


@asiocarpine and Heliotropium CEE( contamination
0urovinsIii
heliotrine lasiocarpum 74R>58;
+nushIin
74R>58
Trichodesmine and Trichodesma CEE( contamination
Ehtener!
Z
incanine incanum Orlova 74R>>8;
Funosov
Z
PleIhanova
74R>R8



a
Adapted -rom: %ulvenor 74RQ98 and +attocIs 74RQO8. (e-er also to Tale
4> -or
details and section P.


9.9 PathYa:s o- &xposure
)aturall:-occurrin! animal disease is caused : the alIaloid-
containin! plants !roYin! in -ields and pastures or ein! -ed
accidentall: as -odder. The: are mostl: heraceous or small shrus
and man: thrive in dr: and arid climates. One such plant
containin! toxic PA alIaloids has een reported to !roY in the
Yestern desert o- &!:pt 7Hammouda et al.* 4RQ<8. The !roYth o-
this !roup o- plants is particularl: proli-ic durin!* and
-olloYin!* periods o- drou!ht* as has een reported in association
Yith the outreaIs o- human disease in A-!hanistan 7Tandon
Z

Tandon* 4RP>; +ohaat et al.* 4RPO8 and ,ndia 7Tandon* ?.). et
al.* 4RPO8. AlIaloid-containin! plants are Yidespread in the
tropics* especiall:
"rotalaria
* o- Yhich there are over 9SS
species in A-rica. Ordinaril:* the alIaloid-containin! plants have
a itter taste and !raGin! animals Yill re;ect them* unless their
normal -odder is scarce. HoYever* PAs o-ten occur lar!el: as

/
-oxides* Yhich are said not to e itter* and plants containin!
PAs are readil: eaten : some animal species.
Human intoxication ma: result -rom the in!estion o- the toxic
sustance in either contamined -ood or heral in-usion.

9.9.4 %ontamination o- staple -ood crops
The products o- p:rroliGidine alIaloid-containin! plants*
!enerall: seeds* ma: contaminate the staple -ood and ma: e eaten
over lon! periods o- time. The -act that these plants ma: cause
disease is !enerall: not reco!niGed : the people and such
contamination is InoYn to have resulted in lar!e-scale outreaIs o-
poisonin! 70urovinsIii* 4R>5; +nushIin* 4R>5; Ehtener!
Z
Orlova*
4R>>; Tandon
Z
Tandon* 4RP>; +ohaat et al.* 4RPO; Tandon* ?.). et
al.* 4RPO* 4RPP; Tandon* (.b. et al.* 4RPO; brishnamachari et al.*
4RPP; Tandon* H.0. et al.* 4RPP8 7Tale 5* section 9.48.

9.9.5 Heral in-usions
Plants have een used traditionall: -or medicinal purposes all
over the Yorld. Hers have een the mainsta: o- the indi!enous
s:stems o- medicine* especiall: in %hina* 6reece* and ,ndia* since
ancient times. Tale 9 includes a list o- some plants that are
suspected* or InoYn* to contain PAs and have een used as heral
medicines in di--erent countries 7+attocIs* 4RQO8.
Eeveral PA-containin! plants are included amon! the list o-
plants used in indi!enous s:stems o- medicine in ,ndia 7%hopra*
4R998. As a part o- a research stud: on the etiolo!ical -actors o-
chronic liver disease in Eri @anIa* Arseculeratne et al. 74RQ48
chemicall: screened the -irst >S plants used in Eri @anIa[s
traditional medicine pharmacopoaea* and -ound that 9 o- them
contained PAs. All 9 Yere hepatotoxic in rats. O- the 9* the
presence o- alIaloids in
"assia auriculata
and that o- PAs in

Aollar#ena antidysenterica
had not previousl: een recorded. ,t
should e noted that the amount o- experimental plant material used
in this stud: Yas approximatel: O.> !'I! od: Yei!ht per da:* in
contrast to the approximate intaIe : a human ein! estimated to e
in the ran!e o- S.9 - S.O !'I! od: Yei!ht per da:. Eome* ut not
all* o- the plants reported to e etiolo!ical a!ents in human cases
o- veno-occlusive disease can e -ound in an inventor: o- medicinal
plants used in di--erent countries 7NHO* 4RQS8* Yhich also
indicates the countries that the: are used in. The aove lists ma:
not e complete as man: such plants ma: e used in -olI medicine
ut have not een mentioned in the scienti-ic literature. HoYever*
the lists do indicate the Yide and varied use o- such toxic hers
in all parts o- the Yorld.
@atel:* there has een a !roYin! interest in the developed
countries in or!anicall: !roYn products -or -ood* as Yell as home
remedies 7Tale 98* and some o- the PA-containin! hers have een
-reel: availale in heral shops 7Echoental* 4ROQ; ?urns* 4RP58.
0annin!er et al. 74RQ98 listed plants containin! PAs that are
commonl: used in the 1ederal (epulic o- 6erman: as medicaments
7Tale <8. He also listed R plants in Yhich alIaloids have onl:
een identi-ied $ualitativel:* the toxicit: o- Yhich has not een*
or has een insu--icientl:* investi!ated 7Tale >8. Eimilarl:*
(oitman 74RQ98 listed 4S plants* in Yhich the presence o- PAs is
suspected or has een proved and Yhich are used as heral teas in
the CEA. The lists include 4S plants containin! PAs* most o- Yhich
have een proved hepatotoxic experimentall:* some havin! hi!hl:
carcino!enic promoter activit:. Eome o- these alIaloids have een
associated Yith human case reports o- PA toxicit:. The more recent
reports 7Tale 58 o- instances o- PA poisonin! throu!h the use o-
heral medicines are -rom developed countries 7@:-ord et al.* 4RPO;
Etillman et al.* 4RPP; 1ox et al.* 4RPQ; bumana et al.* 4RQ>;
(idIer et al.* 4RQ>8. Euch use o- the hers is the reason that
veno-occlusive disease is endemic in Wamaica 7?ras et al.* 4R><;
Welli-e et al.* 4R><a*; ?ras
Z
Natler* 4R>>; Etuart
Z
?ras* 4R>>*
4R>P8. There are ovious di--iculties in exercisin! an: Iind o-
control to restrict this use onl: to plants that have een tested
and certi-ied as sa-e -or human use. ,t is impossile to identi-:
man: such hers* as the: are sold as plants or their amorphous
products in the heral shops.
Tale 9. Eome plants containin! 7or suspected o- containin!8 PAs*
Yhich have een used
: people either as heral medicines 7+8 or -oods 718


Plant +ode %ountr: (e-erence
a
o- use or re!ion


LORAKIHACEAE
Anchusa o--icinalis + &urope ?roch-0ue
Z
Aasen 74RQS8 ?
?ora!o o--icinalis + CEA 0elorme et al. 74RPP8
A
%:no!lossum + &ast A-rica Echoental
Z
%oad: 74ROQ8 A
!eometricum
%:no!lossum + ,ran %oad: 74RP98 ?
o--icinale
Heliotropium + ,ndia 6andhi et al. 74ROOa8;
?
eichYaldii 0atta et al. 74RPQa*8 A
H. europaeum + ,ndia* 6reece ,A(% 74RPO8
A
H. lasiocarpum + Hon! bon! bumana et al. 74RQ>8;
A
%ulvenor et al. 74RQO8 A
H. indicum + ,ndia* A-rica* Echoental 74ROQa8;
?
Eouth America* Ho$ue et al. 74RPO8 ?
and elseYhere
H. ramossissimum + Araia +acIsad et al. 74RPS8;
?
7ramram8 %oad: 74RP98 ?
H. supinum + TanGania Echoental
Z
%oad: 74ROQ8 A


Tale 9 7contd.8


Plant +ode %ountr: (e-erence
a
o- use or re!ion


Pulmonaria spp. + CEA 0elorme et al. 74RPP8
A
E:mph:tum o--icinale 1* + Wapan and Hirono et al. 74RPQ*
4RPR8 A
+ CEA 1uru:a
Z
HiIichi 74RP48; A
0elorme et al. 74RPP8 A
E. x uplandicum 1* + 6eneral Hills 74RPO8
?
CEA %ulvenor et al. 74RQSa*8 A
E. asperum + CEA Pedersen 74RP>8 A

COAPOSI?AE
%acalia decomposita + CEA Eullivan 74RQ48
?
7matari$ue8
%. :ataei 1 Wapan HiIichi
Z
1uru:a 74RPQ8 ?
1ar-u!ium ;aponicum + Wapan 1uru:a et al. 74RP48
?
@i!ularia dentata 1 Wapan Asada
Z
1uru:a 74RQ<8 ?
Petasites ;aponicus 1* + Wapan Hirono et al. 74RP9* 4RPR8
A
Eenecio a:ssinicus + )i!eria Nilliams
Z
Echoental 74RPS8 ?
E. aureus + CEA Nade 74RPP8 ?


Tale 9 7contd.8


Plant +ode %ountr: (e-erence
a
o- use or re!ion


E. upleuroides + A-rica Natt
Z
?re:er-?randYi;I 74RO58 A
E. urchelli 1* + Eouth A-rica (ose 74RP58
A
E. coronatus + Eouth A-rica (ose 74RP58
A
E. discolor + Wamaica Aspre:
Z
Thornton 74R>>8 ?
E. doronicum + 6erman: (oeder et al. 74RQSa8
?
E. inae$uidens 1 Eouth A-rica (ose 74RP58
?
E. ;acoaea + &urope Echoental
Z
Pullin!er 74RP58; ?
7ra!Yort8 Nade 74RPP8 ?
E. lon!ilous + CEA Etillman et al. 74RPP8;
A
7E. dou!lassi8 Huxtale 74RPRa8 ?
E. monoensis + CEA Huxtale 74RQS8
A
E. nemorensis + 6erman: Has et al. 74RQ58
A
spp. -uchsii
E. pierotti 1 Wapan Asada
Z
1uru:a 74RQ58 ?
E. retrorsus + Eouth A-rica (ose 74RP58 A
7E. lati-olius8


Tale 9 7contd.8


Plant +ode %ountr: (e-erence
a
o- use or re!ion


E. vul!aris + &urope Natt
Z
?re:er-?randYi;I 74RO58 A
7common !roundsel8
)etherlands Nade 74RPP8 ?
+ ,ran %oad: 74RP98 ?
E:neilesis palmata 1 Wapan HiIichi
Z
1uru:a 74RPO8 ?
Trichodesma a-ricana + Asia Omar et al. 74RQ98
?
Tussila!o -ar-ara + Wapan %ulvenor et al. 74RPOa8
A
7colts-oot8
+ %hina Hirono et al. 74RPO8 A
+ )orYa: ?orIa
Z
Onshuus 74RPR8 ?
+ CEA ?orIa
Z
Onshuus 74RPR8; ?
%ulvenor et al. 74RPO8; ?

LEKJAIHOSAE
%rotalaria revidens 1 &ast A-rica %oad: 74RP98
?
%. -ulva + Wamaica ?arnes et al. 74RO<8; A
+c@ean 74RPS* 4RP<8 A


Tale 9 7contd.8


Plant +ode %ountr: (e-erence
a
o- use or re!ion


%. incana + &ast A-rica Echoental
Z
%oad: 74ROQ8 A
Natt
Z
?re:er-?randYi;I A
74RO58
%. laurni-olia + TanGania Echoental
Z
%oad: 74ROQ8 A
1 Asia %oad: 74RP98 ?
%. mucronata + TanGania %oad: 74RP98
?
%. recta +* 1 TanGania Echoental
Z
%oad: 74ROQ8; A
%oad: 74RP98 ?
%. retusa +* 1 A-rica ,A(% 74RPO8 A
,ndia Natt
Z
?re:er-?randYi;I 74RO58 A
%. verrucosa + Eri @anIa Arseculeratne et al. 74RQ48
A



a
A ^ (e-erence in the re-erence list o- this document.
? ^ (e-erence in +attocIs 74RQO8.

+anu-actured preparations ma: also contain PA-containin! hers*
e.!.* com-re:-pepsin capsules sold as a di!estive aid 7Huxtale et
al.* 4RQO8.

9.9.9 Cse o- PA-containin! plants as -ood
Eeveral PA-containin! plants are used as -ood as can e seen in
Tale 9 7+attocIs* 4RQO8.
Petasites Xaponicus
+axim*
$ussilago
farfara
@. 7colts-oot8* and
Symp#ytum officinale
@. 7com-re: or
(ussian com-re:8 are InoYn as edile plants in Wapan* and have een
proved to contain carcino!enic p:rroliGidine alIaloids 7Hirono et
al.* 4RP9* 4RPRa*8. The :oun! -loYer-stalIs o-
P. Xaponicus
and
the uds o- colts-oot have een used in Wapan as human -ood or
heral remedies. The lea- and root o- com-re: are also used as an
edile ve!etale or tonic 7Hirono et al.* 4RPQ8 in Wapan and other
countries 7%ulvenor* 4RQ>8. The carcino!enic PAs in these plants
are petasitenine
FP. XaponicusH
* senIirIine 7colts-oot8* and the
!roup includin! s:mph:tine 7com-re:8. The: Yere also muta!enic in
the Ames s:stem o-
Salmonella typ#imurium
and TPR hamster cell line
and induced trans-ormation in cr:o-preserved hamster emr:onic
cells 7Hirono et al.* 4RPR8. Other such PA-containin! plants*
used as -ood in Wapan* include :oun! leaves o-
Syneilesis palmata
*
various
"acalia
species* and :oun!
Senecio pierotti
7+attocIs*
4RQO8. Accordin! to %ulvenor 74RQ>8* consumers o- com-re: could e
in!estin! up to > m! PAs per da:. (ose 74RP58 listed a numer o-
plants o- the !enus
Senecio
that are used as spinach in Eouth
A-rica. These include
S. burc#elli
* Yhich is InoYn to have caused
an episode o- PA poisonin! throu!h the in!estion o- contaminated
read 7Nilmot
Z
(oertson* 4R5S8.

9.9.< %ontaminated hone:
,n the CEA* 0einGer et al. 74RPP8 reported the presence o- all
PAs contained in
Senecio Xacobaea
7ra!Yort8 and proved to e
hepatotoxic* in the hone: secreted : ees -eedin! on the plant.
The total alIaloid content ran!ed -rom S.9 to 9.R m!'I!. ,t has
een estimated that an avera!e annual human intaIe o- hone: 7OSS !8
at the hi!hest alIaloid level $uoted Yould contain less than 9 m!
o- PAs 7+attocIs* 4RQO8. %ulvenor et al. 74RQ48 and %ulvenor
74RQ9* 4RQ>8 dreY attention to the same potential haGard in hone:
-rom
.c#ium plantagineum
* a Yeed that !roYs Yidel: in Eouthern
Australia and is a ma;or source o- hone:* :ieldin! an estimated
5SSS - 9SSS tonnes per annum -or human consumption. &chimidine is
the ma;or component o- the alIaloids o-
.c#ium
* Yhich are present
in concentrations o- up to 4 m!'I!. %ulvenor 74RQ98 estimated that
individuals ma: consume up to QS ! hone:'da: Yith a correspondin!
alIaloid intaIe o- QS s!'da:* i- onl: the
.c#ium
hone: Yere used.
)o reports o- acute human toxicit: throu!h this source are
availale.

Tale <. +edicinal plants containin! PAs o- InoYn hepatotoxicit:*
reported as commonl:
used in the 1ederal (epulic o- 6erman:* and the PAs contained in
them
a

1amil: 6enus Epecies P:rroliGidine
alIaloids


%ompositae &upatorium &. cannainum amailineu
7hemp a!rimon:8 supinine

Petasites P. h:irdus senecionine

*c
inte!errimine

senIirIine

Eenecio E. nemorensis -uchsisenecionine

7!roundsel8 sp. -uchsii senecionine
*c
71uch[s !roundsel8
E. vul!aris senecionine
*c
7!roundsel8 senecioph:lline

retrorsine

riddelline
*c
E. Wacoaea ;acoine

7ra!Yort8 senecionine
*c
seneciph:lline

;acoline* ;aconine
chlorinated PAs
d
E. aureus senecionine
*c
7American !olden
ra!Yort8
Tussila!o T. -ar-ara senIirIine

7colts-oot8 7colts-oot8 senecionine

*c
tussila!ine


Tale < 7contd.8


1amil: 6enus Epecies P:rroliGidine
alIaloids


AlIanna A. tinctoria P-an!el:lretronecine
trian!ularine
dih:drox:trian!ularine
Anchusa A. o--icinalis l:copsamine
?ora!inaceae ?ora!o ?. o--icinalis
l:copsamine'intermedineu
7ora!e8 acet:ll:copsamine'
acet:lintermedine
amailine
supinine
E:mph:tum E. o--icinale s:mph:tine

7com-re:8 7com-re:8 echimidine7K8

l:copsamine
acet:ll:copsamine

lasiocarpine
*c
heliosupine )-oxide
E. pere!rinum l:copsamine

E. x uplandicum intermedine

s:mph:tine

echimidine

P-acet:ll:copsamine
P-acet:lintermedine
s:mlandine
uplandicine
E. asperum asperumine
7pricIl: com-re:8 heliosupine )-oxide
echimidine

echinatine


Tale < 7contd.8


1amil: 6enus Epecies P:rroliGidine
alIaloids


%:no!lossum %. o--icinale heliosupine )-oxide
7hound[s 7hound[s ton!ue8 echinatine
ton!ue8 acet:l heliosupine

O-P-an!el:lhelio-
tridine

Heliotropium H. europaeum heliotrine

*c*e
7Heliotrope8 7common heliotrope8 lasiocarpine
*c*e
supinine
heleurine
europine
acet:llasiocarpine

a
+odi-ied -rom: 0annin!er et al. 74RQ98.

Toxic alIaloids.

c
AlIaloids InoYn to have caused human toxicit:.

d
AlIaloids Yith hi!hl: carcino!enic promoter activit:.

e
Csed onl: in homeopath:.

Tale >. +edicinal plants containin! PAs* reported as
commonl: used in the 1ederal (epulic o- 6erman:*
the toxicit: o- Yhich has not een* or has een
insu--icientl:* investi!ated
a
-----------------------------------------------------------
1amil: 6enus Epecies
-----------------------------------------------------------
%ompositae
.upatorium .. perforatum
Brac#yglottis B. repens
1rnica 1. montana
7mountain arnica8
?ora!inaceae
,appula ,. intermedia
7sticIseed8

Pulmonaria P. officinalis
7lun!Yort8
-----------------------------------------------------------

a
+odi-ied -rom: 0annin!er et al. 74RQ98.

9.9.> +ilI
PAs have een shoYn to produce toxic e--ects via trans-erence
into the milI o- dams 7Echoental* 4R>R8. (etrorsine Yas
administered orall: to 4P* and intraperitoneall: to O* lactatin!
rats Yei!hin! 4Q> - 9>S ! in > - 4S m! doses dail:* the -irst dose
ein! !iven durin! the -irst 5< h a-ter parturition. The rats
received -rom 4 to 4< doses* the total intaIe amountin! to
54 - 99> m!'I! od: Yei!ht. The litters Yere separated -rom the
mothers -or v h -olloYin! the administration o- PA to avoid direct
contamination o- the -ormer : licIin!. Apparentl: the milI
production Yas not a--ected as the stomachs o- man: o- the :oun!*
examined postmortem* Yere distended Yith milI. All animals Yhose
mothers had received a total dose o- 49Q m! PA or more died Yithin
9S da:s. +an: o- the :oun! Yhose mothers had received smaller
doses survived until the: Yere Iilled at O months. ?iops: o- the
liver o- the :oun! at various intervals or at autops: shoYed marIed
chan!es* even in cases Yhere the mothers did not appear to e
a--ected. Animals d:in! at 4Q - 9S da:s shoYed h:dropic or -att:
vacuolation o- liver cells. ,n the liver o- animals d:in! or
Iilled later* various de!rees o- haemorrha!ic necrosis and increase
in the centriloular reticulin o- the liver* and some thicIenin! o-
centriloular veins Yere seen. ,n animals that survived O months*
the appearance Yas less anormal* ut some h:perplastic nodules and
ile-duct proli-eration Yere seen. The lactatin! rats dosed Yith
the PAs !enerall: survived lon!er than the sucIlin! animals and
usuall: did not shoY an: ill e--ects* su!!estin! that the
susceptiilit: o- the sucIlin! rats Yas !reater than that o- the
mothers.
0icIinson et al. 74RPO8 demonstrated the presence o- PAs in the
milI o- dair: cattle -ed or dosed Yith ra!Yort
FSenecio XacobaeaH.
Nhen < coYs Yere administered the dried plant material at levels o-
up to 4S !'I! od: Yei!ht per da: throu!h rumen cannula* PA levels
o- up to S.Q< m!'I! Yere oserved in the milI. HoYever* onl: one
7;acoline8 o- the several PAs contained in the plant Yas secreted.
%alves* ucIet -ed on the milI did not shoY an: si!ns o- PA
toxicit:.
0icIinson 74RQS8 repeated the stud: on !oats. 1our milI !oats
Yere -reshl: prepared Yith rumen cannulae. The Iids Yere separated
-rom their dams and Yere -ed milI tYice a da:. 0ried tans: ra!Yort
plant material Yith a PA content o- S.4O\ 7dr: Yei!ht8 Yas
administered throu!h the cannulae to each !oat at a dosa!e rate o-
4S !'I! od: Yei!ht per da: over 45> da:s. 0urin! this period*
each o- the < Iids received milI -rom their dams at approximatel:
45> ml'I! per da: in addition to
ad lib
-eedin! on al-al-a !rass
ha:. Eix PAs Yere isolated -rom the plant material: ;acoine*
;aconine* ;aconline* ;acoGine* senecionine* and seneciph:lline.
+ilI samples collected tYice dail: shoYed PA contents o-
55> - >9S s!'litre Yith a mean o- 9Q4 s!'litre. )o apparent health
e--ects Yere noted in the Iids* and onl: mild hepatic dama!e Yas
suspected in the dams* on the asis o- liver -unction tests. 1i-t:
percent o- the Iids Yere Iilled a-ter 4S YeeIs. )o lesions o- PA
toxicit: Yere seen. The dams Yere rered and appeared normal
throu!hout the !estation period. HoYever* three dams aorted at
almost -ull term* and the -etuses Yere orn dead. One o- the dams
died shortl: a-ter parturition and shoYed evidence o- severe liver
dama!e characteristic o- PA toxicit:. Another* Yhich delivered
normall:* also shoYed a lesser de!ree o- liver dama!e at iops:.
0ata relatin! to PA secretion Yere compared Yith similar
earlier data on coYs. +ean secretion o- PAs in coYs appeared much
hi!her* e.!.* OQ< s!'litre. The authors concluded that the amount
o- PAs secreted in the !oat[s milI did not cause an: serious
deleterious e--ects in the Iids.
Wohnson 74RPO8 -ed lon!-term lethal doses o-
Senecio Xacobaea
*
: stomach tue* to O coYs. 1eedin! started at term or Yithin 9S
da:s post-partum* and continued until Yhat Yas considered to e a
lethal dose had een -ed. The dail: dose o- the plant ran!ed -rom
4 to <.< !'I! od: Yei!ht* the total amount -ed representin! > -
4>\ o- od: Yei!ht over a period o- >< - 45O da:s. 1ive coYs died
Yithin RQ da:s; one* in a moriund state* Yas Iilled on da: 45O.
The calves sucIled -or 9S - 45O da:s. EucIlin! started immediatel:
a-ter irth in the case o- < calves and 4S and 9S da:s later*
respectivel:* in the 5 remainin! calves. Three calves Yere Iilled
Yith their dams or soon a-ter* and 9 Yere retained -or 4 :ear -or
oservation. +ilI samples -rom 5 coYs Yere collected and pooled in
4<- to 4O-da: lots durin! O< da:s o- -eedin! o- the
Senecio
plant.
&ach pooled sample Yas administered intra!astricall: to a !roup o-
rats in dail: doses o- 45 ml -or 4> - 9S da:s. A control !roup o-
rats Yere -ed raY milI -rom coYs not -ed
Senecio.
?lood samples o-
the dams and the calves Yere anal:sed -or !lutamic oxaloacetic
transaminase 76OT8* lactic deh:dro!enase 7@0H8* and !amma-!lutam:l
transpeptidase 766TP8. Eerum-enG:me levels in all coYs indicated
statisticall: si!ni-icant deviations su!!estin! liver d:s-unction*
and the livers at autops: had characteristic -eatures o- PA
toxicosis. The @0H and 6OT levels in calves Yere !enerall:
anormal a-ter 5S - <> da:s o- sucIlin!. The anormalities ran!ed
-rom mild to a 4>- to 4PS--old increase. One cal- Yas autopsied at
the peaI increase o- serum-enG:mes and Yas -ound to have mild -ocal
hepatitis. )o si!ni-icant patholo!ical -eatures Yere seen in the
livers o- other animals* nor o- the rats* some o- Yhich Yere
retained -or up to 4>S da:s.
6oe!er et al. 74RQ58 -ed dried
Senecio Xacobaea
7tans: ra!Yort8
to lactatin! !oats in a proportion o- 5>\ o- the -eed. The milI
contained P.> s! PA'I! dr: Yei!ht. The milI produced : the !oats
Yas pooled and then ottle -ed to appetite to 5 Werse: ull calves
74 da: old8 that also had access to tans: ra!Yort--ree ha: -or 4SR
and 45< da:s* respectivel:. The: Yere then Yeaned and !iven normal
-eed and oserved -or O months* a-ter Yhich the: Yere Iilled and
autopsied. ,n another stud:* rats Yere -ed a diet containin! the
-reeGe-dried milI at QS\ level -or 4QS da:s Yith a calculated total
PA intaIe o- S.RO m!'rat. Other !roups o- rats Yere -ed tans:
ra!Yort at dietar: levels o- S.S4 - 4S !'I! 7correspondin! to PA
intaIes o- 9R.PP* >.S<* S.>5* and S.S> m!'rat8. The cal- livers
onl: shoYed ver: mild non-speci-ic chan!es* ut the livers o- rats
-ed tans: ra!Yort or the milI -rom tans: ra!Yort--ed !oats
shoYed de-inite* ut mild* chan!es includin! sYollen
hepatoc:tes* me!aloc:tosis* iliar: h:perplasia* and -irosis.
Histopatholo!ical chan!es in milI--ed rats Yere similar to those in
the !roup -ed tans: ra!Yort in the diet at S.S4 !'I!. The authors
concluded that there Yas evidence o- PA trans-er into milI* Yhich
proved hepatotoxic -or rats. ,t Yas also noted that the !oats had
een -ed hi!h levels o- tans: ra!Yort at the upper limit o- their
acceptance* and that the hepatic chan!es oserved in rats -ed hi!h
levels o- milI* -or extensive periods* Yere sli!ht.
@uth: et al. 74RQ98 produced direct evidence o- excretion o-
macroc:clic esters o- retronecine o- the senecionine and
seneciph:lline-t:pe into rat milI.
9
H-retronecine* an
9
H-necic
acid-laelled senecionine* and seneciph:lline Yere prepared
ios:ntheticall: Yith seedlin!s o-
Senecio vulgaris
@. TYo
lactatin! rats 7,vanovas* Epra!ue 0aYle:8* Yei!hin! 9SS - <SS !*
Yere -ed the -irst o- the second compound : stomach tue* in doses
o- 5.P m!'I! and >.> m!'I! od: Yei!ht* respectivel:. Eamples o-
lood Yere examined 4* 9* and O h a-ter treatment* and those o-
milI 4 and 9 h a-ter. Animals Yere Iilled a-ter O h. The: Yere
-ound to have excreted approximatel: S.SQ\ o- the applied
radioactivit: in the milI Yithin 9 h* mainl: as unidenti-ied
retronecine-derived metaolites* and approximatel: S.S5\ as
unchan!ed PAs. The hi!hest levels o- PAs and metaolites in
tissues Yere -ound in the liver and lun!s* O h a-ter
administration.
%andrian et al. 74RQ<a8 also demonstrated that
?rosop#ila
melanogaster
-lies -ed on milI -rom lactatin! rats that had een
administered an oral dose o- seneciph:lline shoYed 4.5\ sex-linIed
recessive lethals* compared Yith S.9\ in controls* indicatin! the
trans-er o- the muta!enic properties o- the PA via milI 7section
O.<.P8.
The implications o- the aove studies on the possiilit: o-
carr:-over o- PAs into -oodstu--s o- animal ori!in are ovious.
HoYever* no reports o- human cases o- acute PA toxicit:* ascried
to the consumption o- contaminated milI* are availale.

9.9.O +eat
There have not een an: reports o- the detection o- PAs in meat
products -rom livestocI exposed to them.

9.9.P Cse o- PAs as chemotherapeutic a!ents -or cancer
An alIaloid o-
Aeliotropium indicum
@. 7indicine
/
-oxide8 has
een -ound to have antitumour activit: and has een used in
experimental clinical chemotherap: -or cancer 7section P.R8.

<. +&TA?O@,E+
<.4 Asorption* &xcretion* and Tissue 0istriution
<.4.4 Asorption
There have een -eY studies on the asorption o- PAs in man*
ut asorption has een in-erred -rom studies on tissue
distriution and the amounts o- alIaloids and their metaolites
excreted in the urine* -aeces* and ile o- animals 7section <.4.58.
EYicI et al. 74RQ5c8 measured the trans-er o- a mixture o-
p:rroliGidine alIaloids extracted -rom
Senecio Xacobaea
* across
isolated intestine and stomach se!ments -rom raits. The alIaloid
mixture contained seneciph:lline* ;acoine* ;acoGine* ;acoline* and
senecionine. The alIaloids Yere trans-erred across the ileum and
;e;unum* ut not the stomach. ?rauchli et al. 74RQ58 compared the
oral and percutaneous asorption in rats o- a crude alIaloid
mixture otained -rom com-re: 7
Symp#ytum officinale
@.8. The
mixture consisted o-
/
-oxides o- P alIaloids* principall: P-acet:l-
intermedine and P-acet:l-l:copsamine. A dose o- 4R< m!'I! Yas
either !iven : !ava!e* or Yas applied to the shaved sIin and le-t
-or << h. A-ter the dermal application* the excreted
/
-oxides in
urine 7up to <Q h8 amounted to S.4 - S.<\ o- the dose. A-ter oral
dosa!e the excreted level o-
/
-oxides and alIaloid ases Yas $uoted
as ein! 5S - >S times !reater.

<.4.5 &xcretion and distriution
The excretion and distriution o- heliotrine in rats has een
reported in ?ull et al.* 4ROQ. Foun! rats 74>S !8* !iven the @0
>S

o- heliotrine : ip in;ection* Yere Iilled at intervals* led
$uicIl:* and the or!ans and tissues anal:sed. Heliotrine Yas
present in the liver a-ter 5 min 79.P\ o- total dose8* the level
peaIin! at > min 7O.9\8* and droppin! to 5.5\ at 4 h and S.>\ at
5.> h. ,n adult rats* the level in the liver at > h Yas S.SP\ o-
the total dose. 1ive min a-ter dosin!* 9S - <S\ o- the initial
dose remained in the peritoneal cavit:* and the lood level o-
heliotrine Yas OS m!'litre* droppin! to 9 m!'litre at 4 h. The
urinar: excretion o- ase and metaolites other than p:rrolic
metaolites* collected and measured 4O h a-ter administration o-
several alIaloids : ip in;ection* is shoYn in Tale O. The
proportion o- ase excreted unchan!ed increased Yith the
h:drophilicit: o- the alIaloid* ein! O5\ -or heliotrine
/
-oxide*
9S\ -or heliotrine* and onl: 4 - 4.>\ -or lasiocarpine.
Heliotridine* the h:drol:sis product -rom heliotrine and
lasiocarpine* Yas excreted in the -orm o- the
/
-oxide in lar!er
$uantities a-ter the administration o- each o- these alIaloids.
The distriution and excretion o- monocrotaline Yas studied in
rats : Ha:ashi 74ROO8 Yho -ound that >S - PS\ Yas excreted in the
urine Yithin the -irst da:. HoYever* the anal:sis Yas : a non-
speci-ic chemical method that did not distin!uish etYeen the
unchan!ed alIaloid and its metaolites. +attocIs 74ROQa8 !ave
toxic p:rroliGidine alIaloids intraperitoneall: to male rats and
measured the urinar: excretion o- the unchan!ed alIaloid* and o-

/)
oxide and p:rrolic metaolites. The excretion o-
/
-oxide and
unchan!ed alIaloid Yas rapid and almost complete in the -irst 5< h.
&xcretion o- p:rroles Yas also rapid ut continued -or a little
lon!er. 1or example* in rats !iven retrosine 7OS m!'I! od:
Yei!ht8* the urine in the -irst 5< h contained 4S.O\ unchan!ed
alIaloid* 49.9\
/
-oxide* and 49.<\ p:rrolic metaolites. 0urin!
the second da:* onl: S.4\ alIaloid* S.5\
/
-oxide* and 4.Q\ p:rroles
Yere excreted. ?iliar: excretion also occurred. Aout one-$uarter
o- an iv dose o- retrosine in rats Yas excreted in the ile as
p:rrolic metaolites* and <\ as unchan!ed alIaloid; most o- this
excretion occurred durin! the -irst hour a-ter the in;ection
7Nhite* 4RPP8.
Wa!o et al. 74ROR8 !ave heliotrine iv to sheep; urinar:
excretion o- the unchan!ed alIaloid to!ether Yith metaolites
7
/
-oxide* and demeth:lation and h:drol:sis products8 occurred
rapidl: and continued -or up to Q h. &xcretion in the ile Yas
onl: 5\ o- that in the urine.
The tissue distriution o- radioactivit: -rom a tritiated toxic
p:rroliGidine alIaloid analo!ue Yas studied : +attocIs
Z
Nhite
74RPO8 usin! s:nthanecine A is-
/
-eth:lcaramate 7<S m!'I! od:
Yei!ht8. The hi!hest concentrations o- radioactivit: Yere seen in
the liver 7Yhere metaolism occurs8* lun!s* Iidne:s* and spleen
7respectivel:* 9.R\* S.4R\* S.4Q\* and S.5P\ o- the dose !iven8*
and aout OR\ o- the dose Yas eliminated in the urine durin! the
-irst da:. (adioactivit: in the expired air Yas ne!li!ile. The
indin! o- radioactivit: in the liver* and especiall: the lun!s*
Yas more persistent than in other or!ans. Eimilar results Yere
!iven : the semis:nthetic p:rroliGidine alIaloid analo!ue*
retronecine is-
/
-eth:lcaramate 7+attocIs* 4RPP8.
Tale O. Crinar: metaolites o- p:rroliGidine ases in the rat 74O-h
urine8
a

Jrine !onstituent Camount in #er!entage of "ose
inGe!te"D
?ase Cnchan!ed ?ase Heliotridine Heliotridine
Heliotridine Heliotridine
administered ase )-oxide trachelanthate trachelanthate
)-oxide
7ip in;ection8 )-oxide


Heliotrine 9S Trace 4S > 9 4>
Heliotrine O5 7O58 5.P ca. O ca. 4 ca.
4S
)-oxide
@asiocarpine 4-4.> 4.>-9 O
Heliotridine 9> ca. 4 79>8 7ca. 48 > 5S
trachelanthate
Heliotridine <S 5S 7<S8 75S8



a
1rom: ?ull et al. 74ROQ8.
The distriution o- the uni-orml:
4<
%-laelled natural
p:rroliGidine alIaloid senecionine in lactatin! mice Yas studied :
&astman et al. 74RQ58. A-ter 4O h* P>\ o- the radioactivit: had
een recovered in the urine* 4<\ in the -aeces* ut onl: S.S<\ Yas
in the milI; the liver contained 4.R5\. The mice Yere milIed usin!
teat cups. %andrian et al. 74RQ>8 studied the distriution o-
radioactivit: in rats !iven small doses o- senecionine or
seneciph:lline 7S.9 - 9.9 m!'I!8* tritiated in the p:rroliGidine
7retronecine8 moiet:. +ost radioactivit: Yas eliminated in the
urine and -aeces Yithin < da:s. Csin! mass spectrometr:* 0icIinson
et al. 74RPO8 -ound a concentration o- up to S.Q< m! PAs'litre in
the milI o- coYs -ed
Senecio Xacobaea.
?lood levels o- senecionine
in rats !iven S.4 @0
>S
ip Yere determined : %ulvenor 74RPQ8. The
levels Yere S.9Q* S.95* and S.4< m!'litre at S.>* 4* and 5 h a-ter
in;ection* respectivel:.
To summariGe* the availale evidence su!!ests that in!ested
toxic p:rroliGidine alIaloids are rapidl: metaoliGed and that the
excretion o- unchan!ed alIaloid and o- most metaolites is also
rapid. Thus* Yithin a -eY hours* onl: a relativel: small
proportion o- the dose remains in the od:* much o- this in the
-orm o- metaolites ound to tissue constituents. ,t appears
improale that a si!ni-icant amount o- unchan!ed alIaloid Yill
remain in the od: a-ter the -irst da:.
P:rroliGidine
/
-oxides are much more Yater solule than their
parent alIaloids. ,ndicine
/
-oxide 7Yhich is exceptionall: Yater
solule8 is ver: rapidl: excreted* either unchan!ed or con;u!ated.
Thus* indicine
/
-oxide !iven iv to mice* monIe:s* or raits
disappeared -rom the serum Yith initial hal--lives ran!in! -rom 9
to 5S min 7PoYis et al.* 4RPR; &l 0areer et al.* 4RQ58. Over QS\
o- tritium-laelled indicine
/
-oxide !iven iv Yas excreted in the
urine o- mice or monIe:s Yithin 5< h 7&l 0areer et al.* 4RQ58; at
5 h* the hi!hest concentrations o- radioactivit: Yere in the
Iidne:s* liver* and intestines. Crinar: excretion o- indicine

/
-oxide Yas also rapid in raits* ut someYhat sloYer in human
ein!s 7PoYis et al.* 4RPR8.

<.5 +etaolic (outes
The ma;or metaolic routes o- unsaturated p:rroliGidine
alIaloids in animals are: 7a8 h:drol:sis 7o- the ester !roups8;
78
/
-oxidation; and 7c8 deh:dro!enation 7o- the p:rroliGidine
nucleus8 to deh:dro-alIaloids 7p:rrolic derivatives8. Other minor
routes o- metaolism are InoYn* ut the three pathYa:s account -or
the ma;or InoYn toxic e--ects o- these alIaloids 71i!. >8. (outes
7a8 and 78 are elieved to e detoxi-ication mechanisms. (oute
7c8 leads to toxic metaolites and appears to e the ma;or
activation mechanism. (oute 7a8 ma: occur in various tissues*
includin! the liver and lood. (outes 78 and 7c8 are rou!ht
aout in the liver : the microsomal mixed--unction oxidase s:stem.

<.5.4 H:drol:sis
The h:drol:sis o- a PA leads to the -ormation o- the amino-
alcohol moiet: 7necine ase8 and the acid moiet:. )either o- these
is hepatotoxic 7Echoental
Z
+attocIs* 4ROS; %ulvenor et al.*
4RPOa8. The hi!hl: Yater-solule necine ase is readil: excreted*
is not accessile to the microsomal s:stem* and is not activated to
a toxic metaolite. Thus* p:rroliGidine alIaloids that are ver:
susceptile to 7enG:mic8 h:drol:sis have loY toxicit: 7+attocIs*
4RQ58. A ma;or -actor contriutin! to resistance to esterase is
the steric hindrance in the acid moiet:. Thus* the chain ranchin!
near the caron:l !roups sloYs h:drol:sis alloYin! the -ormation o-
relativel: hi!h levels o- p:rrolic metaolites; a con-ormation o-
the asic moiet:* Yhich rin!s the tYo ester !roups close to!ether*
thus leadin! to mutual steric hindrance* can also prevent
h:drol:sis 7+attocIs* 4RQ4a8.
The in-luence o- h:drol:sis
in vivo
on alternative metaolic
pathYa:s is demonstrated : the -act that treatment o- rats Yith an
esterase inhiitor* e-ore !ivin! p:rroliGidine alIaloids 7or
s:nthetic analo!ues8* can lead to !reatl: increased production o-
p:rrolic metaolites -rom alIaloids that are normall: susceptile
to h:drol:sis* ut little increase in those -rom alIaloids normall:
resistant to h:drol:sis 7+attocIs* 4RQ4a8.

<.5.5 )-oxidation
The
/
-oxidation o- p:rroliGidine alIaloids is induced : the
hepatic microsomal enG:mes. The
/
-oxide metaolites are hi!hl:
Yater solule and are rapidl: excreted in the urine 7+attocIs*
4ROQa8. P:rroliGidine
/
-oxides are not converted to an:
si!ni-icant extent to p:rrolic metaolites : microsomal enG:mes
7Wa!o et al.* 4RPS; +attocIs
Z
Nhite* 4RP4a8* and there is no
evidence that the: are toxic* unless -irst reduced to the
correspondin! asic alIaloids* Yhich can then e activated : the
microsomal s:stem 7+attocIs* 4RP4c8. Thus* it appears that the
-ormation o-
/
-oxides represents a detoxi-ication pathYa:.

<.5.9 %onversion to p:rrolic metaolites
,n laorator: animals* toxic p:rroliGidine alIaloids are
metaoliGed to p:rrolic derivatives* so-called ecause the
unsaturated rin! o- the p:rroliGidine s:stem loses 5 h:dro!en atoms
to -orm Yhat is in e--ect a p:rrole rin! 7thou!h the structure is
more correctl: a dih:drop:rroliGidine8. P:rrolic metaolites are
easil: detectale in the tissues shortl: a-ter !ivin! a toxic
p:rroliGidine alIaloid to an animal* : treatin! the tissue Yith an
&hrlich rea!ent containin! oron tri-luoride* Yhen a red colour is
produced; this reaction also occurs Yith the urine 7+attocIs*
4ROQa; +attocIs
Z
Nhite* 4RPS8. ,n rats !iven retrosine* p:rrolic
metaolites Yere -ound principall: in the liver* Yith hi!hest
levels associated Yith the microsomal and solid deris -ractions
and less in the mitochondrial -raction; loY levels Yere -ound in
the lun!s* heart* spleen* and Iidne:s* Yithin < h o- !ivin!
retrosine. (ats !iven OS m! retrosine'I! od: Yei!ht excreted 4<\
o- the dose in the urine* Yithin <Q h.
P:rrolic metaolites are -ormed : the hepatic mixed--unction
oxidase s:stem* Yith a re$uirement -or c:tochrome P<>S* ox:!en* and
)A0PH* as has een demonstrated
in vitro
7Wa!o et al.* 4RPS;
+attocIs
Z
Nhite* 4RP4a8. %onversion o- p:rroliGidine alIaloids to
p:rrolic metaolites : the lun! tissue o- the human emr:o
7Armstron!
Z
cucIerman* 4RPS8* rat 7+attocIs
Z
Nhite* 4RP4a;
HilliIer et al.* 4RQ98* or rait 76uen!erich* 4RPP8 Yas
ne!li!ile. The -ormation o- p:rrolic metaolites does not proceed
via
/
-oxide intermediates* ut appears to result -rom an initial
h:drox:lation o- the unsaturated p:rroliGidine rin! ad;acent to the
nitro!en atom 7+attocIs
Z
Nhite* 4RP4a; +attocIs
Z
?ird* 4RQ98.
This Yould lead to a chemicall: unstale intermediate that Yould e
expected to decompose spontaneousl: to the p:rrolic product. The
primar: p:rrolic metaolites 7or deh:dro-alIaloid8 -ormed :
deh:dro!enation o- p:rroliGidine alIaloids are chemicall:
deh:drop:rroliGidine esters 71i!. >8. These are hi!hl: reactive
compounds that can rapidl: react Yith tissue constituents or
h:drol:se to the correspondin! p:rrolic alcohols* or deh:dro-
necines* Yhich can thus e re!arded as secondar: metaolites. The
latter can also react Yith tissue constituents* ut more sloYl:.
?ecause o- their hi!h chemical reactivit:* the primar: metaolites
Yould e expected to have a short li-e in the liver cell 7minutes
or seconds8 e-ore the: are h:drol:sed or react Yith nucleophilic
tissue constituents. Eome mi!ht escape into the lood stream and
reach other or!ans* especiall: the lun!s. 0eh:dro-necines are more
stale and also more Yater solule* and can ecome more Yidel:
distriuted throu!hout the od:. HoYever* the: are also capale o-
reactin! Yith tissue constituents. Thus* measurements o- p:rroles
-ormed -rom p:rroliGidine alIaloids in tissue samples* usin! a
colour reaction 7+attocIs
Z
Nhite* 4RPS8* Yill not represent a
sin!le metaolite* ut mixtures o- the metaolites to!ether Yith
various reaction products o- these Yith tissue constituents. ,t
Yill e seen 7section >8 that p:rrolic metaolites are elieved to
e responsile -or ma;or toxic actions o- p:rroliGidine alIaloids
7+attocIs* 4RP5a8.
A p:rrolic metaolite Yith reactivit: midYa: etYeen that o-
deh:dromonocrotaline and deh:droretronecine has een reported to e
-ormed -rom monocrotaline in isolated* per-used rat liver
7@a-ranconi et al.* 4RQ>8. Etudies on this metaolite 7isolated
-rom ile8 indicated that it is a monoester* and that it is toxic
in per-used rat lun!. This su!!ests that monoester p:rrolic
metaolites ma: pla: a part in the toxic actions o- PAs in extra-
hepatic tissues.
Nhen rats or other laorator: animals are !iven a toxic
p:rroliGidine alIaloid* p:rrolic metaolites accumulate rapidl: in
the liver 7+attocIs* 4RP9; Nhite et al.* 4RP98* reachin! a peaI
Yithin 4 - 5 h* then -allin! sloYl: durin! the next 5< h; the
metaolites ma: still e detectale a-ter 5 da:s. Accumulation is
especiall: rapid a-ter intraperitoneal in;ection* a ver: hi!h level
o- p:rrolic metaolites ein! attained Yithin 5S min; this
indicates hoY rapid the metaolism o- p:rroliGidine alIaloids can
e.
The level o- p:rrolic metaolites in rat liver is !enerall:
directl: related to the amount o- alIaloid !iven 5 h previousl:* at
least up to an acute @0
>S
dose. The p:rrole level depends on the
alIaloid used* and is related to the acute hepatotoxicit: o- the
alIaloid 7+attocIs* 4RP5a8.
To e converted to the t:pe o- chemicall: reactive* toxic
p:rrolic metaolites descried aove* an alIaloid must possess a
4-h:drox:meth:l p:rroliGidine s:stem* unsaturated in the
4*5-position 7this maIes the rin! susceptile to deh:dro!enation8*
and at least one h:drox:l !roup must e esteri-ied* usuall: : a
ranched-chain acid. Otonecine esters are converted to similar
p:rrol metaolites : a di--erent media involvin!
/
-demeth:lation.
P:rroliGidine amino-alcohols 7e.!.* retronecine8 are not
metaoliGed to more than small amounts o- p:rroles 7Wa!o et al.*
4RPS; +attocIs* 4RQ4a8* possil: ecause the: are too Yater solule
to reach the microsomal enG:mes.
The metaolic -ormation o- p:rroles is catal:sed : c:tochrome
P<>S and speci-icit: exists in the various isoG:mes 76uen!erich*
4RPP; Wune;a et al.* 4RQ<8.
A -eY non-toxic p:rroliGidine alIaloids 7e.!.* rosmarinine and
h:!roph:lline8 are converted to p:rrolic metaolites
in vivo
7+attocIs* 4RP98. Euch metaolites are chemicall: di--erent -rom
the p:rroles o- toxic alIaloids* and the: are neither reactive nor
toxic 7+attocIs
Z
Nhite* 4RP48. The alance o- structural
-eatures necessar: -or a p:rroliGidine alIaloid to e converted to
!ive hi!h concentrations o- toxic p:rrolic metaolite has een
discussed : +attocIs 74RQ4a8; the optimum conditions appear to e
met in some alIaloids that are macroc:clic diesters* such as
retrosine.

<.9 &--ects o- Treatments A--ectin! +etaolism
The -ormation o- p:rrolic metaolites 7and o-
/
-oxides8 is
altered : treatments that a--ect the hepatic microsomal enG:mes.
Euch e--ects have een studied : measurin! rates o- metaolism o-
p:rroliGidine alIaloids
in vitro
usin! microsomal preparations
-rom animals pre-treated in various Ya:s 7Tale P8. 1or example*
microsomes -rom rats !iven the microsomal enG:me inducers
phenoaritone or 00T 7ut not those -rom rats !iven
9-meth:lcholanthrene8 induce !reatl: increased p:rrole -ormation
and smaller increases in
/
-oxide -ormation* -rom the alIaloid
retrorsine 7+attocIs
Z
Nhite* 4RP4a8. &nG:me preparations -rom
rats treated Yith inhiitors o- microsomal enG:mes* includin! Eb1
>5>A and chloramphenicol* are much less active in convertin!
monocrotaline to p:rroles 7%hesne: et al.* 4RP<8. The ailit: to
metaoliGe retrorsine is diminished in microsomes -rom rats -ed a
protein--ree diet* or -rom rats acutel: poisoned Yith retrorsine
7+attocIs
Z
Nhite* 4RP4a8.
Tale P. &--ect o- pre-treatment o- male rats on the conversion o- PAs
to
p:rrolic derivatives and to
/
-oxides : liver microsomes

in vitro
----------------------------------------------------------------------------
AlIaloid Pre-treatment* and &nG:me activit: as (e-erence
time e-ore enG:me \ o- control values
measurements
-or -ormation o-:
P:rroles
/
-oxides
----------------------------------------------------------------------------
retrorsine phenoaritone* ip* 944 595 +attocIs
Z
9 x 4SS m!'I!* Nhite 74RP4a8
4 - 9 da:s
retrorsine 00T* ip* P> m!'I!* <SP 5S9 +attocIs
Z
9 da:s Nhite 74RP4a8
retrorsine 9-meth:lcholanthrene* R> 7ns8 44O 7ns8 +attocIs
Z
ip* 9 x 5S m!'I!* Nhite 74RP4a8
4 - 9 da:s
retrorsine retrorsine* ip* O9 - +attocIs
Z
9> m!'I!* 5S h Nhite 74RP4a8
retrorsine protein--ree diet* 9R - +attocIs
Z
9 da:s Nhite 74RP4a8
monocrotaline phenoaritone* sc* <<Q 4O> %hesne: et al.
< x P> m!'I!* 74RP<8
4 - < da:s
monocrotaline chloramphenicol* sc* 4S 4SR 7ns8 %hesne: et al.
5SS m!'I!* 4 h 74RP<8
monocrotaline Eb1 >5>A* ip* P> m!'I!* 4S QP 7ns8 %hesne: et al.
4 h 74RP<8
----------------------------------------------------------------------------
ns ^ not si!ni-icantl: di--erent -rom controls.
The e--ects o-
in vivo
treatment Yith several t:pes o- enG:me
inducers on the toxicit: o- lasiocarpine and senecionine -or
primar: rat hepatoc:te cultures Yas investi!ated : Ha:es et al.
74RQ>8. Pre-treatment Yith phenoaritone potentiated the
c:totoxicit: o- senecionine toYards the cultured cells* Yhereas
pre-treatment Yith 9-meth:lcholanthrene diminished the toxic action
o- senecionine* ut had little e--ect on lasiocarpine c:totoxicit:.
The c:tocidal e--ects o- oth alIaloids Yere sustantiall:
inhiited in the presence o- Eb1 >5>A.

<.< Other 1actors A--ectin! +etaolism
Tariations etYeen animal species have een investi!ated :
Nhite et al. 74RP98 and Ehull et al. 74RPO8. 1or instance*
metaolism to -orm p:rroles is hi!h in rats and ver: loY in !uinea-
pi!s* Yhich* hoYever* have hi!her rates o-
/
-oxidation. 1or
example* 5 h a-ter an ip dose o- retrosine 74SS m!'I! od: Yei!ht8*
the liver-p:rrole level in male rats Yas 49 times hi!her than that
in male !uinea-pi!s 7Nhite et al.* 4RP98. @iver microsome
preparations -rom male rats Yere 5Q times more active than
microsomes -rom male !uinea-pi!s in the deh:dro!enation o-
monocrotaline 7%hesne:
Z
Allen* 4RP9a8.
The development Yith a!e o- the ailit: o- Nistar rats to
metaoliGe retrosine Yas studied : +attocIs
Z
Nhite 74RP98. The
ailit: to -orm p:rroles is ver: loY in neY-orn rats* ut* : >
da:s o- a!e* it is nearl: as hi!h as in adult males. This activit:
continues at a similar level in male rats* ut* in -emales* it
-alls a-ter the a!e o- aout 5S da:s until* : OS da:s* it is aout
one-ei!hth that in males. Euch a sex di--erence Yas not oserved
in mice 7Nhite et al.* 4RP98.

<.> Other +etaolic (outes
The actions o- hepatic microsomal enG:mes on p:rroliGidine
alIaloids can produce other metaolites as Yell as p:rroles and

/
-oxides* ut there are -eY reports o- these. &astman
Z
Ee!all
74RQ58 demonstrated h:drox:lation o- the acid moiet: o- senecionine
: liver microsomes -rom -emale mice. Euch metaolism should not
prevent the suse$uent conversion o- the product to p:rrolic or

/
-oxide metaolites. The -ormation o- other microsomal metaolites
o- senecionine has een reported : Ee!all et al. 74RQ<8.
The
:
-demeth:lation o- the acid moiet: o- heliotrine has een
demonstrated : Wa!o et al. 74ROR8 and represents a partial
detoxi-ication mechanism* since the product is aout hal- as toxic
as heliotrine. Other detoxi-ication mechanisms exist in the rumen
o- sheep 70icI et al.* 4RO9; @ani!an
Z
Emith* 4RPSa*8* Yhich are*
thus* particularl: resistant to the e--ects o- p:rroliGidine
alIaloids.

<.O +etaolism o- P:rroliGidine
/
-Oxides
As mentioned in section <.5* the
/
-oxides o- p:rroliGidine
alIaloids are not converted to p:rrolic metaolites : liver
microsomes. ,t appears that their main route o- metaolism in
animals is reduction to the correspondin! asic alIaloids* Yhich
ma: then e -urther metaoliGed as alread: descried. This
reduction has een shoYn to occur in the rat or rait !ut
7+attocIs* 4RP4c; PoYis et al.* 4RPR8* and ma: e rou!ht aout :
intestinal acteria or possil: : !ut enG:mes. Euch reduction can
also e rou!ht aout : hepatic microsomal -ractions 7PoYis et
al.* 4RPR8 in the presence o- )A0H or o- )A0PH* and : sheep rumen
-luid 7@ani!an et al.* 4RPSa* 8.
The reduction o- p:rroliGidine
/
-oxides
in vivo
is o- !reat
importance as a step in the ioactivation o- these compounds
7+attocIs* 4RP4c8* as shoYn in section <.5.5.

<.P +etaolism in +an
PoYis et al. 74RPR8 -ound that indicine
/
-oxide !iven iv to
9 human patients as an antitumour dru! Yas partiall: reduced to
indicine ase* detectale in the urine and plasma. Armstron!
Z

cucIerman 74RPS8 shoYed that human emr:o liver slices* ut not
lun! slices* converted the p:rroliGidine alIaloids lasiocarpine*
retrorsine* and -ulvine to p:rrolic metaolites
in vitro.
>. +&%HA),E+E O1 TOL,%,TF A)0 OTH&( ?,O@O6,%A@
A%T,O)E
>.4 +etaolites (esponsile -or Toxicit:
>.4.4 +etaolic asis o- toxicit:
The toxic e--ects o- p:rroliGidine alIaloids are mediated
throu!h their toxic metaolites and not : the alIaloids
themselves. The -olloYin! oservations are evidence -or the aove
statement 7+attocIs* 4RP5a8:
7a8 The alIaloids are chemicall: rather unreactive and it is
hard to envisa!e reactions Yith cell constituents that the:
could under!o readil: under ph:siolo!ical conditions. On the
other hand* chemicall: prepared derivatives* similar or
identical to InoYn metaolites o- these alIaloids* are hi!hl:
reactive and are capale o- causin! toxic e--ects similar to
those o- PAs* o-ten at dose levels much loYer than those
re$uired : the alIaloids themselves.
78 The liver is usuall: the main or!an a--ected* Yhatever the
route o- administration o- the alIaloid. The alIaloids are
InoYn to e metaoliGed in the liver.
7c8 0irect application o- these alIaloids to the sIin does not
cause local toxic e--ects 7Echoental et al.* 4R><8* nor do
c:totoxic e--ects occur at sites o- in;ection.
7d8 The susceptiilit: o- animals to the toxic actions o- PAs
is related to the ailit: o- the animal to metaoliGe the
alIaloids. 1or example* the hepatic microsomal enG:mes o- rats
less than 4 h old have ver: loY activit: toYards retrorsine and
these rats are relativel: resistant to it* Yhereas rats a!ed
several da:s have a hi!h enG:me activit: and are hi!hl:
susceptile to the alIaloid 7+attocIs
Z
Nhite* 4RP98. 6uinea-
pi!s are ver: resistant to retrorsine* unless the: have een
!iven phenoaritone* Yhich potentiates the enG:mes that
metaoliGe it 7Nhite et al.* 4RP98. (ats pre-treated Yith
microsomal enG:me inhiitors* such as Eb1 >5>A or
chloramphenicol* have increased resistance to retrorsine or
monocrotaline 7Allen et al.* 4RP5; +attocIs* 4RP98. ,n
!eneral* there is a !ood relationship etYeen the rate o-
hepatic metaolism o- PAs to p:rrole
in vitro
7Ehull et al.*
4RPO8 and chronic toxicit:. Hi!hl: resistant species* e.!.*
!uinea-pi!s* Wapanese $uail* and sheep* have a loY rate o-
p:rrole -ormation* Yhile susceptile species* such as the
horse* cattle* and rat* have a hi!h rate. )otale exceptions
are the rait and hamster* Yhich have hi!h rates o- p:rrole
-ormation* ut are resistant. ,t is possile that this ma: e
due to chan!es in the alance etYeen activation and the
involvement o- other -actors* such as activit: o-
detoxi-ication. 1or example* sheep have a hi!h epoxide
h:drolase activit: in the liver 7EYicI et al.* 4RQ98* Yhich ma:
a--ect PA detoxi-ication 7%heeIe
Z
Pierson-6oe!er* 4RQ98.

>.4.5 ,solation o- p:rrolic metaolites
There is plent: o- evidence that man: unsaturated PAs are
converted into p:rrolic esters 7deh:dro-alIaloids8 in the mammalian
liver 7section <.5.98. These primar: p:rrolic metaolites cannot
e isolated* ecause o- their hi!h reactivit: and rapid rate o-
h:drol:sis. HoYever* their more stale h:drol:sis products
7p:rrolic alcohols; deh:dronecines8 have een isolated and
identi-ied. Thus deh:droheliotridine has een otained -rom the

in vitro
incuation o- oth the heliotridine-ased alIaloids*
lasiocarpine and heliotrine* Yith rat liver microsomes 7Wa!o et
al.* 4RPS8 and deh:dro-retronecine Yas -ound to e the main
detectale p:rrolic metaolite in the liver* lood* and urine o-
rats in;ected Yith the retronecine-ased alIaloid* monocrotaline
7Hsu et al.* 4RP98. There is evidence that these materials are
identical* i.e.* the 7u8--orm resultin! -rom racemiGation durin!
h:drol:sis o- the parent p:rrolic esters 7bedGiersIi
Z
?uhler*
4RQ>8.
The results o- these studies con-irm that rat liver enG:mes
convert PAs into metaolites Yith InoYn c:totoxic activit: 7section
>.58* and impl: that these metaolites are -ormed via the :et more
toxic and short-lived deh:dro-alIaloids 7Wa!o et al.* 4RPS8.

>.4.9 %hemical aspects o- p:rrolic metaolites
>.4.9.4 Preparation
%hemical methods are availale -or convertin! unsaturated PAs
into p:rrolic esters 7deh:dro-alIaloids8* the putative primar:
toxic metaolites* enalin! the ph:sical* chemical* and
toxicolo!ical properties o- the latter to e studied.
Emall amounts o- deh:dro-p:rroliGidine alIaloids are usuall:
prepared : the reaction o- the correspondin! alIaloid
/
-oxides
Yith either acetic anh:dride 7+attocIs* 4ROR; %ulvenor et al.*
4RPSa8 or methanolic -errous sul-ate 7+attocIs* 4ROR8. The
products must e protected -rom moisture and -rom acids* Yhich can
cause their immediate decomposition.
A variet: o- rea!ents can deh:dro!enate the alIaloid ases to
p:rrolic derivatives* these include man!anese dioxide 7%ulvenor et
al.* 4RPSa*; +attocIs* 4ROR8* potassium perman!anate 7%ulvenor et
al.* 4RPSa8* chloranil 7%ulvenor et al.* 4RPSa8* 5*9-dichloro->*O-
dic:anoenGo$uinone 7+attocIs* 4ROR8* iodine 7%ulvenor et al.*
4RPS8* and ar:l thiols 7Wune;a et al.* 4RQ<8. Eome PAs are sloYl:
oxidiGed to p:rroles : molecular ox:!en 7?icI et al.* 4RP>8.
The more stale p:rrolic alcohol* deh:droretronecine 71i!. O8*
is prepared -rom retronecine usin! chloranil 7%ulvenor et al.*
4RPSa8 or a$ueous potassium nitro-sodisul-onate 7+attocIs* 4RQ4c8
or -rom retronecine
/
-oxide 7isatinecine8 usin! -errous sul-ate
7+attocIs* 4ROR8. The enantiomeric deh:droheliotridine can e
prepared -rom heliotridine in similar Ya:s. (acemic deh:dro-
heliotridine has een s:nthesiGed 7Tiscontini
Z
6ilho--
Echau-eler!er* 4RP4; ?ohlmann et al.* 4RPR8.

>.4.9.5 %hemistr: associated Yith toxic actions
0eh:dro-p:rroliGidine alIaloids and deh:dronecines 7p:rrolic
esters and alcohols8 act chemicall: as alI:latin! 7electrophilic8
a!ents* i.e.* the: can react Yith compounds possessin! electron-
rich 7nucleophilic8 !roups* such as amines* thiols* and some
h:drox:l compounds. The products o- alI:lation consist o- the
]p:rrole] moiet: covalentl: onded to the sustrate molecule. The
mechanism o- alI:lation is illustrated in 1i!. P 7+attocIs* 4RP5a8.
An ester 7( ^ %O(8 or h:drox:l !roup 7( ^ H8 attached to the
p:rrole rin! via one caron atom 7i.e.* at %P or %R8 is hi!hl:
reactive* ein! easil: cleaved* leavin! a positivel: char!ed
p:rrole moiet: Yith a hi!h a--init: -or electron-rich sustrates.
P:rrolic esters are the most reactive* (%OO ein! a etter ]leavin!
!roup] than HO. Nhen 5 ox:!en -unctions are present 7as
illustrated8* either 7in turn8 can act as an alI:latin! centre.
Euch i-unctional alI:lation could lead to cross linIin! o-
macromolecules 7+attocIs* 4ROR; Nhite
Z
+attocIs* 4RP5; Petr: et
al.* 4RQ<* 4RQO8. Nhen the !roups 7(8 are the same or similar* %P
is the more reactive site. &xamples o- such alI:lations usin! pure
chemicals 7amines or alcohol8 have een !iven : +attocIs 74ROR8
and %ulvenor et al. 74RPSa8. +attocIs
Z
?ird 74RQ98 shoYed that a
variet: o- nucleophiles o- iolo!ical interest could e alI:lated
: deh:droretronecine. ?lacI
Z
Wa!o 74RPS8 demonstrated the

in vitro
alI:lation o- 0)A : deh:droheliotridine* and (oertson
74RQ58 and NicIramana:aIe et al. 74RQ>8 the alI:lation o-
deox:!uanosine : deh:droretronecine. The alI:lation o- mouse or
rat liver 0)A : p:rroliGidine alIaloids has een shoYn
in vivo
:
&astman et al. 74RQ58 and %andrian et al. 74RQ>8.

>.4.< Possile -urther metaolites
The possiilit: that p:rrolic metaolites o- PAs mi!ht
themselves e metaoliGed : microsomal enG:mes to -urther
c:totoxic derivatives Yas su!!ested : 6uen!erich
Z
+itchell
74RQS8. These authors shoYed that the tritium-laelled model
compounds 4*5*9-trimeth:lp:rrole and 4-meth:l-9-< ish:drox:-
meth:lp:rrole could e metaoliGed in rats or : rat liver
microsomes to unidenti-ied derivatives ale to ind covalentl: to
proteins and nucleic acids. ,t is possile that liver dama!e* seen
in some rats !iven iv in;ections o- pneumotoxic p:rrolic esters*
mi!ht have een due to metaolites o- the latter -ormed in the
liver 7+attocIs
Z
0river* 4RQ98. Ee!all et al. 74RQ>8 have
identi-ied trans-<-h:drox:-5-hexenal in an
in vitro
mouse liver
microsomal s:stem metaoliGin! the PA senecionine and su!!ested
that it mi!ht have een -ormed -rom the alIaloid via a p:rrolic
intermediate. The compound is capale o- causin! liver dama!e and
mi!ht contriute to the acute hepatotoxicit: o- senecionine and
other alIaloids. HoYever* this has not een proved* and the hi!hl:
reactive and toxic primar: p:rrolic metaolites -rom PAs are
themselves capale o- causin! the InoYn hepatotoxic e--ects o-
these alIaloids.

>.5 Toxic Actions o- P:rrolic +etaolites
P:rrolic derivatives prepared chemicall: -rom PAs* as Yell as
some analo!ous compounds* have een tested in experimental animals
and
in vitro
s:stems* and shoYn to have a variet: o- toxic actions.

>.5.4 Animals
>.5.4.4 P:rrolic esters 7deh:dro-alIaloids8
0eh:dro-p:rroliGidine alIaloids are ver: reactive and their
e--ects
in vivo
are lar!el: con-ined to the -irst tissues the:
encounter. Nhen !iven orall: to rats* the: are destro:ed almost
immediatel: in the a$ueous acid o- the stomach and shoY no toxic
action. Nhen !iven ip* the: cause severe local irritation and
peritonitis 7+attocIs* 4ROQa; ?utler et al.* 4RPS8; sucutaneous
in;ection leads to sIin lesions 7Hooson
Z
6rasso* 4RPO8. A-ter iv
in;ection o- p:rroles* such as deh:dromonocrotaline 7monocrotaline
p:rrole8* into the tail veins o- rats* the toxic in;uries appear
principall: in the lun!s. 0ependin! on the dose* these include
vascular lesions and pulmonar: oedema 7Plestina
Z
Etoner* 4RP58; a
pro!ressive alveolar proli-eration similar to that produced :
ver: much lar!er doses o- the parent alIaloid 7?utler et al.*
4RPS8 and pulmonar: h:pertension 7HilliIer et al.* 4RQ98.
0eh:dromonocrotaline does not re$uire -urther metaolism to express
its pneumotoxicit:* and it is rapidl: rendered inactive a-ter
exposure to a$ueous media 7?runer et al.* 4RQO8. Eimilar
pneumotoxicit: is produced : totall: s:nthetic p:rrolic esters
havin! a simpler structure ut the same t:pe o- chemical reactivit:
as the alIaloid derivatives 7+attocIs
Z
0river* 4RQ98* thus
con-irmin! the chemical mechanism o- this action.
,n;ections o- deh:dro-p:rroliGidine alIaloids or s:nthetic
analo!ues into mesenteric veins o- rats lead to liver dama!e a-ter
smaller doses than the alIaloids themselves 7?utler et al.* 4RPS;
EhumaIer et al.* 4RPO8. The liver dama!e di--ers someYhat -rom the
alIaloid dama!e* consistent Yith the toxin ein! introduced via the
hepatic vascular s:stem rather than ein! produced Yithin the
hepatoc:tes* as is the case Yith the alIaloids. )evertheless* the
pro!ressive liver lesions are ver: similar to those produced : PAs
7?utler et al.* 4RPS8. The lun! dama!e a-ter tail vein in;ections
ears a closer resemlance to p:rroliGidine dama!e* since the
latter is also elieved to e caused : metaolites enterin! the
lun!s via the loodstream 7?arnes et al.* 4RO<8.
>.5.4.5 P:rrolic alcohols 7deh:dro-necines8
0eh:droheliotridine 71i!. O8* a secondar: p:rrolic metaolite
-rom heliotridine-ased PAs* such as heliotrine and lasiocarpine*
is less acutel: toxic than its parent alIaloids; it has an @0
>S
7P
da:s8 o- aout 5>S m!'I! od: Yei!ht in mice 7Perc:
Z
Pierce*
4RP48. ,ts e--ects on 4<-da:-old rats Yere studied : Peterson et
al. 74RP58. All rats !iven ip doses o- S.< mmol'I! od: Yei!ht
survived* ut a dose o- S.O mmol'I! Iilled most animals Yithin 4S
da:s. Toxic e--ects Yere mainl: -ound in rapidl: developin!
tissues. ,n :oun! rats* it caused -ur loss* tooth de-ects* and
atroph: o- hair -ollicles* !ut mucosa* spleen* th:mus* testis* and
one marroY. The lun!s Yere not a--ected. Patholo!ical e--ects in
the liver Yere con-ined to necrosis o- isolated cells and
antimitotic action* Yhich Yas mani-ested as a mild me!aloc:tosis
7development o- !iant hepatoc:tes8 in rats survivin! < YeeIs or
more. The persistent antimitotic action o- deh:droheliotridine and
o- its parent alIaloid lasiocarpine in the liver o- rats Yas
investi!ated : Eamuel
Z
Wa!o 74RP>8* Yho located the mitotic locI
as ein! either late in the 0)A s:nthetic 7E8 phase or earl: in the
post s:nthetic 7658 phase o- the cell c:cle.
0eh:droheliotridine is also carcino!enic. Peterson et al.
74RQ98 shoYed that rats !iven R ip in;ections o- this compound
7OS - PO.> m!'I! od: Yei!ht8 over 59 YeeIs had a shorter li-e span
and su--ered a si!ni-icantl: hi!her incidence o- tumours than control
rats. The authors concluded that deh:droheliotridine is responsile
-or some* or possil: all* o- the carcino!enicit: o- its parent
alIaloids.
0eh:droheliotridine Yas -ound to e terato!enic Yhen !iven ip
to -emale hooded rats on the 4<th da: o- pre!nanc:. A dose o-
<S m!'I! od: Yei!ht produced e--ects similar to those produced : the
alIaloid heliotrine at a dose o- 5SS m!'I! 7Peterson
Z
Wa!o* 4RQS8.
1or the immunosuppressant activit: o- this compound* see section
O.<.4S.
The toxic actions o- deh:droretronecine 70H(8 71i!. P8 Yhen
!iven sc to rats are similar to those o- deh:droheliotridine 7Hsu
et al.* 4RP9; EhumaIer et al.* 4RPO8. (epeated lar!e doses also
caused ulceration o- the !landular stomach. 0ail: sc doses
7< m!'I! od: Yei!ht8* administered to rats -or 4 YeeI* caused lun!
dama!e leadin! to ri!ht ventricular h:pertroph: 7Huxtale et al.*
4RPQ8. 0H( Yas carcino!enic Yhen applied repeatedl: to mouse sIin
7Wohnson et al.* 4RPQ; +attocIs
Z
%aral* 4RQ58.

>.5.5 %ell cultures
0eh:droheliotridine and deh:drosupinidine oth have an
inhiitor: action in cultures o- b? cells 7human epidermoid
carcinoma o- the nasophar:nx8 Yith &0
>S
concentrations o- 4S
-<
mol
and 4S
->
mol* respectivel: 7%ulvernor et al.* 4ROR8.
?icI
Z
%ulvenor 74RP48 -ound deh:droheliotridine 70H(8 to e
consideral: more e--ective than the alIaloid heliotrine in
suppressin! cell division and causin! chromosome reaIs* in
cultures o- leuIoc:tes -rom the marsupial
Potorus tridactylus
; at a
concentration o- O x 4S
->
mol* the mitotic index Yas Gero* and more
than hal- the cells had disinte!rated. ,n a stud: : +attocIs
Z

@e!! 74RQS8* deh:droretronecine and several s:nthetic analo!ues
completel: inhiited cell division in a cultured rat liver cell
line at a concentration o- 4S
-<
mol. Ord et al.* 74RQ>8 -ound that
0H( induced sister chromatid exchan!e in human l:mphoc:tes Yithout
the need -or metaolic activation. Analo!ous p:rroles Yith onl:
one -unctional 7reactive8 !roup Yere much less e--ective. 0H( Yas
also YeaIl: active in inducin! mutations in the
Salmonella
typ#imurium
ase sustitution strain* TAR5* and !ave positive
results in an
in vitro
cell trans-ormation test usin! a culture
derived -rom hamster Iidne: cells 7Et:les et al.* 4RQS8.
The toxicit: o- the p:rrolic ester* deh:dromonocrotaline* -or
cultures o- mouse -irolasts Yas studied
in vitro
: Wohnson
74RQ48. The level o- exposure Yas approximatel: 4 n! per cell.
%ell death Yas preceded* -irst : the sYellin! and disruption o-
or!anelles* includin! mitochondria* and then : the rupture o-
plasma memranes Yith the release o- cell components.
?icI et al.* 74RP>8 investi!ated Yhether the e--ects o- PAs on
leuIoc:te cultures o-
Potorus tridactylus
Yere due to p:rrolic
metaolites. @evels o- dih:drop:rroliGines* Yhich could e
demonstrated in the culture media* Yere insu--icient to account -or
the oserved e--ects o- heliotrine* lasiocarpine* and monocrotaline
on the cells* ut the actual amounts -ormed Yithin the cells ma:
have een hi!her than those oserved.

>.5.9 Possile participation o- memrane lipid peroxidation
0istinct increases in )A0PH- and ascorate-dependent
peroxidation o- microsomal memrane lipids Yere -ound in rats !iven
heliotrine sucutaneousl: 79SS m!'I! od: Yei!ht8 7Eavin 4RQ98.
The primar: iochemical interactions and cellular macromolecular
tar!ets -or the patho!enesis o- PA-induced toxicit: remain
unidenti-ied.

>.9 %hemical and +etaolic 1actors A--ectin! Toxicit:
The toxicit: o- an alIaloid depends on the extent to Yhich it
is converted into active metaolites and on the disposition and
reactivit: o- these metaolites* once -ormed.

>.9.4 Etructural -eatures o- a toxic alIaloid
The essential structural -eatures o- a hepatotoxic PA 71i!. Q8
are:
7a8 a 4-h:drox:meth:lp:rroliGidine rin! s:stem unsaturated in
the 4:5-position* Yith pre-eral: a second h:drox:l !roup
in the P-position;
78 esteri-ication o- at least one o- the h:drox:ls* thou!h
toxicit: is much !reater Yhen oth h:drox:ls are
esteri-ied; and
7c8 ester !roups that are resistant to enG:mic h:drol:sis*
Yhich usuall: means that there is a hi!h de!ree o- chain
ranchin! in the acid moiet:.
The aove re$uirements appl: to natural PAs ut* strictl:
speaIin!* onl: the ri!ht hand 7p:rroline8 rin! is essential* ein!
the rin! that is metaoliGed to a p:rrole derivative. Thus* esters
o- 5*9-is-h:drox:meth:l-4-meth:l-9-p:rroline 7s:nthanecine A8
71i!. R8 have p:rroliGidine-liIe hepatotoxicit: 7+attocIs* 4RP4a;
0river
Z
+attocIs* 4RQ<8.

Etructural re$uirements -or
/
-oxides are the same as those -or
the hepatotoxic alIaloids. HoYever* it is important to note that a
PA
/
-oxide is not hepatotoxic itsel-; toxicit: depends on it ein!
reduced to the correspondin! asic alIaloid* chie-l: in the !ut
7+attocIs 4RP4c8* ut possil: in other or!ans* such as the liver
7PoYis et al.* 4RPR8.

>.9.5 Activation and detoxication
1actors a--ectin! the proportion o- an in!ested alIaloid that
is converted into toxic metaolites in an animal include the
-olloYin!:
7a8
,ipid solubility
Hi!hl: Yater-solule alIaloids 7such as indicine8 are easil:
excreted and have loY toxicit:. AlIaloids that are more lipophilic
are more open to activation : liver microsomes 7+attocIs* 4RQ4a8.
78
Subceptibility to #ydrolysis
This is determined : the molecular structure and con-ormation
o- the alIaloid 7+attocIs* 4RQ4a*8. ,- the alIaloid is open to
esterase attacI* it ma: e lar!el: detoxi-ied : h:drol:sis.
7c8
Susceptibility to /)o%idation
The relative amounts o- an alIaloid converted : hepatic
microsomal enG:mes to
/
-oxide and to p:rrolic metaolites depends
on its molecular structure and con-ormation 7+attocIs
Z
?ird*
4RQ98.
/
-oxidation represents a detoxication pathYa: 7+attocIs*
4RP58.

>.9.9 1actors a--ectin! the toxicit: o- active metaolites
>.9.9.4 (eactivit: o- the metaolite
Toxic metaolites are -ormed in liver cells. Primar: p:rrolic
metaolites 7deh:dro-alIaloids8 are ver: reactive and* thus* are
$uicIl: h:drol:sed or deactivated : reaction Yith cell constituents.
To dama!e tissues other than the cells in Yhich the: are -ormed*
active metaolites must cross the cell memrane and survive Yhile
ein! transported in the loodstream. The more stale p:rrolic
metaolites* such as deh:dromonocrotaline -rom the alIaloids
monocrotaline* are ale to reach* and ecome ound to* lun! tissue
7+attocIs* 4RP98. Thus* monocrotaline -re$uentl: dama!es the lun!s*
Yhereas retrorsine* Yhich :ields a more reactive p:rrolic metaolite*
normall: does not.
Eecondar: metaolites 7p:rrolic alcohols* e.!.* deh:droretronecine8*
-ormed : the h:drol:sis o- primar: p:rrolic metaolites* are Yater
solule* relativel: stale compounds that can ecome more Yidel:
distriuted throu!hout the od: or excreted; these are not acutel:
toxic.
>.9.9.5 The numer o- reactive !roups
The toxicit: o- a p:rrolic alI:latin! a!ent is a--ected : the
numer o- reactive ester or h:drox:l !roups 74 or 58 present as the
-olloYin! examples shoY:
7a8 +an: p:rrolic esters can cause acute lun! dama!e Yhen
!iven iv to rats* ut onl: i-unctional ones also cause
dela:ed e--ects on the lun!s 7+attocIs
Z
0river* 4RQ98.
78 ?i-unctional p:rrolic alcohols are more e--ective
inhiitors o- mitosis in cultured cells than mono-unctional
p:rroles 7+attocIs
Z
@e!!* 4RQS8.
7c8 ?i-unctional p:rrolic alcohols are much etter inducers
o- sister chromatid exchan!e 7E%&8 in l:mphoc:tes than
monoalcohols 7Ord et al.* 4RQ>8.
(easons -or these di--erences mi!ht e that the i-unctional
p:rroles are ale to crosslinI macromolecules or simpl: that the:
can ind more stron!l: to tar!et molecules.

>.< +etaolites Associated Yith the ?iolo!ical Actions o-
P:rroliGidine AlIaloids
>.<.4 Acute hepatotoxicit:
The -olloYin! is !ood evidence that acute liver necrosis is
caused : primar: p:rrolic ester metaolites 7deh:dro-alIaloids8:
7a8 The liver* in Yhich these metaolites are -ormed* is the
onl: or!an exposed to them in relativel: hi!h concentrations.
78 There are !ood correlations etYeen amounts o- p:rroles
ound to liver tissue and acute hepatotoxicit: 7+attocIs*
4RP98.
7c8 P:rrolic alcohols are not acutel: hepatotoxic* even Yhen
!iven to animals in ver: lar!e amounts.
7d8 P:rrolic esters in;ected iv into the liver are much more
acutel: hepatotoxic than the parent alIaloids 7?utler et al.*
4RPS8.
,t is possile that other metaolites* such as <-h:drox:
5*9-unsaturated aldeh:des* mi!ht also contriute to the acute
hepatotoxicit: o- some PAs 7Ee!all et al.* 4RQ>8. HoYever* this
has still to e con-irmed.

>.<.5 %hronic hepatotoxicit:
The persistent antimitotic action on the liver that leads to
the -ormation o- !iant hepatoc:tes can e produced oth : p:rrolic
ester metaolites* such as deh:dromonocrotaline 7Hsu et al.* 4RP98*
and : p:rrolic alcohols* such as deh:droheliotridine 7Peterson et
al.* 4RP58. ?oth Iinds o- metaolites can lead to similar
alI:lation products and oth are liIel: to e present in the liver
Yhen the alIaloids are metaoliGed. Thus* either could e
responsile -or chronic hepatotoxic e--ects. HoYever* the
antimitotic action alone is not su--icient. ,t must e accompanied
or -olloYed : a stimulus o- cell division. This ma: e provided
: the acute necrotic e--ect o- primar: p:rrolic metaolites or :
an: other cause o- acute liver in;ur: that leads to tissue
re!eneration. ,n ver: :oun! animals* the stimulus can e the
enhanced rate o- replication that alread: exists in them.

>.<.9 Pneumotoxicit:
%haracteristic p:rroliGidine lun! dama!e is produced : iv
in;ections o- p:rrolic ester metaolites* Yhich are e--ective at
much loYer doses than the parent alIaloids. The latter are not
metaoliGed in lun! tissue; thus* lun! dama!e -rom PAs is elieved
to e due to p:rrolic esters reachin! the lun!s -rom the liver
7?utler et al.* 4RPS8. %hronic lun! dama!e appears to e caused :
i-unctional rather than : mono-unctional p:rrolic alI:latin!
a!ents 7+attocIs
Z
0river* 4RQ98 7section >.9.9.58.
There is some evidence that p:rrolic alcohol metaolites mi!ht
also e ale to contriute to chronic 7ut not acute8
pneumotoxicit: 7Huxtale et al.* 4RPQ8.

>.<.< Toxicit: in other tissues
%hronic heart dama!e includin! ri!ht ventricular h:pertroph: is
a conse$uence o- p:rroliGidine lun! dama!e 7pulmonar: h:pertension8
7Ha:ashi et al.* 4ROP8. ?rain dama!e is attriuted to ammonia
intoxication secondar: to severe p:rroliGidine liver in;ur:
7Hooper* 4RP58. This vieY has een contested and some PAs are
InoYn to have direct e--ects on the central nervous s:stem 7section
O.<.98. There is no evidence that PAs are apprecial: metaoliGed
in tissues other than the liver. Thus* dama!e to other or!ans is
proal: due to metaolites transported -rom the liver. 1or
example* in the relativel: uncommon cases o- chronic Iidne: dama!e
a-ter p:rroliGidine intoxication 7Hooper* 4RP<; Hooper
Z
Ecanlan*
4RPP8 me!aloc:tosis in this or!an su!!ests that p:rrolic
metaolites 7either ester or alcohol8 are involved. Overall*
patterns o- disease* as oserved in extrahepatic sites* are
consistent Yith a ]spillover] e--ect o- the p:rroles produced in
the liver 7Hooper* 4RPQ8. Toxicit: o- an alIaloid re-lects its
rate o- metaolism to a p:rrole 7TuchYeer et al.* 4RP<8 and so the
spillover e--ect is liIel: to e more evident at hi!her doses.
Etudies o- %ulvenor et al. 74RPOa8 su!!est that the PAs that are
hepatotoxic -or rats should also e pneumotoxic Yhen administered
at hi!her doses. ,n acute poisonin!* the hepatotoxic e--ects could
outYei!h the pneumotoxic e--ects or those on other or!ans* to such
a de!ree that the latter are not mani-ested. Tariation in
expression o- disease 7primaril: hepatic or extrahepatic8 also
depends on the reactions o- host tissues in di--erent species o-
animals* in addition to the $uantities o- the p:rroles 7Hooper*
4RPQ8. The sensitivit: o- the lood vessels mi!ht explain severe
interstitial pneumonias in some animals* or severe nephroses in
pi!s 7+c6rath et al.* 4RP>8.

>.<.> %arcino!enicit:
The p:rrolic alcohols deh:droretronecine and deh:droheliotridine
are InoYn carcino!ens 7Wohnson et al.* 4RPQ; Peterson et al.* 4RQ98*
Yhereas the p:rrolic esters deh:dromonocrotaline and deh:droretrorsine
are onl: carcino!enic in con;unction Yith a tumour promotor 7+attocIs

Z
%aral* 4RPR* 4RQ58. This su!!ests that the more persistent
secondar: metaolites 7p:rrolic alcohols8 mi!ht account -or the rather
YeaI carcino!enicit: o- some PAs.

>.<.O Antitumour activit:
Eome PAs and their
/
-oxides are active as tumour inhiitors in
test s:stems 7%ulvenor* 4ROQ; Eu--ness
Z
%ordell* 4RQ>8. ,ndicine

/
-oxide* in particular* shoYed hi!h activit: a!ainst ?4O melanoma*
mammar: xeno!ra-t* +>SPO sarcoma* P9QQ leuIaemia* and NalIer 5>O
carcinoma. ,n clinical studies* indicine
/
-oxide has shoYn
si!ni-icant activit: a!ainst some -orms o- leuIaemia* Yith dosa!e
limited mainl: : m:elosuppression and sometimes : hepatotoxicit:.
,t is temptin! to suppose that this action is related to the
poYer-ul antimitotic action o- their p:rrolic metaolites* even
thou!h some o- these alIaloids and derived p:rroles are themselves
carcino!enic. On the other hand* there is evidence su!!estin! that
indicine
/
-oxide oYes it activit: to a propert: o- the compound
itsel- rather than to the p:rrolic metaolites* Yhich could e
-ormed throu!h reduction to indicine 7PoYis et al.* 4RPR8. The
evidence* that indicine is less e--ective than indicine
/
-oxide* is
not conclusive and other structure-activit: data 7+ilIoYsI:* 4RQ>8
point to a need -or a structural capailit: to -orm a p:rrolic
metaolite. ,t is also possile that indicine
/
-oxide is converted
directl: to deh:droindicine : mitochondrial enG:mes in liver or
tumour cells* since the t:pe o- reaction re$uired has een oserved
in the mitochondrial metaolism o- the
/
-oxides o- tr:ptamine
alIaloids and certain meth:lated amino acids 71ish et al.* 4R>O;
Emith et al.* 4RO58.

>.> Prevention and Treatment o- P:rroliGidine Poisonin!
There is no InoYn Ya: to prevent p:rroliGidine liver dama!e*
once a hepatotoxic dose o- the alIaloid has een in!ested. A
numer o- dietar: re!imes have een -ound to partiall: protect
animals 7chie-l: rodents8 -rom the acute e--ects o- suse$uent
alIaloids in!estion. )one o- these are o- an: practical use -or
preventin! p:rroliGidine intoxication in livestocI. 1urthermore*
chronic toxic e--ects in the liver or in other or!ans are sometimes
more severe in animals receivin! hi!her doses o- alIaloids a-ter
ein! protected a!ainst acute hepatotoxict:.

>.>.4 +odi-ied diets
The mechanism o- action o- modi-ied diets is not clear* ut
the: ma: e associated Yith the decreased metaolic activation o-
the alIaloids. Eome examples -olloY:
7a8 A protein-rich diet can !ive some protection to rats
a!ainst
Senecio Xacobaea
alIaloids 7%heeIe
Z
6orman* 4RP<8.
(ats -ed a hi!h casein diet survived lon!er than rats !iven a
normal diet* Yhen poisoned Yith retrorsine or riddelline* ut
the survivors Yere more liale to develop liver tumours
7Echoental
Z
Head* 4R>P8. HoYever* Yhether this Yas simpl: due
to a prolon!ation o- li-e o- the animals : the diet is open to
$uestion.
78 +ale rats previousl: -ed a sucrose-onl: diet -or < da:s
Yere consideral: protected a!ainst the acute hepatotoxicit: o-
retrorsine 7@0
>S
45S m!'I! od: Yei!ht compared Yith 9< m!'I!
in normal rats8. HoYever* lun! dama!e* rare in control rats*
Yas -re$uentl: seen in ]protected] rats !iven hi!h doses o-
retrorsine 7+attocIs* 4RP98.
7c8 (estriction o- -eed intaIe to <S\ o- normal attenuated the
increase in lun! Yei!ht and lava!e protein concentration in
cell--ree ronchopulmonar: lava!e -luid and aolished the ri!ht
ventricular h:pertroph: in monocrotaline-treated rats.
1urthermore* the percenta!e o- diet-restricted animals that
survived Yas si!ni-icantl: hi!her than that in animals that had
eaten ad liitum up to da: 5Q* ut* -rom this time onYards*
there Yas no di--erence. Alterations o- dietar: sodium intaIe
alone did not a--ect the results o- monocrotaline-induced
toxicit: 76ane: et al.* 4RQ>8.

>.>.5 Pretreatment to enhance the detoxication o- active metaolites
Treatments that have a--orded some protection a!ainst
p:rroliGidine hepatotoxicit: 7proal: : increasin! the liver
level o- sul-:dr:l compounds* Yhich are InoYn to react Yith
p:rrolic metaolites8 7Nhite* 4RPO8 include the -olloYin!:
7a8 Pre-treatment o- rats Yith mercaptoeth:lamine 74>S m!'I!
od: Yei!ht ip8 partiall: protected rats a!ainst the acute
hepatotoxicit: o- monocrotaline !iven 4> min later 7Ha:ashi
Z

@alich* 4ROQ8; it !ave no protection Yhen administered 5 h
a-ter the alIaloid. +ercaptoeth:lamine* Yhen !iven orall:
79SS m!'I! od: Yei!ht8 at the same time as the lasiocarpine*
also increased the resistance o- rats to the alIaloid 7(o!ers
Z

)eYerne* 4RP48.
78 %:steine 74\ in the diet8 partiall: protected rats a!ainst

Senecio Xacobaea
alIaloids 7?ucImaster et al.* 4RPP8 and mice
a!ainst monocrotaline 7+iranda et al.* 4RQ4c8.
7c8 The antioxidant ethox:$uin -ed at a level o- 5.> !'I! diet
to -emale mice -or 9Q da:s* increased the liver thiol
concentration and raised the acute @0
>S
o- monocrotaline* !iven
ip on the 4Sth da:* to 9O< m!'I! compared Yith 5<9 m!'I! in
control mice 7+iranda et al.* 4RQ4a8.
7d8 (ats or mice also had increased resistance to acute
p:rroliGidine hepatotoxicit: Yhen -ed the antioxidant ut:lated
h:drox:anisole 7?HA8 7up to P.> !'I! diet8 7+iranda et al.*
4RQ4c* 4RQ5a*; bim
Z
Wones* 4RQ58.
7e8 Heliotrine-induced toxicit: can e modi-ied : the
co-administration o- cupir 7a copper-containin! complex8 at a
level o- 4 m!'I! per da: -or 5S da:s. ,t prevented the exit o-
hepatic c:tosolic enG:mes into the lood and improved all the
ener!: reactions studied in the mitochondria o- heliotrine-
intoxicated rats 7Fuldasheva
Z
Eultanova* 4RQ98. ,nhiition o-
lipid peroxidation : c:toplasmic copper Yas shoYn later
7Nitti!
Z
Etephen* 4RO<8. Eavin 74RQ98 -ound that lethalit: to
rats o- heliotrine 79SS m!'I! sc8 Yas completel: prevented :
co-administration o- alpha-tocopherol 7O ml'I! ip8.
7-8 (ats pre-treated Yith ip doses o- Ginc chloride 7P5 smol'I!
od: Yei!ht8 had increased resistance to the hepatotoxicit: o-

Senecio Xacobaea
alIaloids* as assessed : histolo!: and enG:me
measurements 7+iranda et al.* 4RQ5c8. The Ginc treatment increased
the liver level o- metallothionein* a sul-h:dr:l-rich protein that
mi!ht react Yith p:rrolic metaolites.
+etaolic inhiitors o- the microsomal P<>S mixed--unction
oxidase s:stem* Eb1 >5>A* met:rapone* and all:lisoprop:l acetamide*
Yhich inhiit the -ormation o- toxic p:rroles in the liver* have
een tried success-ull: in the prevention o- the toxic e--ects o-
monocrotaline in rats 7&isenstein
Z
Huxtale* 4RPR8. The use o-
P<>S inhiitors Yas stated to shoY ]potential therapeutic promise].
HoYever* this Yould seem impracticale considerin! that* at least
in the rat* PAs under!o a hi!h rate o- metaolism commencin! a -eY
minutes a-ter in!estion 7+attocIs* 4RP58. ,n some instances* the:
have een InoYn to lead to an increase in toxicit:* e.!.* Yith
lasiocarpine as reported : TuchYeer et al. 74RP<8.

>.>.9 Other treatments
@ani!an
Z
Nhittem 74RPS8 attempted* unsuccess-ull:* to protect
sheep a!ainst
Aeliotropium europaeum
poisonin! : treatin! them
Yith coalt* in the hope that this Yould enhance the vitamin
?
45
-mediated detoxication o- the alIaloids in the rumen 70icI et
al.* 4RO98.
@ani!an et al. 74RPQ8 -ound that the resistance o- sheep to
dietar:
Aeliotropium europaeum
Yas increased : !ivin! them lar!e
dail: doses o- the antimethano!enic dru!* iodo-orm. HoYever* EYicI
et al.* 74RQ98 -ound that
Senecio Xacobaea
alIaloids Yere not
detoxi-ied : incuation -or <Q h Yith sheep rumen -luid
in vitro.
O. &11&%TE O) A),+A@E
O.4 Patterns o- 0isease %aused : 0i--erent Plant 6enera and o-
Or!an ,nvolvement in 0i--erent Epecies
The most important !enera o- PA-containin! plants listed in
section 9.4 are all hepatotoxic. Amon! these*
"rotalaria spp.

cause dama!e in the roadest ran!e o- tissues in most domestic
species. ,n pi!s* the: are InoYn to e severel: nephrotoxic
7PecIham et al.* 4RP<; +c6rath et al.* 4RP>; Hooper
Z
Ecanlan*
4RPP8. Eome species are InoYn to e pneumotoxic -or horses 7Natt
Z

?re:er-?randYi;I* 4RO5; 6ardiner et al.* 4RO>8* cattle 7Eanders et
al.* 4R9O; ?err:
Z
?ras* 4R>P8* sheep 7@aYs* 4ROQ8* and pi!s
7PecIham et al.* 4RP<; Hooper
Z
Ecanlan* 4RPP8* as Yell as
hepatotoxic.
Althou!h several
"rotalaria spp.
are InoYn to e pneumotoxic
-or horses 76ardiner et al.* 4RO>8*
". retusa
is an exception. ,t
is an important cause o- disease in horses in northern Australia
7Hooper* 4RPQ8 and has een shoYn to e pneumotoxic -or pi!s in the
same area 7Hooper
Z
Ecanlan* 4RPP8; :et it produces onl: hepatic
disease in horses 7(ose et al.* 4R>Pa*8.
Eimilarl:*
Senecio spp.
are primaril: hepatotoxic* ut

S. Xacobaea
has een demonstrated to e pneumotoxic -or pi!s
7Hardin! et al.* 4RO<8* thou!h it could proal: e an inconsistent
chan!e 7?ull et al.* 4ROQ8. This plant is also InoYn to cause
pulmonar: disease in rats and mice 7Hooper* 4RP<8. HoYever* there
are no reports o- its a--ectin! the lun!s in cattle* sheep* horses*
or chicIen. (enal me!aloc:tosis and mild nephrosis are reported in
most species poisoned Yith
S. Xacobaea
7Hardin! et al.* 4RO<; ?ull
et al.* 4ROQ8.
Aeliotropium spp., 1msinckia spp.,
and
.c#ium
spp.
are all mainl: hepatotoxic.
(oitman 74RQ98 summariGed the pattern o- or!an involvement
oserved in man and di--erent species o- -arm and experimental
animals a--ected : p:rroliGidine alIaloids 7Tale Q8. &ven Yithin
a sin!le species* the nature o- a toxic e--ect* as Yell as the
or!an a--ected* can e altered : chan!in! the dose rate and
duration.

O.5 1ield Oservations - OutreaIs in 1arm Animals
The veterinar: prolem o- PA toxicit: has een revieYed : ?ull
et al. 74ROQ8 and +c@ean 74RPS8. +attocIs 74RQO8 listed the cases
o- livestocI poisonin! and -eedin! trials since 4ROQ* and cited
relevant literature. Peterson
Z
%ulvenor 74RQ98 produced a use-ul
and comprehensive tale o- the plant species InoYn or suspected o-
causin! natural outreaIs o- poisonin! in each animal species. The
in-luence o- -actors such as species* a!e* sex* and diet* on
toxicit: is also revieYed in the same paper.
Tale Q. Animal species and or!ans a--ected : p:rroliGidine
alIaloids
a
---------------------------------------------------------------
Epecies @iver @un! bidne: Heart Pancreas 6astric +uscle
mucos
a
---------------------------------------------------------------
+an i
+onIe: i i i i
Horse i i i
Pi! i i i
Home k produtos e servi.os k in-orma."o mdica k ordens k nutrition
modular



Prolemas no alimento
Toxins )aturais


Pes$uisa 0e &nvironmed

Toxins 0e Alimento )ativos
Aditivos 0e Alimento
%ontaminadores Bu#micos
,n-ec."o %arre!ada Alimento
Eensiilidade Bu#mica

Eolu.Ues
Al-a &)1
1eriado 0o Alimento
Pro!ramas 0o )utrition 0o Al-a



+uitas sust/ncias naturais do non-nutriente ] em alimentos ] naturais
comportam-se mal. )s podemos pensar de sua atividade como
$uimicamente stress-ul. Os stressors $u#micos ou molecular aumentam o
caos e diminuem a -un."o em ordem* sensile do corpo. Cm stressor
$u#mico um pouco de asurdo* uma sust/ncia com nenhum papel
si!ni-icativo ao ;o!o ou um papel txico $ue se;a destrutivo. )esta revis"o*
um per-il reve dos stressors e os toxins s"o desenvolvidos mais para ilustrar
o papel de stressors $u#micos naturais do $ue para es!otar este assunto vasto
e complicado.
Etephen 6islason +0
O alimento est cheio das sust/ncias extra $ue devem ser processadas no
corpo e ent"o excreted* mas $ue n"o tenha nenhum valor nutriente e possa
ter a dro!a e e-eitos txicos. Os stressors $u#micos podem ser encontrados
nos alimentos como in!redientes nativos e n"o s"o necessariamente aditivos
ou contaminadores. &stas sust/ncias tm o chemistr: complexo; incluem
sais inor!nicos e or!/nicos* minerais txicos* lcoois* alde#dos* alcalides*
compostos pol:phenolic* salic:lates* aminos-cido do non-nutriente e
peptides.
Cm stressor do produto $u#mico de alimento torna-se -ranIl: txico $uando
in!ested demasiado -re$uentemente* em um dose demasiado !rande* ou
$uando in!ested por uma pessoa $ue -alte a ma$uinaria metaolic para
detoxi-: a. Os stressors molecular podem simplesmente re$ue o corpo
se!ur-lo e excrete sem dano. O traalho metaolic desta atividade ] o
custo ] de in!estin! estas sust/ncias. Buando ns consumimos stressors no
excesso* o e-eito torna-se txico. )ossa capacidade se!urar stressors
$u#micos limitada e varia de individual ao indiv#duo.
A sensiilidade ] $u#mica ] relatada $uando a exposi."o aos produtos
$u#micos transportados por via area* tais como o -umo do ci!arro* a
exaust"o do motor* os per-umes* os deter!entes da casa e os solventes
causa sintomas. Os pacientes $ue est"o recuperando das doen.as aller!ic do
alimento relatar"o -re$uentemente a conscincia aumentada de produtos
$u#micos transportados por via area; isto parece representar um
h:persensitivit: !eneraliGado. A parte da estrat!ia da recupera."o deve
evitar a exposi."o $u#mica tanto $uanto poss#vel.
+uitos stressors $u#micos competem para os mesmos pathYa:s metaolic
para o excretion. O -#!ado responsvel para remover muitos toxins. Cm de
seus mtodos deve unir !rupos do acet:l Xs molculas txicas $ue as -aGem
mais solule para o excretion do Iidne:. Al!uns povos s"o ] acet:lators
pores ] e relatam a intolerance ao escalas lar!as das dro!as* dos alimentos*
e de produtos $u#micos transportados por via area. Ee muitas molculas
competirem para os mesmos pathYa:s do excretion* -cil ima!inar $ue
sorecarre!ar ocorre re!ularmente nos cidad"os modernos $ue s"o expostos
a uma escala lar!a dos produtos $u#micos no alimento* na !ua e no ar. Cma
veG $ue a sorecar!a ocorre* mesmo as $uantidades pe$uenas de stressors
$u#micos extra trans-ormam-se sintomas e d:s-unction txicos e do produto.
Os stressors $u#micos inhaled e in!ested simultaneamente. A polui."o de ar
reduGir a toler/ncia para a polui."o do alimento e o versa do visto. Cm
;antar t#pico em um restaurante a!radvel pode ser iochemicall: e
metaolicall: stress-ul* como -umo inhaled e lcool* ca-* ch* spices* e li!a
in!ested do a.=car com o complexo ; no alimento. Toc pode ser em mais
prolema se voc estiver lidando tamm com os e-eitos das dro!as da
prescri."o -eitas exame para aliviar seus sintomas da sorecar!a $u#mica`
As plantas s"o nossas -ontes mais dese;veis do alimento. )s tendemos a
pensar os ve!etais do e a -ruta como inteiramente ami!vel e eni!na;
entretanto isto n"o necessariamente verdadeiro. Os ve!etais* as -rutas* os
hers* e os spices s"o $uimicamente complicados* e contm uma variedade
das sust/ncias $u#micas $ue se;a dro!a-como* txica* e aller!enic. As
plantas s"o inerente txicas desde $ue evolu#ram as de-esas $u#micas $ue
desanimam predadores de os comer.
H muitas sust/ncias molecular nos alimentos $ue n"o o-erecem nenhum
ene-#cio nutritivo* e deve ser processado e excreted. O cido oxalic* para o
exemplo* excreted no urine* e seus cristais s"o encontrados !eralmente no
urinal:sis microscpico. 0emasiado cido oxalic no urine resultar em
pedras do Iidne: ou da exi!a. O clcio comina com o cido oxalic para
dar -orma ao sal mais menos solule* o oxalate do clcio* $ue encontrado
tamm em pedras do Iidne:. A planta sae* especial rhuar* repolho*
spinach* e os altos de eterraa* contm o cido oxalic. O cido oxalic
encontrado tamm as atatas e as ervilhas. A vitamina % metaoliGed ao
cido oxalic; contriui ao sore-over-saturation do urine com cristais e para
apedre;ar possivelmente a -orma."o.
0iversos produtos $u#micos usados como aditivos de alimento s"o
encontrados tamm naturalmente em muitos alimentos. Os nitrates e os
nitrites s"o ui$uitous nas plantas. 0"o -orma X parte do chemistr: essencial
os solos e as plantas. %omo cada !ardener sae* o nitro!nio essencial para
o crescimento de planta; os -ertiliGantes do nitro!nio* contendo nitrates* s"o
os produtos $u#micos a!riculturais os mais aundantes. As eterraas* os
radishes* o spinach* e a al-ace contm os n#veis os mais elevados dos
nitrates. O consumo dirio estimado para estar na escala de 4SS m!'da:.
Eust/ncias Aromatic
Todas as plantas contm as molculas $ue tm e impacto em nossos sentidos
$u#micos. Provam e cheiram. Os compostos aromticos atraem-nos a um
alimento. A ind=stria de alimento usa $uantidades !randes dos compostos
aromticos* das -ontes naturais e sintticas. O chemistr: destas sust/ncias
pode ser ima!inado pensando da -orma de sua estrutura molecular. O anel
sico uma molcula six-sided* enGene. As correntes laterais di-erentes
unidas ao anel mudam seus cor* !osto* e cheiro. Ee os anis do enGene
-orem li!ados ;unto* uma variedade de estruturas do anel causa classes
di-erentes das sust/ncias. As molculas aseadas na estrutura do anel do
enGene s"o comuns na natureGa. Cm nome ocasional para muitas das
sust/ncias ] phenolics ].
%om estruturas aromatic do anel inclua molculas das dro!as do alimento a
ca-e#na e cido salic:lic; a c/n-ora dos saores* o cido cinnamic* o eu!enol
7nutme! e cravos-da-#ndia8* o sa-role* o anethole 7anis8* o tannin 7ch8* o
cido !allic* e o vanillin 7vanilla8; e as vitaminas cido ascoric e niacin. Os
compostos phenolic est"o dro!a-como; al!uns s"o txicos e outros parecem
ser en-icos.
Cm outro !rupo de produtos $u#micos interessantes da planta os leos
essenciais das plantas* $ue s"o tamm aromatic. )s tendemos como ao
cheiro dos turpenes e usamo-los em nossos per-umes* !arnishes* e chs. Os
turpenes aromatic comuns em plantas do alimento incluem turpenes
complexos* tais como o lanosterol 7no lanolin8* um se!undo primo do
cholesterol* e o s$ualene* encontrou no -ermento* no !erme do tri!o* e no
leo verde-oliva. Al!uns turpenes s"o -ranIl: txicos mas remanescem em
nossa -onte de alimento como saores. Os extratos do lcool das plantas
contm -re$uentemente turpenes txicos. Outros turpenes s"o molculas ou
ao menos eni!nos positivo. A vitamina A n"o uma sust/ncia; uma
-am#lia de turpenes relacionados com atividade iol!ica compartilhada. O
eta-carotene o pi!ment amarelo nas cenouras $ue podem ser convertidas
na vitamina ativa A 7(etinols8 depois $ue ns in!est a. O l:copene um
turpene vermelho similar encontrado nos tomates. O consumo excessivo os
tomates e as cenouras de pode induGir um complexion colorido $ue alarme
ami!os mas do parece -aGer pouco dano e do pode ter ene-#cios tais como a
preven."o do cancer.
6arlic e ceolas
O !arlic 7alium sativum8 e as ceolas 7allium %epa8 s"o amos os memros
da -am#lia do l#rio. Amos contm as sust/ncias aromatic -ortes $ue ns
usamos como -lavorin! para o alimento. As propriedades medicinal destes
alimentos -oram usadas por sculos. Allicin o princ#pio aromatic do !arlic.
Allicin um turpene sulphur-containin!. Cm ulo intato do !arlic tem
pouco odor. O odor -orte do allicin aparece somente depois $ue um ulo do
!arlic cortado ou esma!ado. O trauma da exposi."o do ar excita um
enG:me $ual mude uma molcula inodora do precursor* Alliin* a Allicin.
As propriedades medicinal dos produtos $u#micos cominados no !arlic
incluem a atividade antiseptic e 7uma atividade anticlottin! da platelet-
viscosidade reduGida8. O -ator anticlottin! o a;oene 7<*>*R-trithiadodeca-
4*O*44-triene R-oxide`8. Os entusiastas do !arlic devem anotar $ue nenhum
a;oene* ou a atividade anticlottin!* estiveram encontrados em prepara.Ues
proprietrias do !arlic* includin! o leo do !arlic ou as tauletas do !arlic. O
in!estion do !arlic recentemente esma!ado parece necessrio para este
e-eito de dro!a. O e-eito anticlottin! do a;oene similar ao e-eito da aspirina
7AEA8. Os respira."o-odores desa!radveis $ue se!uem o in!estion do
!arlic s"o os metaolites sulphur-containin! temporrios do allicin.
As ceolas s"o -amosas para seu e-eito ras!ando. A sust/ncia $ue nos -aG
Yeep s-oxide propanethial. O e-eito ras!ando pode ser reduGido chillin! a
ceola antes do corte* ou processando a ceola so a !ua -uncionando da
torneira.
Epices
Todas as plantas contm uma variedade das sust/ncias $u#micas $ue a!em
em a dro!a-como a maneira. Os hers e os spices tendem a ser
$uimicamente complexos e dro!a-como em sua atividade. A maioria de
culturas nativas s"o relutantes comer plantas non--ood para a raG"o oa. )s
come.amos provavelmente a-astado com in!estion do her e do spice
somente em doses pe$uenos e in-re$uwntemente. O nutme!* um spice
comum -avorecido nos desserts e eidas* rende muitos produtos $u#micos
tais como o eu!enol* isoeu!enol* sa-role* m:risticin* elemicin* limolene. O
uso therapeutic do eu!enol como um antidiarreico* anticlottin!* e a!ente
anti-in-lammator: podia ser su!erido; entretanto* se ns devssemos usar o
leo do nutme! como a terapia* ns en-rentar#amos a dro!a* e e-eitos txicos
dos outros produtos $u#micos no nutme!. )s ser#amos concernidos sore
os e-eitos hallucino!enic do ps:chotropic* m:risticin. )s ser#amos
concernidos tamm sore a ailidade do sa-role de induGir o cancer do
-#!ado nos ratos. A aproxima."o pharmaceutical apropriada deveria isolar a
sust/ncia medicinal* eu!enol* e decidir-se* aps testar cuidadoso de seu
e--icac: contra seu toxicit:* se o uso therapeutic -osse sio.
As ervilhas e os -ei;Ues s"o le!umes edile comuns. &stes alimentos s"o
!rampos eee T(A)E@AT,O) &)0E H&(& eeeYorld-Yide and have
desirale nutritional properties* ut several interestin! iochemical prolems
ma: arise Yith their use. Eo:eans* -or example* ma: e poorl: tolerated
unless Yell prepared. The process o- maIin! to-u illustrates the e--ort
re$uired to process a raY -ood to otain a reliale nutrient source. Eo:eans
contain indi!estile caroh:drates and inhiitors o- di!estive enG:mes
7so:ean tr:psin inhiitor8. ?oth prolems contriute to di--icult: di!estin!
eans* excessive !as* and* occasionall:* adominal pain and diarrhea.
@ima and Iidne: eans are toxic uncooIed. ?oth eans contain c:anide
producin! compounds 7 c:ano!enic !l:cosides 8* Yhich can e destro:ed :
ade$uate cooIin!. Emall amounts o- c:ano!enic !l:cosides Yill e
detoxi-ied : the liver. %:ano!enic !l:cosides are also -ound in -ruit pits
millet* sprouts* :ams* maiGe* chicI peas* and cassava root.
%assava 7manioc8 is an important ve!etale o- Eouth &ast Asia* A-rica and
Eouth America and is inherentl: toxic. These tuer contain linamarin Yhich
can e converted to h:droc:anic acid . The: must e processed : soaIin!*
oilin!* dr:in!* and -ermentation to reduce toxic c:anide e--ects.
)eurolo!ical disorders and th:roid enlar!ement occur in A-rican peoples
Yho eat lar!e amounts o- inade$uatel: processed cassava.
An unusual !enetic condition* ]-avism ]* maIes some people sensitive to
vicine* a nucleotide in -ave eans; these people develop red lood cell
dama!e 7hemol:tic anemia8 a-ter eatin! the eans. %ooIin! the eans
thorou!hl: can reduce this e--ect. This is a speci-ic example o- the c:totoxic
mechanism o- -ood molecules* and illustrates the advanta!es o- cooIin!
-oods.
)i!htshades
Plants o- the ni!htshade -amil: contain toxic sustances. ]0eadl: ] re-ers to
the toxicit: o- the leaves o- this plant !roup Yhich includes tomato* potato*
peppers* e!!plant* and toacco. All the ni!htshades contain nicotine;
toacco has the hi!hest concentration* e!!plant is next. %ountr: lore tells us
not to eat !reen potatoes and to store potatoes in the darI to avoid the
!reenin! e--ect o- li!ht. The !reen potato contains toxic compounds
7!l:coalIaloids8 similar to those -ound in the leaves. Eolanine poisonin!
-rom !reen potatoes Yill produce throat urnin!* YeaIness* diarrhea* and
even convulsions Yith collapse and coma. Adverse and aller!ic reactions to
tomatoes and peppers are common* and these ve!etales are not on our most
-avored -ood list. )i!htshades have o-ten een implicated in arthritis.
The occurrence o- toxic non-nutrient amino acids is not unusual in plants
Yho produce toxic compounds to deter predators -rom eatin! them. Over a
4>S non-protein amino acids derived -rom plant materials have een
chemicall: characteriGed. One o- the prolems Yith these amino acids is
their ailit: to imitate and replace normal amino acids in protein s:nthesis.
%anavanine in al-al-a seeds and sprouts ma: a cause h:persensitivit: illness.
The toxic a!ent in inI: cap mushrooms 7coprinus atramentarius8 Yhich
produces alcohol intolerance is the amino acid* %oprine . Toxic amino acids
?+AA in c:cad seeds are thou!ht to cause a severe neurolo!ical disease in
6uam; this amino acid resemles ?OAA in the !rass pea* lath:rus sativa*
Yhich can cause a paral:tic illness. %arnosine and its meth:lated -orm*
anersine * in sIeletal muscle* and rain are associated Yith seiGures and
carnosinemia ma: lead to mental retardation.
Eome ve!etales also ecome undesirale Yhen the: are dama!ed or
diseased. 1un!al !roYth is a ma;or cause o- toxic alteration o- plant tissue.
EYeet potato * -or example* supports a -un!al !roYth 71usarium solani8*
especiall: Yhen the tuer[s sur-ace is dama!ed. The -un!us alters the
potatoes[ metaolism* and toxic stressors are produced. ,pomeanol is one
such chemical that is liver and lun! toxic. @un! disease in cattle is caused :
in-ected sYeet potatoes. )o similar human s:ndrome has een descried.
A-latoxins
A variet: o- -un!i 71usaria* Trichothecium* %ephalosporium* etc.8 ma:
contaminate !rains* and cause illness Yith s:mptoms such as vomitin!*
diarrhea* headaches* chills* diGGiness* and lurred vision. A-latoxins are
produced : molds Yhich -avor nuts* corn* millet* and -i!s. Hi!her
concentrations o- these toxins ma: produce acute s:mptoms such as loss o-
appetite and ;aundice 7hepatitis8 and the: are also carcino!enic i- eaten in
loY concentrations over a lon!er period o- time. Eome o- these -un!al
metaolites are also neurotoxins Yhich produce tremors as a conspicuous
s:mptom. The same -un!i Yhich produce a-latoxin produce a tremor!en*
InoYn to cause ]sta!!ers ] in sheep and cattle. The common -un!i Yhich
!roY on our -ood* even in the re-ri!erator and cupoard* are Penicillium*
Asper!illus* and %laviceps.
Over 4> tremor!enic m:cotoxins have een isolated -rom these -un!i. The
role o- these m:cotoxins in human rain d:s-unction has not een
determined and is usuall: not considered in medical evaluations. Asper!illus
is a ui$uitous -un!us that can -atall: in-ect patients Yith reduced immunit:.
The rules -or sa-e stora!e o- -ood to reduce -un!al !roYth include
immediate re-ri!eration* properl: covered containers* and limits on the
duration o- stora!e. ,n !eneral* proper reheatin! o- re-ri!erated -oods can
reduce toxicit:. ?otulinis toxin is an example o- a -ood poison destro:ed :
ade$uate cooIin! o- preserved -oods.
?rassicas
The common and popular caa!e or ?rassica -amil: is not Yithout
prolems. The !as-producin! properties o- ?rassica ve!etales are Yell
InoYn. Eome ?rassicas 7roccoli8 have hi!h vitamin b content. The
therapeutic e--ect o- anticoa!ulant dru!s Yhich inter-ere Yith the conversion
o- vitamin b to prothromin ma: e reduced : rassica in!estion.
?rassicas also contain hi!h levels o- chemicals that ma: inter-ere Yith
th:roid -unction* promotin! th:roid enlar!ement 7!oitre8 . %aa!e* russel
sprouts* and Iohlrai contain pro!oitrin 7in the ran!e o- O>-4<S m! per 4SS
!ram o- -resh ve!etale8. %ooIin! reduces the !oitre e--ect o- these
ve!etales. 6oitro!ens are also -ound in turnips* so:eans* radishes*
rapeseed* and mustard. On the plus side o- the ?rassica pro-ile* there is some
evidence that re!ular in!estion o- ?rassicas ma: o--er protection a!ainst
oYel cancer.
Hers and Teas
+an: patients in$uire aout the use o- heral teas and heral treatments.
1rom a medical point o- vieY* all plant materials are potentiall: aller!enic.
1rom a iochemist[s point o- vieY* plant materials contain man: active
sustances in complex cominations Yhose od:-e--ects are !enerall: not
InoYn. ?ene-icial e--ects o- plant materials can e associated Yith ne!ative
metaolic and toxic e--ects Yhich need to e considered Yhen an: plant is
used Yith increasin! intensit:* especiall: on a dail: asis.
+edicinal hers are dru!-containin! plants Yhich should not e used
ever:da:. @iIe other dru!s* medicinal hers have side e--ects* toxic e--ects*
and aller!enic e--ects* and the: ma: not e help-ul. The prolem Yith
Yhole-plant medicines is that the active in!redients are mixed Yith
ever:thin! else in the plant. This means that the control over the dru! e--ect
that is achieved Yith puri-ied sustances is not possile Yith plant
preparations. The appearance on the marIet o- man: ]natural ] and ]heral ]
teas is unprecedented. The sa-et: o- these products is in $uestion. A $uicI
revieY o- toxicit: reported to occur Yith popular tea-plants -olloYs.
%athartic teas* includin! those Yith senna leaves* -loYers and arI*
ucIthorn arI* docI roots* or aloe leaves* do cause diarrhea. ,- used
continuousl:* these hers ma: induce laxative-dependence* o-ten Yith
adominal discom-ort* oYel d:s-unction* and malasorption o- nutrients.
@axatives* heral aller!enic teas* such as those -rom camomile* !oldenrod*
mari!old* and :arroY* can cause aller!ic reactions in persons that are
sensitive to ra!Yeed* asters* chr:santhemums* and other related plants.
0ela:ed aller!ic reactions and sun sensitivit: can -olloY consumption o- tea
-rom the leaves o- man: plant products. Et. Wohn[s Nort is InoYn to e
photosensitiGin!. Tannins in tea* includin! ordinar: tea and peppermint tea*
are sur-ace irritants to the !astrointestinal tract and have een linIed to
cancer o- the esopha!us and stomach. Addin! milI to the tea inds the plant
tannins and ma: protect the di!estive tract -rom irritant e--ects.
0iuretics are present in teas made -rom uchu* $uacI !rass* and dandelion.
0iuretics increase urine production Yith Yater and mineral losses. %o--ee
and tea are potent diuretics; the other plant teas are similar in their stress-ul
diuretic e--ects. A variet: o- rain-active chemicals are also -ound in catnip*
;uniper* h:dran!ea* ;imson Yeed* loelia* and YormYood. Teas made -rom
the petals o- -loYerin! plants 7rose* hiiscus* h:dran!ea8 are also neurotoxic
and cause headaches* thinIin! disturances* irritailit:* and depression.
Al-al-a tea contains saponins Yhich can disrupt di!estion and respiration.
Nhile the saponins o- al-al-a have een -ound experimentall: to clear the
arteries o- -att: pla$ues in monIe:s* the in!estion o- al-al-a teas ma: have
adverse e--ects.
@iver toxicit: has een linIed Yith a numer o- heral teas.
%om-re: is a popular her that is potentiall: hepatotoxic ecause o-
p:rroliGidine alIaloids* InoYn to cause hepatocellular adenomas and
increased incidence o- ladder tumors in rats.
Eassa-ras contains sa-role 7as in nutme!8* another potentiall: hepatotoxic
sustance.
6insen!has caused reast enlar!ement in men 7!:necomastia8* due to the
presence o- an estro!en-liIe sustance.
@icorice has een -ound to have sustances that aid healin! o- stomach
ulcers; hoYever* it also causes sodium and Yater retention and loss o-
potassium. Hi!h lood pressure ma: result -rom excessive consumption o-
licorice.
+istletoe contains alIaloids* small proteins 7viscotoxins8* and lectins 7Yhich
collectivel: have h:potensive* diuretic* and antispasmodic properties8.
+istletoe has een used : some heral therapists as an anti-cancer dru!.
The complex o- alIaloids ma: e c:totoxic. As Yell* hepatitis has een
reported Yith mistletoe in!estion.
Penn:ro:al extract has lon! een recommended to produce aortions* a
dout-ul e--ect* ut death due to liver dama!e has een lamed on re!ular
penn:ro:al in!estion.
There are man: possile interactions o- heral medicines and prescription
dru!s. @il: o- the Talle:* -or example* contains cardiac !l:cosides and ma:
lead to di!italis toxicit: in a person taIin! ade$uate doses o- the prescription
dru!. Horse chestnut contains natural anticoa!ulants and ma: increase the
e--ect o- coumarin anticoa!ulants. ,nI %ap is a natural source o- disul-iram*
Yith the risI o- an ]Antause ] reaction Yith alcohol. 0isul-iram inter-eres
Yith the metaolism o- alcohol and increases the accumulation o- a toxic
metaolite* acetaldeh:de.
The Eolution
The Alpha )utrition Pro!ram is a standardiGed method o- diet revision that
is help-ul in resolvin! a surprisin! numer o- health prolems. 1ood
selection and preparation in the pro!ram has taIen in account man: o- the
prolems associated Yith native -ood chemistr: and contamination Yith
chemicals. A -ood holida: on Alpha &)1 is a $uicI Ya: to eliminate all
-ood contaminants and native -ood toxins.
&nvironmed (esearch ,nc.


%ontact Cs k Alpha )utrition Pro!rams k Ecope o- Eervices k e+ail Eupport k
AnsYerin! Buestions

Home k produtos e servi.os k in-orma."o mdica k ordens k nutrition modular



Prolemas no alimento
Toxins )aturais


Pes$uisa 0e &nvironmed

Toxins 0e Alimento )ativos
Aditivos 0e Alimento
%ontaminadores Bu#micos
,n-ec."o %arre!ada Alimento
Eensiilidade Bu#mica

Eolu.Ues
Al-a &)1
1eriado 0o Alimento
Pro!ramas 0o )utrition 0o Al-a



+uitas sust/ncias naturais do non-nutriente ] em alimentos ] naturais
comportam-se mal. )s podemos pensar de sua atividade como
$uimicamente stress-ul. Os stressors $u#micos ou molecular aumentam o
caos e diminuem a -un."o em ordem* sensile do corpo. Cm stressor
$u#mico um pouco de asurdo* uma sust/ncia com nenhum papel
si!ni-icativo ao ;o!o ou um papel txico $ue se;a destrutivo. )esta revis"o*
um per-il reve dos stressors e os toxins s"o desenvolvidos mais para ilustrar
o papel de stressors $u#micos naturais do $ue para es!otar este assunto vasto
e complicado.
Etephen 6islason +0
O alimento est cheio das sust/ncias extra $ue devem ser processadas no
corpo e ent"o excreted* mas $ue n"o tenha nenhum valor nutriente e possa
ter a dro!a e e-eitos txicos. Os stressors $u#micos podem ser encontrados
nos alimentos como in!redientes nativos e n"o s"o necessariamente aditivos
ou contaminadores. &stas sust/ncias tm o chemistr: complexo; incluem
sais inor!nicos e or!/nicos* minerais txicos* lcoois* alde#dos* alcalides*
compostos pol:phenolic* salic:lates* aminos-cido do non-nutriente e
peptides.
Cm stressor do produto $u#mico de alimento torna-se -ranIl: txico $uando
in!ested demasiado -re$uentemente* em um dose demasiado !rande* ou
$uando in!ested por uma pessoa $ue -alte a ma$uinaria metaolic para
detoxi-: a. Os stressors molecular podem simplesmente re$ue o corpo
se!ur-lo e excrete sem dano. O traalho metaolic desta atividade ] o
custo ] de in!estin! estas sust/ncias. Buando ns consumimos stressors no
excesso* o e-eito torna-se txico. )ossa capacidade se!urar stressors
$u#micos limitada e varia de individual ao indiv#duo.
A sensiilidade ] $u#mica ] relatada $uando a exposi."o aos produtos
$u#micos transportados por via area* tais como o -umo do ci!arro* a
exaust"o do motor* os per-umes* os deter!entes da casa e os solventes
causa sintomas. Os pacientes $ue est"o recuperando das doen.as aller!ic do
alimento relatar"o -re$uentemente a conscincia aumentada de produtos
$u#micos transportados por via area; isto parece representar um
h:persensitivit: !eneraliGado. A parte da estrat!ia da recupera."o deve
evitar a exposi."o $u#mica tanto $uanto poss#vel.
+uitos stressors $u#micos competem para os mesmos pathYa:s metaolic
para o excretion. O -#!ado responsvel para remover muitos toxins. Cm de
seus mtodos deve unir !rupos do acet:l Xs molculas txicas $ue as -aGem
mais solule para o excretion do Iidne:. Al!uns povos s"o ] acet:lators
pores ] e relatam a intolerance ao escalas lar!as das dro!as* dos alimentos*
e de produtos $u#micos transportados por via area. Ee muitas molculas
competirem para os mesmos pathYa:s do excretion* -cil ima!inar $ue
sorecarre!ar ocorre re!ularmente nos cidad"os modernos $ue s"o expostos
a uma escala lar!a dos produtos $u#micos no alimento* na !ua e no ar. Cma
veG $ue a sorecar!a ocorre* mesmo as $uantidades pe$uenas de stressors
$u#micos extra trans-ormam-se sintomas e d:s-unction txicos e do produto.
Os stressors $u#micos inhaled e in!ested simultaneamente. A polui."o de ar
reduGir a toler/ncia para a polui."o do alimento e o versa do visto. Cm
;antar t#pico em um restaurante a!radvel pode ser iochemicall: e
metaolicall: stress-ul* como -umo inhaled e lcool* ca-* ch* spices* e li!a
in!ested do a.=car com o complexo ; no alimento. Toc pode ser em mais
prolema se voc estiver lidando tamm com os e-eitos das dro!as da
prescri."o -eitas exame para aliviar seus sintomas da sorecar!a $u#mica`
As plantas s"o nossas -ontes mais dese;veis do alimento. )s tendemos a
pensar os ve!etais do e a -ruta como inteiramente ami!vel e eni!na;
entretanto isto n"o necessariamente verdadeiro. Os ve!etais* as -rutas* os
hers* e os spices s"o $uimicamente complicados* e contm uma variedade
das sust/ncias $u#micas $ue se;a dro!a-como* txica* e aller!enic. As
plantas s"o inerente txicas desde $ue evolu#ram as de-esas $u#micas $ue
desanimam predadores de os comer.
H muitas sust/ncias molecular nos alimentos $ue n"o o-erecem nenhum
ene-#cio nutritivo* e deve ser processado e excreted. O cido oxalic* para o
exemplo* excreted no urine* e seus cristais s"o encontrados !eralmente no
urinal:sis microscpico. 0emasiado cido oxalic no urine resultar em
pedras do Iidne: ou da exi!a. O clcio comina com o cido oxalic para
dar -orma ao sal mais menos solule* o oxalate do clcio* $ue encontrado
tamm em pedras do Iidne:. A planta sae* especial rhuar* repolho*
spinach* e os altos de eterraa* contm o cido oxalic. O cido oxalic
encontrado tamm as atatas e as ervilhas. A vitamina % metaoliGed ao
cido oxalic; contriui ao sore-over-saturation do urine com cristais e para
apedre;ar possivelmente a -orma."o.
0iversos produtos $u#micos usados como aditivos de alimento s"o
encontrados tamm naturalmente em muitos alimentos. Os nitrates e os
nitrites s"o ui$uitous nas plantas. 0"o -orma X parte do chemistr: essencial
os solos e as plantas. %omo cada !ardener sae* o nitro!nio essencial para
o crescimento de planta; os -ertiliGantes do nitro!nio* contendo nitrates* s"o
os produtos $u#micos a!riculturais os mais aundantes. As eterraas* os
radishes* o spinach* e a al-ace contm os n#veis os mais elevados dos
nitrates. O consumo dirio estimado para estar na escala de 4SS m!'da:.
Eust/ncias Aromatic
Todas as plantas contm as molculas $ue tm e impacto em nossos sentidos
$u#micos. Provam e cheiram. Os compostos aromticos atraem-nos a um
alimento. A ind=stria de alimento usa $uantidades !randes dos compostos
aromticos* das -ontes naturais e sintticas. O chemistr: destas sust/ncias
pode ser ima!inado pensando da -orma de sua estrutura molecular. O anel
sico uma molcula six-sided* enGene. As correntes laterais di-erentes
unidas ao anel mudam seus cor* !osto* e cheiro. Ee os anis do enGene
-orem li!ados ;unto* uma variedade de estruturas do anel causa classes
di-erentes das sust/ncias. As molculas aseadas na estrutura do anel do
enGene s"o comuns na natureGa. Cm nome ocasional para muitas das
sust/ncias ] phenolics ].
%om estruturas aromatic do anel inclua molculas das dro!as do alimento a
ca-e#na e cido salic:lic; a c/n-ora dos saores* o cido cinnamic* o eu!enol
7nutme! e cravos-da-#ndia8* o sa-role* o anethole 7anis8* o tannin 7ch8* o
cido !allic* e o vanillin 7vanilla8; e as vitaminas cido ascoric e niacin. Os
compostos phenolic est"o dro!a-como; al!uns s"o txicos e outros parecem
ser en-icos.
Cm outro !rupo de produtos $u#micos interessantes da planta os leos
essenciais das plantas* $ue s"o tamm aromatic. )s tendemos como ao
cheiro dos turpenes e usamo-los em nossos per-umes* !arnishes* e chs. Os
turpenes aromatic comuns em plantas do alimento incluem turpenes
complexos* tais como o lanosterol 7no lanolin8* um se!undo primo do
cholesterol* e o s$ualene* encontrou no -ermento* no !erme do tri!o* e no
leo verde-oliva. Al!uns turpenes s"o -ranIl: txicos mas remanescem em
nossa -onte de alimento como saores. Os extratos do lcool das plantas
contm -re$uentemente turpenes txicos. Outros turpenes s"o molculas ou
ao menos eni!nos positivo. A vitamina A n"o uma sust/ncia; uma
-am#lia de turpenes relacionados com atividade iol!ica compartilhada. O
eta-carotene o pi!ment amarelo nas cenouras $ue podem ser convertidas
na vitamina ativa A 7(etinols8 depois $ue ns in!est a. O l:copene um
turpene vermelho similar encontrado nos tomates. O consumo excessivo os
tomates e as cenouras de pode induGir um complexion colorido $ue alarme
ami!os mas do parece -aGer pouco dano e do pode ter ene-#cios tais como a
preven."o do cancer.
6arlic e ceolas
O !arlic 7alium sativum8 e as ceolas 7allium %epa8 s"o amos os memros
da -am#lia do l#rio. Amos contm as sust/ncias aromatic -ortes $ue ns
usamos como -lavorin! para o alimento. As propriedades medicinal destes
alimentos -oram usadas por sculos. Allicin o princ#pio aromatic do !arlic.
Allicin um turpene sulphur-containin!. Cm ulo intato do !arlic tem
pouco odor. O odor -orte do allicin aparece somente depois $ue um ulo do
!arlic cortado ou esma!ado. O trauma da exposi."o do ar excita um
enG:me $ual mude uma molcula inodora do precursor* Alliin* a Allicin.
As propriedades medicinal dos produtos $u#micos cominados no !arlic
incluem a atividade antiseptic e 7uma atividade anticlottin! da platelet-
viscosidade reduGida8. O -ator anticlottin! o a;oene 7<*>*R-trithiadodeca-
4*O*44-triene R-oxide`8. Os entusiastas do !arlic devem anotar $ue nenhum
a;oene* ou a atividade anticlottin!* estiveram encontrados em prepara.Ues
proprietrias do !arlic* includin! o leo do !arlic ou as tauletas do !arlic. O
in!estion do !arlic recentemente esma!ado parece necessrio para este
e-eito de dro!a. O e-eito anticlottin! do a;oene similar ao e-eito da aspirina
7AEA8. Os respira."o-odores desa!radveis $ue se!uem o in!estion do
!arlic s"o os metaolites sulphur-containin! temporrios do allicin.
As ceolas s"o -amosas para seu e-eito ras!ando. A sust/ncia $ue nos -aG
Yeep s-oxide propanethial. O e-eito ras!ando pode ser reduGido chillin! a
ceola antes do corte* ou processando a ceola so a !ua -uncionando da
torneira.
Epices
Todas as plantas contm uma variedade das sust/ncias $u#micas $ue a!em
em a dro!a-como a maneira. Os hers e os spices tendem a ser
$uimicamente complexos e dro!a-como em sua atividade. A maioria de
culturas nativas s"o relutantes comer plantas non--ood para a raG"o oa. )s
come.amos provavelmente a-astado com in!estion do her e do spice
somente em doses pe$uenos e in-re$uwntemente. O nutme!* um spice
comum -avorecido nos desserts e eidas* rende muitos produtos $u#micos
tais como o eu!enol* isoeu!enol* sa-role* m:risticin* elemicin* limolene. O
uso therapeutic do eu!enol como um antidiarreico* anticlottin!* e a!ente
anti-in-lammator: podia ser su!erido; entretanto* se ns devssemos usar o
leo do nutme! como a terapia* ns en-rentar#amos a dro!a* e e-eitos txicos
dos outros produtos $u#micos no nutme!. )s ser#amos concernidos sore
os e-eitos hallucino!enic do ps:chotropic* m:risticin. )s ser#amos
concernidos tamm sore a ailidade do sa-role de induGir o cancer do
-#!ado nos ratos. A aproxima."o pharmaceutical apropriada deveria isolar a
sust/ncia medicinal* eu!enol* e decidir-se* aps testar cuidadoso de seu
e--icac: contra seu toxicit:* se o uso therapeutic -osse sio.
As ervilhas e os -ei;Ues s"o le!umes edile comuns. &stes alimentos s"o
!rampos eee T(A)E@AT,O) &)0E H&(& eeeYorld-Yide and have
desirale nutritional properties* ut several interestin! iochemical prolems
ma: arise Yith their use. Eo:eans* -or example* ma: e poorl: tolerated
unless Yell prepared. The process o- maIin! to-u illustrates the e--ort
re$uired to process a raY -ood to otain a reliale nutrient source. Eo:eans
contain indi!estile caroh:drates and inhiitors o- di!estive enG:mes
7so:ean tr:psin inhiitor8. ?oth prolems contriute to di--icult: di!estin!
eans* excessive !as* and* occasionall:* adominal pain and diarrhea.
@ima and Iidne: eans are toxic uncooIed. ?oth eans contain c:anide
producin! compounds 7 c:ano!enic !l:cosides 8* Yhich can e destro:ed :
ade$uate cooIin!. Emall amounts o- c:ano!enic !l:cosides Yill e
detoxi-ied : the liver. %:ano!enic !l:cosides are also -ound in -ruit pits
millet* sprouts* :ams* maiGe* chicI peas* and cassava root.
%assava 7manioc8 is an important ve!etale o- Eouth &ast Asia* A-rica and
Eouth America and is inherentl: toxic. These tuer contain linamarin Yhich
can e converted to h:droc:anic acid . The: must e processed : soaIin!*
oilin!* dr:in!* and -ermentation to reduce toxic c:anide e--ects.
)eurolo!ical disorders and th:roid enlar!ement occur in A-rican peoples
Yho eat lar!e amounts o- inade$uatel: processed cassava.
An unusual !enetic condition* ]-avism ]* maIes some people sensitive to
vicine* a nucleotide in -ave eans; these people develop red lood cell
dama!e 7hemol:tic anemia8 a-ter eatin! the eans. %ooIin! the eans
thorou!hl: can reduce this e--ect. This is a speci-ic example o- the c:totoxic
mechanism o- -ood molecules* and illustrates the advanta!es o- cooIin!
-oods.
)i!htshades
Plants o- the ni!htshade -amil: contain toxic sustances. ]0eadl: ] re-ers to
the toxicit: o- the leaves o- this plant !roup Yhich includes tomato* potato*
peppers* e!!plant* and toacco. All the ni!htshades contain nicotine;
toacco has the hi!hest concentration* e!!plant is next. %ountr: lore tells us
not to eat !reen potatoes and to store potatoes in the darI to avoid the
!reenin! e--ect o- li!ht. The !reen potato contains toxic compounds
7!l:coalIaloids8 similar to those -ound in the leaves. Eolanine poisonin!
-rom !reen potatoes Yill produce throat urnin!* YeaIness* diarrhea* and
even convulsions Yith collapse and coma. Adverse and aller!ic reactions to
tomatoes and peppers are common* and these ve!etales are not on our most
-avored -ood list. )i!htshades have o-ten een implicated in arthritis.
The occurrence o- toxic non-nutrient amino acids is not unusual in plants
Yho produce toxic compounds to deter predators -rom eatin! them. Over a
4>S non-protein amino acids derived -rom plant materials have een
chemicall: characteriGed. One o- the prolems Yith these amino acids is
their ailit: to imitate and replace normal amino acids in protein s:nthesis.
%anavanine in al-al-a seeds and sprouts ma: a cause h:persensitivit: illness.
The toxic a!ent in inI: cap mushrooms 7coprinus atramentarius8 Yhich
produces alcohol intolerance is the amino acid* %oprine . Toxic amino acids
?+AA in c:cad seeds are thou!ht to cause a severe neurolo!ical disease in
6uam; this amino acid resemles ?OAA in the !rass pea* lath:rus sativa*
Yhich can cause a paral:tic illness. %arnosine and its meth:lated -orm*
anersine * in sIeletal muscle* and rain are associated Yith seiGures and
carnosinemia ma: lead to mental retardation.
Eome ve!etales also ecome undesirale Yhen the: are dama!ed or
diseased. 1un!al !roYth is a ma;or cause o- toxic alteration o- plant tissue.
EYeet potato * -or example* supports a -un!al !roYth 71usarium solani8*
especiall: Yhen the tuer[s sur-ace is dama!ed. The -un!us alters the
potatoes[ metaolism* and toxic stressors are produced. ,pomeanol is one
such chemical that is liver and lun! toxic. @un! disease in cattle is caused :
in-ected sYeet potatoes. )o similar human s:ndrome has een descried.
A-latoxins
A variet: o- -un!i 71usaria* Trichothecium* %ephalosporium* etc.8 ma:
contaminate !rains* and cause illness Yith s:mptoms such as vomitin!*
diarrhea* headaches* chills* diGGiness* and lurred vision. A-latoxins are
produced : molds Yhich -avor nuts* corn* millet* and -i!s. Hi!her
concentrations o- these toxins ma: produce acute s:mptoms such as loss o-
appetite and ;aundice 7hepatitis8 and the: are also carcino!enic i- eaten in
loY concentrations over a lon!er period o- time. Eome o- these -un!al
metaolites are also neurotoxins Yhich produce tremors as a conspicuous
s:mptom. The same -un!i Yhich produce a-latoxin produce a tremor!en*
InoYn to cause ]sta!!ers ] in sheep and cattle. The common -un!i Yhich
!roY on our -ood* even in the re-ri!erator and cupoard* are Penicillium*
Asper!illus* and %laviceps.
Over 4> tremor!enic m:cotoxins have een isolated -rom these -un!i. The
role o- these m:cotoxins in human rain d:s-unction has not een
determined and is usuall: not considered in medical evaluations. Asper!illus
is a ui$uitous -un!us that can -atall: in-ect patients Yith reduced immunit:.
The rules -or sa-e stora!e o- -ood to reduce -un!al !roYth include
immediate re-ri!eration* properl: covered containers* and limits on the
duration o- stora!e. ,n !eneral* proper reheatin! o- re-ri!erated -oods can
reduce toxicit:. ?otulinis toxin is an example o- a -ood poison destro:ed :
ade$uate cooIin! o- preserved -oods.
?rassicas
The common and popular caa!e or ?rassica -amil: is not Yithout
prolems. The !as-producin! properties o- ?rassica ve!etales are Yell
InoYn. Eome ?rassicas 7roccoli8 have hi!h vitamin b content. The
therapeutic e--ect o- anticoa!ulant dru!s Yhich inter-ere Yith the conversion
o- vitamin b to prothromin ma: e reduced : rassica in!estion.
?rassicas also contain hi!h levels o- chemicals that ma: inter-ere Yith
th:roid -unction* promotin! th:roid enlar!ement 7!oitre8 . %aa!e* russel
sprouts* and Iohlrai contain pro!oitrin 7in the ran!e o- O>-4<S m! per 4SS
!ram o- -resh ve!etale8. %ooIin! reduces the !oitre e--ect o- these
ve!etales. 6oitro!ens are also -ound in turnips* so:eans* radishes*
rapeseed* and mustard. On the plus side o- the ?rassica pro-ile* there is some
evidence that re!ular in!estion o- ?rassicas ma: o--er protection a!ainst
oYel cancer.
Hers and Teas
+an: patients in$uire aout the use o- heral teas and heral treatments.
1rom a medical point o- vieY* all plant materials are potentiall: aller!enic.
1rom a iochemist[s point o- vieY* plant materials contain man: active
sustances in complex cominations Yhose od:-e--ects are !enerall: not
InoYn. ?ene-icial e--ects o- plant materials can e associated Yith ne!ative
metaolic and toxic e--ects Yhich need to e considered Yhen an: plant is
used Yith increasin! intensit:* especiall: on a dail: asis.
+edicinal hers are dru!-containin! plants Yhich should not e used
ever:da:. @iIe other dru!s* medicinal hers have side e--ects* toxic e--ects*
and aller!enic e--ects* and the: ma: not e help-ul. The prolem Yith
Yhole-plant medicines is that the active in!redients are mixed Yith
ever:thin! else in the plant. This means that the control over the dru! e--ect
that is achieved Yith puri-ied sustances is not possile Yith plant
preparations. The appearance on the marIet o- man: ]natural ] and ]heral ]
teas is unprecedented. The sa-et: o- these products is in $uestion. A $uicI
revieY o- toxicit: reported to occur Yith popular tea-plants -olloYs.
%athartic teas* includin! those Yith senna leaves* -loYers and arI*
ucIthorn arI* docI roots* or aloe leaves* do cause diarrhea. ,- used
continuousl:* these hers ma: induce laxative-dependence* o-ten Yith
adominal discom-ort* oYel d:s-unction* and malasorption o- nutrients.
@axatives* heral aller!enic teas* such as those -rom camomile* !oldenrod*
mari!old* and :arroY* can cause aller!ic reactions in persons that are
sensitive to ra!Yeed* asters* chr:santhemums* and other related plants.
0ela:ed aller!ic reactions and sun sensitivit: can -olloY consumption o- tea
-rom the leaves o- man: plant products. Et. Wohn[s Nort is InoYn to e
photosensitiGin!. Tannins in tea* includin! ordinar: tea and peppermint tea*
are sur-ace irritants to the !astrointestinal tract and have een linIed to
cancer o- the esopha!us and stomach. Addin! milI to the tea inds the plant
tannins and ma: protect the di!estive tract -rom irritant e--ects.
0iuretics are present in teas made -rom uchu* $uacI !rass* and dandelion.
0iuretics increase urine production Yith Yater and mineral losses. %o--ee
and tea are potent diuretics; the other plant teas are similar in their stress-ul
diuretic e--ects. A variet: o- rain-active chemicals are also -ound in catnip*
;uniper* h:dran!ea* ;imson Yeed* loelia* and YormYood. Teas made -rom
the petals o- -loYerin! plants 7rose* hiiscus* h:dran!ea8 are also neurotoxic
and cause headaches* thinIin! disturances* irritailit:* and depression.
Al-al-a tea contains saponins Yhich can disrupt di!estion and respiration.
Nhile the saponins o- al-al-a have een -ound experimentall: to clear the
arteries o- -att: pla$ues in monIe:s* the in!estion o- al-al-a teas ma: have
adverse e--ects.
@iver toxicit: has een linIed Yith a numer o- heral teas.
%om-re: is a popular her that is potentiall: hepatotoxic ecause o-
p:rroliGidine alIaloids* InoYn to cause hepatocellular adenomas and
increased incidence o- ladder tumors in rats.
Eassa-ras contains sa-role 7as in nutme!8* another potentiall: hepatotoxic
sustance.
6insen!has caused reast enlar!ement in men 7!:necomastia8* due to the
presence o- an estro!en-liIe sustance.
@icorice has een -ound to have sustances that aid healin! o- stomach
ulcers; hoYever* it also causes sodium and Yater retention and loss o-
potassium. Hi!h lood pressure ma: result -rom excessive consumption o-
licorice.
+istletoe contains alIaloids* small proteins 7viscotoxins8* and lectins 7Yhich
collectivel: have h:potensive* diuretic* and antispasmodic properties8.
+istletoe has een used : some heral therapists as an anti-cancer dru!.
The complex o- alIaloids ma: e c:totoxic. As Yell* hepatitis has een
reported Yith mistletoe in!estion.
Penn:ro:al extract has lon! een recommended to produce aortions* a
dout-ul e--ect* ut death due to liver dama!e has een lamed on re!ular
penn:ro:al in!estion.
There are man: possile interactions o- heral medicines and prescription
dru!s. @il: o- the Talle:* -or example* contains cardiac !l:cosides and ma:
lead to di!italis toxicit: in a person taIin! ade$uate doses o- the prescription
dru!. Horse chestnut contains natural anticoa!ulants and ma: increase the
e--ect o- coumarin anticoa!ulants. ,nI %ap is a natural source o- disul-iram*
Yith the risI o- an ]Antause ] reaction Yith alcohol. 0isul-iram inter-eres
Yith the metaolism o- alcohol and increases the accumulation o- a toxic
metaolite* acetaldeh:de.
The Eolution
The Alpha )utrition Pro!ram is a standardiGed method o- diet revision that
is help-ul in resolvin! a surprisin! numer o- health prolems. 1ood
selection and preparation in the pro!ram has taIen in account man: o- the
prolems associated Yith native -ood chemistr: and contamination Yith
chemicals. A -ood holida: on Alpha &)1 is a $uicI Ya: to eliminate all
-ood contaminants and native -ood toxins.
&nvironmed (esearch ,nc.


%ontact Cs k Alpha )utrition Pro!rams k Ecope o- Eervices k e+ail Eupport k
AnsYerin! Buestions


] E,)TA O PO0&( 0O ,)%A` ]

Bue +aca Z o $ue ele -aGK A cincia atrs da conversa Propriedades Z
0os )utrientes +aca Anti!o
Histor:
Eore nossos !roYers O Tale +!ico )ossa @inha 0e Produto 1acilidades
da emala!em
Eore ns Torna-se a
0istriuidor 9 n#veis do poder de compra %onversa 0e +aca`
+edicinas 0e AmaGon %ontate-nos
] &stas s"o as (A,c&E da +n6,%A de +A%A... ]
Todo o preto de Werome do cop:ri!ht das -otos'hers Amrica* 4RR<-5SS5.
Os hers Amrica cultivam a raiG de +aca da $ualidade superior; o alimento
super novo das ind=strias ] dos produtos naturais ]...
%O+P(& +A%A no mart de +aca a!ora`
O vare;o* os clientes pre-eridos* e todos os n#veis da compra por atacado de
+aca compra a$ui.
%artUes de crdito aceitados em um usurio se!uro

--------------------------------------------------------------------------------
A P@A)TA EC(P(&&)0&)T& 0& +A%A
+aca tem um histor: mais complexo do $ue a maioria dos hers $ue
ns ouvimos assim !eralmente sore ho;e... sua raiG $ue a -onte do poder*
+aca* 7 @epidium Peruvianum %h. 8 crescido apenas aaixo do !laciated
inclina.Ues dos Andes peruvian. +aca -oi usado primeiramente pelo ,ncas
mais de 9SSS anos h para a ener!ia e a resistncia e ne!ociado ainda
!eralmente como uma medicina e uma ener!ia $ue d"o o her durante todo
as cidades e as vilas de Peru ho;e. Os alcalides recentemente descritos de
+aca* os sterols e os vrios poders surpreendentes -iGeram completamente
le!endrio durante todo o mundo* emora* at a!ora* remanesceram
raGoavelmente elusive a respeito de suas -ontes.
)o vale m!ico de Perus* os cultivars de +aca -oram desenvolvidos pelo
,nca para a ener!ia e a resistncia.

&mora este memro raro da -am#lia do radish -osse usado por povos
ind#!enos para milhares dos anos * muitos consideraram +aca ser ]um her
perdido] ao mundo tornando-se at recentemente. A!ora* tudo est mudando
en$uanto +aca est sendo procurado ansiosamente em se!uida para seus
poders e atriutos medicinal extraordinrios. 7PA(A Cm O@HA(
1AE%,)A)T& & 0&TA@HA0O )o H,ETO(F 0e +A%A* T&WA )OEEA
Pn6,)A 0o H,ETO(F.8
)o mundo moderno de ho;e* +acaroot comido at 9 veGes um o dia
por Peruvians e pelos povos toda ao redor do mundo* 7dos atletas
pro-issionais Xs pessoas idosas8* dar-lhes a ener!ia e a;ud-la recuperar do
depression* dos addictions* dos traumas* ou da doen.a.
PO( BC& TO%r E&)T& AEE,+ ?O+K
M +n6,%A de +A%A naturalmente` A ns* esta indica."o muito
mais do $ue um slo!an` M uma maneira de vida Yorth compartilhar com o
outro. Toc sentir om o dia inteiro`

%ada raiG m!ica do h:pocot:lo de +aca contem sore >> naturais*
ph:to-produtos $u#micos en-icos. &stes nutrientes naturais tm a ailidade
de a;udar no nourishment dirio de nossos corpos e de -aGer povos -#sicos
das di-eren.as sentir`
BC& 1Ac PA(A TO%rK
+A%A +A6,%x considerado por investi!adores superiores ser um
adapto!en verdadeiro* traalhando com os ritmos naturais dos corpos para
a;udar reconstruir sistemas imunes da semana* re-re-mineraliGe corpos mal
nourished* e aumentar a ener!ia e a resistncia. Outros exemplos de como a
raiG de +aca a-eta diretamente o corpo humano incluem reduGir o stress
-#sico ou mental* irre!ularidades hormonal alan.ando* promovendo o
crescimento do caelo saudvel* os ossos* e os dentes* e promover o tom do
m=sculo. A maioria de povos sentem seu n#vel do modo e de ener!ia
levantar em um instante`
] O Tia!ra )atural ]
+aca tamm om conhecido para ele -ertilidade $ue aumenta e
desempenho sexual $ue real.a propriedades. )o mundo conscious moderno
de ho;e da sa=de e da ;uventude* esta a propriedade touted de +aca mais
provvel e a!ressivel: introduG#da no mercado a melhor. &st !anhando
rXpidamente o nicIname ] do Tia!ra natural ].
A %,r)%,A AT(nE 0A %O)T&(EA
+aca uma raiG com mais de 9SSS anos do uso histrico; seu mrito
touted pela cincia e por estudos atuais de ho;e. %om seu muito a sa=de $ue
real.a as propriedades $ue tornam-se -inalmente puliciGed extensamente*
raiG de +aca um produto $ue possa -aGer povos sentir* olhar* e executar
mais melhor...
Os doutores* os naturalopaths* e os heralists o excesso do mundo est"o
estudando ativamente e a!!ressivel: esta raiG surpreendente e pulicam seus
muitos relatrios.
&stale sore as li!a.Ues do interesse aaixo ou T&WA )OEEA Pn6,)A da
%,r)%,A A6O(A`
e +aca elevates o modo e melhora a ailidade mental 7concentra."o8 e a
resistncia -#sica.
e +aca aumenta a circula."o do san!ue na pele $ue d X pele uma aparncia
;ovem.
e Os sterols naturais na a;uda de +acaroot constroem o m=sculo especial
$uando usados con;untamente com o exerc#cio.
e +aca d um sentido !eral do em estar 7em de nourished.8
e +aca tem a ailidade de levantar povos do depression.
e +aca ener!iGa o stimulation Yithout excedente.
e 1un."o sexual dos enlivens de +aca em anos avan.ados 7Tia!ra provado
!osta do e-eito* sem e-eito lateral8
e M non addictive.
e %omo anti--orce a medicina homeopathic* um aura calmo acompanha o
uso de +A%A +A6,%x
e +aca pode a;udar re!ular irre!ularidades hormonal das mulheres.
)CT(,&)T&E & P(OP(,&0A0&E
Cma =nica raiG +n6,%A de +A%A contem $uase OS ph:to-nutrientes`
As anlises $u#micas de +aca +a!icx revelam um per-il crero-rain-
poYerin! dos aminos-cido* dos minerais* dos sterols* e de cidos -att:. Cma
avaria destes produtos $u#micos como se!ue:
A+,)OE-cido: alanina* ar!ine* aspartime* !lutamine* !l:cine* histidine*
OH-oH-proline* isoleucine* leucine* l:sine* methionine* phen:lalanine*
proline* sarcosine* serine* threonine* t:rosine* e valine.
+,)&(A,E: clcio* core* -erro* ma!nsio* phosphorus* potassium e Ginco.
ET&(O@E: rassicasterol* ero!osterol* er!ostadienol* campesterol*
sitosterol* e sti!masterol.
5S n%,0OE 1ATTF: laric* m:ristic* palmitic* palmitoleic* linoleic*
arachidic* steric* ehanic* nervonic* li!noceric* tridecanoic* P-tridecanoic*
perntadecanoic* P-pentadecanoic* heptadecanoic* R-heptadecanoic*
nonadecanoic* 44-nonadecanoic* e 4>-eicosenoic.
Todos estes ph:tochemicals cominaram com a disposi."o cheia da
m!ica de +A%A das vitaminas* includin! A* ?4* ?5* ?9* ?45* %* 0 e &;
;unto com saponins* os tannins* hidratos de carono* protien* e
isothioc:anate enG:l* isothioc:anate do p-methox:enG:l* e maIes de ,-
ecd:sone a planta uma de +aca das plantas medicinal as mais poderosas na
terra`

+aca conhecido em nas ruas
de %usco* Peru
H,ETO(F 0& )OEEO +A%A
Buando o espanhol che!ou a Peru em 4>99* estas plantas pe$uenas -oram
escondidas a-astado e remanescidas na orda do rinI da extin."o por
sculos. &mora este memro raro da -am#lia do radish -osse usado por
povos ind#!enos para milhares dos anos * muitos consideraram +aca ser
]um her perdido] ao mundo tornando-se at recentemente.
7PA(A Cm O@HA( 1AE%,)A)T& & 0&TA@HA0O )o H,ETO(F 0e
+A%A* T&WA )OEEA Pn6,)A 0o H,ETO(F A6O(A.8
Os hers-Americax-Americax exploraram os hi!hlands peruvian
assim $ue 4RR5 e -oram os primeiros para introduGir 5S cultivars de raiGes
vivas de +aca aos &CA em 4RR<` &stes cultivars nurtured no tipo especial
de A+M(,%A dos H&(?E de +aca +aca chamado raiG +!ica. M*
completamente simplesmente* a $ualidade a mais -ina +aca dispon#vel* e
para esta raG"o $ue ns somos or!ulhosos a estar em uma posi."o para
compartilhar -inalmente desta raiG surpreendente ao mundo`
%O+&%& E&CE P(O0CTOE 0& +A%A HOW&` 7e comece a experimentar
os ene-#cios de sa=de ons e a ener!ia positiva da raiG pura de +aca ho;e`8
)ecessite mais ener!ia ou sinta-a lento com para -ora de ca-e#na ou
outras misturas $u#micas deleteriousK Tente nossos ps crus ou rindados da
raiG de +A%A +A6,%x* extratos io-ativos puros e termine a linha de
sucos inteiramente enG:matic e as arras nutrientes dos rich -iGeram toda da
raiG inteira de 4SS\ +A%A +A6,%x.
O eee TA, AO +A(T 0& +A%A A6O(A %O+P(A( +A%A` e e e

Para encontrar para -ora mais sore nossa linha de produto* os detalhes em
nossos n#veis de compra di-erentes* discontos* specials* e mais*
T&(,1,%A+ PA(A 1O(A de )OEEOE P(O0CTOE N&?PA6& de
+A%A A6O(A`
--------------------------------------------------------------------------------
%O)TATO &. C. HOW&`
&-mail
Tele-one: ><4-Q<O-maca 7O5558* 1AL: ><4-Q<O-R<QQ
--------------------------------------------------------------------------------
%ontato postal em P&(C: H&(?E Amrica E.A.%. Peru* Avoirdupois. 5Q de
Wulio ><R* +ira-lores* @ima 4Q P&(C
%ontato postal nos &CA: %aixa <<O 0e Amrica Po. dos H&(?E* +urph:*
Ore!on &CA RP>99
(&POCEO +n6,%O 0& +A%A k 6(ON&( 0& +A%A HO+& k
P(O0CTOE 0& +A%A HO+&
%op:ri!ht 5SSS- 5SS9* (&0& de A+M(,%A dos H&(?E.
Todo o texto e propriedade das -otos da rede de Amrica dos hers e para
n"o reprinted em al!um -ormulrio sem permiss"o escrita da companhia. ]
Os hers Amrica ] e ] a m!ica de +aca ] s"o marcas re!istradas
internacionais re!istadas.
--------------------------------------------------------------------------------
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NOTAS NO MUITOS MEI!INA" E !URATI#E
$RO$RIEAES A RAI% E MA!A
Artigos& estudos& 'atos& e (ais...
Artigo> CnotaD "o m."i!o 7-onte: 0r. 6arr: P. 6ordan* -aculdade americana
para o avan.o na medicina.8
Aa!a !omo um &erb "o AntiEEn<e$&e!imento #ara &omens e mu$&eres
6arr: P. 6ordon* +0* presidente anterior da -aculdade americana para o
avan.o na medicina* -ounder a!ora e presidente da -aculdade internacional
de medicina avan.ada do lon!evit:* situada em %hica!o* ,llinois* ases sua
aprecia."o do maca em sua prpria experincia com ele. 1alando com mim
de Pa:son* ariGona* o 0r. 6ordon disse* ] ns todos ouvimos oatos sore
vrios produtos como o maca. +as usando esta raiG peruvian eu mesmo* eu
experimentei pessoalmente uma melhoria si!ni-icativa na resposta erectile
do tecido. &u chamo-a [ resposta da natureGa a Tia!rax ].
] O $ue eu v no maca meios de normaliGar nossos hormones steroid como
o testosterone* o pro!esterone* e o estro!en. %onse$hentemente tem a
-acilidade para prevenir as mudan.as hormonal do envelhecimento* ] 0r.
6ordon acredita. ] A!e em homens para restaur-los a um status -uncional
saudvel em $ue experimentam um l#ido mais ativo. Os lotes dos homens e
das mulheres $ue acreditaram previamente seus prolemas sexual eram
psicol!icos a!ora est"o indo claramente procurar al!o ph:siolo!ical para
melhorar a $ualidade de vida na rea de sexualit:* ] diGem o 0r. 6ordon. ]
)aturalmente* como al!um interessado no lon!evit:* eu estou ciente $ue o
mortalit: se aproxima muito mais lo!o para a$ueles indiv#duos cu;a a
atividade sexual diminu#da ou inexistente. Ou se;a eu acredito $ue os
povos $ue acoplam no sexo duas veGes uma semana ou mais mais lon!o
vivo. &u encontrei a atividade sexual para ser um marcador de con-ian.a
para o envelhecimento total.]
Artigo> CHotaD Do A."i!o 71onte: 0r. 6ariel %ousens* +08
Aa!a "' uma res#osta aos efeitos "o en<e$&e!imento no sistema "o
en"o!rine
O mdico americano 6ariel %ousens* +0* acredita este her tem o
potencial de uma resposta e$uilirada aos e-eitos do envelhecimento no
sistema do endocrine. +uitos $ue tentaram ph:toestro!ens e'ou hormones
do precursor tais como 0H&A ou pre!nenolone* ou mesmo a terapia natural
da recoloca."o do hormone e -oram descontentadas* est"o come.ando
resultados excelentes de seu uso da raiG do maca. 6ariel %ousens* +0*
medicina interna praticando em Pata!onia* ariGona* diG* ]sempre $ue
poss#vel* eu pre-iro usar a terapia do maca melhor $ue a terapia da
recoloca."o do hormone por$ue H(T envelhece realmente o corpo $ue
diminui o hormone produGindo a potencialidade das !l/ndulas. +aca provou
ser muito e-icaG com os pacientes menopausal em eliminar -lashes e o
depression $uentes e em n#veis de ener!ia crescentes. _ encontr direito
dosa!e n#vel* Xs veGes eu t come. paciente maca tratamento com um metade
um teaspoon p ou trs cpsula um dia. &m al!uns casos eu levantei o
dosa!e para um teaspoon ou seis cpsulas um o dia para a e-iccia cheia.]
Artigo> Cnota "o m."i!o e ?estimonia$D 7-onte: 0r. Henr: %ampanile* +08
O "outor ofere!e Aa!a !omo uma raiT ba$anUan"o a"rena$
O henr: %ampanile* +.0.* o-erece a raiG alan.ando adrenal de +aca a seus
pacientes. 0e acordo com sua modalidade de a!ir atravs do h:pothalamus e
pituitar:* +aca tem um e-eito alan.ando e nourishin! nas !l/ndulas
adrenal. O henr: %ampanile* +0* um specialist >S-:ear velho na medicina
interna e de -amil:'complementar: $ue pratica em Et. Petersur!* 1lorida*
relaciona-se: ] &u aconte.o ter sido nascido com a uma !l/ndula adrenal
apenas como meu pai. &u comecei -aGer exame da cortisona em meus
tYenties atrasados para aliviar a -ati!a $uais eu estava sentindo ;. Eaendo
os peri!os do uso a lon!o praGo da cortisona* eu olhei ao redor para uma
alternativa* e esta circunst/ncia $ue come.ado me interessado na medicina
complementar. &u comecei usar o pre!nenelone aproximadamente 4S anos
h e -oi raGoavelmente satis-atrio. +as um de meus pacientes disse-me $ue
sore +aca* e mim come.ou -aGer exame d aproximadamente um ms h. M
phenomenal` &u n"o senti este om desde $ue eu tinha 5S anos velho. &u
tenho assim muita ener!ia e olho assim em* meus pacientes oservaram
nela e disseram-me como descansado eu pare.o. &u have.!ot assim muita
ener!ia tenho come.ado a!ora um pro!rama do exerc#cio. ]
Aps ter tentado o para -ora nhimsel-* 0r.%ampanile come.ou a usar o maca
com seus pacientes. ] +eu primeiro paciente para -aGer exame das cpsulas
do maca experimentava -lashes $uentes e outros sintomas menopausal.
%ome.ou sentir muito mais melhor aps ter usado este her por somente
$uatro dias. &u estou empre!ando-o tamm com pacientes $ue tm a
-un."o adrenal aixa. ]
Artigo> CHotaD Do A."i!o 71onte: 0r. Wor!e Cm %alderon* +08
O #ioneiro #eru<ian #res!re<e Aa!a
Cm outro pioneiro peruvian na aplica."o therapeutic do maca inte!rou em
uma prtica mdica moderna Wor!e A!uila %alderon* +0. Cm intemist*
0r.A!uila %alderon che-e anterior do departamento de cincias iol!icas
e de decano da -aculdade da medicina humana na universidade nacional de
1ederico Tillarreal em @ima.
%omo o 0r. +alaspina e outro* 7ve;a notas em outras p!inas da cincia8*
prescreve o maca para uma variedade lar!a das condi.Ues includin! o
osteoporosis e healin! de -raturas do osso no muito idoso. ] +aca tem
muitos do clcio -Xcilmente asorale nele* mais o ma!nsio* e uma
$uantidade ;usta de aliados $ue ns estamos encontrando muito =teis em
tratar o decalci-ication dos ossos nas crian.as e nos adultos. ]
Wunto com prescrever uma dieta excelente e um determinado li-est:le muda*
0r. A!uila %alderon a;udou a pacientes com impotence masculino* sterilit:
masculino* e sterilit: -mea empre!ando a terapia do maca. Os prolemas
$ue adicionais trata com o maca s"o os ricIets* vrios -ormulrios do
anemia* sintomas menopausal tais como -lashes $uentes e a noite sua*
di-iculdades climacteric e erectile nos homens* envelhecimento prematuro* e
estados !erais da -ra$ueGa tais como a -ati!a crVnica.
Artigo> CHotaD Do A."i!o 71onte: 0r. Harold %larI* +08
9aro$" C$ar)2 AD2 faT a Aa!a um rem."io !&a<e
Cm outro doutor americano $ue tivesse recentemente come.ou a usar o
maca therapeuticall: para al!uns pacientes de (ochelle novo* :orI novo.
O 0r. %larI* $ue utiliGa a terapia do chelation e a terapia do oGVnio alm aos
hers* vitaminas e minerais em sua prtica indicou* ] mim espantado em
como rapidamente o maca traalhou em dois pacientes $ue eu estive
concernido aproximadamente por al!uma hora. ]
0escreveu um paciente como >> :ear-old +ar: T* uma postmenopausal*
mulher. +ar: T -oi possu#da de prolemas de sa=de numerosos* includin! o
a.=car um tanto elevated do san!ue* o h:pertension* o -irillation atrial* e o
h:poma!nesemia. Tinha sido a!uda doente por dois meses com
osteom:elitis e o sepsis !eneraliGado. ,ncapaG de traalhar* estava so-rendo
da -ati!a e do depression !randes e estava sentindo [ mais m e mais m [
sore os =ltimos cinco anos. ] 0entro de apenas $uatro dias de -aGer exame
das cpsulas do maca* +ar: T atravessou uma rota."o enorme* ] disse o 0r.
%larI. ] Eaiu comprar nas lo;as; limpeGa sua casa; sente -orte e vi!orosa; e
seu depression ido. ]
Nota e disclai(er)
Esta in'or(a*+o , apresentada so(ente t+o (aterial do
interesse geral e n+o -uanto u(a prescri*+o para toda a pessoa
espec.'ica ou -ual-uer circunst/ncia e( u( caso espec.'ico.
Ns n+o rei0indica(os -ue algu(as destas e1peri2ncias
estar+o duplicadas por outras& e ns incenti0a(os todos
procurar o dae 3dispositi0o auto(4tico de entrada5 de u(
practitioner -uali'icado da sa6de para o conselho -ue pertence
ela7suas condi*+o e necessidades particulares.
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!op8right 2999:2992& REE de AM;RI!A dos <ER=S.
Todo o te1to e propriedade das 'otos da rede de A(,rica dos
her>s e para n+o reprinted e( algu( 'or(ul4rio se( per(iss+o
escrita da co(panhia. ? Os her>s A(,rica ? e ? a (4gica de
Maca ? s+o (arcas registradas internacionais registadas.
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NOTAS EM REA"@AR SEAUA" O ESEM$EN<O
$RO$RIEAES A RAI% E MA!A
Artigo>
Viagra FQmeaO 7pulicado com permiss"o dos meios de not#cia heral
scottish8
&m Ecotland* um aphrodisiac natural $ue touted como o Tia!ra -mea est
sendo -ornecido. O extrato l#$uido dito ser do ene-#cio em impulsionar o
l#ido de amos os sexos mas do valor particular Xs -meas. %olhido 49.SSS
ps acima nos Andes centrais* o her -oi considerado assim potent $ue o
,ncas con-inou seu uso a sua -am#lia real. Aps $uase tornar-se extinct* as
propriedades da planta para melhorar vidas do sexo e -ertilidade est"o sendo
apreendidas outra veG sore na vi!#lia da mania Yorld-Yide de Tia!ra.
Eomente de al!uns acres da colheita em 4RR>* h a!ora 4>SS acres com as
plantas para plantar uns >SSS acres mais adicionais. O l#$uido +aca*
&xtractx expresso* ]destrava inteiramente o potencial de o $ue o ,ncas se
chamou seu super-ood]* propionates heral da palavra em &uropa* ]
material muito $uente e est indo ser muito !rande por$ue n"o tem nenhuns
side-e--ects ]. Aparte de aumentar o stamina sexual e a -ertilidade* seus
outros usos incluem do hormone a terapia da recoloca."o e -acilitar da
tens"o pre-pre-menstrual. Buando al!umas companhias procurarem patentes
nos produtos derivados de +aca* outras consideram-no um presente ao
mundo e o-erecem-no sem uma patente.
Estu"o e re$atVrio !&ineses "o $aboratVrio "e Aa!a>
7d 5SSS* &lsevier %incia ,nc.* pulicado com permiss"o do ;ornal o
urolo!:* o volume y de >>* de 5SSS8
Efeitos "e um e@trato $i#i"i! "e Le#i"ium Ae1enii no !om#ortamento
se@ua$ os ratos e os ratos
&ste estudo revela para a primeira veG uma atividade aphrodisiac de @.
+e:enii* um her andean da montanha.
OLWE?IVOS ALS?RA?OS> Para determinar o e-eito de da administra."o
oral de um extrato lipidic puri-ied do lepidium me:enii'peruvianum 7+-S4
+-S58 no n=mero o- intromissions completos e acoplamento em ratos
normais* e no per#odo latente da ere."o 7@P&8 nos ratos com d:s-unction
erectile.
AR?ODOS> Os ratos e os ratos -oram divididos aleatzria em diversos
!rupos experimentais e de controle. 0e 4S\ do ethanol uma suspens"o de
+-S4 e +-S5 -oi administrado oral por 55 dias aos !rupos experimentais de
acordo com o dosa!e especi-icado pelo pro;eto experimental. )o dia 55* 9S
minutos depois $ue o dose -oi administrado aos ratos masculinos* 5 ratos
-meas vir!ens -oram colocados com o 4 rato masculino. O n=mero de
intromissions completos de cada rato masculino em 9 horas -oi !ravado. &m
uma avalia."o de 4 dia do acoplamento* cada rato masculino cohaited com
os > ratos -meas estrous durante a noite. O n=mero de -meas sperm-
positivas -oi !ravado. O @P& -oi medido aos urros a -un."o sexual nos
ratos com d:s-unction erectile. Csando um instrumento multi-unction de
Fsd-<!* um pulso eltrico em 5S T -oi aplicado para estimular o penis dos
rat{s* e a dura."o do come.o ao stimulus X ere."o cheia -oi medida nos
se!undos como o @P&.
RESJL?ADOS> )os ratos masculinos normais* o n=mero de intromissions
completos durante o per#odo 9-hour era 4O*99 o u 4*PQ* <O*OP u 5*9R* e
OP*S4 o u 5*>> para o !rupo de controle* o !rupo +-S4* e o !rupo +-S5*
respectivamente. )a avalia."o do acoplamento* o n=mero do increasede
sperm-positivo das -meas de S*O u S*P no !rupo de controle 4*> ao u S*> no
!rupo +-S4 experimental. @P& dos ratos masculinos com d:s-unction
erectile era o u 445 49 se!undos com uma dieta re!ular 7!rupo de controle8.
A administra."o oral de +-S4 em um dose do peso de corpo de 4QS ou 4QSS
m!'I! e do +-S5 em um dose de <>* 4QS* peso de corpo de 4QSS m!'I!
reduGiu o @P& ao u >< 45 se!undos* >< u 49 se!undos* o u P4 45 se!undos*
os P9 se!undos do u* e o u <4 49 se!undos* respectivamente. O @P& dos
ratos cir=r!icos tratou com o +-S4 no dose o mais aixo 7<> m!'I!8 era o u
454 45 se!undos; assim* a mudan.a n"o era si!ni-icativa.
COHCLJSXES> A administra."o oral +-S4 e +-S5 real.ou a -un."o
sexual os ratos e ratos* do como evidenciado por um aumento o n=mero de
intromissions completos e o n=mero de -meas sperm-positivas em ratos
normais* e diminui."o no @P& nos ratos masculinos com d:s-unction
erectile.
Este estu"o foi !on"uTi"o #erto> ?o @in chen!* ban ele* :en Huan! de
%alvin H:un!chan bim* de @in!lin! (o!ers* de Fu Ehao* de chen* chen!
Bien de Fan! lu* de Eui ;unho Fan* de @u* e :i chen! de Bun na -aculdade
mdica de @iaonin! Z da -aculdade de Ehen:an! da medicina chinesa
tradicional em Ehen:an! %hina* e tamm no academ: chins da medicina
preventiva* ?ei;in!* (ep=lica Popular da %hina.
ReferQn!ias> 4. @eon T: [ o +aca [ 7me:enii de @epidium8: pouca planta
conhecida do alimento de Peru. &con ?ot 4Q: 455-45P* 4RO<. 5. %hacn (%:
+e:enii Nalp de de @epidium do -ito$u#mico de &studio. Thesis*
universidade )ac. ma:or de Ean +arcos* @ima* Peru* 4RO4. 9. chen! ?@*
bim %H* ele b* et al: Cm processo para a isola."o e puri-ication do me:enii
de @epidium. Patente pendente* 4RRR. <. Procedimento de teste cl#nico
nacional* 10A de %hina* 4RRQ. >. Hermann +* e Heller W: (aiGes e tuers
andean: Ahipa* arracacha* +aca e Facom (oma* ,P6(,* 4RRP* pp 4P>-4R>.
O. %oo ?: Historia del )uevo +undo. ?ilioteca de Autores &spa|oles Q4:
<9S* 4R>O. P. (uiG H: (elacin histrica del via;e um del Peru : o %hile dos
reinos dos los* 4PPP-4PPQ* +adrid Acad. 0e %iene &xaetas: 1is : 4 nat: >5O*
4R>5. Q. Pul!ar TW: 1ecundante de Poderoso dos sp. de @as +aca @epidium
ve!etal. ToG de Huanca:o do la 5<:4S* 4RO<. R. Wohn T: O anu e o maca. W
&thnoiol 4: 5SQ-545.4RQ4.
Estu"o e re$atVrio #eru<ian "o $aboratVrio "e Aa!a> 70r. 6loria %hacon*
Peru @ima- 0o d8
Efeitos "e Aa!a nas g$Yn"u$as "o en"o!rine
O 0r. 6loria %hacon isolou $uatro alcalides da raiG do maca e realiGou os
estudos animais com os ratos masculinos e -meas dados a raiG pulveriGada
maca ou os alcalides isolados das raiGes. &m compara."o com os !rupos de
controle animais* a$ueles $ue receem ou o p da raiG os alcalides
mostraram o maturation m=ltiplo do -ollicle do ovo nas -meas e* nos
machos* umas taxas si!ni-icativamente mais elevadas da produ."o e do
motilit: do sperm do $ue !rupos de controle. O 0r. %hacon estaeleceu em
$ue era os alcalides na raiG do maca* n"o seus hormones da planta* $ue
produGiram e-eitos da -ertilidade os ovaries e testes dos ratos. &stes e-eitos
s"o measurale dentro de P5 horas de dosin! os animais* [ ela o-ereceram em
uma entrevista recente do tele-one de @ima* Peru.
%om as experincias* deduGiu $ue os alcalides estavam a!indo na !l/ndula
h:pothalamus-h:pothalamus-pituitar:* $ue explica por$ue os ratos
masculinos e -meas a--licted em uma maneira !ender-apropriada. ,sto a
explica tamm por$ue os e-eitos nos seres humanos n"o s"o limitados os
ovaries e os testes* mas ao a!e tamm nos adrenals* dando um sentimento
de uma ener!ia mais !rande e vitalit:* e em o pancreas e th:roid tamm.
As implica.Ues da descoerta do 0r. %hacon dos e-eitos estimulando
pituitar: do maca s"o enormes. O $ue parece si!ni-icar essa terapia da
recoloca."o do hormone* mesmo as variedades naturais* $uer se;a n"o mais
por muito tempo o padr"o de ouro para optimisin! um ponto hol#stico da
vista.
Artigo> CHota Dos A."i!osD
Z Viagra natura$ Z 7notas dos doutores +alaspina* muller* e %hacon. 7ve;a
vrios estudos em nossas p!inas da cincia por estes doutores8
Os doutores +alaspina* muller e %hacon* as.Yell.as doutores os os &CA e
%anad* tm a not#cia oa para os homens $ue est"o so-rendo d:s-unction
sexual a!e-related. Podem es$uecer-se de Tia!ra caro* possivelmente
peri!oso. +aca traalha extremamente om e com se!uran.a.
O 0r. Wor!e A!uila %alderon* decano da -aculdade da medicina humana na
universidade nacional de 1edericoTillareal em @ima* prescreve o maca para
uma variedade lar!a das condi.Ues* includin! o osteoporosis e healin! de
-raturas do osso no muito idoso. 0iG* no ]+aca tem muitos do clcio
-Xcilmente asorale neles* mais o ma!nsio* e uma $uantidade ;usta de
silicone* $ue ns este;amos encontrando muito =til no decalci-ication de
tratamento dos ossos as crian.as e os adultos.]
O 0r. %alderon a;udou tamm a pacientes superar o impotence masculino*
o sterilit: masculino* e o sterilit: -mea empre!ando a terapia do maca. Os
prolemas $ue adicionais trata com o maca s"o os ricIets* vrios -ormulrios
do anaemia* sintomas menopausal tais como -lashes $uentes e a noite sua*
di-iculdades climacteric e erectile nos homens* envelhecimento prematuro* e
estados !erais da -ra$ueGa* tais como a -ati!a crVnica.
Artigo> Cm."i!os testimonia$ e notaD
?urton 6older!* presidente da medicina alternativa $ue pulica em
Tiuron* %ali-rnia* cu;o o livro o mais atrasado ] uma !uia de-initive da
medicina alternativa ao cancer ] um outro entusiasta do maca. 0iG $ue
$uando tentou o maca era muito pleased com os resultados e come.ava a
-aGer exame d re!ularmente. ] &u sou um homem velho de P5 anos e este
maca -G exame de 5> anos -ora de minha vida de sexo do envelhecimento* ]
declara ?urton 6older!. [ $ue consideravelmente importante para mim` ]
O 0r. 6arr: 6ordon concernido sore prolemas reproductive no mundo
de ho;e. ] A sociedade en-renta um prolema enorme de deixar cair
conta!ens do sperm e di-iculdades do hormone do sexo. +as o maca
promete uma solu."o nontoxic com nenhuns e-eitos doYnside. M uma
terapia $ue pare.a o-erecer homens e mulheres a possiilidade para o
re;uvenation hormonal* ] concli o 0r. 6ordon. ] )s vivemos atualmente em
uma era em $ue $uase todos estar -aGendo al!o tratar das conse$hncias
hormonal do envelhecimento. & +aca est a!ora prontamente dispon#vel.]
Nota e disclai(er)
T esta in'or(a*+o , apresentado so(ente t+o (aterial do
interesse geral e n+o -uanto u(a prescri*+o para toda a pessoa
espec.'ica ou -ual-uer circunst/ncia e( u( caso espec.'ico.
Ns n+o rei0indica(os -ue algu(as destas e1peri2ncias
estar+o duplicadas por outras& e ns incenti0a(os todos
procurar o dae 3dispositi0o auto(4tico de entrada5 de u(
practitioner -uali'icado da sa6de para o conselho -ue pertence
ela7suas condi*+o e necessidades particulares.
M,;,6OOT HOME \ M,;,M,G%; HOME
M,;,G6OPE6 HOME \ M,;,P6OD:;TS HOME
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http\9A\51
\51YYY.hers-
america.com http:''ael-ish.altavista.com'ael-ish'urltrurlK
lp^en_ptZurl^http\9A\51\51YYY.hers-america.com
!op8right 2999:2992& REE de AM;RI!A dos <ER=S.
Todo o te1to e propriedade das 'otos da rede de A(,rica dos
her>s e para n+o reprinted e( algu( 'or(ul4rio se( per(iss+o
escrita da co(panhia. ? Os her>s A(,rica ? e ? a (4gica de
Maca ? s+o (arcas registradas internacionais registadas.
Nesite pro;etado e hospedado por ?AE&%A+P ,)T&()A%,O)A@
7visto melhor nos pixels QSSLOSS monitore o a;uste com explorador <*> de
+icroso-t ou mais novo8
NOTAS EM REA"@AR SEAUA" O ESEM$EN<O
$RO$RIEAES A RAI% E MA!A
Artigo>
Viagra FQmeaO 7pulicado com permiss"o dos meios de not#cia heral
scottish8
&m Ecotland* um aphrodisiac natural $ue touted como o Tia!ra -mea est
sendo -ornecido. O extrato l#$uido dito ser do ene-#cio em impulsionar o
l#ido de amos os sexos mas do valor particular Xs -meas. %olhido 49.SSS
ps acima nos Andes centrais* o her -oi considerado assim potent $ue o
,ncas con-inou seu uso a sua -am#lia real. Aps $uase tornar-se extinct* as
propriedades da planta para melhorar vidas do sexo e -ertilidade est"o sendo
apreendidas outra veG sore na vi!#lia da mania Yorld-Yide de Tia!ra.
Eomente de al!uns acres da colheita em 4RR>* h a!ora 4>SS acres com as
plantas para plantar uns >SSS acres mais adicionais. O l#$uido +aca*
&xtractx expresso* ]destrava inteiramente o potencial de o $ue o ,ncas se
chamou seu super-ood]* propionates heral da palavra em &uropa* ]
material muito $uente e est indo ser muito !rande por$ue n"o tem nenhuns
side-e--ects ]. Aparte de aumentar o stamina sexual e a -ertilidade* seus
outros usos incluem do hormone a terapia da recoloca."o e -acilitar da
tens"o pre-pre-menstrual. Buando al!umas companhias procurarem patentes
nos produtos derivados de +aca* outras consideram-no um presente ao
mundo e o-erecem-no sem uma patente.
Estu"o e re$atVrio !&ineses "o $aboratVrio "e Aa!a>
7d 5SSS* &lsevier %incia ,nc.* pulicado com permiss"o do ;ornal o
urolo!:* o volume y de >>* de 5SSS8
Efeitos "e um e@trato $i#i"i! "e Le#i"ium Ae1enii no !om#ortamento
se@ua$ os ratos e os ratos
&ste estudo revela para a primeira veG uma atividade aphrodisiac de @.
+e:enii* um her andean da montanha.
OLWE?IVOS ALS?RA?OS> Para determinar o e-eito de da administra."o
oral de um extrato lipidic puri-ied do lepidium me:enii'peruvianum 7+-S4
+-S58 no n=mero o- intromissions completos e acoplamento em ratos
normais* e no per#odo latente da ere."o 7@P&8 nos ratos com d:s-unction
erectile.
AR?ODOS> Os ratos e os ratos -oram divididos aleatzria em diversos
!rupos experimentais e de controle. 0e 4S\ do ethanol uma suspens"o de
+-S4 e +-S5 -oi administrado oral por 55 dias aos !rupos experimentais de
acordo com o dosa!e especi-icado pelo pro;eto experimental. )o dia 55* 9S
minutos depois $ue o dose -oi administrado aos ratos masculinos* 5 ratos
-meas vir!ens -oram colocados com o 4 rato masculino. O n=mero de
intromissions completos de cada rato masculino em 9 horas -oi !ravado. &m
uma avalia."o de 4 dia do acoplamento* cada rato masculino cohaited com
os > ratos -meas estrous durante a noite. O n=mero de -meas sperm-
positivas -oi !ravado. O @P& -oi medido aos urros a -un."o sexual nos
ratos com d:s-unction erectile. Csando um instrumento multi-unction de
Fsd-<!* um pulso eltrico em 5S T -oi aplicado para estimular o penis dos
rat{s* e a dura."o do come.o ao stimulus X ere."o cheia -oi medida nos
se!undos como o @P&.
RESJL?ADOS> )os ratos masculinos normais* o n=mero de intromissions
completos durante o per#odo 9-hour era 4O*99 o u 4*PQ* <O*OP u 5*9R* e
OP*S4 o u 5*>> para o !rupo de controle* o !rupo +-S4* e o !rupo +-S5*
respectivamente. )a avalia."o do acoplamento* o n=mero do increasede
sperm-positivo das -meas de S*O u S*P no !rupo de controle 4*> ao u S*> no
!rupo +-S4 experimental. @P& dos ratos masculinos com d:s-unction
erectile era o u 445 49 se!undos com uma dieta re!ular 7!rupo de controle8.
A administra."o oral de +-S4 em um dose do peso de corpo de 4QS ou 4QSS
m!'I! e do +-S5 em um dose de <>* 4QS* peso de corpo de 4QSS m!'I!
reduGiu o @P& ao u >< 45 se!undos* >< u 49 se!undos* o u P4 45 se!undos*
os P9 se!undos do u* e o u <4 49 se!undos* respectivamente. O @P& dos
ratos cir=r!icos tratou com o +-S4 no dose o mais aixo 7<> m!'I!8 era o u
454 45 se!undos; assim* a mudan.a n"o era si!ni-icativa.
COHCLJSXES> A administra."o oral +-S4 e +-S5 real.ou a -un."o
sexual os ratos e ratos* do como evidenciado por um aumento o n=mero de
intromissions completos e o n=mero de -meas sperm-positivas em ratos
normais* e diminui."o no @P& nos ratos masculinos com d:s-unction
erectile.
Este estu"o foi !on"uTi"o #erto> ?o @in chen!* ban ele* :en Huan! de
%alvin H:un!chan bim* de @in!lin! (o!ers* de Fu Ehao* de chen* chen!
Bien de Fan! lu* de Eui ;unho Fan* de @u* e :i chen! de Bun na -aculdade
mdica de @iaonin! Z da -aculdade de Ehen:an! da medicina chinesa
tradicional em Ehen:an! %hina* e tamm no academ: chins da medicina
preventiva* ?ei;in!* (ep=lica Popular da %hina.
ReferQn!ias> 4. @eon T: [ o +aca [ 7me:enii de @epidium8: pouca planta
conhecida do alimento de Peru. &con ?ot 4Q: 455-45P* 4RO<. 5. %hacn (%:
+e:enii Nalp de de @epidium do -ito$u#mico de &studio. Thesis*
universidade )ac. ma:or de Ean +arcos* @ima* Peru* 4RO4. 9. chen! ?@*
bim %H* ele b* et al: Cm processo para a isola."o e puri-ication do me:enii
de @epidium. Patente pendente* 4RRR. <. Procedimento de teste cl#nico
nacional* 10A de %hina* 4RRQ. >. Hermann +* e Heller W: (aiGes e tuers
andean: Ahipa* arracacha* +aca e Facom (oma* ,P6(,* 4RRP* pp 4P>-4R>.
O. %oo ?: Historia del )uevo +undo. ?ilioteca de Autores &spa|oles Q4:
<9S* 4R>O. P. (uiG H: (elacin histrica del via;e um del Peru : o %hile dos
reinos dos los* 4PPP-4PPQ* +adrid Acad. 0e %iene &xaetas: 1is : 4 nat: >5O*
4R>5. Q. Pul!ar TW: 1ecundante de Poderoso dos sp. de @as +aca @epidium
ve!etal. ToG de Huanca:o do la 5<:4S* 4RO<. R. Wohn T: O anu e o maca. W
&thnoiol 4: 5SQ-545.4RQ4.
Estu"o e re$atVrio #eru<ian "o $aboratVrio "e Aa!a> 70r. 6loria %hacon*
Peru @ima- 0o d8
Efeitos "e Aa!a nas g$Yn"u$as "o en"o!rine
O 0r. 6loria %hacon isolou $uatro alcalides da raiG do maca e realiGou os
estudos animais com os ratos masculinos e -meas dados a raiG pulveriGada
maca ou os alcalides isolados das raiGes. &m compara."o com os !rupos de
controle animais* a$ueles $ue receem ou o p da raiG os alcalides
mostraram o maturation m=ltiplo do -ollicle do ovo nas -meas e* nos
machos* umas taxas si!ni-icativamente mais elevadas da produ."o e do
motilit: do sperm do $ue !rupos de controle. O 0r. %hacon estaeleceu em
$ue era os alcalides na raiG do maca* n"o seus hormones da planta* $ue
produGiram e-eitos da -ertilidade os ovaries e testes dos ratos. &stes e-eitos
s"o measurale dentro de P5 horas de dosin! os animais* [ ela o-ereceram em
uma entrevista recente do tele-one de @ima* Peru.
%om as experincias* deduGiu $ue os alcalides estavam a!indo na !l/ndula
h:pothalamus-h:pothalamus-pituitar:* $ue explica por$ue os ratos
masculinos e -meas a--licted em uma maneira !ender-apropriada. ,sto a
explica tamm por$ue os e-eitos nos seres humanos n"o s"o limitados os
ovaries e os testes* mas ao a!e tamm nos adrenals* dando um sentimento
de uma ener!ia mais !rande e vitalit:* e em o pancreas e th:roid tamm.
As implica.Ues da descoerta do 0r. %hacon dos e-eitos estimulando
pituitar: do maca s"o enormes. O $ue parece si!ni-icar essa terapia da
recoloca."o do hormone* mesmo as variedades naturais* $uer se;a n"o mais
por muito tempo o padr"o de ouro para optimisin! um ponto hol#stico da
vista.
Artigo> CHota Dos A."i!osD
Z Viagra natura$ Z 7notas dos doutores +alaspina* muller* e %hacon. 7ve;a
vrios estudos em nossas p!inas da cincia por estes doutores8
Os doutores +alaspina* muller e %hacon* as.Yell.as doutores os os &CA e
%anad* tm a not#cia oa para os homens $ue est"o so-rendo d:s-unction
sexual a!e-related. Podem es$uecer-se de Tia!ra caro* possivelmente
peri!oso. +aca traalha extremamente om e com se!uran.a.
O 0r. Wor!e A!uila %alderon* decano da -aculdade da medicina humana na
universidade nacional de 1edericoTillareal em @ima* prescreve o maca para
uma variedade lar!a das condi.Ues* includin! o osteoporosis e healin! de
-raturas do osso no muito idoso. 0iG* no ]+aca tem muitos do clcio
-Xcilmente asorale neles* mais o ma!nsio* e uma $uantidade ;usta de
silicone* $ue ns este;amos encontrando muito =til no decalci-ication de
tratamento dos ossos as crian.as e os adultos.]
O 0r. %alderon a;udou tamm a pacientes superar o impotence masculino*
o sterilit: masculino* e o sterilit: -mea empre!ando a terapia do maca. Os
prolemas $ue adicionais trata com o maca s"o os ricIets* vrios -ormulrios
do anaemia* sintomas menopausal tais como -lashes $uentes e a noite sua*
di-iculdades climacteric e erectile nos homens* envelhecimento prematuro* e
estados !erais da -ra$ueGa* tais como a -ati!a crVnica.
Artigo> Cm."i!os testimonia$ e notaD
?urton 6older!* presidente da medicina alternativa $ue pulica em
Tiuron* %ali-rnia* cu;o o livro o mais atrasado ] uma !uia de-initive da
medicina alternativa ao cancer ] um outro entusiasta do maca. 0iG $ue
$uando tentou o maca era muito pleased com os resultados e come.ava a
-aGer exame d re!ularmente. ] &u sou um homem velho de P5 anos e este
maca -G exame de 5> anos -ora de minha vida de sexo do envelhecimento* ]
declara ?urton 6older!. [ $ue consideravelmente importante para mim` ]
O 0r. 6arr: 6ordon concernido sore prolemas reproductive no mundo
de ho;e. ] A sociedade en-renta um prolema enorme de deixar cair
conta!ens do sperm e di-iculdades do hormone do sexo. +as o maca
promete uma solu."o nontoxic com nenhuns e-eitos doYnside. M uma
terapia $ue pare.a o-erecer homens e mulheres a possiilidade para o
re;uvenation hormonal* ] concli o 0r. 6ordon. ] )s vivemos atualmente em
uma era em $ue $uase todos estar -aGendo al!o tratar das conse$hncias
hormonal do envelhecimento. & +aca est a!ora prontamente dispon#vel.]
Nota e disclai(er)
T esta in'or(a*+o , apresentado so(ente t+o (aterial do
interesse geral e n+o -uanto u(a prescri*+o para toda a pessoa
espec.'ica ou -ual-uer circunst/ncia e( u( caso espec.'ico.
Ns n+o rei0indica(os -ue algu(as destas e1peri2ncias
estar+o duplicadas por outras& e ns incenti0a(os todos
procurar o dae 3dispositi0o auto(4tico de entrada5 de u(
practitioner -uali'icado da sa6de para o conselho -ue pertence
ela7suas condi*+o e necessidades particulares.
M,;,6OOT HOME \ M,;,M,G%; HOME
M,;,G6OPE6 HOME \ M,;,P6OD:;TS HOME
http:''ael-ish.altavista.com'ael-ish'urltrurlKlp^en_ptZurl^http\9A\51
\51YYY.hers-
america.com http:''ael-ish.altavista.com'ael-ish'urltrurlK
lp^en_ptZurl^http\9A\51\51YYY.hers-america.com
!op8right 2999:2992& REE de AM;RI!A dos <ER=S.
Todo o te1to e propriedade das 'otos da rede de A(,rica dos
her>s e para n+o reprinted e( algu( 'or(ul4rio se( per(iss+o
escrita da co(panhia. ? Os her>s A(,rica ? e ? a (4gica de
Maca ? s+o (arcas registradas internacionais registadas.
Nesite pro;etado e hospedado por ?AE&%A+P ,)T&()A%,O)A@
7visto melhor nos pixels QSSLOSS monitore o a;uste com explorador <*> de
+icroso-t ou mais novo8
<ISTORB E MA!A EM $ERU
Artigos& histrias& 'atos& e (ais...
Artigo> 77c8 Por Ecott Nilson* Pantera 6ulch Permaculture- Nilliams*
Ore!on8
Segre"os "a raiT #er"i"a E um &istor1 bre<e "a m'gi!a "e Aa!a nas
#$an!ies e$e<a"as
&mora se acredita $ue +aca estve cultivado assim $ue <SSS ?.%.* era
mais provvel domesticated inteiramente entre 45SS e 4SS ?.%. pelo
Pumpush* tries -eroGes do !uerreiro $ue mi!raram acima das selvas.
%ontinuou a ser cultivado durante todo os hi!hlands andean e -oi traGido a
uma per-ei."o mais !rande pelo Faro* $ue che!ou entre 44SS e 4<PS A.0.
%ultivaram os campos immense de +aca* altamente dese;veis para sua
]-ertilidade -aulous e propriedades aphrodisiacal.] Aps o con$uest de ,nca
destes tries* emitiram $uantidades !randes a %usco como o triuto a suas
r!uas novas. +uita dele -oi alimentada Xs tropas para aumentar seu vitalit:
e -ortitude.
&m sua volta* o ,ncas con$uistado e seus minions pa:ed o triuto ao
espanhol +aca e outros ens. &m 4><R* alistado nos re!istros como o
=nico om emitido como o triuto ao !overno colonial* um 4>SSS-4QSSS
Yhoppin! martela. +esmo $ue o espanhol despised o-icialmente alimentos
nativos* podem ter mer!ulhado no saco de +aca para dois reasons:4. As
alturas elevadas dos Andes -iGeram os spaniards $uase in-ertile. 5. +aca teve
uma tradi."o ind#!ena lon!a a -ertilidade crescente e o -ortitude.
0entro do conceito andean tradicional da medicina de -rio e de $uente* +aca
uma planta $uente. As propriedades atriu#das a esta planta sin!ular
incluem o aumento na -ertilidade em todos os mam#-eros* aphrodisiac*
revitaliGor e re!ulador* anti-arthritic* =til em maladies respirator:. )enhum
consumidor tradicional da maravilha de +aca tem um provrio: +aca
vida* +aca sa=de.
O conhecimento do este propriedades pe$uenas das raiGes* passado palavra
da oca atravs das !era.Ues desde o tempo em immemorial* diG de seu uso
aumentar i!ualmente a -ertilidade os seres humanos e os animais
domsticos; sua ailidade de aliviar o -ri!idit: as mulheres e o impotence
nos homens; seus virtues adapto!enic do revitaliGer r!"os e re!ulador do
menstruation* e do apaGi!uador interno dos sintomas do menopause.
(ecomenda-se tamm para o malnutrition* convalescense* perda da
memria* deilit: mental* e como um tonic !eral; Euas propriedades anti-
arthritic como uma planta $uente; Eeu uso em ailments respirator: de
tratamento. Al!uns heralists recomendam n"o usar +aca para povos com
h:pertension. &ntretanto* este counterindication n"o -oi testado
scienti-icall:.
&m pocas anti!as* +aca era inteiro coGinhado nos po.os* mer!ulhados com
carvUes da terra charred e as raiGes. ,sto chamaram o ]huatia]. Ou -iGeram o
]atunca] -ervendo* mashin!* e rolando o em es-eras e coGinhando o em uns
potenciVmetros de ar!ila alinhados com palha. Ho;e os usos de +aca s"o
completamente variados. Eeu uso mais popular no mercado internacional
como cpsulas e tauletas. +as a diversidade deve ser seu nome mdio
por$ue tamm um in!rediente excelente nos concoctions doces e savor:.
O carter pi$uant do caramelo de mantei!a de +aca a -unda."o dos
produtos ori!inais $ue variam dos li$ueurs aos ens coGidos.
Para toda a $ue histor: surpreendente de +aca e seu servi.o induitale aos
seres humanos* virtualmente incomprehensile encontrar t"o tarde $uanto
4RR5* ele estve alistado como no peri!o da extin."o. &m 4RPR* o ano o
mais escuro de +aca* o dept. peruvian da a!ricultura encontrou o
hectares7aout somente 5> PS acres8 de +aca so o cultivation no pa#s
inteiro` 0esde os 4RQS thou!h* o cultivation de +aca tem-se levantado
lentamente* e a!ora h um renascimento verdadeiro a-oot. A vida nova est
sendo respirada outra veG nos solos dos Andes elevados en$uanto os
se!redos da raiG perdida est"o sendo revelados em torno do mundo.
Artigo> 7desconhecido da -onte8
A im#ortYn!ia "e Aa!a no &istor1 "e Peru
O cultivation de +aca vai para trs talveG cinco millennia. &ra uma parte
inte!ral da re!i"o elevada da dieta e o comrcio de Andes. Buando
controlaram essa determinada re!i"o americana sul* o ,ncas encontrou o
maca assim potent $ue restrin!iram seu uso a sua corte do ro:alt:. &m cima
de overrunnin! os povos de ,nca* con$uistar spaniards tornou-se ciente do
valor desta planta e coletou-se o triuto em raiGes do maca para a exporta."o
a Epain.
+aca -oi usado como um enhancer da ener!ia e para o nutrition pelo ro:alt:
espanhol tamm. +as eventualmente o conhecimento de $ualidades
especiais dos maca morreu para -ora* sendo preservado somente em al!umas
comunidades peruvian remotas. )os 4ROSs e mais tarde nos cientistas dos
4RQSs* os alem"es e os norte-americanos $ue pes$uisam otanicals em Peru*
interesse reaceso no maca com as anlises nutritivas de o $ue -oi desi!nado
como [ as colheitas perdidas dos Andes.[ A pulica."o de um livro por esse
maca introduGido conhecido ao mundo.
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O 0ossier 0e ,o!aine

%on-erncia de )FC sore ,o!aine novemro >-O* 4RRR
(aiGes do io!a do T.
,o!aine extra#do de
o arI da raiG
%ano principal k ?usca k %incia k Opini"o k @iteratura k @i!a.Ues k
Tratamento k @ivraria k 6aarito

Pharmacolo!: ,o!aine do e alcalides ,o!aine-(elacionados
Piotr PopiI * instituto do pharmacolo!:* academ: polons das cincias* 94-
9<9 braIY* Poland
e Phil EIolnicI * descoerta do neuroscience* laoratrios de pes$uisa de
@ill:* centro incorporado de @ill:* ,ndianapolis* em <O5Q>* &CA
Aparecido como o cap#tulo y 9* ])OE A@%A@A,0&E]* Tol.>5* pp. 4RP-
594. 4RRQ* Ean 0ie!o* ,E?) S-45-<OR>>5-9 dos &CA. &ditado por 6.A.
%ordell. d 4RRQ pela imprensa academic
(e$uisite Os Alcalides* Tol. >5
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,T. PHA(+A%Ob,)&T,%E .
T. PHA(+A%O@O6,%A@ 6&(A@ A2q&E.
A. Animal &studos
4. @ocomotor atividade.
a. &-eitos na atividade locomotor induGida por outras dro!as
5. Tremor.
9. Ansiedade e medo.
<. &-eitos no sel--administration de outras dro!as.
>. &-eitos na dependncia de dro!a.
O. 0or e anal!esia.
P. A!!ression.
Q. ,nteroceptive propriedades.
R. (e-or.ar e-eitos.
4S. &-eitos na aprendiGa!em e a memria.
44. %ardiovascular a.Ues.
?. Humano &studos.
T,. @&THA@,TF & &1&,TOE 0& )&C(OTOL,%.
T,,. &1&,TOE )O &EP&%D1,%O E,ET&+AE 0O
)&C(OT(A)E+,TT&(
A. ,o!aine &-eitos em sistemas dopaminer!ic.
4. 0opaminer!ic e-eitos: Epeci-icit: Pharmacolo!ical.
5. ,o!aine altera os e-eitos de dro!as ausadas em sistemas dopaminer!ic.
?. Opioid Eistemas
%. Eerotoner!ic Eistemas.
0. %lcio (e!ulamento.
&. %holiner!ic Eistemas.
1. 6amma-6amma-Aminout:ric Eistemas 0e Acider!ic H 6A?Aer!ic J.
6. Tens"o-0ependente %analetas 0o Eodium.
H. 6lutamater!ic Eistemas.
,. Ei!ma (eceptors.
W. Tariado A.Ues de ,o!aine.
T,,,. %O)%@CEq&E.
,L. (econhecimentos
L. (&1&(r)%,AE
L, Taela 4. ,ntera.Ues do io!aine com sistemas do neurotransmitter:
estudos radioli!and do emperramento.
,. ,)T(O0C23O
,o!aine 745-methox:io!amine* ),H 4S>OP* &ndause8 um dos
alcalides ps:choactive do indole encontrados no shru a-ricano ocidental*
Taernanthe io!a . Por sore um sculo* amos os extratos de T. ,o!a e
seu os alcalides constituent* includin! o io!aine* -oram usados como
medicinals 748. O $ue -aG este alcalide do interesse particular ao
comtempor/neo o pharmacolo!: oserva.Ues anecdotal $ue indicam $ue o
io!aine possui propriedades ]anti-anti-addictive]. Assim* o io!aine 7O-5>
m!'I!* nos seres humanos8 tem reivindicado atenuar sintomas da
dependncia e da retirada a a variedade de dro!as ausadas includin!
opiates* lcool* nicotine e ps:chostimulants 7 5-R 8. &studos de Preclinical
$ue demonstram $ue o io!aine reduG o sel--administration a coca#na do e o
morphine* e atenua os sintomas da morphine-retirada* se;a consistente com
estas reivindica.Ues H revistas dentro 7PopiI e 6licI 7 4S 8 J. &ste cap#tulo
rev as propriedades pharmacolo!ical do io!aine e relacionadas alcalides.
0esde nossa =ltima revis"o detalhada 7 44 8* mais de uma cem relatrios
novos nas a.Ues pharmacolo!ical do io!aine e io!aine-como os alcalides
apareceram. O chemistr: do io!aine -oi revisto perto Al-aiate nesta srie
7 45.49 8.
A@TO
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,o!aine derivado do io!a de Taernanthe * um shru ind#!eno ao
%entral-Oeste n-rica. O shru do io!a* um memro de a -am#lia
Apoc:naceae 7ordem %ontortae8* encontrada tipicamente no under!roYth
das -lorestas tropicais 7 4< 8. As raiGes do io!a de Taernanthe -oram
usadas nos rites triais da inicia."o 7 4>.4O 8. &mora os detalhes de tais
ceremonies varie* ele -oi acreditado $ue a raiG do io!a permitiu novatos
para -aGer o contato com os antepassados no mundo do esp#rito. ,o!aine -oi
tamm encontrado no crassa de Taernanthe 7 4P 8. 0cimos nonos
relatrios do sculo dos exploradores -ranceses e el!as descreveu
primeiramente o stimulant e o aphrodisiac e-eitos de comer a raiG do io!a
7 4.4O 8. A primeira descri."o otanical da planta* -oi -eito por ?aillon em
4QQR 7 4Q 8.
0:ovsI: e @andrin 7 4R 8* as.Yell.as Haller e HecIel 7 5S 8* era o
primeiro para isolar um alcalide cristalino de raiG do io!a* $ue chamaram
o ]io!aine] ou o ]io!ine]. &m 4RS4 1ranceses os pharmacolo!ists
encontraram o io!aine para ter um tipo incomun de e-eito excitator: nos
animais 7 54-59 8. Phisalix 7 59 8 su!eriu esse io!aine podia produGir os
hallucinations aseados em oserva.Ues do comportamento incomun nos
c"es. O alcalide -oi testado suse$hentemente em a;ustes cl#nicos
ocidentais* e -oi recomendado como um stimulant para o tratamento do
convalescence e neurasthenia 7 5< 8. Apesar de tais recomenda.Ues* io!aine
nunca o uso cl#nico lar!o apreciado e -oi ne!li!enciado por investi!adores
para $uase 9S anos. )os 4R<S (a:mond-Hamet e os cole!as de traalho
pulicaram uma srie de papis $ue descrevem as propriedades
pharmacolo!ical do io!aine no isolado tecidos e o sistema cardiovascular
7 5>-95 8.
@amarene* um extrato de as raiGes do manii relativo de Taernanthe
do io!a * -oram vendidas em 1rance durante os 4R9S. %onteve ma!nsio
aproximadamente Q do io!aine* e -oi descrito como um stimulant. ,perton*
um outro extrato do io!aine* -oi usado tamm como um tonic ou stimulant
7 99 8. ,o!aine -oi usado por atletas como um desempenho real.ando a
dro!a 7 9< 8. &m muitos pa#ses* includin! os estados unidos* o uso do
io!aine proiido* talveG por causa do seu hallucino!enic purported e-eitos
7puliciGed extensamente nos 4ROS atrasados8 e sua aparncia no mercado
illicit da dro!a. &m 4RPS* o alimento dos estados e a administra."o unidos
da dro!a io!aine classi-icado como uma sust/ncia da pro!rama."o , 7todo
o uso da non-pes$uisa proiido8.
%ome.ando em 4RQ>* uma srie das patentes -oi emitida para o uso do
io!aine como meios rpidos de interromper o addiction aos narcotics
7morphine e heroin8 798* coca#na e amphetamine 7<8* lcool 7>8* nicotine 7O8
e s:ndrome da dependncia da pol:-dro!a 7 9> 8. (eivindica."o destas
patentes $ue um dose oral ou rectal do io!aine 7<-5> m!'I!8 interrompe a
dependncia s:ndrome* permitindo $ue os pacientes mantenham um li-est:le
dro!a-livre para ao menos O meses.
?aseado em estudos cl#nicos aertos* reivindicou-se 7 9O 8 essa terapia do
io!aine resultou em 5>\ de pacientes restantes dro!a-livre sem cravin! por
O meses. &ste !rupo incluiu a$ueles $ue eram amos motivated altamente
para parar e tiveram amientes home relativamente estveis. Cns outro <S-
>S\ dos pacientes tiveram seus addictions interrompidos com sucesso* e
ps:chotherap: re$uerido. Tinte a 9S\ dos pacientes tinham retornado X
dro!a uso dentro de um ms $ue se!ue o tratamento. Aaixe um tanto as
taxas do sucesso 74S-4>\8 cited por Touchette 7 9P 8.
)a ausncia de cl#nico apropriadamente controlado os estudos* o e--icac:
do io!aine como um a!ente anti-anti-addictive n"o podem ser avaliado
ri!orousl: no tempo atual. )onetheless* interesse no io!aine como um
tratamento para o addiction aumentou. &m 4RQ> )0A ,nternacionais* O ,nc.
7console de Etaten* )F* &CA8 come.ou uma campanha a persuadir o
!overno de &ETA0OE C),0OE para iniciar experimenta.Ues cl#nicas
controladas com io!aine 7 9Q 8. )o o mesmo tempo* o uso do io!aine para
tratar a dependncia do opioid aumentou em &uropa 7 9R 8. )as
experimenta.Ues atuais* cl#nicas para avaliar a se!uran.a do io!aine este;a
underYa: na universidade de +iami e s"o planeados dentro ForI )ovo.
&xperimenta.Ues cl#nicas para testar o e--icac: anti-anti-addictive do
io!aine est underYa: in os Pa#ses ?aixos e Panam 7 9Q.<S-<< 8.
%oncordar a Ali et a al .* 7 <> 8* ao alimento de &ETA0OE C),0OE e X
administra."o da dro!a e o instituto nacional para o auso da dro!a aprovou
o uso do io!aine em uma ase limitada para tratar o addiction da coca#na.
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1i!ura 4.
%omposto (4 (5 (9 (<
,o!aine %H 5 %H 9 H O%H 9 H
O - 0esmeth:lio!aine %H 5 %H 9 H Oh H
78-,o!amine do u %H 5 %H 9 H H H
78-%oronaridine do u %H 5 %H 9 %O 5 %H 9 H H
Taernanthine %H 5 %H 9 H H O%H 9
O-t- ?ut:l-O-0esmeth:lio!aine-O-0esmeth:lio!aine %H 5 %H 9 H
O%7%H 98 9 H
&mora o io!aine primeiramente -osse isolado e identi-icado em 4RS4*
7 4R-54.<O 8* na estrutura do este e em alcalides relacionados 7o 1i!. 48 -oi
estaelecido primeiramente por Al-aiate em 4R>P 7 <P 8 H ve;a tamm
Al-aiate 7 45.49 8 J. A s#ntese total do nicotinamide -oi relatada usando 49-
7 <Q 8 ou 7um <R 8 se$hncia 4<-step. Os 49 % Os spectra )+( de diversos
alcalides do io!a -oram pulicados em 4RPO 7 >S 8. A s#ntese de io!aine
tritiated -oi relatada recentemente 7 >4.>5 8.
,o!aine 7mol. do peso. 94S.<<8 tm um ponto de derretimento de 4>9t
em S*S4 mil#metros hecto!rama e um p b a de Q*4 no meth:lcellosolve de
QS\. Os mximos do asorption no metanol s"o 55O 7re!istro e <*9R8 e 5RO
7re!istro e 9*R98 nm. ,o!aine cristaliGa-se das solu.Ues alcolicas em
a!ulhas prismatic pe$uenas* avermelhadas; levorotator: H a J 0 ->9t 7no
ethanol de R>\8 e solule no ethanol* no metanol* no cloro-rmio e na
acetona* mas em insolule dentro !ua. H:drochloride de ,o!aine 7o ponto
se con!elando 5RRt%* H a J 0 -O9t 7ethanol8* H a J 0 -<Rt 7H 5 O88 solule
na !ua* ethanol e metanol* li!eiramente o solule a acetona e o
cloro-rmio* e praticamente insolule no ether 7 >9 8. ,o!aine calor e
li!ht-sensitive 7 >< 8 e lata oxide espont/neamente na solu."o* dando o
ioluteine e o iochine 7 4O.9< 8. Os alcalides relacionados estrutural ao
io!aine incluem o taernanthine* io!amine* ioxi!aine* !aonine*
io$uine* Iisantine e iolutenine. Eimilaridades estruturais entre o io!aine
e o outro alcalide do indole hallucino!ens estiveram tamm relatado
7 >> 8. A s#ntese de diversos derivatives do io!aine tem recentemente
pulicado por (epIe e por cole!as de traalho 7 >O 8.
A@TO
,T. PHA(+A%Ob,)&T,%E.
Aps a administra."o parenteral* o io!aine -oi identi-icado em vrios
materiais iol!icos* includin! o san!ue e o urine 7seres humanos8 e no
-#!ado* em Iidne: e no crero dos animais de laoratrio 7 ><.>P->R 8. Cma
hora aps a administra."o intraperitoneal* concentra.Ues elevadas do
io!aine estavam atuais no 7o -#!ado do rato e os Iidne:s OS 8. Aps a
in;e."o intravenous de 4S m!'I! aos ratos* concentra.Ues mximas do
crero 7<Q s!'! do peso molhado H s+ }499 J8 -oram conse!uidos em 4S
se!undo 7 O4 8.
(ecentemente* 6alla!her et o al .* 7 O5 8 tm desenvolveu um mtodo
altamente sens#vel e espec#-ico para $uanti-: dentro o io!aine plasma e
tecidos. &ste mtodo usa a extra."o or!/nica* derivatiGation com tr eee
T(A)E@AT,O) &)0E H&(& eeei-luroacetic anh:dride* and detection :
!as chromato!raph:-mass spectrometr: 76%'+E8. Eimilar methods Yere
developed : Hearn et al .* 7 O9 8* Alur!es et al .* 7 O< 8 and @e: et al .*
7 O> 8. Csin! a 6%'+E method* Pearl and collea!ues 7 OO 8 reported that 4* >
and 4R hours a-ter intraperitoneal administration o- <S m!'I! o- io!aine*
the Yhole rain levels o- io!aine Yere 4S* 4 and S.P s+ in -emale rats and
O* S.R and S.5 s+ in male rats* respectivel:. Hou!h et al .* 7 OP 8 studied the
tissue distriution o- io!aine a-ter i.p. and s.c. administration in rats. One
hour a-ter i.p. dosin! 7<S m!'I!8* dru! levels ran!ed -rom 4SO n!'ml 7} S.9
s+8 in plasma to 44*9SQ n!'! 7} 9O s+8 in -at* Yith si!ni-icantl: hi!her
values a-ter s.c. administration o- the same dose. 0ru! levels Yere 4S-5S
-old loYer 45 hours later. These data indicate that io!aine is su;ect to a
si!ni-icant ]-irst pass] e--ect a-ter i.p. dosin!* and that there is a marIed
propensit: -or io!aine to e deposited in adipose tissue* re-lectin! its
lipophilicit:. %onsistent Yith its lipophilicit:* io!aine levels in adipose
tissue Yere ver: hi!h -or at least 45 hours a-ter administration. ?ased on
these data* it Yas su!!ested that a sin!le dose o- io!aine ma: provide a
lon!-actin!* depot-liIe time course o- action 7 OP 8.
The reported lon!-term e--ects o- io!aine 7e.!. 7 OQ-PS 88* have led to the
h:pothesis that this alIaloid ma: e metaoliGed to an active principle Yith
a lon! hal- li-e 7 P4 8. At present* there is no direct evidence to support this
h:pothesis. ,o!aine Yas reported to disappear -rom the rat at a rate o- }<\
o- the administered dose per hour Yith } >\ o- the in;ected dose eliminated
unchan!ed in urine. &limination Iinetics -rom rain :ielded a hal--li-e o- OS
min in rodents 7 OS*O4 8 and su!!est a one-compartment model. A-ter
administration o- io!aine 74S m!'I!* p.o.8 to raits* urine concentrations
reached a maximum <-> hours later* then decreased rapidl: and disappeared
a-ter O hours 7 ><*OS 8. TaIen to!ether* these data su!!est that io!aine is
extensivel: metaoliGed. ,nspection o- io!aine[s structure 71i!. 48 led us to
h:pothesiGe that a liIel: de!radation pathYa: is O -demeth:lation at %45.
?ased on this h:pothesis* O -desmeth:lio!aine 7also InoYn as norio!aine
or 45-h:drox:io!amine8* Yas s:nthesiGed : 0r. %. ?ertha at the )ational
,nstitutes o- Health in 4RR<. At the same time* O - tert -ut:l- O
-desmeth:lio!aine Yas s:nthesiGed in an attempt to maIe an io!aine
derivative resistant to O -demeth:lation 71i!. 48. Thus* the -irst compound
Yas s:nthesiGed to investi!ate the potential pharmacolo!ical actions o- a
liIel: io!aine metaolite. The second compound permitted examination o-
the pharmacolo!ical e--ects o- an io!aine derivative that Yould not e
de!raded : O -demeth:lation. The s:nthesis o- these compounds Yas
descried : @a:er et al .* 7 P5 8.
(ecent studies have indeed demonstrated that io!aine is metaoliGed*
and that O -desmeth:lio!aine can e detected in human plasma 7 P9 8 as
Yell as in the plasma and rains o- io!aine-treated rats 7 OO 8. ?ehavioral
and neurochemical studies in rodents have estalished that O
-desmeth:lio!aine is pharmacolo!icall: active 7discussed later8.
1olloYin! an i.p. dose o- io!aine 7<S m!'I!8* Pearl et al .* 7 OO 8 reported
rain O -desmeth:lio!aine concentrations o- 5S* 4S and S.Q s+ in -emale
rats and 49* P and S.4 s+ in male rats* respectivel:* at 4* >* and 4R hours
a-ter administration. These data su!!est that !ender di--erences in
pharmacolo!ical responses to io!aine ma: e attriuted to
pharmacoIinetic* rather than pharmacod:namic* -actors. Nhile a report o-
one human su;ect 7 P9 8 indicated that O -desmeth:lio!aine persisted in
plasma at hi!h levels -or at least 5< hours a-ter oral io!aine administration*
it is not clear i- this pattern Yill e representative.
There is evidence indicatin! that the various pharmacolo!ical e--ects o-
io!aine ma: e attriutale* at least in part* to its metaolite7s8. 1or
example* the tremori!enic e--ects o- io!aine dissipate much more rapidl:
than its ailit: to attenuate the morphine YithdraYal s:ndrome in rats 7 P< 8.
This -indin! su!!ests that an active principle7s8 responsile -or one action
ma: e more rapidl: metaoliGed than compound7s8 involved in other
actions. Alternativel:* the various pharmacolo!ical e--ects o- io!aine ma:
involve di--erent neurotransmitter pathYa:s 7discussed later8.
TOP
T. 6&)&(A@ PHA(+A%O@O6,%A@ A%T,O)E.
A. Animal Etudies
4. @ocomotor activit:.
,o!aine produces complex e--ects on locomotor activit: in rodents. A
dose o- 5S m!'I! 7i.p.8 sli!htl: increased locomotor activit: in mice 7 P> 8
Yhile Eershen et al.* 7 PO 8 reported that <S m!'I! 7i.p.8 decreased locomotor
activit: in male mice at 4* ut not 5<* hours a-ter in;ection. The same dose
inhiited locomotion in -emale rats durin! the -irst hour a-ter in;ection*
Yhereas one YeeI later locomotor activit: Yas increased 7 OR 8.
(ecentl:* Pearl and collea!ues 7 OO 8 noted !ender di--erences in the
e--ects o- io!aine on locomotor activit: 7<S m!'I!* i.p.* > or 4R hours
e-ore test8. ,n control males and -emales the locomotor activit: decreased
durin! the second hour o- oservation. ,o!aine treatment in -emales
prevented this decrease in locomotor activit:. ,n -emales* ut not males*
io!aine decreased locomotor activit: Yhen !iven 4R hours e-ore the test
7 OO 8. Another stud: revealed that in male rats* a sin!le dose o- <S m!'I!
inhiited locomotor activit: < hours a-ter in;ection; a dose o- QS m!'I!
decreased motor activit: 5< hours a-ter in;ection 7 PP 8.
(ats in;ected Yith doses o- 5S-OS m!'I! o- io!aine displa:ed sloYer
response times on sensor: and sensor:-motor tests and Yere also impaired in
per-ormin! speci-ic motor re-lexes at doses o- <S-OS m!'I!. 1urthermore*
these rats exhiited a marIed reduction in locomotor activit: as Yell as in
emotionalit: at doses ran!in! -rom 4S- <S m!'I!. At hi!her doses 7<S
m!'I!8* rats appeared virtuall: inactive 7 PQ 8. ,n other studies* at doses
aove 5> m!'I!* io!aine produced ataxia* spla:ed hind lims* outstretched
-orelims* Etrau tail and h:perexcitailit: 7 PR 8.
One hour a-ter O -desmeth:lio!aine or 4Q-methox:-coronaridine
in;ection 7<S m!'I!8* locomotor activit: Yas increased durin! the second
hour o- oservation 7 OO*QS 8. ,n our studies* hi!h doses 745S m!'I!8 o- O
-desmeth:lio!aine and O - t -ut:l- O -desmeth:lio!aine produced
pro-ound ataxia and convulsions 7 P5 8. ,o!aine* O -desmeth:lio!aine* and
O - t -ut:l- O -desmeth:lio!aine* 7QS m!'I!8 did not si!ni-icantl:
in-luence rotorod per-ormance in mice 7 P5 8.
TOP
a. &--ects on locomotor activit: induced : other dru!s
,o!aine has een -ound to a--ect the motor stimulant properties o-
amphetamine* cocaine* and morphine in rodents 7h:perlocomotion induced
: these dru!s is elieved to re-lect their ]ps:chotomimetic] $ualities in
man8. Althou!h the results o- these studies are not uni-orm* in !eneral* it has
een -ound that in -emale rats this alIaloid potentiates the locomotor
response to amphetamine and cocaine* Yhereas opposite e--ects Yere
reported in male rats and mice.
Eershen et al.* 7 Q4 8 -ound that io!aine 7<S m!' I! i.p.* 5 or 4Q hours
e-ore amphetamine8 enhanced amphetamine 74 m!'I!8 - induced
h:permotilit: in -emale rats. ,n other studies* an amphetamine-induced
increase in locomotor activit: Yas potentiated in -emale rats pretreated Yith
io!aine 7<S m!'I!* i.p.8 4R hours earlier 7 Q5 8. %ocaine-induced
h:permotilit: in -emale rats Yas also potentiated : io!aine 7 Q9*Q< 8.
?rodericI et al. * 7 Q>*QO 8 reported that io!aine 75S-<S m!'I!* i.p.8
administration to male rats -or -our da:s reduced cocaine 75S m!'I!8 -
induced h:permotilit:. ,o!aine 7<S m!'I!* i.p.8 administration also reduced
cocaine- 75> m!'I!* s.c.8 induced h:permotilit: in male mice 7 PO 8* a
-indin! in a!reement Yith the amphetamine 74 m!'I!8 - io!aine interaction
7 Q4 8 in this !ender and species. (ecent data demonstrate that the e--ects o-
io!aine on cocaine 75S m!'I!8 -induced h:peractivit: in -emale rats are
time dependent. Thus* !iven 4 h e-ore cocaine* io!aine and O
-desmeth:lio!aine 7<S m!'I!8 inhiited cocaine-induced h:peractivit:* ut
Yhen !iven 4R h e-ore cocaine the: produced the opposite e--ect 7 QS 8.
,o!aine pretreatment 7<S m!'I!* i.p. 4R hours e-ore measurement8
decreased or locIed the locomotor stimulation induced : morphine 7S.>-
5S m!'I!8 in rats 7 OR*P4 8. ,o!aine administered one YeeI 7ut not one
month8 e-ore morphine 7> m!'I!8 reduced the motor stimulant e--ects o-
this opiate 7 OR 8. Pearl et al .* 7 QP 8 -ound that io!aine 7>-OS m!'I!8 is
more potent in inhiitin! morphine-induced h:perlocomotion in rats
pretreated Yith morphine -or several 74-<8 da:s compared to non-pretreated
rats. 0oses o- io!aine 7>-4S m!'I!8 that alone Yere inactive in dru!-naive
animals attenuated morphine-induced h:peractivit: in the morphine
pretreated rats. The inhiitor: e--ects o- io!aine on morphine-induced
h:perlocomotion appear !ender related* ecause io!aine is more potent in
-emale rats 7 OO 8. ,o!aine-induced inhiition o- morphine - induced
h:perlocomotion can e reversed : coadministration o- a Iappa anta!onist
7norinaltorphine* 4S m!'I!8 and an )+0A a!onist 7)+0A* 5S m!'I!8.
HoYever* neither norinaltorphine nor )+0A alone locIed this action o-
io!aine 7 QQ 8.
O -0esmeth:lio!aine 74S-<S m!'I!8 also inhiited morphine-induced
h:perlocomotion in -emale rats. HoYever in male rats* the dose o- 4S m!'I!
potentiated and <S m!'I! inhiited morphine-induced h:perlocomotion
7 OO*QR 8.
TOP
5. Tremor.
@iIe the someYhat structurall: related alIaloid harmaline* io!aine
produces tremors. ,n mice* io!aine is tremori!enic oth Yhen !iven
intracererall: 7&0 >S 45P nmol'! rain* } <O s !'! Yith a latenc: to tremor
o- aout 4 minute8 7 RS 8* and s:stemicall: 7&0 >S 45 m!'I!* s.c.8 7 O4 8. ,n
rats* io!aine produced -ine tremors* -lattenin! o- od: posture* and -laccid
hind lims up to 5 hours a-ter administration o- <S m!'I! 7i.p.8 7 R4 8. @oY-
amplitude Yhole od: tremors appearin! Yithin 4S min a-ter administration
o- as little as 4S m!'I! o- io!aine have also een reported 7 R5 8. O[Hearn
et al .* 7 R9 8 reported that a hi!h dose o- io!aine 74SS m!'I!8 produced
ataxia and hi!h--re$uenc: tremor o- the head and trunI in rats. ,o!aine-
induced tremor pre-erentiall: involves the head and upper extremit: in rats
and mice 7 R< 8. ,o!aine 75S m!'I!8 - induced tremors in mice Yere
locIed more potentl: : %%b-Q and ceruletide compared to other re-erence
compounds* includin! prol:l-leuc:l!l:cine amide 7+,18* atropine*
haloperidol* iperiden* ethopropaGine* trihex:phenid:l* methixene and
clonaGepam 7 R> 8.
cetler et al.* 7 O4 8 estalished the tremori!enic structure-activit:
relationship o- several io!aine-liIe compounds in descendin! order o-
potenc:: taernanthine g io!aline g io!aine g iox:!aine g O
-desmeth:lio!aine. 6licI et al.* 7 RO 8 -ound that at ehaviorall: e--ective
doses 75-QS m!'I!8 io!aine* deseth:lcoronaridine* harmaline and
taernanthine produced tremors -or at least 5-9 hours. ?oth the ( and E
enantioners o- io!amine and coronaridine Yere devoid o- this action. The
io!aine-liIe alIaloids* 4Q-methox:coronaridine and O -desmeth:lio!aine
Yere also -ound to lacI tremori!enic e--ects 7 QR*RP 8.
The tremori!enic properties o- io!aine and related compounds have een
attriuted to an action on 6A?Aer!ic pathYa:s 7 RQ-4SS 8 and to the
locIade o- volta!e-dependent sodium channels.
TOP
9. Anxiet: and -ear.
Echneider and Ei!! 7 4S4 8 descried the ehavioral e--ects o- io!aine in
cats. The authors concluded that a-ter intravenous administration o- 5-4S
m!'I!* io!aine produced -ear-liIe reactions that persisted -or 4S-5S
minutes Yith a normal appearance oserved 4-5 hours a-ter in;ection. The
electroencephalo!raphic pattern otained a-ter io!aine administration 75->
m!'I!8 shoYed a t:pical arousal s:ndrome* resemlin! that oserved a-ter
direct stimulation o- the reticular -ormation. This arousal s:ndrome Yas
inhiited : atropine 75 m!'I!8 7 4S4 8. 6ershon and @an! 7 4S5 8 descried
the e--ects o- io!aine in do!s* Yhich ecome more tense and alert*
interpreted as the appearance o- anxiet:. +oreover* the: oserved that the
do!s exhiited a lacI o- reco!nition o- oth their re!ular handlers and
environment.
(ecentl:* ?enYell et al .* 7 4S9 8 reported reductions in open arm entries
in the elevated plus-maGe test Yhen rats Yere tested 55 hours a-ter
pretreatment Yith io!aine 7<S m!'I!* i.p.8. ,n mice* io!aine 75.> m!'I!8
exhiited anxio!enic actions* Yhereas a dose o- 4 m!'I! had anxiol:tic
e--ects 7 4S< 8. These are perhaps the most compellin! preclinical data that
io!aine ma: in-luence anxiet: levels ecause anxiol:tic a!ents 7e.!.
enGodiaGepines8 increase open arm entries in this test.
TOP
<. &--ects on sel--administration o- other dru!s.
,o!aine 7<S m!'I!* i.p.8 inhiits the sel--administration o- cocaine in
rodents. %appendi;I and 0Gol;ic 7 4S> 8 trained male Nistar rats to
intravenousl: sel--administer cocaine; a sin!le dose o- io!aine 7<S m!'I!8
decreased cocaine intaIe : <S-OS\ -or several da:s* and repeated treatment
Yith io!aine at one-YeeI intervals decreased cocaine sel--administration
: OS-QS\. This decrease Yas maintained -or several YeeIs. Eimilar e--ects
Yere -ound in mice that developed a pre-erence -or cocaine in the drinIin!
Yater. Thus* io!aine administration 7tYo YeeIs a-ter the e!innin! o- a
choice period* 5 doses o- <S m!'I!* O hours apart8 diminished cocaine
pre-erence -or -ive da:s 7PS8. Accordin! to Tocci and @ondon 7 4SO 8* some
investi!ators have -ailed to replicate io!aine[s e--ect on cocaine sel--
administration in the rat 7 4SP 8 and rhesus monIe: 7 4SQ 8. Also 0YorIin et
al .* 7 4SR 8 reported that neither <S m!'I! o- io!aine !iven OS min prior to
the session* nor QS m!'I! !iven 5< hour e-ore the session* suppressed
respondin! maintained : intravenous cocaine in-usions. ,n this stud:*
cocaine sel--administration Yas inhiited : pretreatment Yith io!aine 7QS
m!'I!8 either OS or RS min prior to the session 7 4SR 8. HoYever* ecause
this dose o- io!aine reduced scheduled -ood intaIe* these latter e--ects o-
io!aine on cocaine sel--administration appear to e unspeci-ic.
6licI et al.* 7 RO 8 demonstrated that io!aine and several io!a alIaloids
7taernanthine* ( - and E -coronaridine* ( - and E - io!amine*
deseth:lcoronaridine* and harmaline8 reduced cocaine sel--administration in
rats in a dose-related -ashion 75.>-QS m!'I!8. 1or some alIaloids* these
e--ects Yere seen the da: a-ter in;ection. O -0esmeth:lio!aine 7<S m!'I!8 7
QR 8 and 4Q-methox:coronaridine 7 RP 8 Yere also reported to inhiit cocaine
sel--administration.
,o!aine dose dependentl: 75.>-<S m!'I!8 reduced intravenous morphine
sel--administration in -emale Epra!ue-0aYle: rats immediatel: a-ter
in;ection as Yell as on the next da: 7 OQ 8. ,n some animals* a reduced
morphine intaIe Yas oserved -or several da:s; other rats re$uired several
doses o- io!aine to achieve a prolon!ed reduction. Eimilar e--ects Yere
demonstrated -or other io!aine-liIe alIaloids includin! O
-desmeth:lio!aine 7 QR 8* taernanthine* ( - and E -coronaridine* ( - and E
- io!amine* deseth:lcoronaridine* harmaline 7 RO 8 and 4Q-
methox:coronaridine 7 RP 8. HoYever* data -rom another stud: revealed
someYhat di--erent results. Thus* 0YorIin et al .* 7 4SR 8 -ound that io!aine
7<S or QS m!'I!8 diminished heroin sel--administration in male 1isher rats
onl: on the da: it Yas administered. +oreover* the same stud: revealed that
io!aine treatment resulted in a RP\ decrease in respondin! -or a -ood
rein-orcement schedule* su!!estin! that its e--ects on heroin sel--
administration Yere unspeci-ic.
,o!aine-induced inhiition o- morphine sel--administration has een
-ound to e reversed : se$uential administration o- a Iappa anta!onist
7norinaltorphine* 4S m!'I!8 and an )+0A a!onist 7)+0A* 5S m!'I!8.
)either norinaltorphine nor )+0A alone Yere e--ective in this respect
7QQ8.
,o!aine 74S-OS m!'I!8 reduced alcohol intaIe in alcohol-pre-errin!
1aYn Hooded rats* Yithout a--ectin! either lood alcohol concentrations or
-ood intaIe 7 44S*444 8. The authors concluded that a metaolite could e
involved* ecause io!aine Yas e--ective in this measure Yhen administered
intraperitoneall: and intra!astricall:* ut not sucutaneousl: 7 445 8. A
recent stud: demonstrated an attenuation o- alcohol consumption : the
io!aine con!ener* 4Q-methox:coronaridine in rats 74498.
TOP
>. &--ects on dru! dependence.
(epeated administration o- io!aine 74S or <S m!'I!8 did not produce
dependence in rats as measured usin! the Primar: Ph:sical 0ependence test
7 44< 8.
,n morphine-dependent rats* the opioid anta!onist naloxone induces a
YithdraYal s:ndrome* characteriGed 7in rats8 : increased rearin!* di!!in!*
;umpin!* salivation and ]Yet-do!] head shaIin!. ,o!aine dose-dependentl:
reduced the -re$uenc: o- some o- these YithdraYal s:mptoms 7;umpin!*
rearin!* di!!in!* head hidin!* cheYin!* teeth chatterin!* Yrithin!* penile
licIin!8 a-ter oth intracereroventricular 7<-4O s!8 7 44> 8 and i.p.
administration 7<S and QS m!'I!8 7 P<*44O 8. HoYever* these e--ects could
not e replicated in other studies in either rats 7 9R*44P 8 or mice 7 44Q 8. At
least the second -ailure to replicate can e attriuted to the -act that in the
1rances et al .* 7 44Q 8 stud:* io!aine Yas administered to animals that
developed a -ull YithdraYal s:ndrome. ,n morphine-dependent monIe:s*
io!aine 75 and Q m!'I!* s.c.8 partiall: suppressed the total numer o-
YithdraYal si!ns 7 44< 8. Our studies 7 P5*44R 8 demonstrate that io!aine
inhiits the morphine YithdraYal s:ndrome in mice in a dose-related
-ashion. This e--ect Yas reversed : cominin! io!aine treatment Yith
!l:cine. Etructure-activit: studies revealed that amon! various io!aine-liIe
compounds 7includin! O -desmeth:lio!aine and O - t -ut:l- O
-desmeth:lio!aine8* onl: io!aine inhiited the intensit: o- morphine
YithdraYal 7 P5 8. ?oth the ailit: o- !l:cine to inhiit this e--ect o- io!aine
and the -ailure o- other io!aine derivatives to potentl: inhiit the indin! o-
noncompetitive )+0A anta!onists 7e.!.* H 9 HJ~)-H4-75-thien:l8c:clo-
hex:lJ-9*<-pipenoline 7T%P8 and H 9 HJ~+b-QS48 su!!ests that the )+0A
anta!onist actions o- io!aine are responsile -or its anti-YithdraYal e--ects.
This h:pothesis is supported : the oservation that Yhile O
-desmeth:lio!aine and O - t -ut:l- O -desmeth:lio!aine had much hi!her
a--inities -or Iappa opioid receptors than io!aine did* onl: io!aine
exhiited a si!ni-icant a--init: -or )+0A receptors.
TOP
O. Pain and anal!esia.
,o!aine did not mimic the anal!esic action o- morphine in either the tail
-licI 74-<S m!'I!* i.p.8 or hot plate 7up to 5S m!'I!* i.p.8 tests* althou!h it
exhiited anal!esic activit: in the phen:l$uinone Yrithin! test 7&0 >S R.P
m!'I!8 7 44<*45S*454 8. ,o!aine did not exhiit antinociceptive activit:
Yhen !iven tYice a da: -or < da:s 7 455 8. ,o!aine either increased
7 45S*459 8 or did not a--ect 7 44<*454 8 morphine anal!esia in the tail -licI
test. Eimilarl:* it did not in-luence anal!esia produced : either a Iappa
opioid a!onist 7C->S*<QQH8 or a delta opioid a!onist H0-Pen 5 *0-Pen > J
enIephalin 70P0P&8 7 454 8. ,o!aine has een reported to decrease
anal!esia in rats Yhen !iven 4R hours prior to morphine 7 459 8* ut another
report indicates io!aine is not e--ective Yhen !iven <-5< hours prior to
morphine administration in mice 7 454 8. ,n addition* %ao and ?har!ava
7 455 8 demonstrated that io!aine 7<S-QS m!'I!8 inhiited the development
o- anal!esia to mu* ut not Iappa or delta* a!onists in mice.
O -0esmeth:lio!aine 7<S m!'I!8 potentiated morphine-induced
anal!esia in rats 7 459 8 and mice 7 454 8. This e--ect Yas no lon!er apparent
4R hours a-ter its administration 7 459 8. The potentiation o- morphine-
induced anal!esia ma: e attriuted to the relativel: hi!h a--init: o- O
-desmeth:lio!aine at opioid mu 7b i 5.OO u S.O5 s+8 and Iappa 7b i S.RO
u S.SQ s +8 receptors 7 45< 8. HoYever* this interpretation appears unliIel:
ecause O -desmeth:lio!aine pretreatment did not in-luence either Iappa -
or delta - opioid a!onist - induced antinociception 7 454 8.
,o!aine 74S-<S m!'I!8 completel: locIed the antinociceptive e--ect o-
7~8-epiatidine in rodents* ut Yas ine--ective Yhen !iven at a dose o- <S
m!'I! 5< h e-ore epiatidine. These data su!!est that this Yas an e--ect o-
io!aine and not that o- its putative* lon!-lastin! metaolite 7 45> 8. This
locIade o- the antinociceptive e--ect o- epiatidine is not surprisin!*
ecause epiatidine-induced anal!esia is mediated : a mechanism
-undamentall: di--erent -rom that o- the opioids.
TOP
P. A!!ression.
%ompared to other ps:choactive compounds 7e.!. psiloc:in* W?-99O* and
u-otenine8* io!aine 74S m!'I!8 had a ne!li!ile e--ect on the
a!!ressiveness o- isolated mice and muricidal ehavior in rats 7 45O 8.
TOP
Q. ,nteroceptive properties.
Animals can e trained to ]reco!niGe] similarities amon! dru!s. Euch
discriminative 7interoceptive8 properties ma: su!!est a similar mechanism
o- action not necessaril: related to the structure o- a compound.
)o !eneraliGation etYeen io!aine and serotoner!ic li!ands 7e.!.
-en-luramine* ) -79-tri-luorometh:lphen:l8piperaGine HT1+PPJ* 4-75*>-
dimethox:-<-iodophen:l8-5-aminopropane H0O,J* meth:l-
enediox:methamphetamine H+0+AJ* $uipaGine or @E08 Yas -ound in
dru!-discrimination paradi!ms 7 45P*45Q 8. HoYever* Palumo and Ninter
7 45R 8 did oserve a !eneraliGation etYeen io!aine 74>-5S m!'I!8 and
dimethox:meth:lamphetamine H0O+J 7S.O m!'I!8* as Yell as etYeen
io!aine and @E0 7S.4 m!'I!8 in a tYo-lever discrimination tasI. ?ecause
piGot:line 7?%-4S>8 locIed 0O+-appropriate and @E0-appropriate
responses* an involvement o- >-HT 5 or >-HT 4 receptors in the stimulus
properties o- io!aine Yas su!!ested. Eimilarl:* no !eneraliGation etYeen
io!aine and %6E 4S<PO? 7a dopamine release-inhiitin! a!ent8 Yas -ound
in a dru!-discrimination paradi!m 7 45P 8.
,n contrast* io!aine sustituted as an interoceptive cue in mice trained to
reco!niGe +b-QS4 7diGocilpine8 7 44R 8* ut not to H7i8-HA-ROOJ 7a loY
e--icac: partial a!onist o- the !l:cine site at the )+0A receptor8 7 49S 8 in a
T-maGe dru! discrimination paradi!m.
Helsle: and collea!ues 7 494 8 studied the interoceptive cue produced :
io!aine in male 1isher rats. The time course o- the io!aine 74S m!'I!8 cue
revealed that a maximum o- io!aine-appropriate responses Yere oserved
at a OS min pretreatment time* and* that at the pretreatment time o- Q hours*
no io!aine-liIe responses Yere oserved. These -indin!s* to!ether Yith
oservation that O -desmeth:lio!aine sustituted onl: partiall: to the
io!aine cue* su!!est that the su;ective e--ects o- io!aine are not due to
this putative metaolite. The same stud: hoYever* revealed that harmaline
completel: sustituted as an io!aine cue 7 494 8. This later -indin! indicates
that animals ma: reco!niGe the tremori!enic e--ects o- io!aine.
TOP
R. (ein-orcin! e--ects.
,o!aine does not appear to possess reYardin! or aversive e--ects as
measured in the conditioned place pre-erence'aversion test 7 495 8* a
preclinical procedure that can predict ause potential in humans.
)onetheless* the same authors reported that io!aine 7<S m!'I!8 ma:
attenuate the ac$uisition* ut not expression o- morphine and amphetamine
place-pre-erence in male rats 7 PP*495*499 8. This dose o- io!aine did not
inter-ere Yith the ac$uisition o- conditioned place aversion induced : either
naloxone or lithium chloride 7 495 8. ,o!aine 7<S m!'I!* 55 hours e-ore
the test8 attenuated the estalishment o- lithium- and morphine-induced
conditioned taste aversion 7 49< 8. These results su!!est a speci-ic action o-
io!aine on the neurochemical and ehavioral 7oth rein-orcin! and
aversive8 actions o- morphine rather than on opioid s:stem7s8* ecause the
rein-orcin! e--ects o- naloxone Yere una--ected. ,n support to these -indin!s*
it has een reported that io!aine 75S or <S m!'I!* 5< h e-ore the test8
neither decreased the pre-erence -or a sYeet solution nor attenuated
conditioned pre-erence -or a -lavor previousl: associated Yith sYeet taste
7 49> 8.
TOP
4S. &--ects on learnin! and memor:.
At a dose used in the ma;orit: o- contemporar: ehavioral studies in
rodents 7<S m!'I!8* io!aine has een -ound to attenuate the ac$uisition o-
spatial memor:* perhaps due to reductions in locomotor activit: and in
detection o- sensor: in-ormation 7 PQ 8. HoYever* at much loYer doses 7S.5>
- 5.> m!'I!8* io!aine as Yell as O -desmeth:lio!aine 7ut not O - t -ut:l-
O -desmeth:lio!aine8 -acilitated spatial memor: retrieval 7 49O 8. Csin! a
spatial memor: tasI* Helsle: et al .* 7 R5 8 -ound that: 48 tYo doses o-
io!aine 7>S m!'I!* spaced : Q hours8 decreased the response rate* ut did
not a--ect ac$uisition rate; 58 io!aine* even at the hi!hest doses o- 9S and
<O m!'I! !iven 5S min e-ore the learnin! trial did not a--ect tasI
ac$uisition; 98 9S m!'I! o- io!aine administered ;ust a-ter the learnin! trial
-acilitated the consolidation o- memor: trace.
TOP
44. %ardiovascular actions.
6ershon and @an! 7 4S5 8 -ound that io!aine produced a rise in lood
pressure and increased heart rate in conscious do!s. These e--ects Yere
locIed : atropine 7 49P 8. HoYever* in anesthetiGed do!s* io!aine
produced a -all in lood pressure and reduced heart rate reduction* leadin!
the authors to propose an interaction etYeen anaesthesia and the
cardiovascular e--ects o- io!aine 7 4S5 8. Echneider and (inehart 7 49P 8
postulated a centrall: mediated stimulator: e--ect o- io!aine. ,o!aine also
potentiated the pressor response to oth adrenaline and noradrenaline. +ore
recentl:* Ha;o-Tello et al.* 7 49Q 8 -ound that taernanthine 7an alIaloid
closel: related to io!aine8 induced a ne!ative inotropic e--ect in electricall:
stimulated m:ocardial tissue and a ne!ative chronotropic e--ect in the
per-used rat heart. Taernanthine also produced rad:cardia and
h:potension in anesthetiGed rats and do!s 7 49R 8. ?inienda et al . 7 4<S 8
reported that io!aine 7>S m!'I!8 reduced heart rate in rats immediatel:
a-ter in;ection; this reduction persisted up to RS minutes a-ter in;ection.
TOP
?. Human Etudies.
)umerous ps:chotropic actions o- io!aine have een reported. These
actions seem to depend on oth dose and settin!. ,n addition* the
ps:choactive e--ects o- io!a extracts 7Yhich are liIel: to contain additional
alIaloids and are usuall: taIen in a ritualistic settin!8 ma: e di--erent -rom
those o- io!aine. Thus* users o- the crude extract o- Taernanthe io!a
taIen in su--icientl: hi!h doses have reported -antastic visions* -eelin!s o-
excitement* drunIenness* mental con-usion and hallucinations Yhen 7 4S4 8.
The total extract o- io!a shru is certainl: a central stimulant* and in hi!her
doses ma: lead to convulsions* paral:sis and -inall: respirator: arrest. The
ps:chotropic actions o- the plant extract include visual sensations; o;ects
are seen to e surrounded : specters or rainoYs. ,n hi!h doses it ma:
produce auditor:* ol-actor: and taste s:nesthesias. The state o- mind has
een reported to var: -rom pro-ound -ear to -ranI euphoria 7 4<4 8.
Nhen !iven orall:* oth io!aine and the total io!a extract elicits
su;ective reactions that last -or approximatel: O hours. 1i-t: percent o-
su;ects are reported to experience diGGiness* incoordination* nausea* and
vomitin! 7 P*99*4<5 8. T:picall:* the dru! produced a state o- droYsiness in
Yhich su;ects did not Yant to move* open their e:es* or attend to the
environment. +an: su;ects Yere li!ht-sensitive* and covered their e:es or
asIed that the li!hts e turned o--. Eounds or noises Yere disturin!.
,o!alin 7S.4-4.5 m!'I!* p.o.8* an alIaloid closel: related to io!aine and a
constituent o- the total io!a extract* did not produce ps:chotomimetic
e--ects in humans 7 4<9 8. ,o!alin also di--ers -rom io!aine in
pharmacoIinetics and tremori!enic activit: 7 RS 8.
The ps:choactive properties o- io!aine and related compounds Yere
studied : )aran;o 7 99*4<5 8 Yho reported that patients descried the
ps:chic state produced : io!aine 7} 9SS m!8 as similar to a dream state
Yithout loss o- consciousness. ,o!aine-induced -antasies Ho-ten descried
as a ] movie run at hi!h speed ] or ] slide shoY ] 7 P 8J Yere reported as rich
in archet:pal contents* involvin! animals and'or the su;ect Yith or Yithout
other individuals. These -antasies Yere eas: to manipulate : oth the
su;ects and the ps:chotherapist 7 99*4<5 8. At hi!her doses* io!aine
appears to produce visual and other hallucinations associated Yith severe
anxiet: and apprehension 7 4S4*4<<*4<> 8.
TOP
T,. @&THA@,TF A)0 )&C(OTOL,% &11&%TE.
The @0 >S o- io!aine has een determined in !uinea pi! 7Q5 m!'I!* i.p.8
and rat 795P m!'I!* intra!astricall: and 4<> m!'I!* i.p.8 7 OS*4<O 8.
)o si!ni-icant patholo!ical chan!es in rat liver* Iidne:* heart and rain
-olloYin! chronic io!aine treatment 74S m!'I!* -or 9S da:s or <S m!'I!*
-or 45 da:s* i.p.8 Yere reported 7 OS 8. EancheG-(amos and +ash 7 <5 8
-ound no evidence o- !ross patholo!: in A-rican !reen monIe:s !iven
io!aine in doses o- >-5> m!'I!* p.o. -or < consecutive da:s.
HoYever* O[Hearn et al .* 7 4<P*4<Q 8 and O[Hearn and +olliver* 7 R9 8
reported that repeated administration o- io!aine 74SS m!'I!* i.p.8 to rats
caused the de!eneration o- a suset o- PurIin;e cells in the cereellar
vermis. This de!eneration Yas accompanied : a loss o- microtuule-
associated protein 5 7+AP-58 and calindin. Ar!:rophilic de!eneration*
astroc:tosis and micro!liosis Yere also oserved. The dama!e seemed to e
dependent on the presence o- an intact in-erior olivar: nucleus 7 4<R 8.
,o!aine-induced cereellar toxicit: seem to e independent on its action at
)+0A receptors* ecause neither +b-QS4 nor phenc:clidine produce the
same pattern o- de!eneration 7 4>S 8. The neurotoxic e--ects o- hi!h doses o-
io!aine Yere con-irmed in rats* ut not mice* : Ecallet et al .* 7 4>4*4>5 8
and +olinari et al .* 7 4>9 8* Yho* in addition -ound that the ]t:pical] dose o-
<S m!'I! did not produce si!ni-icant dama!e to -emale rat cereellum. The
lacI o- neurotoxicit: a-ter loYer* ehaviorall: active doses o- io!aine Yas
also demonstrated : shoYin! that chronic administration 7OS da:s8 o- 4S
m!'I! o- io!aine produced no chan!e in the numer o- PurIin;e cereellar
cells 7 4>< 8.
,n spite o- these -indin!s* examination o- cellular marIers that are more
sensitive toneurotoxic a!ents than !ross histolo!: indicates that io!aine
administration ma: produce si!ni-icant chan!e in man: other rain
structures. Thus* O[%alla!han et al .* 7 4>>*4>O 8 examined the e--ects o-
acute and chronic administration o- io!aine on !lial -irillar: acidic protein
761AP8 levels. Acutel:* io!aine increased 61AP in oth sexes; Yhereas
chronic administration 74< da:s8 produced increases onl: in -emales.
,o!aine - induced chan!es in 61AP Yere dose-related* and* contrar: to
other studies* oserved in other rain structures includin! hippocampus*
ol-actor: ul* rain stem and striatum. ,n addition* these authors reported
that in -emales treated chronicall: Yith io!aine* severe hippocampal
dama!e Yas present as measured : increases in the c:tosIeletal proteins
neuro-ilament OQ 7)1-OQ8 and eta-tuulin. These latter marIers indicate a
dama!e-induced sproutin! response 7 4>O 8. ,o!aine administration also
produced an increase in c--os immunostainin! in several rain re!ions o-
mice and rats; the e--ects in rats Yere oserved in all cortical la:ers Yhile in
mice the response Yas limited to cortical la:er 5 7 4>5 8. Human Eb-)-EH
neurolastoma cells cultured in the presence o- 9-9S s + io!aine 7ut not
O -desmeth:lio!aine or 4Q-methox:coronaridine8 demonstrated
concentration- and time-dependent morpholo!ical chan!es characteriGed :
the loss o- processes* cell roundin!* detachment and ultimatel: cell death
7 4>P 8. Eimilar results Yere oserved Yith primar: cultures o- rat cereellar
!ranulae cells. ?ecause in this stud: onl: alIaloids that had marIed a--init:
at si!ma 5 sites Yere neurotoxic* Tilner et al .* 7 4>P 8 proposed that si!ma 5
sites ma: e implicated in the neurotoxicit: o- io!aine. The neurotoxic
e--ects o- io!aine have een recentl: revieYed : Tocci and @ondon
7 4SO 8.
Acute treatment Yith the io!aine-liIe alIaloid* 4Q-methox:coronaridine
74SS m!'I!8 did not produce !ross patholo!ical chan!es in the cereellum
7 RP 8. ,n contrast* another indole alIaloid* harmaline* produced io!aine-
liIe de!eneration o- PurIin;e cells in the cereellar vermis 7 R9 8.
,t has een reported that multiple doses o- a non-)+0A anta!onist
76Fb, >5<OO8 resulted in a sustantiall: !reater loss o- PurIin;e cells and
micro!lial activation compared to io!aine 7>S-4SS m!'I!8 alone 7 4>Q 8.
On the other hand* the noncompetitive )+0A anta!onist +b-QS4 74
m!'I!8 marIedl: attenuated the de!ree o- PurIin;e cell loss caused :
io!aine 7 4>Q 8. This later -indin! stron!l: supports the notion that the loss
o- cereellar PurIin;e cells produced : io!aine is unrelated to its )+0A
anta!onist properties 7 4>R 8. ,n -act* io!aine can also exhiit
neuroprotective properties* reducin! !lutamate-induced neurotoxicit: in
primar: cultures o- cereellar !ranule cell neurons Yith an &% >S o- <-> s+
7 44R 8. These neuroprotective e--ects o- io!aine have recentl: een
patented : Olne: 7 4OS 8. %onsistent Yith its properties as an )+0A
anta!onist* io!aine inhiited )+0A - induced lethalit: in mice in a dose-
dependent manner 7 4O4 8* and also protected mice -rom maximal
electroshocI seiGures 7&0 >S } 94 m!'I!8 7 4O5 8.
Phase , toxicit: studies in dru!-addicted individuals are in pro!ress at the
Cniversit: o- +iami 7 <5*4O9 8.
TOP
T,,. &11&%TE O) EP&%,1,% )&C(OT(A)E+,TT&( EFET&+E
A. ,o!aine &--ects on 0opaminer!ic E:stems.
,o!aine 7at concentrations 4SS s+8 does not a--ect radioli!and indin!
to dopamine receptors 70 4 * 0 5 * 0 9 * 0 < 8 7 4O<-4OO 8. The a--init: o-
io!aine -or dopamine transporters as measured : inhiition o- H 9 HJN,)
9>*5<Q* H 45> ,J(T,-454 or H 45> ,J(T,->> indin! Yas } 4.> - < s +
7 P9*PO*4OO*4OP 8. HoYever* in another stud:* io!aine did not a--ect indin!
o- H 9 HJ6?(-45R9>* a li!and that also appears to lael dopamine
transporters 7 Q> 8. ,o!aine inhiited H 9 HJdopamine uptaIe in porcine
Iidne: cells trans-ected Yith dopamine transporter Yith a b i }QO s+
7 4OQ 8.
The in vivo and ex vivo e--ects o- io!aine on dopamine metaolism in
mesolimic areas o- the rodent rain 7striatum* nucleus accumens8 are
controversial and hi!hl: inconsistent. ,n an attempt to reconcile several
contradictor: -indin!s* one ma: note the -olloYin!.
0opamine concentrations are reduced and dopamine metaolites
dih:drox:phen:l-acetic acid 70OPA%8 and homovanilic acid 7HTA8 are
increased : io!aine under certain experimental conditions. 1or example*
Yhen either measurements are taIen shortl: 7Yithin 5 h8 a-ter io!aine
administration or Yhen relativel: hi!h concentrations 7 4SS s+8 are used 7
OR*P4*PO*Q4*4OR-4P9 8. (eductions in extracellular dopamine concentrations
Yere also oserved a-ter administration o- a numer o- io!aine derivatives*
includin! O -desmeth:lio!aine 7 QR 8 and 4Q-methox:coronaridine 7 RP 8.
Nhen dopamine is measured at lon!er periods a-ter io!aine
administration 7e.!.* up to a YeeI8 or loY concentrations 7e.!.* 4S s+8 are
applied* rain concentrations appear unchan!ed and metaolite
concentrations are decreased 7 OR*P4*PO*Q4*Q5*4OR*4PS*4P5 8.
The increased levels o- extracellular dopamine metaolites to!ether Yith
decreased or unchan!ed levels o- dopamine su!!ests that io!aine increases
dopamine turnover shortl: a-ter administration. This ma: e -olloYed : a
decrease in turnover that ma: persist -or some time a-ter io!aine
administration. 1rench et al .* 7 R4 8 demonstrated that doses o- io!aine 7}
4.> m!'I!* i.v.8* much loYer than a ]t:pical] dose o- <S-QS m!'I!* marIedl:
excited dopaminer!ic neurons in the ventral te!mental area o- the rat.
TOP
4. 0opaminer!ic e--ects: Pharmacolo!ical Epeci-icit:.
Administration o- a Iappa anta!onist 7norinaltorphimine* 4S m!'I!8 and
)+0A 74S m!'I!8 7either ;ointl: or individuall:8 reversed io!aine 7<S
m!'I!8 induced decreases in striatal dopamine and increases in dopamine
metaolites 7 QQ 8. Eimilarl:* (eid et al .* 7 4P5 8 oserved that the decrease
in dopamine levels produced : io!aine 74SS s + 8 Yas reversed : either
naloxone 74 s+8 or norinaltorphimine 74-4S s+8. HoYever* -unctionall:
opposite e--ects Yere oserved : Eershen et al .* 7 4P<*4P> 8 Yho reported
that the ailit: o- the Iappa opioid a!onist 7C-O5SOO8 to inhiit electrical- or
cocaine-induced H 9 HJdopamine release -rom mouse striatum Yas
attenuated : pretreatment o- mice Yith io!aine 7<S m!'I!* i.p.* 5 hours
prior; or 5 x <S m!'I!* O hours apart* Iilled 4Q hours later8 7 4P<*4P> 8.
,o!aine-induced dopamine release -rom the isolated mouse striatum has
een studied : Harsin! et al.* 7 4PO 8. ,o!aine increased asal tritium
out-loY 7H 9 HJdopamine 70A8 and H 9 HJ0OPA%8* ut Yas Yithout e--ect
on electricall: stimulated tritium over-loY. This dopamine releasin! e--ect
Yas: a8 reduced : the dopamine uptaIe inhiitors cocaine and nomi-ensine*
8 unaltered : omission o- %a ii -rom the per-usion u--er* c8 tetrodotoxin
insensitive* d8 una--ected : an a!onist 7$uinpirole8 or an anta!onist
7sulpiride8 o- the 0 5 dopamine receptor* and e8 una--ected : pretreatment
Yith reserpine. ,n this stud:* io!aine did not a--ect dopamine uptaIe*
Yhereas (eid et al .* 7 4P5 8 -ound that oth io!aine and harmaline 74S s+-
4 m+8 inhiited it. As mentioned aove* io!aine has een reported to
inhiit radioli!and indin! to the dopamine transporter Yith relativel: hi!h
a--init:.
Eershen et al .* 7 4PP 8 reported an involvement o- serotonin receptors in
the re!ulation o- dopamine release : io!aine. Thus* administration o-
io!aine locIed the ailit: o- a >HT 4? a!onist 7%6E-45SOOA H4S s+J8 to
increase H 9 HJdopamine increase in striatal slices. ,n other studies* a
concentration o- io!aine 74 s+8 that Yas Yithout e--ect on dopamine e--lux
inhiited oth )+0A 75> s +8 and 7 u 8pentaGocine 74SS n+8 - induced
dopamine release in striatal slices 7 4PQ 8.
There are -eY reports o- the e--ects o- io!aine-liIe alIaloids on
dopamine metaolism. @iIe io!aine* O -desmeth:lio!aine acutel:
decreases dopamine release in the rat nucleus accumens and striatum 7 QR 8.
Administration o- the ( - entantiomers o- coronaridine and io!amine
decreased dopamine levels in oth nucleus accumens and striatum* Yhereas
the E -enantiomers produced no si!ni-icant chan!es in dopamine levels in
either re!ion 7 RO 8.
,n an attempt to reconcile several con-lictin! -indin!s* Etale: et al .*
7 4OP 8 proposed that io!aine mi!ht promote redistriution o- intraneuronal
dopamine -rom vesicular to c:toplasmic pools. ,o!aine displa:s
micromolar a--init: -or vesicular monoamine transporters laeled Yith H 45>
,J-tetraenaGine 7 4OP 8; these sites are crucial -or the translocation o-
dopamine into s:naptic vesicles. The inhiitor: e--ect o- io!aine on
vesicular monoamine transporters could result in redistriution o- dopamine
in the c:toplasm. Cnder such conditions* rapid metaolism o- dopamine :
monoamine oxidase Yould account -or the decrease in tissue dopamine
content and the parallel increase in its metaolites.
+ultiple transmitter s:stems have een shoYn to modulate dopaminer!ic
-unction in the central nervous s:stem. ?ecause io!aine can interact Yith
man: o- these s:stems* includin! Iappa opioid receptors* )+0A receptors*
serotonin receptors* and dopamine transporters* it is not surprisin! that this
alIaloid can produce complex 7and sometimes apparentl: opposite8 e--ects
on dopaminer!ic -unction. Thus* the e--ects o- io!aine on dopaminer!ic
-unction descried in this section liIel: re-lect the dose 7or concentration8 o-
alIaloid* preparation emplo:ed 7e.!.* slice versus intact animal8* and rain
re!ion studied.
TOP
5. ,o!aine alters the e--ects o- aused dru!s on dopaminer!ic s:stems.
,n !eneral* io!aine attenuates the increases in mesolimic dopamine
produced : dru!s 7e.!* nicotine* morphine8 that appear to act pre-erentiall:
at dopaminer!ic cell odies. ,n the case o- dru!s that act at terminal re!ions
7e.!.* cocaine and amphetamine8* a !ender di--erence has een oserved. ,n
-emale rats* io!aine enhances stimulant-induced increases in dopamine
concentrations* Yhereas it decreases the e--ects o- these stimulants in male
rats and mice.
)eurochemical studies Yere per-ormed in male mice !iven tYo doses o-
io!aine 7<S m!'I!* i.p.* 4Q hours apart8 -olloYed : amphetamine 7>
m!'I!8 administered 5 hours a-ter the second dose o- io!aine 7 Q4 8. Etriatal
levels o- dopamine and dopamine metaolites H0OPA%* HTA and 9-
methox:t:ramine 79-+T8J measured 4 hour a-ter amphetamine Yere
decreased in mice that received io!aine relative to saline-pretreated*
amphetamine-treated controls. %ompared to controls* levels o- 0OPA% and
HTA Yere decreased in the amphetamine and io!aine !roups* and -urther
decreased in the !roup that received io!aine and amphetamine. HoYever*
in -emale rats* amphetamine-induced increases in extracellular dopamine
concentrations in oth the striatum and the nucleus accumens Yere -urther
potentiated : io!aine 7<S m!'I!* i.p.* 4R hours precedin! amphetamine8
7 Q5 8. Eimilarl:* 6licI et al.* 7 4OR 8 -ound that io!aine potentiated
amphetamine-induced increases in extracellular dopamine concentrations in
-emale rat nucleus accumens and striatum. ,n this stud:* hoYever* no e--ect
o- io!aine Yas seen on amphetamine-induced decreases in extracellular
concentrations o- dopamine metaolites. Eimilarl:* io!aine potentiated
cocaine-induced increases in extracellular dopamine levels in striatum and
nucleus accumens o- -emale rats 7 Q< 8. HoYever* $uite opposite data Yere
otained : ?rodericI et al.* 7 Q>*QO 8 Yho examined dopamine release in
male rats usin! semiderivative in vivo voltametr:. ,n these experiments*
io!aine 7<S m!'I! i.p. !iven -or -our da:s8 reduced the increase in
dopamine release -rom nucleus accumens induced : cocaine 75S-<S
m!'I!* s.c.8. A pres:naptic mechanism -or these actions Yas su!!ested. An
inhiitor: e--ect o- io!aine on amphetamine metaolism has een proposed
7 4PR 8* ecause amphetamine levels Yere hi!her a-ter io!aine
administration in -emale rats. HoYever* io!aine administration had no
e--ect on rain cocaine levels 7 4OR 8.
,o!aine 7<S m!'I!* i.p. in rats8 !iven 4R hours e-ore morphine 7>
m!'I!8 prevented the increase in extracellular dopamine concentration in the
striatum* pre-rontal cortex and nucleus accumens t:picall: oserved in rats
7 P4*Q9 8. HoYever* in the io!aine plus morphine !roup* the levels o-
dopamine metaolites Yere increased 7as Yas oserved in the morphine
!roup8* su!!estin! that io!aine did not prevent morphine -rom activatin!
dopamine neurons. The authors su!!est that io!aine treatment ma: chan!e
the properties o- dopaminer!ic neurons in such a Ya: that dopamine release
is una--ected under normal conditions* ut altered Yhen stimulated 7in this
case* : morphine8. )ineteen hours a-ter placeo or io!aine 74S m!'I!*
i.p.8* -emale rats responded similarl: Yith increased dopamine release in
nucleus accumens -olloYin! a morphine challen!e 7 4QS 8. HoYever* in rats
that received tYo doses o- morphine durin! tYo da:s precedin! the
experiment* io!aine pretreatment had inhiitor: e--ects on dopamine
response to a morphine challen!e. A pharmacoIinetic explanation -or the
e--ects o- io!aine on morphine-induced actions is unliIel:* ecause
io!aine 7<S m!'I!* i.p. 4R hours e-ore measurement8 did not modi-: rain
levels o- morphine 74S m!'I!8 in rats 7 P4 8.
?enYell et al .* 7 4S9 8 reported that io!aine 7!iven 55 hours e-ore
nicotine8 attenuated the increase in dopamine over-loY in the nucleus
accumens evoIed : nicotine administration. Eimilar e--ects Yere
demonstrated* Yhen io!aine Yas administered 4R hours prior to nicotine
in-usion 7 4Q4 8.
TOP
?. Opioid E:stems
At concentrations o- up to 4SS s+* io!aine Yas reported not to a--ect H 9
HJcar-entanil or H 9 HJenIephalin indin! indicatin! that this alIaloid does
not a--ect mu or delta opioid receptors 7 45<*4O> 8. ,n contrast* Pearl et al .* 7
45< 8 and EYeetnam et al .* 7 4OO 8 demonstrated that io!aine inhiited
radioli!and indin! to mu opioid receptors Yith b i values } 44-5S s+. &x
vivo studies demonstrated that io!aine and O -desmeth:lio!aine enhanced
the inhiition o- aden:l:l c:clase activit: : a maximall: e--ective
concentration o- morphine in the rat -rontal cortex* midrain and striartum
7 4Q5 8. This later e--ect is not liIel: mediated via a direct action at opioid
receptors ecause it Yas oserved at maximall: e--ective concentration o-
morphine.
,o!aine inhiits 7b i }5-< s+8 H 9 HJC-OR>R9 indin! to Iappa opioid
receptors 7 >O*P5*45<*4O> 8. This indin! is reversile* su!!estin! that the
lon!-term e--ects o- io!aine cannot e attriuted to an irreversile e--ect at
this site. (ecentl:* %odd 7 4Q9 8 demonstrated that io!aine inhiits indin!
to sites laeled : H 9 HJnaloxone characteriGed : a tYo-site model* Yith b
i values o- 49S n+ and < s+.
O -0esmeth:lio!aine had a hi!her a--init: than io!aine -or all o- the
opioid receptors studied: Iappa b i } 4 s+* mu b i } 5.P s+ and delta b i }
5<.P s+ 745<8 7a recent stud: shoYed much hi!her a--init: o- O
-desmeth:lio!aine at the mu receptor; b i } 4OS n+ 7 4Q< 88. Our YorI 7 P5
8 demonstrated that O -desmeth:lio!aine had a 4S- to 4SS--old hi!her
a--init: -or Iappa receptors compared to io!aine. The ma!nitude o- this
potenc: di--erence Yas species-speci-ic 7e.!.* in rats: ,% >S } S.9 s+ -or O
-desmeth:lio!aine and ,% >S }9S s+ -or io!aine8. The same stud:
demonstrated a moderate a--init: o- O - t -ut:l- O -desmeth:lio!aine -or
Iappa receptors 7,% >S }4P s+ in rat -orerain8 su!!estin! that i- an: o-
io!aine[s in vivo actions are produced at Iappa receptors* then O - t -ut:l-
O -desmeth:lio!aine Yould e active. ,n this respect* O - t -ut:l- O
-desmeth:lio!aine did not in-luence the morphine YithdraYal s:ndrome
7 P5 8 at doses comparale to io!aine.
TOP
%. Eerotoner!ic E:stems.
,o!aine 7at concentrations up to 4 s+8 had no e--ect on H 9 HJserotonin
indin! 7 4Q> 8 and concentrations o- up to 9.> s+ had no e--ect on H 9
HJ@E0 indin! 7 4QO 8. +ore recent studies usin! serotonin sut:pe
selective li!ands are discrepant. 0eecher et al .* 7 4O> 8 reported that
io!aine did not displace li!ands actin! at >-HT 4a * >-HT 4 * >-HT 4c * >-
HT 4d * >-HT 5 * or >-HT 9 receptors. HoYever* (epIe et al .* 7 >O 8 reported
that io!aine inhiited indin! o- >-HT 4a * >-HT 5a * or >-HT 9 li!ands
Yith loY a--init: 7b i values: g4SS* 45.> and g4SS s+* respectivel:8 and
EYeetnam et al .* 7 4OO 8 reported ,% >S values o- } < s+ to inhiit
radioli!and indin! to oth >-HT 5 * and >-HT 9 receptors.
0espite these discrepancies* oth ex vivo and in vivo studies su!!est that
io!aine can a--ect serotoner!ic transmission. &x vivo studies indicate that
io!aine and O -desmeth:lio!aine enhance the inhiitor: e--ects o-
serotonin on aden:l:l c:clase activit: in rat hippocampus 7 4Q5 8. ?rodericI
et al.* 7 QO 8 reported that io!aine 7<S m!'I!* i.p. -or < da:s8 increased >-
HT concentrations in rat nucleus accumens. %onsistent Yith this -indin!*
Ali et al .* 7 4P4 8 demonstrated that io!aine increased >-HT levels in
striatum. Eershen et al .* 7 PO 8 reported that io!aine 7<S->S m!'I!8
decreased levels o- the serotonin metaolite >-h:drox:-indoleacetic acid H>-
H,AAJ in mouse -rontal cortex* hippocampus and ol-actor: tuercle 5 and
5< hours a-ter in;ection. ,o!aine also decreased >-H,AA levels in rat
nucleus accumens and striatum 7 4S9*4P4 8* ut increased >-H,AA and
decreased >-HT 7lastin! at least P da:s8 in medial pre-rontal cortex 7 4S9 8.
@on! and @errin 7 4QP 8 demonstrated that io!aine is a reversile inhiitor
o- the active transport o- serotonin into lood platelets* a -indin! supported
: a recent oservation that io!aine inhiited serotonin transporters 7in a
porcine Iidne: cell line8 Yith a b i } 4S s+ 74OQ8.
Eershen et al.* 7 4PP 8 demonstrated that io!aine inhiited the ailit: o- a
>-HT 4 a!onist 7%6E-45SOOA8 to increase stimulation-evoIed H 9
HJdopamine release -rom oth rat and mouse striatal slices. Additionall:*
io!aine increased the ailit: o- a >-HT 9 a!onist 7phen:li!uanide8 to
enhance stimulation-evoIed H 9 HJdopamine release -rom the mouse striatal
slice 7 4P< 8. ,n these studies* io!aine 7<S m!'I!* i.p.8 Yas administered 5
hours prior to slice preparation. ,n other studies* io!aine 75S m!'I!8
enhanced cocaine-induced reductions in serotonin concentration in the
nucleus accumens 7rat8* an action attriuted to a pres:naptic release
mechanism 7 Q>*QO 8. HoYever* Eershen et al .* 7 4P> 8 reported that cocaine
increased H 9 HJserotonin e--lux in striatal slices and this e--lux Yas asent
in mice pretreated Yith either io!aine or a >-HT 4 a!onist. These later
-indin!s led Eershen to su!!est an action o- io!aine at the HT 4 receptor
that is liIel: unrelated to the ailit: o- cocaine to inhiit serotonin reuptaIe
locIade 7 4QQ 8. The inhiitor: e--ect o- the Iappa-opioid a!onist C-O5SOO
74s+8 on H 9 HJserotonin release in striatal slices could e locIed : in
vivo io!aine administration 7 4P> 8.
TOP
0. %alcium (e!ulation.
,o!aine 7QS s+8 non-competitivel: anta!oniGed calcium-induced
contraction o- rat aorta and mesenteric arter: 7 49Q 8* Yhich Yas interpreted
as an action on intracellular calcium metaolism. Taernanthine* an alIaloid
related to io!aine* inhiited depolariGation-stimulated <> %a in-lux and
contractions in the rat aorta 7 4QR 8. ,o!aine inhiited the indin! o- H 9
HJisradipine 7an @-t:pe calcium channel locIer8 in the mouse cereral
cortex Yith an ,% >S o- }5Q s+ 7 44 8.
TOP
&. %holiner!ic E:stems.
,o!aine 7at concentrations o- up to 4SS s+8 Yas reported not to inhiit
the indin! o- li!ands actin! at nicotinic or muscarinic receptors 7 4O> 8.
HoYever* suse$uent studies demonstrated that io!aine inhiited the
indin! o- muscarinic + 4 * + 5 and + 9 li!ands at concentrations o- } 94*
>S and 45.> s+* respectivel: 7 >O 8. EYeetnam et al .* 7 4OO 8 shoYed that
io!aine inhiited radioli!and indin! to + 4 * and + 5 receptors Yith ,%
>S values o- >-P s+. These authors also reported that io!aine did not
inhiit the indin! o- H 9 HJ)+%,* a nonselective li!and at nicotinic
receptors. &x vivo studies have shoYn that neither io!aine nor O
-desmeth:lio!aine a--ect the inhiitor: action o- the muscarinic
acet:lcholine a!onist* carachol on aden:l:l c:clase activit: in the rat
7 4Q5 8.
,n a recent stud:* ?adio et al .* 7 45> 8 demonstrated that io!aine potentl:
7,% >S } 5S n+8 locIed 55 )a%l in-lux throu!h nicotinic receptor channels
in rat pheochromoc:toma cells. This e--ect Yas seen in the cells expressin!
!an!lionic* ut not neuromuscular* nicotinic receptor sut:pes. This
inhiition Yas noncompetitive ecause it Yas not overcome : increasin!
concentrations o- a!onist. +oreover* the locIade Yas not completel:
reversile* su!!estin! that io!aine ma: have a lon!-lastin! e--ect. O
-0esmeth:lio!aine and O - t -ut:l- O -desmeth:lio!aine Yere P>- and
5S--old less potent* respectivel:* than io!aine in locIin! nicotinic
receptor-mediated responses. The same stud: demonstrated that io!aine* as
expected -or a noncompetitive locIer* had a relativel: loY a--init: 7b i } <
s+8 as an inhiitor o- the indin! o- an a!onist H 9 HJnicotine. ,n support to
these -indin!s* Echneider et al .* 7 4RS 8 reported recentl: that io!aine 7 4S
s +8 had an inhiitor: action on nicotinic receptor-mediated catecholamine
release in ovine adrenal chroma--in cells. %onsistent Yith the ?adio et al .*
7 45> 8 stud:* these inhiitor: e--ects appeared to e lon!-lastin!.
TOP
1. 6amma-Aminout:ric Acider!ic H6A?Aer!icJ E:stems.
TYo independent studies 7 4O>*4OO 8 did not -ind an: e--ect o- io!aine 7at
concentrations o- up to 4SS s+8 on radioreceptor indin! to 6A?A A
receptors. ,n addition* io!aine did not in-luence 9O %l - uptaIe throu!h
6A?A-!ated channels 7 4O> 8 or 6A?A-evoIed currents in rat cultured
hippocampal neurons 7 4O5 8.
TOP
6. Tolta!e-0ependent Eodium %hannels.
,o!aine inhiited 7b i } Q.4 s+8 H 9 HJatrachotoxin A 5S-a-enGoate
indin! to volta!e-dependent sodium channels in depolariGed mouse
neuronal preparations 7 4O> 8. ,o!aine analo!s* includin! io!amine*
taernanthine and coronaridine* exhiited potencies similar to io!aine in
this assa:.
TOP
H. 6lutamater!ic E:stems.
Our studies 7 4>R 8 indicate that io!aine is a competitive inhiitor o- H 9
HJ+b-QS4 indin! 7b i }4 s+8 to )+0A receptor-coupled ion channels.
,n contrast* io!aine did not a--ect H 9 HJ7 u 8- a -amino-9-h:drox:->-
meth:lisoxaGole-<-propionic acid 7H 9 HJA+PA8* H 9 HJIainate or H 9
HJ!lutamate to either the )+0A or metaotropic receptor sites* indin!.
These -indin!s are consistent Yith a speci-icit: o- io!aine -or )+0A
receptor-coupled cation channels 7 4>R*4O5*4OO 8. The potenc: o- io!aine
to inhiit H 9 HJ+b-QS4 indin! Yas also examined in Q distinct rain
re!ions o- Epra!ue-0aYle: male rats and compared Yith the dissociation
constants -or H 9 HJ+b-QS4 estimated usin! saturation anal:ses. A hi!h
correlation 7r^S.RPO* p^S.SSS<8 Yas otained etYeen the b i o- io!aine
and b d o- H 9 HJ+b-QS4 in these rain re!ions 7 44R 8* consistent Yith the
notion that these compounds share a common indin! site. The ailit: o-
io!aine to act as a non-competitive )+0A anta!onist can also e
demonstrated usin! H 9 HJ4-H4-75-thien:l8c:clohex:lJpiperidine 7H 9
HJT%P8* a thien:l derivative o- phenc:clidine* resultin! in a b i }4.> s+ in
rat -orerain 7 44R 8.
Etructure-activit: studies Yere per-ormed usin! a series o- io!aine
analo!s* includin! the putative io!aine metaolite O -desmeth:lio!aine*
its metaolism resistant analo! O - t -ut:l- O -desmeth:lio!aine* the io!a
alIaloids H7 u 8-io!amine* 7 u 8-coronaridine* taernanthineJ* harmaline* and
indolotropanes. ,o!aine Yas the most potent inhiitor o- H 9 HJ+b-QS4
indin! 7b i } 4.5 s+8; the compounds Yith the !reatest structural
similarit: to io!aine* O -desmeth:lio!aine and O - t -ut:l- O
-desmeth:lio!aine Yere much less potent 7b i } >.> and 4PR.S s +
respectivel:8 7 P5 8. A } > -old loYer a--init: o- O -desmeth:lio!aine
compared to io!aine at H 9 HJ+b-QS4 indin! sites Yas also reported :
+ash et al .* 7 4R4 8.
%onsistent Yith these neurochemical studies* io!aine produced a
volta!e-dependent locI o- )+0A-evoIed currents in hippocampal cultures
7 44R*4O5 8. ,n addition* io!aine 74SS s +8 and O -desmeth:lio!aine 74
m+8 locIed the ailit: o- )+0A 74SS s +* > sec8 to depolariGe -ro!
motoneurons in a non-competitive and use-dependent manner 7 4R5 8.
TOP
,. Ei!ma (eceptors.
,n our studies 7448* io!aine inhiited H 9 HJpentaGocine 7a si!ma 4
receptor li!and8 indin!* to hi!h 7,% >S }QO n+8 and loY 7,% >S }>.O s+8
a--init: sites in mouse cereellum. ?oYen et al .* 7 4R9 8 demonstrated that
io!aine had hi!h a--init: -or si!ma 5 sites 7b i } 5SS n+8 and loY a--init:
-or si!ma 4 sites 7b i } Q.> s+8* a } <9- -old selectivit: -or si!ma 5 sites.
The a--inities o- taernanthine 749-methox:io!amine8 and 7 u 8-io!amine
-or si!ma 5 sites Yere similar to that o- io!aine. O -0esmeth:lio!aine*
had a marIedl: reduced a--init: -or si!ma 5 sites 7b i } > s+8 and also
lacIed a--init: -or si!ma 4 sites. The related alIaloids* 7 u 8-coronaridine
H7 u 8-4Q-caromethox:io!amineJ and harmaline lacIed a--init: -or oth
si!ma receptor sut:pes. O -t-?ut:l- O -desmeth:lio!aine inhiited
radioli!and indin! to si!ma 4 sites Yith a b i } 9.> s+ and si!ma 5 sites
Yith a b i } 9<O n+ Hc.-. ?oYen et al * 7 P5 8J. The much hi!her a--init: o-
io!aine -or si!ma 5 sites compared to si!ma 4 sites Yas also reported :
+ach et al .* 7 4R< 8. ?oYen et al .* 7 4R> 8 examined the ailit: o- io!aine
and related compounds to modulate calcium release -rom intracellular stores
in indo-4 loaded human Eb-)-EH neurolastoma cells. %onsistent Yith its
a--init: at si!ma 5 sites* io!aine produced a concentration-dependent
increase 749-<>\8 in intracellular calcium levels. O -0esmeth:lio!aine*
Yas ine--ective in this measure at concentrations up to 4SS s +. These data
su!!est that the shared in vivo e--ects o- io!aine and O -desmeth:lio!aine
are proal: not mediated : si!ma sites.
TOP
W. +iscellaneous Actions o- ,o!aine.
0eecher et al.* 7 4O> 8 reported that io!aine 7up to 4SS s+8 did not
inhiit radioli!and indin! to cannainoid receptors. ,o!aine and O
-desmeth:lio!aine had no in-luence on asal or -orsIolin-stimulated
aden:l:l c:clase in the rat -rontal cortex* midrain or striatum 7 4Q5 8. O
-0esmeth:lio!aine* ut not io!aine* produced concentration - dependent
increases in the !eneration o- H 9 HJinositol phosphates that Yere not altered
: inclusion o- tetrodotoxin* cadmium or ome!a-conotoxin 7 4RO 8. These
results su!!est that the e--ect o- O -desmeth:lio!aine on phosphoinositide
h:drol:sis Yas not secondar: to the release o- one or more
neurotransmitters. Ali et al .* 7 <> 8 reported that io!aine 7S.>-5>S s +8
reduced nitric oxide s:nthase activit: in mouse rain; similar e--ects Yere
noted in the striatum* hippocampus and cereellum o- mice treated
parenterall: Yith io!aine 7>S m!'I!8. ,n radioli!and indin! studies* no
e--ect o- io!aine has een -ound on alpha 4 * alpha 5 or eta 4 adrener!ic
receptors 7 4O> 8. +oreover* io!aine 75S m!'I!8 did not modi-: cereral
noradrenaline levels in rats 7 4RP 8. ?inienda et al .* 7 4<S*4RQ 8 reported that
althou!h io!aine 7>S m!'I!8 challen!e in rats Yas associated Yith a
decrease in delta* theta* alpha and eta poYer spectra o- cortical &&6 durin!
the -irst 9S min* and suse$uent recover: o- all except delta ands in the
next 4> min* +b-QS4 74 m!'I!8 treatment Yas -olloYed : a decrease in
poYer o- all -our -re$uenc: ands -or the entire time o- recordin!. The
selective poYer decrease in delta &&6 -re$uenc: and o- the cortical &&6
ma: su!!est the activation o- dopamine receptors.
,n the anesthetiGed rat* io!aine produced a sli!ht h:po!l:cemia 7 OS 8.
A-ter administration o- >S m!'I! o- io!aine* elevations o- corticosterone
levels Yere noted 4> - 45S min* ut not 5< hours later 7 4PS*4P4*4P9 8. The
same dose o- io!aine rapidl: and transientl: increased plasma prolactin
levels 74P4*4P98. ?una! and NalasGeI 7 4RR 8 reported that io!aine
anta!oniGed the contractile responses produced in !uinea pi! ileum :
sustance P and an!iotensin. Alur!es and Hanson 7 5SS 8 reported that
io!aine administration produced increases o- neurotensin-liIe
immunoreactivit: in striatum* nucleus accumens and sustantia ni!ra and
sustance P -liIe immunoreactivit: in striatum and sustantia ni!ra.
,o!aine or harmaline suppressed several 7T-cell re!ulator: and e--ector* ?-
cell* and natural Iiller cell8 immune -unctions in vitro 7 5S4 8. Tan ?eeI et al
.* 7 4P 8 reported that io!aine shoYed activit: a!ainst the !ram-positive
?acillus sutilis . ,o!aine did not alter colonic temperature in mice* nor did
it a--ect morphine- or Iappa HC->S*<QQHJ ~ opioid induced h:pothermia
7 454 8.
TOP
T,,,. %O)%@CE,O)E.
The reneYed interest in io!aine durin! the past decade stems -rom
anecdotal clinical oservations that io!aine o--ers a novel means o- treatin!
dru! addictions. Preclinical studies are* in !eneral* consistent Yith these
claims. Thus* io!aine reduces sel--administration o- cocaine and morphine*
attenuates morphine YithdraYal* and locIs conditioned place pre-erence
produced : morphine and amphetamine. Preclinical studies also su!!est
there is no ause liailit: associated Yith io!aine. At doses that inter-ere
Yith tolerance and dependence phenomena* rain concentrations o- io!aine
are at levels that can a--ect a variet: o- neurotransmitter s:stems. +an: o-
these e--ects 7e.!.* use dependent locI o- )+0A receptor-coupled cation
channels* interactions Yith dopamine transporters and Iappa opioid
receptors8 have previousl: een implicated in dru! seeIin! phenomena.
HoYever* at the present time* the onl: mechanism that can e invoIed to
explain io!aine[s e--ects on dru! seeIin! phenomena Yith some certaint: is
its ailit: to inhiit naloxone-precipitated ;umpin! throu!h locIade o-
)+0A receptors. )onetheless* it is still uncertain Yhether the anti-addictive
properties o- io!aine result -rom a sin!le mechanism or are produced at
multiple loci.
The involvement o- dopaminer!ic pathYa:s in dru! seeIin! phenomena
can e considered do!ma* and io!aine undoutedl: a--ects these pathYa:s.
)onetheless* ased on availale data no clear picture has emer!ed aout
hoY this interaction contriutes to the anti-addictive properties o- io!aine*
or an: other anti-addictive medications. Additional s:stematic studies are
oviousl: needed. Anecdotal reports claim lon! term e--ects o- io!aine on
dru! seeIin! -olloYin! a sin!le administration or short course o- therap:.
This claim has een orne out* at least in part* : preclinical studies. ?ased
on these oservations* it is unliIel: that io!aine serves simpl: as
sustitution therap:. ,t has een h:pothesiGed that a lon!-lived metaolite is
responsile -or io!aine[s putative anti-addictive properties* ut additional
studies are re$uired in this area.
One o- the central issues re!ardin! the molecular mechanisms responsile
-or the anti-addictive actions o- io!aine is Yhether its )+0A anta!onist
action is su--icient to explain these e--ects. Thus* there is an estalished
od: o- preclinical data 7and an emer!in! od: o- clinical data8
demonstratin! that )+0A anta!onists interrupt dru! seeIin! phenomena to
a variet: o- addictive sustances. Althou!h it is noY Yell estalished that
io!aine is a noncompetitive )+0A anta!onist 7aleit 4SSS--old less potent
than the protot:pe compound* diGocilpine8* Yith the exception o- its ailit:
to locI naloxone precipitated ;umpin! in morphine-dependent mice* it is
uncertain i- these e--ects can e attriuted to other mechanisms.
(ecent structure activit: studies demonstrate that O -desmeth:lio!aine*
Yhich is less potent than io!aine at )+0A receptors* appears as active as
io!aine in acutel: locIin! morphine and cocaine sel--administration. This
oservation stron!l: su!!ests that other mechanisms ma: e operative. A
similar ar!ument can e made -or harmaline* Yhich is someYhat structurall:
related to io!aine and shares some o- its pharmacolo!ical actions 7e.!.*
tremor and neurotoxic e--ects* reductions in cocaine and morphine sel--
administration8* ut is not an )+0A anta!onist. Althou!h inhiition o- dru!
sel--administration : harmaline ma: e due to unspeci-ic e--ects 7e.!.*
!eneral malaise8* these -indin!s nonetheless raise the possiilit: that
io!aine[s anti-addictive properties ma: e produced throu!h multiple
mechanisms. The involvement o- si!ma sites in these phenomena appears to
e even more oscure ecause in contrast to io!aine* harmaline has no
appreciale a--init: at si!ma sites Yhereas O -desmeth:lio!aine lacIs
a--init: at a si!ma 5 site* :et all three locI cocaine and morphine sel--
administration.
,o!aine can a--ect several aspects o- serotoner!ic transmission at
concentrations that are readil: achieved in the rain -olloYin!
pharmacolo!icall: relevant doses HrevieYed : Eershen et al .* 7 4QQ 8J.
?ecause multiple serotonin receptor sut:pes* as Yell as serotonin reuptaIe*
are modulated : io!aine* it is not surprisin! that the e--ects o- this alIaloid
on stead: state levels o- serotonin and its metaolites 7Yhether measured in
situ or ex vivo 8 are complex. %learl:* additional clinical studies are
necessar: to examine the e--icac: o- io!aine as an anti-addictive a!ent.
Eimilarl:* additional preclinical studies Yill e re$uired to elucidate the
molecular mechanism7s8 responsile -or these pharmacolo!ical actions.
TOP
,L. AcInoYled!ments
The authors thanI 0r. H. Eershen -or help-ul discussions on the e--ects o-
io!aine on dopaminer!ic and serotoner!ic transmission.
TOP
L. (&1&(&)%&E
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>O. 0.?. (epIe* 0.(. Artis* W.T. )elson* and &.H. Non!* W. Or!. %hem. >R*
54O< 74RR<8.
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>Q. H.,. 0hahir* ).%. Wain* and W.,. Thornton* W. 1oren. Eci. 45* 9SR 74RP58.
>R. &. ?ertol* 1. +ari* and (. 1roldi* W. %hromato!r. 44P* 59R 74RPO8.
OS. H.,. 0hahir* 0iss. Astr. ,nt. 95'S<-?* 5944 74RP48.
O4. 6. cetler* 6. Ein!arth* and @. Echlosser* Pharmacol. P* 59P 74RP58.
O5. %.A. 6alla!her* @.?. Hou!h* E.+. bee-ner* A. Ee:ed +oGa--ari* E.
Archer* and E.0. 6licI* ?iochem. Pharmacol. <R* P9 74RR>8.
O9. N.@. Hearn* W. Palo* 6.N. Hime* and 0.%. +ash* W. Anal. Toxicol. 4R*
<5P 74RR>8.
O<. +.&. Alur!es* (.@. 1oltG* and 0.&. +ood:* W. Anal. Toxicol. 4R* 9Q4
74RR>8.
O>. 1.(. @e:* A.(. We--coat* and ?. Thomas* W. %hromato!r. A P59* 4S4
74RRO8.
OO. E.+. Pearl* @.?. Hou!h* 0.@. ?o:d* and E.0. 6licI* Pharmacol.
?iochem. ?ehav. >P* QSR 74RRP8.
OP. @.?. Hou!h* E.+. Pearl* and E.0. 6licI* @i-e Eci. >Q* P@44R 74RRO8.
OQ. E.0. 6licI* b. (ossman* E. Eteindor-* ,.+. +aisonneuve* and W.).
%arlson* &ur. W. Pharmacol. 4R>* 9<4 74RR48.
OR. ,.+. +aisonneuve* b.@. (ossman* (.N. beller* Wr.* and E.0. 6licI*
?rain (es. >P>* OR 74RR58.
PS. H. Eershen* A. Hashim* and A. @a;tha* Pharmacol. ?iochem. ?ehav. <P*
49 74RR<8.
P4. ,.+. +aisonneuve* (.N. beller* and E.0. 6licI* &ur. W. Pharmacol. 4RR*
9> 74RR48.
P5. (.T. @a:er* P. EIolnicI* %.+. ?ertha* +.&. buehne* and P. PopiI* &ur. W.
Pharmacol. 9SR* 4>R 74RRO8.
P9. 0. +ash* W.b. Etale:* +.H. ?aumann* (.?. (othman* and N.@. Hearn*
@i-e Eci. >P* P@<> 74RR>8.
P<. E.0. 6licI* b. (ossman* ).%. (ao* ,.+. +aisonneuve* and W.). %arlson*
)europharmacolo!: 94* <RP 74RR58.
P>. 6. %hen and ?. ?ohner* W. Pharmacol. &xp. Ther. 459* 545 74R>Q8.
PO. H. Eershen* A. Hashim* @. Harsin!* and A. @a;tha* @i-e Eci. >S* 4SPR
74RR58.
PP. T. @uxton* @.A. ParIer* and E. Eie!el* Pro!. )euro-Ps:ch. ?iol. Ps:ch.
5S* Q>P 74RRO8.
PQ. (.P. besner* P. WacIson-Emith* %. Henr:* and b. Amann* Pharmacol.
?iochem. ?ehav. >4* 4S9 74RR>8.
PR. W.6. Pa!e* @.&. (odan* 0.(. 1ranell* and W.1. +artin* ),0A %ontract
(eport E(,-%?&-R<-SS5-P<QO* 74RR<8.
QS. ,.+. +aisonneuve* b.&. TisIer* 6.@. +ann* C.b. ?andara!e* +.&.
buehne* and E.0. 6licI* &ur. W. Pharmacol. 99O* 459 74RRP8.
Q4. H. Eershen* @.6. Harsin!* Wr.* A. Hashim* and A. @a;tha* @i-e Eci. >4*
4SS9 74RR58.
Q5. ,.+. +aisonneuve* (.N. beller* Wr.* and E.0. 6licI* ?rain (es. >PR* QP
74RR58.
Q9. ,.+. +aisonneuve* 0iss. Ast. ,nt. 4 74RR58.
Q<. ,.+. +aisonneuve and E.0. 6licI* &ur. .W Pharmacol. 545* 5O9 74RR58.
Q>. P.A. ?rodericI* 1.T. Phelan* and E.P. ?er!er* in ] ),0A (esearch
+ono!raph )o. 44R. Prolems o- 0ru! 0ependence] 7@. Harris* ed.8* p.
5Q>* C.E. 6overnment Printin! O--ice* Nashin!ton* 0.%.* 4RR5.
QO. P.A. ?rodericI* 1.T. Phelan* 1. &n!* and (.T. Nechsler* Pharmacol.
?iochem. ?ehav. <R* P44 74RR<8.
QP. E.+. Pearl* 0.N. Wohnson* and E.0. 6licI* Ps:chopharmacolo!: 454*
<PS 74RR>8.
QQ. E.0. 6licI* ,.+. +aisonneuve* and E.+. Pearl* ?rain (es. P<R* 9<S
74RRP8.
QR. E.0. 6licI* E.+. Pearl* W. %ai* and ,.+. +aisonneuve* ?rain (es . P49*
5R< 74RRO8.
RS. 6. Ein!arth* 6. cetler* and @. Echlosser* )europharmacolo!: 45* 59R
74RP98.
R4. &.0. 1rench* b. 0illon* and E.1. Ali* @i-e Eci. >R* P@4RR 74RRO8.
R5. E. Helsle:* 0. 1iorella* (.A. (ain* and W. %. Ninter* Pharmacol.
?iochem. ?ehav. >Q* 9P 74RRP8.
R9. &. O[Hearn and +.&. +olliver* )euroscience >>* 9S9 74RR98.
R<. E.@. %ostache ]Pharmacolo!ical attenuation o- the tremori!enic e--ects
o- io!aine.] Cnpulished +.E. thesis. Alan: +edical %olle!e* Alan:*
)F* CEA* 4RR>.
R>. 6. cetler* )europharmacolo!: 55* P>P 74RQ98.
RO. E.0. 6licI* +.&. buehne* W. (aucci* T.&. Nilson* 0. @arson* (.N.
beller* and W.). %arlson* ?rain (es. O>P* 4< 74RR<8.
RP. E.0. 6licI* +.&. buehne* ,.+. +aisonneuve* C.b. ?andara!e* and H.H.
+olinari* ?rain (es. P4R* 5R 74RRO8.
RQ. E.+. bin! and 6. Tunnicli--* ?iochem. ,nt. 5S* Q54 74RRS8.
RR. &. (oerts* &. Non!* 6. Evenne:* and P. 0e!ener* ?rain (es. 4>5* O4<
74RPQ8.
4SS. W.H. Trouvin* P. Wac$min* %. (ouch* +. @esne* and %. Wac$uot* &ur. W.
Pharmacol . 4<S* 9S9 74RQP8.
4S4. W.A. Echneider and &.?. Ei!!* Ann. )F Acad. Eci. OO* PO> 74R>P8.
4S5. E. 6ershon and N.W. @an!* Arch. ,nt. Pharmacod:n. Ther. 49>* 94
74RO58.
4S9. +.&.+. ?enYell* P.&. Holtom* (.W. +oran* and 0.W.b. ?al-our* ?r. W.
Pharmacol. 44P* P<9 74RRO8.
4S<. &.E. Onaivi* E.1. Ali* and A. %haIraarti* Ann. ). F. Acad. Eci. in
press* 74RRQ8.
4S>. E.@.T. %appendi;I and +.(. 0Gol;ic* &ur. W. Pharmacol. 5<4* 5O4
74RR98.
4SO. 1.W. Tocci and &.0. @ondon* Ann. ). F. Acad. Eci. Q5S* 5R 74RRO8.
4SP. Anon:mous* Presented to the 1ood and 0ru! Administration[s 0ru!
Advisor: %ommittee y5O* 74RR98.
4SQ. (.E. +ansach* (.@. ?alster* +. 6re!or:* and &. Eoen!hen* ),0A
%ontract (eport EAR5.4O* 74RR58.
4SR. E.,. 0YorIin* E. 6leeson* 0. +eloni* T.(. boves* and T.W. +artin*
Ps:chopharmacolo!: 44P* 5>P 74RR>8.
44S. F.N. @ee* A.H. (eGvani* and 0.H. Overstreet* Eoc. )eurosci. Astr. 5S*
4OSQ 74RR<8.
444. A.H. (eGvani* 0.H. Overstreet* and F.N. @ee-* Pharmacol. ?iochem.
?ehav. >5* O4> 74RR>8.
445. A.H. (eGvani* 0. +ash* 0.H. Overstreet* N.@. Hearn* and F.N. @ee*
Alcoholism - %lin. &xp. (es* 4R* 4>A 74RR>8.
449. A.H. (eGvani* 0.H. Overstreet* F. Fan!* ,.+. +aisonneuve* C.b.
?andara!e* +.&. buehne* and E.0. 6licI* Pharmacol. ?iochem. ?ehav. >Q*
O4> 74RRP8.
44<. +.0. Aceto* &.(. ?oYman* and @.E. Harris* ),0A. (es. +ono!r. R>*
>PQ 74RRS8.
44>. &.0. 0Gol;ic* %.0. baplan* and +.(. 0Gol;ic Arch ,nt Pharmacod:n
5R<* O< 74RQQ8.
44O. E.@.T. %appendi;I* 0. 1eIIes* and +.(. 0Gol;ic* ?ehav. ?rain (es. O>*
44P 74RR<8.
44P. @.6. Eharpe and W.H. Wa--e* ),0A (es. +ono!r. 4S>* <PP 74RR48.
44Q. ?. 1rances* (. 6out* W. %ros* and W.+. ca;ac* 1undam. %lin. Pharmacol.
O* 95P 74RR58.
44R. P. PopiI* (.T. @a:er* @. 1ossom* +. ?enveniste* ?. 6etter-0ou!las*
W.+. NitIin* and P. EIolnicI* W. Pharmacol. &xp. Ther. 5P>* P>9 74RR>8.
45S. W.A. Echneider and +. +cArthur* &xperientia 45* 959 74R>O8.
454. H.). ?har!ava* F.W. %ao* and 6.+. chao* ?rain. (es. P>5* 59< 74RRP8.
455. F.W. %ao and H.). ?har!ava* ?rain (es. P>5* 5>S 74RRP8.
459. A.A. ?a!al* @.?. Hou!h* W.N. )alYalI* and E.0. 6licI* ?rain (es. P<4*
5>Q 74RRO8.
45<. E.+. Pearl* b. HerricIdavis* +. Teitler* and E.0. 6licI* ?rain (es. OP>*
9<5 74RR>8.
45>. ?. ?adio* N.@. Pad!ett* and W.N. 0al:* +ol. Pharmacol. >4* 4 74RRP8.
45O. N. bostoYsIi* N. (eYersIi* and T. PiechocIi* Pharmacolo!: P* 5>R
74RP58.
45P. +.0. Echechter and T.@. 6ordon* &ur. W. Pharmacol. 5<R* PR 74RR98.
45Q. +.0. Echechter* @i-e Eci. OS* P@Q9 74RRP8.
45R. P.A. Palumo and W.%. Ninter* Pharmacol. ?iochem. ?ehav. <9* 4554
74RR58.
49S. W.+. NitIin* E. ?rave* 0. 1rench* and ?. 6eterdou!lass* . W Pharmacol.
&xp. Ther. 5P>* 45OP 74RR>8.
494. E. Helsle:* (.A. (ain* and W.%. Ninter* @i-e Eci. OS* P@4<P 74RRP8.
495. @.A. ParIer* E. Eie!el* and T. @uxton* &xp. %lin* Ps:chopharm. 9* 9<<
74RR>8.
499. ,. +oroG* @.A. ParIer* and E. Eie!el* &xp. %lin. Ps:chopharm. >* 44R
74RRP8.
49<. @.A. ParIer and E. Eie!el* @earn. +otiv. 5P* 4PS 74RRO8.
49>. W.(. ?lacIurn and b.b. EGumlinsIi* Eoc. )eurosci. Astr. 54* 4<OP
74RR>8.
49O. P. PopiI* @i-e Eci. >R* P@9PR 74RRO8.
49P. W.A. Echneider and (.b. (inehart* Arch. ,nt. Pharmacod:n. Ther. %L*
R5 74R>P8.
49Q. ). Ha;o-Tello* %. 0upont* W. Nepierre* F. %ohen* (. +iller* and T.
6od-raind* Arch. ,nt. Pharmacod:n. Ther. 5PO* 9> 74RQ>8.
49R. ). Ha;o* %. 0upont* and W. Nepierre* W. Pharmacol. 45* <<4 74RQ48.
4<S. c. ?inienda* +.A. ?eaudoin* ?.T. Thorn* 0.(. Prapurna* W.(. Wohnson*
%.+. 1o!le* N. EliIIer* and E.1. Ali* Ann. )F Acad. Eci. in press* 74RRQ8.
4<4. &.@. +andrile and 6.+. ?on!iorno de P-irter* Acta. 1arm. ?onaerense
<* <R 74RQ>8.
4<5. %. )aran;o* ]The healin! ;ourne:. )eY approaches to consciousness].
).F. Pantheon.)eY ForI* 4RP9.
4<9. P.?. Ton Echmid* ArGneim.-1orsch. 4P* <Q> 74ROP8.
4<<. (.E. Eloviter* &.6. 0rust* ?.P. 0amiano* and W.0. %onnor* W.
Pharmacol. &xp. Ther. 54<* 594 74RQS8.
4<>. ).(. 1arnsYorth* Ecience 4O5* 4SQO 74ROQ8.
4<O. W. 0elourme-Houde* Ann. Pharm. 1r. <* 9S 74R<O8.
4<P. &. O[Hearn* 0.?. @on!* and +.&. +olliver* )euro(eport <* 5RR 74RR98.
4<Q. &. O[Hearn* P. chan!* and +.&. +olliver* )euro(eport O* 4O44 74RR>8.
4<R. &. O[Hearn and +.&. +olliver* W. )eurosci. 4P* QQ5Q 74RRP8.
4>S. &. O[Hearn and +.&. +olliver* Eoc. )eurosci. Astr. 59* 59SQ 74RRP8.
4>4. A.%. Ecallet* L. Fe* (. (ountree* P. )on:* and E.1. Ali* Ann. )F Acad.
Eci. QS4* 54P 74RRO8.
4>5. A.%. Ecallet* L. Fe* and E.1. Ali* Ann. )F Acad. Eci. QS4* 55P 74RRO8.
4>9. H.H. +olinari* ,.+. +aisonneuve* and E.0. 6licI* ?rain (es. P9P* 5>>
74RRO8.
4><. E. Helsle:* %.A. 0lu!os* (.W. Pentne:* (.A. (ain* and W.%. Ninter*
?rain (es. P>R* 9SO 74RRP8.
4>>. W.P. O[%alla!han* @.&. (odman* T.E. (o!!ers* W.?. Terril* and W.6.
Pa!e* Eoc. )eurosci. Astr. 5S* 4O>S 74RR<8.
4>O. W.P. O[%alla!han* T.E. (o!ers* @.&. (odman* and W.6. Pa!e* Ann. )F
Acad. Eci. QS4* 5S> 74RRO8.
4>P. ?.W. Tilner* C.b. ?andara!e* +.&. buehne* %.+. ?ertha* and N.0.
?oYen* in ] Prolems o- 0ru! 0ependence. Proceedin!s o- the >Rth Annual
Ecienti-ic +eetin!* ),0A (es. +ono!raph.] 7@.E. Harris* ed.8* C.E.
6overnment Printin! O--ice* Nashin!ton* 0.%. 4RRP.
4>Q. &. O[Hearn and +.&. +olliver* Eoc. )eurosci. Astr. 54* 49<S 74RR>8.
4>R. P. PopiI* (.T. @a:er* and P. EIolnicI* Ps:chopharmacolo!: 44<* OP5
74RR<8.
4OS. W.N. Olne:* C E Patent >*O5R*9SP* 74RRP8.
4O4. b. %hen* T.6. boIate* E. Fama!ishi* 1.,. %arroll* and +.A. (o!aYsIi*
Eoc. )eurosci. Astr. 54* 44S> 74RR>8.
4O5. b. %hen* T.6. boIate* E.0. 0onevan* 1.,. %arroll* and +.A. (o!aYsIi*
)europharmacolo!: 9>* <59 74RRO8.
4O9. 0.%. +ash* (. 0ou:on* N.@. Hearn* ).%. Eamol* and W.
EancheGramos* ?iol. Ps:chiat. 9P* O>5 74RR>8.
4O<. P.+. NhitaIer and P. Eeeman* W. Pharm. Pharmacol. 5R* >SO 74RPP8.
4O>. 0.%. 0eecher* +. Teitler* 0.+. Eoderlund* N.6. ?ornmann* +.&.
buehne* and E.0. 6licI* ?rain (es. >P4* 5<5 74RR58.
4OO. P.+. EYeetnam* W. @ancaster* A. EnoYman* W. %ollins* E. PerschIe* %.
?auer* and W. 1erIan:* Ps:chopharmacolo!: 44Q* 9OR 74RR>8.
4OP. W.b. Etale:* B. Ou:an!* W. Palo* N.@. Hearn* 0.0. 1l:nn* (.?.
(othman* b.%. (ice* and 0.%. +ash* Ps:chopharmacolo!: 45P* 4S 74RRO8.
4OQ. %. +esser and 6. (udnicI* Eoc. )eurosci. Astr. 54* 49Q9 74RR>8.
4OR. E.0. 6licI* b. (ossman* E. Nan!* ). 0on!* and (.N. beller* Wr.* ?rain
(es. O5Q* 5S4 74RR98.
4PS. E.1. Ali* 6.0. )eYport* N. EliIIer* (.?. (othman* and +.H. ?aumann*
Eoc. )eurosci. Astr. 54* 54SP 74RR>8.
4P4. E.1. Ali* 6.0. )eYport* N. EliIIer* Wr.* (.?. (othman* and +.H.
?aumann* ?rain (es. P9P* 54> 74RRO8.
4P5. +.E. (eid* b. Hsu* b.H. EouGa* P.A. ?rodericI* and E.P. ?er!er* W.
)eural. Transm. 4S9* ROP 74RRO8.
4P9. +.H. ?aumann* (.?. (othman* and E.1. Ali* Ann. )F Acad. Eci. in
press* 74RRQ8.
4P<. H. Eershen* A. Hashim* and A. @a;tha* ?rain (es. ?ull. 9O* >QP 74RR>8.
4P>. H. Eershen* A. Hashim* and A. @a;tha* Pharmacol. ?iochem. ?ehav. >9*
QO9 74RRO8.
4PO. @.6. Harsin!* H. Eershen* and A. @a;tha* W. )eur. Trans. RO798* 54>
74RR<8.
4PP. H. Eershen* A. Hashim* and A. @a;tha* )eurochem. (es. 4R* 4<O9
74RR<8.
4PQ. H. Eershen* A. Hashim* and A. @a;tha* ?rain (es. ?ull. <S* O9 74RRO8.
4PR. E.0. 6licI* %.A. 6alla!her* @.?. Hou!h* b.@. (ossman* and ,.+.
+aisonneuve* ?rain (es. >QQ* 4P9 74RR58.
4QS. E.+. Pearl* ,.+. +aisonneuve* and E.0. 6licI* )europharmacolo!: 9>*
4PPR 74RRO8.
4Q4. ,.+. +aisonneuve* 6.@. +ann* %.(. 0eiel* and E.0. 6licI*
Ps:chopharmacolo!: 7?erlin8 45R* 5<R 74RRP8.
4Q5. (.A. (ain and W. %. Ninter* &ur. W. Pharmacol. 94O* 9<9 74RRO8.
4Q9. &.&. %odd* @i-e Eci. >P* P@94> 74RR>8.
4Q<. W.P. Palo and 0.%. +ash* )euro(eport* in press* 74RRQ8.
4Q>. P.+. NhitaIer and P. Eeeman* Ps:chopharmacolo!: >R* 4 74RPQ8.
4QO. P.+. NhitaIer and P. Eeeman* Proc. )at. Acad. Eci. CEA P>* >PQ9
74RPQ8.
4QP. (.1. @on! and A.N. @essin* ?iochem. W. Q5* <P 74RO58.
4QQ. H. Eershen* A. Hashim* and A. @a;tha* ?rain (es. ?ull. <5* 4O4 74RRP8.
4QR. (.%. +iller and T. 6od-raind* &ur. W. Pharmacol. RO* 5>4 74RQ98.
4RS. A.E. Echneider* W.&. )a!el* and E.W. +ah* &ur. W. Pharmacol. 94P* (4
74RRO8.
4R4. 0. +ash* W.b. Etale:* W.P. Palo* A.+. Holohean* W.%. HacIman* and
(.A. 0avido--* )eurosc. @ett. 4R5* >9 74RR>8.
4R5. W. Palo* W.b. Etale:* A.+. Holohean* W.%. HacIman* (.A. 0avido--*
and 0.%. +ash* Eoc. )eurosci. Astr. 54* 45O< 74RR>8.
4R9. N.0. ?oYen* ?.W. Tilner* N. Nilliams* %.+. ?ertha* +.&. buehne* and
A.&. Wacoson* &ur. W. Pharmacol. 5PR* (4 74RR>8.
4R<. (.H. +ach* %.(. Emith* and E.(. %hilders* @i-e Eci. >P* P@>P 74RR>8.
4R>. N.0. ?oYen* ?.W. Tilner* C.b. ?andara!e* and +.&. buehne* Eoc.
)eurosci. Astr. 55* 5SSO 74RRO8.
4RO. (.A. (ain and W.%. Ninter* ?rain (es. P94* 55O 74RRO8.
4RP. &. %retet* +. Prioux-6u:onneau* %. Wac$uot* H. Eentenac* and W.
Nepierre* Arch. Pharmacol. 949* 44R 74RQS8.
4RQ. c. ?inienda* W. Wohnson* ?. Thorn* and E.1. Ali* Eoc. )eurosci. Astr.
59* 455P 74RRP8.
4RR. (.0. ?una! and &.W. NalasGeI* Ann. )F Acad. Eci. 4S<* <9P 74ROQ8.
5SS. +.&. Alur!es and 6.(. Hanson* Eoc. )eurosci. Astr. 59* 5<SQ
74RRP8.
5S4. (.T. House* P.T. Thomas* and H.). ?har!ava* Pharmacolo!: >4* >O
74RR>8.
5S5. F. ,tGhaI and E.1. Ali* Eoc. )eurosci. Astr. 54* 54SQ 74RR>8.
TOP
L,. Tale 4. ,nteractions o- io!aine Yith neurotransmitter s:stems:
radioli!and indin! studies.


(eceptor s:stem @i!and b i or ,% >S H s +J (e-erence
Alpha-adrener!ic 4 praGosin P.5 u 9.S 4OO
0opamine transporter N,) 9>*5<Q 4.> PO
0opamine transporter N,) 9>*5<Q 9.> u S.O 4OO
0opamine transporter (T,-454 5.S P9
0opamine transporter (T,->> <.44 u S.<> 4OP
+onoamine transporter 7vesicular8 tetraenaGine 5.59 u S.55 4OP
+uscarinic + 4 pirenGepine P.O u S.P 4OO
+uscarinic + 5 A1-0L9Q< >.R u 4.< 4OO
)icotinic nicotine <.S u S.O 45>
)icotinic noncompetitive caram:lcholine-induced 55 )a%l in-lux S.S5 u
S.SSP 45>
)+0A ion channel +b-QS4 4.S u S.4 4>R
)+0A ion channel +b-QS4 4.4 u S.S9 P5
)+0A ion channel +b-QS4 >.O u S.Q 4OO
)+0A ion channel +b-QS4 <-4S 4R4
)+0A ion channel +b-QS4 or T%P S.S4-S.S> and 5-< 5S5
)+0A ion channel T%P 4.> u S.9 44R
Opioid naloxone S.49 u S.S9 4Q9
Opioid 7Iappa8 COR*>R9 5.4 u S.5 4O>
Opioid 7Iappa8 COR*>R9 5R.Q u Q.9 7rat8
49.Q u S.O 7mouse8
54.S u 4.4 7!iunea-pi!8
P5
Opioid 7Iappa8 COR*>R9 >.> >O
Opioid 7Iappa8 COR*>R9 9.PP u S.Q4 45<
Eerotonin 5 Ietanserin <.Q u 4.< 4OO
Eerotonin 9 6(-P>>>Q 9.R u 4.4 4OO
Eerotonin transporter (T,->> S.>> u S.S9 P9
Eerotonin transporter (T,->> 4S 4OQ
Eerotonin transporter (T,->> S.>R u S.SR 4OP
Eerotonin transporter paroxetine R.9S u 4.PS 4OP
Ei!ma haloperidol S.SS9 4O<
Ei!ma pentaGocine S.SQO 44
Ei!ma 4 pentaGocine R.9 u S.O9 4R<
Ei!ma 4 pentaGocine Q.O u 4.4 4R9
Ei!ma 4 pentaGocine 4.>-9 5S5
Ei!ma 5 0T6 S.SRS< u S.S4S4 4R<
Ei!ma 5 0T6 S.5S4 u S.S59 4R9
Ei!ma 5 0T6 4.>-9 5S5
Tolta!e-dependent sodium channels atrachotoxin A 5S-a- enGoate Q.4 u
4.9 4O>
@&6&)0 TO TA?@& 4. Presented are b i or ,% >S 78 values -or various
neurotransmitter s:stems a--ected : io!aine Yith a--inities hi!her than 4S
s +. The a--inities o- O -desmeth:lio!aine -or the correspondin! receptors
are presented in -ootnotes.
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Top o- pa!e k +ain k Eearch k Ecience k Opinion k @iterature k @inIs k
Treatment k ?ooIshop k 1eedacI


T. io!a -loYer
d 4RRR
The ,o!aine 0ossier
O Rainforests Desa#are!en"o
)s estamos perdendo os tesouros iol!icos os mais !randes da
terra apenas en$uanto ns estamos come.ando a apreciar seu valor
verdadeiro. (ain-orests coriu uma veG 4<\ da super-#cie da terra
da terra; a!ora corem um mero O\ e os peritos estimam $ue os
=ltimos rain-orests restantes poderiam ser consumidos em menos
de <S anos
Cm e um meio de acre de mais rain-orest perdido cada
se!undo com conse$hncias tr!icas para amos $ue tornam-se
e pa#ses industriais.
(ain-orests est sendo destru#do por$ue o valor da terra a mais
rain-orest percieved como somente o valor de sua madeira por
!overnos short-si!hted* por companhias re!istrando
multinacionais* e por proprietrios de terra.
Buase a metade da espcie do mundo das plantas* dos animais e
dos microo!anisms ser destru#da ou amea.ada severamente
sore o sculo de um $uarto se!uinte devido ao de-orestation
de (ain-orest.
Os peritos estimam $ue ns estamos perdendo a espcie de 49P
planta* de animal e de inseto cada =nico dia devido ao
de-orestation o mais rain-orest. ,sso i!uala a >S.SSS espcies
um o ano. %omo a espcie a mais rain-orest dissapear* assim
$ue -a.a muitas curas poss#veis para doen.as li-e-threatenin!.
Atualmente* 454 dro!as da prescri."o venderam vindo
YorldYide das -ontes planta-derivadas. Buando 5>\ de
pharmaceuticals ocidentais -orem derivados dos in!redientes os
mais rain-orest* menos $ue 4\ destas rvores e plantas
tropicais -oram testadas por cientistas.
A maioria de rain-orests s"o cancelaram por chainsaYs* por
escavadoras e por -o!os para seu valor da madeira e s"o
se!uidos ent"o cultivando e ranchin! as opera.Ues* uni-ormes
por !i!antes do mundo como +itsuishi %orporation* 6ero!ia
o Pac#-ico* Texaco e Cnocal.
Havia os deG milh"o indians estimados $ue vivem no
AmaGonian (ain-orest cinco sculos h. Ho;e h menos de
5SS.SSS.
&m ?rasil soGinho* os colonos europeus destru#ram mais de RS
tries ind#!enos desde os 4RSS[s. %om eles tenha sculos idos
do conhecimento acumulado do valor medicinal da espcie a
mais rain-orest. %omo seus homelands continuam a ser
desto:ed pelo de-orestation* os povos os mais rain-orest
dissappearin! tamm.
A maioria homens de medicina e de shamans restantes no
(ain-orests tm ho;e PS anos velhos ou mais. %ada veG $ue um
homem de medicina de (ain-orest morre* como se uma
ilioteca se $ueimou para aixo.
Buando um homem de medicina morre sem passar suas artes
sore X !era."o se!uinte* o trie e o mundo perdem milhares
dos anos do conhecimento insustitu#vel sore plantas
medicinal.
A riqueTa "o Rainforests
As tampas de AmaGonian (ain-orest sore ilh"o acres* reas
aran!endo em ?rasil* TeneGuela* %olVmia e a re!i"o andean
oriental de &$uador e de Peru. Ee AmaGonia -osse um pa#s*
seria o nono maior no mundo.
O AmaGon (ain-orest -oi descrito como os ]pulmUes de nosso
planeta] por$ue -ornece o servi.o amiental essencial do
mundo do dixido de carono continuamente rec:lin! no
oxi!nio . +ais de 5S por cento do oxi!nio do mundo s"o
produGidos no AmaGon (ain-orest.
+ais do $ue a metade do mundo estimada 4S milh"o espcies
das plantas* dos animais e dos insetos vivem nos rain-orests
tropicais. Cm $uinto da !ua -resca do mundo est"o na acia de
AmaGon.
Cm hectare 75*<P acres8 pode conter sore P>S tipos de rvores
e de 4>SS espcies de umas plantas mais elevadas.
Ao menos QS\ da dieta do mundo desenvolvido ori!inou no
mais rain-orest tropical. Eeus presentes ounti-ul ao mundo
incluem -rutas como aacates* cocos* -i!s* laran;as* limUes*
!rape-uit* ananas* !uavas* pinapples* man!os e tomates;
ve!etais includin! o milho* as atatas* o arroG* o s$uash de
inverno e os :ams; os spices !ostam da pimenta* de pimenta de
%aiena* do chocolate* da canela* de cravos-da-#ndia* do !in!er*
do ast"o de a.=car* do tumeric* do ca- e do vanilla e de
porcas pretos includin! porcas de ?rasil e ca;us.
Ao menos 9SSS -rutas s"o encontradas nos rain-orests; destes
somente 5SS a!ora dentro o uso no mundo ocidental. Os
indians do uso o mais rain-orest sore 5.SSS.
As plantas de (ain-orest s"o ricas em metaolites secundrios*
particularmente alcalides. Os io$u#micos acreditam
alcalides prote!em plantas dos ata$ues da doen.a e do inseto.
+uitos alcalides de umas plantas mais elevadas provaram ser
do valor medicinal e ene-iciam-se.
Atualmente* 454 dro!as da prescri."o venderam atualmente
vindo YorldYide das -ontes planta-derivadas. & $uando 5>\ de
pharmaceuticals ocidentais -orem derivados dos in!redientes os
mais rain-orest* menos de 4\ destas rvores tropicais e as
plantas -oram testadas por cientistas.
O instituto nacional do cancer de &ETA0OE C),0OE
identi-icou 9SSS plantas $ue s"o ativas de encontro Xs pilhas do
cancer. PS\ destas plantas s"o encontradas no mais rain-orest.
TYent:--ive por cento dos in!redientes ativos em dro!as
cancer-de comate de ho;e vm dos or!anismos encontrados
somente no mais rain-orest
Tincristine* extra#do da planta a mais rain-orest* periYinIle *
uma das dro!as anticancer as mais poderosas do mundo.
Aumentou dramXtica a taxa da sorevivncia para o leuIemia
a!udo da in-/ncia desde sua descoerta.
&m 4RQ9* n"o havia nenhum -aricante pharmaceutical de
&ETA0OE C),0OE envolvido em pro!ramas de pes$uisa para
descorir dro!as novas ou curas das plantas. Ho;e* sore 4SS
companhias pharmaceutical e diversas -iliais do !overno dos &.
C.* includin! !i!antes !oste de +ercI e o instituto nacional do
cancer* acoplado em pro;etos de pes$uisa da planta para
dro!as poss#veis e curas para v#rus* in-ec.Ues* cancer e A,0E
uni-ormes.
AUPo De Rainforest
Os peritos concordam $ue deixando os rain-orests intatos e
colhendo os s"o muitas porcas* -rutas* plantas oil-producin!* e
plantas medicinal* o mais rain-orest tm um valor mais
econVmico do $ue se -orem reduGidos para -aGer pastar a terra
para o !ado ou para a madeira. .
Os statistics os mais atrasados mostram $ue a terra a mais
rain-orest convertida Xs opera.Ues do !ado rende o proprietrio
de terra jOS por o acre e se a madeira -or colhida* a terra valem
a pena j<SS por o acre. &ntretanto* se estes recursos reneYale
e sustainale -orem colhidos* a terra render o proprietrio de
terra j5.<SS por o acre.
Ee controlada corretamente* a lata a mais rain-orest -ornece a
necessidade do mundo para estes recursos naturais em uma
ase perpetual.
Promover o uso destas -ontes sustainale e reneYale podia
parar a destrui."o do (ain-orests. %riando uma -onte de renda
nova $ue colhe as plantas medicinal* porcas das -rutas* leo e
outros recursos sustainale* os rain-orests s"o este;am uns vivos
mais valioso do $ue cortados e $ueimados.
A demanda su-iciente de sustainale e havested ecolo!icall:
produtos de (ain-orest necessria para es-or.os da
preserva."o suceder. %ompra produtos os mais rain-orest
sustainale pode e-etuar a mudan.a positiva criando um
mercado para estes produtos ao suportar a economia de pessoa
nativo e -ornece a solu."o e a alternativa econVmicas a cortar a
-loresta apenas para o valor de sua madeira.
O se!uinte excerpted do livro* segredos herbal do Rainforest 7Prima
$ue pulica* (ocIlin* %A8 #or Les$ie A$faiate
A destrui."o do (ain-orest ma;estoso
A eleGa* o ma;est: e o timelessness de um o mais rain-orest
preliminar s"o indescriale. M imposs#vel capturar na pel#cula*
descrever nas palavras ou explicar X$uelas $ue nunca tiveram a
experincia aYe-inspirando de estar no cora."o de um o mais
rain-orest preliminar. (ain-orests evoluiu sore milhUes dos anos para
!irar nos amientes $ue incredil: complexos s"o ho;e. Cm o mais
rain-orest representa uma lo;a de viver e de respirar os recursos
naturais reneYale* $ue tm para eons* pelo virtue de seu richness na
espcie do animal e da planta* contriu#da uma ri$ueGa dos recursos
para a sorevivncia e o em estar do homem. &stes inclu#ram -ontes
de alimento sicas* roupa* ari!o* comust#vel* spices* materiais crus
industriais e medicina para o todo o a$ueles $ue viveram sustainal:
no ma;est: da -loresta. &ntretanto* a din/mica interna de um o mais
rain-orest tropical um sistema intricado e -r!il onde tudo se;a assim
interdependente $ue virar uma por."o pode conduGir aos danos ou
mesmo a destrui."o desconhecida do todo. Eadl:* -G exame somente
de um sculo da interven."o do homem para destruir o $ue a natureGa
tem pro;etado assim intricada ao =ltimo para sempre.
&m 4R>S* 4>\ da super-#cie da terra da terra -oi coerto por mais
rain-orest. Ho;e* mais do $ue meio tem ido ; acima no -umo. Cm
sculo h* a metade de ,ndia e um third de &tipia -oram coertos pela
-loresta* a!ora somente $uatorGe por cento no remains de ,ndia e
somente um ter.o s"o deixados em &tipia. Oito -ora de deG rvores
em 6hana -oram reduGidos. Trs $uartos das rvores da costa de
mar-im s"o idos. +ais de vinte por cento do AmaGon (ain-orest est"o
idos ; e muito mais amea.ados severamente en$uanto a destrui."o
continua a escalar. Os statistics relataram em 4RRO relataram o
AmaGon mostraram um aumento de 9< por cento no de-orestation
desde 4RR5. Cm relatrio novo por um comit con!ressional diG o
AmaGon est desaparecendo em uma taxa de 5S.SSS milhas $uadradas
um o ano. A$uele mais de trs veGes a taxa de 4RR<* o ano passado
para $ue as -i!uras o-iciais est"o dispon#veis. ]se nada -eito* o
AmaGon inteiro estar ido dentro de >S anos*] disse o autor do
relatrio 44S-pa!e* (epresentante 6ilne: Tianna do partido do
traalhador le-tist no estado de AmaGon de +ato 6rosso. %ontudo
umas outras -i!uras novas ditas do relatrio recente mostraram $ue no
AmaGon raGilian* -o!os da -loresta aumentados por mais de >S por
cento sore 4RRO.
&m menos de >S anos* mais do $ue a metade dos rain-orests tropicais
do mundo tm a v#tima ca#da ao -o!o e a corrente viu e a taxa da
destrui."o est acelerando ainda. ,nacreditXvel* sore 5SS.SSS acres
de mais rain-orest s"o $ueimados cada dia. ,sso est sore 4>S acres
perdidos cada minuto de cada dia* e PQ milh"o acres s"o perdidos
cada ano` Cma -loresta mais tropical $ueimou-se em torno do mundo
em 4RRP do $ue em toda a outra hora no histor: !ravado* um relatrio
pelo -undo lar!o do mundo para a natureGa. O -undo dito ]4RRP ser
recordado como o ano o -o!o travado mundo*] disse Wean-Paul
Weanrenaud* cae.a de seu pro!rama da -loresta.
O de-orestation maci.o traG com ele muitas conse$hncias -eias -
polui."o do ar e da !ua* eros"o do solo* epidemias da malria* a
liera."o do dixido de carono na atmos-era* o eviction e o
decimation de tries indian ind#!enos* e a perda do iodiversit: com a
extin."o das plantas e dos animais. +enos (ain-orests si!ni-ica
menos chuva* menos oxi!nio para $ue ns respirem* e uma amea.a
mesmo mais !rande de a$uecer-se !loal.
+as $uem deve realmente responsailiGarK %onsidere o $ue ns
industrialiGed americanos -iGemos a nosso prprio homeland... ns
convertemos n eee T(A)E@AT,O) &)0E H&(& eeeinet: percent
o- )orth America[s vir!in -orests into -ireYood* shin!les* -urniture*
railroad ties and paper. Other industrialiGed countries have done no
etter. +ala:sia* ,ndonesia and ?raGil* amon! other tropical countries
Yith rain-orests* are o-ten randed as ]environmental villains] o- the
Yorld* mainl: due to their reported levels o- destruction o- their
rain-orests. ?ut despite the levels o- de-orestation* the: are still
covered : up to OS\ o- their territor: : natural tropical -orests. ,n
-act* much o- the pressure toda: on their remainin! rain-orests come
-rom servicin! the needs and marIets -or Yood products in
industrialiGed countries Yho have alread: depleted their oYn natural
resources. ,ndustrial countries Yould not e u:in! rain-orest
hardYoods and timer had Ye not cut doYn our oYn trees lon! a!o
nor Yould poachers in the AmaGon ;un!le e slau!hterin! ;a!uar*
ocelot* caiman and otter i- Ye did not provide lucrative marIets -or
their sIins in ?erlin* Paris and ToI:o.
The ?iodiversit: o- the (ain-orest
Eo Yh: should the loss o- tropical -orests e o- an: more concern to
us in li!ht o- our oYn poor mana!ement o- natural resourcesK The
loss o- tropical rain-orests has a pro-ound and devastatin! Yorld
impact ecause rain-orests are so much more iolo!icall: diverse.
%onsider these -acts:
A sin!le pond in ?raGil can sustain a !reater variet: o- -ish than
are -ound in all o- &urope[s rivers;
A tYent:--ive acre plot o- rain-orest in ?orneo ma: contain
over seven hundred species o- trees - a numer e$ual to the
total tree diversit: o- )orth America;
A sin!le rain-orest reserve in Peru is home to more species o-
irds than the entire Cnited Etates;
One sin!le tree in Peru Yas -ound to haror -ort:-three di--erent
species o- ants - a total that approximates the entire ant species
in the ?ritish ,sles.
The iodiversit: o- the tropical rain-orest is so immense that less than
one percent o- its millions o- species have een studied : scientists
-or active constituents and their possile uses -or man. Nhen an acre
o- topical rain-orest is lost* the impact to the numer o- plant* animal
and insect species lost and their possile uses is sta!!erin!. Ecienti-ic
experts estimate that Ye are losin! over 49P species o- plants* animals
and insects ever: sin!le da: ecause o- rain-orest de-orestation.
Eurprisin!l:* scientists have a etter understandin! o- hoY man: stars
there are in the !alax: than hoY man: species there are on &arth.
&stimates o- !loal species diversit: have varied -rom 5 million to
4SS million species* Yith a est estimate o- someYhere near 4S
million* and onl: 4.< million have actuall: een named. Toda:*
(ain-orests occup: onl: 5\ o- the entire earth[s sur-ace and O\ o- the
Yorld[s land sur-ace* :et these remainin! lush rain-orests support over
hal- o- our plants Yild plants and trees and one-hal- o- the Yorld[s
Yildli-e. Hundreds and thousands o- these rain-orest species are ein!
extin!uished e-ore the: have even een identi-ied* much less
catalo!ed and studied. The ma!nitude o- this loss to the Yorld Yas
most poi!nantl: descried : Harvard[s PulitGer PriGe-Yinnin!
iolo!ist* &dYard O. Nilson* over 4S :ears a!o...
!$#e -orst t#ing t#at can #appen during t#e (+*D>s is not energy
depletion, economic collapses, limited nuclear -ar, or conMuest by a
totalitarian government. 1s terrible as t#ese catastrop#es -ould be
for us, t#ey can be repaired -it#in a fe- generations. $#e one process
ongoing in t#e (+*D>s t#at -ill take millions of years to correct is t#e
loss of genetic and species diversity by t#e destruction of natural
#abitats. $#is is t#e folly t#at our descendants are least likely to
forgive us for.!
Fet still the destruction continues. ,- de-orestation continues at current
rates* scientists estimate nearl: QS to RS percent o- tropical rain-orest
ecos:stems Yill e destro:ed : the :ear 5S5S. This destruction is the
main -orce drivin! a species extinction rate unmatched in O> million
:ears.
The AmaGon (ain-orest...
The @ast 1rontier on &arth
,- AmaGonia Yere a countr:* it Yould e the ninth lar!est in the Yorld.
The AmaGon (ain-orest* the Yorld[s !reatest remainin! natural
resource* is the most poYer-ul and io-activel: diverse natural
phenomenon on the planet. ,t has as een descried as the ]@un!s o-
our Planet] ecause it provides the essential environmental Yorld
service o- continuousl: rec:clin! caron dioxide into ox:!en. ,t is
estimated that over tYent: percent o- earth[s ox:!en is produced in
this area.
The AmaGon rain-orest covers over 4.5 illion acres representin! tYo-
-i-ths o- the enormous Eouth American continent and is -ound in nine
Eouth American countries: ?raGil* %olumia* Peru* TeneGuela*
&cuador* ?olivia and the three 6u:anas. Nith 5.> million s$uare
miles o- rain-orest* the AmaGon (ain-orest represents >< percent o-
the total rain-orests le-t on the planet.
The li-e -orce o- the AmaGon (ain-orest is the mi!ht: AmaGon (iver.
,t starts as a tricIle hi!h in the snoY-capped Andes mountains and
-loYs over <*SSS miles across the Eouth American continent until it
enters the Atlantic ocean at ?elem* ?raGil Yhere it is 5SS to 9SS miles
across* dependin! on the season. &ven 4*SSS miles inland* it is still P
miles in Yidth. The river is so deep that ocean liners can travel 5*9SS
miles inland* up its len!th. The AmaGon (iver -loYs throu!h the
center o- the rain-orest and is -ed : 4*4SS triutaries* seventeen o-
Yhich are over 4*SSS miles lon!. The AmaGon is : -ar the lar!est
river s:stem in the Yorld and over tYo-thirds o- all the -resh Yater
-ound on earth is in the AmaGon asin[s rivers* streams and triutaries.
Nith so much Yater its not unusual that that the main mode o-
transportation throu!hout the area is : oat. The smallest and most
common oats used toda: are still made out o- holloYed tree trunIs*
Yhether the: are poYered : outoard motors or more o-ten : man-
poYered paddles. Almost 4<*SSS miles o- AmaGon YaterYa: are
navi!ale and several million miles throu!h sYamps and -orests are
penetrale : canoe. The enormous AmaGon (iver carries massive
amounts o- silt -rom run-o-- -rom the rain-orest -loor. +assive
amounts o- silt deposited at the mouth o- the AmaGon river has
created the lar!est river island in the Yorld* +ara;o ,sland* Yhich is
rou!hl: the siGe o- EYitGerland. Nith this massive -resh Yater s:stem*
it not unusual that the li-e eneath the Yater is as aundant and
diverse as the surroundin! rain-orest[s plant and animal species. Over
5*SSS species o- -ish have een identi-ied in the AmaGon ?asin - more
species than the entire Atlantic Ocean.
The AmaGon ?asin Yas -ormed in the PaleoGoic period* someYhere
etYeen >SS and 5SS million :ears a!o. The extreme a!e o- the re!ion
in !eolo!ic terms has much to do Yith the relative in-ertilit: o- the
rain-orest soil and the richness and uni$ue diversit: o- the plant and
animal li-e. There are more -ertile areas in the AmaGon (iver[s -lood
plain* Yhere the river deposits richer soil rou!ht -rom the Andes*
Yhich onl: -ormed 5S million :ears a!o. The rich diversit: o- plant
species in the AmaGon (ain-orest is the hi!hest on earth. &xperts
shoY that one hectare 75.<P acres8 ma: contain over P>S t:pes o- trees
and 4>SS species o- hi!her plants and it is estimated that one hectare
o- AmaGon rain-orest contains aout RSS tons o- livin! plants.
Alto!ether it contains the lar!est collection o- livin! plants and animal
species in the Yorld. The Andean mountain ran!e and the AmaGon
;un!le are home to more than hal- o- the Yorld[s species o- -lora and
-auna and one in -ive o- all the irds in the Yorld live in the
rain-orests o- the AmaGon.. To date* some <9Q*SSS species o- plants o-
economic and social interest have een re!istered in the re!ion and
man: more have :et een catalo!ed or even discovered.
Once a vast sea o- tropical -orest* the AmaGon rain-orest toda: is
scarred : roads* -arms* ranches and dams. CSee figure 1D ?raGil is
!i-ted Yith a -ull third o- the Yorld[s remainin! rain-orests and
un-ortunatel:* it is also one o- the Yorld[s !reat rain-orest destro:ers*
urnin! or -ellin! over 5.P million acres each :ear. Toda:* more than
5S percent o- rain-orest in the AmaGon has een raGed and is !one
-orever. This ocean o- !reen nearl: as lar!e as Australia* is the last
!reat rain-orest in the InoYn universe and it is ein! decimated liIe
the others e-ore it. Nh:K @iIe other rain-orests alread: lost -orever*
the land is ein! cleared -or lo!!in! timer* lar!e scale cattle
ranchin!* minin! operations* !overnment road uildin! and
h:droelectric schemes* militar: operations* and the susistence
a!riculture o- peasants and landless settlers. Eadder still* in man:
places the rain-orests are urnt simpl: to provide charcoal to poYer
industrial plants in the area.
The 0rivin! 1orces o- 0estruction
%ommercial lo!!in! is the sin!le lar!est cause o- rain-orest
destruction oth directl: and indirectl:. CSee figure -D The simple -act
is that the: are destro:in! the AmaGon (ain-orest and the rest o- the
rain-orests o- the Yorld ecause ]the: can[t see the -orest -or the
trees.] @o!!in! tropical hardYoods liIe teaI* maho!an:* roseYood
and other timer -or -urniture* uildin! materials* charcoal and other
Yood products is i! usiness and i! pro-its. Eeveral species o-
tropical hardYoods are imported : developed counties* includin!
America* ;ust to uild co--ins Yhich are then uried or urned. The
demand* extraction and consumption o- tropical hardYoods has een
so massive that some countries Yhich have een traditional exporters
o- tropical hardYoods are noY importin! them ecause the: have
alread: exhausted their suppl: : destro:in! their native rain-orests in
slash and urn operations. ,t is anticipated that The Phillippines*
+ala:sia* The ,vor: %oast* )i!eria and Thailand Yill soon -olloY as
all these countries Yill run out o- rain-orest hardYood timer -or
export in less than -ive :ears. Wapan is the lar!est importer o- tropical
Yoods. 0espite recent reductions* Wapan[s 4RR> tropical timer import
total o- 44*OR>*SSS cuic meters is still !luttonous; dama!in! to the
ecolo!ical* iolo!ical and social -aric o- tropical lands* and clearl:
unsustainale -or an: len!th o- time.
?ehind the hardYood lo!!er come others doYn the same roads uilt
to transport the timer. The cardoard pacIin! and the Yood
chipoard industries use 4> ton machines that !ole up the rain-orest
Yith Q -oot cuttin! discs that have ei!ht lades revolvin! 95S times a
minute Yhich cut entire trees into chips hal- the siGe o- a matchox.
+ore than 5SS species o- trees can e !oled up : these machines
Yhich are currentl: clearin! 95S s$uare miles o- rain-orest in Papua
)eY 6uinea to provide a -raction o- the demand o- these tYo
industries. These same land devourin! machines are meetin! the
remainin! Yorld demand in the AmaGon and Australian rain-orests.
@o!!in! rain-orest timer is a lar!e economic source* and in man:
cases* the main source o- revenues -or servicin! the national det o-
developin! countries. @o!!in! pro-its are real to these countries Yho
must service their dets* ut are the: are -leetin!. 6overnments are
sellin! their assets too cheapl:* and once the rain-orest is !one* their
source o- income is !one. Eadl:* most o- the real pro-its o- the timer
trade are made not : the developin! countries* ut : multi-national
companies and industrialists o- the northern hemisphere. These hu!e
pro-it driven companies pa: !overnments a -raction o- the timer[s
Yorth -or lar!e lo!!in! concessions on immense tracts o- rain-orest
land and reap hu!e pro-its : harvestin! the timer in the most
economical manner -easile Yith little re!ard to the destruction le-t in
their YaIe. @o!!in! concessions in the AmaGon are sold -or as little
as j5 per acre Yith lo!!in! companies -ellin! timer Yorth thousands
o- dollars per acre. 6overnments are sellin! their natural resources*
haYIin! -or pennies* resources that soon Yill e Yorth illions o-
dollars. Eome o- these !overnment concessions and land deals made
Yith industrialists maIe the sale o- +anhattan -or tYent:--our dollars
Yorth o- trinIets looI shreYd. ,n 4RQO* a hu!e industrial timer
corporation ou!ht thousands o- acres in the ?orneo rain-orest :
!ivin! 5*SSS +ala:sian dollars to 45 lon!houses o- local tries. This
sum amounted to the price o- tYo ottles o- eer -or each memer o-
the communit:. Eince then this compan: and others have mana!ed to
extract and destro: aout a third o- the ?orneo rain-orest - aout O.R
million acres and the local tries have een evicted -rom the area or
-orced to YorI -or the lo!!in! companies at slave Ya!es.
,n addition to lo!!in! -or exportation* rain-orest Yood sta:s in
developin! countries -or -uel Yood and charcoal. One sin!le steel
plant in ?raGil maIin! steel -or Wapanese cars needs millions o- tons
o- Yood each :ear to produce charcoal that can e used in the
manu-acture o- steel. Then there is the paper industr:. A pulpYood
pro;ect in the ?raGilian AmaGon consists o- a Wapanese poYer plant
and pulp mill. To set up this sin!le plant operation* >*OSS s$uare miles
o- AmaGon (ain-orest Yas urned to the !round and replanted Yith
pulpYood trees. This sin!le manu-acturin! plant consumes 5*SSS tons
o- surroundin! rain-orest Yood ever: da: to produce >> me!aYatts o-
electricit: to run the plant. The plant* Yhich has een in operation
since 4RPQ* produces over P>S tons o- pulp -or paper ever: 5< hours*
Yorth approximatel: j>SS*SSS and has uilt 5*QSS miles o- roads
throu!h the AmaGon rain-orest to e used : its PSS vehicles. ,n
addition to this pulp mill* the Yorld[s i!!est pulp mill is the AracruG
mill in ?raGil; its tYo units produce one million tons o- pulp a :ear
and displaced thousands o- indi!enous tries harvestin! the rain-orest
to Ieep the plant in usiness. Nhere does all this pulp !oK AracruG[s
i!!est customers are the Cnited Etates* ?el!ium* 6reat ?ritain* and
Wapan. +ore and more rain-orest is destro:ed to meet the demand o-
developed Yorld[s paper industr: Yhich re$uires a sta!!erin! 5SS
million tons o- Yood each :ear simpl: to maIe paper. ,- the Yorld
continues at the present rate* < illion tons o- Yood is estimated to e
consumed annuall: : the :ear 5S5S in the paper industr: alone.
&ven more rain-orest is destro:ed : minin! operations. ?raGil sits on
one o- the Yorlds lar!est reserves o- iron ore and has ample !old*
semiprecious and precious stones* natural !as and oil reserves as Yell.
Etrip minin! is common in the AmaGon and hu!e chunIs o- rain-orest
land is lost ever: :ear to minin! operations. &ven more lands are lost
to the polution caused : these minin! operations as the constant
Yater runo-- in the rain-orest carries the Yaste oil* mercur:* and other
pollutinates and contaminants used. +ecur: poisonin! : animal and
human inhaitants aliIe is ecommin! a !ommon #rob$em as the
mecur: used in strip minin! and !old minin! operations runs o-- into
the rivers and streams and is carried hundreds o- miles. CSee figure 0D
Once an area o- rain-orest has een lo!!ed* even i- !iven the rare
chan!e to re-!roY* it can never ecame Yhat it once Yas. The intricate
ecos:stem nature devised is lost -orever. Onl: 4-5 percent o- li!ht at
the top o- a rain-orest canop: mana!es to reach the -orest -loor eloY.
+ost times Yhen timer is harvested* the plants and animals o- the
ori!inal -orest ecomes extinct* and trees and other plants that have
evolved over centuries to !roY in the darI* humid environment eloY
the canop: simpl: cannot live out in the open. &ven i- onl: sections o-
land throu!hout an area are destro:ed* these remnants chan!e
drasticall:. ?irds and other animals cannot cross -rom one to another
in the canop:* so plants are not pollinated* seeds are not dispersed :
the animals and the plants around the ed!es are not surrounded : the
hi!h ;un!le humidit: Yhich the: need to !roY properl:. As a result*
the remnants sloYl: ecome de!raded and die. (ains come and Yash
aYa: the thin topsoil that Yas previousl: protected : the canop: and
this arren un-ertile land results in erosion. Eometimes the land is
replanted in A-rican !rasses -or cattle operations and other times*
more vir!in rain-orest is destro:ed -or cattle operations ecause
plantin! !rass on recentl: urned land has a etter chan!e to !roY.
As the demand in the Nestern Yorld -or cheap meat increases* more
and more rain-orest is destro:ed to provide !raGin! land -or animals.
,n Eouth America alone* there are an estimated 55S million head o-
cattle* 5S million !oats* OS million pi!s and PSS million chicIens.
+ost o- %entral and @atin America[s tropical and temperate
rain-orests have een lost to cattle operations to meet the Yorld
demand* and still the cattle operations continue to move southYard
into the heart o- the Eouth American (ain-orests. To !raGe one steer in
AmaGonia* it taIes tYo -ull acres. +ost o- the ranchers in the AmaGon
operate at a loss* :ieldin! onl: paper pro-its purel: as tax shelters.
(ancher[s -ortunes are made onl: Yhen ranchin! is supported :
!overnment !iveaYa:s. A anIer or rich land oYner in ?raGil can
slash and urn a hu!e tract o- land in the AmaGon rain-orest* seed it
Yith !rass -or cattle and realiGe millions o- dollars Yorth o-
!overnment-susidiGed loans* tax-credits and Yrite o--s in return -or
developin! the land. These !overnment development schemes rarel:
maIe a pro-it actuall: sellin! cheap ee- to industrialiGed nations.
One sin!le cattle operation in ?raGil that Yas co-oYned : ?ritish
?arcla:s ?anI and one o- ?raGil[s Yealthiest -amilies Yas responsile
-or the destruction o- almost >SS*SSS acres o- vir!in rain-orest. The
cattle operation never made a pro-it ut !overnment Yrite-o--s
sheltered hu!e lo!!in! pro-its earned o-- o- lo!!in! other land in the
?raGilian rain-orest oYned : the same investors. These !enerous tax
and credit incentives have created over 5R million acres o- lar!e cattle
ranches in the ?raGilian AmaGon* even thou!h the t:pical ranch could
cover less that hal- its costs Yithout these susidies.
This t:pe o- !overnment-driven destruction o- rain-orest land is
promoted : a common attitude amon! !overnments in rain-orest
re!ions that the -orest is an economic resource to e harnessed to aid
in the development o- their countries. The same attitudes that
accompanied the coloniGation o- our oYn -rontier are -ound toda: in
?raGil and other countries Yith Yild unharnessed rain-orest
Yilderness. These elie-s are exempli-ied in a ?raGilian o--icial[s
pulic statement that ]not until all AmaGonas is coloniGed : real
?raGilians* not ,ndians* can Ye trul: sa: Ye oYn it.] Nere Ye
Americans an: di--erent Yith our oYn coloniGation decimatin! the
)orth American ,ndian triesK @iIe ?raGil* Ye sent out a call to all the
Yorld that America had land -or the landless in an e--ort to increase
coloniGation o- our land at the expense o- our ,ndi!enous ,ndian
tries. And liIe the -irst America colonists* coloniGation in the
rain-orest reall: means susistence -armin!.
Eusistence -armin! has -or centuries een a drivin! -orce in the loss
o- rain-orest land and as populations explode in third Yorld countries
in Eouth American and the 1ar &ast* the impact has een pro-ound. ?:
tradition* Yildlands and unsettled lands in the rain-orest are -ree to
those Yho clear the -orest and till the soil. ]E$uatter[s (i!hts] still
prevail and poor* hun!r: people shoY little enthusiasm -or ar!uments
aout the value o- iodiversit: or the pli!ht o- endan!ered species.
The present approach to rain-orest cultivation produces Yealth -or a
-eY* -or a short time ecause -armin! urned-o-- tracts o- AmaGon
rain-orest seldom YorIs -or lon!. @ess than ten percent o- AmaGonian
soils are suitale -or sustained conventional a!riculture. HoYever lush
the: looI* rain-orests o-ten -lourish on such nutrient-poor soils that
the: are essentiall: ]Yet deserts*] easier to dama!e and harder to
cultivate than an: other soil. +ost are exhausted : the time the:
have produced three or -our crops. +an: o- the thousands o-
homesteaders Yho mi!rated -rom ?raGil[s cities to the Yilds o- the
rain-orest* respondin! to the !overnment[s call o- ]land Yithout men
-or men Yithout land*] have alread: had to aandon their depleted
-arms and move on* leavin! ehind -ields o- aIed cla: dotted Yith
sta!nant pools o- polluted Yater. &xperts a!ree that the path to
conservation e!ins Yith helpin! these local residents meet their oYn
dail: needs. ?ecause o- the in-ertilit: o- the soil* and the lacI o-
InoYled!e o- sustainale cultivation practices* this t:pe o- a!riculture
strips the soil o- nutrients Yithin a -eY harvests and the -ar-----mers
continue to move -arther into the rain-orest in search o- neY land.
The: must e helped and educated to reaI -ree o- the need to
continuall: clear rain-orest in search o- -resh* -ertile land i- the
rain-orest is to e saved.
0irectl: and indirectl:* the leadin! threats to rain-orest ecos:stems are
!overnments and their unridled* unplanned and uncoordinated
development o- natural resources. (ain-orest timer exports and lar!e
scale development pro;ects !o a lon! Ya: in servicin! national det in
man: developin! countries Yhich is Yh: !overnments and*
international aid-lendin! institutions liIe the Norld ?anI supports
them. ,n the tropics* !overnments oYn or control nearl: QS percent o-
tropical -orests* so these -orests stand or -all accordin! to !overnment
polic: and in man: countries* !overnment policies lie ehind the
Yasta!e o- -orest resources. ?esides the tax incentives and credit
susidies Yhich !uarantee lar!e pro-its to private investors Yho
convert -orests to pastures and -arms* !overnments alloY private
concessionaires to lo! the national -orests on terms that induce
uneconomic or Yaste-ul uses o- the pulic domain. +assive pulic
expenditures on hi!hYa:s* dams* plantations* and a!ricultural
settlements* too o-ten supported : multilateral development lendin!*
convert or destro: lar!e areas o- -orest -or pro;ects o- $uestionale
economic Yorth.
Tropical counties are amon! the poorest countries on &arth. ?raGil
alone spends <S percent o- its annual income simpl: servicin! its
loans and the per capita income o- ?raGil[s people is less than j5*SSS
annuall:. Eadl:* these numers don[t even represent an accurate
picture in the AmaGon ecause ?raGil is one o- the richer countries in
Eouth America. These stru!!lin! AmaGonian countries must also
mana!e the most complex* delicate and valuale -orests remainin! in
the planet and the economic and technolo!ical resources availale to
them are limited. The: must also endure a dramatic social and
economic situation* plus deepl: adverse terms o- trade and -inancial
relationships Yith industrial countries. Cnder such conditions* the
possiilit: o- them reachin! sustainale models o- development alone
are nearl: impossile. There is a clear need -or industrial countries to
sincerel: and e--ectivel: assist the tropics in a $uest -or sustainale
-orest mana!ement and development i- the remainin! rain-orests are
to e saved. The !overnments o- these developin! countries need help
in learnin! hoY to mana!e and protect their natural resources -or lon!
term pro-its Yhile still mana!in! to service their dets and the: must
e !iven the incentives and tools to do so. Pro!rams to rede-ine the
timer concessions so concessionaires have !reater incentives to
!uard the lon!-term health o- the -orest and pro!rams to revive and
expand communit:-ased -orestr: schemes* Yhich ensure more
rational use o- -orests and a etter li-e -or the people Yho live near
them must e developed 1irst-Yorld capital must seeI out
opportunities to partner Yith or!aniGations that have the technical
expertise to !uide these pro!rams o- sustainale economic
development. ,n addition* pro!rams teachin! techni$ues -or
sustainale harvestin! practices and identi-:in! pro-itale* :et
sustainale -orest products can enale developin! countries to
improve the standard o- livin! -or its people* service national det*
and contriute meanin!-ull: to the countr:[s land use plannin! and
conservation o- natural resources.
(ain-orests*
Pharmac: to the Norld
,t is estimated that nearl: hal- o- the Yorld[s estimated 4S million
species o- plants* animals and micro-or!anisms Yill e destro:ed or
severel: threatened over the next $uarter centur: due to (ain-orest
de-orestation. Harvard[s PulitGer PriGe-Yinnin! iolo!ist* &dYard O.
Nilson* estimates that Ye are losin! 49P plant* animal and insect
species ever: sin!le da:. That[s >S*SSS species a :ear` A!ain* Yh:
should Ye in the Cnited Etates e concerned aout the destruction o-
distant tropical rain -orestsK ?ecause rain -orest plants are complex
chemical storehouses that contain man: undiscovered iod:namic
compounds Yith unrealiGed potential -or use in modern medicine. Ne
can !ain access to these materials onl: it Ye stud: and conserve the
species that contain them. (ain-orests currentl: provide sources
providin! one--ourth o- toda:[s medicines* and PS\ o- the plants
-ound to have anti-cancer properties are -ound onl: in the rain-orest.
The (ain-orest and it[s immense undiscovered iodiversit: holds the
Ie: to unlocIin! tomorroY[s cures -or devastatin! diseases. HoY
man: cures to devastatin! disease have Ye alread: lostK
TYo dru!s otained -rom a rain-orest plant InoYn as the +ada!ascar
periYinIle* noY extinct in the Yild due to de-orestation o- the
+ada!ascar rain-orest* has increased the chances o- survival -or
children Yith leuIemia -rom 5S percent to QS percent. ThinI aout it -
Q out o- 4S children are noY saved rather than Q o- 4S children d:in!
-rom leuIemia. HoY man: children have een spared and hoY man:
more Yill continue to e spared ecause o- this sin!le rain-orest
plantK Nhat i- Ye -ailed to discover this one important plant amon!
millions e-ore it Yas extinct due to man[s destructionK Nhen our
remainin! rain-orests are !one* the rare plants* animals Yill e lost
-orever and so Yill their possile cures to diseases liIe cancer.
)o one can challen!e the -act that man is still lar!el: dependant on
plants -or treatin! his aliments. Almost RS percent o- people in
developin! countries still rel: on traditional medicine--ased lar!el:
on species o- plants and animals---or their primar: health care. ,n the
Cnited Etates* some 5> percent o- prescriptions are -illed Yith dru!s
Yhose active in!redients are extracted or derived -rom plants. Eales o-
these plant-ased dru!s in the C.E. amounted to some j<.> illion in
4RQS. NorldYide sales o- these plant-ased dru!s Yere estimated at
j<S illion in 4RRS. Etill even more dru!s are derived -rom animals
and microor!anisms. %urrentl: 1-1 #res!ri#tion "rugs so$"
3or$"3i"e come -rom plant derived sources -rom onl: RS species o-
plants.
The C.E. )ational %ancer ,nstitute has identi-ied over 9*SSS plants
that are active a!ainst cancer cells* and PS\ o- these plants are -ound
onl: in the rain-orest. Toda:* over 5>\ o- the active in!redients in
toda:[s cancer--i!htin! dru!s come -rom or!anisms -ound onl: in the
(ain-orest. Amon! the thousands o- species o- rain-orest plants that
have not een anal:Ged* are man: more thousands o- unInoYn plant
chemicals* man: o- Yhich have evolved to protect the plants -rom
patho!ens. These plant chemicals ma: Yell help us in our oYn
constant stru!!le Yith constantl: evolvin! patho!ens such as evolvin!
acteria-resistant patho!ens in tuerculosis* measles* and H,T.
&xperts noY elieve that i- there is a cure -or cancer and even A,0E*
it Yill proal: e -ound in the rain-orest.
,n 4RQ9* there Yere no C.E. pharmaceutical manu-acturers involved in
research pro!rams to discover neY dru!s or cures -rom plants. Toda:*
over 4SS pharmaceutical companies and several ranches o- the CE
!overnment* includin! !iants liIe +ercI* Aott* ?ristol-+:ers
E$ui* &li @ill:* +onsanto* Emithbline ?eecham and the )ational
%ancer ,nstitute are en!a!ed in plant-ased research pro;ects -or
possile dru!s and cures -or viruses* in-ections* cancer and A,0E.
+ost o- this research is currentl: taIin! place in the rain-orest in an
industr: that is noY called ]io-prospectin!.] This neY
pharmacolo!ical industr: has sprun! up* draYin! to!ether an unliIel:
con-ederac:: plant-collectors and anthropolo!ists; ecolo!ists and
conservationists; natural product companies and nutritional
supplement manu-acturers* A,0E and cancer researchers; executives
in the Yorld[s lar!est dru! companies* and native indi!enous shamans.
The: are part o- a radical experiment - to preserve the Yorld[s
rain-orests : shoYin! hoY much more valuale the: are standin!
than cut doYn. And it is a race a!ainst a clocI Yhose ever: ticI means
another acre o- charred -orest. Fet it is also a race that pits one
explorer a!ainst another* -or those Yho score the -irst i! hit in
chemical io-prospectin! Yill secure Yealth and a piece o- scienti-ic
immortalit:.
,n )ovemer 4RR4* +ercI Pharmaceutical %ompan: announced a
landmarI a!reement to otain samples o- Yild plants and animals -or
dru!-screenin! purposes -rom %osta (ica[s )ational ?iodiversit:
,nstitute 7,)?io8. Epurred : this and other iodiversit: prospectin!
ventures* interest in the commercial value o- plant !enetic and
iochemical resources is ur!eonin! toda:. Nhile the +ercI-,)?io
a!reement provides a -ascinatin! example o- a private partnership that
contriutes to rural economic development* rain-orest conservation*
and technolo!: trans-er* virtuall: no precedent exists -or national
policies and le!islation to !overn and re!ulate Yhat amounts to a
rand neY industr:.
Eince Yealth and technolo!: are as concentrated in the )orth as
iodiversit: and povert: are in the Eouth* the $uestion o- e$uit: is
particularl: hard to ansYer in Ya:s that satis-: ever:one Yith a staIe
in the outcome. The interests o- ioprospectin! corporations are not
the same as those o- people Yho live in a iodiversit: ]hot spot*]
man: o- them arel: eIin! out a livin!. As the search -or Yild species
Yhose !enes can :ield neY medicines and etter crops !athers
momentum* these rich haitats also sport more and more io-
prospectors. @iIe the nineteenth-centur: %ali-ornia !old rush or its
present-da: counterpart in ?raGil* this ]!ene rush] could YreaI havoc
on ecos:stems and the people livin! in or near them. 0one properl:*
hoYever* ioprospectin! can olster oth economic and conservation
!oals Yhile underpinnin! the medical and a!ricultural advances
needed to comat disease and sustain !roYin! populations.
The ma;orit: o- our current plant-derived dru!s Yere discovered
throu!h these traditional uses o- plants : the indi!enous people
Yhere the: !reY and -lourished. Histor: has shoYn that the rain-orest
is no di--erent* and these ioprospectors noY are YorIin! side : side
Yith rain-orest trial shamans and heral healers to learn the Yealth o-
their plant InoYled!e and man: uses o- indi!enous plants Yhere
dru!s and pharmacies are virtuall: unInoYn.
Jn$o!)ing t&e Se!rets of t&e Rainforest
A-ter the Ameri-,ndians discovered America* aout 5S millennia
e-ore %olumus* all their clothin!* -ood* medicine and shelter Yere
derived -rom the -orests. Those millennia !ave the ,ndians time to
discover and learn empiricall: the virtues and vices o- the thousands
o- edile and medicinal species in the rain-orest. +ore than QS\ o-
the developed Yorld[s diet ori!inated -rom the rain-orest and this
empirical indi!enous InoYled!e o- the Yealth o- edile -ruits*
ve!etales and nuts. O- the estimated 9*SSS edile -ruits -ound in the
rain-orest* onl: 5SS are cultivated -or use toda:* despite the -act that
the ,ndians use more than 4*>SS. +an: secrets and untold treasures
aYait discover: Yith the medicinal plants used : shamans* healers
and the indi!enous people o- the rain-orest Tries. @on! re!arded as
hocus- pocus : science* ,ndi!enous People[s empirical plant
InoYled!e is noY thou!ht : man: to e the AmaGon[s neY !old.
This indi!enous use o- the plants provides the ioprospector Yith the
necessar: clues to tar!et speci-ic species to research in the race -or
time e-ore the species are lost to de-orestation. +ore o-ten the race is
de-ined as to e the -irst compan: to patent a neY dru! utiliGin! a
neYl: discovered rain-orest ph:tochemical* and o- course* pro-its -or
the pharmaceutical companies.
@aorator: s:ntheses o- neY medicines is increasin!l: costl: and not
as -ruit-ul as companies Yould liIe. ,n the Yords o- one ma;or dru!
compan:: ]Ecientists ma: e ale to maIe an: molecule the: can
ima!ine on a computer* ut +other )ature...is an in-initel: more
in!enuous and excitin! chemist.] Ecientists have developed neY
technolo!ies to assess the chemical maIeup o- plants and the: realiGe
usin! medicinal plants identi-ied : ,ndians maIes research more
e--icient and less expensive. Nith these neY trends* dru! development
has actuall: returned to its roots - traditional medicine. ,t is noY
understood : ioprospectors that trial people o- the rain-orest
represent the Ie: to -indin! neY and use-ul tropical -orest plants. The
de!ree to Yhich the: understand and are ale sustainal: to use this
diversit: is astoundin!. The ?arasan ,ndians o- AmaGonian %olumia
can identi-: all o- the tree species in their territor: Yithout havin! to
re-er to the -ruit or -loYers* a -eat that no universit:-trained otanist is
ale to accomplish` A sin!le AmaGonian trie o- ,ndians ma: use over
5SS species o- plants -or medicinal purposes alone.
O- the 454 pharmaceutical dru!s that are plant-derived toda:* P<\
Yere discovered throu!h -olloY up research to veri-: the authenticit:
o- in-ormation concernin! the ethnic medical uses o- the plant.
)evertheless* to this da:* ver: -eY rain-orest tries have een
su;ected to a complete ethnootanical anal:sis. (oert 6oodland o-
the Norld ?anI Yrote*
],ndi!enous InoYled!e is essential -or the use*
identi-ication and catalo!uin! o- the HtropicalJ iota. As
trial !roups disappear* their InoYled!e vanishes Yith
them. The preservation o- these !roups is a si!ni-icant
economic opportunit: -or the Hdevelopin!J nation* not a
luxur:.]
Eince AmaGonian ,ndians are o-ten the onl: ones Yho InoY oth the
properties o- these plants and hoY the: can est e used* their
InoYled!e is noY ein! considered an essential component o- all
e--orts to conserve and develop the rain-orest. Eince -ailure to
document this lore Yould represent a tremendous economic and
scienti-ic loss to the industrialiGed Yorld* the ioprospectors are noY
are YorIin! side : side Yith the rain-orest trial shamans and heral
healers to learn the Yealth o- their plant InoYled!e. ?ut
ioprospectin! has a darI side. ,ndian InoYled!e that has resisted the
pressure o- ]moderniGation] is ein! used : ioprospectors Yho* liIe
oil companies and lo!!ers destro:in! the -orests* threaten to leave no
ene-its ehind them.
,ts a nole idea* the ethnootanist Yho YorIs Yith the ,ndians seeIin!
a cure -or cancer or even A,0E* liIe Eean %onner: in the movie*
+edicine +an. Fet* ehind this lurIs a s:stem that* at its Yorst* steals
the ,ndian InoYled!e to ene-it %&Os* stocIholders and academic
careers and reputations. The real !oal o- these poYer-ul io-
prospectors is to tar!et novel and active ph:tochemicals Yith medical
applications* s:nthesiGe them in a laorator: and have them patented
-or suse$uent dru! manu-acture and resultin! pro-its. ,n this process*
man: active and ene-icial plants have een -ound in the Ehaman[s
medicine chest* ut have een discarded Yhen it Yas -ound that the
active in!redients o- the plant numered too man: to e s:nthesiGed
into a patentale dru! cost e--ectivel:. ,t doesn[t matter hoY active or
ene-icial the plant Yas or hoY lon! the 10A process mi!ht taIe to
patent and approve the neY dru! - i- the ioprospector can[t capitaliGe
on it - the pulic Yill rarel: hear aout a neYl: discovered plant[s
ene-its. The -act is* there is a lot o- mone: at staIe. ,n an article
pulished in &conomic ?otan:* 0r. (oert +endelsohn* an economist
at Fale Cniversit:* and 0r. +ichael W. ?alicI* director o- the ,nstitute
o- &conomic ?otan: at the )eY ForI ?otanical 6ardens* estimate the
minimum numer o- pharmaceutical dru!s potentiall: remainin! to e
extracted -rom the rain-orests. ,t is sta!!erin!` The: estimate that
there are at least 95Q neY dru!s that still aYait discover: in the
rain-orest Yith a potential value o- j9-< illion to a private
pharmaceutical compan: and as much as j4<P ?illion to societ: as a
Yhole.
Nhile the ,ndi!enous ,ndian shamans !o aout their dail: lives carin!
-or the Yell ein! o- their trie* thousands o- miles aYa: in CE
laoratories* the Ehaman[s rain-orest medicines are ein! tested*
s:nthesiGed* patented and sumitted -or 10A approval. Eoon children
Yith viral in-ections* adults Yith herpes* cancer patients and man:
others ma: ene-it -rom neY medicines -rom the AmaGon (ain-orest.
?ut Yhat Yill the ,ndi!enous Tries see o- these Yonder-ul neY
medicinesK As corporations rush to patent indi!enous medicinal
InoYled!e* the ori!inatin! ,ndi!enous communities have received
-eY* i- an: ene-its.
Losing t&e [no3$e"ge
The destruction o- the rain-orest has -olloYed the pattern o- seein!
natural land and natural Yorld peoples as resources to e used* and
seein! Yilderness as idle* empt: and unproductive. 0estruction o- our
rain-orests is not onl: causin! the extinction o- plant and animal
species* it is also is Yipin! out ,ndi!enous Peoples Yhich live in the
rain-orest. Oviousl:* rain-orests are not idle land* nor are the:
uninhaited. ,ndi!enous Peoples have developed technolo!ies and
resource use s:stems that have alloYed them to live on the land*
-armin!* huntin! and !atherin! in a complex sustainale relationship
Yith the -orest. ?ut Yhen rain-orests die* so do the ,ndi!enous
Peoples.
,n 4>SS* there Yere an estimated six to nine million ,ndi!enous
People inhaitin! the rain-orests in ?raGil. Nhen Nestern and
&uropean cultures Yere draYn to ?raGil[s AmaGon in the hopes o-
-indin! riches e:ond comprehension and arti-acts -rom civiliGations
that have lon! since expired Yith the passa!e o- time* the: le-t ehind
decimated cultures in their ravenous YaIe. ?: 4RSS there Yere onl:
one million ,ndi!enous People le-t in ?raGil[s AmaGon. Althou!h the
-aled 1ountain o- Fouth Yas never discovered* man: treasures in
!old and !ems Yere spirited aYa: : the more success-ul invaders o-
the da: and the ,ndi!enous inhaitants o- the rain-orest ore the runt
o- these maraudin! explorers and con$uistadors.
Toda: there are less than 5>S*SSS ,ndi!enous People o- ?raGil
survivin! this catastrophe and still it continues. These survivin!
,ndi!enous People still demonstrate the remarIale diversit: o- the
rain-orest ecause the: comprise 54> ethnic !roups Yith 4PS di--erent
lan!ua!es. The: live in >5O territories nationYide* Yhich to!ether
comprise an area o- 4RS million acres... tYice the siGe o- %ali-ornia.
Aout 4QQ million acres o- this land is inside the ?raGilian AmaGon*
in the states o- Acre* Amapa* AmaGonas* Para* +ato 6rosso*
+aranhao* (ondonia* (oraima* and Tocantins. There ma: also e >S
or more indi!enous !roups still livin! in the depths o- the rain-orest
that have never had contact Yith the outside Yorld.
Throu!hout the rain-orest* -orest-dYellin! peoples Yhose a!e-old
traditions alloY them to live in and o-- the -orest Yithout destro:in! it
are losin! out to cattle ranchin!* lo!!in!* h:droelectric pro;ects* lar!e-
scale -arms* minin!* and coloniGation schemes. Aout hal- o- the
ori!inal AmaGonian Tries have alread: een completel: destro:ed.
The !reatest threat to ?raGil[s remainin! trial people* most o- Yhom
live in the AmaGon (ain-orest* is the invasion o- their territor: :
these ranchers* miners* land speculators and the con-licts Yhich
-olloY. ,n AmaGonia* thousands o- peasants* ruer tappers* and
,ndi!enous Tries have een Iilled in the past decade in violent
con-licts over -orest resources and land.
As their homelands continue to e invaded and destro:ed* rain-orest
people and their cultures are disappearin!. Nhen these ,ndi!enous
Peoples are lost -orever* !one too is their empirical InoYled!e
representin! centuries o- accumulated InoYled!e o- the medicinal
value o- rain-orest plant and animal species. Ter: -eY tries have
een su;ected to a complete ethnootanical anal:sis o- their plant
InoYled!e and most medicine men and shamans remainin! in the
rain-orests toda: are PS :ears old or more. Nhen a medicine man dies
Yithout passin! his arts on to the next !eneration* the trie and the
Yorld loses thousands o- :ears o- irreplaceale InoYled!e aout
medicinal plants. &ach time a (ain-orest medicine man dies* it is as i-
a lirar: has urned doYn.
?9E SOLJ?IOH
Profits 3it&out P$un"er
The prolem and the solution o- the destruction o- the rain-orest are
oth economic. 6overnments need mone: to service their dets*
s$uatters and settlers need mone: to -eed their -amilies* and
companies need to maIe pro-its. The simple -act is that the rain-orest
is ein! destro:ed -or the income and pro-its it :ields - hoYever
-leetin!. +one: still maIes the Yorld !o around... even in Eouth
America and even in the rain-orest.
?ut this also means that i- land oYners* !overnments and those livin!
in the rain-orest toda: Yere !iven a viale economic reason )OT to
destro: the rain-orest* it could and Yould e saved. And this viale
economic alternative 0O&E exist and it is YorIin! toda:. +an:
or!aniGations have demonstrated that i- the medicinal plants* -ruits*
nuts* oils and other resources liIe ruer* chocolate and chicle 7used
to maIe cheYin! !ums8* Yere harvested sustainal:* rain-orest land
has much more economic value toda: and more lon! term income and
pro-its than i- ;ust timer Yere harvested or i- it Yere urned doYn -or
cattle or -armin! operations. ,n -act* the latest statistics prove that
rain-orest land converted to cattle operations :ields the land oYner
jOS per acre and i- timer is harvested* the land is Yorth j<SS per
acre. HoYever* i- these reneYale and sustainale resources are
harvested* the land Yill :ield the land oYner j5*<SS per acre.This
value provides an income not onl: toda:* ut :ear a-ter :ear - -or
!enerations. These sustainale resources are the true Yealth o- the
(ain-orest - not the trees.
This is no lon!er a theor:. ,t is a -act and it is ein! implemented
toda:. Wust as importantl:* to Yild-harvest the Yealth o- sustainale
rain-orest resources e--ectivel:* local people and indi!enous tries
must e emplo:ed. Toda:* entire communities and tries earn > to 4S
times more mone: in Yild harvestin! medicinal plants* -ruits* nuts and
oils than the: can earn : choppin! doYn the -orest -or susistence
crops. This much needed income source creates the aYareness and
economic incentive -or this population in the rain-orest to protect and
preserve the -orests -or lon! term pro-its -or themselves and their
children and is an important solution in savin! the rain-orest -rom
destruction.
Nhen the timer is harvested -or short term !ain and pro-its* the
medicinal plants* nuts* oils and other important sustainale resources
Yhich thrive in this delicate ecos:stem are destro:ed. The real
solution to savin! the rain-orest is to maIe them see the -orest A)0
the trees : creatin! a consumer demand and consumer marIets -or
these sustainale rain-orest products... marIets that are lar!er and
louder than toda:[s tropical timer marIet.... marIets Yhich Yill put
as much mone: in their pocIets and !overnment co--ers as the timer
companies do.... marIets Yhich Yill !ive them the economic incentive
to protect their sustainale resources -or lon! term pro-its rather than
short term !ain.
This is the onl: solution that maIes a real impact and it can maIe a
real di--erence. &ach and ever: person here in America can taIe a part
in this solution : helpin! to create this consumer marIet and demand
-or sustainale rain-orest products. ?: purchasin! reneYale and
sustainale rain-orest products and resources and demandin!
sustainale harvestin! o- these resources utiliGin! local communities
and indi!enous tries o- the rain-orests* Ye all can e part o- the
solution and the rain-orests o- the Yorld and it[s people can e saved.
9e$# 3it& s!&oo$ re#orts on rainforest subGe!ts
Raintree Hutrition
Pro"u!ts
Com#an1 Aission
On$ine S&o##ing
Rainforest
P&i$oso#&1
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