Drugs 32 (Suppl.

4): 60-70 (1986)

00 12-6667/86/0400-0060/$5.50/0
© ADIS Press Limited
All rights reserved.

Pyrazolone Derivatives
Rex N. Brogden
ADIS Drug Information Services, Auckland

Summary In many countries. the pyrazolone derivatives. which include dipyrone. antipyrine. ami-
nopyrine and propyphenazone. are widely used analgesics. Dipyrone. the most widely used
pyrazolone. has been the most studied. The pyrazolidine derivatives. phenylbutazone and
oxyphenbutazone. which are not generally used for analgesia since they differ from the
pyrazolones in terms of efficacy and tolerance. are not discussed in this article.
Dipyrone is an inhibitor of cyclo-oxygenase but. unlike aspirin. its effect is rapidly
reversible. The inhibition ofprostaglandin biosynthesis contributes to the analgesic activity
of the pyrazolone derivatives.
Peak plasma concentrations ofthe pyrazolone derivatives generally occur 1 to 1.5 hours
after oral administration. Half-lives vary from 1 to 2 hours with propyphenazone. to about
7 hours with dipyrone (2 hours for the active metabolite of dipyrone. 4-methylaminoan-
tipyrine. MAA). Half-life of antipyrine varies considerably between individuals (5 to 35
hours). Unlike the NSAIDs generally. the pyrazolone derivatives antipyrine. aminopyrine
and propyphenazone are minimally bound to plasma proteins. The pyrazolones undergo
extensive biotransformation. aminopyrine and dipyrone being converted to active meta-
bolites.
Dipyrone is the only drug for which results of recent double-blind trials are available.
Oral dipyrone has been shown to be more effective than an equal dose of aspirin or par-
aceta mol in alleviating postoperative pain. and intravenous dipyrone 2.5g was similar in
efficacy to pethidine 50mg. In patients with acute ureteral or biliary colic. dipyrone 2.5g
intravenously was similar in efficacy to indomethacin 50mg or pethidine 50mg.
The most frequently reported side effects of the pyrazolone derivatives are skin rashes.
Gastrointestinal side effects are rare. Blood dyscrasias. mostly associated with amino-
pyrine. have received wide attention in the medical literature. but their true incidence with
dipyrone is considerably lower than the often quoted incidence for amidopyrine reported
more than 30 years ago.

1. Structural Relationships of the
Pyrazolones
The compounds described as pyrazolones are
derivatives of 3-pyrazoline. These drugs are among
the oldest synthetic pharmaceuticals, antipyrine
being first prepared in 1883. The therapeutic ac-
tivity of antipyrine (phenazone) was increased by
substitution of an isopropyl radical for the hydro-
gen on C-4 to produce propyphenazone (fig. 1),
which has improved antipyretic and analgesic
properties and also possesses anti-inflammatory
Pyrazoione Derivatives
activity. Substitution of a dimethylamino group for
the isopropyl radical of propyphenazone resulted
in aminophenazone, more commonly referred to
as aminopyrine or amidopyrine. A disadvantage
of aminopyrine is its relative insolubility in water.
The search for a more soluble compound led to the
production of dipyrone, the sodium salt of
antipyrinyl-methylaminomethane-sulphonic acid,
(noraminopyrine methane sulphonic acid).
Also chemically related to aminopyrine are
phenylbutazone and its active metabolite oxyphen-
butazone. These drugs have been widely used
throughout the world as anti-inflammatory anal-
gesics but since they, like azapropazone, are not
generally indicated for analgesia, these drugs are
not discussed in this article.
2. Pharmacodynamic Studies
Nearly all of the available data on the antipy-
retic and analgesic activity of the pyrazolone de-
rivatives are concerned with the effects of dipy-
rone. Apart from antipyrine, the pyrazolones have
demonstrated anti-inflammatory activity in animal
screening tests, the metabolites of dipyrone
4-methylaminoantipyrine and 4-acetylaminoanti-
pyrine, exhibiting activity comparable with that of
aspirin (Weithmann and Alpermann, 1985). Anal-
gesic activity is apparent at dosages lower than are
required for anti-inflammatory effects (Lorenzetti
and Ferreira, 1985).
2.1 Analgesic Effects
The exact mechanism of the analgesic effect of
the pyrazolones is not known. It is considered that
dipyrone, in particular, may produce analgesia by
inhibition of prostaglandin biosynthesis, especially
in the brain. This proposed mechanism arises from
the observed potency of dipyrone in inhibiting
prostaglandin production in brain microsomes (e.g.
Dembinska-Kiec et ai., 1976). However, this ob-
servation may not necessarily indicate that brain
cyclo-oxygenase is particularly sensitive to dipy-
rone, but rather to rapid generation of the active
metabolite 4-methylaminoantipyrine (noramino-
61
Antipyrine Propyphenazone
Isopropylantipyrine
I:
(C H312 N
o
ICH3
. . . NCH 3
Aminopyrine
6
Aminophenazone
Dipyrone
Sodium noraminopyrine methane
sulphonate
Amidopyrine
Metamizole
Fig. 1. Structural formulae of the pyrazolone derivatives, anti-
pyrine, prophenazone, aminopyrine and dipyrone.
pyrine) which was found to be active in inhibiting
prostaglandin synthesis in macrophages and in ram
seminal vesicles (Brune and Alpermann, 1983;
Weithmann and Alpermann, 1985).
Unlike the arylalkanoic acid derivatives, dipy-
rone seems to have central analgesic activity, as
evidenced by its activity in the hot plate test (e.g.
Schiantarelli et ai., 1979) and in increasing the pain
threshold in the normal as well as the inflamed
paws of mice used in the Randall-Selitto test (fig.
2) and inhibition of nociceptive impulse transmis-
sion (Jurna, 1985). It has further been suggested
that dipyrone acts directly on a hyperalgesic event,
either by inhibiting adenylate cyclase activation by
hyperalgesic substances or by causing a direct
blockade of calcium ion influx into the nociceptor
(Lorenzetti and Ferreira, 1985). Thus it appears that
several mechanisms contribute to the analgesic ef-
fect of dipyrone.
Pyrazolone Derivatives
Acetic acid
writhing contact
paw
Fig. 2. Relative analgesic activity of dipyrone • and aspirin 0
in various animal pain models. Data after Nikolova et al. (1978).
2.2 Effects on Prostaglandin Biosynthesis
Studies using rat brain homogenates and ram
seminal vesicles have demonstrated that dipyrone
and its metabolites, like aspirin and indomethacin,
inhibits prostaglandin biosynthesis (e.g. Schaefer et
aI., 1978; Weithmann and Alpermann, 1985). In
these models dipyrone was less active than indo-
methacin but at least as active as aspirin. Prosta-
glandin production from mouse peritoneal mac-
rophages was inhibited by propyphenazone and by
the active metabolites of dipyrone, aminoantipyr-
ine and methylaminoantipyrine (Brune and Alper-
mann, 1983).
The inhibitory activity of propyphenazone was
similar to that of aspirin. Basal and stimulated re-
lease of prostaglandins F 2a and E2 and prostacyclin
from human skin fibroblasts was inhibited dose-
dependently to a similar degree by dipyrone and
aspirin (Llithy et al., 1983). Although both drugs
appeared to inhibit cyclo-oxygenase, the effect of
dipyrone, unlike that of aspirin, was rapidly re-
versible, suggesting that it was unlikely that dipy-
rone inhibited the enzyme by binding covalently
to it. Thus it appears likely that dipyrone inhibi-
tion of cyclo-oxygenase would cease as soon as di-
pyrone was eliminated from the extracellular fluid
(Llithy et aI., 1983). 4-Methylaminoantipyrine de-
creased the higher than normal platelet aggregabil-
ity in arthritic rats and weakly inhibited the release
62
of 'antiaggregatory activity' from rat aortae, being
less active than aspirin (Weithmann and Alper-
mann, 1985). In vivo, dipyrone inhibited diarrhoea
in mice induced by prostaglandin E2 and F 2a, and
oedema in the rat's paw induced by prostaglandin
E2, to a greater extent than either aspirin or in-
domethacin (Nikolov et aI., 1978). These authors
suggested that the effects of dipyrone probably
resulted from antagonism of the pharmacological
effects of the prostaglandins rather than from in-
hibition of their synthesis.
paw
2.3 Other Effects
Oipyrone possesses antipyretic activity, as evi-
denced by inhibition of fever in goats and rabbits
induced by bacterial or leucocyte pyrogen (Van
Ouin et al., 1975; Van Miert et al., 1972), yeast-
induced fever in rats (Brune and Alpermann, 1983),
fever induced by typhoid-paratyphoid vaccine in
healthy volunteers (Kulkarni et aI., 1985) and re-
duction of body temperature in adult male patients
with typhoid fever (Ajgaonkar and Pinto Pereira,
1985). These findings were confirmed in a double-
blind trial in which single doses of dipyrone 500mg
and nimesulide lOOmg were similarly effective, and
more effective than aspirin 500mg in reducing
fever (Reiner et aI., 1984). Oipyrone oral liquid
effectively lowered fever in 100 infants and child-
ren with (mainly) respiratory tract infections
(Karim, 1967).
Studies in animals and in man (Schroth et aI.,
1985) have shown dipyrone to possess anti-
spasmodic activity, to inhibit human neutrophil
chemotaxis (Matzner et aI., 1984) and to have an
inhibiting effect on secondary platelet aggregation
which resembles that of other NSAIOs (Eldor et
aI., 1984; Rupp et aI., 1982; Weinberger et al., 1979;
Weithmann and Alpermann, 1985).
The ulcerogenic activity of dipyrone in rats was
similar to that of paracetamol (Oaas et aI., 1978).
The good gastrointestinal tolerability of dipyrone
may result from the inability of dipyrone and
4-methylaminoantipyrine to inhibit gastric mucosal
cyclo-oxygenase ex vivo (Weithmann and Alper-
mann, 1985).
Pyrazolone Derivatives 63

3. Pharmacokinetic Properties patients by insulin treatment and in hyperthyroid-

3.1 Antipyrine (phenazone)
After intravenous administration, antipyrine
rapidly equilibrates between plasma and tissues.
The drug has been extensively studied as an in-
dicator of the rate of drug metabolism in individ-
ual patients. There is considerable interindividual
variation in elimination half-life, which may be due
to genetic differences, with values of between 5 and
35 hours being reported by Sj6qvist et al. (1980).
The rate of elimination and plasma clearance of
antipyrine is influenced by age, sex, liver disease,
and certain other diseases. The elimination half-
life of antipyrine is increased in the elderly (fig. 3),
in whom the plasma clearance is decreased (Bach
et aI., 1981; Crooks et aI., 1976). The half-life is
shorter in women than in men (O'Malley et aI.,
1971) and the plasma clearance is markedly re-
duced in patients with cirrhosis or chronic active
hepatitis. Plasma clearance is increased in diabetic
ism. A decrease in clearance occurs in hypothyroid
patients.
The chief metabolites of phenazone are 4-hydro-
xyphenazone, its O-glucuronide, the N-desmethyl
derivative (norphenazone) and its hydroxylated
derivative. The rate of metabolism of antipyrine is
increased by a diet containing a high pro-
tein : carbohydrate ratio and vegetables which are
members of the brassica family, such as brussels
sprouts and cabbage. Protein binding of antipyrine
is low, about 10% (table I).
3.2 Aminopyrine (amidopyrine)
Following oral administration of aminopyrine,
peak plasma concentrations are attained at 1.5
hours. After rectal administration, absorption is
slower and plasma concentrations are lower but
more constant. After single oral doses, maximum
plasma concentrations increase from about 6 mgJ

32

28

24
0 Control group Mean = 12.0 ± 3.5 h

II Geriatric group Mean = 17.4 ± 6.8 h

20

s: 16
~
i
~
12
CD
..:::c
fca 8
ca
E
."

~ 4
Subjects

Fig. 3. Plasma antipyrine half-life values in young and old subjects (after O'Malley et aI., 1971, with permission).
Pyrazolone Derivatives 64

Table I. Some pharmacokinetic variables of the pyrazolone derivatives following oral administration

Drug Tmax8 Tv,l Vdc Plasma Protein

(h) (h) (L) clearance binding
(L/h) (%)

Antipyrine 1-2 5-35 '" 40 2.4-3.7 10

Aminopyrine 1.5 2-4 '" 45 '" 11.2 15

Propyphenazone 0.5-1.2 1-2 '" 90 '" 42 '" 10

Dipyrone (for MAAe) 1-1.5d '" 2-4.6 '" 30 "'8 MAAe58

6.9d AA 48

a Time to maximum plasma concentration.

b Elimination half-life.
c Values based on an assumed bodyweight of 70kg.
d Values from total radioactivity measurements after oral administration of a radiolabelled dose
e Netabikutes MAA = methylaminoantipyrine; AA = aminoantipyrine

L to 38 mg/L after doses of 4S0 to 8S0mg respec-
tively. The volume of distribution is similar to that
of antipyrine at about 4SL. In the dose range ISO
to 8S0mg the half-life is between 2 and 3 hours.
Like antipyrine, amidopyrine is fairly evenly dis-
tributed throughout body water and is about 15%
bound to plasma protein.
The biotransformation of aminopyrine results
in the formation ofthe active metabolites 4-amino-
antipyrine and 4-methylaminoantipyrine and two
further main metabolites 4-acetylaminoantipyrine
and 4-formylaminoantipyrine which are probably
not active. The dominant metabolite in urine is 4-
acetylaminoantipyrine, which accounts for 20 to
48% of a dose and 4-formylaminoantipyrine. Only
about 10% is excreted unchanged in the urine. The
half-life is increased in liver disease, but in patients
with uraemia appears similar to that in healthy
subjects.
3.3 Propyphenazone
After a single oral dose of 220mg, peak plasma
concentrations of about 1.5 to 3.S mgfL are at-
tained at between 0.5 and 1.2 hours. Doubling the
dose results in concentrations of 3.5 to 12.S mg/L
(Volz and Kellner, 1980). The volume of distri-
bution is 1.3 to 2 L/kg.
The main metabolic process in the biotrans-
formation of propyphenazone is oxidative
demethylation to form the active metabolite N-
desmethylpropyphenazone. The enol glucuronide
of this is the main metabolite and accounts for
about 80% of the metabolites in the urine. Plasma
protein binding is about 10%.
3.4 Dipyrone
(metamizole, noramidopyrine-methane-
sulphonate)
Results of recent studies support the concept that
following oral administration dipyrone is a 'pro-
drug' hydrolysed in vivo to biologically active me-
tabolites (Rohdewald et aI., 1983; Weithmann and
Alpermann, 1985). However, there are few data on
the bioavailability, distribution, multiple dose ki-
netics and kinetics in renal or hepatic impainnent
of the principal metabolites of dipyrone.
After oral administration of 14C-dipyrone, peak
concentrations of radioactivity occur at 1 to 1.5
hours (Christ et aI., 1973). It was reported by Volz
and Kellner (1980) that dipyrone itself is not de-
tectable in the serum, but that at least 7 metabo-
lites occur, 4 of which are identifiable.
For 4-aminoantipyrine, the peak plasma con-
centrations were higher and occurred later in slow
Pyrazo1one Derivatives
acetylators than in rapid acetylators. On the other
hand, peak concentrations of the inactive meta-
bolite acetylaminoantipyrine were lower in slow
acetylators (Levy, 1984; Levy et aI., 1984). The ac-
tive metabolites 4-methylaminoantipyrine (nor-
aminopyrine, MAA) and 4-aminoantipyrine (AA)
are barely detectable in the serum 24 hours after a
single oral dose, whereas about 50% of the maxi-
mum concentration of 4-acetylaminoantipyrine is
still present at this time.
The saliva concentration of these metabolites
was higher 20 minutes after ingestion of a solution
than after taking tablets of dipyrone and correlated
with onset of analgesia in subjects with experi-
mentaly induced pain (Drehsen et aI., 1984;
Rohdewald et aI., 1983). The extent of protein
binding of 4-methylaminoantipyrine and 4-ami-
noantipyrine is 58 and 48%, respectively (Zylber-
Katz et aI., 1985).
Concentrations of dipyrone in breast milk of
patients with mastitis receiving 1.5g daily were 10
to 20 mgfL. The drug was not detectable in the
urine of infants breastfed by these mothers
(Schrooer et aI., 1983).
The mean elimination half-life of total radio-
activity after oral administration of 14C-dipyrone
was 6.9 hours, when determined over an 8-hour
period. The half-life of the methylamino- and
amino-metabolites was 3.3 and 4.8 hours, respec-
tively. The half-life of dipyrone metabolites is in-
creased late in pregnancy and during labour (Nos-
chel et aI., 1980), and in patients with myxoedema
(Brunk et aI., 1974). No significant changes in the
plasma half-life or in the cumulative urinary ex-
cretion of 4-aminoantipyrine in 2 hyperthyroid
patients were found by Brunk et ai. (1974). The
findings of Eichelbaum (1976) suggest that thyroid
function might have an influence on the N-de-
methylation of dipyrone in man.
Six metabolites of dipyrone are detectable in the
urine after oral administration. The 4 identifiable
metabolites (4-formylaminoantipyrine [FAA],
4-acetyl-aminoantipyrine [AAA], 4-aminoantipyr-
ine [AA] and 4-methylaminoantipyrine [MAA]) are
the same as those in the plasma and account for
65% of the metabolites excreted in the urine over
65
the first 24 hours after ingestion (Volz and Kellner,
1980).
4. Drug Interactions
Several drugs cause nonspecific stimulation of
drug metabolism in animals through induction of
hepatic microsomal enzyme activity. A similar ef-
fect has been demonstrated in man with antipy-
rine, barbiturates, phenytoin (diphenylhydantoin),
rifampicin and other drugs. The administration of
an inducing drug may cause stimulation of its own
metabolism as well as that of other unrelated drugs.
Such induction generally results in reduced drug
effects, although an increased effect will result if
metabolites are more active than the parent drug.
Antipyrine is an inducer of drug metabolising
enzymes and may accelerate the metabolism of such
drugs as oral anticoagulants, phenytoin, barbitu-
rates, methadone and many others. If the dosage
of an oral anticoagulant is increased to maintain
the desired level of effect in a patient receiving an
enzyme-inducing drug, there is a risk of bleeding
if the enzyme inducer is subsequently withdrawn
without concomitant reduction in the dosage of the
anticoagulant. Other important induction interac-
tions which could occur with antipyrine include
failure of oral contraceptive therapy, renal trans-
plant rejection in patients receiving corticosteroids
for immunosuppression, and methadone with-
drawal reactions in patients on methadone main-
tenance (Prescott, 1980).
Antipyrine clearance was significantly reduced
by at least 30% by concomitant propranolol treat-
ment (Bax et aI., 1981; Greenblatt et aI., 1978) and
to a lesser extent by metoproioi. There is no inter-
action between dipyrone and the anticoagulants
phenprocoumon and ethylbiscoumacetate in
healthy Caucasian subjects (Badian et aI., 1984).
Dipyrone appears not to cause any clinically rel-
evant interactions.
5. Clinical Efficacy in Pain
Dipyrone is the only pyrazolone derivative for
which results from a number of recent double-blind
Pyrazolone Derivatives 66

Table II. Analgesic efficacy of the pyrazolone derivatives dipyrone (Dip) and antipyrine (phenazone) [A) in double-blind, placebo-
controlled, representative trials in postoperative pain

Drug Dose (mg) Comparative Duration Population Results References

drug (mg) (no. of patients)

Oral administration
Dipyrone 500 Z 100 SO Postoperative Z> Dip
(various) [90)

Dipyrone 500, 1000 Par 500, 1000 SO Postepisiotomy Dip> Par 2,3
(563)

Dipyrone 500 ASA 500 SO Postepisiotomy Dip> ASA 4

(267) at 5-6 hours

Dipyrone 300 Pe 50 6 doses Postoperative (dental) Dip = Pe 5

[138)

Antipyrine 1000 Placebo 4 days Dental pain A> placebo 6

(24)

Parenteral administration
Dipyrone 2500 (IV) P 50 SO Abdominal and Dip =P 7,8
other surgery

Abbreviations: Z = =
zomepirac; Par paracetamol; ASA = = = =
aspirin; P pethidine; SO single dose; Pe pentazocine.
Reference key: 1 =Barrosa et al. (1982); 2 =
Daftary et al. (1980); 3 =
Gomez-Jimenez et al. (1980); 4 =
Mukherjee and Sood
= = = =
(1980); 5 Paeile and Gallardo (1974); 6 Skjelbred and 10kken (1980); 7 Mehta (1967); 8 Lal et al. (1973).

placebo-controlled trials in pain of varying origin
are available.
Recent studies have compared oral dipyrone
with zomepirac, pentazocine, paracetamol and
aspirin (table II), and intravenous dipyrone with
pethidine in patients with pain resulting from ep-
isiotomy, dental surgery and abdominal or other
surgery. Intravenous dipyrone has been compared
with indomethacin, diclofenac, tramadol or
pethidine in the treatment of ureteral and biliary
colic and pain of other origin.
5.1 Postoperative Pain
moderate to severe intensity is necessary to test the
full analgesic capacity of active drugs mild pain has
been included in some recent studies of dipyrone.
Oral dipyrone has been shown to be a more ef-
fective analgesic than equivalent oral doses of as-
pirin (SOOmg) [fig. 4] or paracetamol (SOO to
lOOOmg) [table II] and indistinguishable from
pethidine SOmg when given intravenously at a dos-
age of 2.Sg. Dipyrone was better tolerated than
pethidine and no respiratory depression occurred.
Antipyrine 1000mg was more effective than pla-
cebo when given over a 4-day period to patients
with pain following dental surgery.

Studies comparing oral dipyrone with other
analgesics in patients with postoperative pain have
in some instances been deficient in some import-
ant aspects of trial design. However, the active drugs
have invariably been more effective than placebo,
thus confirming the sensitivity of the pain model,
despite the use of only one dose level of each active
drug. Although it is generally accepted that pain of
5.2 Ureteral and Biliary Colic
Dipyrone has long been used as an alternative
to morphine in the treatment of ureteral and bili-
ary colic. Early reports noted the rapid and effec-
tive analgesia produced by dipyrone (e.g. Gross-
mann, 1942; Viktorov et aI., 1980) and, more
recently, it has become the standard against which
Pyrazolone Derivatives 67

Table III. Analgesic efficacy of intravenous dipyrone plus pitofenone compared with that of indomethacin. diclofenac or pethidine in
patients with acute ureteral or biliary colic

Drug Number of Relative efficacy (%) References

(dose mg) patients
complete good moderate

Ureteral colic
Dipyrone 2500· 169 44 44 Lehtonen et al. (1983)
Indomethacin 50 59 35
Pethidine 50 52 42

Dipyrone 1000· 75 42 b Comeri et al. (1984)

Indomethacin 50 79
Diclofenac 75 74

Biliary colic
Dipyrone 2500· 60 33 54 Niinikoski et al. (1984)
Indomethacin 50 27 60

Dipyrone 2500· 50 52 Rejman (1984)

Indomethacin 50 52

a Dipyrone was administered as a combination product containing the antispasmodic drug pitofenon.
b Dipyrone was less effective than the other 2 drugs (p < 0.02).

50mg or diclofenac 75mg administered by the same

route.
3
~ 6. Side Effects
8
rJ)

2
6.1 Skin Reactions
l
ec
as
CI)
The most frequently reported side effects asso-
::E ciated with the use of the pyrazolone derivatives
have been skin rashes and fixed drug eruptions. A
report from the Boston Collaborative Drug Sur-
2 3 4 5 6
Hours after administration
veillance Program (1973) indicated that the esti-
mated risk of skin rashes attributable to dipyrone
Fig. 4. Analgesic efficacy of single doses of dipyrone 500mg was 2.4%, but dipyrone was identified as the cause
(____). aspirin 500mg (e--e) and placebo (t.-t.) in 267 of rash in only 4 of the 467 patients (0.8%). A later
patients with postepisiotomy pain (after Mukherjee and Sood. report from the Boston group (Arndt and Jick,
1980); • indicates significantly greater pain relief with dipyrone
1976) indicated that allergic skin reactions oc-
than with aspirin.
curred in about 11 of 1000 recipients of dipyrone,
compared with 36 per 1000 of those treated with
other drugs have been compared. In recent studies semisynthetic penicillins. Skin reactions to dipy-
in which dipyrone 2500mg plus pitofenone intra- rone usually appear within the first 7 days of drug
venously has been compared with indomethacin administration and may at times be severe. The
(fig. 5) and diclofenac (table III), similar efficacy causative relationship between intake of pyrazo-
was demonstrated. Dipyrone 1000mg plus pitofen- lones and skin reactions remains obscure in some
one was less effective than either indomethacin patients because of negative tests with the impli-
Pyrazolone Derivatives 68

blood dyscrasias. Cross-sensitivity between dipy-

rone and aminopyrine was demonstrated in man
in 1937, an association which may have led to an
assumption that. the risk of agranulocytosis was
similar for all pyrazolones and which may have
80
contributed to the withdrawal of these drugs from
the market in some countries. The true incidence
70 of the immunologically determined haematological
reaction to dipyrone has recently been investigated
60
Ql in a case-controlled study. The results confirm the
'"<:
0 50 long-held belief that the early reported incidence
a.
'"!!? of pyrazolone-induced agranulocytosis, noted by
Ql
0> Discombe (1952), lacks validity. These results are
!!!
<:
Ql
discussed by Miescher and Pola elsewhere in this
~ publication (p. 90).
Ql
Q.

Dipyrone Indomethacin
Fig. 5. Composite time-effect curve from 2 separate clinical
studies comparing aspirin 650mg with placebo, and paraceta-
mol 650mg with placebo in patients with pain following oral sur-
gery (from Cooper, 1981, with permission).
cated drugs, or concomitant administration of other
drugs (Gebel and Hornstein, 1984). Toxic epi-
dermal necrolysis, exfoliative dermatitis, Stevens-
Johnson syndrome and acute anaphylactic shock
have all been reported with the pyrazolone deriv-
atives. A distinct group of patients develop ana-
phylactic shock or urticaria after administration of
pyrazolone drugs but can tolerate aspirin and other
cyclo-oxygenase inhibitors (Czerniaw8ka-Mysik and
Szczeklik, 1981).
6.2 Gastrointestinal Toxicity
Gastrointestinal toxicity seldom occurs during
administration of antipyrine and is infrequent with
other pyrazolone derivatives, including dipyrone.
6.3 Haematological Reactions
Aminopyrine, in usual therapeutic doses, has
been associated with many documented cases of
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pyretic drug efficacy. Current Therapeutic Research 37: 440-
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Badian, M.; Le Normand, Y.; Rupp, W. and Zapf, R.: There is
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Barroso, M.H.; Carranza, J.A.V.; Garcia, J.L.G. and Rodriguez,
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Bax, N.D.S.; Lennard, M.S. and Tucker, G.T.: Inhibition of anti-
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Author's address: Rex N. Brogden, ADIS Press Limited, Cento-
rian Drive, Private Bag, Mairangi Bay, Auckland 10 (New Zea-
land).