Dimethyl Sulfoxide (DMSO)

by D. C. Pope and W. T. Oliver*

The role of DMSO for the treatment of SO reaches the taste buds in this species
various disorders of man and animals has as well as man (5) ; reports of extreme
received considerable attention in both lay lethargy in man following topical applica-
and professional publications. A variety tion (6) suggest the possibility of its trans-
of pharmacological claims have been des- port across the blood-brain barrier. In the
cribed for the drug including analgesic, cat, the drug is reduced to dimethylsulfide
anti-inflammatory agent, bacteriostat, diu- and the breath of this species (7) and the
retic, penetrant-carrier and tranquilizer dog (8) acquires a characteristic odour af-
activity (1, 2). This review is intended to ter topical application. An alternative me-
provide some information to practitioners tabolic fate, that of conversion to a sulfone,
regarding the pharmacology and present has been proposed by Block (9).
clinical status of this drug.
Pharmacological Actions
Properties Early reports (1, 2) dealing with the
0 pharmacotherapeutic uses of dimethylsul-
foxide described seven basic pharmacolo-
CH3-S-CH3 gical actions: 1) anti-inflammatory activi-
DMSO is a clear, colourless to yellowish ty against baker's yeast granuloma, 2) bac-
liquid with a characteristic bitter odour teriostatic activity in 20% solutions against
and taste. It is soluble in water, ethanol, E. coli, Pseudomonas and S. aureus, 3) diu-
acetone, diethyl ether, benzene and chloro- retic activity in dogs in which a transient
form and is a good solvent for unsaturated, two-fold increase in urine excretion occur-
nitrogen-containing and aromatic com- red after intravenous administration, 4)
pounds; saturated aliphatics are essential- local analgesia in which conduction was
ly insoluble in it. DMSO should not be used blocked in treated, isolated nerves but which
with strong oxidizing or reducing agents, returned when the treated nerve was
and because of its hygroscopic property, washed free of DMSO, 5) penetrant-car-
should be kept in sealed containers. rier with enhanced absorption of amino-
phylline, Evans Blue, heparin, insulin, so-
Metabolism dium salicylate and sulfadiazine through
Little has been published on the metabo- the intact urinary bladder, 6) potentiation
lism of DMSO. It is readily absorbed per- of insulin in the dog, 7) tranquilizer when
cutaneously and orally and, in view of its topically applied.
tissue penetrability (3, 4), is probably wid- With respect to the intact animal, the
ely distributed throughout the body. In intravenous injection of 50 per cent DMSO
this regard, the clinical behaviour of some in doses up to one g/kg did not alter the
horses indicates that topically-applied DM- ECG of anesthetized dogs or monkeys (10).
However, studies using the cat have shown
that when sufficiently high doses were ad-
*Division of Veterinary Medicine, Food and Drug ministered to this species, DMSO produced
Directorate, Department of National Health and Welfare,
Ottawa, Canada. changes in the nervous, cardiovascular and
Vol. 30 January, 1966 3
respiratory systems (11). At higher doses
DMSO interfered with ganglionic and myo-
neural transmissions; apnea, hypotension
and bradycardia were seen in cats follow-
ing intravenous injection of 200 mg/kg,
effects which were significantly attenuat-
ed by atropine. Fluid concentrations of 12
to 15 per cent did not affect the capacity of
perfused cardiac muscle to contract and
concentrations up to 30 per cent caused
only minimal changes in capillary and me-
sentric circulation of a rodent species (12).
Hypothermia was produced in mice by in-
traperitoneal administration of 4.5 gm/kg
(13).
Early studies using DMSO showed that it
altered the natural selectivity of plant mem-
branes (14). This property was then inves-
tigated in animals using intact urinary
bladders of anesthetized dogs and it was re-
ported that the permeability of this mem-
brane to five chemicals was increased (1).
The results of subsequent studies (10, 15,
16, 17) using a variety of drugs have been
considerably less encouraging. The results
of these investigations have shown that
DMSO when pre-administered orally or pa-
renterally, does not greatly alter either
the rate of absorption or the penetrability
of the majority of drugs tested to date,
although the cutaneous absorption of some
drugs is increased when incorporated in
concentrated solutions of DMSO (4, 31).
The mechanism by which DMSO in-
creases membrane permeability is unknown.
Its unique solvation properties have been
reported (18) and Jacob et al (3) have
listed properties which, in their view, could
bear on the "carrier mechanism". These
include: 1) its exceptional ionizing powers
with solutions of organic or inorganic com-
pounds; 2) complexing of organic com-
pounds in DMSO, evinced as spectral
shifts; 3) its ability to form complexes
with metal salts. Block (9) questions
that the first of these two properties would
increase penetration through a biological
membrane, and advances as other possible
explanations: 1) its solvency towards lipoi-
dal and non-lipoidal material; 2) its ability
to chelate metals; 3) its semi-polar na-
ture and small molecular size; 4) its hy-
groscopic nature; 5) its heat of dissolution.
As has been observed (9), the removal
of calcium from biological membranes in-
creases membrane permeability (27). Thus,
if DMSO is able to form calcium or other
metallic chelates in the membrane, it may
explain, in part, its ability to influence cell
4 Can. J. Comp. Med. Vet. Sci.
membrane permeability.
Clinical effects
Because of the present paucity of re-
ports in the veterinary literature, a sum-
mary of the clinical effects of the drug
in man will be included to give some mea-
sure of its possible therapeutic spectrum in
other mammalian species.
a) Muscvloskeletal disorders
It is a common experience with new
drugs that the results of later clinical stu-
dies are usually less enthusiastic than ear-
ly reports, and DMSO appears to be follow-
ing this pattern. However, on the basis of
clinical reports, DMSO appears to have a
useful role in the treatment of certain mus-
culoskeletal injuries and inflammation in
man. "Unequivocal improvement" has been
reported (6) in 437 of 548 patients with
disorders such as musculoskeletal trauma,
subacromial bursitis, ostheo-arthritis, rheu-
matoid and goutry arthritis. The improve-
ment obtained by the topical administra-
tion of DMSO varied with both the disease
and its severity. Thus, greater improve-
ment was observed in the number of pa-
tients suffering from acute musculoskeletal
trauma 93%, than rheumatoid arthritis
(75 % ); with respect to the severity of the
disease, the investigators found 75% of
the patients improved in rheumatoid arth-
ritis grades 1 or 2, as opposed to 43% with
grades 3 or 5. There was a 25 per cent
reduction in calcium in patients with chro-
nic bursitis and early calcification. The
site of the condition also influences the
response, thus whereas subcutaneous ede-
ma and periarticular swellings were re-
duced following topical application, swel-
lings due to intra-articular and intrabur-
sal effusions were unaffected (19). In
acute cases of some musculoskeletal disor-
ders, pain relief and an increased joint mo-
bility was obtained within 30 minutes and
lasted from two to twelve hours. In chronic
cases, relief of symptoms required up to
three months of twice daily treatment (6).
For use in the treatment of musculoske-
letal disorders the drug was measured into
a medicine glass and applied by swab onto
intact, clean skin after removing oil and
sweat. Adequate dosage in man was de-
fined as 60 to 90 per cent solutions of DM-
SO applied in volumes of 6 to 8 ml over
the knee, 8 to 15 ml over the shoulder and
10 to 15 ml over the hip. This was obtained
by reapplication over several minutes using
a swab. Treatment was individualized but to respond to conventional therapy. In these
usually 30 ml/day was used (6); chronic cases, up to 30 ml of 90% DMSO was used
cases were treated twice daily and acute daily in divided doses for several months.
cases as often as every 4 hours. Bottomly These authors were unable to specify the
et al (19) concluded that the pain relief basis for the pain relief which was ob-
obtained using DMSO for the treatment of tained.
connective tissue diseases was comparable The relief of pain in cases of acute in-
to that obtained using methylsalicylate. In juries has been reported to occur within
the opinion of these clinical investigators, 30 minutes and last from 2 to 12 hours;
DMSO will not gain precedence over cur- chronic pain, however, required prolonged
rent therapeutic measures used in the treat- therapy, for example, patients suffering
ment of chronic rheumatoid arthritis and chronic subacromial bursitis required con-
osteoarthritis (19). tinuous treatment twice daily for three
The absorption of saline wheals was pro- months before symptoms disappeared (24).
moted by 90 per cent solutions of DMSO
(31); however, its value in the treatment c) Viral infections
of other localized edematous states, for Significant clinical improvement was re-
example post-surgical edema, has not been ported (25) in seven patients with severe
reported. large herpes simplex treated with idoxur-
Reports on the use of DMSO in veteri- idine in 90% DMSO. All patients were
nary medicine are characterized by the treated four times daily within 48 hours
lack of controlled studies and specific des- after the onset of the lesions. In view of
criptions; for example, a mixture of nitro- the results obtained, the authors consider
furazone, neomycin, aqueous kymar and that additional studies of anti-viral chemo-
soluble steroid combined with DMSO was therapeutic agents in DMSO is warranted.
recommended as a topical treatment for These investigators pointed out, however,
pharyngitis (20). DMSO applied topically the possibility that systemic toxicity may
was reported to have "promoted" the re- develop if solutions containing antimetabo-
duction of swollen tendons in a horse (21) lites are applied over large areas.
and improvement was observed when a
"DMSO preparation" was applied to a dis- d) Skin diseases and wound healting
located sacroiliac articulation (22). No re- improvement was reported (6,
sults were obtained using DMSO for the 26)Clinical in patients with scleroderma. The ini-
treatment of bog spavin (23). tial 50% concentration of DMSO was in-
b) Pain relief creased to 100% over one to three weeks
and when ulcers were present, the direct
The evaluation of DMSO as an analgesic application of 90% DMSO effected com-
per se is not easily separated from its abili- plete cure in two to six weeks. These in-
ty to relieve pain by improving the patholo- vestigators found that the concentrations
gical state of the disease. Although the of DMSO must be individualized both to the
compound can block conduction in isolated patient and the area of the body (26).
nerves (1, 2), Dixon et al (10) were un- Histopathological studies showed that DM-
able to demonstrate analgesic action or to SO caused a destruction and removal of
produce either spinal blockade or local an- collagen in the skin of these patients,
aesthesic activity by corneal anesthesia though it has not been determined whether
tests using rabbits and rats. the drug destroys collagen directly or ini-
The failure to produce local anaesthesia tiates its destruction by increasing cellular
or analgesia in the intact animal may re- permeability thus permitting the release
flect the problem under clinical conditions of increased quantities of proteolytic en-
of achieving the necessary DMSO concen- zymes (26).
tration (>25%) to effect nerve block (2). DMSO has also been used successfully as
On the basis of the results of a series of a solvent for antifungal drugs in the treat-
clinical trials, Rosembaum et at (24) re- ment of ringworm (31); wider study will
ported that DMSO produced marked pain be required to adequately assess its value
relief in cases of post-amputation phantom in the treatment of these and other fungal
pain, tic douloureux, post-traumatic and diseases.
post-operative intractable pain, all of at The rate of healing of experimental ther-
least one year's duration, which had failed mal and ultraviolet burns in laboratory ani-
Vol. 30 - January, 1966 5
mals was neither hindered nor improved by
the topical application of 90% solutions of
DMSO in one control study. This investi-
gation did not include the effects of the
drug in cases of infected burns (31).
e) Penetrant-carrier
Reports to date indicate that although
DMSO increases membrane permeability,
the inclusion of DMSO as a solvent does
not guarantee the increased absorption of
drugs following either oral or parenteral
administration. Jacob et al (1, 3) reported
increased absorption from the urinary
bladder in the case of five drugs, including
sodium sulfadiazine and heparin sodium
dissolved in DMSO. However, Ben et al
(15) were unable to detect any effect on
the rate of absorption or the actions of
eight compounds including morphine and
chlorpromazine when dissolved in DMSO
and administered orally or intravenously.
Similarly, Dixon et al (10) were unable
to show that DMSO increased the rate of
oral or intravenous absorption of eleven
compounds including benzylpenicillin and
pentobarbital. The solvent did not alter the
induction time of phenobarbital sodium and
pretreatment with DMSO failed to alter
hexobarbital sleeping time (4). These in-
vestigators concluded that DMSO is an
effective solvent of low toxicity but there
was no evidence that it altered oral absorp-
tion or that when administered systemi-
cally it increased drug penetrability. It was
considered not unreasonable to assume that
increased absorption follows the topical ap-
plication of a drug dissolved in undiluted
DMSO, which conclusion was supported by
Kligman's report that solutions of DMSO
at and greater than 70 %, increased the
cutaneous penetration of various dyes and
steroids (31).
Thus the nature of the solute, the site of
administration, as well as concentration of
both solvent and solute all appear to con-
tribute to the role of DMSO as a penetrant-
carrier.
Toxicity
a) Local administration
DMSO has been used in man for as long
as 10 months without evidence of serious
toxicity (26); however, topical application
of small quantities to some patients can
produce local irritation as well as systemic
effects. Erythema and vesication have been
6 Can. J. Comp. Med. Vet. Sci.
reported (26, 28) and repeated application
has produced dryness and flakiness of the
skin (22). Quite severe skin irritation and
maceration have been observed in DMSO-
treated areas of patients with chronic rheu-
matoid or osteoarthritis (11). The systemic
effects due to absorption following topical
application include lethargy (6), reduction
of circulating platelets, increases of indi-
rect bilirubin, alkaline phosphatase, blood
urea nitrogen, SGOT and SGPT levels (28).
The recently reported death of a woman,
possibly due to hypersensitivity, following
topical therapy (29) may be taken by the
veterinarian as a reminder of the possibil-
ity of similar sequelae in other mamma-
lian species.
b) Systemic administration
DMSO has a low order of toxicity in la-
boratory animals (8, 11, 16, 30); for exam-
ple, the oral LD5,, in mice and rats has been
reported to be 21.4 and 28.3 gm/kg respec-
tively; the intravenous LD50 to be 5.75 and
5.36 gm/kg respectively (8). In dogs the
intravenous administration of 1.2 gm/kg/
day for 24 days caused no deaths, although
hematuria and hemoglobinuria were ob-
served (8). Repeated injections of undilut-
ed DMSO caused perivascular inflamma-
tion, intravascular thrombosis and gradual
occlusion of the infused veins. However, on-
ly minimal reaction occurred with repeated
injections of from 10 to 25 per cent solu-
tions. Repeated intraperitoneal injections
of the undiluted DMSO produced local re-
actions and a reversible anemia was ob-
served at the highest dose level (8 gm/kg/
day). Cloudy swelling and granularity of
the parenchymal cytoplasm of the liver was
noted in all dose levels (8).
Cats appear to be somewhat less tolerant
of DMSO than other species (11). The in-
travenous LD50 of single doses is reported
to be from 400 to 800 mg/kg. Single intra-
venous doses of 200 mg/kg produced apnea
which, at times, was severe; however, in-
traperitoneal administration of doses as
high as 400 mg/kg did not cause this ef-
fect. Repeated intravenous administration
of 200 mg/kg led to a gradual lowering of
blood pressure and death occurred at about
4 gm/kg.
Hemolytic anemia was observed in this
species following the intravenous adminis-
tration of pure, undiluted DMSO but this
effect was markedly reduced when the drug
was diluted 4 or 8 fold with isotonic saline.
Deep red "colourization" of the urine after
DMSO administration was due to the ex-
cretion of hemoglobin and methemoglobin
(11).
Although the results of a standard test-
ing method gave no evidence that DMSO
had any toxic affect on the eye, it has been
reported recently that the topical or oral
use of from 1 to 40 ml/kg of undiluted DM-
SO daily for several weeks will produce
changes in the refractive index of the lens
of the eye of rabbits, swine and dogs, which
changes appeared dose-related (32).
Summary
From a review of the clinical evidence
presently available, it appears that DMSO
may have a limited role in the treatment of
some musculoskeletal diseases. The success
of therapy varied with the disease, its
stage, site and also the therapeutic regime,
clinical reports of its use in humans indi-
cating that early treatment offers the best
chance to effect an improvement, the suc-
cessful use of the drug requiring measured
and frequent application. There is nothing
in any of the clinical literature to date
which indicates that the indiscriminate use
of DMSO can be expected to improve even
those conditions in which it has been re-
ported to be most effective; for example,
acute trauma and bursitis.
DMSO appears to be useful in the relief
of some types of post-surgical and post-
traumatic pain and pain, particularly of
superficial and moderate degree, arising
from certain musculoskeletal diseases. Cli-
nical evidence shows that pain relief in
these conditions usually depends upon re-
peated and careful administration. There
is little pharmacological evidence that DM-
SO has any reliable primary activity as
either a local anaesthetic or analgesic.
On the basis of limited trials, the drug
appears to offer promise for the treatment
of sclerodermatous conditions. Some care
should be exercised in the treatment of
cases of these conditions in which large
areas are involved both because systemic
effects are readily produced by topical ap-
plication and also because of the different
sensitivities of various parts of the body.
Its value as a solvent and carrier for
anti-viral therapeutic agents is being in-
vestigated. In the one condition in which it
has proven successful, herpes simplex, suc-
cessful therapy required early treatment
and frequent applications. It appears to be
Vol. 30 - January, 1966
a useful vehicle for antifungal agents in
the treatment of ringworm; it had no ef-
fect on the rate of healing of non-infected
burns.
The use of DMSO as a penetrant-carrier
to increase penetrability of drugs appears
to depend upon the physico-chemical nature
of the solutes. It would be presumptuous
to hope the empiric incorporation of DMSO
as a solvent will necessarily serve to en-
hance drug penetrability; nor is there evi-
dence to show that the parental administra-
tion of DMSO in any way alters the pene-
trability or pharmacological actions of ma-
ny drugs.
A more complete assessment of the
clinical value of DMSO in veterinary med-
icine will depend upon objective clinical
trials. Until then, its therapeutic value in
veterinary medicine is uncertain despite
its unique properties as a solvent.
REFEREN CES
1. JACOB, S. W., BISCHEL, M., HERSCHLER. R. J.
Dimethyl Sulfoxide (DMSO): A new concept in
pharmacotherapy. Current Therap. Res. 6: 134-135.
1964.
2. ROSENBAUM, W. M., ROSENBAUM, E. E., JA-
COB, S. W. The use of Dimethyl Sulfoxide for the
treatment of intractable pain in surgical patients.
Surgery 58: 258-266. 1965.
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Dimethyl Sulfoxide: effects on the permeability of
biological membranes (preliminary report). Current
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K. A toxicologic study of Dimethyl Sulfoxide. Tox-
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465. 1964.
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D. P. Apparent lack of interaction between Dime-
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11. DISTEFANO, U., KLAHN, J. J. Observations on
the pharmacology and hemolytic activity of Dime-
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12. SMITH, A. U. Effects of glycerol and dimethyl sul-
foxide on the capillary circulation of the golden
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Dimethyl Sulfoxide: Effects on the permeability
of biologic membranes (Preliminary Report) Cur-
rent Therap. Res. 6: 193-198. 1964.
15. BEN, M., DIXON, R. L., ADAMSON, R. H., FINE-
7
 MAN, H., RALL D. P. Toxicity of various drugs
using Dimethyl Sulfoxide (DMSO) as a solvent. The
Pharmacologist 6: 189. 1964.
16. ROSENKRATZ, H., HADIDIAN, Z., SEAY, H. and
MASON, M. M. Dimethyl Sulfoxide: Its steroid solu-
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17. HORITA, A. and WEBER, L. J. Skin penetrating
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18. PARKER, A. J. The effects of solvation on the
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MAN, D. M. Controlled study of Dimethyl Sulfoxide
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Arthritis Rheum. 7: 294. 1964.
20. BURCH, J. E. Panel on practice tips. J.A.V.M.A.
146: 267-268. 1965.
21. TEIGLAND, M. B. Panel on practice tips. J.A.V.M.
A. 146: 268. 1965.
22. KOGER, L. M. Cows with sacro-iliae luxation treat-
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of DMSO. Comments. Modern Veterinary Practice
36-37 (1965) August.
24. ROSENBAUM, W. M., ROSENBAUM, E. E. and
Acute Aspergillosis in Chicken Under Conditions of Intensive Poultry
Raising
Postmortem examinations of 58.137 car-
casses of poultry, performed in the course of
4 years at 7 farms, served to establish that
aspergillosis accounted for 14.4 per cent of
the total number of cases. Acute aspergillosis
in its epizootic form broke out in chicks aged
two days or more. A. fumigatus was isolated
from the carcasses, the litter in the chicken
house, the stored litter and the air in the in-
cubators.
A decisive role in the occurrence and spread
of acute aspergillosis in chickens was played
by increased humidity in the air and the litter
at a certain temperature level in the chicken
house. In addition to the macroclimate the oc-
currence of aspergillosis in chickens was fur-
The Effect of Various Coccidiostats on Chicks Experimentally Infected
with Eimeria Tenella
The effect of various coccidiostats on chicks,
artificially infected with Eimeria tenella was
tested and the degree of immunity of the
treated birds to reinfection was examined. The
coccidiostats tested under the conditions de-
scribed, could be classified in the following
order of efficacy (beginning with the most ef-
fective): 1) Amprolium, 2) Nicarbazine,
Darvisul, 3) Unistat, Zoalene, 4) sulphaqui-
8 Can. J. Comp. Med. Vet. Sci.
JACOB, S. W. The use of Dimethyl Sulfoxide (DM-
SO) for the treatment of intractible pain in sur-
gical patients. Surgery 58: 258-266. 1965.
25. GOLDMAN, L. and KITZMILLER, K. W. Topical
5-iodo-2'-deoxyuridine in Dimethyl Sulfoxide (DM-
SO); a new treatment for herpes simplex. Ohio
Med. J. 61: 532-533. 1965.
26. SCHERBEL, A. L., McCORMACK, L. J. and POP-
PO, M. J. Alteration of collagen in generalized
scleroderma (progressive systemic sclerosis). Cleve-
land Clin. Quart. 32: 47-56. 1965.
27. LEVINE, R. R. and PELLIKAN, E. W. Mechanisms
of drug absorption and excretion. An. Rev. Phar-
macol. 4: 69-84. 1964.
28. BACHMAN, D. R., BOTTOMLY, D. R. and SCHI-
MIZAKI, Y. Additional observations of Dimethyl Sul-
foxide effects in patients with connective tissue dis-
eases. Arthritis Rheum. 7: 725. 1964.
29. The Medical Letter on Drugs and Therapeutics 7:
80. 1965. A further warning on DMSO.
30. BROWN, V. K., ROBINSON, J. and STEVENSON,
D. E. A note on the toxicity and solvent properties
of Dimethyl Sulfoxide. J. Pharm. Pharmacol. 15:
688-692. 1963.
31. KLIGMAN, A. M. Topical Pharmacology and Toxic-
ology of Dimethyl Sulfoxide, Part I. J.A.M.A. 193:
796-804, 1965; Part II, 193: 923-98. 1965.
32. BROWN, T. A. Personal Communication, November
1965.
thered by unfavourable relations of tempera-
ture and humidity resulting from inadequate
thermoisolation, ventilation and heating of the
poultry house. Because of the low tempera-
tures no acute aspergillosis occurred in the
winter months. The highest incidence of asper-
gillosis was found to be in spring and autumn,
i.e. in correlation with the highest level of
humidity in the air and the litter of the poul-
try house in that period.
Inadequate disinfection of the incubators
also played a considerable role in the spread
of aspergillosis.
Asaj A., Hajsig M., Kralj M., Marzan B.
Veterinarski Arhiv XXXV 76-83, 1965.
noxaline and 5) nitrofurazone.
Amprolium administered therapeutically to
chicks artificially infected with E. tenella was
found to be effective when given on three con-
secutive days, on condition that treatment was
started not later than 24 hours after infec-
tion.
Samberg Y., Kohane J. Refuah Vete-
rinarith 21: 246-248, 1964.