Dimethyl Sulfoxide (DMSO)

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

The role of DMSO for the treatment of various disorders of man and animals has received considerable attention in both lay and professional publications. A variety of pharmacological claims have been described for the drug including analgesic, anti-inflammatory agent, bacteriostat, diuretic, penetrant-carrier and tranquilizer activity (1, 2). This review is intended to provide some information to practitioners regarding the pharmacology and present clinical status of this drug.
SO reaches the taste buds in this species (5) ; reports of extreme

as well as man lethargy in man

tion (6) suggest the possibility of its transport across the blood-brain barrier. In the cat, the drug is reduced to dimethylsulfide and the breath of this species (7) and the dog (8) acquires a characteristic odour after topical application. An alternative metabolic fate, that of conversion to a sulfone, has been proposed by Block (9).

following topical applica-

Early reports (1, 2) dealing with the pharmacotherapeutic uses of dimethylsulfoxide described seven basic pharmacoloCH3-S-CH3 gical actions: 1) anti-inflammatory activiDMSO is a clear, colourless to yellowish ty against baker's yeast granuloma, 2) bacliquid 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) diuacetone, 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 occurnitrogen-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-carrier with enhanced absorption of aminoshould be kept in sealed containers. phylline, Evans Blue, heparin, insulin, soMetabolism dium salicylate and sulfadiazine through the intact urinary bladder, 6) potentiation Little has been published on the metabolism 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. With respect to the intact animal, the tissue penetrability (3, 4), is probably widely 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
0

Properties

Pharmacological Actions

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respiratory systems (11). At higher doses DMSO interfered with ganglionic and myoneural transmissions; apnea, hypotension and bradycardia were seen in cats following intravenous injection of 200 mg/kg, effects which were significantly attenuated 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 mesentric circulation of a rodent species (12). Hypothermia was produced in mice by intraperitoneal administration of 4.5 gm/kg (13). Early studies using DMSO showed that it altered the natural selectivity of plant membranes (14). This property was then investigated in animals using intact urinary bladders of anesthetized dogs and it was reported that the permeability of this membrane 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 parenterally, 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 increases 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 compounds; 2) complexing of organic compounds 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 lipoidal and non-lipoidal material; 2) its ability to chelate metals; 3) its semi-polar nature and small molecular size; 4) its hygroscopic nature; 5) its heat of dissolution. As has been observed (9), the removal of calcium from biological membranes increases 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

membrane permeability.

Clinical effects
Because of the present paucity of reports in the veterinary literature, a summary of the clinical effects of the drug in man will be included to give some measure 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 studies are usually less enthusiastic than early reports, and DMSO appears to be following this pattern. However, on the basis of clinical reports, DMSO appears to have a useful role in the treatment of certain musculoskeletal 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, rheumatoid and goutry arthritis. The improvement obtained by the topical administration of DMSO varied with both the disease and its severity. Thus, greater improvement was observed in the number of patients 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 arthritis 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 chronic bursitis and early calcification. The site of the condition also influences the response, thus whereas subcutaneous edema and periarticular swellings were reduced following topical application, swellings due to intra-articular and intrabursal effusions were unaffected (19). In acute cases of some musculoskeletal disorders, pain relief and an increased joint mobility 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 musculoskeletal 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 defined as 60 to 90 per cent solutions of DMSO 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

Can. J. Comp. Med. Vet. Sci.

a swab. Treatment was individualized but usually 30 ml/day was used (6); chronic cases were treated twice daily and acute cases as often as every 4 hours. Bottomly et al (19) concluded that the pain relief obtained using DMSO for the treatment of connective tissue diseases was comparable to that obtained using methylsalicylate. In the opinion of these clinical investigators, DMSO will not gain precedence over current therapeutic measures used in the treatment of chronic rheumatoid arthritis and

osteoarthritis (19). The absorption of saline wheals was promoted 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 reexample post-surgical edema, has not been ported (25) in seven patients with severe reported. large herpes simplex treated with idoxurReports 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 chemosoluble 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 antimetaboduction 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 reClinical improvement was reported (6, sults were obtained using DMSO for the 26) in patients with scleroderma. The initreatment of bog spavin (23). tial 50% concentration of DMSO was increased to 100% over one to three weeks b) Pain relief and when ulcers were present, the direct The evaluation of DMSO as an analgesic application of 90% DMSO effected comper se is not easily separated from its abili- plete cure in two to six weeks. These inty 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 DMable 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 iniThe 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 enof 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 treatclinical 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. The rate of healing of experimental therpost-operative intractable pain, all of at least one year's duration, which had failed mal and ultraviolet burns in laboratory ani-

to respond to conventional therapy. In these cases, up to 30 ml of 90% DMSO was used daily in divided doses for several months. These authors were unable to specify the basis for the pain relief which was obtained. The relief of pain in cases of acute injuries has been reported to occur within 30 minutes and last from 2 to 12 hours; chronic pain, however, required prolonged therapy, for example, patients suffering chronic subacromial bursitis required continuous treatment twice daily for three months before symptoms disappeared (24).

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mals was neither hindered nor improved by the topical application of 90% solutions of DMSO in one control study. This investigation 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 investigators concluded that DMSO is an effective solvent of low toxicity but there was no evidence that it altered oral absorption or that when administered systemically it increased drug penetrability. It was considered not unreasonable to assume that increased absorption follows the topical application 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 contribute to the role of DMSO as a penetrantcarrier.

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

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 DMSOtreated areas of patients with chronic rheumatoid or osteoarthritis (11). The systemic effects due to absorption following topical application include lethargy (6), reduction of circulating platelets, increases of indirect 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 possibility of similar sequelae in other mammalian species. b) Systemic administration DMSO has a low order of toxicity in laboratory animals (8, 11, 16, 30); for example, the oral LD5,, in mice and rats has been reported to be 21.4 and 28.3 gm/kg respectively; 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 observed (8). Repeated injections of undiluted DMSO caused perivascular inflammation, intravascular thrombosis and gradual occlusion of the infused veins. However, only minimal reaction occurred with repeated injections of from 10 to 25 per cent solutions. Repeated intraperitoneal injections of the undiluted DMSO produced local reactions and a reversible anemia was observed 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 intravenous LD50 of single doses is reported to be from 400 to 800 mg/kg. Single intravenous doses of 200 mg/kg produced apnea which, at times, was severe; however, intraperitoneal administration of doses as high as 400 mg/kg did not cause this effect. 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 administration of pure, undiluted DMSO but this effect was markedly reduced when the drug was diluted 4 or 8 fold with isotonic saline.

Can. J. Comp. Med. Vet. Sci.

Deep red "colourization" of the urine after DMSO administration was due to the excretion of hemoglobin and methemoglobin (11). Although the results of a standard testing 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 DMSO 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 indicating that early treatment offers the best chance to effect an improvement, the successful 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 reported 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 posttraumatic pain and pain, particularly of superficial and moderate degree, arising from certain musculoskeletal diseases. Clinical evidence shows that pain relief in these conditions usually depends upon repeated and careful administration. There is little pharmacological evidence that DMSO 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 application 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 investigated. In the one condition in which it has proven successful, herpes simplex, successful therapy required early treatment and frequent applications. It appears to be

a useful vehicle for antifungal agents in the treatment of ringworm; it had no effect 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 enhance drug penetrability; nor is there evidence to show that the parental administration of DMSO in any way alters the penetrability or pharmacological actions of many drugs. A more complete assessment of the clinical value of DMSO in veterinary medicine 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., JACOB, S. W. The use of Dimethyl Sulfoxide for the treatment of intractable pain in surgical patients. Surgery 58: 258-266. 1965. 3. JACOB, S. W., BISCHEL, M., HERSCHLER, R. J. Dimethyl Sulfoxide: effects on the permeability of biological membranes (preliminary report). Current Therap. Res. 6: 193-198. 1964. 4. STOUGHTON, R. B., FRITCH, W. Influences of Dimethyl Sulfoxide (DMSO) on human percutaneous absorption. Arch. Derm. 90: 512-517. 1964. 5. The Medical Letter on Drugs and Therapeutics. 7: 42-44. 1965. Dimethyl Sulfoxide (DMSO). 6. ROSENBAUM, E. E., HERSCHLER, R. J., JACOB, S. W. Dimethyl Sulfoxide in musculoskeletal diseases. J.A.M.A. 192: 309-313. 1965. 7. DISTEFANO, U., BORGSTEDT, H. H. Reduction of Dimethyl Sulfoxide to Dimethyl Sulfide in the cat. Science 144: 1137-1138. 1964. 8. WILLSON, J. E., BROWN, D. E., TIMMENS, E. K. A toxicologic study of Dimethyl Sulfoxide. Toxicol. Appl. Pharm. 7: 104-112. 1965. 9. BLOCK, L. H. DMSO: Medicinal and Pharmaceutical Aspects. Drug and Cosmetic Industr. 95: 342465. 1964. 10. DIXON, R. L., ADAMSON, R. H., BEN, M., RALL, D. P. Apparent lack of interaction between Dimethyl Sulfoxide (DMSO) and a variety of drugs. Proc. Soc. Exp. Biol. Med. 118: 756-759. 1965. 11. DISTEFANO, U., KLAHN, J. J. Observations on the pharmacology and hemolytic activity of Dimethyl Sulfoxide. Toxic Appl. Pharmacol. 7: 660-666. 1965. 12. SMITH, A. U. Effects of glycerol and dimethyl sulfoxide on the capillary circulation of the golden hamster and on the isolated heart. Blood 19: 519. 1962. 13. ASHWOOD, SMITH, M. J. The radioprotective action of Dimethyl Sulfoxide and various other Bulfoxides. Intern. J. Radiation Biol. 3: 41-48. 1961. 14. JACOB, S. W., BISCHEL, M., HERSCHLER, R. J. Dimethyl Sulfoxide: Effects on the permeability of biologic membranes (Preliminary Report) Current Therap. Res. 6: 193-198. 1964. 15. BEN, M., DIXON, R. L., ADAMSON, R. H., FINE-

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MAN, H., RALL D. P. Toxicity of various drugs using Dimethyl Sulfoxide (DMSO) as a solvent. The Pharmacologist 6: 189. 1964. ROSENKRATZ, H., HADIDIAN, Z., SEAY, H. and MASON, M. M. Dimethyl Sulfoxide: Its steroid solubility and endocrinologic and pharmaeologic toxicological characteristics. Cancer Chemotherapy Reports 31: 7-24. 1963. HORITA, A. and WEBER, L. J. Skin penetrating property of drugs dissolved in dimethyl sulfoxide (DMSO) and other vehicles. Life Seience 3: 13891395. 1964. PARKER, A. J. The effects of solvation on the properties of anions in dipolar aprotic solvents. Quarterly Rev., London, Chem. Soc. 16: 163-187. 1962. BOTTOMLY, D. R., SHIMAZAKI, Y. and BACHMAN, D. M. Controlled study of Dimethyl Sulfoxide effects in patients with connective tissue diseases. Arthritis Rheum. 7: 294. 1964. BURCH, J. E. Panel on practice tips. J.A.V.M.A. 146: 267-268. 1965. TEIGLAND, M. B. Panel on practice tips. J.A.V.M. A. 146: 268. 1965. KOGER, L. M. Cows with sacro-iliae luxation treated with DMSO. J.A.V.M.A. 147: 345. 1965. METCALF, F. L. Laboratory and clinical evaluation of DMSO. Comments. Modern Veterinary Practice 36-37 (1965) August. ROSENBAUM, W. M., ROSENBAUM, E. E. and

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JACOB, S. W. The use of Dimethyl Sulfoxide (DMSO) for the treatment of intractible pain in surgical patients. Surgery 58: 258-266. 1965. GOLDMAN, L. and KITZMILLER, K. W. Topical 5-iodo-2'-deoxyuridine in Dimethyl Sulfoxide (DMSO); a new treatment for herpes simplex. Ohio Med. J. 61: 532-533. 1965. SCHERBEL, A. L., McCORMACK, L. J. and POPPO, M. J. Alteration of collagen in generalized scleroderma (progressive systemic sclerosis). Cleveland Clin. Quart. 32: 47-56. 1965. LEVINE, R. R. and PELLIKAN, E. W. Mechanisms of drug absorption and excretion. An. Rev. Pharmacol. 4: 69-84. 1964. BACHMAN, D. R., BOTTOMLY, D. R. and SCHIMIZAKI, Y. Additional observations of Dimethyl Sulfoxide effects in patients with connective tissue diseases. Arthritis Rheum. 7: 725. 1964. The Medical Letter on Drugs and Therapeutics 7: 80. 1965. A further warning on DMSO. 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. KLIGMAN, A. M. Topical Pharmacology and Toxicology of Dimethyl Sulfoxide, Part I. J.A.M.A. 193: 796-804, 1965; Part II, 193: 923-98. 1965. BROWN, T. A. Personal Communication, November 1965.

Acute Aspergillosis in Chicken Under Conditions of Intensive Poultry Raising

Postmortem examinations of 58.137 carcasses 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 incubators. 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 occurrence of aspergillosis in chickens was fur-

thered by unfavourable relations of temperature and humidity resulting from inadequate thermoisolation, ventilation and heating of the poultry house. Because of the low temperatures no acute aspergillosis occurred in the winter months. The highest incidence of aspergillosis 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 poultry 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.

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 described, could be classified in the following order of efficacy (beginning with the most effective): 1) Amprolium, 2) Nicarbazine, Darvisul, 3) Unistat, Zoalene, 4) sulphaquinoxaline and 5) nitrofurazone. Amprolium administered therapeutically to chicks artificially infected with E. tenella was found to be effective when given on three consecutive days, on condition that treatment was started not later than 24 hours after infection. Samberg Y., Kohane J. Refuah Veterinarith 21: 246-248, 1964.

Can. J. Comp. Med. Vet. Sci.