Domoso Solution (Canada)

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Domoso Solution

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Manufacturer: Zoetis

DIMETHYL SULFOXIDE

90% Dimethyl Sulfoxide, Medical Grade

DIN 02233030

Veterinary Use Only

General

Dimethyl sulfoxide (DMSO), an oxidation product of dimethyl sulfide, is an exceptional solvent possessing a number of commercial uses.

DMSO is the lowest member of the group of alkyl sulfoxides with a general formula of RSOR. Its structural formula is:

It freely mixes with water with the evolution of heat and lowers the freezing point of aqueous solutions. It is soluble in many other compounds including ethanol, acetone, diethyl ether, glycerin, toluene, benzene and chloroform. DMSO is a solvent for many aromatic and unsaturated hydrocarbons as well as inorganic salts and nitrogen-containing compounds. DMSO has a high dielectric constant due to the polarity of the sulphur-oxygen bond. Its basicity is slightly greater than water due to enhanced electron density at the oxygen atom. It forms crystalline salts with strong protic acids and co-ordinates with Lewis acids. It modifies hydrogen bonding.

DMSO is a hygroscopic stable organic liquid essentially odourless and water white in colour. Other physical characteristics include:

Molecular weight

78.13

Melting point

18.45°C

Boiling point

189°C

Each mL of DOMOSO Solution contains 90% dimethyl sulfoxide and 10.0% water.

Metabolism

Dimethyl sulfoxide, when administered topically or orally, is rapidly absorbed and distributed in living material.

Using S35-labeled DMSO (1) the maximal blood concentration after cutaneous application was achieved in approximately 10 minutes in rats and less than 1 hour in dogs. In rats and dogs, the substance did not accumulate in the organs, but the concentration in the treated skin and underlying muscle was increased. The main route of excretion is via the urine partially dependent on the species and route of application. In rats, there was no significant difference in the elimination half time of 6 to 8 hours after intravenous or cutaneous administration; in the dog, the elimination half time was 1.5 to 2 days after intravenous or oral administration. In the dog, however, after cutaneous application about 55% of the administered material was eliminated within 14 days. The radioactivity eliminated via the lungs, and identified as dimethyl sulfide, was about 3% of the administered dose.

In another S35-labeled study (2) with DMSO, following intravenous or cutaneous administration, the only metabolite detectable in the urine of humans and rats, was dimethyl sulfone (DMSO2).

In another S35-labeled rat study (3), DMSO was administered by the oral, intraperitoneal and dermal routes at a level of 500 mg/kg of body weight. Plasma radioactivity after an intraperitoneal dose was highest at 0.5 hours, the half-time being 5 to 6 hours. When applied dermally, levels remained constant for 6 hours. Radioactivity in the urine collected for 22 hours represented 60% to 85% of the intraperitoneal and oral doses and 36% to 50% of the dermal dose. The skin contained 3% to 7% of the labeled dosage in all cases.

A peculiar sweetish odour was noted in the exhaled breath of cats treated with dimethyl sulfoxide (4). The compound responsible for this was identified as dimethyl sulfide. The same odour has been noted in all species treated with the compound.

In rabbits, dimethyl sulfone was detected in the urine following treatment with DMSO (5).

It has been shown that dimethyl sulfone is a constituent of normal cow's milk (6).

Pharmacology

The original biological applications of DMSO were primarily confined to its use in preserving various tissues and cellular elements including blood (7), blood cells and bone marrow (8), leukocytes (9), lymphocytes (10), platelets (11), spermatozoa (12,13,14), corneal grafts (15,16), skin (17), tissue culture cells (18,19,20,21) and trypanosomes (22), by freezing techniques. DMSO has also been investigated as a radioprotective agent (23,24).

In one of the first studies reported in animals, various drugs were added to 15% solution of DMSO instilled into the urinary bladder of intact, anesthetized dogs through which an enhancement of absorption was demonstrated (25). Utilizing a similar technique, the transport of physiologically active insulin across the intact bladder mucosa was demonstrated. Results were judged on a decrease in blood sugar levels over that of controls (26).

In vivo and in vitro methods demonstrated that DMSO enhanced human percutaneous absorption of various compounds including steroids, vasoconstrictors, antiperspirants and dyes, as well as an anthelmintic (thiabendazole) and a skin antiseptic (hexachlorophene) (27,28,29,60,61,62). Enhancement was not due to irreversible damage to the stratum corneum (28).

DMSO has been stated to increase the penetration of low molecular weight allergens such as penicillin G, but not large molecular weight allergens such as house dust (30).

The rate of passage of tritiated water in the presence of DMSO on the epidermis of the hairless mouse was measured in vitro. DMSO did not appear to promote the passage of water by its presence, but when concentrated solutions (60% to 100%) were used, permanent changes were produced in the rate of passage of water. It was concluded that the concentration of DMSO used seemed more significant than the time of exposure in establishing the effect on the water barrier (31).

When the tails of mice were immersed in a 5% solution of various psychoactive drugs in DMSO, the drugs appeared to exert their usual pharmacological effects, indicating drug penetration as judged by the behavioural effects observed in the experimental subjects. Other solvents, including water, also appeared to permit some drug penetration in this study (32).

Using ten quaternary ammonium salts as test compounds and either water or DMSO as solvents, the oral LD50 values were determined in rats and mice. Toxicity changes were obtained in some instances by 50% DMSO and more changes were observed in rats than mice although the results in the two species were not always parallel. When toxicity was altered by DMSO, it increased in all instances except one (33).

When administered systemically in another study, however, various drugs dissolved in DMSO did not differ significantly in their lethality or cellular penetration as compared to the same drug administered in saline (34).

When evaluated as a solvent for biologic screening tests, low doses of hormones in DMSO stimulated a response similar to that of the hormone in the control vehicle. Higher doses of hormone, however, failed to give the expected response, suggesting a partition coefficient in favour of the solvent (35). DMSO was also shown to carry physostigmine and phenylbutazone through the skin of the rat (36).

The absorption of phenylbutazone dissolved in an aqueous solution of DMSO was impaired when administered orally to the rabbit. Absorption of the same drug was not improved using the subcutaneous route simultaneously with DMSO.

However, phenylbutazone could be detected in rabbit's blood for several hours when an ointment containing DMSO and 5% phenylbutazone was applied to the skin. When the DMSO content of the ointment was increased, the phenylbutazone levels increased. An increase of phenylbutazone in the muscle tissues underlying the site of application over a control ointment containing phenylbutazone without DMSO could be demonstrated in rats (37).

Based on the above evidence as well as gas chromatographic and radio-isotope studies, it is established that DMSO can effectively penetrate the stratum corneum of the epidermis and enter the systemic circulation. DMSO also has the ability to allow some substances ordinarily unable to penetrate the skin barrier to be carried through it. The mechanism of penetrant action is not yet understood although some theories have been advanced as explanations (25,38).

DMSO has been claimed to show anti-inflammatory activity against the baker's yeast granuloma in guinea pigs, and when administered orally, against the carrageenin granuloma in rats. The dose needed to achieve these effects is quite high, requiring 1 to 5 g/kg of body weight (39).

In a number of other studies in experimental animals (32,36,40) where DMSO has been chiefly administered orally or by injection, no anti-inflammatory or analgesic activity could be established.

Following experimental hypersensitization to human gamma-globulin in the horse, antigen challenge resulted in massive erythema, necrosis and slough. This reaction could be markedly reduced by the hourly application of undiluted DMSO to the reaction site, after challenge (30).

In experimentally induced thermal edema of the legs of rabbits, the leg volume was the same for DMSO treated and untreated groups at 3 and 24 hours, but less at 6 hours for the treated group. The DMSO in this experiment was applied at a site distant to the injury (30).

Sedative effects have been noted in dogs when 90% DMSO was administered at 10 mg/kg dosage levels and mild reserpine-like actions of the drug have also been described in mice (30).

DMSO, by itself, at concentrations of 100%, 66%, and 33%, has been shown to produce neurolysis following perineural injection in the rat's sciatic nerve (41).

The conflicting reports cited above for the anti-inflammatory and analgesic properties of DMSO are partially dependent upon the experimental models and methods used to measure these parameters. DMSO fails to show analgesic or anti-inflammatory activity in certain of these situations, particularly when used by the systemic route or when administered topically preceded by an irritant substance. In clinical studies in the horse, it was noted that when iodine, liniments or other strong irritants were present on the skin from previous therapy and DMSO applied, a temporary, but marked local reaction would occur. This was due to the ability of DMSO to carry these substances into the underlying skin tissues where their irritant actions could be displayed. When DMSO was used clinically, it was applied topically to the involved area, while in the experimental situation, this procedure was seldom used. In clinical situations, a marked reduction of pain and edema has often been noted following topical application. The mechanism of action, although not understood, may be partially related to the heat of dissolution of DMSO. It has been demonstrated that following cutaneous application of DMSO in dogs, the skin, dermis and underlying muscle tissues show a local rise in temperature (30).

The analgesic and anti-inflammatory activity of DMSO, as observed clinically and the differences noted by classical pharmacological methods, may be partially due to the ability of the compound to alter the underlying pathology of the disease state under treatment (42).

Using the isolated guinea pig heart, it was found that DMSO did not influence the amplitude of cardiac contractions, heart rate, or coronary flow, although high intravenous doses in the rat and cat resulted in a transient lowering of blood pressure (36).

Isolated, innervated guinea pig preparations were also used to study the effects of DMSO on skeletal, smooth and cardiac muscles. The compound depressed diaphragm response to both muscle and nerve stimulation and also caused spontaneous skeletal muscle fasciculation. Actual contraction amplitude was augmented although the contraction rate appeared unaffected. Vagal threshold was lowered almost 50% by a bath concentration of 6% DMSO. The fasciculations and increased tone of skeletal muscle, and lowering of the vagal threshold by DMSO could be due to cholinesterase inhibition (43). Intravenous doses of 50% DMSO in doses as high as 1 g/kg failed to alter the EKG of anesthetized dogs or monkeys (26).

With single intravenous doses of 200 mg/kg of DMSO to anesthetized cats, apnea and a transient fall in blood pressure were produced. Subsequent doses caused only a transient hypotension and apnea was no longer observed. Vagotomy failed to influence the course of DMSO-induced hypotension and bradycardia, but atropine (1 mg/kg) significantly attenuated these effects. Repeated intravenous administration of DMSO where each succeeding dose was doubled, led to a gradually lowered blood pressure until death ensued at about 4 g/kg. Myoneural transmission, ganglionic transmission and force of cardiac contraction also deteriorated gradually with repeated doses until death. The transient fall in blood pressure occurred only rarely after intraperitoneal administration. One cat exhibited hypotension following a 1 g/kg dose of DMSO, but the remainder received dosages of 4 g/kg without showing this effect (44).

The in vitro oxygen consumption of liver, brain and hemidiaphragm tissues of rats is not affected by the intravenous administration of 75 mg DMSO/100 g of body weight during the 7 subsequent days. Urease, trypsin and chymotrypsin are inhibited by DMSO, dependent upon its concentration. The in vitro metabolism of corticosterone by rat liver slices is not affected by the intravenous administration of 100 mg DMSO/100 g of body weight during 3 subsequent days (2).

DMSO treatment administered intraperitoneally to rats for 35 days decreased experimentally induced intestinal adhesions by 80% over controls as compared to saline, cortisone acetate or a combination of cortisone and DMSO administered separately (45).

In rabbits, the application of 70% DMSO, adjacent to, but not on the wound incision site, appeared to increase the development of wound tensile strength over controls (46).

Increasing the concentration of DMSO resulted in an increasing inhibition of fibroblast proliferation in vitro, which was reversible (30).

There is an increase in urinary production following the dermal or systemic administration of DMSO, and a transient doubling of urine volume after the intravenous administration of the drug (48).

Some studies have indicated that DMSO may potentiate the action of certain compounds including insulin (39), endogenous steroids and others. It was suggested that in the case of steroids it might be due to improved penetration at their sites of action on lysosomal membranes (30).

The minimal inhibitory concentration (MIC) of DMSO to the nearest 10% was determined for two isolates each of Staphylococcus aureus, Staphylococcus aureus var. albus, β-hemolytic Streptococci, Corynebacterium acnes, Corynebacterium species, Alcaligenes faecalis, Escherichia coli and Proteus species. Twenty percent DMSO was found to be bacteriostatic. For Staphylococcus aureus, the bactericidal concentration of 50% was 2.5 times that of the MIC; for the remainder, it ranged from 30% to 40% with the gram-negative bacteria being somewhat more susceptible (29).

No growth of Staphylococci, Pseudomonas or Escherichia coli occurred in the presence of 36%, 25%, 33% or greater concentrations, respectively, of DMSO (49).

The minimal inhibitory concentration of DMSO in Sabouraud's broth to the nearest 10% was determined for three dermatophytes: Trichophyton mentagrophytes, Microsporum gypseum, and Microsporum canis. Ten percent DMSO was inhibitory to all three species. The fungicidal concentrations were 30% for the Microsporum species, while T. mentagrophytes survived the highest test concentrations of 50% (29).

Toxicology

Absorption of topically applied DMSO results in degranulation of the mast cells at the site of application and a release of histamine followed by characteristic histamine whealing of the overlying skin. Following repeated applications of the compound to the same skin area, the mast cells are eventually depleted and the wheal no longer occurs (28).

The erythema of the skin following topical application of DMSO is considered to be partially due to the release of histamine. In addition, DMSO has the typical action of most solvents in causing drying and defatting of the skin.

In a study designed to evaluate the effects of DOMOSO (dimethyl sulfoxide) Solution at a total daily dose of 100-300 mL administered for a total period of 90 days, no essential or clinically meaningful ophthalmological effects were seen in the horse. There were not significant variations in glucose, sodium, potassium, SGOT, or SGPT measurements. There were a few fluctuations in hematologic values, but no changes appear to be drug-related or of significance.

Another study was conducted in the dog to determine the effects of DOMOSO Solution at a total daily dose of 20-60 mL administered topically for 21 consecutive days. Clinically meaningful ophthalmological effects were not noted. Significant variations were not observed in blood measurements, including glucose, BUN, SGOT and plasma electrophoresis. Hematologic values were similar to control animals used in the study.

Long-term topical applications of the drug to guinea pigs resulted in histopathologic changes similar to those observed in allergic contact dermatitis. The observed clinical changes were compatible with either an allergic contact dermatitis or a primary irritant effect (50). DMSO was shown to cause erythema and blistering of human and rat skin resulting in increased permeability of venules and capillaries (51).

In most cases the local irritation of the skin characterized by erythema, vesicle or blister formation and scurfing abates even with continued treatment. This phenomenon has been described as “accommodation” or “hardening” of the skin, and has been noted with other solvents.

The undiluted compound has low systemic toxicity, but a marked local necrotizing and inflammatory effect when it is injected subcutaneously. In rats, the subcutaneous injection of 10 g/kg or the intravenous injection of 2.5 g/kg of undiluted DMSO for 2 weeks showed no definite indication of systemic toxicity. The local necrotizing effects produced at these dose levels, however, prevented a longer period of treatment. No significant hematologic or biochemical changes were noted in 3 dogs receiving 0.4 g/kg for 33 days (35).

Four dogs were administered topical DMSO at 1 g/kg of body weight, 5 days weekly for 18 months. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), prothrombin time, alkaline phosphatase, bilirubin, total protein and albumin:globulin (AG) ratio, and blood urea nitrogen (BUN) were determined at the beginning of treatment and at monthly intervals. Significant abnormalities did not occur (39).

Upon injection of DMSO into the rat pleura, there is an accumulation of fluid, initially appearing as a transudate, but later as a protein-rich exudate. Exudate formation is thought to be due to increased vascular permeability, predominantly in venules, brought about by a delayed release of histamine together with activation of a vaso-active slow contracting substance (51).

Rats were orally dosed 5 days a week for 2 weeks at levels of 1, 3.5, 5 and 10 mg/kg of DMSO. The only deaths in this group were due to dosing injuries. Signs of dermal sensitization were not noted following a course of intradermal injection of a 10% v/v aqueous solution of DMSO in guinea pigs, nor did the same species show signs of injury following 28 daily applications of the undiluted drug to the clipped skin of the back (52).

A compilation of the results for a number of acute toxicity (LD50) determinations derived from several published reports (35,52,53,54,55) in several experimental animal species are as follows:

Species

 

Rt. of Administr.

 

LD50 g/kg

Mouse

-

SQ

-

13.9 - 20.5

Mouse

-

IV

-

3.82 - 10.73

Mouse

-

Oral

-

15.0 - 22

Mouse

-

IP

-

20.06

Rat

-

IV

-

5.25 - 5.36

Rat

-

Oral

-

16.0 - 28.3

Rat

-

IP

-

5.5 - 13.621

Dog

-

IV

-

2.5

Guinea Pig

-

IP

-

5.5

Chicken

-

Oral

-

12.5

Hemolysis resulting in hemoglobinuria and methemoglobinuria was noted in anesthetized cats following single intravenous doses of 200 mg/kg DMSO. The intraperitoneal administration of DMSO or the dilution of DMSO with isotonic saline prior to intravenous administration reduced its hemolytic activity (44).

Tests in vitro showed that washed rabbit erythrocytes are hemolyzed in a short time with 40% to 60% DMSO solution. Higher concentrations caused, without hemolysis, an agglutination of the erythrocytes (55).

Teratology

The intraperitoneal administration of 5.5 g/kg for DMSO as a single dose to pregnant hamsters induced developmental malformations of their embryos (56). Both dimethyl sulfoxide and diethyl sulfoxide are teratogenic when injected into the chick embryo, the classification of malformations being dependent upon the stage of embryonic development at the time of treatment. The same drugs when administered by various techniques to mice, rats and rabbits in which fertility had been established did not cause any embryonic malformations (57).

Ocular Effects

In a variety of experimental animals including rats, dogs, swine, rabbits and primates, following oral or topical administration of DMSO, certain eye changes have been noted. These consist mainly of a change in the refractive index of the lens described as a “lens within a lens”. The lens changes are characterized by a decrease in the normal relucency of the lens cortex, causing the normal central zone of the lens to act as a biconvex lens. When viewing the fundus of affected animals, it is necessary to interpose biconcave lenses in order to see the retinal vessels clearly. The functional effect would be a tendency toward myopia (58).

The lens changes were first observed in dogs receiving 5 g/kg after 9 weeks of administration. At lower dose levels, the change was observed later. In rabbits, these changes were seen after 90 days of dermal application, (8 mg 50% DMSO/kg/day and 4 mg 100% DMSO/kg/day and higher). In swine, dermal application of 4.5 g 90% DMSO/kg twice daily caused similar lens changes by 90 days of treatment (59).

The lens changes appear earlier with oral administration, and also bear a relation to the dosage employed; the higher the dose the more rapid their appearance.

The eye changes are slowly reversible, but with a definite species difference, the dog being the slowest to exhibit improvement.

No effects were seen following direct application of aqueous solutions varying from 10% to full strength into the eyes of albino rabbits for a total dosage of DMSO between 0.1 and 0.2 g/kg of body weight per day for six months. Rabbits which received daily doses as high as 10 g/kg orally or topically showed lines of discontinuity in their lenses. No cataract was seen after ten weeks of such daily treatment, although discontinuous lens lines could be detected in about two weeks by slit lamp examination. Chemical studies on these lenses revealed reduction in the usual concentrations of urea, glutathione, uric and amino acids (30).

Domoso Solution Indications

Canine And Equine

DOMOSO (dimethyl sulfoxide) Solution is recommended as a topical application to reduce acute swelling due to trauma.

Administration And Dosage

DOMOSO Solution is to be administered topically to the skin over the affected area.

Dogs

In long or medium haired dogs, areas to be treated must be clipped before applying the drug.

Apply DOMOSO Solution three to four times daily. Total daily dosage should not exceed 20 mL. Total duration of therapy should not exceed 14 days.

Horses

Apply DOMOSO Solution two to three times daily. Total daily dosage should not exceed 100 mL. Total duration of therapy should not exceed 30 days.

Contraindications

DOMOSO Solution is contraindicated in horses and dogs with known eye disease, liver or kidney dysfunction or with a history of allergy.

DOMOSO Solution is contraindicated in pregnant mares and bitches or horses and bitches intended for breeding purposes.

This drug should not be administered to dogs weighing less than 10 lbs.

Domoso Solution Caution

Total daily dosage should not exceed 100 mL in horses and 20 mL in dogs.

Total duration of therapy should not exceed 30 days in horses and 14 days in dogs.

DOMOSO Solution is restricted to topical use in horses and dogs only.

Do not administer by any other route.

Application of DOMOSO to mucous membranes should be avoided. DOMOSO Solution may mask certain musculoskeletal disease signs such as seen in fractures. This does not obviate the need for specific therapy in such conditions.

Since DOMOSO Solution effectively alters the biologic membrane and will, in some cases, facilitate the systemic absorption of other topically applied drugs, it should not be used as a vehicle for other drugs. The user should make certain that other medications are not present prior to its application. If other topical medications are indicated, they should not be applied until DOMOSO Solution is thoroughly dry.

As DOMOSO Solution may have a potentiating effect on drugs administered systemically, it should be judiciously used when administered in conjunction with other pharmaceutical preparations, especially those affecting the cardiovascular and central nervous systems.

DOMOSO Solution should not be used under occlusive dressings.

DOMOSO Solution is a potent solvent and may have a deleterious effect on fabrics, plastics and other materials. Care should be taken to prevent physical contact between DOMOSO Solution or DOMOSO treated areas and these materials.

Frequently, due to the heat of resolution, a “smoking” effect following application is noted due to vaporization of the drug.

Side Effects

Changes in the refractive index of the lens of the eye and nuclear cataracts have been observed in animals treated with this drug. This appears to be related to dosage and duration of therapy.

In general, adverse reactions are local, and while they may prove annoying to some patients, they are usually not of a serious nature. Upon topical application, an occasional animal may develop transient erythema, associated with local “burning” or “smarting”. Even when erythema or vesiculation occur, they are self-limiting reversible states, and are not necessarily an indication to discontinue medication.

Dryness of the skin and an oyster-like breath odour have been reported. These effects are temporary and are not considered to be of a serious consequence.

Contraindications

DOMOSO Solution is contraindicated for administration to horses and dogs by pregnant or lactating women, by children, by individuals with known eye disease, liver or kidney dysfunction and by individuals with a history of allergy.

Warnings

Contact between DOMOSO Solution and the skin should be avoided. Rubber gloves should be worn while applying this drug. Forceps and swabs may be used to facilitate application. If absorbed through the skin, DOMOSO Solution may cause mild sedation, dizziness or drowsiness in users if exposed to excessive quantities. Users showing these symptoms should not drive or operate machinery until these effects have disappeared. DOMOSO Solution may cause sensations of warmth, burning, irritation, itching and mild erythematous localized dermatitis at the site of exposure and occasionally it may cause a generalized dermatitis. Also, if absorbed, DOMOSO Solution may cause headache and nausea. Absorption of DOMOSO Solution following exposure to the skin will result in odorous breath and unpleasant mouth taste. Treatment of such side effects is symptomatic.

DOMOSO Solution must not be administered to horses that are to be slaughtered for use in food.

Consult a physician immediately if adverse effects occur.

Keep DOMOSO Solution out of the reach of children.

Storage Information

Extremely hygroscopic. Close the bottle cap tightly after use. Avoid freezing.

Packaging

DOMOSO Solution. Bottles of 480 mL.

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31. Sweeney, T.M., Downes, A.M. and Matoltsy, A.G., THE EFFECT OF DIMETHYL SULFOXIDE ON THE EPIDERMAL WATER BARRIER. 1966 J. Invest. Derm. 46, 300-302 Mar 1966.

32. Horita, A. and Weber, L.J., SKIN PENETRATING PROPERTY OF DRUGS DISSOLVED IN DIMETHYL SULFOXIDE, DMSO, AND OTHER VEHICLES. 1964 Life Sci. 3, 1389-1395 Dec 1964.

33. Rosen, H., Blumenthal, A., Panasevich, R. and McCallum, J., DIMETHYL SULFOXIDE (DMSO) AS A SOLVENT IN ACUTE TOXICITY DETERMINATIONS. 1965 Proc. Soc. Exp. Biol. Med. 120, 511-514 Nov 1965.

34. Dixon, R.L., Adamson, R.H., Ben, M. and Rall, D.P., APPARENT LACK OF INTERACTION BETWEEN DIMETHYL SULFOXIDE AND A VARIETY OF DRUGS. 1965 Proc. Soc. Exp. Biol. Med. 118, 756-759 Mar 1965.

35. Rosenkrantz, H., Hadidian, Z., Seay, H. and Mason, M.M., DIMETHYL SULFOXIDE, ITS STEROID SOLUBILITY AND ENDOCRINOLOGIC AND PHARMACOLOGIC-TOXICOLOGIC CHARACTERISTICS. 1963 Cancer Chemother. Rep. No. 31, 7-24 Sep 1963.

36. Haeusler, G. and Jahn, U., UNTERSUCHUNGEN ZUR PHARMAKOLOGIE VON DIMETHYLSULFOXYD (DMSO). 1966 Arch. Int. Pharmacodyn 159, 386-400 Feb 1966.

37. Pantio, M. and Kaerki, N.T., THE INFLUENCE OF DIMETHYL SULFOXIDE ON THE ABSORPTION OF PHENYLBUTAZONE. Spanish Translation. 1965 Air 8, 133-147 1965.

38. Block, L.H., DMSO. MEDICINAL AND PHARMACEUTICAL ASPECTS. 1964 Drug Cosmet. Industr. 95, 342-346, 462-464 Sep 1964.

39. Jacob, S.W., Herschler, R.J. and Rosenbaum, E.E., DIMETHYL SULFOXIDE (DMSO) LABORATORY AND CLINICAL EVALUATION. 1965 J. Amer. Vet. Med. Assoc. 147, 1350-1359 1965.

40. Preziosi, P. and Scapagnini, U., ACTION OF DIMETHYL SULFOXIDE ON ACUTE INFLAMMATORY REACTIONS. 1966 Curr. Ther. Res. 8, 261-264 May 1966.

41. Katz, J., Knott, L.W. and Rubinstein, L.J., THE NEUROHISTOLOGICAL CHANGES INDUCED BY PHENOL, DIMETHYL SULFOXIDE, AND HYALURONIDASE ON THE SCIATIC NERVE OF THE RAT. Special Abstract From Fall Pharmacology Meeting April 1966.

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43. Sams, W.M., Carroll, N.V. and Crantz, P.L., EFFECTS OF DIMETHYL SULFOXIDE ON ISOLATED-INNERVATED SKELETAL, SMOOTH, AND CARDIAC MUSCLE. 1966 Proc. Soc. Exp. Biol. Med. 122, 103-107 May 1966.

44. DiStefano, V. and Klahn, J.J., OBSERVATIONS ON THE PHARMACOLOGY AND HEMOLYTIC ACTIVITY OF DIMETHYL SULFOXIDE. 1965 Toxic. Appl. Pharmacol. 7, 660-666 Sep 1965.

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46. Huu, N. and Albert, H.M., EFFECT OF DMSO ON WOUND HEALING TENSILE STRENGTH MEASUREMENTS IN RABBITS. 1966 Amer. Surg. 32, 421-424 Jun 1966.

47. Scherbel, A.L., McCormack, L.J. and Poppo, M.J., ALTERATION OF COLLAGEN IN GENERALIZED SCLERODERMA (PROGRESSIVE SYSTEMIC SCLEROSIS) AFTER TREATMENT WITH DIMETHYL SULFOXIDE. 1965 Cleveland Clin. Quart. 32, 47-56 Apr 1965.

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52. Brown, V.K., Robinson, J. and Stevenson, D.E., A NOTE ON THE TOXICITY AND SOLVENT PROPERTIES OF DIMETHYL SULFOXIDE. 1963 J. Pharm. Pharmacol. 15, 688-692 Oct 1963.

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56. Marin-Padilla, M., MESODERMAL ALTERATIONS INDUCED BY DIMETHYL SULFOXIDE. 1966 Proc. Soc. Exp. Biol. Med. 122, 717-720 Jul 1966.

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58. Rubin, L.F. and Mattis, P.A., DIMETHYL SULFOXIDE, LENS CHANGES IN DOGS DURING ORAL ADMINISTRATION. 1966 Science 153, 83-84 1 Jul 1966.

59. Unpublished data 1966.

60. Stoughton, R.B., HEXACHLOROPHENE DEPOSITION IN HUMAN STRATUM CORNEUM. ENHANCEMENT BY DIMETHYLACETAMIDE, DIMETHYLSULFOXIDE, AND METHYLETHYL-ETHER. 1966 Arch. Derm. 94, 646-648 Nov 1966.

61. Katz, R. and Hood, R.W., TOPICAL THIABENDAZOLE FOR CREEPING ERUPTION. 1966 Arch. Derm. 94, 643-645 Nov 1966.

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