1 Introduction
Dimethyl sulfoxide (DMSO), in trace amounts occurs naturally in fresh and ocean water and in rain. It is commercially produced quite inexpensively from lignin, a by product of paper making industry in the United States and coal and petroleum in Europe (Bartfeld and Goldstein, 1975; Jacob and Herschler, 1983). It occurs as a waste product from processing wood pulp (Booth and McDonald, 1982).

The FDA approved therapeutic veterinary preparations are DOMOSO® and SYNOTIC^® (Diamond Laboratories Inc., Des Moines, Iowa). While the FDA approved medical preparation is RIMSO-50^® (Research Industries Inc.), which contains 50% DMSO solution.

Dimethyl sulfoxide is having a pyramidal structure, CH³-SO-CH³. The sulfur-oxygen bond is quite polar, giving the liquid a high dielectric constant. It is a clear liquid with a boiling point of 189℃ at 1 atmosphere pressure and has a specific gravity of 1.0958 at 25℃ (Booth and McDonald, 1982).

It is a dipolar, aprotic and highly hygroscopic solvent (MacGregor, 1967; Weissman et al., 1967; David, 1972; Kharasch and Thyagarajan, 1983; Windholz, 1983). Pure DMSO is rapidly diluted to a concentration of 66% to 67% when it is exposed to room air (MacGregor, 1967; Szmant, 1967; Kharasch and Thyagarajan, 1983). Hydration of DMSO is an exothermic reaction, the heat evolved is readily appreciated when DMSO is applied to skin and react with water from air and from underlying tissue (MacGregor, 1967; David, 1972; Jacob and Herschler, 1983; Kharasch and Thyagarajan, 1983).

2 History
Earliest history on Dimethyl sulfoxide can be traced to 1867 when a Russian Chemist, Alexander Saytzeff, described the oxidation of Dimethyl sulfide into Dimethyl sulfoxide and further described some of its remarkable solvent properties (Leake, 1967; Bartfeld and Goldstein, 1975). There was a little interest in DMSO until 1950 when its solvent properties were exploited for use in many industrial processes. Industrial researchers discovered that it is a solvent for many herbicides, fungicides, antibiotics and hormones. It can greatly enhance their penetrance and efficacy in plants and trees and enhance plant growth by 15% to 20% (Garren, 1967; Kiehl, 1967; Leake, 1967; Leonard, 1967; Scuchetti, 1967; Smale et al., 1975).

Scientists working with DMSO soon reported other unusual properties such as its ability to penetrate skin to produce offensive garlic or oyster halitosis.

This smell is due to its metabolite, dimethyl sulfide (Distefano and Klahn, 1965; Brown, 1982).

Robert Herschler and Stanley Jacob were the strong proponents of the early study of DMSO as a therapeutic agent (Leake, 1967; Bartfeld and Goldstein, 1975; Leake, 1975; Douglass and Walker, 1983). DMSO was found to be superior to glycerol for cryopreservation of bovine spermatozoa (Lovelock and Bishop, 1959). It is also used as cryoprotectant added to cell media in order to prevent the cells from dying as they are being frozen (Pegs, 2007). The first report of DMSO as a pharmacologic agent was published in 1964. Investigational new drug (IND) status was then granted by the Food and Drug Administration (FDA) (Harter, 1983).

In November 1965, the FDA terminated clinical studies on DMSO because Rubin demonstrated that DMSO induced lenticular changes in some laboratory animals (Rubin and Barnett, 1967). In 1966, the FDA relaxed the policy to permit clinical evaluation in the treatment of serious conditions such as scleroderma, persistent herpes zoster and severe rheumatoid arthritis, for which no satisfactory therapy was available (Harter, 1983). In 1968, the policy was further relaxed to permit topical application for less than 14 days (Kligman, 1965). In 1970, the FDA approved DMSO for veterinary use in musculoskeletal injuries in horses. In 1972, approval was extended for use in dogs. In 1978, the FDA authorized the use of 50% DMSO (RIMSO-50^®) for the treatment of interstitial cystitis in humans (Leake, 1967; Harter, 1983).

3 Physiological and Pharmacological Properties
3.1 Absorption or penetration of DMSO
Dimethyl sulfoxide readily penetrates the skin within 5 minutes after cutaneous application. Radiolabeled DMSO can be detected in the blood and characteristic garlic halitosis is evident due to reduction of its metabolite called dimethyl sulfide within 20 minutes. It can be found in all the organs of the body and within one hour, radiolabeled DMSO is detected in bones and teeth (Kolb et al., 1967). The penetrating ability of DMSO is believed to be due to its exchange and interchange for water in biological membranes (Szmant, 1967; Weissman et al., 1967; David, 1972; Kharasch and Thygarajan, 1983).

3.2 DMSO as a carrier agent
Dimethyl sulfoxide facilitates penetration of many other substances across the membranes. Cutaneous penetration of various steroids (Dkan and Gunberg, 1967; Maibach and Feldman, 1967; Wood and Wood, 1975), insulin, heparin, sulfadiazine (Potts et al., 1967) and phenylbutazone (Jimenez and Wilkens, 1982) is enhanced by DMSO. Anaesthetic, cardioactive, anticholinesterase and other not-innocuous therapeutic agents may have enhanced penetration or modified activity in the presence of DMSO (Distefano and Klahn, 1965; Banthorpe and Lamont, 1967; Braude and Monroe, 1967; Smith et al., 1967; Steinberg, 1967; Rubin, 1975; Yellowless et al., 1980). In clinical situations, it is used as a vehicle and or potentiator of antibacterial agents (Potts et al., 1967; Feldmen et al., 1975; Miranda-Tirado, 1975; Van Risjwick, 1981), antiprotozoal and antifungal agents (Post and Saunders, 1979), antiviral agents (Sehtman, 1975; Zuniga et al., 1975; Spruance et al., 1983) and chemotherapeutic agents (Garrido and Lagos, 1975; Setala, 1983; Warren et al., 1983).

3.3 Radioscavenging property of DMSO
Dimethyl sulfoxide traps free radical hydroxide and its reduction metabolite dimethyl sulfide (DMS) traps the free radical oxygen (Misch and Misch; 1975; Repine et al., 1979; Hill et al., 1983; Rosenblum, 1983). Their free radical scavenging capabilities are believed to be responsible for some of the antiinflammatory, cryoprotective, radioprotective and antiischemic properties when used in vivo, topically or parenterally (Brayton, 1986).

3.4 Enzyme inhibition action of DMSO
Dimethyl sulfoxide inhibits acetylcholinesterase and depresses the diaphragm response to muscle and nerve stimulation under in vitro condition. It causes spontaneous fasciculation, increases gastric smooth muscle tone and the amplitude of contraction of atrial muscle and reduces the cardiac vagal threshold (Sams, 1967). Dimethyl sulfoxide has cardiovascular and vasoactive effects and these are attributed, atleast in part, to its anticholinesterase activity (Shlafer and Karow, 1975; Hameroff et al., 1983).

3.5 Therapeutic applications of DMSO
The FDA-approved preparation of DMSO, DOMOSO^® is recommended for acute sprains, strains, bursitis and their associated soft tissue swellings and haematoma. It relieves pain and swelling and improves the function of the affected part more rapidly than the conventional therapies (Knowles, 1967; Levesque, 1967; Tiegland and Saurino, 1967). Postoperative swelling due to surgical trauma, pain and swelling are reduced and healing is improved (Arno et al., 1967; Kleberger, 1967; Penrod et al., 1967; Riis, 1984).

SYNOTIC^® (Diamond Laboratories, Desmoines, Iowa) is recommended for the relief of inflammation and pruritis associated with acute and chronic otitis. RIMSO-50® is recommended for the direct instillation into the urinary bladder in the treatment of refractory interstitial cystitis in human patients (A. M. A. Department of drugs, 1980; Santos et al., 2003; Fourcroy et al., 2004). It can also improve healing by topical application of DMSO to treat oral ulcers (Kutscher et al., 1967), diabetogenic skin ulcers (Miranda-Tirado, 1975), varicose skin ulcers (Sehtman, 1975), chronic skin ulcers (Scott and Walton, 1983), burns (Miranda-Tirado, 1975; Sehtman, 1975), open wounds (Levesque, 1967; Dubinsky and Skager, 1975), skin grafts (Sehtman, 1975) and corneal ulcers.

Chronic musculoskeletal conditions such as chronic osteoarthritis and degenarative disc disease in humans (Demos et al., 1967; John and Laudahn, 1967; Paul, 1967; Steinberg, 1967) and scarred or bowed tendon in horses (Tiegland and Saurino, 1967) have been treated with DMSO in clinical trials. Topical application of DMSO gel was evaluated in treating endotoxin induced synovitis in horses (Smith et al., 1998). Intraarticular administration of DMSO reduced severity of chemically induced synovitis in horses (Welch et al., 1991).

Proud flesh is reduced when DMSO is applied to wounds below the equine tarsus or carpus that heal by secondary or tertiary intention (Levesque, 1967). DMSO reduces fibroplasia as a result of its inhibition of fibroblastic proliferation in vitro (Alsup and De Bowes, 1984). It would be a valuable adjunct in the treatment of surgical colic cases (Davis, 1984). It decreases the severity of liver damage caused by ischemia-reperfusion after portal vein clamping (Sahin et al., 2004). Its combination with carolina rinse solution would be protective against ischemia-reperfusion injury in the equine jejunum (Dabareiner, 2005).

Combination therapy of DMSO with antibiotics or steroids enhance the healing of cutaneous habronemiasis or summer sores (McMullan, 1982; Faddock and Mullowney, 1983; Moore et al., 1983), bumble foot (Halliwell, 1975), acral lick dermatitis (Scott and Walton, 1983), arthritis and mastitis (Figueiredo et al., 1993). Antifungal and steroids along with DMSO are used for treating scratches (McMullan, 1982) and phytomycosis (McMullan, 1983). Topical application of DMSO, phenylbutazone and acetyl salicylic acid ointment is used for the treatment of udder edema (Szalbierz et al., 1996). Topical antiviral agents along with DMSO are used for the treatment of Herpes simplex virus infection (Hamuy and Berman, 1998). Synovial fluid along with DMSO has been tried for treating aseptic arthritis in experimental calves (Tayal et al., 1998 and 2000). The deleterious effect of nicotine was effectively blocked by DMSO in experimental rats (Leite, 2007). Diagnosis of Dermatophytosis of the ear was done by potassium hydroxide and Dimethyl sulfoxide test (Morinaka, 2005).

Acute CNS trauma, inflammation, edema and ischemia have been treated with intravenous DMSO in laboratory (De la Torre et al., 1975; Brown et al., 1980; Rucker et al., 1983) and clinical cases (Lee, 1983; Reed, 1983; Waller et al., 1983; Newton, 1998; Santos et al., 2003). Potential veterinary applications for DMSO in CNS disorders include intervertebral disc disease in dogs (Lee, 1983), brain and spinal cord trauma in horses (Mayhew and Mackay, 1982; Reed, 1983). Other possible applications of DMSO are the prevention or treatment of post traumatic myocarditis or the myocardial infarctions and consequent arrhythmias that occur secondary to gastric dilatation and torsion in dogs (Finney et al., 1967).

Dimethyl sulfoxide has been tried in human patients to treat various rheumatic diseases such as rheumatoid arthritis (Rosenbaum et al., 1965; Zuckner et al., 1967; Gorog and Kovacs, 1975; Jimenez and Wilkens, 1982; Rosenstein, 1999), renal amyloidosis (Gruys et al., 1981; Jimenez and Wilkens, 1982; Scheinberg et al., 1984; Santos et al., 2003) and scleroderma (Scherbel et al., 1967; Fleischmajer, 1975; Jimenez and Wilkens, 1982; Scherbel, 1983). DMSO’s anticholinesterase activity may help in the treatment of auto immune disorders like myasthenia gravis in which immunologic attack is directed at acetylcholine receptors at neuromuscular junctions (Pestronk and Drachman, 1980).

Intractable pain such as post amputation phantom pain (Rosenbaum et al., 1965), post thoracotomy incisional pain (Penrod et al., 1967), headaches (Blumenthal and Fuchs, 1967) and other painful conditions of various etiologies (Asen, 1967; Blumenthal and Fuchs, 1967; Dubinsky and Skager, 1975; Brown, 1982; Douglass and Walker, 1983) that could not be alleviated by any therapy or could only be alleviated by narcotic analgesia have responded to topical application of DMSO.

DMSO has been classified as a “maturational agent” in some neoplastic cell lines (Borenfreund et al., 1975; Stewart et al., 1975; Patel and Lodish, 1984; Spremulli and Dexter, 1984). DMSO is reported to potentiate cyclophosphamide (Garrido and Lagos, 1975; Warren et al., 1983) and to be effective in a “cytostatic complex” with vinblastin (Setala, 1983).

3.6 Toxicity of dimethyl sulfoxide
Dimethyl sulfoxide is considered to have a low toxicity. Median lethal dose (LD-50) of DMSO administered topically, orally or parenterally to laboratory animals are high (Smith et al., 1967; Rubin, 1975). The therapeutic intravenous dose is about 1.0 g/kg in 10%~45% solution administered slowly in humans (Waller et al., 1983), Cats (Hoerlein et al., 1983), dogs (De la Torre et al., 1975; Rucker et al., 1983) and horses (Mayhew and Mackay, 1982; Reed, 1983). With lethal doses of DMSO, death is usually preceded by prostration, convulsions, dyspnea or tachypnea, hypotension, pulmonary edema and respiratory arrest (Caujolle et al., 1967; Smith et al., 1967; Santos et al., 2003).

Skin sensitivity to topical application of DMSO usually is greater with higher concentrations of DMSO (70%~100%), but 10% DMSO can also cause irritation (Sulzberger et al., 1967; Rubin, 1975). Ocular toxicity due to DMSO has been reported (Rubin and Barnett, 1967; Harter, 1983). In rabbits, dogs and swine, the characteristic changes were altered lucency of the lens and myopia (Kleberger, 1967; Rubin and Barnett, 1967) or function as double focussed lenses (Wood et al., 1967).

Hemolysis is seen both in vitro and in vivo after the use of DMSO (Distefano and Klahn, 1965; Caujolle et al., 1967; Smith et al., 1967; Waller et al., 1983). Nephrotoxicity has been reported with oral and intravenous administration of DMSO in mice, rats, dogs and cats (Caujolle et al., 1967; Smith et al., 1967). Signs of renal damage include hematuria, hemoglobinuria and mild tubular nephrosis or nephritis at postmortem examination (Caujolle et al., 1967; Smith et al., 1967). Its exposure to developing mouse brains @ 0.3 mL/kg can produce brain degeneration (Hanslick et al., 2009). Hepatotoxicity has been reported in chronic toxicity trials involving laboratory animals (Caujolle et al., 1967; Smith et al., 1967; Rubin, 1975). Various toxic agents if present in DMSO solution can readily penetrate rubber gloves and skin (Banthorpe and Lamont, 1967).

In solution with DMSO, effects of some hepatotoxic agents, such as aromatic hydrocarbons are potentiated (Kocsis et al., 1968; Kocsis et al., 1975). DMSO enhances hepatic binding and metabolism of some carcinogens (Levine, 1975). Teratogenic effects of DMSO have been reported in birds and mammals (Caujolle et al., 1967). Chronic thermal, chemical exposure of DMSO solvent and higher levels of chemical contaminants with severe electrical burns causes the invasive squamous cell carcinoma of the upper extremities in human beings (Chang, 2011). It requires reduction in exposure to DMSO and reduction in toxic effects before the use of DMSO in stem cell cryopreservation (Windrum et al., 2005).

4 Conclusion
Dimethyl sulfoxide’s effectiveness as a penetrant, penetrant carrier, cryoprotectant, radioprotectent, antiischemic, anti-inflammatory and analgesic agent is well established. Side effects of DMSO such as mast cell degranulation, diuresis and volume depletion may exacerbate patient’s preexisting problems and should be considered before the treatment is initiated. Dimethyl sulfoxide will have a role in veterinary patients for the treatment of sprain, bursitis, proud flesh, synovitis, postoperative swelling, otitis, pruritis, burn, ulcers and pain management if suitable preparation is introduced commercially as a drug in India.

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