Pharmacology and Clinical Use of Dimethyl Sulfoxide (DMSO): A Review

Dimethyl sulfoxide is having a pyramidal structure, CH3-SO-CH3. It is a dipolar, aprotic and highly hygroscopic solvent. It readily penetrates the skin within 5 minutes after cutaneous application. It enhances penetration of Anaesthetic, cardioactive, anticholinesterase and other not-innocuous therapeutic agents. It is recommended for acute sprains, strains, bursitis and their associated soft tissue swellings and haematoma. Combination therapy of DMSO with antibiotics or steroids enhances the healing of cutaneous habronemiasis or summer sores, bumble foot, acral lick dermatitis, arthritis, and mastitis. It is considered to have a low toxicity. 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. The therapeutic intravenous dose is about 1.0 g/kg in 10~45% solution administered slowly in humans, cats, dogs and horses. Intra articular administration of DMSO reduced severity of chemically induced synovitis in horses.


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).
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).

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.
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;and Harter, 1983).

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).

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;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).

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).
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 and2000). 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  (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).
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;and Kocsis et al., 1975). DMSO enhances hepatic binding and metabolism of some carcinogens (Levine, 1975). Teratogenic effects of  (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).

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.