Farmacologia do DMSO Pharmacology of DMSO

A wide range of primary pharmacological actions of dimethyl sulfoxide (DMSO) has been documented in laboratory studies: membrane transport, effects on connective tissue, anti-inflammation, nerve blockade (analgesia), bacteriostasis, diuresis, enhancements or reduction of the effectiveness of other drugs, cholinesterase inhibition, nonspecific enhancement of resistance to infection, vasodilation, muscle relaxation, antagonism to platelet aggregation, and influence on serum cholesterol in emperimental hypercholesterolemia. This substance induces differntiation and function of leukemic and other malignant cells. DMSO also has prophylactic radioprotective properties and cryoprotective actions. It protects against ischemic injury. (1986 Academic Press, Inc.) The pharmacologic actions of dimethyl sulfoxide (DMSO) have stimulated much research. The purpose of this report is to summarize current concepts in this area. When the theorectical basis of DMSO action is described, we can list literally dozens of primary pharmacologic actions. This relatively brief summary will touch on only a few: (A) membrane penetration (B) membrane transport (C) effects on connective tissue (D) anti-inflamation (E) nerve blockade (analgesia) (F) bacteriostasis (G) diuresis (H) enhancement or reduction of effectiveness of other drugs (I) cholinsterase inhibition (J) nonspecific enhancement of resistance of infection (K) vasodilation (L) muscle relaxation (M) enhancement of cell differentiation and function (N) antagonism to platelet aggregation (O) influence on serum cholesterol in experimental hypercholesterolemia (P) radio-protective and cryoprotective actions (Q) protection against ischemic injury Primary Pharmocological Actions A. Membrane Penetration DMSO readily crosses most tissue membranes of lower animals and man. Employing [35S] DMSO, Kolb et al,59 evaluated the absorption and distribution of DMSO in lower animals and man. Ten minutes after the cutaneous application in the rat, radioactivity was measured in the blood. In man radioactivity appeared in the blood 5 minutes after cutaneous application. One hour after application of DMSO to the skin, radioactivity could be detected in the bones. Denko22 and his associates applied 35S-labeled DMSO to the skin of rats. Within 2 hour a wide range of radioactivity was distributed in all organs studied. The highest values occurred in decreasing order in the following soft tissues; spleen, stomach, lung, vitreous humor, thymus, brain, kidney, sclera, colon, heart, skeletal muscle, skin, liver, aorta, adrenal, lens of eye, and cartilage. Rammler and Zaffaroni80 have reviewed the chemical properties of DMSO and suggested that the rapid movement of this molecule through the skin, a protein barrier, depends on a reversible configurational change of the protein occurring when DMSO substitutes for water. B. Membrane Transport Nonionized molecules of low molecular wight are transported through the skin with DMSO. Substance of high molecular weight such as insulin do not pass through the skin to any significant extent. Studies in our laboratory have revealed that a 90% concentration of DMSO is optimal for the passage of morphine sulfate dissoved in DMSO.77 It would have been expected that 100% would provide better transport than 90%, and the reason for an optimal effect at 90% DMSO remains unexplained. It is of course well known that 70% alcohol has a higher phenol:water partition coefficient than 100% alcohol. Elfbaum and Laden27 conducted an in vitro skin penetration study employing guinea pig skin as the membrane. They concluded that the passage of picrate ion through this membrane in the presence of DMSO was a passive diffusion process which adhered to Fick's first law of diffusion. It is demonstrated by diffusion and isotope studies that the absolute rate constant for the penetration of DMSO was approximately 100 times greater than that for the picrate ion. Thus, the two substances were transferred through the skin independently of each other. The exact mechanisms involved in the membrane penetrant action of DMSO have yet to be elucidated. Studies on membrane penetration and carrier effect have been carrier effect have been carried out in agriculture, basic biology, animals, and man. In field tests with severely diseased fruit, Keil55 demonstrated that oxytetracycline satisfactorily controlled bacterial spot in peaches. Control was significantly enhanced by adding DMSO to the antibiotic spray. DMSO was applied to 0.25 and 0.5% with 66 ppm of oxytetracycline. This application gave control of the disease similar to that produced alone by 132 ppm of oxytetracycline and suggested the possibility of diluting the high-priced antibiotic with relatively inexpensive DMSO. There is no good evidence in animals that 0.5% DMSO has significant carrier effects. It could well be that Keil's results were attributable to a carrier effect, but the possibility should always be considered that when DMSO is combined with another substance a new compound results which can then exert a greater or lesser influence on a given process. Leonard63 studied different concentrations of several water-soluable iron sources applied as foliage sprays to orange and grapefruit trees whose leaves showed visible signs of iron deficiency. The application of iron in DMSO as a spray was followed by a rapid and extensive greening of the leaves, with a higher concentration of chlorophyll. Amstey and Parkman2 evaluated the influence of DMSO on the infectivity of viral nucleic acid, an indication of its transmembrane transport. It was found that DMSO enhanced polio RNA infectivity in kidney cells from monkeys. Enhancement occurred with all DMSO concentrations from 5 to 80% and was optimal at 40% DMSO, with a 20-minute absorption period at room temperature. A significant percentage of nucleic acid infection was absorbed within the first 2 minutes. Cochran and his associates14 concluded that concentrations of DMSO below 20% did no influence the infectivity of tobacco mosaic virus (TMV) or the viral RNA. With concentrations between 20 and 60% the infectivity of TMV and TMV RNA varied inversely with the DMSO concentration. Nadel and co-workers72 suggested that DMSO enhanced the penetration of the infectious agent in experimental leukemia of gunea pigs. Previously Schreck et al.97 had demonstrated that DMSO was more toxic in vitro to lymphocytic leukemia than to lymphocytes from normal patients. Djan and Gunberg24 studied the percutaneous absorption of 17-estradiol dissolved in DMSO in the immature female rat. These steroids were given in aqueous solutions subcutaneously or were applied topically in DMSO. Vaginal and uterine weight increases resulting from estrogen in DMSO administered topically were comparable to results obtained in animals in which the drugs were administered in pure form subcutaneously. Smith102 reported that a mixture of DMSO and diptheria toxoid applied frequently to the backs of rabbits causes a reduction of the inflammation produced by the Shick test, indicating that a partial immunity of diphtheria has been produced. Finney and his associates29 studied the influence of DMSO and DMSOhydrogen peroxide on the pig myocardium after acute coronary ligation with subsequent myocardial infaction. The addition of DMSO to a hydrogen peroxide perfusion system fascilitated the difffusion of oxygen into the ischemic myocardium. Maddock et al.66 designed experiments to determine the usefulness of DMSO as a carrier for antitumor agents. The agents were dissoved in 85-100% concentrations of DMSO. One of the tumors studied was the L1210 leukemia. Survival time without treatment was appoximately 8 days. The standard method of employing Cytoxan intraperitoneally produced a survival time of 15.5 days. When Cytoxan was applied topically in water, the survival time was 12.6 days, and topical Cytoxan dissolved in DMSO resulted in survival time of 15.3 days. Spruance recently studied DMSO as a vehicle for topical antiviral agents, concluding that the penetration of acyclovir (ACV) through guinea pigs skin in vitro was markedly greater with DMSO than when ployethylene glycol (PEG) was the vehicle. When 5% ACV in DMSO was compared with 5% ACV in PEG in the treatmental herpes infection in the guinea pig, ACV DMSO was more effective.103 The possibility of altering the blood-brain diffusion barrrier with DMSO needs additional exploration. Brink and Stein10 employed [14C]pemoline dissolved in DMSO and injected intraperitoneally into rats. It was found in larger amounts in the brain than was a similar dose given in 0.3% tragacanth suspension. The authors postulated that DMSO resulted in a partial breakdown of the blood-brain diffusion barrier in vitro. There is conflicting evidence as to whether dimethyl sulfoxide can reversibly open the blood-brain barrier and augment brain uptake of water-soluable compounds, including anticancer agents. To investigate this, 125[-Human serum albumin, horse-radish peroxidase, or the anticancer drug melphalan was administered iv to rats or mice, either alone or in combination with DMSO. DMSO administration did not significantly increase the brain uptake of any of the compounds as compared to control uptakes. These results do not support prior reports that DMSO increases the permeability of water-soluable agents across the blood-brain barrier.43 Maibach and Feldmann67 studied the percutaneous penetration of hydrocortisone and testosterone in DMSO. The authors concluded that there was a threefold increase in dermal penetration by these steroids when they were dissolved in DMSO. Sulzberger and his co-workers107 evaluated the penetration of DMSO into human skin employing methylene blue, iodine, and iron dyes as visual tracers. Biopsies showed that the stratum corneum was completely stained with each tracer applied to the skin surface in DMSO. There was little or no staining below this layer. The authors concluded that DMSO carried substances rapidly and deeply into the horny layer and suggested the usefulness of DMSO as a vehicle for therapeutic agents in inflammatory dermatoses and superficial skin infections such as pyodermas. Perliman and Wolfe76 demonstrated that allergens of low molecular weight such as penicillin G potassium, mixed in 90% DMSO, were readily carried through intact human skin. Allergens having molecular weights of 3000 or more dissolved in DMSO did not penetrate human skin in these studies. On the other hand, Smith and Hegre101 had previously recorded that antibodies to bovine serum albumin developed when a mixture of DMSO and bovine serum albumin was applied to the skin of rabbits. Turco and Canada112 have studied the influence of DMSO on lowering electrical skin resistance in man, In combination with 9% sodium chloride in distilled water, 40% DMSO decreased resistance by 100%. It was postulated that DMSO in combination with electrolytes reduced the electrical resistance of the skin by facilitating the absorption of these electrolytes while it was itself being absorbed. DMSO in some instances will carry substances such as hydrocortisone or hexachlorophene into the deeper layers of the stratum corneum, producing a reservoir.104 This reservoir remains for 16 days and resists depletion by washing of the skin surface with soap, water, or alcohol.105 C. Effect on Collagen Mayer and associates69 compared the effects of DMSO, DMSO with cortisone acetate, cortisone acetate alone, and saline solutions on the incidence of adhesions following vigorous serosal abrasions of the terminal ileum of Wistar rats. Their technique had developed adhesions in 100% of control animals in 35 days. The treatments were administered daily as postoperative intraperitoneal injections for 35 days. The incidence of adhesions in different groups was DMSO alone: 20%, DMSO-cortisone: 80%, cortisone alone: 100%, saline solution: 100%. It has been observed in serial biopsy specimens taken from the skin of patients with scleroderma that there is a dissolution of collagen, the elastic fibers remaining intact.93 Gries et al.44 studied rabbit skin before and after 24 hour in vitro exposure to 100% DMSO. After immersion in DMSO the collagen fraction extractable with neutral salt solution was significantly decreased. The authors recorded that topical DMSO in man exerted a significant effect on the pathological deposition of collagen in human postirradiation subcutaneous fibrosis but did not appear to change the equilibrium of collagen metabolism in normal tissue. Urinary hydroxyproline levels are increased in scleroderma patients treated with topical DMSO.93 Keloids biopsied in man before and after DMSO therapy show histological improvement toward normalcy.28 D. Anti-Inflammation Berliner and Ruhmann7 found that DMSO inhibited fibroblastic proliferation in vitro. Ashley et al.3 reported that DMSO was ineffective in edema following thermal burns of the limbs of rabbits. Formanek and Kovak31 showed that topically applied DMSO inhibited traumatic edema induced by intrapedal injection of autologous blood in the leg of a rat. DMSO showed no anti-inflammatory effect when studied in experimental effect when studied in experimental inflammation induced in the rabbit eye by mustard oil in the rat ear by croton oil.79 Gorog and Kovacs40 demonstrated that DMSO exerted minimal antiinflammation effects on edema induced by carrageenan. These authors also studied the anti-inflammatory potential of DMSO in adjuvant-induced polyarthritis of rats. Topical DMSO showed potent anti-inflammatory properties in this model. Gorog and Kovacs41 have also studied the anti-inflammatory activity of topical DMSO, in contact dermatitis, allergic eczema, and calcification of the skin of thr rat, using 70% DMSO to treat the experimental inflammation. All these reactions were significantly inhibited. The study of Weissmann et al.114 deserves mention in discussing the antiinflammatory effects of DMSO. Lysosomes can be stabilized against a variety of injurious agents by cortisone, and the concentration of the agent necessary to stabilize lysosomes is reduced 10to 1000-fold by DMSO. The possibility was suggested that DMSO might render steroids more available to their targets within tissues (membranes of cells or their organelles). Suckert106 has demonstrated anti-inflammatory effects with intra-articular DMSO in rabbits following the creation of experimental [croton oil] arthritis. E. Nerve Blockade (Analgesia) Immersion of the sciatic nerve in 6% DMSO decreases the conduction velocity by 40%. This effect is totally reversed by washing the nerve in a buffer for 1 hour.89 Shealy99 studied peripheral small fiber after-discharge in the cat. Concentrations of 5-10% DMSO eliminated the activity of C fibers with 1 minute: activity of the fibers returned after the DMSO was washed away. DMSO injected subcutaneously in 10% concentration into cats produced a total loss of the central pain response. Two milliliters of 50% DMSO injected into the cerebrospinal fluid led to total anesthesia of the animal for 30 minutes. Complete recovery of the animal occurred without apparent ill effect.100 Haigler concluded that DMSO is a drug that produced analgesia by acting both locally and systemically. The analgesia appeared to be unrelated to that produced by morphine although the two appear to be a comparable magnitude. DMSO had a longer duration of action than morphine, 6 hr vs 2 hr, respectively.45