Dimethyl sulfoxide (DMSO), a by-product of the wood industry, has been in use as a commercial solvent since 1953. It is also one of the most studied but least understood pharmaceutical agents of our time--at least in the United States. According to Stanley Jacob, MD, a former head of the organ transplant program at Oregon Health Sciences University in Portland, more than 40,000 articles on its chemistry have appeared in scientific journals, which, in conjunction with thousands of laboratory studies, provide strong evidence of a wide variety of properties. (See Major Properties Attributed to DMSO) Worldwide, some 11,000 articles have been written on its medical and clinical implications, and in 125 countries throughout the world, including Canada, Great Britain, Germany, and Japan, doctors prescribe it for a variety of ailments, including pain, inflammation, scleroderma, interstitial cystitis, and arthritis elevated intercranial pressure. Yet in the United States, DMSO has Food and Drug Administration (FDA) approval only for use as a preservative of organs for transplant and for interstitial cystitis, a bladder disease. It has fallen out of the limelight and out of the mainstream of medical discourse, leading some to believe that it was discredited. The truth is more complicated.

DMSO: A History of Controversy

The history of DMSO as a pharmaceutical began in 1961, when Dr. Jacob was head of the organ transplant program at Oregon Health Sciences University. It all started when he first picked up a bottle of the colorless liquid. While investigating its potential as a preservative for organs, he quickly discovered that it penetrated the skin quickly and deeply without damaging it. He was intrigued. Thus began his lifelong investigation of the drug.

The news media soon got word of his discovery, and it was not long before reporters, the pharmaceutical industry, and patients with a variety of medical complaints jumped on the news. Because it was available for industrial uses, patients could dose themselves. This early public interest interfered with the ability of Dr. Jacob--or, later, the FDA--to see that experimentation and use were safe and controlled and may have contributed to the souring of the mainstream medical community on it.

Why, if DMSO possesses half the capabilities claimed by Dr. Jacob and others, is it still on the sidelines of medicine in the United States today?

"It's a square peg being pushed into a round hole," says Dr. Jacob. "It doesn't follow the rifle approach of one agent against one disease entity. It's the aspirin of our era. If aspirin were to come along today, it would have the same problem. If someone gave you a little white pill and said take this and your headache will go away, your body temperature will go down, it will help prevent strokes and major heart problems--what would you think?"

Others cite DMSO's principal side effect: an odd odor, akin to that of garlic, that emanates from the mouth shortly after use, even if use is through the skin. Certainly, this odor has made double-blinded studies difficult. Such studies are based on the premise that no one, neither doctor nor patient, knows which patient receives the drug and which the placebo, but this drug announces its presence within minutes.

Others, such as Terry Bristol, a Ph.D. candidate from the University of London and president of the Institute for Science, Engineering and Public Policy in Portland, Oregon, who assisted Dr. Jacob with his research in the 1960s and 1970s, believe that the smell of DMSO may also have put off the drug companies, that feared it would be hard to market. Worse, however, for the pharmaceutical companies was the fact that no company could acquire an exclusive patent for DMSO, a major consideration when the clinical testing required to win FDA approval for a drug routinely runs into millions of dollars. In addition, says Mr. Bristol, DMSO, with its wide range of attributes, would compete with many drugs these companies already have on the market or in development.

The FDA and DMSO

In the first flush of enthusiasm over the drug, six pharmaceutical companies embarked on clinical studies. Then, in November 1965, a woman in Ireland died of an allergic reaction after taking DMSO and several other drugs. Although the precise cause of the woman's death was never determined, the press reported it to be DMSO. Two months later, the FDA closed down clinical trials in the United States, citing the woman's death and changes in the lenses of certain laboratory animals that had been given doses of the drug many times higher than would be given humans.

Some 20 years and hundreds of laboratory and human studies later, no other deaths have been reported, nor have changes in the eyes of humans been documented or claimed. Since then, however, the FDA has refused seven applications to conduct clinical studies, and approved only 1, for intersititial cystitis, which subsequently was approved for prescriptive use in 1978.

Dr. Jacob believes the FDA "blackballed" DMSO, actively trying to kill interest in a drug that could end much suffering. Jack de la Torre, MD, Ph.D., professor of neurosurgery and physiology at the University of New Mexico Medical School in Albuquerque, a pioneer in the use of DMSO and closed head injury, says, "Years ago the FDA had a sort of chip on its shoulder because it thought DMSO was some kind of snake oil medicine. There were people there who were openly biased against the compound even though they knew very little about it. With the new administration at that agency, it has changed a bit." The FDA recently granted permission to conduct clinical trials in Dr. de la Torre's field of closed head injury.

DMSO Penetrates Membranes and Eases Pain

The first quality that struck Dr. Jacob about the drug was its ability to pass through membranes, an ability that has been verified by numerous subsequent researchers.1 DMSO's ability to do this varies proportionally with its strength--up to a 90 percent solution. From 70 percent to 90 percent has been found to be the most effective strength across the skin, and, oddly, performance drops with concentrations higher than 90 percent. Lower concentrations are sufficient to cross other membranes. Thus, 15 percent DMSO will easily penetrate the bladder.2

In addition, DMSO can carry other drugs with it across membranes. It is more successful ferrying some drugs, such as morphine sulfate, penicillin, steroids, and cortisone, than others, such as insulin. What it will carry depends on the molecular weight, shape, and electrochemistry of the molecules. This property would enable DMSO to act as a new drug delivery system that would lower the risk of infection occurring whenever skin is penetrated.

DMSO perhaps has been used most widely as a topical analgesic, in a 70 percent DMSO, 30 percent water solution. Laboratory studies suggest that DMSO cuts pain by blocking peripheral nerve C fibers.3 Several clinical trials have demonstrated its effectiveness,4,5 although in one trial, no benefit was found.6 Burns, cuts, and sprains have been treated with DMSO. Relief is reported to be almost immediate, lasting up to 6 hours. A number of sports teams and Olympic athletes have used DMSO, although some have since moved on to other treatment modalities. When administration ceases, so do the effects of the drug.

Dr. Jacob said at a hearing of the U.S. Senate Subcommittee on Health in 1980, "DMSO is one of the few agents in which effectiveness can be demonstrated before the eyes of the observers....If we have patients appear before the Committee with edematous sprained ankles, the application of DMSO would be followed by objective diminution of swelling within an hour. No other therapeutic modality will do this."

Chronic pain patients often have to apply the substance for 6 weeks before a change occurs, but many report relief to a degree they had not been able to obtain from any other source.

DMSO and Inflammation

DMSO reduces inflammation by several mechanisms. It is an antioxidant, a scavenger of the free radicals that gather at the site of injury. This capability has been observed in experiments with laboratory animals7 and in 150 ulcerative colitis patients in a double-blinded randomized study in Baghdad, Iraq.8 DMSO also stabilizes membranes and slows or stops leakage from injured cells.

At the Cleveland Clinic Foundation in Cleveland, Ohio, in 1978, 213 patients with inflammatory genitourinary disorders were studied. Researchers concluded that DMSO brought significant relief to the majority of patients. They recommended the drug for all inflammatory conditions not caused by infection or tumor in which symptoms were severe or patients failed to respond to conventional therapy.9

Stephen Edelson, MD, F.A.A.F.P., F.A.A.E.M., who practices medicine at the Environmental and Preventive Health Center of Atlanta, has used DMSO extensively for 4 years. "We use it intravenously as well as locally," he says. "We use it for all sorts of inflammatory conditions, from people with rheumatoid arthritis to people with chronic low back inflammatory-type symptoms, silicon immune toxicity syndromes, any kind of autoimmune process.

"DMSO is not a cure," he continues. "It is a symptomatic approach used while you try to figure out why the individual has the process going on. When patients come in with rheumatoid arthritis, we put them on IV DMSO, maybe three times a week, while we are evaluating the causes of the disease, and it is amazing how free they get. It really is a dramatic treatment."

As for side effects, Dr. Edelson says: "Occasionally, a patient will develop a headache from it, when used intravenously--and it is dose related." He continues: "If you give a large dose, [the patient] will get a headache. And we use large doses. I have used as much as 30ÝmlÝIV over a couple of hours. The odor is a problem. Some men have to move out of the room [shared] with their wives and into separate bedrooms. That is basically the only problem."

DMSO was the first nonsteroidal anti-inflammatory discovered since aspirin. Mr. Bristol believes that it was that discovery that spurred pharmaceutical companies on to the development on other varieties of nonsteroidal anti-inflammatories. "Pharmaceutical companies were saying that if DMSO can do this, so can other compounds," says Mr. Bristol. "The shame is that DMSO is less toxic and has less int he way of side effects than any of them."

Collagen and Scleroderma

Scleroderma is a rare, disabling, and sometimes fatal disease, resulting form an abnormal buildup of collagen in the body. The body swells, the skin--particularly on hands and face--becomes dense and leathery, and calcium deposits in joints cause difficulty of movement. Fatigue and difficulty in breathing may ensue. Amputation of affected digits may be necessary. The cause of scleroderma is unknown, and, until DMSO arrived, there was no known effective treatment.

Arthur Scherbel, MD, of the department of rheumatic diseases and pathology at the Cleveland Clinic Foundation, conducted a study using DMSO with 42 scleroderma patients who had already exhausted all other possible therapies without relief. Dr. Scherbel and his coworkers concluded 26 of the 42 showed good or excellent improvement. Histotoxic changes were observed together with healing of ischemic ulcers on fingertips, relief from pain and stiffness, and an increase in strength. The investigators noted, "It should be emphasized that these have never been observed with any other mode of therapy."10 Researchers in other studies have since come to similar conclusions.11

Does DMSO Help Arthritis?

It was inevitable that DMSO, with its pain-relieving, collagen-softening, and anti-inflammatory characteristics, would be employed against arthritis, and its use has been linked to arthritis as much as to any condition. Yet the FDA has never given approval for this indication and has, in fact, turned down three Investigational New Drug (IND) applications to conduct extensive clinical trials.

Moreover, its use for arthritis remains controversial. Robert Bennett, MD, F.R.C.P., F.A.C.R., F.A.C.P., professor of medicine and chief, division of arthritis and rheumatic disease at Oregon Health Sciences University (Dr. Jacob's university), says other drugs work better. Dava Sobel and Arthur Klein conducted their own informal study of 47 arthritis patients using DMSO in preparation for writing their book, Arthritis: What Works, and came to the same conclusion.12

Yet laboratory studies have indicated that DMSO's capacity as a free-radical scavenger suggests an important role for it in arthritis.13 The Committee of Clinical Drug Trials of the Japanese Rheumatism Association conducted a trial with 318 patients at several clinics using 90 percent DMSO and concluded that DMSO relieved joint pain and increased range of joint motion and grip strength, although performing better in more recent cases of the disease.14 It is employed widely in the former Soviet Union for all the different types of arthritis, as it is in other countries around the world.

Dr. Jacob remains convinced that it can play a significant role in the treatment of arthritis. "You talk to veterinarians associated with any race track, and you'll find there's hardly an animal there that hasn't been treated with DMSO. No veterinarian is going to give his patient something that does not work. There's no placebo effect on a horse."

DMSO and Central Nervous System Trauma

Since 1971, Dr. de la Torre, then at the University of Chicago, has experimented using DMSO with injury to the central nervous system. Working with laboratory animals, he discovered that DMSO lowered intracranial pressure faster and more effectively than any other drug. DMSO also stabilized blood pressure, improved respiration, and increased urine output by five times and increased blood flow through the spinal cord to areas of injury.15-17 Since then, DMSO has been employed with human patients suffering severe head trauma, initially those whose intracranial pressure remained high despite the administration of mannitol, steroids, and barbiturates. In humans, as well as animals, it has proven the first drug to significantly lower intracranial pressure, the number one problem with severe head trauma.

"We believe that DMSO may be a very good product for stroke," says Dr. de la Torre, "and that is a devastating illness which affects many more people than head injury. We have done some preliminary clinical trials, and there's a lot of animal data showing that it is a very good agent in dissolving clots."

Other Possible Applications for DMSO

Many other uses for DMSO have been hypothesized from its known qualities hand have been tested in the laboratory or in small clinical trials. Mr. Bristol speaks with frustration about important findings that have never been followed up on because of the difficulty in finding funding and because "to have on your resume these days that you've worked on DMSO is the kiss of death." It is simply too controversial. A sampling of some other possible applications for this drug follows.

DMSO as long been used to promote healing. People who have it on hand often use it for minor cuts and burns and report that recovery is speedy. Several studies have documented DMSO use with soft tissue damage, local tissue death, skin ulcers, and burns.18-21

In relation to cancer, several properties of DMSO have gained attention. In one study with rats, DMSO was found to delay the spread of one cancer and prolong survival rates with another.22 In other studies, it has been found to protect noncancer cells while potentiating the chemotherapeutic agent.

Much has been written recently about the worldwide crisis in antibiotic resistance among bacteria (see Alternative & Complementary Therapies, Volume 2, Number 3, 1996, pages 140-144) Here, too, DMSO may be able to play a role. Researcher as early as 1975 discovered that it could break down the resistance certain bacteria have developed.23

In addition to its ability to lower intracranial pressure following closed head injury, Dr. de la Torre's work suggests that the drug may actually have the ability to prevent paralysis, given its ability to speedily clean out cellular debris and stop the inflammation that prevents blood from reaching muscle, leading to the death of muscle tissue.

With its great antioxidant powers, DMSO could be used to mitigate some of the effects of aging, but little work has been done to investigate this possibility. Toxic shock, radiation sickness, and septicemia have all been postulated as responsive to DMSO, as have other conditions too numerous to mention here.

DMSO in the Future

Will DMSO ever sit on the shelves of pharmacies in this country as a legal prescriptive for many of the conditions it may be able to address? Will the studies we need to discover when this drug is most appropriate ever be done? Given the difficulties the drug has run into so far and the recent development of new drugs that perform some of the same functions, Mr. Bristol is doubtful. Others, however, such as Dr. Jacob and Dr. de la Torre, see the FDA approval of DMSO for interstitial cystitis and the more recent FDA go-ahead for DMSO trials with closed head injury as new indications of hope. The cystitis approval means that physicians may use it at their discretion for other uses, giving DMSO a new legitimacy.

Dr. Jacob continues to believe that DMSO should not even be called a drug but is more correctly a new therapeutic principle, with an effect on medicine that will be profound in many areas. Whether that is true cannot be known without extensive a publicly reported trials, which are dependent on the willingness of researchers to undertake rigorous studies in this still-unfashionable tack and of pharmaceutical companies and other investors to back them up. That this is a live issue is proved by the difficulty the investigators with approval to test DMSO for closed head injury clinically are having finding funds to conduct the trials.

In 1980, testifying before the Select Committee on Agin of the U.S. House of Representatives, Dr. Scherbel said, "The controversy that exists over the clinical effectiveness of DMSO is not well-founded--clinical effectiveness may be variable in different patients. If toxicity is consistently minimal, the drug should not be restricted from practice. The clinical effectiveness of DMSO can be decided with complete satisfaction if the drug is made available to the practicing physician. The number of patient complaints about pain and the number of phone calls to the doctor's office will decide quickly whether or not the drug is effective."

It may be premature to call for the full rehabilitation of DMSO, but it is time to call for a full investigation of its true range of capabilities.

Current Status of DMSO

Stanley W. Jacob, M.D

Gerlinger Professor • Department of Surgery • Oregon Health Sciences University , 3181 S.W. Sam Jackson Park Road • Portland, Oregon 97201 • (503) 494-8474 January, 1996

DMSO (dimethyl sulfoxide), as a therapeutic principle, was first introduced to the scientific community in 1963 by a research team headed by Stanley W. Jacob, MD, at the University of Oregon Medical School. While DMSO has been called "the most controversial therapeutic advance of modern times," the "controversy" seems to be bureaucratic and economic rather than scientific. Over the past thirty years, more than 11,000 articles on the biologic implications of DMSO have appeared in the scientific literature. The results of these studies strongly support the view that DMSO may be the most significant new therapeutic principle presented to science in the last half of the 20th century.

When organ systems are injured or deteriorate, the damaged tissue produces agents we call "free radicals." These further harm cells and prevent or slow healing. DMSO is a potent scavenger of these radicals, maintaining the normal integrity of cells and tissues.

Another important component of DMSO activity is its synergism with other therapeutic agents. For example, Charles Dake, D.V.M. (Annals of the N.T. Academy of Sciences, 1967, Vol. 141) found that cats with overwhelming viral infection treated with either DMSO alone or conventional therapy for viral infections all died. When DMSO was combined with standard antiviral treatment, the figures were reversed with the majority of the cats surviving.

At this time, DMSO is a respected, approved pharmaceutical agent in over one hundred countries. In 1978, it was approved by the FDA for the therapy of interstitial cystitis (a painful disabling urinary bladder inflammation). Additionally, in 1970, the FDA approved DMSO for the treatment of musculoskeletal disorders in dogs and horses. Many veterinarians consider DMSO to be the most valuable therapeutic substance in their armamentarium. In many ways, DMSO represents the "aspirin" of our era. If aspirin had been introduced in 1963 with its multiple properties, it might very well have been similarly restricted in the scope of its application.

DMSO became prescriptive for humans in the USSR n 1971. Since that time, it has become more and more widely used alone and in combinations. Dr. Balabanova of the Moscow Institute of Rheumatology estimates that about 50% of the Russian arthritic population receive DMSO as a part of their therapy. There are over one hundred articles in the world's literature relating to DMSO and arthritis. These include both clinical results and mechanism of action. Among the well documented pharmacologic properties of DMSO include analgesia, anti-inflammation, softening of scar tissue, and hydroxyl radical scavenging.

Pharmacology of DMSO Stanley W. Jacob and Robert Herschler Department of Surgery • Oregon Health Science University • Portland, Oregon 97201

Abstract

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 DMSO-hydrogen 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 anti-inflammation 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 the 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 anti-inflammatory 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 10- to 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

F. Bacteriostasis

DMSO exerts a marked inhibitory effect on a wide range of bacteria and fungi including at least one parasite, at concentrations (30-50%) likely to be encountered in antimicrobial testing programs in industry.6

DMSO at 80% concentration inactivated viruses tested by Chan and Gadenbusch. These viruses included four RNA viruses, influenza A virus, influenza A-2 virus, Newcastle disease virus, Semliki Forest virus, and DNA viruses.12

Seibert and co-worker98 studied the highly pleomorphic bacteria regularly isolated from human tumors and leukemic blood. DMSO in 12.5-25% concentration caused complete inhibition of growth in vitro of 27 such organisms without affecting the intact blood cells.

Among the intriguing possibilities for the use of DMSO is its ability to alter bacterial resistance. Pottz and associates78 presented evidence that the tubercle bacillus, resistant to 2000Ýg of treptomycin or isoniazide, became sensitive to 10Ýg of either drug after pretreatment with 0.5-5% DMSO.

Kamiya et al.54 found that 5% DMSO restored and increased the sensitivity of antibiotic-resistant strains of bacteria. In particular, the sensitivity of all four strains of Pseudomonas to colistin was restored when the medium contained 5% DMSO. The authors recorded that antibiotics not effective against certain bacteria, such as penicillin to E. coli, showed growth inhibitory effects when the medium contained DMSO.

Ghajar and Harmon35 studied the influence of DMSO on the permeability of Staphylococcus aureau, demonstrating that DMSO increased the oxygen uptake but reduced the rate of glycine transport. They could not define the exact mechanism by which DMSO produced its bacteriostatic effect.

Gillchriest and Nelson37 have suggested that bacteriostasis from DMSO occurs due to a loss of RNA conformational structure required for protein synthesis.

G. Diuresis

Formanek and Suckert32 studied the diuretic effects of DMSO administered topically to rats five times daily in a dosage of 0.5 ml of 90% DMSO per animal. The urine volume was increased 10-fold, and with the increase in urine volume, there was an increase in sodium and potassium excretion.

H. Enhancement or Reduction of Concomitant Drug Action

Rosen and associates84 employed aqueous DMSO to alter the LD50 in rats and mice when oral quaternary ammonium salts were used as test compounds. In rats, the toxicity of pentolinium tartrate and hexamethonium bitartrate was increased by DMSO, while the toxicity of hexamethonium iodide was decreased.

Male68 has shown that DMSO concentrations of upward to 10% lead to a decided increase in the effectiveness of griseofulvin.

Melville and co-workers70 have studied the potentiating action of DMSO on cardioactive glycosides in cats, including the fact that DMSO potentiates the action of digitoxin. This effect, however, does not appear to involve any change in the rate of uptake (influx) or the rate of loss (efflux) of glycosides in the heart.

I. Cholinesterase

Sams et al.90 studied the effects of DMSO on skeletal, smooth, and cardiac muscle, employing concentrations of 0.6-6%. DMSO strikingly depressed the response of the diaphragm to both direct (muscle) and indirect (nerve) electrical stimulation, and caused spontaneous skeletal muscle fasciculations. DMSO increased the response of the smooth muscle of the stomach to both muscle and nerve stimulations. The vagal threshold was lowered 50% by 6% DMSO. Cholinesterase inhibition could reasonably explain fasciculations of skeletal muscle, increased tone of smooth muscle, and the lower vagal threshold observed in these experiments. In vitro assays show that 0.8-8% DMSO inhibits bovine erythrocyte cholinesterase 16-18%.

J. Nonspecific Enhancement of Resistance

In a study of antigen-antibody reactions, Reattig81 showed that DMSO did not disturb the immune response. In fact, the oral administration of DMSO to mice for 10 days prior to an oral infection with murine typhus produced a leukocytosis and enhanced resistance to the bacterial infection.

K. Vasodilation

Adamson and his co-workers1 applied DMSO to a 3-1 pedicle flap raised on the back of rats. The anticipated slough was decreased by 70%. The authors suggested that the primary action of DMSO on pedicle flap circulation was to provoke a histamine-like reponse. Roth87 has also evaluated the effects of DMSO on pedicle flap blood flow and survival, concluding that DMSO does indeed increase pedicle flap survival, but postulating that this increase takes place by some mechanism other than augmentation of perfusion. Kligman56, 57 had previously demonstrated that DMSO possesses potent histamine-liberating properties.

Leon62 has studied the influence of DMSO on experimental myocardial necrosis. DMSO therapy effected a distinct modification with less myocardial fiber necrosis and reduced residual myocardial fibrosis. The author reported that neither myocardial rupture nor aneurysm occured in the group treated with DMSO.

L. Muscle Relaxation

DMSO applied topically to the skin of patients produces electromyographic evidence of muscle relaxation 1 hour after application.8

M. Antagonism to Platelet Aggregation

Deutsch23 has presented experimental data showing that 5% DMSO lessons the adhesiveness of blood platelets in vitro. Gorog39 has shown that DMSO is a good antagonist to platelet aggregation as well as thrombus formation in vivo. Gorog evaluated this in the hamster cheek pouch model.

N. Enhancement of Cell Differentiation and Function

It has been shown that dimethyl sulfoxide induces differentiation and function of leukemic cells of mouse 11, 33, 46, 65, 92, 115, rat,58 and human.9, 15, 16, 34, 109 DMSO was also found to stimulate albumin production in malignantly transformed hepatocytes of mouse and rat49 and to affect the membrane-associated antigen, enzymes, and glycoproteins in human rectal adenocarcinoma cells.111 Hydrocortisone-induced keratinization of chick embryo cells74 and adriamcycin-induced necrosis of rat skin108 were inhibited by DMSO.

Furthermore, modification by DMSO of the function of normal cells has been reported. DMSO stimulates cyclic AMP accumulation and lipolysis and decreases insulin-stimulated glucose oxidation in free white fat cells of [the] rat. It also enhances heme synthesis in quail embryo yolk sac cells.110

Leukemic blasts can be induced by external chemical agents to mature to neutrophils, monocytes, or RBCs. The phenotype of leukemic cells thus results from both internal genetic aberrations and the response of leukemic cells to their external environment. When human myeloid leukemia cells are exposed in vitro to a variety of agents (e.g.vitamin A or dimenthyl sulfoxide) the blasts lose their proliferative potential, the expression of oncogene products is sharply decreased, and after 5 days the leukemic cells become morphologically mature and functional neutrophils. Some patients with myeloid leukemias have responded to therapy designed to induce maturation in vivo. The induced maturation of leukemic cells is a new therapeutic tactic-alternative to cytotoxic drug therapy-wherein leukemic cells are destroyed by transforming them into neutrophils.86

O. Influence on Serum Cholesterol in Experimental Hypercholesterolemia

Rabbits given a high cholesterol diet with 1% DMSO showed one-half as much hypercholesterolemia as control animals.48

P. Radioprotective and Cryoprotective Actions

M.J. Ashwood-Smith has written a comprehensive review of these actions.4

Q. Protection against Ischemic Injury

De la Torre has advanced a scheme based on both investigated and theoretical actions of DMSO on the biochemical events generated after an ischemic injury. He previously proposed this hypothetical model to help conceptualize how DMSO, or similar drugs, mights affect the pathochemical balance that results in lack of tissue perfusion following trauma.19

The biochemical and vascular responses to injury appear to have a cause and effect relationship that can be integrated in terms of substances that either increase or decrease blood flow. The substance's effect can be physical, i.e. reduce or increase the vessel lumen obstruction, or chemical, i.e. reduce or increase the vessel lumen diameter (vasoconstriction/vasodilation).

Platelets, for example, can induce both conditions. Obstruction of the vessel lumen can result from platelet adhesion (platelet buildup in damaged vessel lining) or platelet aggregation. Platelet damage moreover can cause vasoconstriction or vasospasm by liberating vasoactive substances locally with the blood vessel or perivascularly, if penetrating damage to the vessel has occurred. There are two storage sites within platelets that contain most of these vasoactive substances. The alpha granules contain fibrinogen, while the dense bodies store ATP, ADP, serotonin, and calcium, which can be secreted by the platelet into the circulation by a canalicular system.5 Thromboxane A2 has also been shown to be manufactured in the microsomal fraction of animal and human platelets.73 All these vasoactive substances (with the exception of ATP) can cause significant reduction of blood flow by physical or chemical reactivity on the vasculature.

DMSO can antagonize a number of these vasoactive substances released by the platelets, which could consequently induce vasoconstriction, vasospasm, or obstruction of vessel lumen. For example, a study has shown that DMSO can inhibit ADP and thrombin-induced platelet aggregation in vitro.95 It may presumable do this by increasing the evels of cAMP (a strong platelet deaggregator) through inhibition of its degradative enzyme, phosphodiesterase.26, 51 DMSO is reported to deaggregate platelets in vivo following experimental cerebral ischemia.26, 51 This effect may be fundamental in view of the finding that cerebral ischemia produces transient platelet abnormalities that may promote microvascular aggregation formation and extend the area of ischemic injury.25

The biochemical picture is further complicated by the possible activity of DMSO on other vasoactive substances secreted by the platelets during injury or ischemia. For example, the release of calcium from cells from cells or platelets and its effect on arteriolar-wall muscle spasm may be antagonized by circulating DMSO.13, 88 Collagen-induced platelet release may also be blocked by DMSO.44, 94

The following effects of DMSO are likely to be involved in its ability to protect against ischemic injury.

DMSO and PGTX System

Little is known about the actions of DMSO on the prostanoids (PG/TX). Studies have reported that DMSO can increase the synthesis of PGE1, a moderate vasodilator.61. PGE1 can reduce platelet aggregation by increasing cAMP levels and also inhibit the calcium-induced release of noradrenalin in nerve terminals, an affect that may antagonize vasoconstriction and reduction of cerebral blood flow.53

DMSO, it will be recalled, also has a direct effect on cAMP. It increases cAMP presumably by inhibiting phosphodiesterase,113 although an indirect action on PGI2-induced elevation of platelet cAMP by DMSO should not be ruled out. Any process that increases platelet cAMP will exert strong platelet deaggregation.

It has also been reported that DMSO can block PFG2 receptors and reduce PFE2 synthesis.82 Both these compounds can cause moderate platelet aggregation and PFG2 is known to induce vasoconstriction.60 The effects of DMSO on thromboxane synthesis are unknown. It could, however, inhibit TXA2, biosynthesis in much the same way as hydralazine or dipyridamole42 since it shares a number of similar properties with these agents: specifically, their increase of cAMP levels.

DMSO and Cell Membrane Protection

The ability of DMSO to protect cell membrane integrity in various injury models is well documented.38, 64, 91, 114

Cell membrane preservation by DMSO might help explain its ability to improve cerebral and spinal cord blood flow after injury.18 DMSO could be preventing impairment of cerebrovascular endothelial surfaces where PGI2 is elaborated and where platelets can accumulate following injury. The effects of DMSO may be two-fold: reduction of platelet adhesion by collagen,44 and reduction of platelet adhesion by protecting the vascular endothelium and ensuring PGI2 release.

DMSO, Hydroxyl Radicals, and Calcium

Although many hormones, chemical transmitters, peptides, and numerous enzymes can be found in mammalian circulation at any given time, it is the hydrozyl radicals that have drawn attention by playing an important role in the pathogenesis of ischemia.21, 30 Free radicals can be elaborated by peroxidation of cellular membrane-bound lipids where oxygen delivery is not totally abolished, as in ischemia and hypoxia, or when oxygen is resupplied after an ischemic episode.83

One of the significant sites where hydroxyl radicals can form following ischemia is in mitochondria. DMSO is known to be an effective hydroxyl radical scavenger.4, 20, 75 Since it has been shown that DMSO can improve mitochondrial oxidative phosphorylation, it has been suggested that DMSO may act to neutralize the cytotoxic effects of hydroxyl radicals in mitochondria themselves.96 Oxidative phosphorylation is one of the primary biochemical activities to be negatively affected following ischemic injury. DMSO has also been reported to reduce ATPase activity in submitochondrial particles,17, 36 an effect that can lower oxygen utilization during cellular ischemia.

It has been proposed that DMSO may reduce the utilization of oxygen by an inhibiting effect on mitochondrial function. In one experiment the energy loss due to inhibition of oxidative activity after brain tissue was perfused with DMSO was compensated for by an increase in glycolysis.36

It seems probable that the neutralizing action of DMSO on hydroxyl radical damage following injury could diminish the negative outcome of ischemia. However the formation of hydroxyl radicals is dependent on time and oxygen availability, but the development of ischemia is immediate and its reversal may depend on more prevalent subsystems such as the PG/TX and platelet interactions. Maintaining the balance of these subsystems appears more critical in predisposing the outcome of cerebral ischemia.

Another interesting effect of DMSO is on calcium. When isolated rat hearts are perfused with calcium-free solution followed by reperfusion with a calcium-containing solution, a massive release of creatine kinase (indicating cardiac injury) is observed. This creatine kinase level increase is accompanied by electrocardiographic (EKG) changes and ultrastructural cell damage.50 DMSO has been reported to significantly reduce the release of creatine kinase and prevent EKG and ultrastructural changes if it is present during reperfusion of the isolated rat heart with a calcium-containing solution.88 Moreover, examination of the heart tissue by electron microscopy showed that DMSO-treated preparations lacked the mitochondrial swelling and contraction band formation otherwise induced by the reentry of calcium.88 These findings are supported by another investigation showing that DMSO can block calcium-induced degeneration of isolated myocardial cells.13 This protective effect by DMSO on myocardial tissue may be critical during ischemic myocardial infarction when evolutionary EKG changes, serum creates kinase levels are elevated, and myocardial necrosis can develop rapidly.

DMSO2 is not an effective cryoprotective agent; however, Herschler47 has recorded that DMSO (dimethyl sulfone) is a natural source of biotransformable sulfur in plants and lower animals. Jacob and Herschler have reported a number of unique properties possessed by DMSO.52 Since DMSO is oxidized to DMSO2 in vivo, scientists should include DMSO as a control in basic biologic studies on DMSO in plants and animals.

Footnotes

(a) Although the abbreviation "Me2SO" has been recommended for chemists by the IUPAC, the abbreviation for dimethyl sulfoxide most familiar to those concerned with its medicinal uses is "DMSO." Consequently, this generic pharmacological name for dimethyl sulfoxide will be employed throughout this paper.

(b) Supported in part by a grant from The Ronald J. Purer Foundation. Presented at the Symposium Biological Effects of Cryoprotective Agents at the Cryobiology Meeting, June 1985, Madison, Wis.

(c) Stanley W. Jacob, MD, Gerlinger Associate Professor of Surgery and Surgical Research.

New Possibilities in the Treatment of Patients with Alzheimer's Disease S.A. Goppa Department of Neurology & Neurosurgery • Medical University • Kisheinev • 277072 • Moldova

Abstracts

The Fourth International Conference on Alzheimer's Disease and Related Disorders

Conveners

James Mortimer, Ph.D. Khalid Iqbal, Ph.D. Bengt Winblad, MD, Ph.D.

Henry M. Wisniewski, MD, Ph.D. Organized by: Al Snider, Ph.D.

The Role of Amyloid Proteins in Alzheimer's Disease

The effect of the drug, dimethyl sulfoxide, was studied in 18 patients with "probable AD" diagnosed according to NINCDA-ADRDA criteria. Patients were repeatedly tested for a period of 9 months. Efficacy was estimated from the results of neurological and neuropsychological testing, immunological examination of neurospecific proteins (NSP) and autoantibodies (AAB) to them.

The obtained results indicated that the severity of mental-amnestic disturbances and disorientation in time and space reliably decreased after 3 and especially 6 months of treatment. There was also a trend for praxic and speech impairments to decrease from baseline, in addition, indices of concentration and communicability improved.

The results of immunoenzyme analysis of NSP and AAB to them showed a decrease of NSP serum concentration and a stabilizing influence of dimethyl sulfoxide on the blood brain barrier.

The action mechanism, clinical efficacy and adverse reactions will be discussed.

Fybromyalgia Syndrome

Fibromyalgia Syndrome (FMS) is pronounced "fie-bro-my-al-jia sind-rome." The word fibromyalgia is a combination of the Latin roots "fibro" (connective tissue fibers), "my" (muscle), "al" (pain), and "gia" (condition of). The word syndrome simply means a group of signs and symptoms that occur together which characterize a particular abnormality.

For many years the medical profession called FMS many different names, including chronic rheumatism, myalgia, pressure point syndrome, and fibrositis. It is important to understand that FMS is not a catch-all, "wastebasket" diagnosis." FMS is a specific, chronic non-degenerative, non-progressive, non-inflammatory, truly systemic pain condition- a true syndrome.

The Copenhagen Declaration defines FMS as a painful, but not articular (not present in the joints), condition predominantly involving muscles, and as the most common cause of chronic, widespread musculoskeletal pain. Other symptoms include: the presence of unexplained widespread pain or aching, persistent fatigue, generalized morning stiffness, non-refreshing sleep, and multiple tender points. Most patients with these symptoms have 11 or more tender points.

In addition, the Copenhagen Declaration states that fibromyalgia syndrome is "part of a wider syndrome encompassing headaches, irritable bladder, dysmenorrhea, cold sensitivity, Raynaud*s phenomenon, restless legs, atypical patterns of numbness and tingling, exercise intolerance and complaints of weakness."

Over the last few years, we have been treating patients with fibromyalgia. Seventy percent of the patients have experienced benefit. No serious side effects have been encountered.

The properties of our regime contributing to benefit included free-radical scavenging, analgesia, anti-inflammation, softening of scar tissue, reduction of muscle spasm, and stimulation of healing.

DMSO Carries Relief for Birthmark Removal

Research on dimethyl sulfoxide (DMSO) continues, and scientists are finding more and more beneficial uses for this medical and solvent compound first discovered by Dr. Stanley Jacob at the Oregon Health Science University.

Although DMSO has been labeled an "orphan drug," it has proven by researchers to have many useful medical applications.

Recently reported is its use in patients undergoing pulsed dyelaser treatment for vascular malformations.

Scientists at Washington University School of Medicine, St.Louis, and the University of Arkansas departments of dermatology, looking for a topical agent that would wouldproduce anesthesia for painful procedures but would not have to be injected, report that topical lidocaine at 25% concentration indimethyl sulfoxide 70% was most effective.

"Pulsed dye laser treatment of vascular malformations,including strawberry birthmarks in children, has now become avaluable treatment option for capillary vascular malformationsand hemangiomas, but is moderately painful. Since many of the patients are children who do not tolerate painful procedures well, the length of a single treatment is often limited by pain. Many of these lesions are large and may encompass half of theface, or an entire limb.

"The object of the study was to develop a rapidly acting, topicalanesthetic formulation to reduce the pain associated with pulseddye therapy, yet wear off within a few hours and have noprolonged side effects," according to the researchers.

The lidocaine DMSO topical application was "well tolerated onthe evaluated patients, age 6 years and older, and had no sideeffects except transient mild erythema."

This article appeared in "The Oregon Scientist," Spring, 1995.

Treating Extravasation Injury

Soft-tissue damage can be reversed with topical DMSO Stephen B. Strum, MD

Extravasation injury, which occurs in about 1% of patients undergoing chemotherapy, is associated with significant morbidity. Topical application of dimethyl sulfoxide (DMSO), an anti-inflammatory agent, has been shown to be effective in treating this problem in several studies.1-2 In a pilot study, DMSO therapy over 3 months significantly improved anthracycline-associated extravasation in 16 of 20 patients.2

In our experience, regular DMSO application can completely reverse extravasation injury even when treatment is delayed. For example, in one patient receiving continuous-infusiondoxorubicin for hepatoma, chest-wall induration of 5 days standing decreased more than 50% after 4 weeks of DMSO therapy and completely resolved after 8 weeks. The induration resulted from inadvertent extravasation that occurred when the catheter needle worked its way out of the port.

Even days after injury, we instruct patients to liberally apply70% DMSO using cotton swabs and remove any excess remaining after 45 minutes with a white cotton cloth or tissue.This treatment is repeated every 3 to 4 hours during the day untilall evidence of injury has disappeared.

In 20 years of using DMSO, the only toxicity we have seen has been a stinging or burning sensation during initial application. If the problem becomes severe, aloe vera gel can be applied after wiping off the remaining DMSO. Patients treated with DMSO also may develop a characteristic breath odor. Other practitioners and researchers also have had positive results with DMSO.1-10 We suggest that a central repository be formed for the study of extravasation injury and DMSO.

Dr. Strum is a medical oncologist in private practice in CulverCity, Calif.