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Short-term studies with volunteers

Seventy-eight men applied DMSO (1 g/kg, 80% DMSO gel) to the skin once daily for 14 consecutive days, and 33 subjects acted as controls. Extensive physical and laboratory examinations were performed periodically on all subjects. DMSO-related side effects were minor and included, in addition to the anticipated skin reactions and halitosis, sedation (52%), headache (42%), dizziness (18%) and nausea (32%). A modest oesinophilia was consistently observed in some of the subjects, which was attributed to the cutaneous histamine-releasing effect of DMSO. There was no evidence of ophthalmopathy (Brobyn, 1975).

Nine milliliters of 90% DMSO were applied twice daily to the entire trunk of 20 subjects for three weeks. The following laboratory tests were done at the beginning and at the end: complete blood court; urinalysis; blood sedimentation rate; and SGOT, BUN, and fasting blood sugar determinations. The laboratory values remained normal at the end of the study. One individual did not complete the study; on the 12th day a toxic reaction developed: diffuse erythematous, scaling rash accompanied by severe abdominal cramps. These changes promptly resolved after DMSO withdrawal. Another subject with a similar rash from toxic reaction complained of slight nausea, chills, and chest pains on the 13th day. These abated upon continued treatment. Except for cutaneous signs, the remainder of the subjects tolerated the DMSO treatment. At some time during the first two weeks, most subjects complained of stinging and burning. About half displayed a transient erythema after each application. These signs and symptoms generally emerged between the second and tenth day, consistently regressing with continued application. At the end, no subject was significantly discomforted cutaneously. The erythema usually developed within 15 to 30 minutes after the application and lasted for about 20 minutes, maximally one hour. In two subjects the erythematous skin was occasionally studded with irregularly sized wheals. The whealing and the transient erythema, when not accompanied by dermatitis, are readily explained as manifestations of the histamine-liberating effects of DMSO. Histamine depletion by continued exhibition of DMSO satisfactorily accounts for the disappearance of these signs in a week or so. However, DMSO is additionally a primary irritant in high concentration. Biopsy of two subjects with the rash from toxic reaction showed a mild perivascular lymphocytic infiltrate, moderate acanthosis, absence of the granular layer, and a parakeratotic, increased horny layer. In two subjects, who never envinced cutaneous signs, biopsy at the end of the three-week period showed mild epidermal damage: acanthosis and parakeratotic segments without inflammatory changes. These represent subclinical irritant effects, which are probably to be expected in most subjects intensively treated with 90% DMSO. There is no indication in the publication whether the eyes were properly examined (Kligman, 1965).

Long-term studies with volunteers

Male volunteer subjects, ages 21-55, were treated with DMSO, applied as an 80% gel, to the skin in a single daily dose of 1 g/kg body weight (Brobyn, 1975; Hullet al., 1969). DMSO was applied daily for 90 days; a total of 38 subjects completed the entire study. A control group of 18 males, not exposed to DMSO, were studied in a similar manner. Physical examinations consisted of determinations of blood pressure, pulse, temperature, and respiratory rate, examination of the neck and thyroid, lungs, heart, liver, kidney, spleen, abdomen, genitourinary system, rectum, and extremities, and an E.N.T. and neurological examination were performed prior to the start and at the end of the study. Ophthalmological examinations, including slit lamp examinations, ophthalmoscopy, and tests of refraction, tonometry, and tangent field, were conducted prior to the start of the study and then weekly up to the twelfth week, and at the fourth, sixth, ninth, twelfth, and eighteenth month of the study. Blood and urine samples were obtained from all subjects prior to the start of the study and at 1, 2, 4, 6, 8, and 13 weeks. Laboratory examinations included haematology (red blood cells, white blood cells, differential count, haemoglobin, hematocrit, morphology, color and saturation indices, platelets, and reticulocyte count), urinalysis and blood chemistries (creatinine, glucose [fasting], BUN, cholesterol, thymol turbidity, total protein, prothrombin, albumin, globulin, A/G ratio, uric acid, alkaline phosphatase, SGOT, SGPT, protein bound iodine (PBI), PSP, creatinine clearance, bilirubin, BSP, calcium, magnesium, phosphorus, sodium, potassium, chloride, CO2, ICD, CPK, urinary hydroxyproline). In addition, cerebrospinal fluid and bone-marrow examinations were performed.

A transient eosinophilia during the first few weeks of DMSO application occurred in 23 (51%) of the 45 DMSO-treated subjects. Although a similar eosinophilia was noted in 8 (31%) of the 26 control subjects, it is thought that the higher incidence in the DMSO group denotes a true drug effect. It is suggested that this effect is produced by the cutaneous histamine-releasing property of DMSO. There was no evidence of gross blood loss or anemia in the DMSO-treated subjects. A modest decrease in hematocrit, hemoglobin and/or the red blood cell count occurred in two subjects. The MCV, color index, and volume index increased in three other subjects. There were no significant abnormalities in the BUN or urinalyses. A decrease of 15-min PSP excretion was observed in 1 of 8 DMSO-treated subjects. Serum SGOT levels increased (to between 40 and 100 IU/ml) in 3 DMSO-treated subjects. The levels returned to normal while DMSO treatment was continued, in all except one subject. This subject exhibited an SGOT of 78 IU/ml and an SGPT of 60 IU/ml, at the conclusion of treatment; however, other parameters of the liver functions were normal. It was not possible to obtain further follow-up on this subject. It is noteworthy that 5 of the 26 control subjects exhibited elevated transaminase levels at some time during the study. These abnormalities may relate to the observation that 6% of the sampled population had elevated transaminase levels. One subject exhibited increasing concentrations of serum alkaline phosphatase with continuing DMSO treatment; however, all of his other liver function parameters remained normal. For unknown reasons, BSP retention tests were abnormal in 1 of 8 DMSO-treated subjects and 3 of 5 control subjects.Although fasting blood glucose levels were sometimes slightly above or below normal limits in a number of the DMSO-treated and control subjects, there was no consistently abnormal trend. A slight hyperglycemia was more frequent in the control group, whereas the incidence of slight hypoglycemia was similar in the two groups. Glucose tolerance tests were normal in 6 of 8 DMSO-treated subjects so evaluated. The tests were inconclusive in the other 2 subjects. (One of 5 glucose tolerance test conducted among the control subjects was also inconclusive.) An increased prothrombin time was noted in one DMSO-treated subject. Inasmuch as prothrombin times were determined for all DMSO-treated subjects, it seems unlikely that this one instance was DMSO-related. Although some alterations in cerebrospinal fluid protein were observed in the DMSO-treated subjects, there were similar findings in the control group. There were no alterations in the CSF glucose values for either group. DMSO apparently had no significant effect on cerebrospinal fluid. Repeated bone marrow examinations were carried out on 7 DMSO-treated subjects and 4 control subjects. There were no significant abnormalities. An attempt to measure urinary hydroxyproline levels in subjects was not successful. The results were quite inconsistent. Similar laboratory difficulties were encountered in the assessment of urinary hormone assays. Pulmonary function studies were conducted on all subjects, because this was one of the main areas of suspected toxicity. These were done before treatment and after 2, 4, 6, 8, and 13 weeks. There were no significant changes, although 4 DMSO-treated subjects exhibited slight alterations in the forced vital capacity, forced expiratory volume, and pulmonary resistance. Among the control subjects, 2 exhibited the same type of changes. There was no evidence of bronchospasm. DMSO treatment had no effect whatsoever on the serial electrocardiograms obtained on the subjects. Serial EEG tracings were obtained on all the subjects in C2 and D2. They were completely normal. Photostimulation and hyperventilation produced no EEG changes. We can conclude that dermal administration of DMSO at 1 g/kg daily has no effects on the central nervous system. Slit lamp examinations, ophthalmoscopy, and refraction, tonometry, and visual field tests were done throughout the study, and no abnormalities were noted in any of the treated or control subjects. This is a significant result demonstrating the lack of ocular toxicity from DMSO after 3 months treatment at this quite high dose. The skin reaction and breath odour were anticipated and did occur. Numerous other side effects occurred in both the DMSO-treated and control groups. The comparison of the DMSO-treated and control groups suggests that the true side effects of massive doses of DMSO include some sedation and occasional insomnia and nausea. A small amount of dizziness and diarrhoea also occurred in the DMSO-treated group. With the exception of eosinophilia, no significant abnormalities were observed in the large battery of blood chemistries, peripheral blood and urine analyses. Thus according to this very extensive toxicology study of DMSO conducted at 3 to 30 times the usual treatment dose in humans (1000 mg/kg bw/d), for 3 months. DMSO appears to be a very safe drug for human administration, and in particular, the lens changes that occur in certain mammalian species do not occur in man under this very high prolonged treatment regimen. After considerable work in evaluating thousands of cases that were treated in 1964 and 1965, and after this special toxicology study, the author feel that unequivocally DMSO is quite safe and produced no adverse effects with the exception of some side effects like sedation, insomnia, nausea, dizziness, or diarrhea.

Nine milliliters of 90% DMSO were applied to the entire trunk, from the chin to the pelvic girdle, of 20 men once daily for a period of 26 weeks (Kligman, 1965, reliability 2). At 0, 2, 4, 8, 12, 16, and 24 weeks the following laboratory studies were done: complete blood count; urinalysis; thymol turbidity test; and serum glutamic oxaloacetic transaminase (SGOT), sodium sulfobromophthalein, fasting blood sugar, and blood urea nitrogen (BUN) determinations. The subjects were examined and questioned weekly for one month and monthly thereafter.

The occasional systemic symptoms, which appeared during this six-month period, were judged not to be DMSO dependent, because they were transient and varied from subject to subject. Sedative or tranquilizing effects could not be verified. Most subjects did experience the disagreeable oyster-like breath odor, to which they eventually became insensitive. No subject was compelled to forego the daily applications, even temporarily. The laboratory values remained essentially normal throughout. No consistent trends were observed in any of the tests, though occasionally individual ones were temporarily abnormal. Transient erythema was experienced by about one fourth of the subjects immediately following some of the exposures during the first two weeks. Two subjects developed a mild scaling diffuse erythematous dermatitis after two to three weeks; this disappeared despite continued treatment. Transient burning and stinging were reported by about three quarters of the subjects during the first few weeks. Skin biopsies of the backs of six subjects at the conclusion of the study were judged to be normal when examined after use of the following stains: hematoxylin and eosin, Hale-Orcein (for ground substances and elastic tissue), alkaline phosphatase (for blood vessels), Mallory's triple stain (for connective tissue), and periodic acid, Schiff (for glycogen). There were no inflammatory changes nor was the epidermis altered. There is no indication in the publication whether the eyes were properly examined.

Epidemiological studies

DMSO was employed as a topical agent in 500 different cases in a variety of clinical disorders. These constituted mainly acute and chronic musculo-skeletal diseases. The chronic disorders required continued application of the DMSO in order to control the symptoms. Side effects with DMSO occur in the following order: erythema, burning and tingling, itching, scaling at times, vesiculation, erythemetous dermatitis, malodorous breath and foul taste. There is no indication in the publication whether the eyes were properly examined (Steinberg, 1967).

Gordon (1967) reported that none of 43 patients who were treated with dermally applied DMSO (1 to 45 ml/day) for 1 to 21 months exhibited any undue side effects in the area of corneal, retinal, or lenticular changes.

Eighty-four patients with scleroderma hand ulcers were treated 3 times daily for 3 months in a randomized, double-blind clinical trial by immersing their hands into bags of topical 70% DMSO, topical 2% DMSO, or 0.85% normal saline. Fifty-five of the patients completed the study, 46 of whom received blinded initial (0 days) and final (12 weeks) full ophthalmologic examinations. This evaluation included past ocular history, past drug history, family ocular history, pupillary examination, cycloplegic refraction, motility study, applanation tension, indirect dilated funduscopic examination, and slit-lamp examination. No statistical difference in these ocular variables, including visual acuity, lenticular changes, and cataract development, were noted among the three groups. None of the patients exhibited the DMSO-related lenticular changes that have been reported in numerous animal studies. The maximum theoretical dosage of DMSO administered was 2.6 g/kg/day, which is comparable to those used in the animal studies (Shirley et al., 1989).

Gordon and Kleberger (1968) have cited additional clinical reports . None of these reports reveal any DMSO-related lens changes among patients:

- Seven patients who were treated with DMSO cutaneously, received 30 to 40 g/day, with total dosage ranging from 800 to 6,200 g or more over treatment periods as long as 158 days. The dosage used came to an average of from 0.27 to 0.47 gm/kg/day.

- 28 and 84 patients in whom cutaneous applications of DMSO were made during periods of from one to six months and in dosage as high as 30 g/day in individual subjects.

- 43 patients examined by different ophthalmologists before and after DMSO was administered cutaneously over periods lasting up to 21 months.

- 29 patients with serial ophthalmologic checkups repeated for as long as 30 months. Over all, these individuals received a maximal topical dosage of 30 g/day. None of the patients in any of these studies exhibited lenticular changes.

- 108 patients treated with ocular applications of DMSO ranging in concentration from 7.5% to 66% and continued for as long as 19 months. No instances of toxic ocular DMSO manifestations were observed.

- Experience in a total of 9,521 patients, some treated for up to 2.5 years, was reported. Not a single instance of verified lens toxicity or of refractive change due to DMSO was recorded.