It has been demonstrated in the human, by both in vivo and in vitro methods, that DMSO enhances the percutaneous absorption of various compounds including steroids, vasoconstrictors, antiperspirants and dyes, as well as an anthelmintic (thiabendazole) and a skin antiseptic (hexachlorophene) (1,2,3,4,5). It was also shown in immature female rats that both estrogens and corticoids applied topically in DMSO exerted some of their usual biological effects (6,7).
Changes in the refractive index of the lens of the eye and nuclear cataracts have been observed in animals with the oral use of DMSO and appeared to be related to high daily doses or a long duration of daily therapy. The lens changes were first observed in dogs receiving 5 g/kg of DMSO orally daily after 9 weeks of administration. Later studies revealed ocular effects at 4.5 mL/kg in 5-9 weeks and at 0.5-1/mL/kg for 19 weeks. These eye changes were slowly reversible but with a definite species difference, the dog being the slowest to exhibit improvement.
In a subsequent study conducted in dogs to determine the effects of a 90% dimethyl sulfoxide solution applied topically at a total daily dose of 20-60 mL for 21 consecutive days, no clinically meaningful ophthalmological effects were noted. No significant variations were observed in hematologic values or in other blood measurements including glucose, BUN, SGOT and plasma electrophoresis.
DMSO may facilitate the systemic absorption of other topically-applied drugs and may have a potentiating effect on drugs administered systemically. Medications containing DMSO as a vehicle should be used judiciously when administered in conjunction with other pharmaceutical preparations especially those affecting the cardiovascular and central nervous systems. Other medication should not be present at the site of its topical application. If other topical medications are indicated they should not beapplied until after the medication containing DMSO is thoroughly dry.
DMSO is a potent solvent and may have a deleterious effect upon fabrics, plastics and other materials. Care should be taken to prevent physical contact with SYNOTIC (fluocinolone acetonide and dimethyl sulfoxide) Otic Solution Veterinary when the drug is applied. Contact with the treated area should be avoided until drying of the treated ear canal has occurred.
Fluocinolone Acetonide
It is estimated that the maximum dosage dogs will tolerate, when fed fluocinolone acetonide daily for a period of 2 weeks, is less than 0.125 mg/kg. At this dose level animals lost weight and displayed diarrhea and intestinal inflammation. When dogs were fed fluocinolone acetonide daily for a period of three months the maximum daily dose tolerated is estimated to be between 0.05 and 0.125 mg/kg. At the lower dose the adrenal glands of treated dogs appeared somewhat smaller than the controls.
The intravenous lethal dose of fluocinolone acetonide in 50% aqueous propylene glycol is in excess of 50 mg/kg in mice and rabbits, in excess of 40 mg/kg in dogs, and in excess of 30 mg/kg in rats. The compound induced no pyrogenic response in rabbits nor sensitizing effects in guinea pigs. Gross or histologic effects were not encountered.
The lethal dose orally in dogs and cats exceeds 1 g/kg. There was lymphocytopenia in all animals and erythrocytosis in cats employed in this study.
Two g/kg of 0.05 to 0.2% fluocinolone acetonide applied daily 5 days per week for 3 weeks to the abraded skin of rabbits, resulted in neither local nor systemic toxicity.
Similar applications to intact skin for 13 weeks, including an additional group at 0.025%, resulted only in decreased body weight and adrenal size.
A small decrease in body weight was seen in dogs treated for 7 days with 0.5 mL (15 drops)/ear/day of SYNOTIC (fluocinolone acetonide and dimethyl sulfoxide) Otic Solution Veterinary. In dogs which were treated for 21 days with 1.5 mL (45 drops)/ear/day of this formulation there was a slight loss of weight with changes in the adrenal glands consistent with corticosteroid treatment. This indicates absorption from the dogs' ears. This absorption, and concomitant effects, are probably enhanced by the action of DMSO.
In a subsequent study, dogs were treated with the recommended therapeutic dose of SYNOTIC Otic Solution Veterinary at the rate of 12 drops (0.4 mL) per ear daily for 21 consecutive days. No significant changes were detected in clinical chemistry, urinalysis, or hematology. A reversible adrenal cortical atrophy with cortical cytoplasmic vacuolization was noted. An equivocal response was noted following ACTH administration on the day after SYNOTIC Otic Solution Veterinary treatment was suspended, but after a one week recovery period, there was a definite eosinophile depression and recovery following ACTH administration, indicating normal adrenal function.