Chronic toxicity studies with vigabatrin, a GABA-transaminase inhibitor.

The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree of acute toxicity in several animal species. Oral administration of the drug at 1,000 mg/kg/day for 2-4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3-4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas of white matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 mg/kg/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any effect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels of GABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

Eight-year toxicity study in monkeys and reproduction studies in rats and rabbits treated with probucol.

Probucol [4,4'-(isopropylidenedithio)bis(2,6-di-tert-butylphenol)], a hypocholesterolemic agent, was given orally to male and female rhesus monkeys at 0, 60, 125, 250, and 500 mg/kg . d for more than 8 yr without adverse effect. Of 40 monkeys on test, 14 were killed for interim studies (wk 81 and 102), 21 were maintained for more than 8 yr, and 5 were submitted for necropsy for conditions unrelated to treatment. Monitored parameters included growth rate, demeanor, hematology, clinical chemistries, urinalyses, ophthalmoscopy, organ weights, and gross, histopathologic, and electron microscopic evaluations. Bone marrow smears at the conclusion of the test revealed no differences between control and treated animals. Electron microscopy of liver specimens from monkeys treated for 8 yr revealed comparable hepatocellular ultrastructure in control and treated monkeys. Probucol was given orally at 0, 100, 500, and 1000 mg/kg to Sprague-Dawley rats during appropriate time intervals to evaluate effects on fertility and postnatal development. The same dose levels were given during organogenesis, or in some cases prior to breeding and throughout organogenesis, to Sprague-Dawley rats and New Zealand white rabbits. No adverse effects on fertility or postnatal development were observed in rats, and no evidence of teratogenicity was observed in either species. The results indicate that probucol does not affect reproduction of rats, lacks teratogenic potential in the species studied, and is nontoxic to subhuman primates treated for more than 8 yr.

A simple method for obtaining blood pressure in rhesus monkeys (Macaca mulatta).

A relatively simple procedure was devised to obtain blood pressures in rhesus monkeys. This procedure utilized a polygraph, pulse transducer, pressure transducer, blood pressure mixer unit, and pediatric sphygmomanometer cuff. Previous attempts to auscultate the Korotkoff sounds by use of a sphygmomanometer cuff and stethoscope were unsuccessful. Blood pressure can be obtained by cannulation of the femoral artery, but repeated puncture may cause serious trauma to the arterial wall. This procedure was developed and used in our laboratory to obtain repeated blood pressures over a 90-da period. Results from using the cuff and polygraph have been shown to correlate favorably with cannulation of the femoral artery.