CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-
thiadiazole-2(3H)-
thione-2-hydroxy-N,N,N-trimethylethanaminium
salt) is a novel anti-inflammatory compound classified as a dual inhibitor of
cyclooxygenase and
5-lipoxygenase. Studies were undertaken to characterize the preclinical toxicology of the compound.
CI-986 was administered to rats for 2 weeks (0, 50, 250, 750, and 1500 mg/kg) or 13 weeks (0, 20, 250, 500, and 1000 mg/kg), dogs for 2 weeks (0, 50, 150, and 500 mg/kg) or 13 weeks (0, 20, 100, and 200 mg/kg), and to monkeys for 2 weeks (0, 50, 250, and 1000 mg/kg). No
drug-related deaths resulted. Mild clinical signs of toxicity were noted in rats given doses of 250 mg/kg and above.
Drug-related
emesis and
diarrhea were absent at the low dose in the dog and monkey but increased in incidence and severity at higher doses. Severe clinical signs in monkeys (
emesis and
diarrhea) necessitated the lowering of the top dose to 500 mg/kg/day (administered b.i.d.) during the second week of the monkey study. Slight decreases (< 23%) in
serum protein and/or
albumin were noted in all studies at the higher doses. A dose-related increase in
alkaline phosphatase was noted in both dog studies, with no other
drug-related effect on clinical pathology parameters. A
gastric ulcer occurred in one rat administered 500 mg/kg
CI-986 for 13 weeks. Gastrointestinal
ulcers were not noted at any other dose in rats or at any dose in dogs or monkeys. A dose-related
eosinophilia of glandular stomach submucosa was noted in rats after 2 and 13 weeks of
drug administration but not in dogs or monkeys. In the 2-week rat study, mean combined sex plasma
drug concentrations monitored 2 hr after dose on Day 14 were 0.59, 1.10, 2.64, and 3.43 micrograms/ml for the 50, 250, 750, and 1,500 mg/kg dose groups, respectively. In the 2-week dog studies, maximum plasma
drug concentrations on Day 10 or Day 11 were achieved within 2 hr of dose with mean combined sex Cmax values of 0.73, 2.05, and 2.62 micrograms/ml for the 50, 250, and 750 mg/kg groups, respectively. Hepatic microsomal induction characterized by increased microsomal
protein, increased microsomal
cytochrome P450 content, and increased
p-nitroanisole O-demethylation activity was noted in dogs and monkeys but not rats.
CI-986 was well tolerated in rats and dogs at the doses employed and in monkeys at doses up to 500 mg/kg (b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)