COMPARATIVE TOXICITY IN RATS AND DOGS OF INTRAVENOUS 1,3-DI(4-IMIDAZOLINO-2-METHOXYPHENOXY) PROPANE-CENTER-DOT-LACTATE, A POTENTIAL AGENT FOR THE TREATMENT OF PNEUMOCYSTIS-CARINII PNEUMONIA

The subchronic toxicity of DMP lactate [1,3-di(4-imidazolino-2-methoxy phenoxy)propane lactate], a new agent with potential for the treatment of the opportunistic infection of Pneumocystis carinii pneumonia (PCP ) in immunocompromised patients, was defined in rats and dogs after 28 (rats) or 29 (dogs) daily intravenous doses. Dose levels for both spe cies were 0, 0.5, 2.5 and 4.0 mg/kg/day. Tremors were observed in both rats and dogs at the 2.5 and 4.0 mg/kg doses, while incontinence, ano rexia, rhinorrhoea, salivation, convulsions, seizures, moribundity and death occurred in dogs at these doses. All rats sur?vived to the sche duled sacrifice, whereas only 1 male and no female dogs administered 4 .0 mg/kg/day survived to day 28 and 1 female at 2.5 mg/kg/day was mori bund on day 27. Languid behaviour was noted in rats and dogs at the hi ghest dose. An alteration in tapetum lucidum reflection was found in d ogs dosed at 2.5 and 4.0 mg/kg/day. No haematological or urinalysis in dicators of toxicity were seen in either species. Serum alanine amino transferase, aspartate amino transferase and alkaline phosphatase were elevated in dogs at 2.5 and 4.0 mg/kg, while only alkaline phosphatas e was increased dose-dependently in rats. No histopathological lesions were found in rats. Periportal inflammation, cytoplasmic vacuolisatio n of centrilobular hepatocytes and/or hepatocyte hyaline droplet forma tion were seen in dogs at all doses. Thus, dogs appear to be much more sensitive to DMP toxicity than rats. The differential toxicity respon se to DMP could be attributed to the different pharmacokinetics in the rat and the dog.