Cardiopulmonary effects of antimalarial drugs: V. Cycloguanil and a new triazine compound (WR 99,662)

Abstract

This report pertains to the pharmacology of a new antimalarial compound identified as WR 99,662 (2-[3-(dimethylamino) propylamino]-4-(trichloromethyl)-6-(α,α,α-trichloro- m-tolyl)-2-triazine). Its toxicity was compared with that of cycloguanil in three animal species: mouse, rat, and dog. The differences between the two triazines are as follows: (a) The lethal doses for cycloguanil are smaller than those for WR 99,662: in mice the LD50 is 54 mg/kg for cycloguanil and 1350 mg/kg for WR 99,662; in dogs the LD100 is 24.3 ± 2.7 mg/kg for cycloguanil and 159 ± 39 for WR 99,663. (b). The chronic effects of cycloguanil in rats include reduction of the reticulocyte count, while WR 99,662 has no such hematologic effect. (c) Cycloguanil increases cardiac output in dogs, but WR 99,662 does not produce this effect. (d) Sublethal doses of cycloguanil in anesthetized dogs increase pulmonary resitance, whereas sublethal doses of WR 99,662 stimulate respiration and reduce aortic blood pressure and cardiac output. (e) In rats the mortality from cycloguanil can be reduced by concurrent injection of leucovorin. The mortality from WR 99,662 could not be reduced by leucovorin indicating that deaths from WR 99,662 cannot be due to antifolic acid property. However, the possibility that antimalarial activity and other pharmacodynamic effects of WR 99,662 are exerted by inhibiting folic acid has not been ruled out.