GUANYLHYDRAZONES IN THERAPY OF PNEUMOCYSTIS-CARINII PNEUMONIA IN IMMUNOSUPPRESSED RATS

Guanylhydrazones are cationic heteroaromatic drugs similar to the diam idines which are effective in the treatment of African trypanosomiasis and pneumocystosis. On the basis of their antitrypanosomal activity, different guanylhydrazones were selected for evaluation in a rat model of Pneumocystis carinii pneumonia. The most active compounds were the 4'-formylphenyl)-1-methylimidazo-[1,2-a]pyridinium guanylhydrazones w hich, at a dose of 2 mg/kg/day, were about as effective as trimethopri m-sulfamethoxazole at a dose of 50 mg of trimethoprim per kg/day plus 250 mg of sulfamethoxazole per kg/day. The anti-P. carinii activity of these guanylhydrazone derivatives was found with parenteral but not w ith oral administration. The 1,3-arylene diketone bis(guanylhydrazones ) were generally ineffective, although a triacetyl derivative showed s ome anti-P. carinii activity. Nitroimidazole guanylhydrazone derivativ es were also ineffective. Attempts to improve the therapeutic efficacy of the different guanylhydrazones were limited by problems of toxicit y. We conclude that some guanylhydrazone derivatives are potent anti-P . carinii drugs and that further studies should be pursued to develop safer compounds and investigate structure-activity relationships.