Efficacy of DL-alpha-difluoromethylornithine in a rat model of Pneumocystis carinii pneumonia

Abstract

Pneumocystis carinii pneumonia is often the terminal event for patients with the acquired immunodeficiency syndrome. Eflornithine (DL-alpha-difluoromethylornithine [DFMO]; Ornidyl; Merrell Dow Research Institute, Cincinnati, Ohio) has been used successfully against this protozoan disease in limited clinical trials, although not all patients respond to therapy. In contrast, results of the only reported experiments with DFMO in an animal model were negative. We retested DFMO against P. carinii in an immunosuppressed rat model by inclusion of 3% DFMO in the drinking water, a dose rate about twice that used previously. A combination of trimethoprim and sulfamethoxazole, a proven anti-P. carinii agent, was used as a positive control. After 3 weeks of anti-P. carinii pneumonia therapy, the surviving rats were sacrificed and the degree of parasitosis was judged by examination of lung sections stained with silver methenamine to reveal cysts. In three separate experiments, DFMO showed definite anti-P. carinii pneumonia activity; the parasitosis of DFMO-treated animals was significantly less than that of control animals (P less than 0.001 for all experiments). DFMO was not as active as trimethoprim-sulfamethoxazole, however. Several other experimental therapies were tested, including dapsone and two additional antiprotozoal agents: suramin and diminazene aceturate (Berenil; Farbwerke Hoechst, Frankfurt, Federal Republic of Germany). Diminazene aceturate, a veterinary drug related to the standard anti-P. carinii pneumonia agent pentamidine, was very active (P less than 10(-10]. Suramin and dapsone were weakly active. The combinations suramin-diminazene aceturate and suramin-DFMO were tested, but they were antagonistic rather than synergistic.