Suppression of Leishmania donovani by oral administration of a bis(benzyl)polyamine analog

Abstract

We reported previously that intraperitoneal administration of a bis(benzyl)polyamine analog, MDL 27,695, suppressed both pentavalent antimony (Sbv)-susceptible and -resistant Leishmania donovani in vivo. The present studies were performed to optimize parasite suppression by parenteral administration and to evaluate the efficacy of oral treatment with MDL 27,695. L. donovani infections in BALB/c mice were suppressed greater than 99% after intraperitoneal dosing for 20 days with a total dose of 150 mg of MDL 27,695 per kg of body weight or 560 mg of Sbv per kg. Suppression was not increased by a total dose of 400 mg of MDL 27,695 per kg given for 20 days. In mice treated for 2, 4, or 7 days with either MDL 27,695 or Sbv (total doses of 60, 120, and 210 mg/kg, respectively), more liver parasites were killed with MDL 27,695 than with Sbv. Assessment of livers posttreatment showed that parasite killing continued for at least 3 days in MDL 27,695-treated mice but not for longer than 1 day in Sbv-treated mice. Intramuscular administration of drugs resulted in 92% parasite suppression by MDL 27,695 (15 mg/kg three times per day for 5 days) and 64% suppression by Sbv (60 mg/kg once per day for 5 days). Dosing of mice by oral gavage with 100 mg of MDL 27,695 per kg twice per day for 14 days resulted in 99.7% parasite suppression, and the 50% effective dose was approximately 11 mg of MDL 27,695 per kg. MDL 27,695 represents an effective new drug potentially useful for oral or parenteral treatment of visceral leishmaniasis.