LEISHMANIA-DONOVANI - PILOT-STUDY FOR EVALUATION OF THERAPEUTIC EFFECTS OF INOSINE ANALOGS AGAINST AMASTIGOTES IN-VITRO AND IN-VIVO

The inhibition of carbocyclic inosine (C-Ino), 3'-deoxyinosine (3'-dI) , and 3'-deoxy-3'-fluoroinosine (3'-FI) to Leishmania donovani amastig otes was examined. J774.1 cells (a mouse macrophage line) were culture d in GIT medium with lipopolysaccharide and hemin and infected with th e parasite. C-Ino (3 mu M) completely inhibited and 3'-dI (30 mu M) re duced to 40% the infection rate on Day 6 after infection. Pentostam (3 0 mu M) resulted in a 38% infection rate. The therapeutic efficacies o f nonentrapped free and liposome-entrapped inosine analogs were tested in mice infected with L. donovani. The mice were injected intravenous ly five times on alternate days, beginning 2 days after infection. Tre atment with the nonentrapped free inosine analog of C-Ino (100 mg/kg), 3'-dI (100 mg/kg), or 3'-FI (50 mg/kg) resulted in an LDU that was 94 , 68, or 73% lower, respectively, than the control values. Treatment w ith the corresponding entrapped inosine analog (10 mg/kg) caused decre ases of 90, 69, or 68% LDU, respectively. The entrapped inosine analog s were inhibitory at doses one-fifth to one-tenth of the nonentrapped free inosine analogs. C-Ino had the strongest inhibitory effect among the three analogs tested in vitro and in vivo. Liposome-entrapped C-In o had no severe side effects, although spleen weight increased, The ag ent may be useful as an anti-leishmanial drug. (C) 1995 Academic Press , Inc.