title: Leishmania donovani: pilot study for evaluation of therapeutic effects of inosine analogs against amastigotes in vitro and in vivo.
abstract: The inhibition of carbocyclic inosine (C-Ino), 3'-deoxyinosine (3'-dI), and 3'-fluoroinosine (3'-FI) to Leishmania donovani amastigotes was examined. J774.1 cells (a mouse macrophage line) were cultured in GIT medium with lipopolysaccharide and hemin and infected with the parasite. C-Ino (3 microM) completely inhibited and 3'-dI (30 microM) reduced to 40% the infection rate on Day 6 after infection. Pentostam (30 microM) resulted in a 38% infection rate. The therapeutic efficacies of nonentrapped free and liposome-entrapped inosine analogs were tested in mice infected with L. donovani. The mice were injected intravenously five times on alternate days, beginning 2 days after infection. Treatment 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 with the corresponding entrapped inosine analog (10 mg/kg) caused decreases of 90, 69, or 68% LDU, respectively. The entrapped inosine analogs 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-Ino had no severe side effects, although spleen weight increased. The agent may be useful as an anti-leishmanial drug.
authors.affiliation: Department of Parasitology, Okayama University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Morishige
authors.forename: T
authors.initials: T
authors.lastname: Aji
authors.forename: A
authors.initials: A
authors.lastname: Ishii
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: Y
authors.initials: Y
authors.lastname: Wataya
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D004337:Drug Carriers; D007288:Inosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010865:Pilot Projects; D011897:Random Allocation
chemical_list: D000981:Antiprotozoal Agents; D004337:Drug Carriers; D008081:Liposomes; C070277:3'-deoxy-3'-fluoroinosine; C070014:3'-deoxyinosine; C047906:carbocyclic inosine; D007288:Inosine; D000967:Antimony Sodium Gluconate