Synergism between 9-deazainosine and DL-alpha-difluoromethylornithine in treatment of experimental African trypanosomiasis.
Kinetoplastid hemoflagellates are sensitive to growth inhibition by various purine analogs. In this study the activities of 9-deazainosine (9-DINO), formycin B, and sinefungin were compared in experimental murine Trypanosoma brucei subsp. brucei infections, both singly and in combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO, eflornithine). Used singly, all of the purine analogs were able to suppress an acute T. brucei subsp. brucei infection. 9-DINO and formycin B were the most active. None of the purine analogs was curative when used singly against a strain causing chronic central nervous system infection. 9-DINO was highly effective when used in combination with DFMO in curing this central nervous system infection and another more stringent experimental infection. Neither sinefungin nor formycin B was active in combination with DFMO in curing the central nervous system experimental infection. 9-DINO was metabolized to phosphorylated derivatives of 9-deazaadenosine and 9-deazaguanosine by bloodstream trypomastigotes, but not by murine erythrocyte suspensions or kidney or liver homogenates--a potential rationale for the selectivity of the analog. These studies indicate that 9-DINO is a potent, nontoxic purine analog which, in combination with DFMO, is capable of late-stage cures of African trypanosomiasis.
D000818:Animals; D000963:Antimetabolites; D001711:Biotransformation; D004357:Drug Synergism; D000518:Eflornithine / Q000008:administration & dosage*; D005573:Formycins / Q000008:administration & dosage / Q000378:metabolism; D007288:Inosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D009955:Ornithine Decarboxylase / Q000009:adverse effects; D011687:Purines / Q000008:administration & dosage; D013997:Time Factors; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D000963:Antimetabolites; D005573:Formycins; D011687:Purines; C034561:formycin B; D007288:Inosine; C048839:9-deazainosine; D009955:Ornithine Decarboxylase; D000518:Eflornithine