Efficacy of BMS-180194 against experimental cytomegalovirus infections in immunocompromised mice.
A new antiviral nucleoside, BMS-180194 [1R-(1 alpha, 2 beta, 3 alpha)]- 2-amino-9[2,3-bis(hydroxymethyl)cyclobutyl]-1,9dihydro-6H-purin-6- one, is a broad spectrum antiviral agent. The antiviral effectiveness of BMS-180194 against murine cytomegalovirus (MCMV) infection in immunocompromised C57BL/6 mice was investigated and was compared to that of ganciclovir (GCV). LP-BM5 murine retrovirus complex-induced immunocompromised C57BL/6 mice were challenged with MCMV then treated intraperitoneally or per os with various doses of BMS-180194 ranging from 30 to 3 mg/kg/day. When administered intraperitoneally, BMS-180194 was effective against MCMV-mediated mortality in a dose-dependent manner demonstrating a 50% protective dose (PD50) of 3.12 mg/kg/day which was comparable to that of GCV. There was a marked reduction in organ MCMV titers in BMS-180194-treated animals (10-10,000- fold lower than the placebo controls). Similar findings were observed when the compound was administered orally. Interestingly, oral BMS-180194 demonstrated a similar antiviral efficacy as that obtained by the parental route of administration suggesting a high oral bioavailability of the compound. Oral ganciclovir treatment, however, required more than a 4-fold higher amount of GCV to confer the same degree of protection obtained by a parenteral route of administration. Oral BMS-180194 was also effective in reducing the organ MCMV titer in genetically severe combined immunodeficient (SCID) mice. The parenteral or oral antiviral efficacy of BMS-180194 was comparable to that of parenteral ganciclovir against MCMV infection in the present study. Doses of BMS-180194 employed in the present study showed no toxicity to mice. These results suggest that BMS-180194 may be of value as an oral antiviral agent for treatment of opportunistic CMV infections in immunocompromised individuals.
Yang
H
H
Department of Microbiology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7600, USA.
Drain
R L
RL
Franco
C A
CA
Clark
J M
JM
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006566:Herpesviridae Infections / Q000188:drug therapy*; D016867:Immunocompromised Host; D007274:Injections, Intraperitoneal; D009052:Leukemia Virus, Murine; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018146:Muromegalovirus / Q000187:drug effects*
D000998:Antiviral Agents; D006147:Guanine; C063638:lobucavir; D015774:Ganciclovir