Background: Cidofovir is approved for the treatment of cytomegalovirus retinitis in humans. Although highly effective, the drug can cause renal toxicity in patients. There is much interest in cidofovir as a potential treatment for smallpox, monkeypox and other orthopoxvirus infections. A cyclic phosphonate form of cidofovir, 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), was reported to be less nephrotoxic than cidofovir in animals. Thus, it was deemed important to directly compare the activities of cidofovir and cyclic HPMPC against poxvirus infections in mouse models. Methods: The compounds were evaluated by intraperitoneal and intranasal infection routes using multiple doses of each agent, with single doses of compound given 24 h after virus challenge. Results: By intraperitoneal route, cidofovir protected mice from mortality at 40, 80 and 160 mg/kg, whereas cyclic HPMPC was similarly protective only at 160 mg/kg. By intranasal route, cidofovir was active down to 5 mg/kg, compared to cyclic HPMPC efficacy at 20 and 40 mg/kg. Intraperitoneal doses of 40, 80 and 160 mg/kg cidofovir significantly reduced mortality from vaccinia virus infections, compared to doses of 80 and 160 mg/kg cyclic HPMPC. Intranasal treatment with cidofovir at 5–40 mg/kg was comparably effective to cyclic HPMPC doses of 20 and 40 mg/kg in vaccinia virus infections. Active doses significantly reduced lung virus titers and lung consolidation. Overall, the potency of cyclic HPMPC was about 4 times less than that of cidofovir. Conclusions: Although cyclic HPMPC is reported to exhibit reduced nephrotoxicity in vivo, it is also less potent than cidofovir against orthopoxvirus infections. For this reason, cyclic HPMPC may not offer any advantage over cidofovir in treating these infections in humans.

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