Evaluation of HPMPC therapy for primary and recurrent genital herpes in mice and guinea pigs.
The nucleoside analogue (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) inhibited the replication of herpes simplex virus (HSV) types 1 and 2 in tissue culture cells at about 1.0 micrograms/ml, whereas Acyclovir (ACV) had an EC50 of about 0.10-0.50 micrograms/ml. The purpose of these studies was to evaluate the efficacy of topically applied HPMPC in animal models of primary and recurrent genital HSV-2 infections. Mice treated with 5%, 1% or 0.5% HPMPC three times daily, beginning 6 or 24 h after virus inoculation had reduced vaginal viral replication regardless of time of initiation of therapy. ACV at 5% also reduced vaginal viral replication, but not as effectively as HPMPC. In primary infection of guinea pigs, therapy with 5% or 1% HPMPC beginning at 24 h but not 72 h significantly altered lesion development. However, 5% HPMPC was highly toxic to guinea pigs. Vaginal viral replication was reduced significantly with either 1% or 0.3% HPMPC initiated at 24 h. In these studies, HPMPC was also more efficacious than 5% ACV. Topical treatment with 1% HPMPC did not reduce the incidence or severity of spontaneous or UV-induced recurrent genital lesions. These results indicate that topical therapy with 1%, 0.5% or 0.3% HPMPC was more effective than 5% ACV in the treatment of primary genital HSV-2 infections of guinea pigs and mice and suggest that HPMPC should be considered for topical use in humans.
Bravo
F J
FJ
Division of Infectious Diseases, Children's Hospital Research Foundation, Cincinnati, Ohio 45220.
Stanberry
L R
LR
Kier
A B
AB
Vogt
P E
PE
Kern
E R
ER
D000212:Acyclovir / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000188:drug therapy*; D051379:Mice; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D014621:Vagina / Q000382:microbiology / Q000528:radiation effects; D014623:Vaginal Diseases / Q000188:drug therapy / Q000209:etiology / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D000212:Acyclovir