Abstract
The phosphonylmethoxyalkyl derivative (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was evaluated for its in vivo efficacy in several model infections for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and thymidine kinase-deficient (TK-) HSV-1 in mice. In hairless mice infected intracutaneously with HSV-1 or HSV-2, HPMPC completely suppressed all manifestations of the disease (skin lesions, paralysis of the hind legs, and mortality) if it was administered topically at a concentration of as low as 0.1, 0.3, or 1%. Similarly, HPMPC completely suppressed TK- HSV-1 infection in athymic nude mice if it was administered topically at 0.1 or 0.3% or intraperitoneally at 100 or 250 mg/kg/day. HPMPC was also effective against intraperitoneal HSV infection if it was given orally at a dose of 50 mg/kg/day or higher. In mice inoculated intracerebrally with HSV-2, intraperitoneal HPMPC treatment achieved a significant and dose-dependent protection at doses ranging from 5 to 400 mg/kg/day. The protective effect of HPMPC (at 200 mg/kg/day) was accompanied by a complete inhibition of virus multiplication in the brain. In all models of infections studied, the efficacy of HPMPC proved to be superior to that of acyclovir. The most remarkable feature of HPMPC was that a single administration of the compound, even as late as 4 days after infection, conferred significant protection against HSV-1 or HSV-2 infection. Topical or systemic HPMPC treatment is efficacious in murine models of HSV-1, HSV-2, and TK- HSV infections.
Highlights
IntroductionHPMPA, PMEA, and PMEDAP have been the subject of a previous study in which the efficacies of these phosphonylmethoxyalkyl derivatives were demonstrated in a variety of experimental herpes simplex virus type 1 (HSV-1) and HSV-2 infections, including intracutaneous HSV-1 and HSV-2 infections in hairless mice; intracutaneous thymidine kinase-deficient (TK-) HSV-1 infections in athymic nude mice; systemic (intraperitoneal [i.p.]) HSV-1 infections in mice; and intracerebral HSV-1, HSV-2, or TK- HSV-1 infections in mice (12)
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,' and Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, 16610 Prague, Czechoslovakia2
HPMPA, PMEA, and PMEDAP have been the subject of a previous study in which the efficacies of these phosphonylmethoxyalkyl derivatives were demonstrated in a variety of experimental herpes simplex virus type 1 (HSV-1) and HSV-2 infections, including intracutaneous HSV-1 and HSV-2 infections in hairless mice; intracutaneous thymidine kinase-deficient (TK-) HSV-1 infections in athymic nude mice; systemic HSV-1 infections in mice; and intracerebral HSV-1, HSV-2, or TK- HSV-1 infections in mice (12)
Summary
HPMPA, PMEA, and PMEDAP have been the subject of a previous study in which the efficacies of these phosphonylmethoxyalkyl derivatives were demonstrated in a variety of experimental HSV-1 and HSV-2 infections, including intracutaneous HSV-1 and HSV-2 infections in hairless mice; intracutaneous thymidine kinase-deficient (TK-) HSV-1 infections in athymic nude mice; systemic (intraperitoneal [i.p.]) HSV-1 infections in mice; and intracerebral HSV-1, HSV-2, or TK- HSV-1 infections in mice (12) These animal models for HSV infections have been used to assess the in vivo efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), another member of the class of phosphonylmethoxyalkyl derivatives (14), which, according to previous investigations (7), would be more efficacious than acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] in both the systemic and topical treatment of HSV infections in mice and guinea pigs
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