Affiliation:
1. Research and Development, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada H7S 2G5
Abstract
ABSTRACT
This study investigated the oral bioavailability and efficacy of BILS 45 BS, a selective herpes simplex virus (HSV) helicase-primase inhibitor, against acyclovir (ACV)-resistant (ACV
r
) infections mediated by the HSV type 1 (HSV-1)
dl
sptk and PAA
r
5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACV
r
HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 μM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 μM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1
dl
sptk and PAA
r
5 mutant strains induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. Oral treatment with ACV (100 or 125 mg/kg/day, three times a day by gavage) did not affect either mutant-induced infection. In contrast, BILS 45 BS at an oral dose of 100 mg/kg/day almost completely abolished cutaneous lesions mediated by both ACV
r
HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against
dl
sptk- and PAA
r
5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACV
r
HSV-1 infections in nude mice and support the potential use of HSV helicase-primase inhibitors for the treatment of nucleoside-resistant HSV disease in humans.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
32 articles.
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