Oral Bioavailability and In Vivo Efficacy of the Helicase-Primase Inhibitor BILS 45 BS against Acyclovir-Resistant Herpes Simplex Virus Type 1
| Autor: | Jianmin Duan, Michael G. Cordingley, Michel Liuzzi, Bruno Simoneau, Abigail Browne, Anne-Marie Faucher, Francine Liard, Nathalie Dansereau, William Paris |
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| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Pyridines
viruses Acyclovir Administration Oral Biological Availability Mice Nude DNA Primase Herpesvirus 1 Human Biology Pharmacology medicine.disease_cause Antiviral Agents Virus Mice Viral Proteins Pharmacokinetics Oral administration In vivo Drug Resistance Viral medicine Animals Pharmacology (medical) Aciclovir Enzyme Inhibitors Dose-Response Relationship Drug DNA Helicases Herpes Simplex Virology Bioavailability Dose–response relationship Thiazoles Infectious Diseases Herpes simplex virus Area Under Curve Female medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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