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David L Wyles

Publications and source records attributed to David L Wyles.

4 recordsLinked to original sources
PubMed2006

Synergy of small molecular inhibitors of hepatitis C virus replication directed at multiple viral targets.

Chronic hepatitis C virus (HCV) infection is a significant worldwide health problem with limited therapeutic options. A number of novel, small molecular inhibitors of HCV replication are now entering early clinical trials in humans. Resistance to small molecular inhibitors is likely to be a significant hurdle to their use in patients. A systematic assessment of combinations of interferon and/or novel anti-hepatitis C virus agents from several different mechanistic classes was performed in vitro. Combinations of inhibitors with different mechanisms of action consistently demonstrated more synergy than did compounds with similar mechanisms of action. These results suggest that combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.

Antiviral Agents↗
PubMed2005

Development of herpes simplex virus disease in patients who are receiving cidofovir.

BACKGROUND: Cidofovir is a nucleotide analogue with antiviral activity against a wide range of DNA viruses, including herpes simplex virus (HSV). In vitro resistance to cidofovir has been reported with use of laboratory HSV strains; clinical failure of cidofovir therapy for HSV disease has also been reported with an isolate that was susceptible by in vitro testing. PATIENTS AND METHODS: Three patients with HSV disease that was unresponsive to cidofovir therapy had viral isolates obtained and stored; the isolates were analyzed for antiviral susceptibility by an antigen reduction assay (ARA). PCR cloning and automated sequencing were performed for isolates that displayed in vitro resistance. Mutations were identified by comparison with the appropriate HSV consensus sequence. RESULTS: An HSV type 2 (HSV-2) isolate recovered from patient 2 displayed in vitro cidofovir resistance with an inhibitory concentration of 50% (IC50) of 13.06 microg/mL. HSV type 1 isolates recovered from patients 1 and 3 had elevated IC50s to cidofovir (7.32 and 8.23 microg/mL, respectively); however, these isolates did not meet the cutoff point for resistance according to the ARA. Sequencing of a cidofovir-resistant HSV-2 isolate revealed several DNA polymerase mutations that had not been previously described during in vitro resistance selection. CONCLUSIONS: To our knowledge, this is the first report of cidofovir resistance in HSV developing in vivo. The 3 sequenced clones all contained mutations truncating the pol C' end, suggesting that this region may be critical for cidofovir antiviral activity. In addition, the presence of multiple mutations suggests that the altered DNA polymerase of cidofovir-resistant virus may have introduced additional mutations into the viral genome. Introduction of the mutations identified in wild-type HSV strains is needed before the resistance phenotype can be definitively associated with any of the mutations found. Additional studies are needed to delineate the mechanisms of cidofovir resistance in HSV.

Antiviral Agents↗
PubMed2004

Antiretroviral drug pharmacokinetics in hepatitis with hepatic dysfunction.

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Alkynes↗