Abstract |
New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC(50) of 0.5muM. Yield reduction assays demonstrated an ED(90) and ED(99) of 0.4 and 0.6muM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7mg/ml (n=6; range, 17.8-35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs (p<0.05, Mann-Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals (p<0.0001, Fisher's exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model.
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Authors | Mark R Schleiss, David I Bernstein, Michael A McVoy, Greg Stroup, Fernando Bravo, Blaine Creasy, Alistair McGregor, Kristin Henninger, Sabine Hallenberger |
Journal | Antiviral research
(Antiviral Res)
Vol. 65
Issue 1
Pg. 35-43
(Jan 2005)
ISSN: 0166-3542 [Print] Netherlands |
PMID | 15652969
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- 3-hydroxy-2,2-dimethyl-N-(4(((5-(dimethylamino)-1-naphthyl)sulfonyl)amino)phenyl)propanamide
- Antiviral Agents
- Naphthalenesulfonates
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Topics |
- Animals
- Antiviral Agents
(adverse effects, pharmacokinetics, therapeutic use)
- Cytomegalovirus
(drug effects, genetics)
- Cytomegalovirus Infections
(drug therapy, mortality, virology)
- Disease Models, Animal
- Drug Resistance, Viral
- Guinea Pigs
- Immunocompromised Host
- Naphthalenesulfonates
(adverse effects, pharmacokinetics, therapeutic use)
- Treatment Outcome
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