title: The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs.
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.
authors.affiliation: Division of Infectious Diseases, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. schleiss@umn.edu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Schleiss
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.forename: Michael A
authors.initials: MA
authors.lastname: McVoy
authors.forename: Greg
authors.initials: G
authors.lastname: Stroup
authors.forename: Fernando
authors.initials: F
authors.lastname: Bravo
authors.forename: Blaine
authors.initials: B
authors.lastname: Creasy
authors.forename: Alistair
authors.initials: A
authors.lastname: McGregor
authors.forename: Kristin
authors.initials: K
authors.lastname: Henninger
authors.forename: Sabine
authors.initials: S
authors.lastname: Hallenberger
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000401:mortality* / Q000821:virology; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D006168:Guinea Pigs; D016867:Immunocompromised Host; D009282:Naphthalenesulfonates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C434758:3-hydroxy-2,2-dimethyl-N-(4(((5-(dimethylamino)-1-naphthyl)sulfonyl)amino)phenyl)propanamide; D000998:Antiviral Agents; D009282:Naphthalenesulfonates