The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs.
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.
Schleiss
Mark R
MR
Division of Infectious Diseases, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. schleiss@umn.edu
Bernstein
David I
DI
McVoy
Michael A
MA
Stroup
Greg
G
Bravo
Fernando
F
Creasy
Blaine
B
McGregor
Alistair
A
Henninger
Kristin
K
Hallenberger
Sabine
S
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
C434758:3-hydroxy-2,2-dimethyl-N-(4(((5-(dimethylamino)-1-naphthyl)sulfonyl)amino)phenyl)propanamide; D000998:Antiviral Agents; D009282:Naphthalenesulfonates