Clearance of a persistent human enterovirus infection of the mouse central nervous system by the antiviral agent disoxaril.
Enteroviruses can cause persistent central nervous system (CNS) infections in agammaglobulinemic individuals. Because these infections are rarely cured by passive administration of antibody, a chemotherapeutic approach would be advantageous. In this study, the efficacy of the antienterovirus (and antipicornavirus) drug disoxaril was demonstrated in a murine model of persistent enterovirus infection. Disoxaril is a hydrophobic antiviral compound that blocks picornavirus uncoating. The W-2 strain of human poliovirus type 2 (PV2) persists in the CNS of immunosuppressed mice and causes late paralysis. Mice were inoculated intracerebrally with PV2, immunosuppressed with cyclophosphamide, and treated intragastrically with disoxaril at 50, 100, or 200 mg/kg per day in two divided doses beginning on postinfection day 20. At 200 mg/kg per day, disoxaril significantly decreased the incidence of clinical disease, i.e., paralysis and death. Assays for virus revealed more rapid clearance of virus from the CNS in the drug-treated group. No drug-associated toxicity was observed. Residual isolates of virus were not drug-resistant, suggesting that the appearance of drug resistance during prolonged treatment may not be a clinical problem.
Jubelt
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Les Turner Amyotrophic Lateral Sclerosis Research Laboratory, Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
Wilson
A K
AK
Ropka
S L
SL
Guidinger
P L
PL
McKinlay
M A
MA
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology; D003520:Cyclophosphamide; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D004769:Enterovirus Infections / Q000188:drug therapy*; D007165:Immunosuppression Therapy; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000627:therapeutic use*; D011051:Poliomyelitis / Q000188:drug therapy*; D017955:Poliovirus / Q000187:drug effects / Q000302:isolation & purification
D000998:Antiviral Agents; D007555:Isoxazoles; D010080:Oxazoles; D003520:Cyclophosphamide; C045978:disoxaril