Human Enterovirus Infection Research Articles

Treatment of human enterovirus infections

Treatment of human enterovirus infections

Antipicornavirus activity of SCH 47802 and analogs: in vitro and in vivo studies

SCH 47802 and its derivatives are potent inhibitors of enteroviruses in vitro. The IC 50 for SCH 47802 ranges from 0.03 to 10 μg/ml when tested against a spectrum of enteroviruses in plaque reduction assays. The compounds have in vitro therapeutic indices of at least 81 based on viral cytopathic effect (CPE) assays. The in vitro activity of SCH 47802 translates into in vivo activity in the murine model of poliovirus encephalitis. In an oral dosing regimen, SCH 47802 protects mice from mortality at 60 mg/kg per day. Consistent with the in vivo efficacy, pharmacokinetic analyses after oral dosing with SCH 47802 demonstrate serum levels of the compound above the in vitro IC 50 for poliovirus for at least 4 h. SCH 47802 and its active analogs stabilize poliovirus to thermal inactivation indicating that the compounds bind to the virus capsid. Mechanistic studies with poliovirus indicate that SCH 47802 acts early in viral infection. This series of molecules represents potential candidates for the treatment of human enterovirus infections.

Human enterovirus infection in stray dogs. Some aspects of interest to public health.

To investigate the possible role of domestic animals as reservoirs of human enteroviruses, we studied 212 stray dogs captured in different areas of the municipality of São Paulo. The captured animals were divided into 19 groups of 10 to 20 dogs each; faeces of 126 of the 212 dogs were processed for enterovirus isolation. The following viruses were isolated from 12 dogs; poliovirus type 1 (2 dogs), poliovirus type 3 (1 dog), echovirus type 7 (8 dogs) and echovirus type 15 (1 dog). Of the 12 infected animals, four had specific homotypic neutralizing antibody titres > or = 16. All 212 animals were tested for the presence of neutralizing antibodies to human enteroviruses. The frequency of neutralizing antibodies present in titres of > or = 16 was 10.3%, 3.8% and 4.3% for vaccinal prototypes of polioviruses 1, 2 and 3 respectively; 1.9%, 1.4% and 1.5% for wild prototypes of the same viruses, 11.3% for echovirus 7, and 2.4% for echovirus 15. The proportion of dogs with neutralizing antibodies varied with the virus studied. Some indication of the susceptibility of dogs to infection with human enteroviruses was demonstrated, and the importance of this fact for the Plan for Global Eradication of the Wild Poliovirus is discussed.

In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug

WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.

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.

Antiviral Effectiveness of Grape Juice

Grape juice inactivated human enteroviruses, but not parainfluenza type 1 (Sendai) virus, in vitro. The effect was not one of aggregation or of degradation of the virus surface. Some of the inactivated virus adsorbed specifically to host cells, but did not infect them. Most of the inactivated virus could be reactivated by treatment with polyethylene glycol. Grape juice-inactivated virus and coproantibody-neutralized virus were both reactivated by contents of porcine stomach and duodenum, which suggests that ingestion of such viruses would lead to intestinal infection. Grape juice-inactivated virus was efficiently reactivated by human blood serum. Ingested grape juice has not been shown likely to prevent or modify human enterovirus infections.

Detection of specific IgM neutralizing antibodies in naturally acquired sporadic human enterovirus infections

Detection of specific IgM neutralizing antibodies in naturally acquired sporadic human enterovirus infections