Avoiding drug-resistance development by novel approach of combining anti-enteroviral substances against coxsackievirus B1 infection in mice

Abstract

Current study presents a novel scheme for combined application of anti-enteroviral substances in coxsackievirus B1 neuroinfection in newborn mice. It consists of a consecutive alternating, not simultaneous, administration of the substances in combination. A triple combination showing good efficacy was selected as a result of a screening of double, triple and quadruple combinations of enteroviral inhibitors. Its effectiveness is expressed in lengthening of the mean survival time and about 50% reduction of mortality rate in infected newborns as compared both to the placebo group, individual compounds used alone every day, and to the same combination applied simultaneously every day. Chronology of alternation of the individual drug administration plays a key role in the efficacy of the combination. Studies of the drug sensitivity of viral brain isolates from mice, treated with the drug combination indicate that virus isolates from the group treated with the alternating combination not only preserve, but even increase their sensitivity to the drugs. MIC(50) values of virus isolates from groups treated with monotherapies of the compounds manifested development of drug resistance. Obviously, the consecutive alternating administration of anti-enteroviral substances hinders the occurrence of drug resistance in the course of experimental coxsackievirus B1 infection in mice.