viroxime and disoxaril

The existence of synergistic drug combinations against the in vitro replication of poliovirus type 1 (Mahoney) (PV-1) had been established in our previous work. The objective of the present study was to test the combined effects of the different drugs against another representative of the enterovirus genus, i.e. Coxsackievirus B1 (CBV-1). Dual combinations of enviroxime, disoxaril, arildone, PTU-23, HBB and S-7 were evaluated. The susceptibility of CBV-1 to the individual effects of the inhibitors was compared to that of PV-1. CBV-1 was more sensitive to enviroxime, S-7, PTU-23 and HBB and less sensitive to the effects of disoxaril and arildone. The effect of most dual drug combinations tested against CBV-1 replication was additive or synergistic. Enviroxime and S-7, enviroxime and PTU-23, disoxaril and HBB, disoxaril and PTU-23, arildone and HBB, arildone and PTU-23, S-7 and HBB revealed a strong synergistic effect. Synergy against CBV-1 replication was stronger as compared to that noted for the same drug combinations against PV-1 replication.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Drug Combinations; Drug Synergism; Enterovirus B, Human; Humans; Isoxazoles; Ketones; Oximes; Phenylthiourea; Pyrimidines; Sulfonamides; Virus Replication

Effects of enviroxime and disoxaril, inhibitors of replication of some picornaviruses with known mechanisms of action, alone or in combination, on replication of coxsackievirus B1 (CVB1) in FL cells and on experimental CVB1 infection in newborn mice were tested. The combination of enviroxime and disoxaril resulted in vitro in a synergistic interaction. Both compounds were administered in vivo, alone or in combination, daily by subcutaneous (s.c.) route since the day of virus inoculation till the 5th day post inoculation (p.i.). Our findings about the in vivo antiviral effects of the individual compounds correlated with those of other authors, i.e. disoxaril significantly reduced the virus-induced death (the minimum 50% effective dose (ED50) was 12.5 mg/kg; P = 0.0037), while enviroxime was not effective even when applied at a dose as high as 100 mg/kg (P = 0.264). However, when both the substances were combined, the same protective effect was achieved with concentrations of disoxaril two to four times lower than those of the drug administered alone. In this way a higher selectivity ratio was achieved. Namely, the combination of 50 mg/kg enviroxime and 3.125-6.25 mg/kg disoxaril was synergistic. Along with reduction in mortality a marked delay in the course of the disease was observed.

Topics: Animals; Antiviral Agents; Benzimidazoles; Cell Line; Coxsackievirus Infections; Drug Synergism; Enterovirus B, Human; Humans; Isoxazoles; Mice; Mice, Inbred ICR; Oximes; Sulfonamides; Virus Replication

When combined, enviroxime and disoxaril, two selective picornavirus inhibitors, exert a marked synergistic inhibitory effect on poliovirus type 1 replication in FL cells. The cytotoxicity of the compounds applied individually and in combination to the same cells was examined. The quantitative assay of the cytotoxic effect was made by determination of the growth curve of uninfected FL cells in the presence of increasing concentrations of the compounds applied alone and in combination. The obtained results indicate lack of a synergic cytotoxic effect of the combination of enviroxime and disoxaril. The previously established synergistic antiviral effect, and the lack of cross-resistance and synergic cytotoxic effect classify the combination of enviroxime and disoxaril as a very promising chemotherapeutic.

Topics: Antiviral Agents; Benzimidazoles; Cells, Cultured; Drug Synergism; Humans; Isoxazoles; Oximes; Poliovirus; Sulfonamides; Virus Replication

To assess the possible interactions among picornavirus replication inhibitors, inhibitory effects of dual combinations of enviroxime, disoxaril, arildone, S-7, guanidine, PTU-23, and HBB on poliovirus type 1 (Mahoney) replication in FL cells were tested. Beforehand, the 50% inhibitory concentration (IC50) in the plaque inhibition test was been determined for each individual compound, i.e. enviroxime-0.2 micromol/l, disoxaril-0.3 micromol/l, arildone-2.7 micromol/l, (S-7)-100 micromol/l, guanidine-200 micromol/l, (PTU-23)-200 micromol/l, and HBB-300 micromol/l. Each of the dual combinations, in which enviroxime or HBB was one of the partners, showed synergistic or additive effects. Combining disoxaril with enviroxime, HBB or PTU-23 resulted in synergism, while combining it with guanidine, S-7 or arildone led to antagonism. Arildone showed additive or synergistic effects when combined with enviroxime, HBB and PTU-23, and antagonistic ones when combined with disoxaril, S-7 or guanidine. All dual combinations of PTU-23 were synergistic with the exception of the pair of PTU-23 + guanidine that was antagonistic. Guanidine had additive to synergistic interactions with HBB or enviroxime but antagonistic ones with disoxaril, arildone and PTU-23. Guanidine or PTU-23 when combined with S-7 showed an unusual effect - synergistic one with an antagonistic zone. The combinations of S-7 with enviroxime or HBB were synergistic but those with disoxaril or arildone were antagonistic. Research on interactions of picornavirus replication inhibitors could possibly contribute to the development of efficient chemotherapy of infectious diseases caused by picornaviruses as well as to the better understanding of the mode of action of those inhibitors.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Drug Combinations; Drug Interactions; Drug Synergism; Guanidine; Humans; Isoxazoles; Ketones; Oximes; Phenylthiourea; Poliovirus; Pyrimidines; Sulfonamides; Virus Replication

The effects of enviroxime, disoxaril and ribavirin in pair combinations on poliovirus type 1 (Mahoney) replication in FL cells were tested. Beforehand, the fifty percent inhibitory concentration (IC50) was determined for each compound alone: enviroxime - 0.2 mumol/1, disoxaril - 0.3 mumol/1, ribavirin - 3 mumol/1. Combining enviroxime with disoxaril resulted in synergistic interaction, while combinations with ribavirin were markedly antagonistic. Enviroxime-and disoxaril-resistant poliovirus mutants appeared following 10 and 2 consecutive passages in FL cells, respectively. No cross-resistance was observed between these mutants towards disoxaril and enviroxime, respectively.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Drug Resistance; Drug Synergism; Humans; Isoxazoles; Oximes; Poliovirus; Ribavirin; Sulfonamides; Virus Replication