WIN 51711, a new broad-spectrum anti-picornavirus agent, prevented the development of paralysis and subsequent death in mice infected intracerebrally with a lethal dose of human poliovirus type 2 (MEF strain). The prophylactic efficacy of intragastrically administered WIN 51711 was dose dependent over the 3.9-to 62.5-mg/kg (twice daily) dose range, with a minimal significantly effective dose of <15.6 mg/kg per dose (twice daily) (P < 0.008). An oral four times a day dosage regimen initiated 48 h postinfection with WIN 51711 doses as low as 12.5 mg/kg was effective in significantly reducing poliovirus-induced paralysis and death compared with a placebo. Viral titers in the brains-and spines of mice infected intracerebrally with 200 50% lethal doses of poliovirus were reduced by 3 to 5 loglo PFU/g in the WIN 51711-medicated group compared with placebo-medicated animals. The potent in vitro and in vivo anti-picornavirus activity of WIN 51711 makes it a potentially useful drug for the treatment of enterovirus infections in humans.

The systemic efficacy of the antipicornavirus agent WIN 51711 was assessed in suckling mice infected with echovirus type 9 (Barty strain). Single, daily intraperitoneal doses of WIN 51711 as low as 10 mg/kg significantly (P less than .01) slowed the rate of onset of echovirus-induced paralysis and reduced the number of paralyzed animals. Intraperitoneal administration beginning 2 hr before infection or 48 hr after infection was equally effective in preventing paralysis. Oral administration of WIN 51711 twice daily beginning 72 hr after infection was the most-effective dosage regimen, with doses as low as 3 mg/kg preventing paralysis in 75% of the animals. Titers of virus in asymptomatic mice on day 6 after infection were reduced by up to 4.75 log pfu in WIN 51711-medicated mice when compared with placebo. Maximal concentrations of WIN 51711 in adult mice after oral medication with a 100 mg/kg dose were 24.3, 21.5, 10.4, 9.8, 6.9, and 4.1 micrograms/g in heart, kidney, brain, liver, serum (micrograms/ml), and muscle, respectively at 0.5-1.0 hr after medication.

A series of bis(beta-diketones) was synthesized and tested in vitro for antiviral actitity against herpes simplex type 2. Two parameters which were studied in an effort to optimize activity were the nature of the aryl group and the length of the alkyl bridge. One of the more active compounds, 4,4'-[(1,4-phenylenedioxy)bis(6,1-hexanediyl)]-bis[3,5-heptanedione] (6), was evaluated more extensively and found to inhibit the cytopathic effect in tissue culture of herpes simplex virus type 1 as well as type 2. Compound 6 was evaluated in vivo topically against herpes simplex type 1 in experimentally induced skin infections in guinea pigs. A topical treatment with 2% of 6 in a vanishing cream base, administered 24 h postinfection applied five times daily for 4 days, significantly reduced the number and size of herpetic vesicles.

Win 41258-3 (4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-4H-pyrazole methane sulfonate) has in vitro and in vivo activity against herpes simplex virus types 1 and 2. In cell culture, a concentration of 2 pg/ml produced a >50% inhibition of plaque formation of herpes simplex virus.type 2, and 3 yg/ml produced a 100% reduction of herpes simplex virus Win 41258-3, a water-soluble pyrazole, is an analog of arildone (Win 38020), which has previously been reported to be an active antiviral agent (see Fig. 1 for structures of these compounds) (1-4, 8, 10). This pyrazole was among the analogs synthesized in our laboratories after arildone showed topical activity in guinea pig skin infection produced by herpes simplex virus type 1 or 2 (HSV-1 or -2).In vitro evaluation of Win 41258-3 demonstrated that the compound inhibits the cytopathic effect of HSV-1 and -2 in tissue culture. Leibovitz L-15 medium supplemented with 5% heated (56°C for 60 min) fetal calf serum was used as maintenance medium.HSV-1, Sheely strain, and -2, Curtis strain, were were obtained from J. 0. Oh, Francis Procter Foundation. University of California. Virus pools were prepared in BSC-1 cultures and stored at -90°F. Respective titers: HSV-1 Sheely strain-log1o 6.75 50% tissue culture infective doses per 0.2 ml; HSV-2 Curtis strain-log10 6.0 50% tissue culture infective doses per 0.2 ml.(iii) Plaque assay. Four-day-old confluent monolayers grown in 60-cm2 Falcon plastic flasks were used. Nutrient medium was removed, and cultures were infected with approximately 50 plaque-forming units of each virus, contained in 0.5 ml of Eagle minimal essential medium supplemented with 2% fetal calf serum. Virus was allowed to adsorb for 1 h before the addition of agar overlay. Quadruplicate infected monolayers were overlsid with semisolid agar containing equal volumes of 1% Ionagar, L-15 Leibovitz medium, and 5% calf serum. Win 41258-3 was added to the agar overlay to provide the final desired concentration. Cytotoxicity controls consisted of uninfected monolayers overlaid with medium containing various concentrations of Win 41258-3. Cultures were incubated in an inverted position at 37°C and after 3 days were fixed in 10% Formalin (in 2% sodium acetate). The agar overlay was removed, and the monolayers were stained with 0.1% crystal violet. Plaques were counted in each flask, and the average of four culture flasks was established.Only those compound-treated monolayers showing no evidence of cytotoxicity when examined microscopically after 3 days of incubation were used in interpreting antiviral results. 470on May 12, 2018 by guest http://aac.asm.org/ Downloaded from

No abstract