Efficacy of oral WIN 54954 for prophylaxis of experimental rhinovirus infection

Abstract

The efficacy of oral WIN 54954 for the prevention of rhinovirus infection and illness was tested in two randomized, double-blinded, placebo-controlled volunteer challenge studies. Volunteers were inoculated with rhinovirus type 39 (MIC of WIN 54954, 0.17 Lg/ml) or rhinovirus type 23 (MIC, 0.016 ,ug/ml). The volunteers received two doses of drug (600 mg per dose) or placebo on the first day; this was followed by three doses on each of the subsequent 5 days. All volunteers were challenged with virus after the third dose of study drug. No significant antiviral or clinical effect was detected in either study. Pharmacokinetic studies revealed that on the last day of drug administration, 38 of 39 (97%) volunteers had trough levels of WIN 54954 in plasma greater than the MIC for the respective virus. Nasal wash specimens collected on the same day revealed a detectable level in only 6 of 24 (25%) volunteers at the peak (range, 6 to 24 ng/ml) and in only 2 of 14 (14%) volunteers at the trough (range, 6 and 7 ng/ml). These results suggest that the lack of efficacy of WIN 54954 against rhinovirus may be related to an inability to deliver sufficient drug to the site of viral infection.The oxazolines are a class of antipicornavirus compounds which have activity against rhinoviruses and enteroviruses in vitro (4, 6, 16) and against enteroviruses in animal models (4, 5). These compounds bind to a hydrophobic pocket in the picornavirus viral capsid protein (7). Depending on the virus serotype, this interaction inhibits replication either by interfering with uncoating of the virus or by causing a conformational change in the cell receptor site on the viral capsid and inhibiting attachment to the cell (9, 14). WIN 54954 is a representative of the oxazoline compounds and has a broad spectrum of activity against both the human rhinoviruses and enteroviruses in vitro (16). In cell culture, this agent inhibited 80% of 52 rhinovirus serotypes when it was used at a concentration of 0.28 ,ug/ml and 80% of 15 enterovirus serotypes when it was used at a concentration of 0.06 ,ug/ml. The purpose of these two parallel studies done at the University of Virginia (UVa) and at the Medical University of South Carolina (MUSC) was to determine the efficacy of oral WIN 54954 for the prevention of experimentally induced rhinovirus infection and illness.MATERIALS AND METHODS Study design. The clinical trials at both study sites were randomized, double blind, and placebo controlled in design. All volunteers were begun on the study drug or placebo approximately 18 h prior to virus challenge. At UVa the volunteers were isolated in individual motel rooms throughout the treatment period; at MUSC the volunteers were not isolated during the study. The study at UVa was done in January 1990, and the study at MUSC was done in November 1990.Volunteers. Healthy volunteers between 18 and 55 years of age who had a serum neutralizing antibody titer to the study virus of less than 1:8 were selected for participation in the studies. Volunteers who had an upper respir...

Antipicornavirus Drugs: Current Status

“…2) is the most recent entry from the WlN compound series. WlN 54954, an early predecessor,was shown to be clinically effective against an upper respiratory tract infection with coxsackievirus A21 when administered orally prior to infection (Schiff et al, 1992), but did not show a statistically significant effect in challenge trials utilizing rhinovirus 23 and 39 (Turner & Hayden, 1992). WlN 54954 demonstrated a relatively short half-life in vivo, was rapidly metabolized to an array of products and was subsequently dropped from clinical trials as a result of reversible hepatitis which appeared to be associated with metabolites of the drug.…”

“…Several virus-specific compounds have been clinically evaluated 402 against both rhinovirus (Turner & Hayden, 1992;Hayden et al, 1992Hayden et al, , 1993 and enterovirus infections (Schiff et al, (Turner et al, 1989;Monto et al, 1989) and bradykinin antagonists (Higgins et al, 1990) have been unsuccessful. This review will focus on the current status in this area of antiviral chemotherapy and will include the results of clinical trials where available, as well as recently discovered compounds which are active against this family of viruses.…”

Antiviral Therapy for Enteroviruses and Rhinoviruses

“…Shortening of the aliphatic chain from n=7 to n=5 and adding chloro-groups to the phenyl ring (Figure 1) resulted in WIN 54954 which had broad, potent anti-RV and anti-EV activity in vitro and in vivo (Woods et al, 1989), including oral therapeutic efficacy in mice. Clinical efficacy was assessed in two RV (rhinovirus 23 and rhinovirus 39) challenge trials (Turner et al, 1993) and one EV challenge trial (coxsackievirus A21) (Schiff et al, 1992). Despite administering the compound prior to infection and achieving serum concentrations above the in vitro minimal inhibitory concentrations, both RV trials failed to show efficacy of WIN 54954 (Turner et al, 1993); very low concentrations of the drug were found in nasal wash samples, the site of the experimental infection.…”

“…Clinical efficacy was assessed in two RV (rhinovirus 23 and rhinovirus 39) challenge trials (Turner et al, 1993) and one EV challenge trial (coxsackievirus A21) (Schiff et al, 1992). Despite administering the compound prior to infection and achieving serum concentrations above the in vitro minimal inhibitory concentrations, both RV trials failed to show efficacy of WIN 54954 (Turner et al, 1993); very low concentrations of the drug were found in nasal wash samples, the site of the experimental infection. In contrast, WIN 54954 significantly reduced the number and severity of colds induced by coxsackievirus A21, and also significantly reduced nasal mucous discharge, respiratory and systemic symptoms, and viral titres (Schiff et al, 1992).…”

Analysis of three structurally related antiviral compounds in complex with human rhinovirus 16

“…A second compound, WIN 54954, reached phase II clinical trials, but was found to have low efficacy in vivo. Although this compound exhibited some activity when administered prophylactically, some undesirable side effects were observed (25). The third-generation compound, pleconaril (WIN 63843; Fig.…”