Fighting the Flu
Source: Eisenberg EJ, et al. Antimicrob Agents Chemother 1997;41:1949-1952.
Management of influenza infection is presently limited to preventative immunization and prophylaxis, and treatment of influenza A with amantadine or ramantadine. Several neuraminadase inhibitors have been shown to have significant in vitro activity against both influenza A and B viruses, the latter of which is responsible for approximately 35% of influenza cases.
Presently, two of these compounds are racing toward the market. One compound, zanamivir (GG167), which is is not orally bioavailable, was recently shown to shorten the duration of illness (4 vs 5 days) in patients with comfirmed influenza receiving zanamivir either by inhalation or with intranasal administration, compared with those receiving placebo (Hayden FG, et al. N Engl J Med 1997; 337:874-880).
Another potent inhibitor of influenza neuraminidase, GS4071, is also not orally bioavailable, but recent data suggest that its ethyl ester prodrug, GS4104, has good oral bioavailability. Eisenberg et al demonstrate that the oral administration of the prodrug to rats resulted in significantly lower respiratory tract penetration of GS4071, with a peak concentration in bronchoalveolar lavage two hours after administration of the parent compound. No unmetabolized parent compound was found in BAL fluid. The terminal half-life of the metabolite in lung fluids was more than four-fold longer than that in plasma and, six-hours post-dosing, concentrations of GS4071 in lung fluids were ~20-fold higher than those in plasma. The bioavailability of GS4071 following oral administration of the parent compound was estimated to be 36%.
Since replication of influenza virus primarily occurs in respiratory tract epithelium, these data suggest that the oral administration of GS4104 may be effective in the treatment of both influenza A and B in humans. Preliminary data presented at ICAAC indicate that GS4104 was able to reduce the duration of illness in a small number of humans by about one-half (Abstract LB-26).
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