In Vitro Efficacies of Oseltamivir Carboxylate and Zanamivir against Equine Influenza A Viruses

Abstract

ABSTRACT. To investigate the possibilities of two NA inhibitors [oseltamivir carboxylate (OC) and zanamivir (ZA)] as the clinical agents for equine nifluenza A virus (EIV) infection, we examined the efficacies of these inhibitors against twelve EIVs in vitro. OC and ZA inhibited NA activities of all EIVs with 50% inhibitory concentrations with ranging from 0.017 to 0.130 and from 0.010 to 0.074 μM, respectively. OC and ZA inhibited plaque-forming of all EIVs in MDCK cells with 50% effective concentrations with ranging from 0.015 to 0.097 and from 0.016 to 0.089 μM, respectively, except for one strain (13.328 μM and 6.729 μM). These results suggest that these inhibitors are effective against most EIVs and might be useful for treatment of EI in horses. KEY WORDS: equine, equine influenza A virus, neuraminidase inhibitor.

Clinical Pharmacokinetics of Oseltamivir and Its Active Metabolite Oseltamivir Carboxylate after Oral Administration in Horses

“…Whether IC 50 or EC 50 as determined in vitro correlates more closely with the efficacy of OC against EIV in horses has not been established at present. Therefore, it would be safer for veterinarians to retain the concentration of OC above 36.9 ng/ml, which was the highest value for IC 50 s and EC 50 s of the EIV strains as determined in vitro [9]. Therefore, when veterinarians choose 2.0 mg/kg as an oral dose of oseltamivir, the administration intervals should be less than 10 hr (trough concentration: 37.2 ng/ml) in order to retain the concentration of OC above 36.9 ng/ml (Fig.…”

“…1) [3]. We first reported that OC inhibits the neuraminidase (NA) activities and plaque-forming of several EIV strains in vitro [9]. Subsequently, we reported the therapeutic and prophylactic efficacies of oral administration of oseltamivir in horses experimentally infected with EIV [10].…”

“…The standards of oseltamivir and OC ( Fig. 1) were gained by the method described in our previous paper [9]. The internal standard (active metabolite methyl ester, I.S.)…”

“…We previously reported that OC inhibited the NA activities of EIV strains with 50% inhibitory concentrations (IC 50 ) ranging from 4.8 to 36.9 ng/ml and the plaque-forming of EIV strains in MDCK cells with 50% effective concentrations (EC 50 ) ranging from 4.3 to 27.5 ng/ml, except for one resistant strain which had an EC 50 was 3785.1 ng/ml [9]. Since it is known that the binding rate of OC to human plasma proteins is negligible (<3%) and that OC is a timedependent inhibitor of viral NA and replication [3,4], the dosage regimen of oseltamivir for humans is therefore designed to retain the trough OC concentration in plasma Female 13 346 3 Thoroughbred Female 15 329 4 Thoroughbred Male 13 303 5 Thoroughbred Female 12 291 6 Thoroughbred Male 12 304 above IC 50 (and/or EC 50 ) as determined in vitro [3].…”

“…Likewise, since the binding rate of OC to horse plasma proteins was negligible in this study, it would be possible to design a dosage regimen of oseltamivir for horses on the basis of the trough OC concentration in plasma and IC 50 (and/or EC 50 ). Actually, in our previous study which investigated the efficacy of oseltamivir in horses experimentally inoculated with A/equine/La Plata/93 (IC 50 , 8.8 ng/ml; EC 50 , 20.7 ng/ ml) [9,10], therapeutic administration of oseltamivir (2 mg/ kg, at 12 hr intervals for five days from the onset of pyrexia) showed apparent efficacies including rapid reduction of febrile response and disappearance of virus excretion from nostrils. Since the concentration of OC in this pharmacokinetic study 12 hr after administration was 26.6 ng/ml (Fig.…”