Influence of virus strain, challenge dose, and time of therapy initiation on the in vivo influenza inhibitory effects of RWJ-270201

The influenza virus neuraminidase inhibitor RWJ-270201 (cyclopentane carbox ylic acid, 3[cis-1-(acetylamino)-2-ethylbutyl]-4[(aminoiminomethyl)amino]-2 -hydroxy-[cis, 2S, 3R, 4R]) was significantly inhibitory to an infection in mice induced by influenza A/NWS/33 (H1N1) virus when oral gavage (p.o.) tr eatment with 10 mg/kg per day was delayed at least 60 h after virus exposur e. Treatment was 5 mg/kg twice daily for 5 days. Viral challenge doses of i nfluenza A/Shangdong/09/93 (H3N2) virus ranging from the LD70 to the LD100 did not affect the marked antiviral efficacy of 12.5 mg/kg of RWJ-270201 ad ministered p.o. twice daily for 5 days beginning 4 h pre-virus exposure; in fection by an approximate 2 LD100 dose (10(8) cell culture infectious doses /ml) was only weakly inhibited by the same treatment as seen by significant increase in mean day to death. Murine infections induced by influenza A/Ba yern/57/ 93 (H1N1) and B/Lee/40 viruses were significantly inhibited by 100 , 10, and 1 mg/kg per day of RWJ-270201 using the above treatment regimen; influenza A/PR/8/34 (H1N1) virus infections in mice were only moderately in hibited, the antiviral effects using this virus being lessening of arterial oxygen decline, reduced lung consolidation, and inhibition of lung virus t iters primarily at the higher dosages. (C) 2001 Elsevier Science B.V. All r ights reserved.