Tamiflu
The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses.

Leneva IA, Roberts N, Govorkova EA, Goloubeva OG, Webster RG.

Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, PO Box 318, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.

In 1997, an H5N1 avian influenza A/Hong Kong/156/97 virus transmitted directly to humans and killed six of the 18 people infected. In 1999, another avian A/Hong/1074/99 (H9N2) virus caused influenza in two children. In such cases in which vaccines are unavailable, antiviral drugs are crucial for prophylaxis and therapy. Here we demonstrate the efficacy of the neuraminidase inhibitor GS4104 (oseltamivir phosphate) against these H5N1 and H9N2 viruses. GS4071 (the active metabolite of oseltamivir) inhibited viral replication in MDCK cells (EC(50) values, 7.5-12 microM) and neuraminidase activity (IC(50) values, 7.0-15 nM). When orally administered at doses of 1 and 10 mg/kg per day, GS4104 prevented death of mice infected with A/Hong Kong/156/97 (H5N1), mouse-adapted A/Quail/Hong Kong/G1/97 (H9N2), or human A/Hong Kong/1074/99 (H9N2) viruses and reduced virus titers in the lungs and prevented the spread of virus to the brain of mice infected with A/Hong Kong/156/97 (H5N1) and mouse-adapted A/Quail/Hong Kong/G1/97 (H9N2) viruses. When therapy was delayed until 36 h after exposure to the H5N1 virus, GS4104 was still effective and significantly increased the number of survivors as compared with control. Oral administration of GS4104 (0.1 mg/kg per day) in combination with rimantadine (1 mg/kg per day) reduced the number of deaths of mice infected with 100 MLD(50) of H9N2 virus and prevented the deaths of mice infected with 5 MLD(50) of virus. Thus, GS4104 is efficacious in treating infections caused by H5N1 and H9N2 influenza viruses in mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11114412&dopt=Abstract oseltamivir Tamiflu



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Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities.

Smee DF, Huffman JH, Morrison AC, Barnard DL, Sidwell RW.

Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600, USA. dsmee cc.usu.edu

A novel series of cyclopentane derivatives have been found to exhibit potent and selective inhibitory effects on influenza virus neuraminidase. These compounds, designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells. Inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC(50)) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC(50)s (determined by neutral red assay) of the novel compounds were < or =1.5 microM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at <0.3 microM. Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at <0.2 microM, with three other B virus strains inhibited at 0.8 to 8 microM. The novel inhibitors were comparable in potency to (or slightly more potent than) zanamivir and oseltamivir carboxylate. No cytotoxicity was seen with the compounds at concentrations of < or =1 mM in cell proliferation assays. The antiviral activity of RWJ-270201, chosen for clinical development, was studied in greater detail. Its potency and that of oseltamivir carboxylate decreased with increasing multiplicity of virus infection. Time-of-addition studies indicated that treatment with either compound needed to begin 0 to 12 h after virus exposure for optimal activity. Exposure of cells to RWJ-270201 caused most of the virus to remain cell associated, with extracellular virus decreasing in a concentration-dependent manner. This is consistent with its effect as a neuraminidase inhibitor. RWJ-270201 shows promise in the treatment of human influenza virus infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11181354&dopt=Abstract oseltamivir Tamiflu



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In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RJW-270201.

Sidwell RW, Smee DF, Huffman JH, Barnard DL, Bailey KW, Morrey JD, Babu YS.

Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600, USA. Rsidwell cc.usu.edu

The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >10(4) cell culture 50% infective doses (CCID(50))/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 10(1.2) CCID(50)/g, whereas titers from oseltamivir-treated animals were >10(3) CCID(50)/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11181355&dopt=Abstract oseltamivir Tamiflu



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Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir.

Bantia S, Parker CD, Ananth SL, Horn LL, Andries K, Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin T, Hutchison TL, Montgomery JA, Kellog DL, Babu YS.

BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 35244, USA. sbantia biocryst.com

We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (P < 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11257030&dopt=Abstract oseltamivir Tamiflu



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Experience with oseltamivir in the control of a nursing home influenza B outbreak.

[Article in English, French]

Parker R, Loewen N, Skowronski D.

Simon Fraser Health Region, B.C. Centre for Disease Control, Vancouver, British Columbia.

Oseltamivir prophylaxis was very effective in protecting nursing home residents from ILI and in halting this outbreak of influenza B. A portion of the total ILI cases may have been due to influenza A, as this strain was isolated in one resident. The 10% attack rate in this facility, controlled with oseltamivir, compares favourably with another influenza B outbreak in a similar facility in the same region, over the same time frame (ILI onset 27 December to 17 January). Oseltamivir prophylaxis was not used to manage this second outbreak of laboratory-confirmed influenza B. Of the 236 residents, 45 developed ILI for an overall attack rate of 19%, nearly double the rate in the oseltamivir-controlled setting (10%). While oseltamivir was effective in controlling influenza B in this outbreak, further experience and evaluation is required before it can be routinely recommended for prophylaxis of influenza in nursing home outbreaks. Although earlier attempts by others using oseltamivir in the control of influenza A outbreaks have also met with success, it is not yet licensed for this purpose. Compared to amantadine, oseltamivir has a relatively high cost for the control of influenza A outbreaks and this may continue to limit its wider acceptance. The cost-effectiveness of oseltamivir in the control of influenza B outbreaks needs to be specifically addressed given the typically milder nature of influenza B strains. However, such a distinction is not clinically reliable and elderly residents of long-term care facilities remain vulnerable to serious complications associated with influenza infection in general. An alternate agent for influenza chemoprophylaxis that is effective against both influenza A and B, is easily administered and has few side effects, could greatly enhance current prevention and control measures and warrants serious assessment. The spread of this outbreak from the geographically separate ward to other areas of the facility in which residents had not received prophylaxis, underscores the likely role of staff as a vehicle for transmission during facility outbreaks. While accurate staff ILI rates could not be determined, their immunization rates were low, and many staff were ill during the outbreak. Isolation of residents with ILI and prophylaxis of non-ill residents on the initial outbreak wards was insufficient to prevent the spread of the outbreak, although it was subsequently halted once prophylaxis was extended to all residents. In view of the uncertainty over this medication's widespread use, in the absence of licensure or previous studies demonstrating its effectiveness in the prophylaxis and control of influenza B outbreaks, initiation of oseltamivir prophylaxis was staggered by ward. In a declared influenza A outbreak, the protocol in a long term care facility is to initiate amantadine prophylaxis on all residents, rather than ward-by-ward. While anti-viral prophylaxis may be an effective secondary control measure in the management of influenza outbreaks, optimal primary prevention would be more effective. This would require increased vaccine coverage of residents and particularly of staff, who play an important role in the importation and transmission of influenza within these facilities.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11260987&dopt=Abstract oseltamivir Tamiflu