title: Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza.
abstract: The cyclopentane peramivir (BCX-1812, RWJ-270201) is a highly selective inhibitor of influenza A and B virus neuraminidases and a potent inhibitor of influenza A and B virus replication in cell culture. The in vitro potency appears to be greater than either zanamivir or oseltamivir carboxylate based on the generally lower EC(50) values seen using peramivir in studies run in parallel with each compound. In mice infected with influenza A or B viruses, oral treatment with peramivir was highly effective in preventing death, signs of the disease and in lowering lung virus titres. Similar effects were seen in influenza A virus-infected ferrets. Efficacy was seen in mice when therapy began after virus exposure. Peramivir is non-toxic in mice and rats at doses of 1000 mg/kg/day and ferrets tolerated doses of 100 mg/kg/day. Doses of 100 mg/kg/day do not appear to affect murine immune parameters. A pharmacokinetic study of this compound in influenza virus-infected mice indicates once-, twice- or thrice-daily oral dosing was equal in efficacy; once-daily dosing has been recommended in clinical trials of influenza therapy. Treatment of influenza virus infections in cyclophosphamide-immunosuppressed mice was effective in inhibiting the infection; an infection induced in severe combined immunodeficient mice was only weakly affected. Development of viral resistance to peramivir can occur by serial cell culture passage of the virus in the presence of the compound but the resistant virus was less virulent than the wild type virus. Viruses with neuraminidase mutations are not necessarily all cross-resistant to peramivir, zanamivir and oseltamivir carboxylate. In Phase I studies, peramivir was well-tolerated, with single or multiple oral doses up to 800 mg/kg/day evaluated. In clinical trials with patients experimentally infected with influenza A or B viruses, oral treatment with peramivir significantly reduced nasal wash virus titres with no adverse effects. Phase III clinical trials are underway.
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT 84322-5600, USA. rsidwell@cc.usu.edu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sidwell
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002986:Clinical Trials as Topic; D003517:Cyclopentanes / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D015195:Drug Design; D004352:Drug Resistance, Microbial; D006146:Guanidines; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009975:Orthomyxoviridae / Q000187:drug effects
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D009439:Neuraminidase; C414210:peramivir