title: Anti-influenza virus activity of peramivir in mice with single intramuscular injection.
abstract: In the event of an influenza outbreak, antivirals including the neuraminidase (NA) inhibitors, peramivir, oseltamivir, and zanamivir may provide valuable benefit when vaccine production is delayed, limited, or cannot be used. Here we demonstrate the efficacy of a single intramuscular injection of peramivir in the mouse influenza model. Peramivir potently inhibits the neuraminidase enzyme N9 from H1N9 virus in vitro with a 50% inhibitory concentration (IC(50)) of 1.3+/-0.4 nM. On-site dissociation studies indicate that peramivir remains tightly bound to N9 NA (t(1/2)>24h), whereas, zanamivir and oseltamivir carboxylate dissociated rapidly from the enzyme (t(1/2)=1.25 h). A single intramuscular injection of peramivir (10mg/kg) significantly reduces weight loss and mortality in mice infected with influenza A/H1N1, while oseltamivir demonstrates no efficacy by the same treatment regimen. This may be due to tight binding of peramivir to the N1 NA enzymes similar to that observed for N9 enzyme. Additional efficacy studies indicate that a single injection of peramivir (2-20mg/kg) was comparable to a q.d.x 5 day course of orally administered oseltamivir (2-20mg/kg/day) in preventing lethality in H3N2 and H1N1 influenza models. A single intramuscular injection of peramivir may successfully treat influenza infections and provide an alternate option to oseltamivir during an influenza outbreak.
authors.affiliation: Department of Biological Sciences, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. sbantia@biocryst.com
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: C Shane
authors.initials: CS
authors.lastname: Arnold
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Parker
authors.forename: Ramanda
authors.initials: R
authors.lastname: Upshaw
authors.forename: Pooran
authors.initials: P
authors.lastname: Chand
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D053118:Influenza A Virus, H1N1 Subtype; D007273:Injections, Intramuscular; D051379:Mice; D009439:Neuraminidase / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D009439:Neuraminidase; C414210:peramivir