tetano
Editor, Senior Moderator
Am J Respir Cell Mol Biol. 2012 Jun 7. [Epub ahead of print]
Post-Infection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice.
Aeffner F, Bratasz A, Fla?o E, Powell KA, Davis IC.
Source
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States.
Abstract
Acute respiratory disease is associated with significant morbidity and mortality in influenza. Because antiviral drugs are only effective early in infection, new agents are needed to treat non-vaccinated patients presenting in late-stage disease, particularly those who develop acute respiratory distress syndrome. We found previously that the de novo pyrimidine synthesis inhibitor A77-1726 reversed influenza-induced alveolar fluid clearance impairment. Patients with acute respiratory distress syndrome and intact alveolar fluid clearance have lower mortality than those with compromised fluid clearance. We therefore investigated the effects of treatment with nebulized A77-1726 (67.5 mg/kg) on indices of cardiopulmonary function relevant to the diagnosis of acute respiratory distress syndrome in patients. 8-12 week-old BALB/cAnNCr mice were inoculated intranasally with 10,000 pfu/mouse influenza A/WSN/33 (H1N1). Pulse oximetry was performed daily. Alveolar fluid clearance, lung water, and lung mechanics were measured at 2 and 6 days post-inoculation in live, ventilated mice by BSA instillation, magnetic resonance imaging, and forced-oscillation techniques, respectively. A77-1726 treatment at 1 day post-inoculation delayed mortality. Treatment at days 1 or 5 reduced viral replication at day 6, and improved alveolar fluid clearance, peripheral oxygenation, and cardiac function. Nebulized A77-1726 also reversed influenza-induced increases in lung water content and volume, improved pulmonary mechanics, reduced bronchoalveolar lavage fluid ATP and neutrophil content, and increased IL-6 levels. The ability of A77-1726 to improve cardiopulmonary function in influenza-infected mice and to reduce the severity of ongoing acute respiratory distress syndrome late in infection suggests that pyrimidine synthesis inhibitors are promising therapeutic candidates for management of severe influenza.
PMID:
22679275
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22679275
Post-Infection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice.
Aeffner F, Bratasz A, Fla?o E, Powell KA, Davis IC.
Source
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States.
Abstract
Acute respiratory disease is associated with significant morbidity and mortality in influenza. Because antiviral drugs are only effective early in infection, new agents are needed to treat non-vaccinated patients presenting in late-stage disease, particularly those who develop acute respiratory distress syndrome. We found previously that the de novo pyrimidine synthesis inhibitor A77-1726 reversed influenza-induced alveolar fluid clearance impairment. Patients with acute respiratory distress syndrome and intact alveolar fluid clearance have lower mortality than those with compromised fluid clearance. We therefore investigated the effects of treatment with nebulized A77-1726 (67.5 mg/kg) on indices of cardiopulmonary function relevant to the diagnosis of acute respiratory distress syndrome in patients. 8-12 week-old BALB/cAnNCr mice were inoculated intranasally with 10,000 pfu/mouse influenza A/WSN/33 (H1N1). Pulse oximetry was performed daily. Alveolar fluid clearance, lung water, and lung mechanics were measured at 2 and 6 days post-inoculation in live, ventilated mice by BSA instillation, magnetic resonance imaging, and forced-oscillation techniques, respectively. A77-1726 treatment at 1 day post-inoculation delayed mortality. Treatment at days 1 or 5 reduced viral replication at day 6, and improved alveolar fluid clearance, peripheral oxygenation, and cardiac function. Nebulized A77-1726 also reversed influenza-induced increases in lung water content and volume, improved pulmonary mechanics, reduced bronchoalveolar lavage fluid ATP and neutrophil content, and increased IL-6 levels. The ability of A77-1726 to improve cardiopulmonary function in influenza-infected mice and to reduce the severity of ongoing acute respiratory distress syndrome late in infection suggests that pyrimidine synthesis inhibitors are promising therapeutic candidates for management of severe influenza.
PMID:
22679275
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22679275