Ribavirin and cysteinyl leukotriene-1 receptor blockade as treatment for severe bronchiolitis.
In this work we have evaluated the clinical responses of pneumovirus-infected mice to combination therapy with the antiviral agent, ribavirin, and the CysLT1 cysteinyl leukotriene receptor antagonist, montelukast. We observed substantial virus replication in our mouse model of pneumovirus infection and significant accumulation of cysteinyl leukotrienes in lung tissue, the latter detected at levels that correlate directly with granulocyte recruitment to the airways. While administration of the nucleoside analog, ribavirin, reduced virus replication approximately 2,000-fold, the clinical outcomes as measured by morbidity and mortality, in response to ribavirin monotherapy were indistinguishable from those of the no-treatment controls. Similarly, montelukast therapy alone did not reduce granulocyte recruitment nor did it improve the clinical outcome. However, combined therapy with ribavirin and montelukast resulted in a significant reduction in morbidity and a substantial reduction in mortality (50% survival at t = 14 days and onward, compared to 10-20% survival in response to montelukast alone or to ribavirin alone, respectively, p < 0.01). These findings define further the independent contributions made by virus replication and by the ensuing inflammatory response to the detrimental sequelae of pneumovirus infection in vivo.
Bonville
Cynthia A
CA
Department of Pediatrics, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
Rosenberg
Helene F
HF
Domachowske
Joseph B
JB
D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001990:Bronchiolitis, Viral / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D003521:Cyclopropanes; D003545:Cysteine / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D015289:Leukotrienes; D008168:Lung / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D029122:Murine pneumonia virus / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D018186:Pneumovirus Infections / Q000188:drug therapy / Q000401:mortality / Q000821:virology; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D013440:Sulfides; D016896:Treatment Outcome; D014779:Virus Replication
D000085:Acetates; D000998:Antiviral Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D013440:Sulfides; C112381:cysteinyl-leukotriene; D012254:Ribavirin; D003545:Cysteine; C093875:montelukast