Ribavirin and cysteinyl leukotriene-1 receptor blockade as treatment for severe bronchiolitis

Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, New York, United States
Antiviral Research (Impact Factor: 3.94). 03/2006; 69(2):53-9. DOI: 10.1016/j.antiviral.2005.10.004
Source: PubMed


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.

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Available from: Cynthia Bonville, Jul 16, 2014
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    • "The dose of Montelukast (5 mg/kg) was chosen on the basis of published data, where dosages ranging from 5–10 mg/kg have been reported in a wide range of mice experimental models [30], [31], [32]. The dosages of 2 mg/kg and 10 mg/kg were also investigated and the results reveal similar tendencies in xenograft tumor growth inhibition (Data not shown). "
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    ABSTRACT: The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (P<0.01), cleaved caspase 3, and the caspase-cleaved product of cytokeratin 18. Decreased levels of VEGF (P<0.01) and reduced vessel size (P<0.05) were also observed, the latter only in the ZM198,615-pretreatment group. Furthermore, we performed a series of in vitro studies using the colon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.
    PLoS ONE 09/2013; 8(9):e73466. DOI:10.1371/journal.pone.0073466 · 3.23 Impact Factor
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    • "Further support comes from a model of pneumonia virus of mice (PVM), a paramyxovirus that is a close phylogenetic relative of RSV. PVM infection increased levels of cysLTs in the lung [129]. In this model, administration of either the cysLT1 antagonist montelukast or the nucleoside analog ribavirin did not affect disease severity. "
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