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  • In conclusion our data demonstrated that montelukast and

    2019-09-10

    In conclusion, our data demonstrated that montelukast and pranlukast non-competitively blocked P2Y signaling in several cell systems, but in a relatively nonsubtype-specific manner. The functional antagonism was especially evident at heterologously expressed P2Y1 and P2Y6 receptors, at which IC50 values for inhibition of calcium mobilization were <1μM. Since the inhibition of P2Y1 receptor-elicited effects occurred without affecting specific nucleotide binding, if there is a direct interaction, it may be allosteric. The implications of these data for the clinical use of leukotriene antagonists is yet to be explored, with the question if some of their effects at therapeutic doses [44] may be related to their ability to inhibit the signaling pathways of P2Y receptors for extracellular nucleotides. These observations should foster the study of possible implications for the clinical use of these compounds in Diclofenac Sodium and or in other inflammatory conditions.
    Acknowledgements
    Introduction Cysteinyl-leukotrienes, as leukotriene C4, D4 and E4, are potent constrictors and pro-inflammatory mediators in guinea-pig and human airways. They play a crucial role in asthma pathophysiology by causing bronchoconstriction, mucus production, increase in vascular permeability and induce eosinophil-mediated inflammatory responses (Lane, 1998). Inhaled leukotriene D4 and leukotriene E4 provoke constriction of small and large airway smooth muscle and increase bronchial hyperresponsiveness to pharmacologic agents in both normal and asthmatic subjects. In addition, cysteinyl-leukotrienes has been identified in plasma, urine, nasal secretions, sputum and bronchoalveolar lavage fluid of patients during spontaneous exacerbations of asthma or after antigen challenge Smith, 1998, Claesson and Dahlen, 1999. Although the initial focus was linked to bronchoconstrictor activity, it Diclofenac Sodium and is nowadays clear that the role of cysteinyl-leukotriene in asthma also involves a contribution to the underlying inflammation and in airway remodeling. Cysteinyl-leukotrienes exert their biological actions by activating specific receptors on the membranes of target cells. Two types of CysLT receptors have been cloned and pharmacologically characterized, namely CysLT1 and CysLT2Gorenne et al., 1996, Rovati et al., 1997, Lynch et al., 1999, Sarau et al., 1999, Heise et al., 2000, Nothacker et al., 2000, Takasaki et al., 2000: both receptors belong to the superfamily of seven segments trasmembrane-spanning G-protein-coupled receptors. The CysLT1 receptor appears to be the main responsible of the actions of cystenyl-leukotrienes in asthma (Lynch et al., 1999) and is specifically blocked by recently developed leukotriene D4-receptor antagonists such as Montelukast (Jones et al., 1995), Zafirlukast (Krell et al., 1990), and Pranlukast (Obata et al., 1992). In contrast, the human CysLT2 receptor is insensitive to these compounds Heise et al., 2000, Nothacker et al., 2000. Agents developed to specifically antagonize the actions of leukotriene D4 or leukotriene E4 at the receptor level, i.e., CysLT1 receptor antagonists, represent a new class of drugs in therapy of asthma (Lipworth, 1999). Until now three CysLT1 receptor antagonists, namely Montelukast, Pranlukast and Zafirlukast, have been developed and marketed Hamilton et al., 1998, Leff et al., 1998, Nathan et al., 1998. They are orally effective over a wide range of asthma severity, preventing the airway inflammatory response to cysteinyl-leukotrienes action as well as acting as bronchodilators to the leukotriene-induced bronchoconstriction. Furthermore, recent clinical data would suggest that CysLT1 receptor antagonists are also beneficial in upper airways diseases since Montelukast reduce symptoms in seasonal allergic rhinitis (Wilson et al., 2001). This work describes the pharmacodynamic profile of the new CysLT1 receptor antagonist MEN91507 (8-[2-(E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran sodium salt)) (Fig. 1). The investigation has been conducted by means of in vitro studies and in animals models of bronchoconstriction and airway inflammation induced by leukotriene D4. MEN91507 is a new potent, selective and orally effective CysLT1 receptor antagonist: its preclinical profile indicates MEN91507 as a promising candidate for the treatment of inflammatory conditions of the respiratory tract, such as asthma and allergic rhinitis.