Cysteinyl leukotriene antagonist

Leukotrienes form part of the inflammatory process their effect can be antagonised using cysteinyl leukotriene antagonists such as montelukast. 

Ironically, it was only after three cysteinyl leukotriene antagonists had been approved for clinical use that the two currently known cysteinyl leukotriene receptors were identified molecularly. However, two receptors were proposed earlier by Labat et al. (96). The receptors were proposed to be seven transmembrane G-coupled receptors by several groups... 

Zalirlukast, a cysteinyl leukotriene antagonist, has shown therapeutic efficacy in cough-variant asthma, even in patients unresponsive to inhaled bronchodilators and corticosteroids (Dicpinigaitis et al. 2002), whist a similar drug, montelukast has also... 

Cysteinyl leukotrienes can induce an early, transient fall in arterial pressure associated with sympathoadrenergic activation, plus a late rise in small coronary arteriolar resistance [32]. Using specific antagonists of CysFTi and CysFT2 [63] it will be possible to assess the each receptor s contribution to the cardiovascular effects of these vasoactive mediators. 

Spinozzi, F. et al., Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes, Clin. Exp. Allergy, 34, 1876, 2004. 

Reiss, T. L., Altman, L. C., Chervinsky, P., et al. (1996) Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LDT(4)) receptor antagonist, in patients with chronic asthma. J. Allergy Clin. Immunol. 98, 528-534. 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

It is a cysteinyl leukotriene receptor antagonist indicated for the management of persistent asthma. It has been shown to have substantial blockade of airway leukotriene receptors 24 hours after oral dosing. Montelukast appears to be a useful alternative or adjunct to inhaled corticosteroid therapy in adults and an alternative to sodium cro-moglycate in children. 

Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect. 

These block the cysteinyl leukotriene type 1 receptor, which mediates the bronchoconstriction and anti-inflammatory actions of leukotrienes the latter do not seem to be reduced by corticosteroids. Therefore leukotriene receptor antagonists are used to complement steroids when the latter do not effectively control symptoms. 

The leukotriene receptor antagonists are antagonists of cysteinyl leukotrienes at CysLTi receptors and include zafirlukast, montelukast, and pranlukast. 

Churg-Strauss syndrome has been reported in an 18-year-old woman taking cysteinyl leukotriene receptor antagonists and oral rokitamicin 400 mg bd for 10 days (2). 

Taylor, I.K., O Shaughnessy, K.M., Fuller, R.W. and Dollery, C.T. (1991). Effect of cysteinyl-leukotriene receptor antagonist ICl 204.219 on alletgen-induced bronchoconstriction and airway hyperreactivity in atopic subjects [see comments]. Lancet 337, 690-694. 

As a result of their prolonged and potent bronchoconstrictor actions, a role for the cysteinyl leukotrienes (viz. C4, D4, and E4) in the genesis of asthmatic bronchospasm was suspected and is now well established. Consistent with this, inhibition of 5-LO using zileuton has been shown to relieve mild to moderate asthma [70]. Compared to their cysteinyl leukotriene receptor antagonist brethren (vide infra), 5-LO inhibitors are in their early stages of development. Currently, zileuton is the only 5-LO inhibitor available and is administered as an oral formulation. It is likely that more inhalable 5-LO inhibitors will available in the future. 

Leukotriene Antagonists. The leukotrienes are metabolites of arachidonic acid generated de novo after inflammatory cell activation [69,75] and are potent bronchoconstrictors and proinflammatory agents (vide supra). The biological effects of the cysteinyl-leukotrienes (viz. C4, D4, and E4) and of leukotriene B4 are mediated via cysLTi and BLT receptors, respectively [69,76]. The development of potent, selective cysLT receptor antagonists, such as montelukast, pranlukast,... 

LY171883 was the first CysLTl antagonist to be evaluated in broad clinical trials (239). It was eventually withdrawn from clinical evaluation as a result of both long-term toxicity seen in mice and induction of peroxisomal liver enzyme in rats (240,241). In spite of this, it was an especially important compound because it produced encouraging clinical results that appeared to confirm the hypothesis linking the cysteinyl leukotrienes to disease and... 

Two clinically distinct cysteinyl leukotriene receptor antagonists (zafirlukast and montelukast) and one inhihitor of leukotriene synthesis (zUeuton) have been available in the United States since 1996 for both children and adults with persistent asthma. In challenge studies, they reduce allergen-, exercise-, cold-air hyperventilation-, irritant-, and aspirin-induced asthma. Chnical use of zileuton is limited owing to the need for four-times-daily dosing, the potential for elevated liver enzymes (especially in the first 3 months of therapy), and the potential inhibition of drugs metabolized by the CYP3A4 isoenzymes. ... 

Zafirlukast is an oral leukotriene receptor antagonist (LTRA) for the treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. Zafirlukast blocks the action of the cysteinyl leukotrienes on the CysLTl receptors, thus reducing constriction of the airways, build-up of mucus in the lungs and inflammation of the breathing passages. 

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