Disease relevance of zafirlukast

• Zafirlukast and Churg-Strauss syndrome [1].
• COMMENT: Development of pulmonary infiltrates, cardiomyopathy, and eosinophilia may have occurred independent of zafirlukast use or may have resulted from an allergic response to this medication [2].
• CONCLUSION: Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis [3].
• CONCLUSION: The results of this study indicate that only patients with autoimmune (ASST positive) chronic urticaria refractory to H(1)-antagonist monotherapy might benefit from the addition of the leukotriene D(4)-receptor antagonist zafirlukast to their treatment regimen [4].
• In clinical models of asthma, zafirlukast inhibited bronchospasm after allergen or exercise challenge in patients with asthma [5].

Psychiatry related information on zafirlukast

• However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20 mg twice daily than with twice-daily inhaled corticosteroid therapy [6].
• Zafirlukast (2.5 and 5.0 mg/kg, p.o.) also attenuated the carrageenan-provoked hyperalgesia but did not alter the pain threshold in central nociception up to 20 mg/kg [7].

High impact information on zafirlukast

• In a double-blind study ten asthmatic patients with impaired lung function received the cysteinyl-leukotriene receptor antagonist ICI 204,219 (40 mg by mouth) and placebo in random order on 2 days at least 1 week apart [8].
• The increase in forced expiratory volume in 1 s (FEV1) above baseline was significantly greater after ICI 204,219 than after placebo [8].
• INTERVENTION: Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient [3].
• Specific leukotriene receptor antagonists and synthesis inhibitors have been developed and are currently showing promise in clinical trials; one leukotriene receptor antagonist (zafirlukast) and one 5-lipoxygenase inhibitor (zileuton) were recently approved by the United States Food and Drug Administration for the treatment of asthma [9].
• Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks [10].

Chemical compound and disease context of zafirlukast

• Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment [11].
• Intracellular electrophysiological recording of the membrane properties of jugular ganglion neurons, the source of tachykinins in the guinea pig trachea/bronchus, demonstrated that leukotriene D4 caused a membrane depolarization of vagal afferent C-fiber neurons and an increase in input impedance, both of which were abolished by zafirlukast [12].
• OBJECTIVE: Clinical observation of a decrease in migraine frequency in patients with comorbid asthma taking montelukast, a specific D4 leukotriene receptor antagonist, or zafirlukast, another leukotriene receptor antagonist, prompted us to explore a possible role for leukotriene modifiers in the treatment of migraine [13].
• Treatment of acquired cold urticaria with cetirizine and zafirlukast in combination [14].
• METHODS: We report a patient with moderately severe asthma who experienced an episode of anaphylaxis following ingestion of 400 mg of ibuprofen while under therapy with 20 mg of zafirlukast given twice a day [15].

Biological context of zafirlukast

• BACKGROUND: Single doses of zafirlukast attenuate exercise-induced bronchoconstriction (EIB), but previous studies have not measured zafirlukast's effects after regular dosing or its duration of effect beyond 4 hours [16].
• Compared with placebo, zafirlukast produced a significant improvement over baseline in the primary study endpoint of mean morning peak expiratory flow rate (PEFR) (18.7 L/min versus 1.5 L/min, p < 0.001), as well as in evening PEFR (p < 0.01), FEV(1) (p < 0.05), daytime symptom score (p < 0.001), and beta(2)-agonist use (p < 0.001) [17].
• On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group [10].
• The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control) [18].
• By means of heterologous dissociation time courses, we demonstrated that zafirlukast, iralukast, and BAY u9773 selectively competed only for (3)H-LTD(4) binding sites, whereas pobilukast, pranlukast, and CGP 57698 dissociated both (3)H-LTC(4) and (3)H-LTD(4) from their binding sites [19].

Anatomical context of zafirlukast

• Increases in cytosolic calcium induced by LTD 4 -stimulated basophils were inhibited by the cysLT1 receptor antagonist zafirlukast, confirming the presence of functional cysLT1 receptors on basophils [20].
• Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast [21].
• The -log molar KB values for ICI 204,219 were found to be independent of the epithelium in both tissues [22].
• An examination of the influence of the epithelium on contractile responses to peptidoleukotrienes and blockade by ICI 204,219 in isolated guinea pig trachea and human intralobar airways [22].
• The enzyme inhibitory property of zafirlukast was selective for this enzyme among all of the P450 enzymes that were tested in human liver microsomes [23].

Associations of zafirlukast with other chemical compounds

• The cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory disorders, in particular asthma, for which the CysLT receptor antagonists pranlukast, zafirlukast, and montelukast, have been introduced recently as novel therapeutics [24].
• Compared with placebo, ICI 204,219 increased the concentration (PC20FEV1) and dose of LTD4 needed to reduce forced expiratory volume in 1 second (FEV1) by 20% [25].
• Patients, over 80% of whom were on a concurrent inhaled corticosteroid regimen, were treated for 4 weeks with either inhaled salmeterol xinafoate 42 microgram twice daily administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice daily [26].
• METHODS: In a double-blind cross-over study loratadine (10 mg twice daily) and zafirlukast (80 mg twice daily) were evaluated alone and in combination in 16 nonsmoking patients with mild asthma, previously documented EIB, and airways hyperresponsiveness to histamine [27].
• Health-related quality of life improved significantly with fluticasone propionate 88 microg twice daily, but not zafirlukast 20 mg twice daily or placebo [28].

Gene context of zafirlukast

• Inhibition of the CYP2C9 and CYP3A isoenzymes by zafirlukast has been reported in vitro [29].
• Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic alpha,beta-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme [23].
• Our objective was to identify the cytochrome P450 (CYP) enzymes that metabolise pioglitazone and to examine the effects of the CYP2C8 inhibitors montelukast, zafirlukast, trimethoprim and gemfibrozil on pioglitazone metabolism in vitro [30].
• Zafirlukast produced negligible inhibition of CYP2E1 [31].
• Trials of 13- to 26-wks' duration demonstrate that both the cysLT1 receptor antagonist, zafirlukast, and the 5-LO inhibitor, zileuton, improve pulmonary function and decrease daytime and nocturnal symptoms [32].

Analytical, diagnostic and therapeutic context of zafirlukast

• Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast [3].
• Eighteen normal male subjects were recruited for a double-blind, placebo-controlled, randomized, two-period crossover study to determine the effects of a new, potent, highly selective, oral peptide leukotriene antagonist (ICI 204,219) on cutaneous vasculature [33].
• In multicenter trials in patients with chronic, stable asthma, zafirlukast reduced asthma symptoms, decreased as-needed beta-agonist use, and improved pulmonary function without increasing the number of adverse events [5].
• The effect of zafirlukast (Z) to alter the inflammatory response to segmental antigen challenge (SAC) was assessed by bronchoalveolar lavage (BAL) in this double-blind, placebo-controlled, two-period, crossover trial in 11 allergic asthmatic patients [34].
• The overall treatment failure rate was significantly lower in the zafirlukast group compared with the placebo group (P <.003) [35].

References