Safety of antileukotriene agents in asthma management.

Antileukotriene Working Group.

UCLA School of Medicine, University of California at Los Angeles, 90025, USA.

OBJECTIVE: This article presents information on the safety of zafirlukast, montelukast, and zileuton, three antileukotrienes (anti-LTs) approved in the United States for the prophylaxis and treatment of asthma. After reading this article, readers should have an understanding both of the general safety of anti-LTs and their specific adverse effects. DATA SOURCES: Relevant and appropriate controlled clinical studies on the safety of anti-LTs in asthma were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals and appropriate reviews. RESULTS: Antiasthma agents, including corticosteroids, beta2-agonists, and methylxanthines, may be categorized into two classes: those used for the long-term control and prevention of persistent asthma and those used for the prompt relief of acute symptoms and exacerbations of the disease. Although most agents are safe and well tolerated when used properly, adverse effects may occur with use at higher dose levels. The anti-LTs, including zafirlukast, montelukast, and zileuton, are the first new pharmacologic class in the therapeutic armamentarium for asthma management to be approved in the United States in the past 20 years. Both zafirlukast and montelukast carry pregnancy category B classification whereas zileuton carries pregnancy category C classification. The most common adverse effects observed in clinical trials were headache, pharyngitis, abdominal pain, dyspepsia, and cough. CONCLUSIONS: The results of clinical trials and real-world experience indicate that these agents are generally safe and well tolerated, with an incidence of adverse effects comparable with placebo.

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Characterization of cysteinyl leukotriene receptors on human saphenous veins: antagonist activity of montelukast and its metabolites.

Devillier P.

Laboratory of Pharmacology, Faculty of Medicine, University Hospital, Reims, France.

The aims of this study were to determine the cysteinyl leukotriene (CysLT) receptors expressed in the human saphenous vein, to examine contractile response to LTC4 and LTD4, to evaluate antagonist activity of montelukast, a specific CysLT1 receptor antagonist used in asthma, and to characterize the CysLT receptors involved in the contractile response. The analysis by reverse-transcriptase polymerase chain reaction indicated that CysLT1 and CysLT2 receptors are expressed by saphenous veins. In varicose vein rings, the potencies (pD2) of LTC4 and LTD4 were similar: 7.4 +/- 0.2 and 7.4 +/- 0.1, respectively. Pretreatment with acivicin, a gamma-glutamyl transpeptidase (gamma-GT) inhibitor, to prevent potential metabolism of LTC4 to LTD4, did not alter the response to LTC4. In nondistended vein rings from patients undergoing arterial bypass, the LTC4 pD2 was 7.8 +/- 0.1, and pretreatment with S-hexyl-GSH, a potent gamma-GT inhibitor, caused a fourfold rightward shift of the LTC4 concentration-response curve. In varicose and nondistended saphenous vein rings, montelukast (10(-8) and 10(-7) M) exerted a potent activity against LTD4 and LTC4, in the presence or absence of gamma-GT inhibitors. In varicose vein rings, the two active metabolites of montelukast also exerted antagonist activities with potencies similar to montelukast. BAY u9773 (CysLT2 agonist/dual CysLT1/CysLT2 antagonist) did not cause contraction and inhibited the LTC4- and LTD4-induced contractions. In conclusion, human saphenous veins express CysLT1 and CysLT2 receptors, but only CysLT1 receptors are implicated in the contraction.

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Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1.

Stankova J.

Immunology Division, Department of Pediatrics, Faculty of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, J1H 5N4 Canada.

Cysteinyl leukotrienes (CysLTs) are associated with several inflammatory processes, including asthma. Due to this association, considerable effort has been invested in the development of antagonists to the CysLT receptors (CysLT(1)R). Many of these molecules have been shown to specifically interact with CysLT(1)R, but little is known about their impact on the conformation of the receptor and its activity. We were especially interested in possible inverse agonist activity of the antagonists. Using a constitutively active mutant (N106A) of the human CysLT(1)R and the wild-type (WT) receptor coexpressed with the G(alphaq) subunit of the trimeric G protein, we were able to address this issue with ligands commonly used in therapy. We demonstrated that some of these molecules are inverse agonists, whereas others act as partial agonists. In cells expressing the CysLT(1)R mutant N106A exposed to Montelukast, Zafirlukast, or 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. On the other hand, 6(R)-(4-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BayU9773) and 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazole-5-YL)-butoxy]-phenyl ethanone] (LY171883) acted as partial agonists and alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV 5901) as a neutral antagonist. However, in cells expressing CysLT(1)R and G(alphaq), all antagonists used had inverse agonist activity. The decrease in basal inositol phosphate production by ligands with inverse agonist activity could be inhibited by a more neutral antagonist, confirming the specificity of the reaction. We demonstrate here that Montelukast, MK571, and Zafirlukast can act as inverse agonists on the human CysLT(1) receptor.

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Comparison of glucocorticoid and cysteinyl leukotriene receptor antagonist treatments in an experimental model of chronic airway inflammation in guinea-pigs.

Tiberio IF.

Department of Medicine, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

BACKGROUND: Leukotriene receptor antagonists have been demonstrated in several studies to possess bronchodilating and anti-inflammatory properties in asthma. However, there are few experimental studies performed to compare the effects of anti-leukotrienes and glucocorticoids, most used anti-inflammatory agents in asthma. In the present study, we evaluated the effects of treatment with dexamethasone or montelukast on eosinophil and mononuclear cell recruitment in an experimental model of allergen-induced chronic airway inflammation in guinea-pigs (GP). METHODS: GP were submitted to increasing concentrations of aerosols of ovalbumin (OVA) twice a week for 4 weeks. After 2 weeks, animals were treated daily with dexamethasone, montelukast or saline solution. After this period, GP were anaesthetized, tracheostomized, mechanically ventilated and challenged with OVA aerosol. RESULTS: Maximal changes of respiratory system resistance and elastance induced by OVA challenge were attenuated by dexamethasone (P<0.001), but not by montelukast treatment. Neither dexamethasone nor montelukast significantly influenced bronchial oedema formation. Dexamethasone but not montelukast induced a decrease in mononuclear cells in airways (P<0.001). Eosinophil infiltration in the bronchial wall was reduced by both dexamethasone and montelukast (P<0.005). Only dexamethasone treatment reduced the levels of exhaled nitric oxide (P<0.025). CONCLUSION: Although leukotriene receptor antagonist treatment reduces eosinophil accumulation induced by multiple antigen challenges, glucocorticoid treatment attenuates both eosinophil and mononuclear cell infiltration.

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Therapy in the management of the rhinitis/asthma complex.

Greenberger PA.

Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Allergic rhinitis is a risk factor for the development of asthma, and, conversely, asthma often is present in patients with rhinitis (17-25% in children and 20-50% in adults). Up to 80% of patients with asthma have allergic, nonallergic, or mixed rhinitis. Gastroesophageal reflux can be identified in 25-50% of patients with asthma and may be asymptomatic. Topical nasal corticosteroids typically reduce rhinitis symptoms more effectively than oral or topically administered histamine 1 antagonists but are similar in terms of ocular symptom reduction. The leukotriene D4 antagonist montelukast, as well as loratadine (29%), has been found to reduce nasal symptoms (27%) but the combination (33%) provided little additional benefit. Subcutaneous injections with a monoclonal anti-immunoglobulin E antibody for ragweed or birch allergic rhinitis have produced few anaphylactic reactions but when reactions occur, they appear 90-120 minutes after the injection. In the patients who received 300 mg of omalizumab every 3 or 4 weeks for ragweed allergic rhinitis, there were 23% fewer mean nasal symptoms than in placebo-treated subjects. In that study, antihistamines but not nasal corticosteroids were used during the study period. Overall, 70.7% of patients reported treatment as good or excellent compared with 40.8% in placebo-treated patients. The impact of omalizumab or other anti-immunoglobulin E therapies on rhinitis and asthma is being investigated. In patients experiencing acute, purulent, rhinosinusitis, treatment with a nasal corticosteroid helps relieve symptoms sooner than antibiotic and decongestant therapy alone. Treatment of rhinitis or rhinosinusitis and gastroesophageal reflux should be part of the management of patients with asthma.

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