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Antileukotriene Drugs in the Treatment of Asthma

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Antileukotriene Drugs in the Treatment of Asthma REVIEW ARTICLE Antileukotriene drugs in the treatment of asthma Lucyna Mastalerz, Jagoda Kumik 2nd Department of Medicine, Jagiellonian University School of Medicine, Kraków, Poland KEy WoRds AbsTRACT allergic rhinitis, Antileukotriene medications that have been implemented into clinical practice of bronchial asthma and antileukotriene drugs, allergic rhinitis include specific leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast) asthma, leukotrienes and leukotriene bio synthesis inhibitors (zileuton). The current GINA (Global Initiative for Asthma) guide‑ lines, the PRACTALL (Practicing Allergology) report on asthma treatment in children, and ARIA (Allergic Rhinitis and its Impact on Asthma) recommendations classify antileukotriene therapeutic agents as a group of drugs controlling the course of the disease. However, inhaled glucocorticosteroids still remain the first‑line treatment in chronic asthma. According to current guidelines, antileukotriene drugs are recommended as alternative treatment to low‑dose inhaled glucocorticosteroids in the second level of asthma severity and as complementary treatment to inhaled and/or oral glucocorticosteroids, starting from the third level of asthma severity. Recently, clinical efficacy of antileukotriene drugs has been suggested in the treatment of isolated allergic rhinitis, chronic cough in the course of asthma, as a sole symptom of the disease, and as the therapy for episodes of wheezing caused by viral infections. Leukotrienes as mediators of asthma Leukotrienes clearance, enhance mucus secretion, attract eo‑ are bio logically active 5‑lipoxygenase (5‑LO) lip‑ sinophils to the airways, and increase vascular id mediators of arachidonic acid (FIGURE). They in‑ permeability producing edema.1,2 Moreover, in clude 2 classes: an unstable leukotriene A4 (LTA4), patients with asthma, the airways are 100 to 1000 which is further converted into leukotriene B4 times more sensitive to inhaled LTD4 and LTE4 (LTB4), and a separate category of leukotrienes than the airways of normal subjects. Furthermore, that contain cysteine and are termed collective‑ inhaled LTC4 and LTD4 increase bronchial reactivi‑ 3,4 ly as cys‑LTs – leukotriene C4 (LTC4), D4 (LTD4), ty to methacholine or histamine. Such response and E4 (LTE4). Cys‑LTs can be produced via 5‑LO to exogenous leukotrienes indicates the bio logical pathway by a variety of inflammatory cells such role of these compounds in asthma. In addition, as eosinophils, basophils, alveolar macrophages, leukotrienes have been identified in urine, plas‑ monocytes, and mast cells. Endothelial cells do not ma, nasal secretions, induced sputum, and bron‑ express 5‑LO but contain LTC4 synthase and can choalveolar lavage fluid from patients with asth‑ therefore participate in leukotriene production ma. Urinary LTE4 measurements can be used to via a transcellular mechanism. Eosinophils and monitor systemic production of cys‑LTs. During mast cells produce mainly LTC , while neutrophils spontaneous exacerbations of bronchial asthma,5 Correspondence to: 4 6,7 8 Prof. Lucyna Mastalerz, MD, PhD, – LTB4. Cys‑LTs, which cause bronchoconstriction following exercise, allergen, and aspirin chal‑ II Katedra Chorób Wewnętrznych, 9 in asthma patients and are a potent chemoattrac‑ lenge, urinary LTE4 excretion increases. Uniwersytet Jagielloński, tant for leukocytes (LTB ), exert their bio logical The effects of leukotriene bio synthesis inhibi‑ Collegium Medicum, ul. Skawińska 8, 4 31-066 Kraków, Poland, actions through inter actions of specific receptors. tors (inhibitors of 5‑LO) or specific leukotriene re‑ phone: +48-12-430-52-66, There are 2 separate receptors for cys‑LTs called ceptor antagonists in patients with asthma have fax: +48-12-430-52-03, CysLT1 and CysLT2. Bronchoconstriction induced suggested that inter ventions in the 5‑LO path‑ e-mail: [email protected] by cys‑LTs appears to be caused by selective acti‑ way may be of therapeutic use in the treatment of Received: February 16, 2010. 1,2 10,11 Revision accepted: March 1, 2010. vation of the CysLT1 receptors. asthma and rhinitis. These drugs inhibit not Conflict of interests: none declared. Growing evidence suggests that leukotrienes only the early but also the late phases of allergic Pol Arch Med Wewn. 2010; play an important role in the pathogenesis of response, which implicates an anti‑inflammato‑ 120 (3): 103-108 Copyright by Medycyna Praktyczna, bronchial asthma and allergic rhinitis. They cause ry component of such treatment. Kraków 2010 smooth muscle contraction, impair mucociliary REVIEW ARTICLE Antileukotriene drugs in the treatment of asthma 103 phospholipids phospholise A2 arachidonic acid cyclooxygenase lipoxygenase – acetylsalicylic acid – 5-epi-PGF2α cyclic endoperoxis 5-HPETE 5-lipoxygenase inhibitors LTA4 PGD2 PGE2 PGF2 TXB2 9α11βPGF 2 LTB4 LTC4 LTD4 – LTE4 CysLT receptor antagonists FIGURE Arachidonic Clinical division of antileukotriene drugs used in 1 controlled acid meta bolism via asthma and rhinitis Antileukotriene drugs used 2 partly controlled cyclooxygenase and in asthma and rhinitis include: 3 uncontrolled, which may cause exacerbation 5‑lipoxygenase pathways 1 inhibitors of 5‑LO, which inhibit leukotriene of the disease. (Mastalerz L, Kania A. bio synthesis: zileuton (Zyflo), used mainly in Similar criteria are applied to assess the ef‑ Pneumonol Alergol Pol. the USA ficacy of treatment (including antileukotriene 2010; 78: 474‑478). 2 CysLT1 antagonists: montelukast (Singu‑ agents) in the long‑term management of asth‑ Abbreviations: lair), zafirlukast (Accolate), and pranlukast (Ono), ma. According to the GINA guidelines,12 5 steps LTA4 – leukotriene A4, which is used mainly in Japan. in the intensity of asthma management can be LTB4 – leukotriene B4, Still investigated (not yet in clinical practice) distinguished depending on the severity level of LTC4 – leukotriene C4, are the so called FLAP inhibitors that inhibit asthma and its control. In all steps a short acting LTD4 – leukotriene D4, the 5‑LO‑activating proteins. β2‑agonist may be used as needed: LTE4 – leukotriene E4, step 1 PGD2 – prostaglandin D2, Long‑term treatment of bronchial asthma and rhin‑ – short‑acting β2‑agonist as needed PGE2 – prostaglandin E2, itis vs. antileukotriene drugs The current GINA step 2 12 PGF2 – prostaglandin F2, (Global Initiative for Asthma) guidelines, – low‑dose inhaled glucocorticosteroid or TXB2 – thromboxane B2, the PRACTALL (Practicing Allergology) report – antileukotriene 5‑HPETE – 5‑hydro on asthma treatment in children,13 and ARIA (Al‑ step 3 ‑peroxyeicosatetraenoic lergic Rhinitis and its Impact on Asthma) recom‑ – low‑dose inhaled glucocorticosteroid plus long 14 acid, 5‑epi‑PGF2α – mendations classify antileukotriene therapeutic acting β2‑agonist or 5‑epi‑prostaglandinF2α, agents as a group of drugs controlling the course – medium‑ or high‑dose inhaled glucocorticos‑ 9α11βPGF2 – of the disease. teroids or 9α11βprostaglandinF2 The choice of medication used in long‑term – low‑dose inhaled glucocorticosteroid plus anti‑ asthma management depends on the level of leukotriene or disease control. From a clinical point of view, – low‑dose inhaled glucocorticosteroid plus sus‑ the most significant problem concerns the pos‑ tained release theophylline sibility of applying antileukotriene drugs in step 4 the long‑term treatment of asthma. Depending – medium‑ or high‑dose inhaled glucocorticos‑ on life activity limitation, day and night symp‑ teroid plus long‑acting β2‑agonist plus antileu‑ toms, need for use of a short‑acting β2‑agonist, kotriene or lung function (peak expiratory flow/forced ex‑ – medium‑ or high‑dose inhaled glucocorticos‑ piratory volume in 1 second [PEF/FEV1]), and teroid plus long acting β2‑agonist plus sustained the number of exacerbations requiring treatment release theophylline intensification, asthma can be divided into: 104 POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2010; 120 (3) step 5 Antileukotriene drugs in isolated rhinitis and rhini‑ – same as step 4 and additionally oral glucocor‑ tis with coexistent asthma Bronchial asthma is ticosteroid (lowest dose) and/or anti‑immuno‑ usually accompanied by rhinitis. Furthermore, globulin E antibodies. isolated allergic rhinitis increases the risk of de‑ Antileukotrienes are classified according to veloping asthma. The ARIA 2007 report recom‑ standing guidelines as a group of drugs con‑ mends the use of antileukotriene drugs in iso‑ trolling the course of asthma. However, inhaled lated allergic rhinitis as well as rhinitis accompa‑ glucocorticosteroids still remain the first‑line nied by asthma.14 In mild allergic rhinitis, these treatment in chronic asthma. Antileukotriene drugs may be used as monotherapy. For exam‑ agents are recommended as alternative treat‑ ple, montelukast alone (10 mg/day for a 4‑week ment to low‑dose inhaled glucocorticosteroids treatment) effectively reduced day and night na‑ in the second level of asthma, or as complemen‑ sal symptoms and improved rhinoconjunctivitis tary treatment to glucocorticosteroids, starting quality of life in patients with allergic rhinitis.21 from the third level of asthma. However, there is clinical evidence that simulta‑ neous use of a cysteinyl leukotriene receptor an‑ Cysteinyl receptor antagonists in the long‑term treat‑ tagonist with H1‑receptor antagonist provided ef‑ ment of asthma Numerous studies have been fective treatment for allergic rhinitis compared published that supply evidence for the positive ef‑ with placebo and each drug alone.22 fect of
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