CURRENT STATUS OF LEUKOTRIENE ANTAGONISTS IN BRONCHIAL ASTHMA

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1 Page5758 Indo American Journal of Pharmaceutical Research, 2014 ISSN NO: CURRENT STATUS OF LEUKOTRIENE ANTAGONISTS IN BRONCHIAL ASTHMA Priyanka Joshi, Dr. Rajesh Pandey, Dr. Jasbir Singh, Dr. Kuldip Singh Sodhi Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Science and Research (MMIMSR), Mullana, Ambala, Haryana, India. Pin ARTICLE INFO Article history Received 09/12/2014 Available online 19/12/2014 Keywords Bronchial Asthma, Leukotrienes, Antagonists, Montelukast, Zafirlukast. ABSTRACT Leukotrienes are released by several cell types and can cause bronchoconstriction and inflammation. Leukotrienes play an important role in the pathogenesis of bronchial asthma. The cysteinyl-leukotrienes (C4, D4 and E4) are able to induce all components of the asthmatic reaction. Leukotriene antagonists competitively block leukotrienes s on bronchial smooth muscle. The synthesis of adequate antagonists stimulated expectations to develop new and especially effective anti-asthmatic drugs. The results of the first generation compounds were not encouraging. Newer compounds (e.g. montelukast, zafirlukast) are able to protect from bronchoconstriction inducing noxes (especially in analgesic intolerance), to improve chronic asthma (symptoms scores, long-time respiratory rescue medications). Especially remarkable are recent data which prove anti-inflammatory activities. Studies are underway to define the position of these drugs in generally accepted recommendations on asthma therapy, singly or in combination with conventional antiasthmatics. Corresponding author Priyanka Joshi (M.Sc. MLT, Intern), Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, Ambala, Haryana, India. Pin priyankaj725@gmail.com Please cite this article in press as Priyanka Joshi et al. Current Status of Leukotriene Antagonists In Bronchial Asthma. Indo American Journal of Pharm Research.2014:4(12). Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Page5759 INTRODUCTION Bronchial asthma or simply asthma is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment. Asthma is one of the most common diseases globally and currently affects approximately 300 million people worldwide. The prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have stabilized, with approximately 10-12% of adults and 15% of children affected by the disease. [1] As per National Family Health Survey of India, 2468 persons per 100,000 population are reported to be suffering from asthma, which is considerably higher in rural areas (2649 per 100,000 population) than in urban areas (1966 per 100,000 population). [2] According to the Global Burden of Asthma Report (GINA), over 50 million suffer from asthma in Central and Southern Asia and an absolute 2% increase in the prevalence of asthma in India would result in an additional 20 million people with this disease. [2] The epidemiologic observation suggests that there is a maximum number of individuals in the community, who are likely to be affected by asthma, most likely by genetic predisposition. In childhood, twice as many males as females are asthmatic, but by adulthood the sex ratio has equalized. RISK FACTORS AND TRIGGERS Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors have been implicated (Table 1) [1]. Table 1: Risk factors and triggers involved in asthma. Endogenous factors Environmental factors Triggers Genetic predisposition Indoor allergens Allergens Atopy Outdoor allergens Upper respiratory tract viral infections. Airway hyper responsiveness Occupational Exercise and hyperventilation. Gender sensitizers Cold air Ethnicity Passive smoking Sulfur dioxide and irritant gases Obesity Respiratory infections Drugs (β-blockers, aspirin) Early viral infections Stress Irritants (household sprays, paint fumes) The allergens that lead to sensitization are usually proteins that have protease activity, and the most common allergens are derived from house dust mites, cat and dog fur, cockroaches, grass and tree pollens, and rodents. Atopy is genetically determined production of specific IgE antibody, with many patients showing a family history of allergic diseases. LEUKOTRIENES Leukotrienes (LTs) are unsaturated fatty acids generated by action of the 5-lipoxygenase (5-LO) enzyme on the cell membrane-bound arachidonic acid (AA). Two classes of LTs are derived from the 5-LO pathway, the nonpeptide LTs LTA4 and LTB4, and the cysteinyl-lts LTC4, LTD4 and LTE4. Once secreted extracellularly, LTs act on specific s, after which they are rapidly degraded, with a very short half-life. In particular, the activation of the recently cloned Cys-LT1, whose expression has been demonstrated on bronchial smooth muscle cells and various inflammatory cell types in the lung, is responsible for the bronchoconstrictive and proinflammatory actions, including increased microvascular permeability with oedema and increased mucus secretion, possessed by cysteinyl-lts. [3] Pharmacological research for the identification and development of anti-lt drugs started towards the end of the 1970s and the beginning of the 1980s, soon after the discovery by Samuelson and his group at the Karolinska Institute in Sweden of the chemical nature and potent activity of LTs. Since 1987, clinical studies on various compounds with anti-lt properties were initiated, and just 10 years later the first anti-lt drugs zileuton, pranlukast, zafirlukast, and montelukast were almost contemporarily commercialized. Zileuton blocks the synthesis of LTs by inhibiting the 5-LO enzyme, whereas pranlukast, zafirlukast, and montelukast are all orally active cysteinyl-lt antagonists (LTRA). Recommended adult doses are mg twice daily for zafirlukast and 10 mg once daily for montelukast. Only montelukast is licensed for use in children, with a 5-mg dose for children 6 12 years of age and a 4-mg dose (only in USA) for children 2 5 years of age. A number of studies have demonstrated that LTRAs show bronchodilating and anti-inflammatory properties, that make these drugs ideal candidates for the treatment of asthma. [4] In fact, they are capable of blunting both the early and late bronchoconstrictive response and the cellular inflammatory response to inhaled allergen, and to prevent the exercise induced and the aspirin induced bronchoconstriction, without evidence of tolerance with prolonged use. [2] Finally, long-term treatments with LTRAs are able to reduce both the blood and sputum eosinophilia in both adults and children with asthma. [4] Cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma, while leukotriene antagonists (LTRAs) demonstrate hybrid anti-inflammatory and bronchodilatory properties. [5] Current international guidelines [6] recommend using an LTRA as first-line therapy in patients with mild, persistent asthma, or as second-line therapy in conjunction with inhaled corticosteroids, as an alternative to increasing the dose of inhaled corticosteroids. Cells that do not express 5-LO, including platelets, erythrocytes, endothelial cells and epithelial cells, also have the capacity to produce cysteinyl-lts and/or LTB4 through the transcellular metabolism of LTA 4 synthesized by activated neutrophils. [7] After their intracellular formation,

3 Page5760 cysteinyl-lts and LTB4 are released to the extracellular space through specific carrier-proteins that are potential targets for future antileukotriene drugs. [8] Cysteinyl-LTs are functionally involved in airway remodeling that includes eosinophil cell inflammatory response, airway smooth muscle cell hyperplasia, mucus gland hyperplasia, mucus hypersecretion, and collagen deposition beneath the epithelial layer [9, 10] and in the lung interstitium at sites of leukocytes infiltration. LEUKOTRIENE RECEPTOR ANTAGONISTS Selective CysLT1 antagonists that have been approved for clinical use in asthma include montelukast, zafirlukast and pranlukast (Table 2). [11] Zileuton, a 5-LO inhibitor, has been approved for the prevention and chronic treatment of asthma in adults and children 12 years of age and older in the United Kingdom and USA. Montelukast is the most prescribed CysLT1 antagonist in Europe and the USA, whereas pranlukast is only marketed in Japan and other Asian countries. Zafirlukast was the first anti-lt that was approved in Europe, but it is not frequently prescribed due to possible food and drug interactions, and its twice daily [11, 8] administration regimen. The fact that selective CysLT1 antagonists and 5-LO inhibitors have similar efficacy in shortterm treatment studies and challenge models indicates that most of the antiasthmatic effects of anti-lts are due to CysLT1. [8] The use of zileuton is limited because of a small, but distinct, incidence of hepatic enzyme elevation, which is not observed with montelukast, and the short half-life, requiring four daily administrations. [8] A twice-daily controlled-release formulation of zileuton has been approved by the U.S. Food and Drug Administration (FDA). [12] At least two aspects of selective 5-LO inhibitors concerning the inhibition of LTB4 synthesis deserve further investigation: their effects on airway hyper responsiveness (AHR) in patients with asthma [13, 14], that is slightly affected by CysLT 1 antagonists [15] ; the potential efficacy of 5-LO inhibitors in rhinitis and rhinopolyposis as these drugs are very effective in reducing nasal symptoms in patients with aspirin-sensitive asthma (ASA). [13] Table 2: Salient pharmacological characteristics of antileukotrienes [11]. S. No. Drug Mechanism of action 1. Montelukast CysLT1 2. Pranlukast CysLT1 3. Zafirlukast CysLT1 4 Zileuton 5 LO inhibition Benefits Side effects Dose Comments As monotherapy in children with mild persistent asthma; particularly effective in ASA, allergen-induced asthma; as add-on therapy with ICS ASA, allergen-induced asthma; as add-on therapy with ICS. ASA, allergen- induced asthma; as add-on therapy with ICS exercise-induced asthma and ASA abdominal pain; possible association with Churg- Strauss syndrome. Abdominal pain, elevations; possible association with Churg- Strauss syndrome abdominal pain, elevations; possible association with Churg-syndrome abdominal pain; elevations (5%) Adults: 10 mg o.d., Children 6 to 14 years of age: 5 mg o.d., children 2 to 5 years of age: 4 mg o.d. Adults: 225 mg b.i.d. Children 12 years of age and adults: 20 mg b.i.d. Children 5 to 11 years of age: 10 mg b.i.d. Adults and children 12 years of age and older: 600 mg q.i.d. Most widely prescribed CysLT1 antagonist. Only marketed in Asia. First CysLT1 antagonist to be approved; food and drug interactions Virtually abandoned because of poor compliance and hepatic toxicity. Abbreviations: ASA = aspirin-sensitive asthma; CysLT = cysteinyl-leukotrienes; ICS = inhaled corticosteroids. COMPARATIVE ASPECTS CysLT1 antagonists are less effective than inhaled glucocorticoids as first-line agents in both adults [16] and children with asthma. [17] In patients with asthma who are not sufficiently controlled with a constant dose of inhaled budesonide alone, add-on therapy with montelukast improves asthma control [18] to a level comparable to that achieved by doubling the dose of budesonide. [19] The advantage of this therapeutic strategy would be the reduced risk of side effects due to long-term administration of high-dose inhaled glucocorticoids. [19] In patients whose symptoms remain uncontrolled with inhaled fluticasone alone, the addition of montelukast is a therapeutic option [20], although the addition of a long-acting β2-agonist is generally more effective than a CysLT1

4 Page5761 antagonist for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms and the use [21, 22] of rescue β2 agonists. In patients with well-controlled asthma based on symptoms and lung function testing, the addition of pranlukast to the combination of inhaled glucocorticoids and long-acting β2-agoinst gives better control of airway inflammation [23, 24] compared with therapy with the combination of inhaled glucocorticoid/long-acting β2-agoinst alone. LTRAs show some anti-inflammatory activity and, in this context, montelukast is able to prevent in asthmatic patients both the early and late asthmatic response to inhaled allergen [25] and to reduce with long-term treatments the eosinophil levels both in the blood [26] and in the airways. [27] Oral montelukast, 10 mg once a day, with inhaled beclomethasone, 200 mg twice a day, for 12 weeks has demonstrated inhaled beclomethasone to be slightly superior to montelukast in improving clinical and functional indexes in patients with mild to moderate asthma. [28] There are limited prospective, comparative studies examining the safety of CysLT 1 antagonists in pregnancy. [29] Montelukast does not appear to increase the baseline rate of major malformations. [29, 30] The lower birth weight observed in infants [29, 30] born to women treated with montelukast could be attributed to severity/control of the maternal asthma. Treatment with inhaled fluticasone (100 µg b.i.d. for four weeks) reduces LTE 4 concentrations in EBC by 18% in children with intermittent and mild persistent asthma. The therapeutic response to CysLT 1 antagonists as well as to inhaled glucocorticoids in both adults and children with asthma is variable. In children with mild persistent asthma, montelukast withdrawal can result in enhanced airway inflammation, as reflected by increased fractional exhaled nitric oxide concentrations (F E NO) and worsening of lung function. [31] CONCLUSIONS AND FUTURE PERSPECTIVES Bronchial asthma is a multifaceted disease with respect to its etiology as well as its treatment. [32] Most of our knowledge of the pathophysiological role of LTs in asthma is currently limited to CysLT1 -mediated effects, whereas the role of the CysLT2 is largely unknown. The identification of responders to CysLT1 antagonists might be relevant for a more rational therapy of patients with asthma. The bottom line is that regular treatment with LTRAs have proved to be beneficial in asthmatic patients by improving airway function, asthma symptoms, as-needed use of rescue medications, and quality of life. 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