Leukotriene receptor antagonists in the treatment of bronchial asthma

Bronchial asthma is a chronic inflammatory disease of the respiratory tract, which is a serious public health problem in all countries of the world [2]. Asthma is common in all age groups and often has a severe fatal course. More than 100 million people suffer from this disease, and their number is constantly increasing.

The leading role of inflammation in the development of asthma is a recognized fact, in the occurrence of which many cells participate: eosinophils, mast cells, T-lymphocytes [25]. In predisposed individuals, this inflammation leads to repeated episodes of wheezing, shortness of breath, chest pain and coughing, especially at night and early morning hours [3, 4]. These symptoms are accompanied by widespread obstruction of the bronchial tree, which, at least in part, is reversible spontaneously or under the influence of treatment. Inflammation also causes an increase in the response of the respiratory tract to various stimuli.

In the development of inflammation, genetic factors, in particular atopy, are important. At the same time, there is a large amount of evidence that environmental factors are risk factors and may lead to the onset of the disease.

Inhalation of home tick allergens, second-hand smoke are especially important. Risk factors also include exposure to automobile emissions and professional sensitizers. Developing inflammation leads to the development of bronchial hyperreactivity, their obstruction, which is supported by trigger mechanisms [5].

Chronic inflammation is characteristic of asthma, regardless of its severity. Inflammation is accompanied by the development of hyperreactivity of the bronchi and bronchial obstruction, which are two determining factors underlying the violation of pulmonary function. Hyperresponsiveness of the respiratory tract is manifested in an excessive bronchoconstrictor reaction to various irritants. The bronchi are an important component in this reaction. [5].

Bronchial hyperreactivity is a mandatory sign of bronchial asthma and is closely related to the severity of the disease and the frequency of symptoms. The data indicate that there is a close relationship between bronchial hyperreactivity and inflammation of the respiratory tract mucosa [22], with the infiltration of their walls by efferent cells of inflammation, among which mast cells, eosinophils and activated lymphocytes predominate. Eosinophilic airway infiltration is a characteristic feature in asthma and allows you to differentiate this disease from other inflammatory processes of the respiratory tract. [28]. Cells release various inflammatory mediators, including leukotrienes – LTS4, LTB4, thromboxane, oxygen radicals, basic proteins, eosinophilic cationic protein, which are toxic to bronchial epithelium [23].

The pathogenesis of bronchial asthma involves various mediators produced by these cells, which contribute to an increase in bronchial reactivity and the clinical manifestations of asthma. Mediators such as histamine, prostaglandins and leukotrienes directly lead to a reduction in smooth muscles of the respiratory tract, increased vascular permeability, increased secretion of mucus into the lumen of the respiratory tract, and activate other inflammatory cells that release secondary inflammatory mediators.

One of the mechanisms of respiratory dysfunction is bronchial obstruction.

According to P.Devillier et al. [17] at the heart of the airway obstruction is a reduction in the smooth muscles of the bronchi, swelling of the mucosa, increased secretion of mucus, and airway infiltration by inflammatory cells (mainly eosinophils).

In recent years, the role of mediators of inflammation of a new class, called leukotrienes, has been identified in the pathogenesis of bronchial asthma.

The history of the discovery of leukotrienes [15, 22] is associated with the study of the slow-reacting substance anaphylaxis (SAS-A), Broklekast, 1960.

In 1983, B. Samuelsson identified LTC4, LTD4 and LTE4. In 1993, L. Laltlnen et al. and in 1997, Z.Diamant et al. [19] described a trigger reaction upon activation of cysteinyl-leukotriene receptors in the airways and inflammation cells, the effect of bronchoconstriction, tissue edema, mucus secretion in the airways, and stimulation of inflammatory cells in the lung tissue. Cysteinyl-leukotrienes were mediators of airway obstruction in asthma.

Leukotrienes are formed from arachidonic acid with the participation of lipoxygenase. Leukotrienes are synthesized by various cells [31, 26] under the influence of specific stimuli: IgE, IgJ, endotoxins, phagocytosis factors.

The main place of the synthesis of leukotrienes in the human body is the lungs, aorta and small intestine. The most intensive synthesis of leukotrienes is carried out by alveolar macrophages, neutrophils and eosinophils.

The role of leukotrienes in the pathogenesis of bronchial asthma is to enhance the secretion of mucus, suppress its clearance, increase the production of cationic proteins that damage epithelial cells. Leukotrienes increase the flow of eosinophils, increase the permeability of blood vessels. They lead to a reduction in the smooth muscles of the bronchi, promote the migration of cells involved in the development of the inflammatory process (activated T cells, mast cells, eosinophils) [13, 35, 39]. A number of studies have shown that in patients with bronchial asthma, leukotriene E4 is detected in the urine [20].

LTC4 and LTD4 have a powerful bronchoconstrictor action. The effect of bronchospasm, unlike that caused by histamine, develops more slowly, but is longer. Leukotrienes increase vascular permeability 1000 times more effective than histamine. The increased permeability of venules is explained by the formation of cracks due to the reduction of the endothelium. LTD4 more actively affects the process of enhancing the secretion of mucus by the mucous membrane of the bronchi.

It was established that leukotrienes B4, C4, D4, E4 play an important role in the mechanisms of inflammation and cause changes characteristic of bronchial asthma [6, 35]. Leukotrienes C4, D4 lead to early changes and cause cell migration to the airway inflammation zone.

The clinical effects of leukotriene B4 cause leukocyte chemotaxis, adhesion of neutrophils to the endothelium, release of proteases and the formation of superoxide by neutrophils. This helps to increase the permeability of capillaries. Leukotrienes D4, C4 and E4 lead to spasm of the smooth muscles of the bronchi, the development of edema, the involvement of eosinophils, increased secretion of mucus and impaired transport.

It was established that leukotrienes bind to receptors localized on the plasma membranes of cells [7]. Three main types of leukotriene receptors were identified.

1. LTI receptor for LTC / D / E4 leukotrienes. This receptor mediates the bronchoconstrictor effect of leukotrienes.

2. LT2 receptor to LTC / D / E4; he has an important role in controlling vascular permeability.

3. The LTB4 receptor mediates the chemotactic effect of leukotrienes.

Leukotriene Receptor Inhibitors

The concept of leukotrienes as inflammatory mediators allowed us to develop a concept for creating a new class of drugs called “antileukotriene substances” [7, 12].

Antileukotriene substances include cysteine ​​leukotriene receptor antagonists and drugs that inhibit the synthesis of leukotrienes [24].

The creation of drugs that affect the synthesis of leukotrienes is carried out in the following areas. [1, 9, 21, 34, 36].

1. Creation of antagonists of leukotriene receptors. These include zafirlukast (accolate, substance 1С1204219) pranlukast (substance ONO-1078), pobilukast (substance SKF 104353), montelukast (singular, substance ML-0476).

2. Search for 5-lipoxygenase inhibitors. The representative of this group of drugs is zileuton (substance F-64077).

Experimental studies have shown that leukotriene receptor antagonists prevented the development of bronchospasm and reduced the number of inflammatory cells (lymphocytes and eosinophils) in the bronchoalveolar fluid. Clinical studies suggest that antagonists of leukotriene receptors prevent the development of symptoms of bronchial asthma and improve lung function [40].

In vitro, cysteinyl-leukotriene antagonists have been shown to compete with D4 leukotriene for binding to receptors that are present in the membranes of lung cells of guinea pigs and humans [16]. Their similarity with leukotriene D4 exceeds the natural ligand by about two times. Leukotriene antagonists (zafirlukast, montelukast, pobilukast) block leukotrienes D4 and E4, causing smooth muscle contraction of the isolated guinea pig trachea, but do not block the spasm caused by leukotriene C4. Under their influence, the concentration of inflammatory mediators in the zone of development of the inflammatory process decreases, the final phase of antigen-induced bronchospasm is inhibited, and protection is provided for various provocations. [8, 10, 11, 30, 32, 33, 36]

All leukotriene receptor inhibitors with varying degrees of activity prevent LTD4-induced bronchoconstriction [30]. They block the early and late response to antigen exposure, effects on the effects of cold and aspirin, increase FEV in mild to moderate asthma, reduce the use of beta-agonists, and enhance the effect of antihistamines.

Antileukotriene drugs are well tolerated by patients, do not lead to the development of serious complications [38]. Important is the fact that they are used in tablet form once or twice a day.

Recent studies show that leukotriene antagonists can be used as an alternative to corticosteroid therapy for persistent mild asthma [21, 27]. Leukotriene antagonists reduce the dose of inhaled corticosteroids in exacerbation of asthma.

Leukotriene D4, acting on the smooth muscles of the bronchi, does not affect the synthesis of DNA, the content of RNA, collagen, elastin, biglycan, fibronectin [29]. Some antileukotrienes activated microsomal activity and aminotransferase in the liver.

Antileukotrienes are effective in the induction of bronchospasm by allergens, cold air, exercise, aspirin. Clinical observations were made both during short and long-term follow-up [23].

Leukotriene antagonists can reduce the dosage of other drugs used to treat bronchial asthma, in particular, b2-agonists [18]. It is now recognized that corticosteroids have the best anti-inflammatory effect. At the same time, their prolonged use may cause serious side effects [40]. Many patients have difficulty using inhalation devices, as it needs to be done several times a day. Cases of the development of local and systemic tolerance to corticosteroids have been noted [18, 41]. Further studies are needed to determine their effectiveness when combined with inhaled corticosteroids [14, 39].

Thus, the discovery of a new class of inflammatory mediators – leukotrienes, the identification of their binding receptors allowed us to create a new direction in the treatment of asthma based on the development of drugs that are inhibitors of leukotriene receptors. The clinical use of drugs of this group – montelukast sodium, zafirlukast, pranlukast indicate undoubted therapeutic efficacy. They prevent the development of bronchospasm (including at night), prevent the development of inflammation, edema, reduce vascular permeability, reduce mucus secretion, improve sleep quality, and the use of beta-agonists is reduced. The drugs are effective in treating patients suffering from mild to moderate bronchial asthma. This is extremely important in terms of preventing the progression of the disease and the development of severe forms of bronchial asthma.

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