Allergic rhinitis is the most common atopic disorder seen in ENT clinics. It is diagnosed by history, physical exam and objective testing. Patient education, environmental control measures, pharmacotherapy, and allergen-specific immunotherapy are the cornerstones of allergic rhinitis treatment and can significantly reduce the burden of disease. Current treatment guidelines include antihistamines, intranasal corticosteroids, oral and intranasal decongestants, intranasal anticholinergics, intranasal cromolyn, and leukotriene receptor antagonists. In the mechanism of allergic rhinitis, histamine is responsible for major allergic rhinitis symptoms such as rhinorrhea, nasal itching and sneezing. Its effect on nasal congestion is less evident. In contrast, leukotrienes result in increase in nasal airway resistance and vascular permeability. Antihistamines and leukotriene receptor antagonists are commonly used in the treatment of allergic rhinitis. The published literature about combined antihistamines and leukotriene antagonists in mono- or combination therapy is reviewed and presented.
Asthma is one of the most common conditions seen in clinical practice and carries both a significant disease burden in terms of patient morbidity and a high economic burden in both direct and indirect costs. Despite this, it remains a comparatively poorly understood disease, with only modest advances in treatment over the past decade. Corticosteroids remain the cornerstone of therapy. Both patient compliance with medications and physician adherence to evidence-based guidelines are often poor, and a high percentage of patients continue to have inadequately controlled disease even with optimal therapy. Following a contextual overview of the current treatment guidelines, this review focuses on novel asthma therapies, beginning with the introduction of the leukotriene receptor antagonist zafirlukast in the 1990s, continuing through advanced endoscopic therapy and into cytokine-directed biologic agents currently in development. Along with clinically relevant biochemistry and pharmacology, the evidence supporting the place of these therapies in current guidelines will be highlighted along with data comparing these agents with more conventional treatment. A brief discussion of other drugs, such as those developed for unrelated conditions and subsequently examined as potential asthma therapies, is included.
Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis.
Bacterial products such as LPS are critical factors responsible for bone destruction. MMP-13, a member of the matrix metalloproteinase family, plays a critical role in the proteolytic degradation of extracellular matrix components, which includes collagen fibrils in the bone matrix. Montelukast is a selective cysteinyl leukotrienes receptor 1 (cysLT1R) antagonist used clinically for the treatment of asthma, as it reduces eosinophilic inflammation in airways. This study aims to explore the role of montelukast in regulating MMP-13 expression induced by LPS in osteoblasts. Our results indicate that LPS stimulated cysLT1R expression in mouse MC3T3-E1 osteoblasts in a dose- and time-dependent manner. Notably, LPS-induced up-regulation of MMP-13 was ameliorated by treatment with montelukast in a dose-dependent manner. Furthermore, treatment with montelukast stimulated the expression of SOCS3, an inhibitor of MMP-13. Silencing of SOCS3 abolished the inhibitory effects of montelukast on MMP-13 expression. Mechanistically, we found that montelukast suppressed LPS-induced nuclear translocation of NF-κB p65 as well as NF-κB transcriptional activity by inhibiting the phosphorylation and degradation of IκBα. These data suggest that montelukast can modulate inflammatory events in bone diseases.
The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, while small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL-521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other two agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as anti-leukotriene therapy does in asthma.
Eosinophils and mast cells are among the key cells in inflammatory diseases like chronic rhinosinusitis (CRS) and asthma. Leukotriene antagonists have proven to be effective in the treatment of asthma, but data about their efficacy in CRS are scarce, whereas data on montelukast as an add-on treatment to intranasal corticosteroids (INCS) in a postoperative setting are completely lacking.
Cysteinyl leukotrienes (CysLTs) are pro-inflammatory lipid mediators that exacerbate disease state in several asthma phenotypes including asthma induced by allergen, virus and exercise. However, the role of CysLTs in irritant-induced airway disease is not well characterized. The purpose of the current study was to investigate the effect of montelukast (MK), a CysLT1R antagonist, on parameters of irritant-induced asthma (IIA) induced by inhalation of chlorine (Cl2 ) in the mouse.
The tools for asthma control assessment recommended by the current guideline are cognitive function- and effort-dependent, which is substantially impaired in the elderly. The aim of this study is to investigate objective assessment tools of asthma control status and previous asthma exacerbation (AE) in elderly subjects. Asthmatics aged >60 years who were treated with step 2 or 3 by the Global Initiative for Asthma (GINA) guideline were enrolled. During the 12-week study period, the subjects used either 400 μg of budesonide plus 10 mg of montelukast or 800 μg of inhaled budesonide. The occurrence of AE during the 4-week run-in and 12-week treatment period was monitored. After 12-week of treatment, sputum eosinophil count, peripheral eosinophil count, the plasma leukotriene E4 (LTE4), and prostaglandin F2α (PGF2α) metabolite levels were measured using the UHPLC/Q-ToF MS system. The study subjects were divided into group 1 (asthmatics who experienced AE during the study period) and group 2 (those who did not). A total of 101 patients aged 60-85 years were enrolled. Twenty-three patients (22.8%) had experienced AE. The plasma LTE4 level, LTE4/PGF2α ratio, and peripheral eosinophil count were significantly higher in group 1 than in group 2 (P=0.023, P=0.010, P=0.033, respectively). The plasma LTE4/PGF2α ratio and peripheral eosinophil count at week 12 were significantly associated with previous AE (odds ratio [OR]=1.748, P=0.013; OR=1.256, P=0.027). Receiver operating characteristic (ROC) curves to discriminate the subjects with previous AE, including these 2 parameters, showed that the area under the curve was 0.700 (P=0.004), with 73.9% sensitivity and 47.9% specificity. In conclusion, a combination of plasma LTE4/PGF2α ratio and peripheral eosinophil count can be an objective assessment tool which is significantly associated with asthma control status in elderly asthmatics.
Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R(-/-) mice, but not CysLT2R(-/-) mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R(-/-) mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses.
- Lung India : official organ of Indian Chest Society
- Published 10 months ago
The role of leukotriene receptor antagonist is well known in the management of chronic asthma, but their efficacy in acute exacerbation of asthma is unknown. The present study was done to evaluate the clinical efficacy of oral montelukast as an add on therapy to the usual standard therapy of acute attack of bronchial asthma.