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The Pharmacotherapy of Rhinitis and Asthma
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Amanda Grippen Goddard, Harold S. Nelson, Rohit Katial, Flavia Hoyte
Cysteinyl leukotrienes are released from activated mast cells, and nasal challenge with Leukotriene D4 increases nasal airway resistance. It would be logical, therefore, that Leukotriene Receptor Antagonists (LTRAs) might benefit patients with allergic rhinitis (Bisgaard et al. 1986). A meta-analysis covering eight studies of a leukotriene receptor antagonist in seasonal allergic rhinitis found a mean reduction in rhinitis scores of only 5% compared to a placebo, with results being inferior to both antihistamines and intranasal corticosteroids (Wilson et al. 2004). A similar modest degree of effectiveness has been reported in perennial allergic rhinitis (Patel et al. 2005).
Sensory Neuropeptides and Bronchial Hyperresponsiveness
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
D. Spina, C. P. Page, J. Morley
In mild asthmatics in whom baseline airway resistance has been elevated with leukotriene D4, inhalation of capsaicin induced a bronchodilator response that was comparable with that observed in healthy individuals (132), suggesting that the nonadrenergic, noncholinergic inhibitory system was not impaired in mild asthma. Yet it has been suggested that there is a lack of vaso-intestinal peptide (VlP)-like immunofluorescence in asthmatic lung at autopsy and in lung resections from asthmatic patients (133). A more recent study disputes this conclusion, since the amount of extractable VIP from asthmatic lung was not different to that obtained from nonasthmatic controls (47). Whether VIP plays a significant role in the bronchodilator response to a capsaicin is debatable, since it has been demonstrated that the major inhibitory neurotransmitter of airway smooth muscle in humans is nitric oxide and not VIP (134).
Pathways of Arachidonic Acid Metabolism
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
Lipoxygenase enzymes are found in several subcellular fractions and catalyze the formation of hydroperoxyeicosatetraenoic acids (HPETEs) from arachidonic acid (Figures 1 and 2). These derivatives are biologically active and are converted rapidly to their hydroxy (HETE) derivatives which also have biological activity. Other pathways of metabolism exist for the HPETEs, of which the leukotriene pathway is presently considered the most important. This pathway derives from the 5-lipoxygenase pathway and the key step is the conversion of 5-HPETE to leukotriene A4. Thereafter, leukotriene A4 is metabolized either by addition of water at C-12 leading to the opening of the epoxide at C-6 and the formation of leukotriene B4 or by nucleophilic opening of the epoxide at C-6 by the sulfhydryl group of glutathione and the formation of leukotriene C4. The latter compound may be metabolized further by the sequential elimination of glutamic acid and glycine to form leukotriene D4 and leukotriene E4. Conversion of leukotriene E4 to leukotriene F4 occurs by addition of a γ-glutamyl residue to the amino group. The further metabolism of leukotrienes is complex and described in detail elsewhere.3
Montelukast promotes mitochondrial biogenesis via CREB/PGC-1α in human bronchial epithelial cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Huan Wang, Yali Cheng, Ying Liu, Jiang Shi, Zhe Cheng
CysLTs are linked with the pathogenesis of asthma. As an important anti-leukotriene compound, montelukast has displayed its efficacy and safety profile in different age teams with asthma [16]. Montelukast has a significant inhibitory effect against bronchoconstriction caused by leukotriene D4 [17]. Administration of montelukast plays important roles in improving pulmonary function and reducing the risk of exacerbation in patients with asthma. In addition to its bronchoprotective effect, montelukast has exhibited anti-inflammatory and anti-allergic properties in various tissues and cells [18]. However, the physiological function of montelukast on mitochondrial function in human bronchial epithelial cells remains undefined. Here, we identified a novel pharmacological function of montelukast in promoting mitochondrial biogenesis in Beas-2b epithelial cells. First, montelukast treatment stimulated the expression of the “master switch” molecules of mitochondrial biogenesis, PGC-1α, NRF1 and TFAM. Second, montelukast treatment increased mitochondrial mass, mtDNA/nDNA and the expression of cytochrome B. Third, the presence of montelukast led to a functional gain for mitochondria by enhancing the mitochondrial respiratory rate and ATP generation. Mechanistically, we revealed that activation of CREB through elevation of intracellular cAMP participated in montelukast-induced expression of PGC-1α and blockage of CREB activation, while H89 abolished this effect.
Cysteinyl leukotriene receptor 1 (cysLT1R) regulates osteoclast differentiation and bone resorption
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
The MAPK and AKT signalling pathways are the key pathways for regulating bone resorption and contributing to osteoclast differentiation [25]. Stimulation with RANKL induced the interaction of RANK and TRAF6, which then promoted the activation of MAPKs and AKT [26]. Importantly, activation of cysLTR-1 by its ligands such as leukotriene D4 has been shown to induce the phosphorylation of MAPKs [27]. In this study, we found that treatment with montelukast inhibited phosphorylation of ERK, JNK and p38 in the MAPK pathway by preventing the association of RANK and TRAF6, suggesting a novel molecular mechanism. Intracellular ROS acts as a second messenger regulating the receptor-mediated signalling cascades in diverse cells and tissues [28,29]. Increased production of ROS has been found in the pathological development process of osteoclastogenesis caused by RANKL and M-CSF in OC precursor cells [30,31]. Elevated production of ROS reinforces activation of downstream signalling molecules mediated by RANKL and M-CSF. In the current study, we found that montelukast ameliorated the generation of ROS, which is consistent with previous investigations demonstrating that administration of montelukast suppressed H2O2-induced ROS production [32].
Emerging drugs for eosinophilic esophagitis
Published in Expert Opinion on Emerging Drugs, 2018
Robert D. Pesek, Sandeep K. Gupta
As described earlier, there are limited treatment options currently available for EoE. Food-elimination diets or medical management including use of PPIs or swallowed corticosteroids are the mainstay of treatment (Table 1). Other treatments that target allergic pathways have also been investigated including the use of leukotriene receptor antagonists and mast-cell stabilizers. Use of montelukast, a leukotriene D4 receptor antagonist, was studied in 12 adult patients with EoE. After 4 months of therapy at a dose of 20–40 mg/day, half of the subjects had improvement in clinical symptoms but there was no change in numbers of esophageal eosinophils [25]. In a study by Lucendo et al. [26], montelukast was also ineffective at maintaining pathologic and histologic remission as well as symptom improvements in 11 adults with EoE who were previously treated with swallowed fluticasone. A randomized study of montelukast for EoE was performed by Alexander et al. in 2017 and concluded that montelukast was not effective in preventing symptomatic recurrence compared to placebo [27]. Cromolyn sodium, a mast-cell stabilizer, was utilized in a study of 14 children with EoE over 4 weeks, but no improvement was seen in the number of esophageal eosinophils or clinical symptoms after treatment [28]. Systemic corticosteroids and immune-modulating drugs such as 6-mercaptopurine have also been investigated in small cohorts. Both classes of medications are effective in reducing esophageal eosinophilia but may have significant systemic side effects that preclude their use in most patients [28–30].