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International Journal of Biological... 2024Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory...
Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and atopic dermatitis. Thus, blocking CYSLTR1 may be a promising strategy for psoriasis immunotherapy. We prepared a montelukast sodium cream and solution and investigated their effects on psoriasis-like skin lesions induced by imiquimod (IMQ). After the treatment, serum, skin, and spleen samples were collected for evaluation. We treated human T helper (Th) 17 cells with montelukast to study its effect on Th17 differentiation and nuclear factor kappa-B (NF-κB) signaling. We also created a keratinocyte proliferation model induced by M5 cytokines and assessed the influence of montelukast on key psoriasis-related genes. We induced psoriasis in CYSLTR1 knockout (KO) mice using IMQ to explore the role of CYSLTR1 in psoriasis development. Montelukast sodium cream and solution effectively reduced the psoriasis area and severity index (PASI) and alleviated disease symptoms in IMQ-induced mice. Furthermore, reduced infiltration of inflammatory cells (Th1, Th17, and T follicular helper [Tfh] cells), decreased mRNA expression of cytokines in the skin (interleukin [IL]-17/F and IL-23), and lower serum concentrations of various cytokines (IL-2, IL-6, IL-13, and IL-17A/F) were observed. Montelukast cream and solution also decreased spleen size and the proportion of Th17 and Tfh cells, and significantly inhibited NF-κB signaling-related genes after application. Moreover, montelukast inhibited Th17 cell differentiation and suppressed NF-κB signaling . CYSLTR1 KO mice induced with IMQ showed improvement in PASI scores, serum IL-17A/F levels, and lower Th1 and Th17 cells in the spleen and skin compared to wild-type mice. Montelukast also suppressed the proliferation and inflammatory response of keratinocytes by regulating NF-κB signaling. Collectively, our results strongly indicate that inhibition of CYSLTR1 signaling to target the Th17 response holds significant promise as a therapeutic approach to manage psoriasis.
Topics: Humans; Animals; Mice; NF-kappa B; Interleukin-17; Th17 Cells; Psoriasis; Cell Differentiation; Cytokines; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 38617532
DOI: 10.7150/ijbs.92514 -
Chest Feb 2022A 19-year-old, previously healthy man presented with 3 days of cough, high-grade fevers (40 °C), and dyspnea. Apart from a resolved history of seizures not requiring...
A 19-year-old, previously healthy man presented with 3 days of cough, high-grade fevers (40 °C), and dyspnea. Apart from a resolved history of seizures not requiring medications, he had no medical or surgical history. He had no known drug allergies. He took montelukast for allergies and trimethoprim-sulfamethoxazole (TMP-SMX) for 2 weeks before admission for acne, but no other medications, including over-the-counter medications and supplements. He had animal exposures to a new puppy and a friend's bird. He had no history of smoking, vaping, or recreational drug use. His paternal grandmother had rheumatoid arthritis.
Topics: Anti-Bacterial Agents; Biopsy; Diagnosis, Differential; Extracorporeal Membrane Oxygenation; Humans; Male; Pneumothorax; Respiratory Distress Syndrome; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult
PubMed: 35131063
DOI: 10.1016/j.chest.2021.09.006 -
Chest Aug 2018Acute bronchiolitis is common in young children, and some children develop chronic cough after their bronchiolitis. We thus undertook systematic reviews based on key... (Review)
Review
BACKGROUND
Acute bronchiolitis is common in young children, and some children develop chronic cough after their bronchiolitis. We thus undertook systematic reviews based on key questions (KQs) using the PICO (Population, Intervention, Comparison, Outcome) format. The KQs were: Among children with chronic cough (> 4 weeks) after acute viral bronchiolitis, how effective are the following interventions in improving the resolution of cough?: (1) Antibiotics. If so what type and for how long? (2) Asthma medications (inhaled steroids, beta agonist, montelukast); and (3) Inhaled osmotic agents like hypertonic saline?
METHODS
We used the CHEST expert cough panel's protocol and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form these suggestions. Delphi methodology was used to obtain consensus.
RESULTS
Several studies and systematic reviews on the efficacy of the three types of interventions listed in the introduction were found but no data were relevant to our KQs. Thus, no recommendations on using the interventions above could be formulated.
CONCLUSIONS
The panel made several consensus-based suggestions and identified directions for future studies to advance the field of managing chronic cough post-acute bronchiolitis in children.
Topics: Acute Disease; Bronchiolitis, Viral; Child; Chronic Disease; Consensus; Cough; Delphi Technique; Evidence-Based Medicine; Humans; Practice Guidelines as Topic
PubMed: 29704475
DOI: 10.1016/j.chest.2018.04.019 -
European Journal of Pharmacology Jun 2024Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively... (Review)
Review
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT and CysLT subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
PubMed: 38909933
DOI: 10.1016/j.ejphar.2024.176755 -
Royal Society Open Science Dec 2020Sensitive, simple and green analytical methodology for simultaneous estimation of bambuterol and montelukast as a combined medication based on their native fluorescence...
Sensitive, simple and green analytical methodology for simultaneous estimation of bambuterol and montelukast as a combined medication based on their native fluorescence character was developed. The method relies on synchronous spectrofluorimetry to solve the problem of the overlapping emission spectra of the studied drugs. Using second derivative synchronous spectra enabled the simultaneous quantitation of bambuterol and montelukast without interference. The peak amplitudes of the aqueous solutions at Δ = 20 nm were estimated at 284 and 304 nm for bambuterol and at 374 and 384 nm for montelukast. A linear relationship was achieved over the concentration range of 0.2-1.00 µg ml for bambuterol and 0.4-2.00 µg ml for montelukast. All factors and parameters were carefully studied to obtain the highest sensitivity and good precision of the proposed method. Additionally, the validation criteria were assessed in accordance with International Council of Harmonization (ICH) guidelines. The method was used for the estimation of both drugs in their raw materials, synthetic mixtures as well their combined tablets with good agreement between its results and those from the comparison method.
PubMed: 33489270
DOI: 10.1098/rsos.201156 -
Cell Communication and Signaling : CCS Jun 2023Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a...
Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLTR) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLTR in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLTR/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLTR, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLTR with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLTR, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLTR antagonist in cells (Apc or CTNNB1) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APC) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLTR mRNA levels. These results elucidate a previously underappreciated CysLTR/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients. Video Abstract.
Topics: Animals; Mice; Carcinogens; Programmed Cell Death 1 Receptor; Wnt Signaling Pathway; beta Catenin; Colonic Neoplasms
PubMed: 37316937
DOI: 10.1186/s12964-023-01157-6 -
Cureus Oct 2023Background Cough is one of the most common presenting complaints for physicians across the world, with the potential to result in a significant influence on one's daily...
Background Cough is one of the most common presenting complaints for physicians across the world, with the potential to result in a significant influence on one's daily life. It is typically categorized into acute cough (<3 weeks), subacute cough (three to eight weeks), and chronic cough (>8 weeks). The lack of specific treatment guidelines and evidence-based recommendations for resolving cough creates reasonable controversy in the medical field. This retrospective study aims to identify the clinical features of cough and evaluate the comparative efficacy between different anti-asthmatic treatment modalities in the urban city of Dubai, United Arab Emirates. Methods A retrospective cross-sectional study was performed on patients presenting to pulmonology or respiratory outpatient clinics with complaints of cough in the absence of any known history of chronic respiratory illness (e.g., asthma). Analysis was conducted via chi-squared and analysis of variance (ANOVA) testing. Results A total of 308 patients were eligible for inclusion, with 273 patients presenting for follow-up. Overall, patients with acute, subacute, and chronic coughs had similar clinical presentations, with no statistically significant differences noted. However, patients with pets were more likely to develop an acute cough (p = 0.04). Moreover, the follow-up outcomes of acute, subacute, and chronic cough were similar, with no significant statistical difference noted. Furthermore, patients receiving dual therapy using budesonide and montelukast, and patients receiving triple therapy using budesonide, montelukast, and tiotropium/ipratropium were most likely to gain complete relief of their symptoms, although triple therapy treatment was also associated with the highest rate of null improvement (p = 0.012). Additionally, chronic cough patients were more likely to be subject to higher C-reactive protein (CRP) levels in comparison to other cohorts (p = 0.26). Conclusion The comparative superiority of dual therapy using budesonide and montelukast, and triple therapy using budesonide, montelukast, and tiotropium/ipratropium were highlighted in this study. In the sparseness of specific treatment guidelines and evidence-based recommendations for cough, the use of anti-asthmatic therapy for cough patients has shown favorable results. Moreover, the lack of clinical differences between acute, subacute, and chronic cough may result in difficulties with the treatment of cough patients. To arrive at a valid conclusion, further comprehensive studies with larger and more diversified sample populations are encouraged.
PubMed: 38021559
DOI: 10.7759/cureus.47377 -
Scientific Reports Feb 2024Preclinical and clinical data indicate that the 5-lipoxygenase pathway becomes activated in cardiovascular diseases suggesting an important role of CysLTs in...
Preclinical and clinical data indicate that the 5-lipoxygenase pathway becomes activated in cardiovascular diseases suggesting an important role of CysLTs in atherosclerosis and in its ischemic complications. This study aims to investigate the effects of montelukast, a CysLTR-1 antagonist, in a mouse model of myocardial infarction (MI). C57BL/6N female mice were subjected to coronary artery ligation and received montelukast (10 mg/kg/day, intraperitoneal) or vehicle. Montelukast exerted beneficial effects in the infarcted area, decreasing mRNA expression of inflammatory genes, such Il1β and Ccl2 (p < 0.05), at 48 h after MI, and reducing infarct size and preventing ischemic wall thinning (p < 0.05) at 4 weeks. Furthermore, montelukast counteracted maladaptive remodelling of whole heart. Indeed, montelukast reduced LV mass (p < 0.05) and remote wall thickening (p < 0.05), and improved cardiac pumping function, as evidenced by increased global ejection fraction (p < 0.01), and regional contractility in infarcted (p < 0.05) and in remote non-infarcted (p < 0.05) myocardium. Finally, montelukast prevented cardiomyocytes hypertrophy (p < 0.05) in remote myocardium, reducing the phosphorylation of GSK3β, a regulator of hypertrophic pathway (p < 0.05). Our data strongly demonstrate the ability of montelukast to contrast the MI-induced maladaptive conditions, thus sustaining cardiac contractility. The results provide evidences for montelukast "repurposing" in cardiovascular diseases and in particular in myocardial infarction.
Topics: Mice; Animals; Female; Ventricular Remodeling; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 38337010
DOI: 10.1038/s41598-024-53936-x -
Journal of Analytical Methods in... 2021In this study, we present a new, green electrochemical method for potentiometric estimation of desloratadine and montelukast sodium in their pure and binary dosage form....
In this study, we present a new, green electrochemical method for potentiometric estimation of desloratadine and montelukast sodium in their pure and binary dosage form. For that, three pencil graphite sensors were fabricated; the first one was prepared to analyse desloratadine drug (DES) by coating the graphite bar with the coating membrane, which comprises the ion pair of desloratadine and ammonium reineckate reagent (RNK), the polymer poly vinyl chloride (PVC), and the plasticizers dibutyl phthalate (DBP). The second one, which was used to analyse montelukast (MON), was constructed by using the ion pair of cadmium chloride reagent (Cd.) with montelukast and the same earlier named polymer and plasticizer. As a trial to analyse both of the drugs by the same sensor consecutively, we have constructed a combined pencil graphite electrode, which contains the two earlier suggested ion pairs, that is, we can use this electrode to selectively analyse for each drug. The proposed electrodes were effectively used for analysis of DES and MON as a single dosage form and as combined pharmaceutical preparation, without any need for prior separation that was performed depending on the difference in the efficient pH range for each sensor. The proposed sensors exhibited a Nernstian equation slopes of -30.11, 27.70, (-29.16, 29.79) mv. decade in the linearity range 5.00 × 10-1.00 × 10 and 1.00 × 10 - 1.00 × 10 M, respectively. The sensors exhibit high sensitivity according to LOD values ((0.036-0.018) - (0.025-0.026) M), respectively, and important selectivity toward the studied drugs in presence of interfering ions and excipients. The optimum circumstances were studied, and the method was validated by application of ICH rules. Finally, the method was compared with a documented method, and the required statistical values were calculated.
PubMed: 34035974
DOI: 10.1155/2021/5540907 -
Ear, Nose, & Throat Journal Oct 2023The association between increased nasal resistance (NR) and obstructive sleep apnea syndrome (OSAS) is controversial. The purpose of this study was to examine nasal...
The association between increased nasal resistance (NR) and obstructive sleep apnea syndrome (OSAS) is controversial. The purpose of this study was to examine nasal ventilation function (NVF) in children with OSAS, with a focus on its pathogenetic role. Children were recruited and divided into the OSAS group ( = 109) and control group ( = 116). The participants underwent polysomnography (PSG), measurement of NR, and acoustic rhinometry (AR). A combination of intranasal corticosteroids (ICS) and oral montelukast (OM) was administered to 90 children with mild to moderate OSAS for 12 weeks. After excluding participants who dropped out or were lost to follow-up, there were 58 children who responded to the treatment, who were divided into 2 groups-A and B. We compared the size of the tonsil adenoids, the PSG, NR, and AR before and after treatment in the 2 groups. Children aged 6 to 12 years with OSAS had significantly higher NR than the control group ( < .05). The OSAS group had a smaller nasal minimal cross-sectional area (NMCA), nasal cavity volume (NCV) from 0 to 5 cm, and nasopharyngeal volume (NPV) from 6 to 8 cm than the control group, and the difference was statistically significant ( < .05 or < .01). A total of 58 (84.1%) children responded to the 12-week ICS+OM treatment and 11 (15.9%) children did not respond to the treatment. Effective treatment was achieved in 32 children, as evidenced by a significant reduction in tonsil adenoid size and variations in NR and AR values. There were significant improvements in NR, NMCA, and NCV in the remaining 26 children who were successfully treated, but there was no change in tonsil adenoids and NPV value. NVF may play an important pathogenetic role in children with OSAS.
PubMed: 37864363
DOI: 10.1177/01455613231205991