Leukotriene Receptor Research Articles

0543 The association of sleep-disordered breathing and daytime asthma burden among former premature school age children with bronchopulmonary dysplasia

Abstract Introduction Sleep-disordered breathing (SDB) and asthma have a bidirectional relationship. Almost half of former premature school age children with bronchopulmonary dysplasia (BPD) have asthma or asthma-like symptoms. Prematurity is a known risk factor for sleep-disordered breathing. However, little is known about the association of SDB and asthma symptoms in former premature school age children with BPD. Methods Study sample comprised of participants in an ongoing cohort study, the AERO-BPD study. Participants were 6-12 years old, were born < 32 weeks gestational age and had been diagnosed with BPD. We administered the Pediatric Sleep Questionnaire (PSQ) and asthma symptom questionnaires. The prevalence of SDB was determined based on a PSQ > 0.33. The relationship between SDB and daytime asthma symptoms was assessed by multivariate logistic regression, adjusting for sex, race, BMI, rhinitis, asthma controller medication and days on respiratory support in the NICU. Results There were 33 subjects with a mean age of 8.8 years, roughly half were male and one third were overweight/obese. About half (48.5%) had daytime asthma symptoms and 39.4% had SDB. About half were on controller medication (inhaled corticosteroid or leukotriene receptor antagonist) and 39.4% had rhinitis. Among the 13 subjects with SDB, 11 reported daytime asthma symptoms and 5 of the 20 subjects without SDB reported daytime asthma symptoms. Subjects with SDB had over 17 times the odds of daytime asthma symptoms (OR 17.61, 95% CI [1.23, 251.76], p=0.035) compared to subjects without SDB, while adjusting for sex, race, BMI, rhinitis, controller medications and days on respiratory support in the NICU. Conclusion Our findings suggest that SDB is highly prevalent among former premature school age children with BPD. The findings suggest a relationship between SDB and daytime respiratory symptom burden among these patients rather than mere co-existence. Support (If Any)

Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation

The evidence base for the association between montelukast and adverse neuropsychiatric outcomes is mixed and inconclusive. Several methodological limitations have been identified in the evidence base on the safety of montelukast in observational studies. To investigate the association between new montelukast exposure and 1-year incident neuropsychiatric diagnoses with improved precision and control for baseline confounders. This propensity score-matched cohort study was conducted using electronic health records from 2015 to 2019 in the TriNetX Analytics Network patient repository of more than 51 million patients from 56 health care organizations, mainly in the US. Included patients were those aged 15 to 64 years at index prescription for montelukast or for control prescription who had a history of asthma or allergic rhinitis. After propensity score matching for various baseline confounders, including comorbidities and dispensed prescription medicines, we included 154 946 patients, of whom 77 473 individuals were exposed to montelukast. Patients were followed up for 12 months. Data were analyzed from June through November 2021. New dispensed prescription for leukotriene receptor antagonist montelukast or control medication. Incident neuropsychiatric diagnoses at 12 months identified using International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. There were 72 490 patients with asthma (44 726 [61.7%] women; mean [SD] age at index prescription, 35 [15] years) and 82 456 patients with allergic rhinitis (54 172 [65.7%] women; mean [SD] age at index prescription, 40 [14] years). In patients exposed to montelukast, the odds ratio [OR] for any incident neuropsychiatric outcome was 1.11 (95% CI, 1.04-1.19) in patients with asthma and 1.07 (95% CI, 1.01-1.14) in patients with allergic rhinitis compared with patients who were unexposed. The highest OR was for anxiety disorders (OR, 1.21; 95% CI, 1.05-1.20) among patients with asthma exposed to montelukast and insomnia (OR, 1.15; 95% CI, 1.05-1.27) among patients with allergic rhinitis exposed to montelukast. This study found that patients with asthma or allergic rhinitis had increased odds of adverse neuropsychiatric outcomes after montelukast initiation. These findings suggest that clinicians should consider monitoring potential adverse mental health symptoms during montelukast treatment, particularly in individuals with a history of mental health or sleep problems.

The safety of pranlukast and montelukast during the first trimester of pregnancy: A prospective, two-centered cohort study in Japan.

For leukotriene receptor antagonists (LTRAs), especially pranlukast, safety data during pregnancy is limited. Therefore, we conducted a prospective, two-centered cohort study using data from teratogen information services in Japan to clarify the effects of LTRA exposure during pregnancy on maternal and fetal outcomes. Pregnant women who being counseled on drug use during pregnancy at two facilities were enrolled. The primary outcome of this study was major congenital anomalies. The incidence of major congenital anomalies in women exposed to montelukast or pranlukast during the first trimester of pregnancy was compared with that of controls. Logistic regression analysis was performed to analyze the effects of maternal LTRA use during the first trimester of pregnancy on major congenital anomalies. The outcomes of 231 pregnant women exposed to LTRAs (montelukast n=122; pranlukast n=106; both n=3) and 212 live births were compared with those of controls. The rate of major congenital anomalies in the LTRA group was 1.9%. Multivariable logistic regression analysis revealed that LTRA exposure was not a risk factor for major congenital anomalies (adjusted odds ratio, 0.78; 95% confidence interval, 0.23-2.05; p=0.653). In addition, no significant difference was detected in stillbirth, spontaneous abortion, preterm birth, and low birth weight between the two groups. The present study revealed that montelukast and pranlukast were not associated with the risk of major congenital anomalies. Our findings suggest that LTRAs could be safely employed for asthma therapy during pregnancy.

Leukotriene receptor antagonists and risk of neuropsychiatric events in children, adolescents and young adults: a self-controlled case series.

Leukotriene receptor antagonists (LTRAs) are widely used for asthma and allergic rhinitis (AR), but concerns about the risk of neuropsychiatric events (NPEs) have been raised since the first Drug Safety Communication by the US Food and Drug Administration in 2008. This study evaluates the association between LTRA use and NPEs in children, adolescents and young adults with asthma or AR. A self-controlled case series study was conducted using the Korean National Health Insurance Service claims database from two 3-year observation periods (observation period 1 (Obs1): 2005-2007; observation period 2 (Obs2): 2016-2018). Asthma or AR patients aged 3-30 years who were prescribed LTRAs and diagnosed with NPEs were included. The incidence rate ratios (IRRs) for the exposed period and risk periods (1-3, 4-7, 8-14, 15-30, 31-90 and >90 days from initiation of LTRA) compared with unexposed periods were calculated using conditional Poisson regression. Subgroup analysis according to age group, type of NPEs and indication of LTRA was performed. Among 17 001 included patients, the risk of NPEs increased in Obs2 (IRR 1.11, 95% CI 1.00-1.22), but did not increase in Obs1. Risk was increased during risk periods 4-7 days (IRR 2.36, 95% CI 1.99-2.76) and 8-14 days (IRR 1.78, 95% CI 1.46-2.15) after initiation of LTRA, particularly in adolescents (IRR 1.28, 95% CI 1.05-1.55) and young adults (IRR 1.14, 95% CI 1.02-1.28), while risk was decreased in children (3-11 years). Risk was not increased for any single type of NPE. AR patients were at increased risk (IRR 1.19, 95% CI 1.01-1.39), but not those with asthma. Overall, risk of NPEs with LTRA use differed between risk periods and subgroups. Physicians should prescribe LTRAs according to indications and inform patients about possible NPEs.

Prescription Patterns of Asthma Preventers Among Children and Adolescents Between Australia and South Korea.

Purpose: Inhaled Corticosteroids (ICSs) and oral Leukotriene Receptor Antagonists (LTRAs) are commonly prescribed asthma preventers, however, concerns have been raised as to whether montelukast (LTRA) is associated with an increase in occurrences of neuropsychiatric side effects in children. Our study was conducted to observe prescribing patterns of asthma preventers among paediatric patients specifically focusing on ICSs and LTRAs between Australia and South Korea to see intercountry differences in the use of these medicines. Materials and Methods: The Health Insurance Review and Assessment Paediatric Patients Sample dataset for South Korea and data provided by Services Australia were used in the study. Paediatric patients aged between 3 and 19 with more than one dispensing of an asthma preventer and at least one reliever between 1 Jan 2018 and 31 December 2018 were selected. Prevalence per 1,00,000 persons and standardised prevalence were estimated. Results: A total of 3,58,470 patients (2,04,270 from South Korea and 1,54,200 from Australia) were included in the study. A higher prevalence of ICS-based inhalers was seen in Australia with 80.1% compared to 13.5% in South Korea. In addition, Australia showed a stronger tendency of prescribing high dose ICS-based inhalers compared to South Korea with 22.9% vs. 4.9%. In contrast, use of LTRAs was more prevalent in South Korea with 57.6% while in Australia, montelukast was the only LTRA dispensed at a proportion of 18.9%. Moreover, 29.9% of xanthines which are orally available preventers, were prescribed more frequently in South Korea compared to Australia (0.1%). Conclusion: Australia showed a tendency of prescribing ICS-based preventers whereas South Korea exhibited a preference towards the oral LTRAs. Given the potential risk of neuropsychiatric side effects among paediatric patients with montelukast, reasons for the high use of montelukast in South Korea should be investigated further.

Leukotriene receptor antagonism with montelukast as a possible therapeutic for venous thromboembolism prophylaxis: An observational study

BackgroundArachidonic acid (AA), which is metabolized via the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways, was found to be associated with venous thromboembolism (VTE). Metabolites of the LOX pathway include cysteinyl (Cys) Leukotrienes (LT), potent proinflammatory mediators, which have also been implicated in cardiovascular disease. ObjectiveThe purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE. MethodsWe conducted a retrospective cohort study examining VTE risk among COPD patients from the United States Department of Veterans Affairs. We use propensity score matching and Cox survival models to estimate the hazard ratio comparing montelukast exposure to non-exposure. Montelukast exposure was associated with a 15.9% reduction in risk of VTE compared to those unexposed (HR= 0.841; 95% CI= (0.758–0.934)). ConclusionThe results of this study demonstrate that targeting LTs might be beneficial for VTE prophylaxis using the clinically available LT inhibitor, montelukast. Importantly, further research on LTs is warranted to fully understand and validate this relationship.

Real possibilities of treatment of patients with allergic rhinitis

Allergic rhinitis occupies a special place among diseases of the upper respiratory tract. Every year the urgency of the problem increases due to the annual increase in the incidence among all age groups of the population. Allergic diseases are often associated with other respiratory diseases or cause them, which requires early diagnosis and selection of competent therapy. Allergic reactions can range from seasonal allergens, such as tree or weed pollen, to year-round irritants, such as dust and pet dander. Currently, the pathogenesis of allergic rhinitis is being actively studied. There is still debate about the most accurate classification of allergic rhinitis, reflecting all its aspects, such as the time of onset and duration of symptoms, their impact on patients’ lives. This is necessary to find the best methods of treatment with maximum efficiency. The main clinical manifestations of allergic rhinitis are nasal itching, sneezing, swelling of the nasal mucosa and rhinorrhea. Often, to relieve symptoms, patients are forced to take many drugs for a long time, which has a significant impact on their quality of life. All over the world, new ways are being developed to optimize the treatment of this group of patients, among which combinations of several drugs used to treat allergic rhinitis, which meet all safety and efficacy requirements. The most commonly used and most effective combinations of drugs are combinations of intranasal glucocorticosteroids with topical histamine H1 receptor antagonists, as well as leukotriene receptor blockers with oral antihistamines.

The role of leukotriene receptor blockers in the treatment of allergic rhinitis in combination with chronic rhinosinusitis with nasal polyps

Background. Leukotrienes play an important role in the pathogenesis of allergic rhinitis (AR) and eosinophilic type of chronic rhinosinusitis with nasal polyps (CRSwNP). There is a phenotype of CRSwNP in combination with AR, which has specifics of local inflammation.The aim of our study was to investigate the efficacy of using an antileukotriene drug in the treatment of AR in combination with CRSwNP.Materials and methods. 63 patients with AR and bilateral CRSwNP after endoscopic bilateral polypotomy were randomly divided into 2 groups. In the 1st group 32 people (age 50.28 ± 1.37 years) were prescribed a basic therapy with nasal spray of mometasone furoate at a daily dose of 400 µg in combination with montelukast 1 tab. 10 mg at night, in the 2nd group 31 people (age 50.31 ± 1, 16 years old) received only mometasone furoate monotherapy. Endoscopic examination of the nasal cavity was performed once every 3 months. The follow-up period was 1 year.Results. After 3 months in the 1st group of patients there was a recurrence of polyp growth was observed in 25% of cases, in the 2nd group in 35.5% of patients (p < 0.05). After 6 months, the number of relapses of CRSwNP decreased to 15.6% of cases in group 1 and to 22.6% in group 2 (p < 0.05). After 9 months in group 1 recurrence of NP was recorded in 12.5% of patients and nasal polyps were completely absent during endoscopic examination in 9.4% of cases, in the 2nd group, relapse was detected in 19.35% of patients (p < 0.05). 1 year after surgery, in group 1, relapse of NP was found in 12.5% of patients with AR and in 12.5% of cases was remission of the pathological process with cancellation of basic therapy. In group 2, recurrence of NP was in 16.1% of cases, there were no reasons for withdraw treatment of intranasal glucocorticosteroids in this group.Discussion. The clinical effectiveness of the addition of Montelukast to basic therapy has been reflected in a reduction in the growth rate of polyposic vegetation, the number of repeated operations and the stabilization of the flow of chronic inflammatory process.Conclusions. In the case of the clinical phenotype of AR with CRSwNP, the addition of a leukotriene receptor blocker montelukast to the basic therapy of intranasal glucocorticosteroids made it possible to improve drug control of both diseases and reduce the frequency of CRSwNP relapses.

A Dual Role for Cysteinyl Leukotriene Receptors in the Pathogenesis of Corneal Infection.

Cysteinyl leukotrienes (CysLTs) have been defined as central mediators of inflammation. Despite our extensive understanding of these bioactive lipid mediators in the pathogenesis of diseases such as asthma, allergic rhinitis, and even neurological disorders, information regarding the eye is markedly lacking. As a result, this study examined the expression profiles of two major CysLT receptors, CysLT1 and CysLT2, in the cornea using experimental mouse models of Pseudomonas aeruginosa-induced keratitis with contrasting outcomes: susceptible C57BL/6 (B6) and resistant BALB/c. Postinfection, disparate levels of CysLT receptors were accompanied by distinct expression profiles for select proinflammatory and anti-inflammatory cell surface markers detected on macrophages and polymorphonuclear neutrophils between the two strains. Further, inhibition of either CysLT receptor converted the disease response of both strains, where corneal perforation was prevented in B6 mice, and BALB/c mice fared significantly worse. In addition, receptor antagonist studies revealed changes in inflammatory cell infiltrate phenotypes and an influence on downstream CysLT receptor signaling pathways. Although the B6 mouse model highlights the established proinflammatory activities related to CysLT receptor activation, results generated from BALB/c mice indicate a protective mechanism that may be essential to disease resolution. Further, basal expression levels of CysLT1 and CysLT2 were significantly higher in uninfected corneas of both mouse strains as opposed to during infection, suggestive of a novel role in homeostatic maintenance within the eye. In light of these findings, therapeutic targeting of CysLT receptors extends beyond inhibition of proinflammatory activities and may impact inflammation resolution, as well as corneal surface homeostasis.

The comparative effect of Leukotriene receptor antagonist add on therapy and step up inhaled Corticosteroid in partially controlled asthma: An open-labeled randomized controlled trial.

No studies are comparing the impact of the add-on leukotriene-receptor antagonist (LTRA) with a step-up dose of inhaled corticosteroids (ICS) in partly controlled asthma patients with asthma control test (ACT) score ˂ 23. To study the effect of LTRA add-on therapy in comparison to a step-up to medium dose of ICS in partially controlled asthma. An open-labeled randomized controlled trial was conducted in asthma subjects with partly controlled asthma who had been in regular receipt of low dose ICS. All subjects were assessed for asthma using ACT, daytime and nighttime symptoms, rate of relievers used, spirometry, and impulse oscillometry (IOS) at 3 and 6 months. Subjects were randomized to receive daily oral LTRA 10 mg or step-up medium dose of ICS. Between June 2020 and January 2021, 50 participants were enrolled, all patients completing the study. After treatment, mean ACT scores were increased to more than 23 indicating well-controlled asthma in both groups, control being sustained throughout the whole 6-month study period (P ˂ 0.001). Within each group, ACT scores were improved by a minimal clinical important difference (MCID) ≥ 3 points at 6 months, compared to baseline values. There were significant decreases in nighttime and daytime symptoms, and the numbers of rescue relievers used in 4 weeks in both groups compared to baseline (P ˂ 0.001). LTRA add-on therapy in partially controlled asthma patients is comparable with step-up to medium dose of ICS/LABA as regards asthma control.

Cysteinyl–leukotriene and prostaglandin pathways in bronchial versus alveolar lavage in allergic asthmatics

Cysteinyl–leukotriene and prostaglandin pathways in bronchial versus alveolar lavage in allergic asthmatics

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two highly prevalent human diseases caused by excessive fat deposition in the liver. Although multiple approaches have been suggested, NAFLD/NASH remains an unmet clinical need. Here, we report the discovery of a novel class of hybrid molecules designed to function as cysteinyl leukotriene receptor 1 (CysLT1R) antagonists and G protein bile acid receptor 1 (GPBAR1/TGR5) agonists for the treatment of NAFLD/NASH. The most potent of these compounds generated by harnessing the scaffold of the previously described CystLT1R antagonists showed efficacy in reversing liver histopathology features in a preclinical model of NASH, reshaping the liver transcriptome and the lipid and energy metabolism in the liver and adipose tissues. In summary, the present study described a novel orally active dual CysLT1R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development.

Montelukast Inhibits HCoV-OC43 Infection as a Viral Inactivator.

Coronaviruses (CoVs) consist of a large group of RNA viruses causing various diseases in humans and in lots of animals. Human coronavirus (HCoV) OC43, the prototype of beta-coronavirus discovered in the 1960s, has been circulating in humans for long time, and infection with other emerging strains of beta-coronavirus (SARS-CoV, SARS-CoV-2, and MERS-CoV) can lead to severe illness and death. In this study, we found that montelukast, a leukotriene receptor antagonist, potently inhibited the infection of HCoV-OC43 in distinct cells in a dose- and time- dependent manner. Additionally, the results showed that montelukast induced release of HCoV-OC43 genomic RNA by disrupting the integrity of the viral lipid membrane, and irreversibly inhibited viral infection. Considering the similarity among HCoV-OC43, MERS-CoV, and SARS-CoV-2, it suggests that montelukast may be a potential candidate for the treatment of human beta-coronavirus infection.

Combining low-frequency oscillometry and spirometry measurements in relation to asthma control and exacerbations in moderate-to-severe asthma

Combining low-frequency oscillometry and spirometry measurements in relation to asthma control and exacerbations in moderate-to-severe asthma

Cysteinyl Leukotriene Receptor Antagonists Associated With a Decreased Incidence of Cancer: A Retrospective Cohort Study.

AimCysteinyl leukotrienes receptor antagonists (LTRAs) are promising chemoprevention options to target cysteinyl leukotriene signaling in cancer. However, only a number of randomized clinical trials (RCTs) or observational studies have been conducted to date; thus, the effect of LTRAs on patients is yet to be elucidated. Using insurance claim data, we aimed to evaluate whether LTRAs have cancer preventive effects by observing patients who took LTRAs.MethodPatients diagnosed with asthma, allergic rhinitis, chronic cough, and have no history of cancer were followed-up from 2005 to 2017. Cox proportional hazard regression analysis was conducted to estimate the hazard ratios (HRs) for cancer risk of LTRA users.ResultWe followed-up (median: 5.6 years) 188,906 matched patients (94,453 LTRA users and 94,453 non-users). LTRA use was associated with a decreased risk of cancer (adjusted HR [aHR] = 0.85, 95% confidence interval [CI] = 0.83–0.87). The cancer risk showed a tendency to decrease rapidly when LTRAs were used in high dose (aHR = 0.56, 95% CI = 0.40–0.79) or for longer durations of more than 3 years (aHR = 0.68, 95% CI = 0.60–0.76) and 5 years (aHR = 0.33, 95% CI = 0.26–0.42). The greater preventive effects of LTRAs were also observed in patients with specific risk factors related to sex, age, smoking, and the presence of comorbidities.ConclusionIn this study, we found that LTRA use was associated with a decreased risk of cancer. The high dose and long duration of the use of LTRAs correlated with a lower cancer risk. Since LTRAs are not yet used for the prevention or treatment of cancer, our findings could be used for developing a new chemo-regimen or designing feasible RCTs.

Asthma Therapies on Pulmonary Tuberculosis Pneumonia in Predominant Bronchiectasis–Asthma Combination

Background: It is sometimes difficult to distinguish between asthma and bronchiectasis as their symptoms overlap, and these two diseases are associated with pulmonary tuberculosis (PTB) or pneumonia. Objective: The purpose of this study is to determine the effects of bronchodilator drugs, steroids, antidepressants drugs, and antianxiety drugs on the risks of PTB or pneumonia in patients with bronchiectasis–asthma combination or bronchiectasis–asthma–chronic obstructive pulmonary disease combination—BCAS cohort. Methods: After propensity score matching, we retrospectively studied patients with BCAS (N = 620) and without BCAS (N = 2,314) through an analysis. The cumulative incidence of PTB or pneumonia was analyzed through Cox proportional regression. After adjustment for sex, age, comorbidities, and medications [including long-acting beta2 agonist/muscarinic antagonists (LABAs/LAMAs), short-acting beta2 agonist/muscarinic antagonists (SABAs/SAMAs), leukotriene receptor antagonist, montelukast, steroids (inhaled corticosteroids, ICSs; oral steroids, OSs), anti-depressants (fluoxetine), and anti-anxiety drugs (benzodiazepines, BZDs)], we calculated the adjusted hazard ratios (aHR) and their 95% confidence intervals (95% CI) for these risks. Similar to OSs, ICSs are associated with an increased risk of PTB or pneumonia, lumping these two as steroids (ICSs/OSs). Results: For the aHR (95% CI), with non-LABAs/non-OSs as the reference 1, the use of LABAs [0.70 (0.52–0.94)]/OSs [0.35 (0.29–0.44)] was associated with a lower risk of PTB or pneumonia. However, the current use of LABAs [2.39 (1.31–4.34)]/SABAs [1.61 (1.31–1.96)], steroids [ICSs 3.23 (1.96–5.29)]/OSs 1.76 (1.45–2.14)], and BZDs [alprazolam 1.73 (1.08–2.75)/fludiazepam 7.48 (1.93–28.9)] was associated with these risks. The current use of LAMAs [0.52 (0.14–1.84)]/SAMAs [1.45 (0.99–2.11)] was not associated with these risks. Conclusion: The current use of LAMAs/SAMAs is relatively safe with respect to PTB or pneumonia risks, but LABAs/SABAs, steroids, and BZDs could be used after evaluation of the benefit for the BCAS cohort. However, we must take the possible protopathic bias into account.

Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ

Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor β (TGF-β), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-β, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 μM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.

Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells.

Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.

Clinical effects of intranasal corticosteroids on nasal symptoms in subjects with chronic rhinitis during COVID-19

Background: The clinical effects of intranasal corticosteroids (INC) on nasal symptoms and the clinical course of coronavirus disease 2019 (COVID-19) in subjects with chronic rhinitis (CR) seem unclear. Objective: To evaluate the clinical effects of INCs on nasal symptoms in subjects with CR and with COVID-19. Methods: In subjects with CR and diagnosed with COVID-19 at four tertiary centers, quality of life and nasal symptoms were assessed by using the 22-item Sino-Nasal Outcome Test (SNOT-22) and the visual analog scale (VAS), respectively. In subjects with allergic rhinitis, nasal symptoms were also assessed on the total symptom score-6 (TSS-6) scale. The subjects were then allocated into two groups according to whether or not they used INCs while infected with the severe acute respiratory syndrome coronavirus 2 (group 1 and group 2, respectively). The subjects in group 2 were divided into two subgroups according to the use of antihistamines and/or leukotriene receptor antagonist or not (group 2a and group 2b, respectively). All the scores were compared before and during COVID-19 among the three groups. Results: A total of 71 subjects (21 in group 1, 24 in group 2a, and 26 in group 2b) were enrolled. The total scores of the SNOT-22 increased remarkably in all the groups during the infection when compared with the pre-COVID-19 scores (p < 0.001 in each group). However, the difference between the pre-COVID-19 and COVID-19 values revealed a lower decrease in the senses of smell and/or taste in group 1 than in group 2a and group 2b (p = 0.015, adjusted p = 0.045; and p = 0.001, adjusted p = 0.002, respectively). There were no significant differences in other COVID-19 findings, VAS, and TSS-6 scores among the groups (all p > 0.05). Conclusion: INCs in subjects with CR seemed protective against the decrease in smell and/or taste observed during COVID-19 and do not aggravate the clinical course of COVID-19.

Comparing the Efficacy of Leukotriene Receptor Antagonists and Intra-nasal Steroids in the Treatment of Allergic Rhinitis: A Systematic Review and Meta-analysis

We performed a systematic review and meta-analysis of randomized controlled trials to compare the efficacy of leukotriene receptor antagonists (LTRAs) and intranasal corticosteroids (INCSs) in patients with allergic rhinitis (AR). We searched OVID-MEDLINE (1946 to November 6, 2020), EMBASE, and the Cochrane Library databases for original articles. We used a random-effects model for the meta-analysis to determine the mean difference in the nasal symptom scores between the LTRA and INCS groups. Statistical heterogeneity was assessed using the I2 statistic and chi-squared test. A subgroup analysis was performed using the sample size, treatment duration, and comorbidities. We performed a database search on November 6, 2020, which yielded 922 reports. Of these, five studies were included in the metaanalysis. INCS treatment was more effective than LTRA treatment in relieving the nasal symptom of patients with AR (weighted mean difference [WMD] of the total nasal symptom score change=10.77, 95% confidence interval [CI]: 5.41 to 16.12). The results showed moderate heterogeneity (I2=33%, P=0.20). In the subgroup analysis, the results were homogenous, although some showed heterogeneity and some of the differences between the treatments were not statistically significant. There was moderate heterogeneity in the subgroup analysis (I2=63%, P=0.07), owing to the small sample size (n<600). The results of the study with a long treatment duration (more than 15 days) and those of the studies including patients with asthma were that the difference in the efficacy of INCS treatment and that of LTRA treatment was not statistically significant (WMD=3.86, 95% CI: &#8722;5.8 to 13.52; and WMD=8.18, 95% CI: &#8722;0.29 to 16.65, respectively). Although some of the subgroups showed heterogeneity and did not demonstrate statistically significant differences between the two treatments, the subgroup analysis consistently showed the superiority of INCS in treating patients with AR.