-
1.
Levocetirizine and montelukast in the COVID-19 treatment paradigm.
May, BC, Gallivan, KH
International immunopharmacology. 2022;:108412
-
-
Free full text
-
Abstract
Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.
-
2.
Persulfidation of ATG18a regulates autophagy under ER stress in Arabidopsis.
Aroca, A, Yruela, I, Gotor, C, Bassham, DC
Proceedings of the National Academy of Sciences of the United States of America. 2021;(20)
-
-
Free full text
-
Abstract
Hydrogen sulfide (H2S) is an endogenously generated gaseous signaling molecule, which recently has been implicated in autophagy regulation in both plants and mammals through persulfidation of specific targets. Persulfidation has been suggested as the molecular mechanism through which sulfide regulates autophagy in plant cells. ATG18a is a core autophagy component that is required for bulk autophagy and also for reticulophagy during endoplasmic reticulum (ER) stress. In this research, we revealed the role of sulfide in plant ER stress responses as a negative regulator of autophagy. We demonstrate that sulfide regulates ATG18a phospholipid-binding activity by reversible persulfidation at Cys103, and that this modification activates ATG18a binding capacity to specific phospholipids in a reversible manner. Our findings strongly suggest that persulfidation of ATG18a at C103 regulates autophagy under ER stress, and that the impairment of persulfidation affects both the number and size of autophagosomes.
-
3.
Montelukast and Coronavirus Disease 2019: A Scoping Review.
Sharifinejad, N, Sharafian, S, Salekmoghadam, S, Tavakol, M, Qorbani, M
Iranian journal of allergy, asthma, and immunology. 2021;(4):384-393
Abstract
Coronavirus disease 2019 (COVID-19) is an emerging worldwide issue, that has affected a large number of people around the world. So far, many studies have aimed to develop a therapeutic approach against COVID-19. Montelukast (MK) is a safe asthma controller drug, which is considered as a potential antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review has a systematic approach to investigate the reports on the use of MK as a part of treatment or a prophylactic agent in COVID-19. The search was conducted in PubMed, Web of Science, and Scopus databases and yielded 35 studies containing the influence of MK on SARS-CoV-2. Ultimately, MK appears to be worth being used as an adjuvant therapeutic and prophylactic drug against SARS-CoV-2. Nevertheless, more clinical trials are required to accurately investigate its effectiveness.
-
4.
The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial.
Abdallah, MS, Eldeen, AH, Tantawy, SS, Mostafa, TM
European journal of pharmacology. 2021;:174295
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with fat accumulation in the liver which can progress into non-alcoholic steatohepatitis (NASH). There is no specific treatment strategy for NASH. In this context, this study aimed at evaluating the efficacy and safety of montelukast in the treatment of patients with NASH. In this randomized double-blind placebo-controlled study, 52 overweight/obese patients with NASH were randomized into group 1 (n = 26) which received montelukast 10 mg tablets once daily and group 2 (n = 26) which received placebo tablets once daily for 12 weeks. The fibro-scan was used to assess liver stiffness as a primary outcome at baseline and 12 weeks post-treatment. Furthermore, patients were assessed for biochemical analysis of liver aminotransferases, metabolic parameters, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), liver fibrosis biomarkers including hyaluronic acid (HA) and transforming growth factor beta-1 (TGF-β1). Beck depression inventory questionnaire was used to report depressive symptoms. Data were statistically analyzed by paired and unpaired student's t-test, and Chi-square test. A total number of 44 patients completed the study. The two groups were statistically similar at baseline. After treatment and as compared to baseline data and placebo, montelukast showed a statistically significant improvement in liver stiffness, liver enzymes, metabolic parameters (except LDL-C), TNF-α, 8-OHdG, and liver fibrosis biomarkers (HA and TGF-β1). Furthermore, montelukast was well tolerated and didn't provoke depression. In this proof-of-concept study, treatment with montelukast may represent a promising therapeutic strategy for patients with non-alcoholic steatohepatitis secondary to its efficacy and safety. Clinicaltrial.gov ID: NCT04080947.
-
5.
Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity.
Al-Kuraishy, HM, Al-Gareeb, AI, Almulaiky, YQ, Cruz-Martins, N, El-Saber Batiha, G
European journal of pharmacology. 2021;:174196
-
-
Free full text
-
Abstract
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the responsible agent for the coronavirus disease 2019 (Covid-19), has its entry point through interaction with angiotensin converting enzyme 2 (ACE2) receptors, highly expressed in lung type II alveolar cells and other tissues, like heart, pancreas, brain, and vascular endothelium. This review aimed to elucidate the potential role of leukotrienes (LTs) in the pathogenesis and clinical presentation of SARS-CoV-2 infection, and to reveal the critical role of LT pathway receptor antagonists and inhibitors in Covid-19 management. A literature search was done in PubMed, Scopus, Web of Science and Google Scholar databases to find the potential role of montelukast and other LT inhibitors in the management of pulmonary and extra-pulmonary manifestations triggered by SARS-CoV-2. Data obtained so far underline that pulmonary and extra-pulmonary manifestations in Covid-19 are attributed to a direct effect of SARS-CoV-2 in expressed ACE2 receptors or indirectly through NF-κB dependent induction of a cytokine storm. Montelukast can ameliorate extra-pulmonary manifestations in Covid-19 either directly through blocking of Cys-LTRs in different organs or indirectly through inhibition of the NF-κB signaling pathway.
-
6.
Diallyl Sulfide Attenuation of Carcinogenesis in Mammary Epithelial Cells through the Inhibition of ROS Formation, and DNA Strand Breaks.
Darling-Reed, SF, Nkrumah-Elie, Y, Ferguson, DT, Flores-Rozas, H, Mendonca, P, Messeha, S, Hudson, A, Badisa, RB, Tilghman, SL, Womble, T, et al
Biomolecules. 2021;(9)
Abstract
Garlic has long been used medicinally for many diseases, including cancer. One of the active garlic components is diallyl sulfide (DAS), which prevents carcinogenesis and reduces the incidence rate of several cancers. In this study, non-cancerous MCF-10A cells were used as a model to investigate the effect of DAS on Benzo (a)pyrene (BaP)-induced cellular carcinogenesis. The cells were evaluated based on changes in proliferation, cell cycle arrest, the formation of peroxides, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, the generation of DNA strand breaks, and DNA Polymerase β (Pol β) expression. The results obtained indicate that when co-treated with BaP, DAS inhibited BaP-induced cell proliferation (p < 0.05) to levels similar to the negative control. BaP treatment results in a two-fold increase in the accumulation of cells in the G2/M-phase of the cell cycle, which is restored to baseline levels, similar to untreated cells and vehicle-treated cells, when pretreated with 6 μM and 60 μM DAS, respectively. Co-treatment with DAS (60 μM and 600 μM) inhibited BaP-induced reactive oxygen species (ROS) formation by 132% and 133%, respectively, as determined by the accumulation of H2O2 in the extracellular medium and an increase in 8-OHdG levels of treated cells. All DAS concentrations inhibited BaP-induced DNA strand breaks through co-treatment and pre-treatment methods at all time points evaluated. Co-Treatment with 60 μM DAS increased DNA Pol β expression in response to BaP-induced lipid peroxidation and oxidative DNA damage. These results indicate that DAS effectively inhibited BaP-induced cell proliferation, cell cycle transitions, ROS, and DNA damage in an MCF-10A cell line. These results provide more experimental evidence for garlic's antitumor abilities and corroborate many epidemiological studies regarding the association between the increased intake of garlic and the reduced risk of several types of cancer.
-
7.
LTA4H rs2660845 association with montelukast response in early and late-onset asthma.
Maroteau, C, Espuela-Ortiz, A, Herrera-Luis, E, Srinivasan, S, Carr, F, Tavendale, R, Wilson, K, Hernandez-Pacheco, N, Chalmers, JD, Turner, S, et al
PloS one. 2021;(9):e0257396
Abstract
Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.
-
8.
The Montelukast Therapy in Asthmatic Children with and without Food Allergy: Does It Make Any Difference?
Sahiner, UM, Arik Yilmaz, E, Fontanella, S, Haider, S, Soyer, O, Custovic, A, Kalayci, O, Sackesen, C
International archives of allergy and immunology. 2021;(12):1212-1221
Abstract
INTRODUCTION Children with food allergy are at increased risk for asthma and asthma morbidity. Since leukotrienes are implicated in the pathogenesis of both asthma and probably in food allergies, we hypothesized that asthmatic children with concomitant food allergy may have a favorable response to antileukotriene treatment. METHODS Asthmatic children aged 6-18 years with and without food allergy were treated with montelukast and placebo in a double-blind, placebo-controlled cross-over parallel-group study. The primary outcome of the study was improvement in FEV1%. Asthma control tests, spirometry and methacholine challenges were performed as well as Fractional Exhaled Nitric Oxide (FeNO) levels. PGD2, CystLT, and lipoxin levels were measured in exhaled breath condensate (EBC). RESULTS A total of 113 children were enrolled and 87 completed the study in accordance with the protocol. At baseline, children with food allergy and asthma (FAA) had higher levels of PGD2 and CysLT levels in the EBC than children with asthma alone (AA) (p < 0.001 for each). In the montelukast arm, although FEV1% was significantly higher in the FAA group compared to AA (p = 0.005), this effect was linked to the baseline difference of FEV1% between both arms. Montelukast treatment failed to improve FEV1% in both groups compared to the placebo. No effect of montelukast was observed in the remaining study parameters. CONCLUSION Although children with FAA do not show a more favorable response to montelukast treatment compared to AA, a significant difference between baseline PGD2 and CystLT levels between FAA and AA groups may point to a different endotype of childhood asthma.
-
9.
Metal Sulfide Semiconductor Nanomaterials and Polymer Microgels for Biomedical Applications.
Paca, AM, Ajibade, PA
International journal of molecular sciences. 2021;(22)
Abstract
The development of nanomaterials with therapeutic and/or diagnostic properties has been an active area of research in biomedical sciences over the past decade. Nanomaterials have been identified as significant medical tools with potential therapeutic and diagnostic capabilities that are practically impossible to accomplish using larger molecules or bulk materials. Fabrication of nanomaterials is the most effective platform to engineer therapeutic agents and delivery systems for the treatment of cancer. This is mostly due to the high selectivity of nanomaterials for cancerous cells, which is attributable to the porous morphology of tumour cells which allows nanomaterials to accumulate more in tumour cells more than in normal cells. Nanomaterials can be used as potential drug delivery systems since they exist in similar scale as proteins. The unique properties of nanomaterials have drawn a lot of interest from researchers in search of new chemotherapeutic treatment for cancer. Metal sulfide nanomaterials have emerged as the most used frameworks in the past decade, but they tend to aggregate because of their high surface energy which triggers the thermodynamically favoured interaction. Stabilizing agents such as polymer and microgels have been utilized to inhibit the particles from any aggregations. In this review, we explore the development of metal sulfide polymer/microgel nanocomposites as therapeutic agents against cancerous cells.
-
10.
Montelukast's ability to fight COVID-19 infection.
Bozek, A, Winterstein, J
The Journal of asthma : official journal of the Association for the Care of Asthma. 2021;(10):1348-1349
Abstract
Montelukast can be effective in the treatment of SARS-CoV-2 infection.