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BMJ (Clinical Research Ed.) Oct 2001
Meta-Analysis
Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Asthma; Beclomethasone; Chronic Disease; Drug Therapy, Combination; Glucocorticoids; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Randomized Controlled Trials as Topic; Sulfonamides; Tosyl Compounds
PubMed: 11679388
DOI: 10.1136/bmj.323.7319.976 -
Prostaglandins, Leukotrienes, and... Oct 2020
Topics: Acetates; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Betacoronavirus; COVID-19; Coronavirus Infections; Cyclopropanes; Cytokine Release Syndrome; Humans; Hydroxyurea; Immunologic Factors; Indoles; Leukotrienes; Pandemics; Phenylcarbamates; Pneumonia, Viral; Quinolines; SARS-CoV-2; Severity of Illness Index; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 32977289
DOI: 10.1016/j.plefa.2020.102174 -
Canadian Family Physician Medecin de... Apr 2000To examine the role of leukotriene-receptor antagonists (LTRAs) in management of asthma. (Review)
Review
OBJECTIVE
To examine the role of leukotriene-receptor antagonists (LTRAs) in management of asthma.
QUALITY OF EVIDENCE
Most data were derived from randomized, double-blind, controlled trials.
MAIN MESSAGE
Leukotrienes appear to have an important role in the pathophysiology of asthma, including airway inflammation. Leukotriene-receptor antagonists are effective in improving asthma control end points, such as allergen, ASA, and exercise challenge, in clinical models of asthma. In chronic asthma, LTRA administration reduces asthma symptoms and rescue beta 2-agonist use, changes that are paralleled by improvements in lung function. Both zafirlukast and montelukast decrease circulating levels of eosinophils and could have other useful anti-inflammatory properties. Administration of LTRAs allows doses of inhaled corticosteroids to be reduced. Currently available LTRAs are free of serious side effects and are available as oral formulations.
CONCLUSIONS
Leukotriene-receptor antagonists belong to a new class of asthma medication. While inhaled corticosteroids remain first-line therapy for managing chronic asthma, LTRAs should be considered for patients with ASA-sensitive asthma; as adjunct therapy when low to moderate doses of inhaled steroid alone provide incomplete control; or as adjunct therapy to allow reduction in doses of inhaled corticosteroids.
Topics: Acetates; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Bronchial Spasm; Chronic Disease; Cyclopropanes; Double-Blind Method; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Randomized Controlled Trials as Topic; Respiratory Therapy; Sulfides; Sulfonamides; Time Factors; Tosyl Compounds
PubMed: 10790819
DOI: No ID Found -
Metabolites Aug 2022Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic...
Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.
PubMed: 36005620
DOI: 10.3390/metabo12080749 -
Science Advances Oct 2019The G protein-coupled cysteinyl leukotriene receptor CysLTR mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic...
The G protein-coupled cysteinyl leukotriene receptor CysLTR mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLTR antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLTR bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue-coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.
Topics: Anti-Asthmatic Agents; Binding Sites; Chromones; Crystallography, X-Ray; Humans; Indoles; Leukotriene Antagonists; Ligands; Molecular Docking Simulation; Phenylcarbamates; Protein Structure, Tertiary; Receptors, Leukotriene; Recombinant Proteins; Sodium; Sulfonamides; Tosyl Compounds
PubMed: 31633023
DOI: 10.1126/sciadv.aax2518 -
F1000Research 2022Opposing findings have been published on the regulation of the sperm-specific Ca channel CatSper (cation channel of sperm) in human sperm cells by the plant...
Opposing findings have been published on the regulation of the sperm-specific Ca channel CatSper (cation channel of sperm) in human sperm cells by the plant triterpenoids lupeol and pristimerin. While the original study on this topic found these triterpenoids to act as potent inhibitors of human CatSper, subsequent studies have failed to replicate such an inhibitory effect. It has been suggested that these issues could in part be due to purity issues and/or batch variation between the plant-derived extracts of lupeol and pristimerin obtained for the studies. The aim of this study was to elucidate this controversy by investigating the batches of lupeol and pristimerin used in our previous study with state-of-the-art H-, C- and 2D-nuclear magnetic resonance (NMR) methods to reveal potential purity and/or batch variation issues. When comparing the NMR-spectra obtained from H-NMR and C-NMR with previously published NMR-spectra for lupeol and pristimerin, we could confirm that both the lupeol and pristimerin batch were ≥95 % pure. These results confirm the validity of the findings in our previous study for lupeol and pristimerin, showing that lupeol and pristimerin do not inhibit activation of CatSper in human sperm. In conclusion, using H-, C- and 2D-NMR methods, we confirm that the lupeol and pristimerin batches used in our previous study were ≥95 % pure and thereby fail to identify any purity issues and/or batch variation that could explain the observed inability of lupeol and pristimerin to inhibit activation of CatSper in human sperm.
Topics: Calcium Channels; Humans; Male; Pentacyclic Triterpenes; Semen; Spermatozoa
PubMed: 36016990
DOI: 10.12688/f1000research.109279.2 -
Postgraduate Medical Journal Dec 2000Leukotriene receptor antagonists (LTRA) are a new class of drugs for asthma treatment, available in tablet form. Their unique mechanism of action results in a... (Review)
Review
Leukotriene receptor antagonists (LTRA) are a new class of drugs for asthma treatment, available in tablet form. Their unique mechanism of action results in a combination of both bronchodilator and anti-inflammatory effects. While their optimal place in asthma management is still under review, LTRA represent an important advance in asthma pharmacotherapy.
Topics: Acetates; Anti-Asthmatic Agents; Asthma; Asthma, Exercise-Induced; Chronic Disease; Cyclopropanes; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 11085767
DOI: 10.1136/pmj.76.902.767 -
Allergy, Asthma, and Clinical... 2014A significant proportion of patients with chronic urticaria respond inadequately to first line treatment with antihistamines. Leukotreine receptor antagonists (LTRA) are... (Review)
Review
A significant proportion of patients with chronic urticaria respond inadequately to first line treatment with antihistamines. Leukotreine receptor antagonists (LTRA) are also used for chronic urticaria, although firm recommendations on their use are lacking. We performed a systematic review of randomised trials to determine the role of LTRA in treatment of chronic urticaria. A search of PUBMED, EMBASE, SCOPUS, LILACS, the Cochrane Central Register of Controlled Trials, and the Web of Science for relevant randomized control trials or cross over studies yielded 10 eligible studies. The heterogeneity of trials were high, preventing valid meta-analysis of data. Most trials indicated that LTRA are not superior to placebo or antihistamine therapy, while combination therapy of LTRA and antihistamines appear to be more efficacious compared to antihistamine alone. The side effect profile and tolerability of this group of drugs is acceptable. The use of LTRA as monotherapy cannot be recommended. LTRA are effective add-on therapy to anti-histamines, and their use in patients responding poorly to antihistamines is justifiable. Further well designed randomized controlled trials with clear and standardized outcome measures are needed to determine the role of LTRA in chronic urticaria.
PubMed: 24817895
DOI: 10.1186/1710-1492-10-24 -
American Journal of Physiology. Cell... Oct 2019Volume-regulated anion channels (VRACs) encoded by the leucine-rich repeat containing 8 () gene family play critical roles in myriad cellular processes and might...
Volume-regulated anion channels (VRACs) encoded by the leucine-rich repeat containing 8 () gene family play critical roles in myriad cellular processes and might represent druggable targets. The dearth of pharmacological compounds available for studying VRAC physiology led us to perform a high-throughput screen of 1,184 of US Food and Drug Administration-approved drugs for novel VRAC modulators. We discovered the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, pranlukast, as a novel inhibitor of endogenous VRAC expressed in human embryonic kidney 293 (HEK293) cells. Pranlukast inhibits VRAC voltage-independently, reversibly, and dose-dependently with a maximal efficacy of only ~50%. The CysLT1R pathway has been implicated in activation of VRAC in other cell types, prompting us to test whether pranlukast requires the CysLT1R for inhibition of VRAC. Quantitative PCR analysis demonstrated that mRNA is virtually undetectable in HEK293 cells. Furthermore, the CysLT1R agonist leukotriene D4 had no effect on VRAC activity and failed to stimulate G-coupled receptor signaling. Heterologous expression of the CysLT1R reconstituted LTD4-CysLT1R- G-calcium signaling in HEK293 cells but had no effect on VRAC inhibition by pranlukast. Finally, we show the CysLT1R antagonist zafirlukast inhibits VRAC with an IC of ~17 µM and does so with full efficacy. Our data suggest that both pranlukast and zafirlukast are likely direct channel inhibitors that work independently of the CysLT1R. This study provides clarifying insights into the putative role of leukotriene signaling in modulation of VRAC and identifies two new chemical scaffolds that can be used for development of more potent and specific VRAC inhibitors.
Topics: Anions; Cell Size; Chromones; Epithelial Cells; HEK293 Cells; Humans; Indoles; Leukotriene Antagonists; Leukotriene D4; Membrane Proteins; Phenylcarbamates; Receptors, Leukotriene; Signal Transduction; Sulfonamides; Tosyl Compounds
PubMed: 31390227
DOI: 10.1152/ajpcell.00281.2019 -
Frontiers in Pharmacology 2016Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the... (Review)
Review
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the gene, encoding the Met201Val receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca flux and inositol phosphate generation. In addition, the gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.
PubMed: 27990118
DOI: 10.3389/fphar.2016.00299