CysLT1 x GR

Last update 08 May 2025

Basic Info

Related Targets

CysLT1GR

Drugs associated with CysLT1 x GR

Montelukast Sodium/Mometasone furoate

Target

CysLT1 x GR

Mechanism

CysLT1 antagonists [+1]

Active Org.-

Originator Org.

Merck & Co., Inc.

Active Indication-

Inactive Indication

Asthma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CysLT1 x GR

100 Translational Medicine associated with CysLT1 x GR

0 Patents (Medical) associated with CysLT1 x GR

Literatures (Medical) associated with CysLT1 x GR

01 Aug 2015·Journal of physiology and pharmacology : an official journal of the Polish Physiological Society

Proinflammatory genes expression in granulocytes activated by native proteinase-binding fragments of anti-proteinase 3 IgG.

Article

Author: Kaczor, M ; Sanak, M ; Surmiak, M

The classical pathway of neutrophils activation due to cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) involves specific antigen binding to proteinase-3 and activation of the immunoglobulin G receptors by the constant fragment of the antibody. A requirement for this double signaling was suggested also because proteinase-3 is presented within a complex of NB-1 glycoprotein lacking transmembrane domain. An integrin Mac-1 receptor was postulated to cooperate in neutrophil stimulation by anti-proteinase 3 (anti-PR3). A characteristic profile of transcriptional activation of neutrophils by c-ANCA was described by us previously. We ascertained mRNA expression of neutrophils following stimulation with antigen-binding fragments of native anti-PR3 IgG. Expression of targeted transcripts was compared with our previous results, in which intact anti-PR3 IgG was used. Human neutrophils were isolated from healthy volunteers negative for ANCAs. Antigen-binding fragments of human anti-PR3 were prepared from sera of patients with granulomatosis with polyangiitis. We analyzed reactive oxygen species production and abundance of mRNA of 151 genes by quantitative real time-PCR in neutrophils stimulated with anti-PR3 IgG F(ab)(2). We observed a consistent upregulation of 17 genes (CYSLTR1, HPGD, IL1R1, IL1RL1, MAPK1, MAPK8, NR3C1, PLA2G7, PTGDR, CD302, DNAJB1, F2R, F2RL1, IER3, RAC1, RPL41, PTGER3), whereas other 9 genes were up-regulated only in some donors. No reactive oxygen species production was observed in neutrophils stimulated with anti-PR3 F(ab)(2). Stimulation of neutrophils with F(ab)(2) of anti-PR3 autoantibodies activated cells to a lesser extent than intact IgG. However, several cellular pathways were up-regulated, involving calcium and phosphatidylinositol 3-kinase AKT, nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK) signaling. Interestingly, binding of F(ab)(2) to the PR-3 present on the surface of neutrophil is sufficient for lipid mediators and G-protein pathways activation. Specific F(ab)(2) antibodies against PR-3 seems not a good candidate for decoy therapy of granulomatosis with polyangiitis.

01 Mar 2007·Pharmacogenetics and GenomicsQ4 · MEDICINE

Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast

Q4 · MEDICINE

Article

Author: York, Timothy P. ; Sharma, Sanjay S. ; van den Oord, Edwin J. C. G. ; Anderson, Wayne H. ; Pillai, Sreekumar G. ; Vargas-Irwin, Cristina ; Klotsman, Michael

OBJECTIVEInterindividual clinical response to leukotriene modifiers is highly variable, and less efficacious than inhaled corticosteroids in treating asthma. Genetic variability in 5-lipoxygenase biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers.METHODSUsing data from two clinical trials of 12-week duration, post-hoc analyses were performed in 174 patients randomized to montelukast. Associations between polymorphisms in 10 candidate genes (ALOX5, ALOX5AP, LTC4S, CYSLTR1, CYSLTR2, PLA2G4A, CYP2C9, CYP3A4, ADRB2, and NR3C1) and response to montelukast were modeled using change in morning peak expiratory flow and forced expiratory volume in 1 s (FEV1) to define the response phenotype.RESULTSIn our sample, eight out of 25 markers in 10 candidate genes were statistically associated with response to montelukast, with an estimated proportion of false discoveries of 16%. The strongest statistical evidence of clinically relevant pharmacogenetic effects peak expiratory flow were identified in CYSLTR2 (rs91227 and rs912278; P=0.02 and P=0.02, respectively) and ALOX5 (rs4987105 and rs4986832; P=0.01 and P=0.01, respectively). Patients with these variant genotypes, found in roughly 10-13% of patients, had an 18-25% improvement in peak expiratory flow. In contrast, the majority of patients with the wild-type alleles had only a marginal (8-10%) improvement.CONCLUSIONSThe overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.

01 Jan 2007·Journal of Pharmacological SciencesQ3 · MEDICINE

Gastroprotective and Antioxidant Effects of Montelukast on Indomethacin-Induced Gastric Ulcer in Rats

Q3 · MEDICINE

ArticleOA

Author: Dengiz, Gunnur Ozbakis ; Odabasoglu, Fehmi ; Suleyman, Halis ; Halici, Zekai ; Cadirci, Elif

Montelukast, a selective reversible cysteinyl leukotriene D(4)-receptor (LTD(4) receptor) antagonist, is used in the treatment of asthma. We have investigated alterations in the glutathione (GSH) and activity levels of antioxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione reductase (GR)] and myeloperoxidase (MPO), as markers of the ulceration process following oral administration of montelukast, lansoprazole, famotidine, and ranitidine, respectively, in rats with indomethacin-induced ulcers. In the present study, we found that 1) montelukast, lansoprazole, famotidine, and ranitidine all reduced the development of indomethacin-induced gastric damage, with this reduction occurring at a greater magnitude for montelukast, famotidine, and lansoprazole than for ranitidine; 2) montelukast and ranitidine both alleviated increases in the activity levels of CAT and GST enzymes resulting from gastric injury; 3) montelukast and ranitidine both ameliorated depressions in the GSH and activity levels of SOD and GR enzymes caused by indomethacin administration; and 4) all doses of montelukast, lansoprazole, and ranitidine decreased amplification of MPO activity resulting from induced gastric injuries. These results suggest that the gastroprotective effects of montelukast on indomethacin-induced ulcerations can be attributed to its ameliorating effect on oxidative damage and MPO activity.

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