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ACS Bio & Med Chem Au Jun 2023Tumor necrosis factor (TNF) plays an important role in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn's disease. The...
Tumor necrosis factor (TNF) plays an important role in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn's disease. The biological effects of TNF are mediated by binding to TNF receptors, TNF receptor 1 (TNFR1), or TNF receptor 2 (TNFR2), and this coupling makes TNFR1-specific inhibition by small-molecule therapies essential to avoid deleterious side effects. Recently, we engineered a time-resolved fluorescence resonance energy transfer biosensor for high-throughput screening of small molecules that modulate TNFR1 conformational states and identified zafirlukast as a compound that inhibits receptor activation, albeit at low potency. Here, we synthesized 16 analogues of zafirlukast and tested their potency and specificity for TNFR1 signaling. Using cell-based functional assays, we identified three analogues with significantly improved efficacy and potency, each of which induces a conformational change in the receptor (as measured by fluorescence resonance energy transfer (FRET) in cells). The best analogue decreased NF-κB activation by 2.2-fold, IκBα efficiency by 3.3-fold, and relative potency by two orders of magnitude. Importantly, we showed that the analogues do not block TNF binding to TNFR1 and that binding to the receptor's extracellular domain is strongly cooperative. Despite these improvements, the best candidate's maximum inhibition of NF-κB is only 63%, leaving room for further improvements to the zafirlukast scaffold to achieve full inhibition and prove its potential as a therapeutic lead. Interestingly, while we find that the analogues also bind to TNFR2 in vitro, they do not inhibit TNFR2 function in cells or cause any conformational changes upon binding. Thus, these lead compounds should also be used as reagents to study conformational-dependent activation of TNF receptors.
PubMed: 37363080
DOI: 10.1021/acsbiomedchemau.2c00048 -
Journal of the National Medical... Aug 1999The three leukotriene (LT) modifiers approved for use in the United States, zileuton, zafirlukast, and montelukast, are the first new class of therapeutic agents to be... (Review)
Review
The three leukotriene (LT) modifiers approved for use in the United States, zileuton, zafirlukast, and montelukast, are the first new class of therapeutic agents to be introduced in 20 years for the treatment of asthma. These agents are referred to as leukotriene modifiers and have clearly demonstrated the ability to ameliorate bronchoconstriction and indices of airway edema and abnormal mucus production as observed in clinical trials. These agents have been shown to improve airflow, reduce the need for an inhaled bronchodilator, and improve nocturnal awakenings and asthma symptom scores appreciably. When combined with inhaled corticosteroid therapy, they may either provide additional improvement in efficacy or permit the reduction of the dose of inhaled corticosteroid necessary for effective therapy. Physicians should be familiar with these agents and consider them for use in their practice, in conjunction with current asthma management guidelines.
Topics: Acetates; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Asthma, Exercise-Induced; Cyclopropanes; Drug Evaluation; Humans; Hydroxyurea; Indoles; Leukotriene Antagonists; Phenylcarbamates; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds; Treatment Outcome
PubMed: 12653390
DOI: No ID Found -
Multidisciplinary Respiratory Medicine 2014The purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma... (Review)
Review
BACKGROUND AND OBJECTIVE
The purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma exacerbations, but the effect size of zafirlukast for asthma exacerbations of various severity is not systematically explored.
METHODS
Randomized controlled trials were searched in PubMed Central, Web of Science, and Embase, where zafirlukast prevented asthma exacerbations in adults. The primary outcome was asthma exacerbations, the secondary outcomes were asthma exacerbations requiring systemic corticosteroids and emergency visits, respectively. Odds ratio (OR) with 95% confidence intervals (CI) were pooled.
RESULTS
Twelve trials were identified. As first-line therapy, compared to those having placebo, the patients with chronic asthma receiving zafirlukast experienced statistically lower asthma exacerbations (OR = 0.68, 95% CI = [0.45, 1.00]), but it was not found that zafirlukast was superior to placebo in asthma exacerbations requiring systemic corticosteroids (OR = 0.76, 95% CI = [0.45, 1.29]). Furthermore, zafirlukast was inferior to ICs in asthma exacerbations (OR = 2.11, 95% CI = [1.35, 3.30]) and requiring systemic corticosteroids (OR = 3.71, 95% CI = [1.82, 7.59]). As add-on therapy, zafirlukast was not superior to placebo in asthma exacerbations (OR =0.99, 95% CI = [0.54, 1.81] and requiring emergency visits (OR = 0.72, 95% CI = [0.18, 2.99]). Intriguingly, there was not a significant difference in asthma exacerbations between zafirlukast and ICs (OR = 1.12, 95% CI = [0.53, 2.34]).
CONCLUSIONS
Our study suggests that zafirlukast, as the first-line therapy, significantly reduces mild to moderate but not severe asthma exacerbations. In the add-on regimen, zafirlukast could not reduce asthma exacerbations, which would perhaps result from small sample size and needs to be further studied.
PubMed: 24936302
DOI: 10.1186/2049-6958-9-30 -
Archives of Plastic Surgery Sep 2015Capsular contracture is the most common complication following implant based breast surgery and is one of the most common reasons for reoperation. Therefore, it is... (Review)
Review
Capsular contracture is the most common complication following implant based breast surgery and is one of the most common reasons for reoperation. Therefore, it is important to try and understand why this happens, and what can be done to reduce its incidence. A literature search using the MEDLINE database was conducted including search terms 'capsular contracture breast augmentation', 'capsular contracture pathogenesis', 'capsular contracture incidence', and 'capsular contracture management', which yielded 82 results which met inclusion criteria. Capsular contracture is caused by an excessive fibrotic reaction to a foreign body (the implant) and has an overall incidence of 10.6%. Risk factors that were identified included the use of smooth (vs. textured) implants, a subglandular (vs. submuscular) placement, use of a silicone (vs. saline) filled implant and previous radiotherapy to the breast. The standard management of capsular contracture is surgical via a capsulectomy or capsulotomy. Medical treatment using the off-label leukotriene receptor antagonist Zafirlukast has been reported to reduce severity and help prevent capsular contracture from forming, as has the use of acellular dermal matrices, botox and neopocket formation. However, nearly all therapeutic approaches are associated with a significant rate of recurrence. Capsular contracture is a multifactorial fibrotic process the precise cause of which is still unknown. The incidence of contracture developing is lower with the use of textured implants, submuscular placement and the use of polyurethane coated implants. Symptomatic capsular contracture is usually managed surgically, however recent research has focussed on preventing capsular contracture from occurring, or treating it with autologous fat transfer.
PubMed: 26430623
DOI: 10.5999/aps.2015.42.5.532 -
Iranian Journal of Basic Medical... 2023To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats.
OBJECTIVES
To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats.
MATERIALS AND METHODS
Thirty-two male Wistar rats were included in this study and randomly divided into 4 equal groups (n=8); control (normal) group, indomethacin group, Ranitidine group, and Zafirlukast group. Indomethacin was given as a single oral dose of (20 mg/kg) for the induction of ulcers. Both ranitidine (50 mg/kg) and zafirlukast (20 mg/ kg) were given orally for seven days after inducing the ulcer. All animals were sacrificed by an overdose of anesthesia at the end of the experimental period and their gastric tissues have been collected for histopathological and biological assay. Levels of prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARS), and interleukin 1β (IL-1β ) were measured as well as a histopathological study to evaluate the effect of zafirlukast on gastric tissues.
RESULTS
Significant abnormalities were found in both the histological and biochemical parameters of the indomethacin group reflecting the changes seen with gastric ulcers. Significant improvement was found in the Zafirlukast group as reflected by the morphological improvement seen in the gastric tissues. An effect that was associated with an increase in the PGE2 levels along with reductions in IL-1β expression and TBARS concentrations.
CONCLUSION
As per the results of this study, zafirlukast shows promising gastroprotective properties possibly through enhancement of PGE2 levels as well as having anti-inflammatory and anti-oxidant properties.
PubMed: 37396939
DOI: 10.22038/IJBMS.2023.71491.15540 -
Bioengineered Dec 2021Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical...
Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma. In this study, we investigate whether treatment with Zafirlukast could alleviate Docetaxel-induced cytotoxicity in hepatocytes. Our results indicate that Zafirlukast mitigated Docetaxel-induced toxicity in LO-2 hepatocytes. Firstly, Zafirlukast reduced the production of 8-hydroxy-2p-deoxyguanosine (8-OHdG) and increased the levels of reduced glutathione (GSH) against Docetaxel. Secondly, Zafirlukast elevated the levels of mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP). Thirdly, Zafirlukast prevented Docetaxel-induced release of lactate dehydrogenase (LDH) and increased cell viability of LO-2 hepatocytes against Docetaxel. We also found that Zafirlukast ameliorated Docetaxel-induced apoptosis by reducing Caspase-3 and Caspase-9 activity. Mechanistically, our results demonstrate that Zafirlukast inhibited the activation of NOD-like receptor protein 3 (NLRP3), mediated by SIRT1. Based on these findings, we conclude that the administration of Zafirlukast might have a protective effect against Docetaxel-induced cytotoxicity in hepatocytes.
Topics: Animals; Cell Death; Cell Line; Docetaxel; Gene Silencing; Hepatocytes; Humans; Indoles; Inflammasomes; Membrane Potential, Mitochondrial; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phenylcarbamates; Sirtuin 1; Sulfonamides
PubMed: 34787067
DOI: 10.1080/21655979.2021.2005895 -
Clinical Gastroenterology and... May 2010Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early... (Review)
Review
BACKGROUND & AIMS
Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early detection of hepatotoxicity and for developing reliable, interpretable literature. We assessed the extent to which published case reports of drug-induced liver disease include sufficient clinical data for interpreting the cause of toxicity.
METHODS
We developed a list of 42 predetermined, specific minimal elements necessary in evaluating causality of drug-induced liver injury. We then analyzed 97 published case reports or series studies of hepatotoxicity from 6 drugs (from 3 classes): amoxicillin/clavulanic acid (n = 35), troglitazone (n = 32), rosiglitazone (n = 10), pioglitazone (n = 8), zafirlukast (n = 8), and montelukast (n = 4).
RESULTS
Patient age, sex, primary disease, and drug name were reported in most, if not all, published case reports. However, many elements were underreported; some publications did not mention initial bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others provided vague descriptions of how certain diagnoses were excluded, that is, tests for hepatitis A, B, and C were negative. Data on abnormal results from serial liver tests frequently were absent. Exclusions of competing viral etiologies were reported in less than 50% of the studies.
CONCLUSIONS
Reports of drug-induced liver diseases often do not provide the data needed to determine the causes of the adverse effects. Efforts to promote and include a list of essential diagnostic elements in research articles could increase the quality and clinical utility of published case reports of drug toxicity.
Topics: Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Publications
PubMed: 20170750
DOI: 10.1016/j.cgh.2010.02.008 -
International Journal of Molecular... Dec 2023Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was...
Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the genes' CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the and genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = -0.4, = 2.6 × 10; R = -0.21, = 0.015) and cg21886367 (R = -0.45, = 7.3 × 10; R = -0.24, = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan-Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated . To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Line, Tumor; Epigenomics; Receptors, Leukotriene
PubMed: 38139172
DOI: 10.3390/ijms242417343 -
British Journal of Pharmacology Feb 2021Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet...
BACKGROUND AND PURPOSE
Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet responses, aggregation, adhesion and thrombus formation. Recently, the therapeutic potential of TI inhibition has been recognised and drug-development technologies were used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin, is known to be nephrotoxic, which prohibits its systemic therapeutic usage.
EXPERIMENTAL APPROACH
We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. A total of 3,641 compounds were screened for inhibitory effects on the redox activity of ERp5, protein disulphide isomerase (PDI), ERp57, ERp72 and thioredoxin in an insulin turbidity assay. Of the lead compounds identified, zafirlukast was selected for further investigation.
KEY RESULTS
When applied to platelets, zafirlukast diminished platelet responses in vitro. Zafirlukast was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since TIs are known to modulate adhesion receptor function, we explored the effects of zafirlukast on cell migration. This was inhibited independently of cysteinyl LT receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface.
CONCLUSION AND IMPLICATIONS
We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide-ranging effects on platelet function, thrombosis and integrin-mediated cell migration. Zafirlukast is antithrombotic but does not cause bleeding.
Topics: Animals; Bleeding Time; Blood Platelets; Indoles; Mice; Phenylcarbamates; Sulfhydryl Compounds; Sulfonamides; Thrombosis
PubMed: 33080041
DOI: 10.1111/bph.15291 -
The Cochrane Database of Systematic... 2000Leukotriene receptor antagonists are a new class of drug that were initially identified for use in asthma. As they have an effect on neutrophil mediated inflammation,... (Review)
Review
BACKGROUND
Leukotriene receptor antagonists are a new class of drug that were initially identified for use in asthma. As they have an effect on neutrophil mediated inflammation, they may be of benefit in bronchiectasis.
OBJECTIVES
To determine whether leukotriene receptor antagonists have any additive benefit over and above conventional treatment for bronchiectasis (usually consisting of antibiotics and postural drainage).
SEARCH STRATEGY
The Cochrane Airways Group clinical trials register derived from MEDLINE, EMBASE and hand searching of major journals was searched using the terms:Bronchiec* AND leukotrien* OR anti-leuk* OR cysteinyl, Bronchiec* AND monteluk*, Bronchiec* AND zafirluk*
SELECTION CRITERIA
Only randomised, controlled trials were considered
DATA COLLECTION AND ANALYSIS
The results of searches were analysed by both authors
MAIN RESULTS
No randomised, controlled trials were identified
REVIEWER'S CONCLUSIONS
Further research is required to establish any benefit from the use of leukotriene antagonists in bronchiectasis.
Topics: Acetates; Bronchiectasis; Clinical Trials as Topic; Cyclopropanes; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Placebos; Quinolines; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 11034744
DOI: 10.1002/14651858.CD002174