Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis.
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ABSTRACT:
SUBMITTER: Lands LC
PROVIDER: S-EPMC6733592 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
Publications
Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis.
Lands Larry C LC Stanojevic Sanja S
The Cochrane database of systematic reviews 20190909
<h4>Background</h4>Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. This is an update of a previously published review.<h4>Objectives</h4>To assess the effectiveness of treatment with oral non-steroidal anti-inflammatory drugs in cystic fibrosis.<h4>Search methods</h4>We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials R ...[more]
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Project description:Background and objectivesNonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with AKI. Their association with nephrotic syndrome has not been systematically studied. This study aimed to assess the risk of nephrotic syndrome associated with NSAID use.Design, setting, participants, & measurementsA matched case-control study was performed in the UK primary care database. Cases were patients with a first diagnosis of nephrotic syndrome and controls were those without nephrotic syndrome. NSAID exposure (grouped either based on cyclooxygenase enzyme selectivity and chemical groups) was classified as either current (use at the nephrotic syndrome diagnosis date and corresponding date in the control group), recent, or past use. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis.ResultsWe included 2620 cases and 10,454 controls. Compared with non-use, current use of 15-28 days and >28 days of conventional NSAIDs was associated with a higher relative risk of nephrotic syndrome: adjusted OR, 1.34; 95% CI, 1.06 to 1.70, and OR, 1.42; 95% CI, 0.79 to 2.55, respectively. Also, recent use (discontinuation 1-2 months before nephrotic syndrome diagnosis date; OR, 1.55; 95% CI, 1.11 to 2.15) and past use (discontinuation 2 months-2 years; OR, 1.24; 95% CI, 1.07 to 1.43), but not current use of <15 days (OR, 0.78; 95% CI, 0.46 to 1.31) nor past use (discontinuation >2 years; OR, 0.96; 95% CI, 0.85 to 1.09) were associated with a higher relative risk of nephrotic syndrome as well as past use of selective COX-2 inhibitors (discontinuation 2-24 months; OR, 1.24; 95% CI, 0.98 to 1.58). Categorization based on chemical groups showed that acetic acid and propionic acid derivatives were associated with a higher risk of nephrotic syndrome.ConclusionsThe use of conventional NSAIDs was associated with a higher risk of nephrotic syndrome starting from at least 2 weeks of exposure, as well as for recent and past exposure up to 2 years before the diagnosis of nephrotic syndrome. This higher risk appeared mainly attributable to acetic acid and propionic acid derivatives.
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Project description:BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies.Methodology/principal findingsThe analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-α serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the -OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-α levels in vivo.Conclusion/significanceThese findings demonstrate the potential of 2OAA as a NSAID.
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Project description:AimsThe Standard care vs. Celecoxib Outcome Trial (SCOT) found similar risk of cardiovascular events with traditional non-steroidal anti-inflammatory drugs (NSAIDs) and the cyclooxygenase-2-selective drug celecoxib. While pre-clinical work has suggested roles for vascular and renal dysfunction in NSAID cardiovascular toxicity, our understanding of these mechanisms remains incomplete. A post hoc analysis of the SCOT cohort was performed to identify clinical risk factors and circulating biomarkers of cardiovascular events in NSAID users.Methods and resultsWithin SCOT (7295 NSAID users with osteoarthritis or rheumatoid arthritis), clinical risk factors associated with cardiovascular events were identified using least absolute shrinkage and selection operator regression. A nested case-control study of serum biomarkers including targeted proteomics was performed in individuals who experienced a cardiovascular event within 1 year (n = 49), matched 2:1 with controls who did not (n = 97). Risk factors significantly associated with cardiovascular events included increasing age, male sex, smoking, total cholesterol:HDL ratio ≥5, and aspirin use. Statin use was cardioprotective [odds ratio (OR) 0.68; 95% confidence interval (CI) 0.46-0.98]. There was significantly higher immunoglobulin (Ig)G anti-malondialdehyde-modified LDL (MDA-LDL), asymmetric dimethylarginine (ADMA), and lower arginine/ADMA. Targeted proteomic analysis identified serum growth differentiation factor 15 (GDF-15) as a candidate biomarker [area under the curve of 0.715 (95% CI 0.63-0.81)].ConclusionGrowth differentiation factor 15 has been identified as a candidate biomarker and should be explored for its mechanistic contribution to NSAID cardiovascular toxicity, particularly given the remarkable providence that GDF-15 was originally described as NSAID-activated gene-1.
| S-EPMC11630077 | biostudies-literature
Project description:BackgroundNon-steroidal anti-inflammatory drug (NSAID) use is associated with decreased risk of some cancers. NSAID use modulates the epigenetic profile of normal colonic epithelium and may reduce risk of colon cancer through this pathway; however, the effect of NSAID use on the DNA methylation profile of other tissues including whole blood has not yet been examined.FindingsUsing the Sister Study cohort, we examined the association between NSAID usage and whole genome methylation patterns in blood DNA. Blood DNA methylation status across 27,589 CpG sites was evaluated for 871 women using the Illumina Infinium HumanMethylation27 Beadchip, and in a non-overlapping replication sample of 187 women at 485,512 CpG sites using the Infinium HumanMethylation450 Beadchip. We identified a number of CpG sites that were differentially methylated in regular, long-term users of NSAIDs in the discovery group, but none of these sites were statistically significant in our replication group.ConclusionsWe found no replicable methylation differences in blood related to NSAID usage. If NSAID use does effect blood DNA methylation patterns, differences are likely small.
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| S-EPMC7869531 | biostudies-literature
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| S-EPMC7438775 | biostudies-literature
Project description:Neutrophil elastase (NE) is a major protease in the airways of patients with cystic fibrosis (CF) that activates airway inflammation by several mechanisms. NE stimulates epithelial toll like receptors (TLR) resulting in cytokine upregulation and release, upregulates MUC5AC, a major airway mucin, degrades both phagocytic receptors and opsonins resulting in both neutrophil and macrophage phagocytic failure, generates oxidative stress via extracellular generation and uptake of heme free iron, and activates other proteases. Altogether, these mechanisms create a significant inflammatory challenge that impairs innate immune function and results in airway remodeling. Currently, a major gap in our therapeutic approach to CF lung disease is the lack of an effective therapeutic strategy targeting active NE and its downstream pro-inflammatory sequelae. Polysulfated glycosaminoglycans (GAGs) are potent anti-elastase drugs that have additional anti-inflammatory properties. Heparin is a prototype of a glycosaminoglycan with both anti-elastase and anti-inflammatory properties. Heparin inhibits NE in an allosteric manner with high potency. Heparin also inhibits cathepsin G, blocks P-selectin and L-selectin, hinders ligand binding to the receptor for advanced glycation endproducts, and impedes histone acetyltransferase activity which dampens cytokine transcription and High Mobility Group Box 1 release. Furthermore, nebulized heparin treatment improves outcomes for patients with chronic obstructive pulmonary disease (COPD), asthma, acute lung injury and smoke inhalation. However, the anticoagulant activity of heparin is a potential contraindication for this therapy to be developed for CF lung disease. Therefore, modified heparins and other GAGs are being developed that retain the anti-elastase and anti-inflammatory qualities of heparin with minimal to no anticoagulant activity. The modified heparin, 2-O, 3-O desulfated heparin (ODSH), maintains anti-elastase and anti-inflammatory activities in vitro and in vivo, and has little residual anticoagulant activity. Heparan sulfate with O-sulfate residues but not N-sulfate residues blocks allergic asthmatic inflammation in a murine model. Polysulfated hyaluronic acid abrogates allergen- triggered rhinosinusitis in a murine model. Finally, nonsaccharide glycosaminoglycan mimetics with specific sulfate modifications can be designed to inhibit NE activity. Altogether, these novel GAGs or GAG mimetics hold significant promise to address the unmet need for inhaled anti-elastase and anti-inflammatory therapy for patients with CF.
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| S-EPMC5557093 | biostudies-other
Project description:Dysbiosis, an imbalance of intestinal flora, can cause serious conditions such as obesity, cancer, and psychoneurological disorders. One cause of dysbiosis is inflammation. Ulcerative enteritis is a side effect of non-steroidal anti-inflammatory drugs (NSAIDs). To counteract this side effect, we proposed the concurrent use of histamine H2 receptor antagonists (H2RA), and we examined the effect on the intestinal flora. We generated a murine model of NSAID-induced intestinal mucosal injury, and we administered oral H2RA to the mice. We collected stool samples, compared the composition of intestinal flora using terminal restriction fragment length polymorphism, and performed organic acid analysis using high-performance liquid chromatography. The intestinal flora analysis revealed that NSAID [indomethacin (IDM)] administration increased Erysipelotrichaceae and decreased Clostridiales but that both had improved with the concurrent administration of H2RA. Fecal levels of acetic, propionic, and n-butyric acids increased with IDM administration and decreased with the concurrent administration of H2RA. Although in NSAID-induced gastroenteritis the proportion of intestinal microorganisms changes, leading to the deterioration of the intestinal environment, concurrent administration of H2RA can normalize the intestinal flora.
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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are among the frontline treatments for inflammation and pain. Hydrogen sulfide (H2S) and related persulfide (RS-SH) are important mediators of antioxidant response and protect cells from oxidative stress. Hybrids of these pharmacological agents have shown promise in clinical trials and are superior to the parent NSAID. Here, we report a new class of NSAID-H2S hybrids, where a strategic placement of a sulfhydryl group adjacent to a carbonyl of a NSAID facilitates the enzymatic generation of H2S. We show that α-mercapto-nabumetone, a derivative of the clinical drug nabumetone, is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST), an enzyme involved in H2S biosynthesis. The key step of 3-MST catalysis is the cleavage of a C-S bond adjacent to a carbonyl group, which generates an enolate and 3-MST persulfide, which in turn is cleaved under reducing conditions to generate H2S. Guided by a molecular docking study with 3-MST, we prepared two mercapto-nabumetone derivatives, protected as their thioacetates. In the presence of 3-MST, both mercapto-nabumetone derivatives generated H2S and the NSAID in a nearly quantitative yield, produced glutathione persulfide (GS-SH), an important mediator of cellular antioxidant response, and permeated cells to generate H2S. Lastly, to gain insights into the scope of this strategy, we prepared mercapto-NSAID derivatives containing a carboxylic acid. We found that the propensity to generate H2S depended on the nature of the enol that is produced during the transformation of the mercapto-NSAID into the parent NSAID. This offers new insights into 3-MST catalysis and how reaction outcomes can be modulated by the keto-enol equilibrium. Taken together, the atom economical transformation of a clinical NSAID with one strategically placed sulfhydryl group to generate H2S presents new opportunities to enhance the properties of NSAIDs through participation in endogenous H2S biosynthesis.
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