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Naunyn-Schmiedeberg's Archives of... Mar 2021Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete...
Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGFβ was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition-key drivers of fibrosis-were significantly increased upon TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.
Topics: Actins; Cardiotonic Agents; Cell Differentiation; Cell Line; Collagen Type I; Drug Repositioning; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Humans; Mesalamine; Myocardium; Myofibroblasts; NF-kappa B; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta
PubMed: 33064167
DOI: 10.1007/s00210-020-01998-9 -
Drug Design, Development and Therapy Feb 2011The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative... (Review)
Review
The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.
Topics: Colitis, Ulcerative; Delayed-Action Preparations; Humans; Medication Adherence; Mesalamine; Remission Induction
PubMed: 21448448
DOI: 10.2147/DDDT.S5392 -
Molecules (Basel, Switzerland) Jun 2023Chemoprevention is one of the ways to fight colorectal cancer, which is a huge challenge in oncology. Numerous pieces of evidence indicate that chronic inflammation in... (Review)
Review
Chemoprevention is one of the ways to fight colorectal cancer, which is a huge challenge in oncology. Numerous pieces of evidence indicate that chronic inflammation in the course of Crohn's disease or ulcerative colitis (UC) is a significant cancer risk factor. Epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), including mesalazine, has beneficial effects on colitis-associated colorectal cancer. Mesalazine is a first-line therapy for UC and is also widely used for maintaining remission in UC. Data showed that mesalazine has antiproliferative properties associated with cyclooxygenase (COX) inhibition but can also act through COX-independent pathways. This review summarizes knowledge about mesalazine's molecular mechanisms of action and chemopreventive effect by which it could interfere with colorectal cancer cell proliferation and survival.
Topics: Humans; Mesalamine; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Crohn Disease; Colorectal Neoplasms
PubMed: 37446747
DOI: 10.3390/molecules28135081 -
The Cochrane Database of Systematic... Oct 2017Diverticular disease is a common condition that increases in prevalence with age. Recent theories on the pathogenesis of diverticular inflammation have implicated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Diverticular disease is a common condition that increases in prevalence with age. Recent theories on the pathogenesis of diverticular inflammation have implicated chronic inflammation similar to that seen in ulcerative colitis. Mesalamine, or 5-aminosalicylic acid (5-ASA), is a mainstay of therapy for individuals with ulcerative colitis. Accordingly, 5-ASA has been studied for prevention of recurrent diverticulitis.
OBJECTIVES
To evaluate the efficacy of mesalamine (5-ASA) for prevention of recurrent diverticulitis.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), in the Cochrane Library; Ovid MEDLINE (from 1950 to 9 September 2017); Ovid Embase (from 1974 to 9 September 2017); and two clinical trials registries for ongoing trials - Clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform database (9 September 2017).We also searched proceedings from major gastrointestinal conferences - Digestive Disease Week (DDW), United European Gastroenterology Week (UEGW), and the American College of Gastroenterology (ACG) Annual Scientific Meeting - from 2010 to September 2017. In addition, we scanned reference lists from eligible publications, and we contacted corresponding authors to ask about additional trials.
SELECTION CRITERIA
We included randomised controlled clinical trials comparing the efficacy of 5-ASA versus placebo or another active drug for prevention of recurrent diverticulitis.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as defined by Cochrane. Three review authors assessed eligibility for inclusion. Two review authors selected studies, extracted data, and assessed methodological quality independently. We calculated risk ratios (RRs) for prevention of diverticulitis recurrence using an intention-to-treat principle and random-effects models. We assessed heterogeneity using criteria for Chi (P < 0.10) and I tests (> 50%). To explore sources of heterogeneity, we conducted a priori subgroup analyses. To assess the robustness of our results, we carried out sensitivity analyses using different summary statistics (RR vs odds ratio (OR)) and meta-analytical models (fixed-effect vs random-effects).
MAIN RESULTS
We included in this review seven studies with a total of 1805 participants. We judged all seven studies to have unclear or high risk of bias. Investigators found no evidence of an effect when comparing 5-ASA versus control for prevention of recurrent diverticulitis (31.3% vs 29.8%; RR 0.69, 95% confidence interval (CI) 0.43 to 1.09); very low quality of evidence).Five of the seven studies provided data on adverse events of 5-ASA therapy. The most commonly reported side effects were gastrointestinal symptoms (epigastric pain, nausea, and diarrhoea). No significant difference was seen between 5-ASA and control (67.8% vs 64.6%; RR 0.98, 95% CI 0.91 to 1.06; P = 0.63; moderate quality of evidence), nor was significant heterogeneity observed (I = 0%; P = 0.50).
AUTHORS' CONCLUSIONS
The effects of 5-ASA on recurrence of diverticulitis are uncertain owing to the small number of heterogenous trials included in this review. Rates of recurrent diverticulitis were similar among participants using 5-ASA and control participants. Effective medical strategies for prevention of recurrent diverticulitis are needed, and further randomised, double-blinded, placebo-controlled trials of rigorous design are warranted to specify the effects of 5-ASA (mesalamine) in the management of diverticulitis.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Diverticulitis, Colonic; Humans; Mesalamine; Randomized Controlled Trials as Topic; Secondary Prevention
PubMed: 28973845
DOI: 10.1002/14651858.CD009839.pub2 -
Alimentary Pharmacology & Therapeutics Sep 2009Formation of colonic diverticula, via herniation of the colonic wall, is responsible for the development of diverticulosis and consequently diverticular disease.... (Review)
Review
BACKGROUND
Formation of colonic diverticula, via herniation of the colonic wall, is responsible for the development of diverticulosis and consequently diverticular disease. Diverticular disease can be associated with numerous debilitating abdominal and gastrointestinal symptoms (including pain, bloating, nausea, constipation and diarrhoea).
AIMS
To review the state of treatment for diverticular disease and its complications, and briefly discuss potential future therapies.
METHODS
PubMed and recent conference abstracts were searched for articles describing the treatment of diverticular disease.
RESULTS
Many physicians will recommend alterations to lifestyle and increasing fibre consumption. Empirical antibiotics remain the mainstay of therapy for patients with diverticular disease and rifaximin seems to be the best choice. In severe or relapsing disease, surgical intervention is often the only remaining treatment option. Although novel treatment options are yet to become available, the addition of therapies based on mesalazine (mesalamine) and probiotics may enhance treatment efficacy.
CONCLUSIONS
Data suggest that diverticular disease may share many of the hallmarks of other, better-characterized inflammatory bowel diseases; however, treatment options for patients with diverticular disease are scarce, revolving around antibiotic treatment and surgery. There is a need for a better understanding of the fundamental mechanisms of diverticular disease to design treatment regimens accordingly.
Topics: Anti-Bacterial Agents; Dietary Supplements; Diverticulitis, Colonic; Gastrointestinal Agents; Humans; Mesalamine; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin; Risk Factors; Secondary Prevention
PubMed: 19549266
DOI: 10.1111/j.1365-2036.2009.04072.x -
Canadian Journal of Gastroenterology &... 2016Background. Ulcerative proctitis (UP) is typically treated initially with oral 5-aminosalicylate ("5-ASA"), mesalamine suppository, or mesalamine enema ("UP Rx"). Little... (Comparative Study)
Comparative Study
Background. Ulcerative proctitis (UP) is typically treated initially with oral 5-aminosalicylate ("5-ASA"), mesalamine suppository, or mesalamine enema ("UP Rx"). Little is known about their effectiveness in practice. Methods. Using a US health insurance database, we identified new-onset UP patients between January 1, 2005, and December 31, 2007, based on the following: (1) initiation of UP Rx; (2) endoscopy in prior 30 days resulting in diagnosis of UP; and (3) no prior encounters for ulcerative colitis or Crohn's disease. We examined the incidence of therapy escalation and total costs in relation to initial UP Rx. Results. We identified 548 patients: 327 received mesalamine suppository, 138 received oral 5-ASA, and 83 received mesalamine enema, as initial UP Rx. One-third receiving oral 5-ASA experienced therapy escalation over 12 months, 21% for both mesalamine suppository and enema. Mean cumulative total cost of UP Rx over 12 months was $1552, $996, and $986 for patients beginning therapy with oral 5-ASA, mesalamine enema, and mesalamine suppository, respectively. Contrary to expert recommendations the treatments were often not continued prophylactically. Conclusions. Treatment escalation was common, and total costs of therapy were higher, in patients who initiated treatment with oral 5-ASA. Further study is necessary to assess the significance of these observations.
Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Cost-Benefit Analysis; Databases, Factual; Enema; Female; Humans; Male; Mesalamine; Middle Aged; Proctocolitis; Retrospective Studies; Suppositories; United States; Young Adult
PubMed: 27446860
DOI: 10.1155/2016/6928710 -
Alimentary Pharmacology & Therapeutics Oct 2004This review aims to provide an insight into some of the common pathways involved in the development of colorectal cancer--so-called chromosomal instability and... (Review)
Review
This review aims to provide an insight into some of the common pathways involved in the development of colorectal cancer--so-called chromosomal instability and microsatellite instability. There is both clinical and molecular evidence to show that colorectal cancer development occurs over an extended period of time. Together with a knowledge of the molecular pathogenesis of colorectal cancer, this time window allows physicians to counteract cancer development, a strategy known as chemoprevention. In familial and sporadic colorectal cancer, aspirin, other nonsteroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors have been tested for their ability to reduce polyp and cancer development in clinical studies. In inflammatory bowel disease-related colorectal cancer, evidence from retrospective case-control studies shows that mesalazine (mesalamine) can reduce the development of dysplastic lesions or cancer. Although the mechanisms behind this are incompletely understood, general anti-inflammatory, oxygen scavenger and some pro-apoptotic and cyclo-oxygenase inhibitory activities of mesalazine are thought to be involved. New molecular evidence points to a direct DNA stabilizing effect of mesalazine, resulting in a significant reduction of spontaneous microsatellite mutations.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Chemoprevention; Chromosomal Instability; Colitis; Colorectal Neoplasms; Humans; Mesalamine; Microsatellite Repeats; Precancerous Conditions
PubMed: 15352891
DOI: 10.1111/j.1365-2036.2004.02045.x -
Internal Medicine (Tokyo, Japan) Mar 2023In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A...
In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.
Topics: Female; Humans; Adult; Mesalamine; Myocarditis; Lupus Erythematosus, Systemic; Immunoglobulins, Intravenous; Cyclophosphamide; Antibodies, Antinuclear
PubMed: 35945022
DOI: 10.2169/internalmedicine.9613-22 -
Fundamental & Clinical Pharmacology Feb 2021
Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signalling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuate progression of oxazolone-induced colitis.
Topics: Anti-Inflammatory Agents; Atorvastatin; Colitis; Gene Expression; Humans; Interleukin-10; Interleukin-6; Mesalamine; Oxazolone
PubMed: 33289917
DOI: 10.1111/fcp.12638 -
Alimentary Pharmacology & Therapeutics Jun 2015Budesonide and mesalazine (mesalamine) are commonly used in the medical management of patients with mild to moderate Crohn's disease. (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Budesonide and mesalazine (mesalamine) are commonly used in the medical management of patients with mild to moderate Crohn's disease.
AIM
To assess their comparative efficacy and harm using the methodology of network meta-analysis.
METHODS
A comprehensive search of Medline, Embase, the Cochrane Library and ClinicalTrials.gov, through October 2014, was performed to identify randomised controlled trials (RCTs) that recruited adult patients with active or quiescent Crohn's disease, and compared budesonide or mesalazine with placebo, or against each other, or different dosing strategies of one drug.
RESULTS
Twenty-five RCTs were combined using Bayesian network meta-analysis. Budesonide 9 mg/day, or at higher doses (15 or 18 mg/day), was shown superior to placebo for induction of remission [odds ratio (OR), 2.93; 95% credible interval (CrI), 1.52-5.39, and OR, 3.28; CrI, 1.46-7.55 respectively] and ranks at the top of the hierarchy of the competing treatments. For maintenance of remission, budesonide 6 mg/day demonstrated superiority over placebo (OR, 1.69; CrI, 1.05-2.75), being also at the best ranking position among all compared treatment strategies. No other comparisons (i.e. different doses of mesalazine vs. placebo or budesonide, for induction or maintenance of remission) reached significance. The occurrence of withdrawals due to adverse events was not shown different between budesonide, mesalazine and placebo, in both the induction and maintenance phases.
CONCLUSIONS
Budesonide, at the doses of 9 mg/day, or higher, for induction of remission in active mild or moderate Crohn's disease, and at 6 mg/day for maintenance of remission, appears to be the best treatment choice.
Topics: Adult; Bayes Theorem; Budesonide; Crohn Disease; Humans; Mesalamine; Odds Ratio; Randomized Controlled Trials as Topic
PubMed: 25864873
DOI: 10.1111/apt.13190