ArticleLiterature Review

NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs

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Abstract

NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse events in different body systems, although the major, most frequent events occur in the upper and lower gastrointestinal (GI) tracts. Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms. Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been extensively investigated, and some were approved for human use. Celecoxib demonstrated its safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal models and humans they showed some GI advantages over the parent NSAID compounds, but none obtained regulatory approval or were further investigated. Hydrogen sulfide-releasing NSAIDs are currently under clinical development, and more data are needed before clinical use. Alternative therapies, such as modulating gut microbiota, are being explored. Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.

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... В настоящее время нестероидные противовоспалительные препараты (НПВП) являются одними из самых популярных безрецептурных препаратов во всем мире, составляя около 5 % всех назначаемых лекарств [1]. Несмотря на широкое терапевтическое применение, НПВП обладают многочисленными побочными эффектами, наиболее распространенные из которых -воспалительные и язвенные заболевания желудочно-кишечного тракта [2,3]. ...
... Предлагаемые стратегии снижения побочных эффектов НПВП, как, например, повышение селективности действия [2,3,5], использование новых лекарственных форм [6,7], а также комбинированного использования совместно с препаратами, снижающими секреторную активность париетальных клеток желудка [8,9], пока мало эффективны. ...
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INTRODUCTION. Indomethacin is a derivative of indoleacetic acid and has anti-inflammatory, analgesic and antipyretic effects. However, the results of numerous studies show that indomethacin, like many other nonsteroidal anti-inflammatory drugs (NSAIDs), have an inhibitory effect on the viability and functional activity of enterocytes. In this regard, the search for new ways to reduce the severity of side effects from the use of NSAIDs remains relevant. One of these approaches may be to enrich patients’ diets with non-drug biologically active compounds, including proteins. However, the effect of dietary proteins and biologically active peptides on NSAID-induced damage to the wall of the small intestine and stomach has not been sufficiently studied. AIM. To evaluate the ability of a collagen-containing dietary supplement to protect human duodenal epithelial cells (HuTu-80 line) from indomethacin-induced damage. MATERIALS AND METHODS. The composite collagen-containing hydrogel was provided by «FIRST ALIVE COLLAGEN» LLC (Russia) and is a registered dietary supplement. The work used a commercial culture of human skin fibroblast cells and human duodenal epithelial cells (line HuTu-80). The viability of intestinal cells and fibroblasts was assessed using light and fluorescence microscopy and flow cytometry methods. RESULTS AND DISCUSSION. It has been established that indomethacin inhibits cell growth, causes apoptosis and death of enterocytes, and also leads to the accumulation of cells in the S-phase, which indicates a disruption in the regulation of the cell cycle. It was revealed that collagen hydrogel prevents cell death caused by indomethacin and reduces the number of apoptotic cells in the population. The protective effect of collagen hydrogel is characterized by normalization of the cell cycle of enterocytes and restoration of their growth and proliferative activity. CONCLUSION. Thus, collagen hydrogel, in vitro, is able to reduce the pathogenic effect of indomethacin on human intestinal epithelial cells. The protective effect of collagen hydrogel is characterized by maintaining viability, inhibiting apoptotic processes, and maintaining cell cycle stability. The results obtained indicate the prospects of using a dietary supplement based on a composite collagen hydrogel as a prophylactic agent to reduce the risk of NSAID-associated gastrointestinal diseases. However, to confirm the therapeutic effectiveness of the dietary supplement, further research is necessary, both using experimental animal modeling of NSAID-associated diseases of the human gastrointestinal tract, and clinical studies.
... Cyclooxygenase inhibitor is frequently used to treat inflammation. However, oxidative stress, one of their adverse effects, can result in stomach ulcers (García-Rayado et al. 2018). Researchers are looking at substances with anti-inflammatory and antioxidant traits to address this issue and enhance therapeutic effects (García-Rayado et al. 2018;Abdulaziz and Mustafa 2022a). ...
... However, oxidative stress, one of their adverse effects, can result in stomach ulcers (García-Rayado et al. 2018). Researchers are looking at substances with anti-inflammatory and antioxidant traits to address this issue and enhance therapeutic effects (García-Rayado et al. 2018;Abdulaziz and Mustafa 2022a). Exciting options in this area include coumarin and its related derivatives. ...
Article
Phytocoumarins exhibit a range of biological activities, including antibacterial, anti-inflammatory, antiradical, oncolytic, and reduction of monoamine oxidase B effects. These compounds are frequently used by researchers to develop novel, entirely or partially laboratory-made pharmaceutical medicines derived from coumarin. Several of these medications are hybrid chemicals with different pharmacological effects that were purposefully created by applying the molecular hybridization concept. The combinations of compounds exhibit multifunctional characteristics, making them attractive options for developing therapies against complex diseases like cancer, Alzheimer's disease, dysmetabolic syndrome, AIDS, plasmodium infection, and cardiovascular disorders. This study summarizes findings on the development of various coumarin hybrids, groups them based on prospective therapeutic uses, and makes recommendations about possible structure-activity relationships. We searched a number of database servers, including PubMed, Scopus, Google Scholar, Web of Science, and others. Following a sieve, we eventually found and incorporated 45 relevant papers that were released between 2004 and the beginning of 2024. In order to help medicinal chemists cure a range of human ailments, the authors set out to create and produce highly efficient, tailored coumarin hybrid molecules.
... These drugs inhibit the cyclooxygenase (COX) 1 and 2 blocking the prostaglandins synthesis; this reduces the sensitization and excitation of the peripheral nociceptors [21]. ...
... It is important to say COX-1 is present in most of the tissues; it participates in the formation of relevant prostaglandins (PG) to regulate the hemostasis, kidney integrity, platelet function, protection of gastric mucosa (PG12), and so on. Meanwhile, COX-2 is inducible especially in inflammatory processes [21,22]. ...
Chapter
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The temporomandibular joint (TMJ) is an important structure of the facial skeleton and is an important source of pain when inflammatory processes are occurring in it. It is located inferior the skull base, above the neck and anterior to the ear. The principal components include: bone structures, ligaments, intrarticular content, and muscles. Because of the anatomic relations, the temporomandibular joint affections can produce a limitation of the masticatory function and express headache of dental, sinusal, nervous, or muscular type. For this reason, the patients require multiple medical and dental specialties in the search of a solution for the current illness. The myofascial pain refers to a chronic, inflammatory condition of the TMJ and the muscular system of the head and neck. It has an important demand in the health sector, can incapacitate significantly the quality of life of the patients, and requires an appropriate diagnosis and treatment. The aim of this chapter is to guide the clinical practice in the etiology, diagnosis, prevention, and treatment of the myofascial pain as a clinical presentation of the temporomandibular dysfunction.
... Cyclooxygenase inhibitor are frequently used to treat inflammation. However, oxidative stress, one of their adverse effects, can result in stomach ulcers (García-Rayado et al., 2018). Researchers are looking at substances with anti-inflammatory and antioxidant traits to address this issue and enhance therapeutic effects (Noora Thamer NooraThamer Noora Thamer NooraThamer Abdulaziz and Mustafa, 2022; Noora T. NooraT. ...
... Researchers are looking at substances with anti-inflammatory and antioxidant traits to address this issue and enhance therapeutic effects (Noora Thamer NooraThamer Noora Thamer NooraThamer Abdulaziz and Mustafa, 2022; Noora T. NooraT. García-Rayado et al., 2018). Exciting options in this area include coumarin and its related derivatives. ...
Article
Phyto-coumarins demonstrate diverse biological actions, encompassing antiradical, anti-inflammatory, onco-lytic, monoamine oxidase B (MAOB) suppression, and antibacterial properties. Researchers commonly employ these molecules to evolve innovative, fully or partially laboratory-made, medicinal products stemming from coumarin. Many of these medicines are crossbreed chemical compounds that have been strategically constructed using the molecular hybridization principle, resulting in diverse pharmacological actions. The mixtures of compounds possess multifunctional properties, rendering them promising candidates for therapeutic development in treating intricate ailments such as malignant growth, Alzheimer's disease, dysmetabolic syndrome, acquired immune deficiency syndrome (AIDS), plasmodium infection, and cardiovascular conditions. This review compiles research studies about the advancement of several coumarin hybrids, classifies them according to their therapeutic applications, and suggests potential structure-activity correlations. We conducted searches across several databases, including Web of Science, Google Scholar, PubMed, and Scopus. After sieving, we ultimately identified and included 45 pertinent studies published between 2004 and the middle of 2023. The authors aimed to support medicinal chemists in developing and producing highly effective, targeted coumarin hybrid compounds to treat various human illnesses.
... Several studies have explored the epidemiological and clinical factors associated with duodenal ulcer perforation, with findings indicating that male patients, older age, and lower socioeconomic status are major contributors to the incidence of perforation [12,13] . ~ 109 ~ The use of NSAIDs and corticosteroids has been found to significantly increase the risk of perforation in individuals with pre-existing ulcers or chronic gastric irritation [14,15] . Furthermore, untreated H. pylori infection is a major risk factor, emphasizing the importance of eradication therapy in preventing complications [16] . ...
... Endoscopic studies have estimated the prevalence of inflammation in 60-70% of chronic users, blood loss and anemia in 30%, and mucosal ulceration in 30-40%. [5,6] Notably, there is a wide range of inter-individual variation in response to NSAIDsin both safety and efficacywhich cannot be fully explained by genetic differences in host metabolizing enzymes. [7,8] While the mechanisms underlying NSAID-induced gastropathy are well-established, [9][10][11][12][13][14][15][16][17] NSAID-induced enteropathy remains poorly understood, and there is still no treatment or preventative solution for the intestinal symptoms. ...
Preprint
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought mainly due to inhibition of both cyclooxygenases (COX) -1 and -2 resulting in suppression of prostaglandin synthesis. Surprisingly, over 10 months, concomitant postnatal deletion of Cox-1 and -2 failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor. Cox double knockout mice exhibit a distinct gut microbiome composition and cohousing them with controls rescues their dysbiosis and delays the onset of NSAID-induced GI bleeding. Suppression of bile acid synthesis is also protective. In both the UK Biobank and All of US, coadministration of antibiotics with NSAIDs is associated with an increased frequency of GI bleeding. These results show that prostaglandin suppression plays a trivial role in NSAID-induced enteropathy. However, Cox deletion causes dysbiosis of the gut microbiome that amplifies the enteropathic response to NSAIDs.
... However, head-to-head, oxycodone-paracetamol was found to be more effective in improving postoperative pain than celecoxib, which indicates that, in some cases, celecoxib may be insufficient for the relief of postoperative pain [34]. As with all NSAIDs, the side effects of celecoxib include increased cardiovascular risk, including stroke and myocardial infarction, as well as potential gastrointestinal damage such as bleeding and ulceration [35,36]. Celecoxib is metabolized by CYP2C9, which indicates possible drug-drug interactions with medications that inhibit CYP2C9 such as fluconazole [37]. ...
Article
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Opioids are commonly used to reduce pain after surgery; however, there are severe side effects and complications associated with opioid use, with addiction being of particular concern. Recent practice has shifted to reduce opioid consumption in surgery, although a specific protocol for rhinoplasty is still in progress. This paper aims to expand on the protocol previously established by the senior author based on updated evidence and details. This was accomplished by first high-lighting and summarizing analgesic agents with known opioid-reducing effects in the surgical field, with a particular focus on rhinoplasty, then compiling these analgesic options into a recommended protocol based on the most effective timing of administration (preoperative, intraoperative, postoperative). The senior author’s previous article on the subject was referenced to compile a list of analgesic agents of importance. Each analgesic agent was then searched in PubMed in conjunction with “rhinoplasty” or “opioid sparing” to find relevant primary sources and systematic reviews. The preferred analgesic agents included, as follows: preoperative, 1000 mg oral acetaminophen, 200 mg of oral celecoxib twice daily for 5 days, and 1200 mg oral gabapentin; intraoperative, 0.75 μg/kg of intravenous dexmedetomidine and 1–2 mg/kg injected lidocaine with additional 2–4 mg/kg per hour or 1.5 cc total bupivacaine nerve block injected along the infraorbital area bilaterally and in the subnasal region; and postoperatively, 5 mg oral acetaminophen and 400 mg of oral celecoxib. When choosing specific analgesic agents, considerations include potential side effects, contraindications, and the drug-specific mode of administration.
... Aside from aspirin, all NSAIDs enhance stomach motility at toxic levels [14]. They also increase the chances of bleeding, perforation, and gastric cancer, and can even lead to death [15]. In addition to the upper GI tract, the injury may also occur as frequently and severely in the lower intestinal tract, and patients may present with protein deficiency, bowel motility problems, abdominal pain, and iron deficiency anemia [16]. ...
... They function by preventing prostaglandins, which are molecules involved in the inflammatory response, from being produced (Bindu et al., 2020;Ding, 2022). NSAIDs, which are often used to treat ailments including arthritis, include aspirin, ibuprofen, and naproxen (García-Rayado et al., 2018). NSAIDs are useful, but they should be used carefully since they can cause gastrointestinal discomfort and should be taken for extended periods or at high doses (Gurpinar et al., 2014;Panchal and Prince Sabina, 2023). ...
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One of the main causes of death worldwide is lung cancer, which is largely caused by cigarette smoking. The crucial transcription factor NF-κB, which controls inflammatory responses and various cellular processes, is a constitutively present cytoplasmic protein strictly regulated by inhibitors like IκB proteins. Upon activation by external stimuli, it undergoes phosphorylation, translocates into the nucleus, and modulates the expression of specific genes. The incontrovertible association between pulmonary malignancy and tobacco consumption underscores and highlights a public health concern. Polycyclic aromatic hydrocarbons and nitrosamines, potent carcinogenic compounds present in the aerosol emitted from combusted tobacco, elicit profound deleterious effects upon inhalation, resulting in severe perturbation of pulmonary tissue integrity. The pathogenesis of smoking-induced lung cancer encompasses an intricate process wherein NF-κB activation plays a pivotal role, triggered by exposure to cigarette smoke through diverse signaling pathways, including those associated with oxidative stress and pro-inflammatory cytokines. Unraveling the participation of NF-κB in smoking-induced lung cancer provides pivotal insights into molecular processes, wherein intricate crosstalk between NF-κB and pathways such as MAPK and PI3K-Akt amplifies the inflammatory response, fostering an environment conducive to the formation of lung cancer. This study reviews the critical function of NF-κB in the complex molecular pathways linked to the initiation and advancement of lung carcinogenesis as well as potential treatment targets. See also the graphical abstract(Fig. 1).
... 56 However, once these drugs enter the blood circulation, they will not only face the phagocytosis of the reticuloendothelial system and the destruction of proteases, but also be distributed throughout the body, weakening the efficacy and increasing adverse reactions. [57][58][59][60][61] Chondroitin sulfate (CS), is found in the cartilage and ECM. The main factor causing the inflammation of the OA is the activation of NF-κB. ...
Article
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Osteoarthritis (OA) is a degenerative disease commonly seen in middle-aged and elderly people. Multiple cytokines are involved in the local tissue damage in OA. Currently, non-pharmacologic and surgical interventions are the main conventional approaches for the treatment of OA. In terms of pharmaceutical drug therapy, NSAIDs and acetaminophen are mainly used to treat OA. However, it is prone to various adverse reactions such as digestive tract ulcer, thromboembolism, prosthesis loosening, nerve injury and so on. With the in-depth study of OA, more and more novel topical drug delivery strategies and vehicles have been developed, which can make up for the shortcomings of traditional dosage forms, improve the bioavailability of drugs, and significantly reduce drug side effects. This review summarizes the immunopathogenesis, treatment guidelines, and progress and challenges of topical delivery technologies of OA, with some perspectives on the future pharmacological treatment of OA proposed.
... Distances (Å) flow, epithelial cells, and immune response of the mucosa. In addition, NSAIDs promote the exposure of the gastric lumen to aggressive agents such as acid and pepsin (Bastaki et al. 2018;García-Rayado et al. 2018). Nevertheless, studies suggest that NSAIDs exert pro-oxidant activity by promoting lipid peroxidation and generating ROS, which interferes with the endogenous antioxidant systems of the mucus, causing mucosal damage and apoptosis (Chaudhury and Jacobson 1978). ...
Article
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Fridericia chica is an Amazonian plant used to treat stomach disorders. However, the pharmacological activity of flavonoids in the extract has yet to be investigated. Therefore, we considered that a flavonoid-rich F. chica subfraction (FRS) has gastroprotective functions. For this, before the induction of gastric ulcers with ethanol or piroxicam, the rats received vehicle (water), omeprazole (30 mg/kg), or FRS (30 mg/kg), and the ulcer area was measured macro and microscopically, and the antisecretory action was investigated in pylorus-ligated rats. In addition, the roles of nitric oxide (NO) and nonprotein sulfhydryl compounds (NP–SH) in the gastroprotective effects of FRS were studied. FRS reduced ethanol- and piroxicam-induced ulcerations by 81% and 77%, respectively, as confirmed histologically. Antioxidant effects were observed for FRS through the maintenance of GSH and LPO levels, and the SOD and CAT activity similar to those found in the nonulcerated group. Moreover, FRS avoided the increase in MPO activity and TNF, IL-6, IL-4 and IL-10 levels. Moreover, mucin staining increased in ulcerated rats receiving FRS, and the pharmacological mechanism gastroprotective seems to involve the NO and NP–SH in addition to antisecretory actions. The chemical study by mass spectrometry confirmed the presence of flavonoids in FRS, and molecular docking studies have shown that these compounds interact with cyclooxygenase-1 and NO synthase. Furthermore, there was no indication that FRS had cytotoxic effects. Our results support the popular use of F. chica, and we conclude that the gastroprotection effect promoted by FRS can be attributed to the combined effect of the flavonoids. Graphical Abstract
... Although the ulcerogenic mechanism of indomethacin is still unclear, it induces gastric damage via inhibiting cyclooxygenase-1 (COX-1), whereas increasing PGE2 decreases bicarbonate and mucus, increases the oxidant stress, and decreases the antioxidant parameters [11]. Therefore, designing GI-safer (or sparing) NSAIDs [12,13] is undertaken based on these fundamental mechanisms of GI damage, including coxibs as a selective inhibitor of COX-2 [14], NO-NSAIDs [15,16], phosphatidylcholine-NSAID [17], and hydrogen sulfide-releasing NSAID [18]. ...
Article
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Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.
... However, considering the several causative mechanisms of HFS/HFSR and the side effects associated with long-term use of current treatments, novel preventive and therapeutic measures are still required. Celecoxib is associated with long-term cardiovascular or upper gastrointestinal side effects upon long-term use [27,28], and does not have topical keratolytic and moisturizing effects. Urea cream does not have antiinflammatory effects. ...
Article
Purpose: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are relatively common toxicities that interfere with the quality of life (QoL) of patients with cancer. Anti-inflammatory tripeptide cream (ATPC) is a complex formulation of anti-inflammatory tripeptides, the CD99-agonist BinterinTM and the Wnt-antagonist WinhibinTM. The present study aimed to assess the therapeutic effects of ATPC in HFS/HFSR associated with anticancer drugs. Materials and methods: This was a single-center, randomized, double-blind, placebo-controlled trial. Patients who developed grade 1 HFS/HFSR after systemic anticancer treatments were enrolled, and randomly assigned to receive either ATPC or placebo cream (PC) and followed up at 3-week intervals for up to nine weeks. Primary endpoint was the development of grade ≥ 2 HFS/HFSR. Results: Between April 2019 and July 2022, 60 patients (31 in the ATPC and 29 in the PC group) completed the study. The incidence of grade ≥ 2 HFS/HFSR was significantly lower in the ATPC than in the PC group (25.8% vs. 51.7%, p=0.039). The ATPC showed trends towards a better QoL score, assessed by a HFSR and QoL questionnaire at 9 weeks (26.0 vs. 29.9, p=0.574), and a lower frequency of discontinuation, interruption, or dose reduction of anticancer drugs (51.6% vs. 58.6%, p=0.586) than the PC group over 9 weeks, though without statistical significance. Conclusion: Our results showed that ATPC significantly decreased the development of grade ≥ 2 HFS/HFSR in patients already with HFS/HFSR. Therefore, ATPC may be an effective treatment for HFS/HFSR associated with anticancer drugs.
... Traditionally, non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, indomethacine, and piroxicam have been used to combat inflammation 4,5]. However, long-term use is associated with adverse effects, including gastrointestinal damage, bleeding, nephrotoxicity, and hypersensitivity [6,7]. Selective COX-2 inhibitors, such as celecoxib, were developed to mitigate gastrointestinal issues but present risks of thrombosis in patients with cardiovascular histories [5]. ...
Article
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Background: Inflammation is an essential innate immune response aimed at antigen elimination and preventing their spread. Ginger (Zingiber officinale) and bangle (Zingiber cassumunar) rhizomes have been empirically utilized as medicinal components due to their anti-inflammatory potential. However, the combined efficacy of these rhizomes has not been previously explored. Objective: This study aimed to assess the anti-inflammatory activity of a combination of ginger and bangle rhizome extracts. Method: Ginger and bangle rhizomes were individually subjected to extraction through maceration with 96% ethanol, followed by purification with n-hexane. The anti-inflammatory activity was evaluated via motility tests on subjects administered orally with 1% CMC-Na (control), diclofenac sodium (4.5 mg/kg body weight), ginger ethanol extract (200 mg/kg body weight), bangle ethanol extract (400 mg/kg body weight), and a combination of both extracts (100:200 mg/kg body weight). Observations were made over 6 hours, with motility scores subsequently analyzed using ANOVA and the LSD test for statistical significance. Results: Treatments involving ginger extract, bangle extract, and their combination significantly improved motility scores compared to the negative control. Furthermore, these treatments displayed no significant difference in effectiveness compared to the diclofenac sodium group (p > 0.05). Conclusion: The combined ethanol extracts of ginger and bangle rhizomes demonstrate anti-inflammatory activity comparable to diclofenac sodium, as evidenced by motility score evaluations. This suggests their potential as alternative anti-inflammatory agents.
... Most of these drugs exert antipyretic and analgesic effects by inhibiting prostaglandin (PG) synthesis [6] and are suitable for treating rheumatic diseases, acute or chronic pain, and the prevention of Alzheimer's disease. However, among many other problems, NSAID side effects also encompass nephrotoxicity, cardiovascular disease, increased blood pressure, and gastrointestinal harm [7]. ...
Article
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Chronic inflammation is a significant contributor to the development of cancer, cardiovascular disease, diabetes, obesity, autoimmune disease, inflammatory bowel disease, and other illnesses. In the academic field, there is a constant demand for effective methods to alleviate inflammation. Astragalin (AST), a type of flavonoid glycoside that is the primary component in several widely used traditional Chinese anti-inflammatory medications in clinical practice, has garnered attention from numerous experts and scholars. This article focuses on the anti-inflammatory effects of AST and conducts research on relevant literature from 2003 to 2023. The findings indicate that AST demonstrates promising anti-inflammatory potential in various models of inflammatory diseases. Specifically, AST is believed to possess inhibitory effects on inflammation-related factors and protein levels in various in vitro cell models, such as macrophages, microglia, and epithelial cells. In vivo studies have shown that AST effectively alleviates neuroinflammation and brain damage while also exhibiting potential for treating moderate diseases such as depression and stroke; it also demonstrates significant anti-inflammatory effects on both large and small intestinal epithelial cells. Animal experiments have further demonstrated that AST exerts therapeutic effects on colitis mice. Molecular biology studies have revealed that AST regulates complex signaling networks, including NF-κB, MAPK, JAK/STAT pathways, etc. In conclusion, this review will provide insights and references for the development of AST as an anti-inflammatory agent as well as for related drug development.
... Most tissues, including the stomach, express COX-1 constitutively, where it has a housekeeping function [43]. In contrast, the expression of COX-2 appears to result from the response to damage in various tissues; thus, it is referred to as an inducible isoform [44]. Several earlier studies have demonstrated COX-2 induction in inflammatory cells in areas of inflammation [45,46]. ...
... Indomethacin is utilized in different inflammatory diseases [48,49]. However, Indomethacin has numerous side effects on cardiovascular [50], renal [50] and GIT systems [51]. Literature showed that prolonged use of Indomethacin cause liver toxicity [52]. ...
... Mientras que el primer modo se basa en la acción de los AINE sobre la producción y abundancia de prostanoides (los principales mediadores inflamatorios del sistema) para regular la inflamación de los tejidos, como se observa en la Figura 1; el segundo modo de acción depende de la acción tóxica de los AINE contra las células; especialmente, las células subcelulares [7]. Aunque varios órganos pueden verse comprometidos, los efectos adversos de estos medicamentos están enfocados en los efectos gastrointestinales [8]. Pero, a lo largo de los años, diversos estudios se han concentrado en los efectos secundarios cardiovasculares de los AINE, y ahora se cree que estos fármacos tienen un gran riesgo cardiovascular, y esto es especialmente cierto en el caso de los inhibidores de la COX-2 o los AINE selectivos. ...
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INTRODUCTION: Arterial hypertension is defined as high blood pressure, generally speaking of a systolic that reaches at least 140 mmHg and/or an elevation of diastolic blood pressure of at least 90 mmHg. For its part, hypertensive crisis does not have a standardized definition, but it is known as a sudden or acute increase in blood pressure with compromise of the target organ. OBJECTIVES: The main objective of this study was to describe the chronic consumption of non-steroidal anti-inflammatory drugs and its relationship with the development of hypertensive crises. DISCUSSION: Around 10 studies were found that report increased systolic and diastolic pressure after the consumption of certain NSAIDs such as naproxen, ibuprofen and indomethacin. The increase in pressure for this group of drugs ranges from 14 to 20%. CONCLUSION: NSAIDs do not reach the necessary levels for the induction of a hypertensive crisis, however, there is limited literature that reports possible cases of hypertensive crisis secondary to the use of these, for this reason, it is relevant to expand the study of the possibility of crises. hypertensive. for this pharmacological group.
... The third is that the original compound, COMA4, exhibited very weak anti-inflammatory activity and selectivity. The fourth is that the calculated measurements for the two employed qualities are closely similar to those found in the literature, indicating the validity and applicability of the used methodology (García-Rayado et al. 2018;Mustafa 2023c). Finally, the author concluded that the three derivatives having a trisubstituted off-side aromatic ring represent potent and selective anti-inflammatory candidates with mutual COX/5-LOX inhibitory effects. ...
Article
A potent natural combretastatin, combretastatin A-4 (COMA4) targets the condylon active pocket to produce anticancer effects. Studies on inflammation and oxidative stress have been linked to cancer, indicating that lowering these risk variables may have an adverse effect on the progression of cancer. This study utilized COMA4 as a building block to create 28 coumarins with improved therapeutic effects. The first coumarin derivative, COMA4-COU-1, was activated by thionyl chloride and then coupled with various phenols, resulting in 27 COMA4-COU derivatives. Biomedical-related activities were conducted using COMA4 as a reference, including anticancer activity assayed against eight cancerous cellular populations , antioxidant activity evaluated on H 2 O 2-treated human SH-SY5Y populations, and anti-inflammatory activity tested against three enzymatic mediators of inflammation. The biosafety studies included testing the effects of COMA4 and its coumarins on the normal growth of three cell populations and on human erythrocyte hemolysis. Finally, the pharmacokinetic indexes of the building block and its derivatives were computerized using two web-based programs. The results indicated that the biomedical activities are directly improved by the presence of an electron-donating group on the offside aromatic ring. Also, these activities were increased when this group substituted at the para or meta position. The maximum activities were revealed when this aromatic ring was trisubstituted with this group type, with privilege activities for the trimethoxy aromatic ring. Concerning the biocompatibility studies, the synthetic coumarins demonstrated a high level of compatibility with the tested normal cells and also with human erythrocytes. Moreover, the in silico analysis demonstrated the capacity of the synthetic coumarins to present potential drug candidates. The author concluded that the coumarin-structural modification can open the door for developing new, potent, and biosafe COMA4 derivatives. In this regard, this study afforded many insights about the structure-function relationships of the synthesized compounds that can guide future research about COMA4-based derivatives.
... Additionally, patients in group 2 (CKD stages 3-5) had a higher prevalence of gastric lesions than in group 1 (CKD stages 1-2), and peptic ulcers were more abundant in group 2. Patients in group 2 exhibited a higher occurrence of gastric lesions due to their increased consumption of NSAIDs, which could exacerbate gastric lesions [12]. Furthermore, ESR levels were notably elevated in group 2, indicating an active inflammatory state that contributes to the development of transmural inflammation in the mucous membranes of the digestive system [13]. ...
... On the other hand, patients with RA tend to take more NSAIDS than their control groups because of the symptom of RA (Burmester and Pope, 2017;Aletaha and Smolen, 2018;Ben Mrid et al., 2022). Meanwhile, the common adverse reaction of NSAIDS is gastrointestinal, which may induce GERD (Altman et al., 2015;García-Rayado et al., 2018;Bindu et al., 2020). As a result, it is natural to hypothesize about the causal effects of RA on GERD. ...
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Aims/hypothesis: The association between gastroesophageal reflux disease (GERD) and rheumatoid arthritis (RA) has been reported by many observational studies in the Asian population. This study aimed to examine the bidirectional causal effects between GERD and RA by two-sample Mendelian randomization (MR) analyses using genetic evidence. Methods: Two-sample Mendelian randomization analyses were performed to determine the causal effect of GERD (129,080 cases vs. 602,604 control participants) on RA (6,236 cases vs. 147,221 control participants) and RA on GERD, respectively. The inverse-variance weighted (IVW) method was used as the primary analysis. Weighted median and MR-Egger regression were taken as supplementary analyses. Cochran’s Q test evaluated the heterogeneity. Horizontal pleiotropy was detected by estimating the intercept term of MR-Egger regression. Furthermore, multivariable MR analyses were performed to exclude the influence of confounding factors, including the years of schooling, BMI, and time spent watching television, between GERD and RA. Result: Both univariate MR (UVMR) and multivariable MR (MVMR) provided valid evidence that RA was causally and positively influenced by GERD (UVMR: OR = 1.49, 95% CI = 1.25–1.76, p = 6.18*10⁻⁶; MVMR: OR = 1.69, 95% CI = 1.24–2.31, p = 8.62*10⁻⁴), whereas GERD was not influenced by RA (UVMR: OR = 1.03, 95% CI = 1.00–1.06, p = 0.042; MVMR: OR = 1.04, 95% CI = 1.00–1.07, p = 0.0271). Conclusion: Our comprehensive bidirectional MR analysis found that for the European population, GERD can induce the occurrence of RA (OR = 1.69, p < 0.00125), whereas RA only has no significant influence on GERD. In particular, patients with GERD are suffering a 69% increased risk of RA occurrence, which means GERD is a substantial risk factor for RA.
... NSAIDs inhibit cyclooxygenase-1 and -2, converting arachidonic acid to prostaglandins, and thereby exert antipyretic, analgesic, and anti-inflammatory effects [40]. Meanwhile, these prostaglandins also protect the gastric mucosa, and therefore, the inhibitory actions of NSAIDs have adverse effects, mainly on the GI tract [41]. However, the majority of patients taking therapeutic doses of NSAIDs for a short duration, particularly those without underlying GI disorder, usually tolerate them well [42]. ...
... The third is that the original compound, TMHMS, exhibited very weak anti-inflammatory activity and selectivity. The fourth is that the calculated measurements for the two employed qualities are closely similar to those found in the literature, indicating the validity and applicability of the used methodology [31,39]. Finally, the author concluded that the three derivatives having a trisubstituted off-side aromatic ring represent potent and selective antiinflammatory candidates with mutual COX/5-LOX inhibitory effects. ...
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3,4,5-Trimethoxy-3′-hydroxy-4′-methoxystilbene (TMHMS) is an anticancer natural stilbene that targets tubulin polymerization. According to research, oxidative stress and inflammation are linked to cancer, and lowering both of these hazards may have a detrimental influence on tumor development. TMHMS was used as a building block in this investigation to generate 28 coumarins with increased medicinal value. TMHMS-COU-1, the first coumarin derivative, was activated by thionyl chloride and subsequently linked with different phenols, yielding 27 TMHMS-COU variants. This natural product was used as a reference for oxidative stress-alleviated activities such as anticancer activity against eight cancerous cellular lines, antioxidant activity on H2O2-treated human SH-SY5Y populations, and anti-inflammatory activity against three enzyme-based representatives of inflammation. TMHMS and its coumarins were tested for their impact on the normal development of three cell types as well as human erythrocyte hemolysis in biocompatibility tests. Finally, utilizing two web-based programs, the pharmacokinetic profiles of the building component and its variants were computed. The inclusion of an electron-donating group on the off-side aromatic ring directly boosted the oxidative stress-alleviated activities, according to the results. These activities were also boosted when this group occupied the para or meta position. When this aromatic ring was trisubstituted with this group type, the greatest activities were found, with the trimethoxy aromatic ring having preferential activities. In terms of biocompatibility, the synthesized coumarins showed a high level of compatibility with the tested normal cells as well as human erythrocytes. Furthermore, the in silico research confirmed the synthesized coumarins' ability to provide prospective therapeutic candidates. According to the author, the coumarin-structural change might open the way for the development of novel, powerful, and biosafe TMHMS derivatives. This work provided various insights into the structure-function connections that can direct subsequent studies on TMHMS-based derivatives.
... Селективные ингибиторы циклооксигеназы-2 более безопасны в от но шении возможного поражения желудочно-кишечного тракта. Пероральные формы НПВП широко назначаются при ОА, однако в связи с риском развития побочных эффектов их применение должно быть в виде краткосрочных курсов, а не для длительного непрерывного лечения [26][27][28][29][30]. ...
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Introduction . Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the mainstay of the management for relieving pain syndrome in osteoarthritis (OA). NSAIDs are characterized by an individual reaction to medication, as well as a quite high frequency of gastrointestinal side effects. The issue of the disadvantages and advantages of a particular group of NSAIDs is still open. Aim . To evaluate the safety and efficacy of Meloxicam at a dose of 15 mg/day as compared with Nimesulide and placebo in postmenopausal women with an inflammatory phenotype of OA. Results and discussion . The frequency of all adverse events was comparable among the group of patients receiving meloxicam (40.0%), and lower than in the nimesulide group (48.0%), but higher than in the placebo group. A decrease in pain syndrome was observed as early as at 2 weeks of treatment in the group of patients receiving meloxicam. A significant decrease in WOMAC scores (overall result, pain syndrome, stiffness, function) was observed in the group of patients receiving meloxicam, and in the group of patients receiving nimesulide, after 3 weeks of treatment. meloxicam and nimesulide demonstrated high efficacy at 3 weeks compared with the initial VAS scores. The placebo group showed no efficacy. Conclusion . The frequency of all adverse events was lower while taking meloxicam as compared to nimesulide. Our results substantiate the concept to prescribe meloxicam at a dose 15 mg once daily for the treatment of pain and stiffness in post-menopausal women with OA.
... Their anti-inflammatory effect is caused by the inhibition of COX-2, while the inhibition effect of COX-1 causes undesirable side effects. NSAIDs are widely favored because of their strong efficacy, extended history of clinical use, and low abuse potential [8]. They have anti-inflammatory, analgesic, and antipyretic activities [9]. ...
Article
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The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased lately around the world, as they are considered essential and popular drugs for effective reduction of pain and inflammation. They have analgesic, antipyretic, and anti-inflammatory activities; also, it was reported recently that they protect against various critical disorders like heart attacks and cancer. However, oral use of NSAIDs may cause several pulmonary, gastrointestinal, hepatic, cardiovascular, cerebral, and renal complications. Therefore, topical NSAIDs were recommended as a substitute to oral NSAIDs for the treatment of inflammation and pain. Still, the skin permeation of NSAIDs is considered a challenge, as the skin have an effective barrier function. Therefore, this review investigates various advanced vesicular nanocarriers and their applications through the skin, to augment the topical delivery of NSAIDs through stratum corneum over the conventional systems, enhance their effectiveness, and reduce the unwanted side effects. These innovative systems can manage bioavailability, solubility, stability, safety, and efficacy issues present in conventional systems.
... In this regard, many synthetic anti-inflammatory and antioxidant agents have been developed to remediate oxidative stress and inflammation [14,15]. NSAIDs are known to block the biosynthesis of prostaglandins (PGs) from arachidonic acid and thereby suppress the upstream production of cyclooxygenases (COX-1 and -2) [16]. ...
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Considering the large spectrum of side effects caused by synthetic drugs and the development of natural alternatives utilizing Algerian flora, this study aimed to place a spotlight on the chemical profile and antioxidant and anti-inflammatory activities of Myrtus communis L. essential oils (MCEOs). In this study, essential oils (EOs) were collected via hydro-distillation of the plant’s leaves, and a chemical constituent analysis was performed using gas chromatography–mass spectrophotometry (GC–MS). The in vitro antioxidant activity was evaluated using DPPH, ABTS, and hydroxyl radical scavenging tests. The in vitro anti-inflammatory capacity was estimated by studying the antidenaturation effect using bovine serum albumin (BSA) as a protein model. The in vivo anti-inflammatory activity was carried out by utilizing the classical model of carrageenan-induced paw edema in rats, using diclofenac (DCF) as the reference drug. Moreover, the molecular interaction of the compounds obtained from the GC–MS analysis was studied within the binding site of cyclooxygenase-2 (COX-2) using an in silico approach as the confirmatory tool of the in vitro and in vivo experiments. The GC–MS analysis revealed that MCEOs were mainly composed of oxygenated monoterpenes (70.56%), oxygenated sesquiterpenes (3.1%), sesquiterpenes (4.17%), and monoterpenes (8.75%). Furthermore, 1,8-cineole was the major compound (19.05%), followed by cis-geranyl acetate (11.74%), methyl eugenol (5.58%), α-terpineol (4.62%), and β-myrcene (4.40%). MCEOs exhibited remarkable concentration-dependent free radical scavenging activity, with an IC50 of 15.317 ± 0.340 µg/mL, 18.890 ± 2.190 µg/mL, and 31.877 ± 0.742 µg/mL for DPPH, ABTS, and hydroxyl radical, respectively. The significant in vitro anti-inflammatory activity due to the inhibition of BSA denaturation was proportional to the EO concentration, where the highest value was recorded at 100 μg/mL with an approximately 63.35% percentage inhibition and an IC50 of 60.351 ± 5.832 μg/mL. MCEOs showed a good in vivo anti-inflammatory effect by limiting the development of carrageenan-induced paw thickness. The in silico study indicated that, among the 60 compounds identified by the GC–MS analysis, 9 compounds were observed to have a high binding energy to cyclooxygenase-2 as compared to diclofenac. Our study revealed that EOs from Algerian Myrtus communis L. can be considered to be a promising candidate for alleviating many debilitating health problems and may provide new insights in the fields of drug design, agriculture, and the food industry.
... NSAIDs are often used because of their importance as strong antipyretics and analgesics in a variety of illnesses and disorders, from the common cold to rheumatoid arthritis (Day and Graham 2013). However, NSAIDs often increase the risk of developing stomach mucosal ulcers (Musumba et al. 2009;García-Rayado et al. 2018). Indomethacin is one of the most potent NSAIDs with ulcer-inducing activity (Henry and Robertson 1993). ...
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Gastric ulcer is one of the most frequent gastrointestinal ailments worldwide. Indomethacin, one of the most potent NSAIDs, suffers undesirable ulcerogenic activity. Caffeic acid phenethyl ester (CAPE) has known health benefits. The current study examined the potential of CAPE to combat indomethacin-induced gastric ulcers in rats. Animals were randomized into 5 groups: control, Indomethacin (50 mg/kg) mg/kg), Indomethacin + CAPE (5 mg/kg/day), Indomethacin + CAPE (10 mg/kg), and Indomethacin + Omeprazole (30 mg/kg). CAPE prevented the rise in ulcer index, attenuated histopathological changes and preserved gastric mucin concentration. CAPE efficiently significantly prevented accumulation of malondialdehude (MDA) and prevented exhaustion of the enzymatic activities of catalase (CAT) and superoxide dismutase (SOD). Further, CAPE prevented the rise in the expression of tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nuclear factor kapp-B (NFκB). This was associated with down-regulation of Bax and up-regulation of Bcl-2 mRNA. Finally, CAPE prevented induced indomethacin-induced decrease in heat shock protein 70 (HSP70) in gastric tissues. In conclusion, CAPE possesses the ability to prevent indomethacin-induced gastric ulcer in rats. This involves, at least partially, antioxidation, anti-inflammation, anti-apoptosis and enhancement of HSP70 expression.
... nsaiDs usually involves the middle third, with erythema, erosions, ulcers, and multiple small areas of ulceration with bleeding. 13 actually, there is no evidence on the correlation between NSAIDs abuse and digestive tract injuries after an HM. on the other hand, the execution of HM by untrained rescuers, could pose a great risk. in fact, it is very probable that untrained persons will not be able to distinguish a pseudo-choking state from an episode of airway obstruction. 14,15 in this context, the application of an abdominal thrust causes an increase in intraluminal pressures of internal organs. ...
Article
The Heimlich maneuver (HM) is lifesaving in a patient choked by a foreign body. It is safe and effective and does not require specific instruments. Nevertheless, rare severe complications have been reported, such as traumatic injury of the gastrointestinal tract, pneumomediastinum, rib fracture, diaphragm rupture, acute thrombosis of abdominal aortic aneurysm and mesenteric laceration. Abdominal injuries are the most common complications, especially esophageal and gastric wall rupture. This anatomic site is the most common location of organ injuries, in consequence of the main target of the force generated by the HM. Furthermore, the execution of HM by an untrained person may increase the risk for possible serious complications. Usually, HM complications are treated surgically, but based on clinical conditions, a conservative approach is possible. In our report, we described a case of esophageal rupture after a forceful HM, and we made a brief revision of literature concerning HM complications. We have also assessed the correlation between HM complications, abuse of non-steroidal anti-inflammatory drugs and the execution of the abdominal thrusts by untrained rescuers.
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The inhibition of human microsomal prostaglandin E 2 (PGE 2) synthase-1 (mPGES-1) is a promising therapeutic modality for developing next-generation anti-inflammatory medications. In this study, we present novel 2-phenylbenzothiazole derivatives featuring heteroaryl sulfonamide end-capping substructures as inhibitors of human mPGES-1, with IC 50 values in the range of 0.72-3.40 µM in a cell-free assay of PGE 2 formation. Notably, compound 21, featuring a quinoxalinedione ring in its sulfonamide segment, effectively suppresses PGE 2 biosynthesis at a low mi-cromolar concentration (IC 50 = 0.72 µM) with exceptional selectivity against cyclo-oxygenase (COX)-1, COX-2, 5-lipoxygenase (5-LOX), and FLAP. This compound offers a novel chemical scaffold for developing safer and more effective anti-inflammatory agents.
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Microsomal prostaglandin E2 synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC50 values of 0.27–7.0 nM in a cell-free assay for prostaglandin (PG)E2 production. Compound 44 (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC50 = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE2 production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, in vivo studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.
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Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are common drugs in patients with osteoarthritis (OA). NSAIDs are generally used at home by patients, without supervision, requiring proper knowledge and attitudes for correct practice. This study investigated the knowledge, attitude, and practice (KAP) of patients with OA toward NSAIDs. Methods This cross-sectional study enrolled patients with OA at the Qingpu Branch of Zhongshan Hospital of Fudan University between January and March 2024. The KAP scores and demographic information of respondents were collected through a self-designed questionnaire. Results There were 645 participants, with 579 (89.8%) over 45 years old and 394 (61.1%) females. The average scores for knowledge, attitude, and practice were 16.26 ± 3.79 (possible range: 0–24), 18.12 ± 1.99 (possible range: 5–35), and 29.20 ± 5.52 (possible range: 10–50), respectively. The structural equation model (SEM) found that for individuals currently using NSAIDs, the attitude had a direct effect on practice (β = 0.978, P < 0.001). For individuals not using NSAIDs, the attitude had a direct effect on practice (β = 0.936, P < 0.001). Conclusion This study suggested that adequate NSAID knowledge is the prerequisite for correct NSAID-related medical decisions, while attitude has a crucial intermediary effect. Healthcare professionals and society should strengthen education regarding the relevant knowledge of NSAIDs and guide the cultivation of positive attitudes toward NSAIDs.
Article
Introduction: Bariatric surgery, an option for obesity management, can significantly alter gastrointestinal structure and processes. These changes can impact the pharmacokinetics (PK) of medications, which can translate to clinical differences in efficacy and safety. Chronic pain is prevalent in obesity and often persists post-bariatric surgery. Areas covered: This narrative review examines the PubMed literature from 1990 to January 2024 for the impact of bariatric surgery on the management of chronic pain medications including non-opioid (acetaminophen, non-steroidal anti-inflammatory drugs, antidepressants, and cannabinoids) and opioid medications. Expert opinion: An individualized medication management approach is ideal for post-bariatric surgery patients, as PK parameters, type of surgery, time since surgery, and patient-specific factors make it difficult to support blanket recommendations. Close monitoring of efficacy and safety outcomes is essential in chronic pain management. While the PK of acetaminophen and opioids are impacted, the value of these medications in the setting of chronic pain is dwindling as more efficacy and safety data emerges. A life-long ban of NSAIDs due to marginal ulcer risk is not endorsed; rather, we advocate for shifting the focus to marginal ulcer prevention strategies, individualized benefit-risk analysis, and safety monitoring using surrogate markers.
Article
Objectives Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications, but their use can be associated with a number of adverse reactions, including upper gastrointestinal lesions. The aim of the study was to identify clinical and pharmacogenetic factors associated with upper gastrointestinal lesions, including those linked to NSAIDs, in patients at a multidisciplinary hospital. Methods The study included 92 patients (mean age 59.4±16.5 years; 47 women), who underwent esophagogastroduodenoscopy during inpatient treatment. Patients’ intake of NSAIDs and gastroprotectors during the year before hospitalization was considered. Demographic, clinical, laboratory data of patients were compared between groups, including genotyping for CYP2C9*2 rs179985 , CYP2C9*3 rs1057910 , CYP2C8*3 rs11572080 , CYP2C8*3 rs10509681 , PTGS-1 rs10306135 , PTGS-1 rs12353214 , and PTGS-2 rs20417 using real-time PCR. Results In NSAIDs ⁺ patients, PTGS1 rs10306135 AT+TT genotypes increased the chance of developing gastrointestinal complications by 5.4 times (95 % CI=1.30–22.27). In total sample, smoking (OR=3.12, 95 % CI=1.15–8.46), and alcohol intake (OR=4.09, 95 % CI=1.05–15.87) increased odds of gastrointestinal damage. In NSAIDs ⁺ patients omeprazole, famotidine and both famotidine and omeprazole during the last year were as ineffective as not taking gastroprotectors; in total sample famotidine (OR=0.19, 95 % CI=0.04–0.93) and two gastroprotectors (OR=0.13, 95 % CI=0.02–0.75) reduced the chance of upper gastrointestinal lesions. Conclusions Pharmacogenetic features of patients may significantly contribute to the development NSAIDs-induced upper gastrointestinal injuries.
Chapter
Inflammation resolution is a complex system that involves a variety of lipid mediators, proteins, hormones, and gaseous mediators that act in a coordinated manner to counteract the pro-inflammatory signals and promote the resolution of inflammation. Understanding the role of these mediators in inflammation resolution is critical for developing novel therapeutic approaches for inflammatory diseases. In this chapter, we describe the pro-resolving actions of various resolution mediators and the role of miRNAs, drugs, and natural compounds.
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Background Primary dysmenorrhoea occurs in up to 50% of menstruating females. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used therapeutic remedies for dysmenorrhoea in Uganda. However, NSAIDs are associated with a 3–5 fold increase in the risk of gastrointestinal (GI) adverse drug effects. Objectives We aimed to determine the prevalence and associated factors of self-reported NSAID-related GI adverse effects in female students who use NSAIDs in managing dysmenorrhoea-associated pain at Makerere University. Design A cross-sectional study. Setting Makerere University’s main campus, situated North of Kampala, Uganda. Participants 314 female students pursuing an undergraduate programme at Makerere University and residing in different halls of residence and hostels. Outcomes Social demographic data, menstrual history and treatment data. Results Overall, 314 valid responses were received from female students with a median age of 22 years (IQR: 18–29 years). The median age at menarche was 13 years (IQR: 9–18 years). 41% (n=129/314) of the respondents had used medication for dysmenorrhoea and 32% (n=41/129) of whom reported NSAID-associated GI adverse effects with nausea being the most frequently reported (44%, n=18/41)Factors independently associated with GI adverse effects were: age at menarche (p=0.026), duration of menstruation (p=0.030) and use of ibuprofen (p=0.005). Females taking ibuprofen for dysmenorrhoea were about four times as likely to have NSAID-associated GI adverse effects (adjusted OR 3.87, 95% CI 1.51 to 9.91) than those who did not receive ibuprofen. Logistic regression was used to determine factors associated with self-reported adverse effects of NSAIDs among the female students. A p<0.05 was considered statistically significant. Conclusion We found a considerably high prevalence of NSAID-related GI adverse effects driven by factors such as age at menarche and ibuprofen use.
Conference Paper
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Introduction: Pulse wave velocity (PWV) is a widely used measure of arterial stiffness, and its reduction has been associated with improved outcomes in patients with CVD. However, there is uncertainty regarding the comparative effectiveness of different ARBs and CCBs in reducing PWV and improving CVD outcomes. Therefore, this network meta-analysis (NMA) aims to compare the effects of different ARBs and CCBs on PWV and their implications for CVD prevention and management. Methods: PubMed, Web of Science, Scopus, EMBASE and Clinicaltrials.gov databases were searched for RCTs to identify relevant articles published until June 2022. We performed a NMA to estimate the relative effects of each intervention on PWV and major adverse cardiovascular events (MACE). The results of the NMA were expressed as standardized mean differences (SMD) in PWV and odds ratios (OR) for MACE. Heterogeneity was evaluated using Cochran's Q test and the I2 test. The quality of the evidence was assessed using the GRADE approach. Results: A total of 26 RCTs involving 2,660 patients were included in the NMA. Among ARBs, losartan had the largest effect size (SMD 1.44 m/s, 95% CI: -2.08 to -0.81). Among CCBs, amlodipine had the largest effect size (SMD 1.38 m/s, 95% CI: -2.11 to -0.65). However, there was significant heterogeneity and inconsistency among the included studies (τ2 = 0.7096; I2 = 82.9% (95% CI =0% to 92.6%). In terms of MACE, the results showed no significant differences between the interventions. Conclusions: In conclusion, ARBs and CCBs are both effective in reducing PWV, with losartan and amlodipine showing the largest effect sizes. These findings have important implications for the prevention and management of CVD, as reducing arterial stiffness is an important therapeutic target for improving cardiovascular outcomes.
Article
The objective of the current study was to investigate the effects of resveratrol (RSV), a natural herbal remedy used as an adjacent anti-inflammatory supplement on, the pharmacokinetics of celecoxib in healthy male volunteers. Twelve healthy human participants were involved in two-period open-labeled trial. Celecoxib (200 mg) was given as a single oral dose under fasting conditions as a control phase. Afterward, RSV (500 mg) commenced as a single oral dose for ten days as a treatment phase. Blood samples were collected during the control and treatment phases and analyzed using the validated High-performance liquid chromatography (HPLC) method. RSV pre-exposure significantly increased the area under the curve (AUC0–24), peak plasma concentration (Cmax), absorption rate constant (ka), and prolongated half-life (t1/2), along with a decrease in elimination rate constant (ke). Meanwhile, the volume of distribution (Vd/F) and apparent total body clearance (CL/F) were significantly decreased for celecoxib. There was no significant change in the time it takes for celecoxib to reach the maximum concentration (tmax) was observed. The obtained results suggested the presence of a beneficial pharmacokinetic interaction between RSV and celecoxib. Consequently, combining resveratrol as an herbal remedy and celecoxib as an anti-inflammatory drug may synergistically reduce inflammation and osteoarthritis with minimal side effects.
Article
Background: Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. Methods: Male Kunming mice (8-10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). Results: Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. Conclusions: The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain.
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Background: The safety of nonsteroidal anti-inflammatory drug (NSAID) and aspirin coadministration is uncertain. Objectives: The aim of this study was to compare the safety of combining NSAIDs with low-dose aspirin. Methods: This analysis of the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) trial included 23,953 patients with osteoarthritis or rheumatoid arthritis at increased cardiovascular risk randomized to celecoxib, ibuprofen, or naproxen. The on-treatment population was used for this study. Outcomes included composite major adverse cardiovascular events, noncardiovascular death, gastrointestinal or renal events, and components of the composite. Cox proportional hazards models compared outcomes among NSAIDs stratified by aspirin use following propensity score adjustment. Kaplan-Meier analysis was used to compare the cumulative probability of events. Results: When taken without aspirin, naproxen or ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.22 to 1.90, p <0.001; and HR: 1.81; 95% CI: 1.46 to 2.26; p <0.001, respectively). Compared with celecoxib, ibuprofen had more major adverse cardiovascular events (p < 0.05), and both ibuprofen and naproxen had more gastrointestinal (p < 0.001) and renal (p < 0.05) events. Taken with aspirin, ibuprofen had greater risk for the primary composite endpoint compared with celecoxib (HR: 1.27; 95% CI: 1.06 to 1.51; p < 0.01); this was not significantly higher with naproxen (HR: 1.18; 95% CI: 0.98 to 1.41; p = 0.08). Among patients on aspirin, major adverse cardiovascular events were similar among NSAIDs, and compared with celecoxib, ibuprofen had more gastrointestinal and renal events (p < 0.05), while naproxen had more gastrointestinal events (p < 0.05), without a difference in renal events. Similar results were seen on adjusted Kaplan-Meier analysis. Conclusions: Celecoxib has a more favorable overall safety profile than naproxen or ibuprofen when taken without aspirin. Adding aspirin attenuates the safety advantage of celecoxib, although celecoxib is still associated with fewer gastrointestinal events than ibuprofen or naproxen and fewer renal events than ibuprofen. (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen [PRECISION]; NCT00346216).
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Objective To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel. Methods We conducted a retrospective cohort study using Medicaid claims from five US states during 1999–2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models. Results Of 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50.8, 58.6, and 54.3 per 1,000 person-years, respectively. Compared with ibuprofen and controlling for potential confounders, rofecoxib (hazard ratio [HR] = 1.22; 95% confidence interval [CI]: 1.04, 1.43) and valdecoxib (HR = 0.66; 95% CI: 0.48, 0.92) showed higher and lower hazards of mortality, respectively. Indomethacin showed an increased AMI/ischemic stroke hazard (HR = 1.38; 95% CI: 1.09, 1.74). For GIB/ICH, indomethacin (HR = 2.18; 95% CI: 1.74, 2.73), diclofenac (HR = 1.65; 95% CI: 1.39, 1.97), naproxen (HR = 1.47; 95% CI: 1.28, 1.70), and rofecoxib (HR = 1.26; 95% CI: 1.08, 1.48) showed higher hazards, and valdecoxib (HR = 0.73; 95% CI: 0.55, 0.98) showed a lower hazard. Conclusion The bleeding risks of individual NSAIDs varied more markedly than thrombotic risks when used concomitantly with clopidogrel. Moreover, bleeding risk and thrombotic risk among individual NSAIDs did not appear to be inversely related to each other in the presence of clopidogrel. Further studies are needed to elucidate underlying biological mechanisms and help clinical decision-making for a better NSAID choice in clopidogrel users.
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Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or naproxen is limited due to the gastrotoxicity evoked by these compounds. Endogenous hydrogen sulfide (H2S) and delivered via an H2S donor have been shown to play important role in the maintenance of gastric mucosal integrity. This study aimed to compare the effects of naproxen and an H2S-releasing naproxen derivative (ATB-346) on gastric lesion induction by water immersion and restraint stress (WRS), the alterations in gastric blood flow (GBF) and the influence of these drugs on systemic inflammation. Wistar rats were pretreated i.g. with vehicle, naproxen (20 mg/kg) or ATB-346 (equimolar dose) or NaHS (5 mg/kg), the H2S donor, combined with naproxen and exposed to 3.5 hours of WRS. The gastric lesion number and GBF were assessed by planimetry and laser Doppler flowmetry, respectively. Plasma concentrations of interleukins: IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and GM-CSF were determined by Luminex system and gastric mucosal protein expression of cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), hypoxia inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1) and cyclooxygenase (COX-2) were analyzed by Western blot. Pretreatment with naproxen increased the number of WRS stress-induced gastric lesions and significantly decreased GBF as compared with vehicle (p < 0.05). In contrast, pretreatment with ATB-346 or naproxen combined with NaHS significantly reduced WRS-lesions number and elevated GBF as compared with naproxen (p < 0.05). Naproxen significantly increased gastric mucosal protein expression of CSE, Nrf-2 and HIF-1α as compared with vehicle (p < 0.05), but failed to affect CBS, 3-MST and HO-1. ATB-346 significantly increased Nrf-2 and HO-1 protein expression as compared with vehicle (P < 0.05) but did not affect the protein expression of CSE, CBS, 3-MST or HIF-1α. ATB-346 but not naproxen decreased COX-2 protein expression in gastric mucosa compromised by WRS (p < 0.05). Exposure to WRS increased plasma concentration of all investigated cytokines (p < 0.05). ATB-346 but not naproxen decreased plasma content of IL-1α, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α and IFN-γ in rats exposed to WRS (p < 0.05). We conclude that H2S through its vasoactive properties attenuates the gastrotoxic effects of naproxen, which increased stress-induced hypoxia in gastric mucosa. In contrast to naproxen, ATB-346 decreased stress-induced systemic inflammation and pro-inflammatory COX-2 expression in the gastric mucosa. The decreased gastrotoxicity of ATB-346 could be due to upregulation of Nrf-2/HO-1 pathway mediated by the release of H2S.
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Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or COX1) and PTGS1 (COX2), other factors are involved. We review mechanisms of gastrointestinal damage induction by NSAIDs, via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID's inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.
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Introduction. The pharmacological management of pain includes the use of nonsteroidal anti-inflammatory drugs(NSAIDs). They comprise traditional(t) NSAIDs and selective cyclooxygenase(COX)-2 inhibitors (named coxibs). The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites. However, the simultaneous inhibition of COX-2 in the vasculature translates into a prothrombotic phenotype and promotes hypertension and heart failure. Areas covered. The results of the clinical pharmacology of coxibs and the most used tNSAIDs provide a mechanistic interpretation of the cardiovascular(CV) outcomes found in randomized clinical trials(RCTs), meta-analyses of RCTs and epidemiological studies. A critical analysis of the design and results of the PRECISION trial, which compared the CV risk of celecoxib, ibuprofen, and naproxen in high‐risk CV patients, was performed. Expert opinion. tNSAIDs and coxibs may increase the chance of a heart attack or stroke. The reduction of the dose of NSAIDs may mitigate, but not avoid, the risk of CV adverse effects. The development of novel biomarkers which identify susceptibility phenotypes associated with increased risk of CV complications by COX-2 inhibition is an unmet clinical need that once filled will lead to personalized treatments with NSAIDs.
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The intestinal microbiota might contribute to enteropathy associated with use of non-steroidal anti-inflammatory drugs (NSAIDs), but there have been few human studies of this association. We performed a placebo-controlled study to determine whether a delayed release antibiotic formulation (rifaximin-EIR) prevented development of intestinal lesions in persons taking daily NSAIDs. Sixty healthy volunteers (median age 26 years, 42% female) were given the NSAID diclofenac (75 mg twice daily) plus omeprazole (20 mg once daily), and either rifaximin-EIR (400 mg) or placebo, twice daily for 14 days. Subjects were assessed by video-capsule endoscopy at baseline and after 2 weeks of treatment. The primary endpoint was the proportion of subjects developing at least 1 small bowel mucosal break at week 2. Secondary endpoints were the change in mean number of mucosal lesions and number of subjects with large erosions and/or ulcers after 14 days of exposure. We detected mucosal breaks in 20% of subjects given rifaximin and 43% of subjects given placebo (P=.05. in the post hoc sensitivity analysis). None of the subjects in the rifaximin group developed large lesions, compared with 9 subjects in the placebo group (P<.001). Our findings indicate that the intestinal bacteria contribute to development of NSAID-associated enteropathy in humans. Clinical trial no: EudraCT 2013-000730-36.
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Background The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Methods Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. Results A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). Conclusions At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216.)
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Non-steroidal anti-inflammatory drug (NSAID) use increases the risk of gastrointestinal complications such as ulcers or bleeding. The presence of factors like advanced age, history of peptic ulcer, Helicobacter pylori infection and the use of anticoagulants or antiplatelet agents increase this risk further. COX-2 inhibitors and antisecretory drugs, particularly proton pump inhibitors, help to minimize the risk of gastrointestinal complications in high-risk patients. This review presents a practical approach to the prevention and treatment of NSAID-associated peptic ulcer disease and examines the new advances in the rational use of NSAIDs.
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The physiological gaseous molecule, carbon monoxide (CO) becomes a subject of extensive investigation due to its vasoactive activity throughout the body but its role in gastropro-tection has been little investigated. We determined the mechanism of CO released from its donor tricarbonyldichlororuthenium (II) dimer (CORM-2) in protection of gastric mucosa against 75% ethanol-induced injury. Rats were pretreated with CORM-2 30 min prior to 75% ethanol with or without 1) non-selective (indomethacin) or selective cyclooxygenase (COX)-1 (SC-560) and COX-2 (celecoxib) inhibitors, 2) nitric oxide (NO) synthase inhibitor L-NNA, 3) ODQ, a soluble guanylyl cyclase (sGC) inhibitor, hemin, a heme oxygenase (HO)-1 inductor or zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1 activity. The CO content in gastric mucosa and carboxyhemoglobin (COHb) level in blood was analyzed by gas chromatography. The gastric mucosal mRNA expression for HO-1, COX-1, COX-2, iNOS, IL-4, IL-1β was analyzed by real-time PCR while HO-1, HO-2 and Nrf2 protein expression was determined by Western Blot. Pretreatment with CORM-2 (0.5–10 mg/kg) dose-dependently attenuated ethanol-induced lesions and raised gastric blood flow (GBF) but large dose of 100 mg/kg was ineffective. CORM-2 (5 mg/kg and 50 mg/kg i.g.) significantly increased gastric mucosal CO content and whole blood COHb level. CORM-2-induced protection was reversed by indomethacin, SC-560 and significantly attenuated by celecoxib, ODQ and L-NNA. Hemin significantly reduced ethanol damage and raised GBF while ZnPPIX which exacerbated ethanol-induced injury inhibited CORM-2-and hemin-induced gastroprotection and the accompanying rise in GBF. CORM-2 significantly increased gastric mucosal HO-1 mRNA expression and decreased mRNA expression for iNOS, IL-1β, COX-1 and COX-2 but failed to affect HO-1 and Nrf2 protein expression decreased by ethanol. We conclude that CORM-2 released CO exerts gastroprotection against ethanol-induced gastric lesions involving an increase in gastric microcirculation
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The bacterial pathogen Helicobacter pylori commonly colonizes the human gastric mucosa during early childhood and persists throughout life. The organism has evolved multiple mechanisms for evading clearance by the immune system and, despite inducing inflammation in the stomach, the majority of infections are asymptomatic. H. pylori is the leading cause of peptic ulcer disease and gastric cancer. However, disease outcomes are related to the pattern and severity of chronic inflammation in the gastric mucosa, which in turn is influenced by both bacterial and host factors. Despite over 2 decades of intensive research, there remains an incomplete understanding of the circumstances leading to disease development, due to the fascinating complexity of the host–pathogen interactions. There is accumulating data concerning the virulence factors associated with increased risk of disease, and the majority of these have pro-inflammatory activities. Despite this, only a small proportion of those infected with virulent strains develop disease. Several H. pylori virulence factors have multiple effects on different cell types, including the induction of pro- and anti-inflammatory, immune stimulatory, and immune modulatory responses. The expression of multiple virulence factors is also often linked, making it difficult to assess the meaning of their effects in isolation. Overall, H. pylori is thought to usually modulate inflammation and limit acute damage to the mucosa, enabling the bacteria to persist. If this delicate balance is disturbed, disease may then develop.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide. NSAIDs are used for a variety of conditions including pain, rheumatoid arthritis, and musculoskeletal disorders. The beneficial effects of NSAIDs in reducing or relieving pain are well established, and other benefits such as reducing inflammation and anticancer effects are also documented. The undesirable side effects of NSAIDs include ulcers, internal bleeding, kidney failure, and increased risk of heart attack and stroke. Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues. NSAIDs have been shown to induce reactive oxygen species (ROS) in different cell types including cardiac and cardiovascular related cells. Increases in ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways. One of these key pathways is apoptosis which causes cell death when significantly activated. This review discusses the relationship between NSAIDs and cardiovascular diseases (CVD) and the role of NSAID-induced ROS in CVD.
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Helicobacter pylori (H. pylori) infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction between H. pylori infection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use. This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission. H. pylori infection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA and H. pylori infection was estimated by logistic regression analysis. The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): 2.0-3.3) tested positive for H. pylori infection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: 3.0-5.4). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: 1.3-2.7). The RR of PUB for concomitant NSAID use and H. pylori infection suggested an additive effect (RR: 8.0; 95% CI: 5.0-12.8), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: 2.0-6.1). NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies.Am J Gastroenterol advance online publication, 21 April 2015; doi:10.1038/ajg.2015.98.
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Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.
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Helicobacter pylori (H. pylori) have long been associated with a spectrum of disease outcomes in the gastro-duodenal system. Heterogeneity in bacterial virulence factors or strains is not enough to explain the divergent disease phenotypes manifested by the infection. This review focuses on host genetic factors that are involved during infection and eventually are thought to influence the disease phenotype. We have summarized the different host genes that have been investigated for association studies in H. pylori mediated duodenal ulcer or gastric cancer. We discuss that as the bacteria co-evolved with the host; these host gene also show much variation across different ethnic population. We illustrate the allelic distribution of interleukin-1B, across different population which is one of the most popular candidate gene studied with respect to H. pylori infections. Further, we highlight that several polymorphisms in the pathway gene can by itself or collectively affect the acid secretion pathway axis (gastrin: somatostatin) thereby resulting in a spectrum of disease phenotype.
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Significance Inflammatory bowel diseases (IBDs) are debilitating conditions with no known cure. Recent evidence suggests that elevated intestinal hydrogen sulfide (H 2 S) synthesis promotes healing and reduces inflammation. H 2 S is synthesized from cysteine largely via vitamin B 6 -dependent enzymes. People with IBD are also at increased risk of hyperhomocysteinemia, a condition that is often caused by vitamin B deficiency. Dietary induction of vitamin B deficiency markedly increased serum homocysteine levels and worsened colitis in rodents. The latter was due to the absence of the typical injury-induced elevation of H 2 S synthesis. Interleukin-10 plays a key role in increasing H 2 S synthesis, attenuating the severity of colitis, and reducing serum homocysteine levels. The H 2 S–interleukin 10 axis may be a viable target for therapy of IBD.
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Objectives: There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. Methods: MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. Results: Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). Conclusions: SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.
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NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.
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Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.
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Abstract 1. We have previously demonstrated that a small molecule inhibitor of bacterial β-glucuronidase (Inh-1; [1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea]) protected mice against diclofenac (DCF)-induced enteropathy. Here we report that Inh-1 was equally protective against small intestinal injury induced by other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin (10 mg/kg, ip) and ketoprofen (100 mg/kg, ip). 2. Inh-1 provided complete protection if given prior to DCF (60 mg/kg, ip), and partial protection if administered 3-h post-DCF, suggesting that the temporal window of mucosal protection can be extended for drugs undergoing extensive enterohepatic circulation. 3. Pharmacokinetic analysis of Inh-1 revealed an absolute bioavailability (F) of 21% and a short t1/2 of <1 h. This low F was shown to be due to hepatic first-pass metabolism, as confirmed with the pan-CYP inhibitor, 1-aminobenzotriazole. 4. Using the fluorescent probe 5 (and 6)-carboxy-2',7'-dichlorofluorescein, we demonstrated that Inh-1 did not interfere with hepatobiliary export of glucuronides in gall bladder-cannulated mice. 5. These data are compatible with the hypothesis that pharmacological inhibition of bacterial β-glucuronidase-mediated cleavage of NSAID glucuronides in the small intestinal lumen can protect against NSAID-induced enteropathy caused by locally high concentrations of NSAID aglycones.
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Background We evaluated GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. Methods This randomised, double‐blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100‐200 mg b.d., ibuprofen 600‐800 mg t.d.s. or naproxen 375‐500 mg b.d. plus esomeprazole, and low‐dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE—bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. Results Mean treatment and follow‐up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27‐0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32‐0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27‐0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25‐0.62, P < 0.0001) vs naproxen. Even taken with low‐dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29‐0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23‐0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. Conclusions Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co‐prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low‐dose aspirin or corticosteroids.
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Background: The relative safety of long-term utilization of non-steroidal anti-inflammatory drugs (NSAIDs) is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major NSAID toxicity in the PRECISION trial. Methods: We conducted a post-hoc analyses of double-blind randomized controlled multi-center trial enrolling 24,081 patients with osteoarthritis or rheumatoid arthritis at moderate or high cardiovascular risk.Patients were randomized to receive celecoxib 100-200mg twice daily, ibuprofen 600-800mg thrice daily, or naproxen 375-500mg twice daily. All patients were provided with a proton pump inhibitor. The outcome was major NSAID toxicity, including time to first occurrence of major adverse cardiovascular events, important gastrointestinal events, renal events and all-cause mortality. Results: During follow-up, 4.1% of subjects in the celecoxib arm sustained any major toxicity, 4.8% in the naproxen arm, and 5.3% in the ibuprofen arm. Analyses adjusted for aspirin use and geographic region found that subjects in the naproxen arm had a 19% (95% CI 1-39%) higher risk of major toxicity than celecoxib users and ibuprofen users had a 41% (95% CI 21-65%) higher risk. These risks translate into numbers needed to harm of 135 (95% CI 72-971) for naproxen and 82 (95% CI 53-173) for ibuprofen, both compared with celecoxib. Conclusions: Among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events, approximately one in twenty experienced a major toxicity over 1-2 years. Patients using naproxen or ibuprofen experienced significantly higher risk of major toxicity than those using celecoxib.
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Background: The best available evidence regarding non-steroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) bleeding comes from randomized controlled trials including patients who use NSAIDs to manage chronic rheumatic diseases; however, patients with varying background profiles commonly take NSAIDs for many other reasons, often without prescription, and such usage has not been well studied. Objectives and Methods: To define the characteristics of patients hospitalized for upper GI bleeding in clinical practice, we conducted a case-control study among patients with endoscopy-proven major upper GI bleeding due to gastroduodenal peptic lesions and control subjects. We used adjusted logistic regression models to estimate bleeding risks. Data analysis was performed using SPSS 22.0. Results: Our analysis included 3,785 cases and 6,540 controls, including 1,270 cases (33.55%) and 834 controls (12.75%) reporting recent use (<30 days) of NSAIDs including high-dose acetylsalicylic acid (ASA). NSAID use was associated with increased risk of upper GI bleeding, with an adjusted relative risk of 4.86 (95% CI, 4.32-5.46). Acute musculoskeletal pain (36.1%), chronic osteoarthritis (13.5%), and headache (13.6%) were the most common reasons for NSAID use. Among cases, only 17.31% took NSAIDs and 6.38% took high dose ASA due to chronic osteoarthritis. Demographic characteristics significantly differed between subjects with chronic vs. acute musculoskeletal pain. Proton pump inhibitor use was significantly higher in patients who used NSAIDs due to with chronic osteoarthritis compared to patients with acute musculoskeletal pain. NSAID (65.15%) or high-dose ASA use (65.83%) preceding upper GI bleeding was most often short-term. In over half of cases (63.62%), the upper GI bleeding event was not preceded by dyspeptic warning symptoms. Conclusions: The majority of patients hospitalized due to NSAID-related upper GI bleeding reported short-term NSAID use for reasons other than chronic rheumatic disease. These findings suggest that current prevention strategies may not reach a wide population of short-term NSAID users
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Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal. Here, we review many of the proposed adverse consequences of PPI therapy and apply established criteria for the determination of causation. We also consider the potential contribution of residual confounding in many of the reported studies. Evidence is inadequate to establish causal relationships between PPI therapy and many of the proposed associations. Residual confounding related to study design and the over-extrapolation of quantitatively small estimates of effect size have probably led to much of the current controversy about PPI safety. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.
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Introduction: Cardiovascular disease is the most important cause of morbidity and mortality in the world and low dose aspirin is considered the cornerstone of the cardiovascular disease prevention. However, low dose aspirin use is associated with gastrointestinal adverse effects in the whole gastrointestinal tract. In this setting, co-therapy with a proton pump inhibitor is the most accepted strategy to reduce aspirin related upper gastrointestinal damage. In addition, some adverse effects have been described with proton pump inhibitors long-term use. Areas covered: Low dose aspirin related beneficial and adverse effects in cardiovascular system and gastrointestinal tract are reviewed. In addition, this manuscript summarizes current data on upper gastrointestinal damage prevention and adverse events with proton pump inhibition. Finally, we discuss the benefit/risk ratio of proton pump inhibitor use in patients at risk of gastrointestinal damage taking low dose aspirin. Expert commentary: Nowadays, with the current available evidence, the combination of low dose aspirin with proton pump inhibitor is the most effective therapy for cardiovascular prevention in patients at high gastrointestinal risk. However, further studies are needed to discover new effective strategies with less related adverse events.