A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity (original) (raw)
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Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs
Gastroenterology, 2017
Nonsteroidal 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 cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the 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 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 in...
Journal of clinical biochemistry and nutrition, 2011
Non-steroidal anti-inflammatory drugs are the most commonly prescribed drugs for arthritis, inflammation, and cardiovascular protection. However, they cause gastrointestinal complications. The pathophysiology of these complications has mostly been ascribed to non-steroidal anti-inflammatory drugs' action on the cyclooxygenase inhibition and the subsequent prostaglandin deficiency. However, recent clinical demonstrated the prevalence of non-steroidal anti-inflammatory drugs-induced small intestinal mucosal injury is more often than previously expected. In this review, we discuss the defense mechanisms of stomach, and the pathophysiology of non-steroidal anti-inflammatory drugs-induced injury of stomach and small intestine, especially focused on non-steroidal anti-inflammatory drugs' action on mitochondria.
1998
Gastrointestinal side-effects pose a major problem for those taking nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanism by which NSAIDs adversely affect the gastrointestinal tract is still unclear. The aims of this study were to test the hypothesis suggesting that NSAID enteropathy is a multistage process. Firstly, the effect of NSAIDs on mitochondria was examined, as this is the proposed initial site of damage. Secondly, the "transitional stage" of the pathogenesis (increase in intestinal permeability) was studied, by measuring the transepithelial electrical resistance (TER) of intestinal cells in isolation from any effects of NSAIDs on vascular blood flow. I am grateful to Dr Sivagurunathan Somasundaram for his assistance in standardising the oxygen uptake experiments and for his advice throughout. I extend my thanks to Dr Jasvinder Shergill for helping me set up the EPR studies and for making interpretation of the results a much less daunting task. I am indebted to Dr Robert Simpson and Dr Molly Jacob for their assistance and advice with the ATP work. I am grateful to all in the Department of Medicine for giving me room to work in the tissue culture lab. In particular, I thank Professor Bruce Hendry for allowing me use of his Ussing chamber and Dr Chris Stern for his help with the initial studies. I extend my thanks to Dr Gudmundur Sigthorsson for "jumping on the bandwagon" with my Millicell experiments when maternity leave beckoned. I thank all in the Animal House at the Kensington campus for their abundant supply of rat livers. I am grateful also to Roger Crane for working deep into the night making the necessary adjustments to the EM pictures.
Polskie Archiwum Medycyny Wewnętrznej, 2015
Nonsteroidal anti-inflammatory drugs (NSAIDs), especially acetylsalicylic acid (ASA), are commonly used in the therapy of various diseases. However, the serious side effects of these drugs, such as bleedings, acute lesions, gastric ulcers, and even intestinal perforations, are widely recognized. NSAIDs inhibit cyclooxygenase (COX) activity resulting in the suppression of mucosal generation of gastroprotective prostaglandins (PGs) derived from a constitutive isoform, COX-1, as well as an inducible isoform, COX-2. COX-1-derived PGs are responsible for gastroprotection, while PGs generated via COX-2 activity also play an important role in gastroprotection and ulcer healing. Recently, a new class of NSAIDs has been developed by adding NO moiety to conventional NSAIDs. In contrast to native NSAIDs, their NO-releasing derivatives such as NO-ASA were found to exhibit lower gastric toxicity despite inhibiting both COX-1 and COX-2 activity in the gastric mucosa. Similar limited gastrointesti...
NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2
Gastroenterology, 2000
Background & Aims: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested this hypothesis in rats by using a selective COX-1 inhibitor (SC-560). Methods: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combination of both inhibitors on gastric damage and prostaglandin synthesis were determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1-preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed. Results: SC-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 activity, but spared COX-2 and did not cause gastric damage. Celecoxib did not affect gastric prostaglandin E 2 synthesis and did not cause gastric damage. However, the combination of SC-560 and celecoxib invariably caused hemorrhagic erosion formation, comparable to that seen with indomethacin. Ketorolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly increased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gastric blood flow. Conclusions: Inhibition of both COX-1 and COX-2 is required for NSAIDinduced gastric injury in the rat.
Determinants of the short-term gastric damage caused by NSAIDs in man
Alimentary Pharmacology & Therapeutics, 2007
Background The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and ⁄ or lipophilicity (log P 7.4). Aim To study the quantitative relationship between NSAID-induced shortterm gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. Methods We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P 7.4. Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2 ⁄ COX-1 selectivity ratio. Results The gastric damage correlates significantly with pKa (r =)0.69; P < 0.01), log P (r =)0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r =)0.61, P < 0.02), but not with COX-2 inhibition or COX-2 ⁄ COX-1 selectivity. Conclusion Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in shortterm gastric damage.