Evidence of aspirin use in both upper and lower gastrointestinal perforation
Abstract
BACKGROUND & AIMS: Current studies lack appropriate data on aspirin and other risk factors for gastrointestinal perforation. The aim of this study was to obtain the best estimate on aspirin and nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use in these patients.
METHODS: In 76 consecutive patients with gastrointestinal perforation and 152 matched controls, a detailed clinical history supplemented with an objective test of current aspirin use (platelet cyclooxygenase activity) was obtained.
RESULTS: Of the 76 cases, 78.9% were upper and 21% lower gastrointestinal perforations. Evidence of NSAID use was found in 71% of cases (70% upper, 75% lower) vs. 26.9% of controls (odds ratio, 6.64; 95% confidence interval, 3.6-12.2; P < 0.0001). The objective test showed 12.7% more aspirin users than clinical history alone. NSAID use was aspirin (alone or combined) in 66.6% of cases, and 59.25% was nonprescription. Other independent risk factors were smoking, alcohol, and a history of arthritis or peptic ulcer but not a positive Helicobacter pylori serology. Age, but not NSAID use, affected perforation-associated mortality.
CONCLUSIONS: NSAID use is strongly associated with an increased risk of both upper and lower gastrointestinal perforation. The high prevalence of aspirin (over-the- counter) use suggests that future introduction of new NSAIDs may not have a major impact on decreasing gastrointestinal complications if other measures are not taken. Concomitant NSAID use, smoking, and alcohol use is a pervasive association.
(Gastroenterology 1997 Mar;112(3):683-9)
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AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review
2022, GastroenterologyProton pump inhibitors (PPIs) are among the most commonly used medications in the world. Developed for the treatment and prevention of acid-mediated upper gastrointestinal conditions, these agents are being used increasingly for indications where their benefits are less certain. PPI overprescription imposes an economic cost and contributes to polypharmacy. In addition, PPI use has been increasingly linked to a number of adverse events (PPI-associated adverse events [PAAEs]). Therefore, de-prescribing of PPIs is an important strategy to lower pill burden while reducing real costs and theoretical risks. The purpose of this clinical update was to provide Best Practice Advice (BPA) statements about how to approach PPI de-prescribing in ambulatory patients.
Our guiding principle was that, although PPIs are generally safe, patients should not use any medication when there is not a reasonable expectation of benefit based on scientific evidence or prior treatment response. Prescribers are responsible for determining whether PPI use is absolutely or conditionally indicated and, when uncertainty exists, to incorporate patient perspectives into PPI decision making. We collaboratively outlined a high-level “process map” of the conceptual approach to de-prescribing PPIs in a clinical setting. We identified the following 3 key domains that required BPA guidance: documentation of PPI indication; identifying suitable candidates for consideration of de-prescribing; and optimizing successful de-prescribing. Co-authors drafted 1 or more potential BPAs, supported by literature review, for each domain. All co-authors reviewed, edited, and selected or rejected draft BPAs for inclusion in the final list submitted to the American Gastroenterological Association Governing Board. Because this was not a systematic review, we did not carry out a formal rating of the quality of evidence or strength of the presented considerations.
Best Practice Advice Statements
All patients taking a PPI should have a regular review of the ongoing indications for use and documentation of that indication. This review should be the responsibility of the patient’s primary care provider.
All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing.
Most patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step down to once-daily PPI.
Patients with complicated gastroesophageal reflux disease, such as those with a history of severe erosive esophagitis, esophageal ulcer, or peptic stricture, should generally not be considered for PPI discontinuation.
Patients with known Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of de-prescribing.
PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.
Patients at high risk for upper gastrointestinal bleeding should not be considered for PPI de-prescribing.
Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion.
When de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered.
The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PAAEs. The presence of a PAAE or a history of a PAAE in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.
Pretreatment of IEC-6 cells with quercetin and myricetin resists the indomethacin-induced barrier dysfunction via attenuating the calcium-mediated JNK/Src activation
2021, Food and Chemical ToxicologyThis study investigated the protective effect of two flavonols quercetin and myricetin on barrier function of rat intestinal epithelial (IEC-6) cells with indomethacin injury. When the cells were pretreated with the heated or unheated flavonols of 2.5–10 μmol/L for 24–48 h and then injured by 300 μmol/L indomethacin for 24 h, they showed reduced lactate dehydrogenase release (LDH) but increased cell viability; however, the flavonols of 20 μmol/L exerted a little effect to increase cell viability or decrease LDH release. Cell pretreatment with 5 μmol/L flavonols also resisted cell barrier dysfunction by increasing transepithelial resistance, reducing paracellular permeability, and promoting mRNA and protein expression of three tight junction proteins zonula occluden-1, occludin, and claudin-1. Although indomethacin injury increased intracellular Ca2+ concentration ([Ca2+]i) and consequently caused JNK/Src activation, the flavonols could decrease [Ca2+]i and attenuate the calcium-mediated JNK/Src activation. Quercetin with less hydroxyl groups was more efficient than myricetin to resist barrier dysfunction, while the unheated flavonols were more active than the heated counterparts to perform this effect. It is thus proposed that quercetin and myricetin could resist barrier dysfunction of the intestine once injured by indomethacin, but heat treatment of flavonols had a negative impact on barrier-protective function of flavonols.
True or false? Challenges and recent highlights in the development of aspirin prodrugs
2020, European Journal of Medicinal ChemistryCitation Excerpt :It belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and has a number of therapeutic uses: analgesic, anti-inflammatory, anti-platelet and anti-pyretic [1–3]. The most serious and well-known side-effects observed with aspirin and other NSAIDs are gastrointestinal (GI) ulceration and bleeding [4–6]. They can be attributed to the systemic effects of the NSAID on prostaglandin (PG) synthesis, as well as local irritation caused by the carboxylic acid [7].
Aspirin is a widely used medicine for a variety of indications. It is unique amongst non-steroidal anti-inflammatory drugs (NSAIDs) in that it causes irreversible acetylation of COX enzymes. Like all NSAIDs however, aspirin causes severe gastrointestinal side-effects, in particular with chronic administration. Prodrugs of aspirin have been proposed as a solution to these side-effects. However, identifying true prodrugs of aspirin, rather than salicylic acid, has proven challenging. This review details the challenges and highlights recent progress in the development of such prodrugs.
Drug-induced pathology of the upper gastrointestinal tract
2017, Diagnostic HistopathologyDrugs can produce a wide range of pathology in the upper gastrointestinal tract. Often, the injury pattern is non-specific. Pill-induced oesophagitis usually affects the mid oesophagus. In the stomach, many drugs, particularly non-steroid anti-inflammatory drugs (NSAIDs), can cause ulcers, erosions or reactive gastropathy. Some drugs produce specific injury patterns that can be recognized by pathologists. Proton pump inhibitors cause parietal cell hyperplasia and fundic gland polyps. Kayexalate may cause erosions or ulcers, with ‘mosaic’ crystals within the exudate, but other resins may show crystals that can be confused for Kayexalate. Iron therapy, mucosal calcinosis, and mucosal lanthanum deposition share the presence of crystals in the mucosa of affected patients. Various agents can cause non-specific mucosal changes that mimic celiac disease, GVHD, or inflammatory bowel disease, such as olmesartan, idelalisib, and checkpoint inhibitors. Colchicine causes variable injury, and interference with microtubule assembly results in mitotic arrest. Hepatic arterial infusion chemotherapy may cause gastroduodenal ulcers associated with marked epithelial atypia that can be mistaken for carcinoma. Recognition of these histological patterns enables pathologists to make a diagnosis of drug-induced upper gastrointestinal injury and potentially to identify the specific agent responsible.
NSAID and gastrointestinal risk
2016, Atencion PrimariaPerforated peptic ulcer
2015, The LancetPerforated peptic ulcer is a common emergency condition worldwide, with associated mortality rates of up to 30%. A scarcity of high-quality studies about the condition limits the knowledge base for clinical decision making, but a few published randomised trials are available. Although Helicobacter pylori and use of non-steroidal anti-inflammatory drugs are common causes, demographic differences in age, sex, perforation location, and underlying causes exist between countries, and mortality rates also vary. Clinical prediction rules are used, but accuracy varies with study population. Early surgery, either by laparoscopic or open repair, and proper sepsis management are essential for good outcome. Selected patients can be managed non-operatively or with novel endoscopic approaches, but validation of such methods in trials is needed. Quality of care, sepsis care bundles, and postoperative monitoring need further assessment. Adequate trials with low risk of bias are urgently needed to provide better evidence. We summarise the evidence for perforated peptic ulcer management and identify directions for future clinical research.