Drug-induced Gastrointestinal Injury Research Articles

Development of drug-induced gastrointestinal injury models based on ANN and SVM algorithms and their applications in the field of natural products

The broad use of natural products and the accompanied incidences of gastrointestinal injury have attracted considerable interest in investigating the responsible toxic ingredients.

S2126 Sevelamer-Induced Colitis

Introduction: Drug-induced Gastrointestinal (GI) injury has been well established throughout the literature and continues to prevail with the ever-growing expansion of pharmaceutical drug development. Mucosal injuries due to medications ranging from common over-the-counter drugs to novel chemotherapeutics, have been one of the more common findings seen both endoscopically and histologically in drug-induced GI injury. Though frequently seen with NSAIDs, iron pills, and bisphosphonates, lately, resin-based binders like Sevelamer have shown an increased incidence of GI mucosal injuries. Sevelamer is an oral phosphate binder widely used to treat hyperphosphatemia in patients with chronic kidney disease. Here we present a case of Sevelamer induced colitis in a patient on Sevelamer Carbonate therapy for hyperphosphatemia secondary to acute kidney injury. Case Description/Methods: 34 year old male with history of hypertension, obesity class III status post sleeve gastrectomy, OSA, congestive heart failure, and a recent diagnosis of COVID-19 was admitted to the MICU for acute hypoxemic respiratory failure requiring intubation. His hospital course was complicated by worsening renal function and oliguria with creatinine 8.9 and phosphorus 6.4. He was started on hemodialysis (HD), followed by Sevelamer Carbonate 0.8 g TID then increased to 1.6 g TID. Weeks after initiating HD, he developed bright red blood per rectum requiring intermittent transfusions. CT abdomen pelvis and mesenteric angiogram were unremarkable. Upper GI endoscopy showed a Forest Class III duodenal ulcer. Colonoscopy showed localized severe friable ulcerated mucosa with loss of vascular pattern in the cecum and ascending colon. Biopsy at these sites revealed mucosal ulcerations with granulation tissue with Sevelamer crystal deposits. Hematochezia improved on discontinuing Sevelamer (Figure). Discussion: Sevelamer is a calcium-free oral phosphate binder that has replaced calcium-based binders to treat hyperphosphatemia. Common side effects include nausea, vomiting, and diarrhea. GI mucosal injury from resin-based binders has been reported, although colitis induced by Sevelamer crystal deposition is rare. Previous literature shows a wide range of presentations, including ulcerations, GI bleeding, and colonic strictures. As with prior reports, we show similar endoscopic and histological findings from our patient consistent with this rare entity.Figure 1.: A, Colonoscopic finding showing erythematous ulcerated mucosa in the proximal ascending colon. B, Biopsy from proximal ascending colon site showing granulation tissue with ulceration. The black arrow indicates the Sevelamer Crystal deposition, showing the characteristic “Fish Scale” pattern.

Review article: drug-induced small bowel injury.

Drug-induced gastrointestinal injury has been increasingly reported, but its exact incidence is not known. The small and large intestines represent the most affected sites of injury, accounting for 20%-40% of all gastrointestinal side effects. To provide an updated literature review detailing medications linked to the development of small bowel injury. We conducted a literature search on PubMed from its inception to May 1, 2021. We included English-language original studies, meta-analyses, systematic reviews, review articles and case reports. Drug-induced enteropathy can range from asymptomatic histological changes resulting in a subtle, self-limited disease to a chronic inflammatory condition mimicking inflammatory bowel disease, or bowel perforation. Endoscopy can demonstrate erythema, mucosal friability, oedema, erosions, ulcers or strictures in severe cases. Histology may include mucosal erosions and ulcerations, focal active enteritis, villous atrophy, epithelial apoptosis or necrotising enteritis. A well-established association has been found with the use of nonsteroidal anti-inflammatory drugs, immunosuppressants, chemotherapeutic agents, antibiotics, immunotherapies, etanercept and olmesartan. Possible associations have been reported with other biologic agents, medications used for glycemic control, antihypertensives, cholinesterase inhibitors, potassium and iron supplements, with conflicting data regarding contraceptives/hormonal therapy and isotretinoin. Physicians should be aware of the manifestations of drug-induced enteropathy as early recognition can lead to prompt discontinuation of the offending therapy and, therefore, a reduced risk of future complications.

Towards better models and mechanistic biomarkers for drug-induced gastrointestinal injury.

Adverse drug reactions affecting the gastrointestinal (GI) tract are a serious burden on patients, healthcare providers and the pharmaceutical industry. GI toxicity encompasses a range of pathologies in different parts of the GI tract. However, to date no specific mechanistic diagnostic/prognostic biomarkers or translatable pre-clinical models of GI toxicity exist. This review will cover the current knowledge of GI ADRs, existing biomarkers and models with potential application for toxicity screening/monitoring. We focus on the current gaps in our knowledge, the potential opportunities and recommend that a systematic approach is needed to identify mechanism-based GI biomarkers with potential for clinical translation.

A Review of Anti-Inflammatory Drug-Induced Gastrointestinal Injury: Focus on Prevention of Small Intestinal Injury

Capsule endoscopy and balloon endoscopy, advanced modalities that allow full investigation of the entire small intestine, have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Recently, several reports show that traditional NSAIDs (tNSAIDs) and acetylsalicylic acid (ASA) can induce small intestinal injuries. These reports have shown that the preventive effect of proton pump inhibitors (PPIs) does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with tNSAID/ASA use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of mucoprotective drugs against tNSAID/ASA-induced small intestinal injury. These studies show that misoprostol and rebamipide reduce the number and types of tNSAID-induced small intestinal mucosal injuries. However, those studies were limited to a small number of subjects and tested short-term tNSAID/ ASA treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs.

Inhibition of Hydrogen Sulfide Generation Contributes to Gastric Injury Caused by Anti-Inflammatory Nonsteroidal Drugs

Hydrogen sulfide (H(2)S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Here, we have investigated the role of H(2)S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H(2)S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. At a dose of 100 micromol/kg, NaHS attenuated by 60%-70% the gastric mucosal injury, and tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E(2) (PGE(2)) synthesis by NSAIDs. Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H(2)S formation and CSE expression (mRNA and protein) and activity by 60%-70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. These data establish a physiologic role for H(2)S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.

Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the most commonly used medications worldwide. They are effective analgesic and anti-inflammatory agents. A major drawback to their use is a high frequency of adverse gastrointestinal (GI) effects that cause significant morbidity, occasional mortality, and substantial increases in cost of therapy. In this review, mechanisms of NSAID-induced GI injury are presented, and a clinical approach to diagnosis, treatment, and prevention of these adverse GI effects is provided.

Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury

Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury