tegaserod and Colitis--Ischemic

Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT(3) receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT(3) receptor antagonist that is no longer in clinical development. In addition, the 5-HT(4) receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT(4) agonist/5-HT(3) antagonist. Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT(3) receptor antagonists or 5-HT(4) receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death. Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situatio

Topics: Animals; Carbolines; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

More than one decade ago, rising cases of ischemic colitis (IC) prompted the Federal Drug Administration to revoke alosetron's approval as treatment of irritable bowel syndrome (IBS). The aim of this study was to identify medical therapies associated with development of IC.. The Federal Adverse Event Reporting System was queried for the time between January 2004 and September 2015. We identified reports listing IC as treatment complication and extracted suspected causative and concomitantly administered drugs, indications for their use and outcomes.. After eliminating duplicates, we found 2811 cases of IC (68.4 % women; 59.4 ± 0.4 years). Patients with IBS accounted for 3.9 % of the cases, mostly attributed to tegaserod or alosetron. Chemotherapeutic and immunosuppressive drugs, sex hormones, and anticoagulants were the most commonly suspected causes. Bisphosphonates, nonsteroidal anti-inflammatory drugs, antipsychotics, triptans, interferon therapy, and laxative use prior to colonoscopy were among the more commonly listed treatments. In 8 %, the adverse event contributed to the patient's death with male sex and older age predicting fatal outcomes.. Beyond confirming known risks of IC, the results identified several potential culprits of ischemic colitis. This information may not only explain the development of this serious adverse event, but could also guide treatment decisions, cautioning healthcare providers when considering these agents in persons with known risk factors or other drugs that may increase their risk of IC.

Topics: Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antineoplastic Agents; Antipsychotic Agents; Autoimmune Diseases; Bone Density Conservation Agents; Carbolines; Colitis, Ischemic; Colonoscopy; Databases, Factual; Diphosphonates; Estrogens; Female; Gonadal Steroid Hormones; Humans; Immunosuppressive Agents; Indoles; Interferons; Irritable Bowel Syndrome; Laxatives; Male; Mental Disorders; Middle Aged; Neoplasms; Osteoporosis; Preoperative Care; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Tryptamines; United States

Tegaserod, a potent partial agonist of the serotonin 5-HT4 receptor, is used to treat women with constipation-predominant irritable bowel syndrome. Since the drug's approval, the manufacturer has received infrequent although serious reports of diarrhea and ischemic colitis in patients taking the drug. These instances have led to a recent warning letter to physicians and a change in the prescription labeling of tegaserod. We describe the development of ischemic colitis in a woman who was treated with tegaserod and review the relationship among ischemic colitis, tegaserod use, and irritable bowel syndrome. Potential mechanisms involved in the occurrence of ischemic colitis in patients receiving tegaserod are also discussed.

Topics: Adult; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Topics: Colitis, Ischemic; Constipation; Humans; Indoles; Irritable Bowel Syndrome

Topics: Colitis, Ischemic; Diarrhea; Humans; Indoles; Irritable Bowel Syndrome; Serotonin Receptor Agonists

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Colitis, Ischemic; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin Receptor Agonists