Safety Pharmacology and the GI Tract
Shayne C. Gad in Toxicology of the Gastrointestinal Tract, 2018
All compounds believed to have anti-inflammatory activity or have effects on cyclooxygenase should be tested [29]. Because of problems in humans (ischemic colitis) with at least one serotonin3 antagonist, alosetron, this type of compound should also be evaluated [30,31]. Alosetron is a potent and selective serotonin antagonist that became the first FDA-approved agent for diarrhea-predominant irritable bowel syndrome. Since approval, significant side effects have been noted with its use, including severe constipation, fecal impaction, and ischemic colitis. Clinical, endoscopic, and pathologic features of the focal colitis strongly suggested ischemia and were observed in patients who should not have received the compound. Symptoms correlated temporally with alosetron use, and symptoms abated with discontinuation of the drug [30–32].
Functional abdominal disorders
Michael JG Farthing, Anne B Ballinger in Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Pharmaceutical companies have identified agents with visceral analgesic properties, and this has led to a surge in the development of novel drugs for IBS, such as the kappa opioid agonist fedotozine, 5-HT3 and 5-HT4 antagonists specifically aimed at restoring normal visceral sensation, and 5-HT4 agonists with significant colonic prokinetic activity (Table 8.2). Several of these novel approaches are in the process of thorough evaluation in Phase II or Phase III trials, such as the kappa opioid agonist fedotozine.150 Alosetron, a 5-HT3 antagonist, is effective in relieving pain and normalizing bowel frequency and reducing urgency in non-constipated IBS female patients.151,152 The 5-HT4 agonists tegaserod153,154 and prucalopride155 are currently in Phase III trials for constipation-predominant IBS. Other research studies are currently exploring the potential of alpha2 adrenergic agonists (clonidine) and 5-HT1 agonists (buspirone).156,157
Abdominal Pain
Mark V. Boswell, B. Eliot Cole in Weiner's Pain Management, 2005
Serotonin has become a focus of interest because of the rich concentration of this substance in the intestinal tract; in fact, nearly 95% of this hormone is found within the enterochormafin cells of the intestine. Of note are the drugs alosetron HCl (Lotronex™; Glaxo-SmithKline) and tergasarod (Zelnorm®; Novartis). Alosetron, a 5-HT3 receptor antagonist, gained FDA approval for the treatment of diarrhea-predominant IBS (IBS-D); however, it was voluntarily removed from the market secondary to potential adverse events thought to possibly be caused by the drug in November 2000. Some of the adverse events include ischemic colitis and constipation. After additional consideration, the FDA approved the use of alosetron in June 2002 under a restricted prescribing program. As of this writing, only women with severe IBS-D who have failed other traditional therapies are eligible for treatment. Patients and physicians are required to sign an agreement form and special stickers are required to prescribe the medicine. Initial dosage of alosetron is 1 mg daily for 4 weeks which can be increased to a maximum of 1 mg twice daily if it is tolerated. If no symptom improvement is achieved after 4 weeks of treatment at the maximum dose, it is then advised to discontinue alosetron and seek alternative management options. Alosetron has not only been shown to decrease the number of bowel movements, but perhaps just as important, it has also been demonstrated that it has some efficacy in relieving global symptoms of IBS and therefore improving quality of life (Lievre, 2002). For more information regarding the educational materials for Lotronex or to enroll in the prescribing program, call 888-825-5249 or visit www.lotronex.com.
Current and emerging pharmacological approaches for treating diarrhea-predominant irritable bowel syndrome
Published in Expert Opinion on Pharmacotherapy, 2020
Akhil Munjal, Bhavtosh Dedania, Brooks D. Cash
Alosetron is a selective 5-HT3 receptor antagonist approved for IBS-D. Through its mechanism of action, alosetron decreases GI motility and secretion [5,6] and improved abdominal pain. The evidence base for alosetron as an effective IBS-D therapy is strong. In a phase 2 dose-ranging trial, 705 women with IBS-D were treated for 12 weeks with different doses of alosetron vs placebo. This study found statistically significant improvement in the quality of life in IBS-D patients who received alosetron vs placebo, with constipation as the most common adverse event observed with alosetron [5]. Another study involving 647 females with IBS-D or alternating bowel patterns randomized to receive placebo vs 1 mg of alosetron daily showed similar results. A greater proportion of participants in alosetron group reported adequate symptomatic relief compared with placebo (n = 133 (41%) vs n = 94 (29%), respectively) for the 3 months of treatment with a statistically significant difference of 12% (4.7–19.2) between the groups [7]. Since the pivotal trials of alosetron submitted to the FDA for approval were largely comprised of female patients, it was approved only for women with IBS-D symptoms. However, post-marketing surveillance and analysis of clinical trial data highlighted the risk of complications of constipation (CoC) and colon ischemia (CI) in patients exposed to alosetron. As a result, the drug was removed from the market before being re-released under the auspices of a FDA-mandated risk management program. The indications for alosetron were also made more restrictive to include women with severe IBS-D who had not responded to conventional IBD-D therapies.
Emerging therapies in the management of Irritable Bowel Syndrome (IBS)
Published in Expert Opinion on Emerging Drugs, 2022
Jill E. Elwing, Hadi Atassi, Benjamin D. Rogers, Gregory S. Sayuk
Alosetron is a 5-HT3 antagonist indicated for the treatment of IBS-D in a restricted population of women with severe, refractory symptoms not responding to first-line therapies. It has been demonstrated to significantly improve global IBS-D symptoms compared to placebo in two phase 3 trials [25,26]. Following its initial introduction, alosetron was temporarily withdrawn from the market due to AE concerns relating to ischemic colitis and severe constipation. Alosetron was subsequently reintroduced under a Risk Evaluation and Mitigation Strategy (REMS) in June 2002 [27]. ACG Guidelines offer a conditional recommendation for use to address global symptoms in the above restricted patient population [3].
An overview of 5-HT3 receptor antagonists as a treatment option for irritable bowel syndrome with diarrhea
Published in Expert Opinion on Pharmacotherapy, 2023
Karolina Merecz, Mikołaj Hirsa, Olga Biniszewska, Jakub Fichna, Aleksandra Tarasiuk
There are several drugs that are currently under development or already in use for the treatment of different types of IBS. These include ramosetron and granisetron, selective 5-HT3 receptor antagonists, which are used to relieve symptoms in a variety of conditions. Ramosetron alone is commonly used as an antiemetic in chemotherapy, to prevent postoperative nausea and vomiting, and in patients with IBS-D. Also, it has been shown that ramosetron inhibits defecation, colonic dysfunction, and colonic nociception in vivo, while clinical studies have emphasized significant improvements in stool consistency, overall IBS symptoms as well as IBS-related quality of life in IBS-D patients. Granisetron is an antiemetic drug which inhibits 5-HT3 receptors in animal tissues such as heart, ileum, and vagus nerve. In clinical trials in IBS patients, granisetron has been shown to desensitize the rectum and reduce postprandial motility. Ondansetron is the drug used the most for the treatment of IBS-D – it has been shown to improve stool consistency, bowel movements, and bloating. Additionally, ondansetron is most commonly used as an anti-vomiting drug in patients that undergo chemo- and radiotherapy with nausea. Animal studies, performed on mice, have shown that ondansetron reduces also intestinal peristalsis. Another 5-HT3 antagonist, alosetron, is an FDA-approved drug for the treatment of IBS-C as it may prolong colonic transit. Of note, it is currently recommended for women with IBS-D. Alosetron is a gender-dependent drug and has better effects for women, e.g. improved stool consistency. However, adverse effects, as constipation or headaches, are also more frequent in females than in men. According to a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, Black et al. found that all drugs such alosetron, ramosetron, rifaximin, and eluxadoline are superior to placebo, but alosetron and ramosetron appeared to be the most effective [61–63].
Related Knowledge Centers
- 5-Ht3 Antagonist
- Irritable Bowel Syndrome
- Gastrointestinal Tract
- Stenosis
- Toxic Megacolon
- Ischemic Colitis
- Thrombophlebitis
- Crohn's Disease
- Ulcerative Colitis
- Diverticulitis