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Drugs Affecting the Gastrointestinal System
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: Although Alosetron has been assigned with the letter (B), according to the FDA categorization, but it should be used with caution because limited human data is available and the reproduction studies in animals have shown low risk.
Functional abdominal disorders
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Bernard Coulie, Michael Camilleri
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
Safety Pharmacology and the GI Tract
Published in Shayne C. Gad, 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].
How can we develop better antispasmodics for irritable bowel syndrome?
Published in Expert Opinion on Drug Discovery, 2019
Sheyda Ranjbar, Seyed Afshin Seyednejad, Shekoufeh Nikfar, Roja Rahimi, Mohammad Abdollahi
Serotonin (5-HT) is a dominant molecule in GI, exhibiting characteristics of both an NT and a local hormone. Serotonin plays an important role in modulating GI functions including motility [39]. Seven subtypes of serotonin receptors have been identified but currently, 5-HT3 and 5-HT4 subtypes have the greatest potential in drug discovery approaches especially in gut disorders [40]. 5-HT3 antagonists inhibit the excitatory cholinergic motor neurons and SMCs contraction leading to a decrease in GI motility [41]. Alosetron, the serotonin 5-HT3 receptor antagonist, was approved in 2000 but its use due to lethal adverse effects is now restricted to a refractory subgroup of IBS-D patients [42]. Other drugs in this group ramosetron, cilansetron and ondansetron also reduce discomfort in IBS-D patients [43].
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].