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The introduction of selective serotonin reuptake inhibitors (Celexa, Prozac and Zoloft) in the late 1980s revolutionized the management of depression. Ondansetron (Zofran), introduced in 1991 as the first serotonin antagonist, effectively removed the dose-limiting side effects of nausea and vomiting from chemotherapy. Early in 2000, GlaxoWellcome is expected to market alosetron, the first 5-HT3 antagonist for the treatment of irritable bowel syndrome. Alosetron was originally developed for the treatment of schizophrenia based on earlier published results (Guptka SK et al. J Clin Pharmacol 1995; 35(2): 202-7). The link between these diverse clinical entities is the central role of serotonin.

Irritable bowel syndrome (IBS) is a relatively common malady affecting approximately 20% of the population, with a female-to-male ratio of more than two to one. Abdominal cramping, diarrhea and/or constipation, bloating and gas characterize the syndrome. IBS is a functional self-limiting disorder with no known cause or identifiable anatomic abnormalities. Management has traditionally consisted of antispasmodics, antidiarrheals, laxatives, anxiolytics, avoidance of food triggers and stress reduction. All current therapies have met with limited success.

A clearer understanding of the nature of the enteric nervous system and the role of serotonin HT3 receptors have provided clues to the underlying pathophysiology of IBS. The GI tract innervation has been likened to a "little brain" with more similarities to the central nervous system than the peripheral. (Gastroenterologyl Link) While a multitude of neurotransmitters have been identified in the enteric nervous system, three have held predominant roles in research activity: serotonin, somatostatin and Substance P. The enteric nervous system detects bowel distension on the basis of pressure-sensitive cells in the bowel lumen. Once activated, these pressure-sensitive cells promote the release of serotonin, which in turn promotes both secretory and peristaltic function. At least four serotonergic receptors have been identified to be participants in the secretory and peristaltic response. The serotonin 5-HT3 receptor is the fast response receptor. Patients with diarrhea-predominant IBS may have higher post-prandial levels of serotonin than do normal controls. (Gut Link) Patients with carcinoid diarrhea demonstrate similarly increased pre- and post-prandial serotonin levels. Based on this evidence, a hypothesis basing the etiology of IBS on excessive serotonergic activity seems reasonable.

The Gastrointestinal Drugs Advisory Board of the FDA met in November 1999 to review the New Drug Application (NDA) for alosetron submitted by GlaxoWellcome. (FDA Link) The Committee unanimously approved the NDA for female patients with IBS, where the predominant symptom is diarrhea. Why just females? Simply put, alosetron does not work in males. Or at least it did not in the Phase II trials and at any of the doses tested. This is in marked contrast to the result in female patients, where all doses tested produced an improvement in symptoms. There have been two pivotal Phase III trials comparing alosetron to placebo. Based on the Phase II studies, 1 milligram BID alosetron was the lowest effective dose. The population of both Phase III studies was exclusively females with IBS whose predominant symptom was diarrhea. It is important to note that although patients were followed for longer periods, both trials were of 12-week treatment duration only. The primary measure of efficacy in both trials was the answer to the following question, "In the past seven days have you had adequate relief of your irritable bowel syndrome pain and discomfort?" Secondary endpoints included stool consistency, percent days with urgency, stool frequency, percent days with incomplete evacuation, and percent days with bloating. Improvement over placebo was noted in both Phase III clinical trials in all secondary measures except "percent days with bloating."

Based on the two trials, it would appear that alosetron shows reasonable activity. But the efficacy came at some cost. In one trial, the number of subjects withdrawing due to side effects was significantly higher in the alosetron treatment group than in the placebo group (27% vs 5% in the placebo group). Constipation as a side effect is not unanticipated, given the drug’s pharmacology and experience to date with ondansetron. The good news is that as little as a 4-day drug holiday appears to reverse this side effect with patients returning to baseline. Unfortunately, drug discontinuation brings about a rather abrupt return of baseline symptoms.

More disconcerting than the incidence of constipation was a low but significant incidence of what was called ischemic colitis (1 of 300 subjects). The exact mechanism by which a serotonin blocker would induce ischemic colitis is unclear. Given the prevalence of IBS and the benign natural history of the syndrome, this incidence of a major complication associated with alosetron administration is significant. Since the underlying disease produces symptoms of abdominal pain and diarrhea, only the presence of blood in the stool may distinguish ischemic colitis from IBS in some patients. Long-term studies of up to a year of therapy are currently under way. These studies should help elucidate the incidence of ischemic colitis.

It should be noted that the FDA has not yet approved alosetron. However, it is likely to do so early this year. Sales for alosetron are expected to reach $600 million in sales by 2003, with some analysts suggesting sales in excess of $1 billion annually. At least one other pharmaceutical giant, Novartis, is hot on the heels of GlaxoWellcome with its own version of a 5-HT3 antagonist, tegaserod.