Alosetron treatment

Constipation Serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon, secondary colonic ischemia, and death have been reported with use of alosetron. Immediately discontinue alosetron treatment in patients who develop constipation. 

Fig. 13.4 Response of colonic transit to treatment with alosetron is greater in homozygous long vs heterozygous SERT-P genotype. 5-HT, serotonin. (Reproduced from ref. 63.)...

Alosetron (Lotronex) is a 5-HT3 receptor antagonist. Blocking this receptor results in decreased GI motility. Alosetron received FDA approval in February 2000 for the treatment of women with diarrhea-predominant IBS. In November 2000, at the request of the FDA, the drug was voluntarily withdrawn due to reported cases of ischemic colitis, including some fatalities. 

To reveal the cognition-enhancing potential of the S-HTj antagonists, studies in age-related memory impairment have been carried out with psy-chiatrically healthy subjects impaired with scopolamine and patients with dementia. In a randomized double-blind, double-dummy, four-way crossover study in a small number of subjects, each psychiatrically healthy male subject received placebo, scopolamine [0.4 mg im], scopolamine plus alosetron [10 J,g iv], or alosetron [250 Jg] [Preston 1994 Preston et al. 1991). Assessments of verbal and spatial memory, sedation, and sustained attention were performed before and after treatment. The main results from the study were that scopolamine induced robust deficits on all primary variables measured, the reduction in verbal and spatial memories being attenuated by 10- Jg and 250- Jg doses of alosetron, respectively. No effects on the sedation or on changes in attention were noted. 

Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62-5). Four other 5-HT3 antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics) however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied. 

Alosetron is approved for the treatment of women with severe IBS in whom diarrhea is the predominant symptom ("diarrhea-predominant IBS"). Its efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50-60% of patients report adequate relief of pain and discomfort with alosetron compared with 30-40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. Alosetron has not been evaluated for the treatment of other causes of diarrhea. 

Reddy P. Alosetron A 5-HT3 receptor antagonist for treatment of irritable bowel syndrome. Formulary 2000 35 404-11. 

Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mills JG, Jacques LA. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Ahment Pharmacol Ther 2000 14(l) 23-34. 

Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroenterology 2001 120(2) 557-60. 

Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment. Significant side effects noted with the use of alosetron include severe constipation, fecal... 

Alosetron was approved for U. S. use in February 2000 for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea, although the product was withdrawn in November 2001 because of serious side effects, particularly ischemic colitis. Earlier studies in men for anxiety disorder and schizophrenia, and Phase II studies for nonulcer dyspepsia, have also been discontinued. 

HT4 agonists such as tegaserod. Although they also may blunt visceral sensation, a direct effect on spinal afferents has not been fully established. Alosetron was the first agent in this class specifically approved for the treatment of diarrhea-predominant IBS in women. 

CHAPTER 37 Treatment of Disorders of Bowel MotUity and Water Flux 645 Alosetron and Other 5-HTj Antagonists... 

Study and classification of serotonin receptors has resulted in the design and synthesis of highly selective medicines such as Sumatriptan, for the treatment of migraine, Ondansetron for the suppression of the nausea and vomiting caused by cancer chemotherapy and radiotherapy, and Alosetron for treatment of irritable bowel syndrome. 

A quantitative benefit-harm balance analysis of alosetron for the treatment of irritable bowel syndrome from the patient s perspective has been reported pS "]. There was greater than 99% chance that both the incremental benefit and the incremental risk associated with alosetron are greater than with placebo. The incremental net benefit of alosetron was greatest in patients with the worst quality of life at baseline. 

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