Luminary Learning Gastrointestinal Disorder- Issue 1

22  • LUMINARY LEARNING: GASTROINTESTINAL DISORDERS tolerable and effective treatment that should be considered suitable for use as a first-line treatment in functional GI disorders manifested by chronic constipation. Tegaserod Tegaserod is a partial 5-HT4 receptor agonist that reduces visceral sensitivity and stimulates the secretion of chloride from epithelial cells. It has been approved by FDA in 2002 and sub- sequently withdrawn from the market in 2007 due to possible adverse cardiovascular effects (heart attack and stroke) [26]. The putative adverse events caused by tegaserod most likely result from its non-selective binding to other serotonin receptors, such as 5-HT1, 5-HT2a and 5-HT2b [53]. FDA had been criticized for this decision and ultimately reconsidered it and allowed for reintroduction of tegaserod under an investigational new drug protocol for IBS-C and chronic idiopathic constipation in women younger than 55 who are not at risk for certain cardiovascular events [53, 54]. The effect of tegaserod on IBS-C in women has been evaluated in a large (n = 661) randomized, controlled trial [55]. It provided significant improvement and satisfactory relief of IBS symptoms over 4 weeks of treatment in 43.3 % of IBS-C patients. The most frequent adverse events leading to study discontinuation in tegaserod-treated patients were diarrhea (1.5 %) and abdominal pain (0.9 %). Although long-term safety of tegaserod was investigated in a prospective study suggesting that treatment was safe over a 12-month period tegaserod was not approved for use in the EU due to the opinion that its benefits does not out- weigh its risks [56]. Prucalopride Prucalopride, which belongs to benzofurans, is a selective agonist of 5-HT4 receptor that exhibits prokinetic effect in the GI tract. It stimulates colonic peristalsis, which provides the main pro- pulsive force for defecation. On the contrary to other 5-HT4, it does not induce cardiovascular adverse events, which may be attributed to its high selectivity over other types of 5-HT receptors and ion channels. Clinical trials with prucalopride (1974 patients in total; both men and women) demonstrated a significant increase in the proportion of patients achieving at least three sponta- neous complete bowel movements (SCBMs) per week compared with placebo [57–59]. Response rates ranged from 24 to 28 % with 4 mg prucalopride, and 9.6–12 % with placebo. Clinically rel- evant improvement was also demonstrated in other measures, including satisfaction with bowel function, perception of the severity of constipation as well as quality of life. It should be also underlined that prucalopride is not effective in children with functional constipation, as showed by Mugie et al. [60]. Regardless of the patient’s age, prucalopride is well tolerated with no impact on the cardiovascular system [26]. The most frequently reported adverse events include headache, abdominal pain, nausea and diarrhea. Prucalopride has been approved in Europe for both men and women; however, it has not been allowed for sale in the USA.