Rationale for IBS and non-IBS constipation - According to ROME II criteria, Irritable Bowel Syndrome (IBS) is subdivided into 3 major subsets of patients exhibiting either diarrhea (IBS-D), constipation (IBS-C) or alternating constipation and diarrhea (IBS-A) representing 30, 50 and 20% of all IBS patients respectively. However chronic constipation may occur in patients not exhibiting abdominal pain and consequently not included in IBS-C patients.
Chronic constipation as IBS-C is often associated with slow colonic transit or rectal retention with impared rectal sensitivity and/or motility reflex.
Chronic constipation is a common complaint for which pharmacological therapy has not had a dramatic impact, evidenced by the absence of any good controlled trials demonstrating efficacy. Metoclopramide appears to be ineffective in the treatment of chronic constipation (30) and bulking agents have some demonstrated efficacy but many they generate abdominal bloating. Classical laxatives stimulating water secretion may be used in acute situation and osmotic agents such as polyethylene glycol have a demonstrated efficacy with limited side effects, but their prolonged use cannot be recommended.
Serotonergic agents: 5-HTa agonists - Cisapride has shown some promise in the treatment of idiopathic constipation even though its effect on colonic motility is not clear (31). Regardless, there have been several controlled trials in which cisapride increased the number of bowel movements in patients with constipation (32). The most significant results were obtained in patients with idiopathic constipation and children with refractory constipation (33). However, 2 recent studies show no effect in constipation-dominant IBS (34, 35).
Tegaserod (5) (HTF 919) is a partial 5-HT4 receptor agonist in development. In constipation-predominant IBS, oral tegaserod, 2 mg twice daily for 1 week, accelerates small intestinal transit and increases proximal colonic emptying (36). Tegaserod, 2 mg or 6 mg twice daily, was superior to placebo in relieving abdominal discomfort, bloating and constipation. In vitro studies suggest that tegaserod, in a range of concentrations likely to occur during clinical use, does not delay cardiac repolarization or prolong the QT interval of the electrocardiogram, as does cisapride (37). Accordingly, administration of up to 100 mg to humans has not been associated with any detectable change in QT intervals. Tegaserod has gained the FDA approval for IBS-C treatment in females and is presently marketed in the US.
Prucalopride (10) (R093877), the first of a new chemical class of benzofurans, has specific agonist activity at 5-HT4 receptors. In vitro studies suggest it is less potent than cisapride, and approximately equivalent to tegaserod, in producing relaxation in isolated canine smooth muscle strips (38). In a rat model of postoperative ileus, prucalopride (1 and 5 mg/kg) had a modest effect in promoting intestinal transit. The combination of prucalopride (1 mg/kg) and the 5-HT3 antagonist, granisetron (9) (50 pg/kg), significantly improved intestinal transit after laparotomy with or without mechanical stimulation of the intestine (39). In 50 healthy human volunteers, 0.5-4 mg prucalopride daily for 7 days accelerated colonic transit and increased proximal colonic emptying, but had to effect on gastric emptying or small intestinal transit (12).
Serotonergic agents: mixed 5-HTA agonist / 5-HTa antagonist - The assumed advantage of such association is limited to a predominant 5-HT4 agonist effect on colonic transit associated with an antinociceptive activity reducing abdominal pain linked to the 5-HT3 receptor antagonism.
Renzapride (3), a mixed compound with 5-HT4 agonist and 5-HT3 antagonist activities, has recently demonstrated improvement of symptoms in IBS patients. In this pilot study, IBS-C patients were daily treated with renzapride (2 mg bid) during 28 days associated with an increased number of stools and looseming of stool consistently but also a 30-64% decrease in abdominal pain/discomfort without any cardiac effects on QTs interval (13).
CCK antagonists - CCK has been shown to stimulate colonic motility, and despite the existence of CCK receptors on colonic smooth muscle cells, the colonic motor response is indirectly mediated. In dogs and humans, this response involves an opioid component, which also participates in the colonic motor response to eating (40). In dogs, CCK-induced colonic motor stimulation involves opioid receptors in the central nervous system, while postprandial colonic stimulation involves central CCK-A receptors, which have been localized to the ventromedial hypothalamus in the rat
Clinical evidence suggests that CCK plays a part in IBS. An elevated level of plasma CCK in IBS patients with diarrhea and a diminished level of the peptide in IBS patients with slow transit constipation have been demonstrated. A one-week treatment with the CCK-receptor antagonist loxiglumide (800 mg three times daily) strongly accelerated colonic transit in healthy volunteers (42). Since CCK is known to stimulate colonic motility, it seems paradoxical that a CCK antagonist should also stimulate colonic transit. Other data provide further evidence that CCK is involved in the regulation of colonic motility (43). These authors have shown that loxiglumide selectively delayed transit of the ascending colon in IBS patients. Loxiglumide did not affect the more distal parts of the colon, nor did it exert any effect in healthy controls, whatever the colonic site considered. The selectivity of loxiglumide action in IBS patients correlates with the hypersensitivity to CCK observed in this group. Also, the action of loxiglumide was confined to the proximal colon, which is highly innervated; this supports the hypothesis that CCK acts through the afferent fibers of the vagus nerve.
Several CCK antagonists are under consideration for the treatment of IBS. Only proglumide and benzotript have been approved in Europe for use in humans for other indications. Both asperlicin and L-364718 (14) (devazepide) are more potent than the approved CCK antagonists, but only L-364718 is orally effective in animal models. However, no studies were reported with these compounds in constipated patients.
The results of a pilot study in IBS patients with dexloxiglumide (15) have already been published (44). This study has shown a proportion of responders greater than placebo particularly in non D-IBS (dexloxiglumide: 60% vs placebo: 43% of responders). More recently a Phase II clinical trial has been performed in IBS constipated patients showing similar global improvement in terms of percentage of responders (dexloxiglumide: 61% vs placebo: 46%) with significant effects on both pain and bloating and with the increased frequency of stools (unpublished data).
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Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.