cilansetron and alosetron

Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT(3) antagonists and 5-HT(4) agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS.. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT(3) antagonists or 5-HT(4) agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.. The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT(3) antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT(3) antagonists/5-HT(4) agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT(3) antagonists vs. placebo was 0.78 (95% CI: 0.71-0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80-0.90). Renzapride and cisapride had no benefit in IBS.. Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.

Topics: Adult; Age Factors; Aged; Carbazoles; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Education, Medical, Continuing; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Treatment Outcome

We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS).. Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently.. We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups.. 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.

Topics: Administration, Oral; Carbazoles; Carbolines; Constipation; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Irritable Bowel Syndrome; Male; Phenethylamines; Prognosis; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Treatment Outcome

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.

Topics: Carbazoles; Carbolines; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Pyridines; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists

Topics: Antidepressive Agents; Benzofurans; Carbazoles; Carbolines; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Physical Examination; Pyridines

As the use of the 5-HT(3) receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT(4) receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated.. Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance.. Intravenous alosetron (0.03-0.3 mg.kg(-1)) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15-20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT(3) receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3-1.0 mg.kg(-1)) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon.. Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.

Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Carbazoles; Carbolines; Clonidine; Colitis; Colon; Fasting; Female; Heart Rate; Indoles; Mesenteric Artery, Superior; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyridines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Splanchnic Circulation; Vasoconstrictor Agents; Vasodilator Agents

The effects of corticotropin releasing factor (CRF) and serotonin (5-HT)(3) receptor antagonists on intestinal water transport are not well understood. Hence, we established a CRF-induced abnormal water transport model in rat colon, and evaluated the effects of 5-HT(3) receptor antagonists including ramosetron, alosetron, and cilansetron, and the antidiarrheal agent loperamide, in this model. In addition, the effects of 5-HT(3) receptor antagonists and loperamide on abnormal defecation induced by CRF in rats were examined. Colonic water transport was measured in colonic loops in conscious rats. Centrally administered CRF (3-30 microg/kg) markedly decreased colonic fluid loss, whereas oral administration of ramosetron (3, 30 microg/kg), alosetron (300 microg/kg), cilansetron (300 microg/kg), or loperamide (3 mg/kg) significantly inhibited it. Ramosetron (1-10 microg/kg), alosetron (10-100 microg/kg), cilansetron (10-100 microg/kg), or loperamide (0.3-3 mg/kg) also showed dose-dependent inhibition of CRF-induced defecation in rats. These results suggest that 5-HT(3) receptors are involved in both abnormal colonic water transport and defecation induced by CRF, and that the inhibitory effects of 5-HT(3) receptor antagonists on CRF-induced abnormal defecation partly result from their ameliorating action on colonic water transport.

Topics: Animals; Antidiarrheals; Benzimidazoles; Carbazoles; Carbolines; Colon; Corticotropin-Releasing Hormone; Defecation; Dose-Response Relationship, Drug; Injections, Intraventricular; Loperamide; Male; Pyridines; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Water

We examined the pharmacological profile of ramosetron, a 5-HT(3)-receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT(3)-receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT(3) receptors, with K(i) values of 0.091 +/- 0.014 and 0.22 +/- 0.051 nmol/L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT(3) receptor was extremely slow (t(1/2) = 560 min), while alosetron (t(1/2) = 180 min) and cilansetron (t(1/2) = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA(2) values of 8.6 (8.5 - 9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED(50) value of 1.2 (0.93 - 1.6) microg/kg. In addition, oral ramosetron dose-dependently inhibited restraint stress-induced defecation in rats, with an ED(50) value of 0.62 (0.17 - 1.2) microg/kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT(3)-receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.

Topics: Animals; Benzimidazoles; Carbazoles; Carbolines; Carrier Proteins; Colon; Defecation; Gastrointestinal Agents; Guinea Pigs; Humans; Ion Channels; Irritable Bowel Syndrome; Loperamide; Male; Muscle, Smooth; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Restraint, Physical; Serotonin Antagonists; Stress, Psychological

The aim of this study was to establish a pathophysiologic model of irritable bowel syndrome, and then to evaluate the pharmaceutical efficacy of ramosetron, a potent serotonin 3 (5-HT(3)) receptor antagonist, and other anti-irritable bowel syndrome agents in this model. Rats stressed by a conditioned stress procedure exhibited marked prolongation of freezing time, an index of fear level, and an increase in the frequency of defecation (P<0.01). A corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF, inhibited both defecation and freezing behavior, while the antidiarrheal loperamide inhibited defecation only. The 5-HT(3) receptor antagonists ramosetron, cilansetron and alosetron also inhibited defecation (ED(50) values: 0.012, 0.094, 0.078 mg/kg p.o., respectively) without affecting freezing behavior. Ramosetron showed longer-lasting effect on defecation than cilansetron. Stress also resulted in increases in both proximal and distal colonic transit rates. Ramosetron and other 5-HT(3) receptor antagonists at doses inhibiting stress-induced defecation also ameliorated both stress-stimulated colonic transit rates. These results suggest that ramosetron, as well as agents used for the treatment of irritable bowel syndrome with diarrhea, has beneficial effects against emotional stress-induced colonic dysfunction. Furthermore, this emotional stress model may be useful in evaluation of drugs to treat irritable bowel syndrome presenting with diarrhea.

Topics: Animals; Behavior, Animal; Benzimidazoles; Carbazoles; Carbolines; Colon; Colonic Diseases, Functional; Conditioning, Psychological; Corticotropin-Releasing Hormone; Defecation; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Gastrointestinal Transit; Immobilization; Irritable Bowel Syndrome; Loperamide; Male; Peptide Fragments; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological; Time Factors; Treatment Outcome