Clinical Trials of Probiotics in Patients With Irritable Bowel Syndrome: Some Points to Consider

Probiotic products in various formulations are widely used world-wide for a seemingly limitless range of indications––from health maintenance to the alleviation of common intestinal ailments and on to the prevention and treatment of a variety of gastrointestinal diseases and disorders. The profusion of probiotic preparations, together with a very different regulatory climate compared to that which surrounds drugs and devices, leaves the consumer and the health care professional alike bewildered. How can they tell which products truly are what they claim to be? Which probiotics should be chosen for a particular clinical situation? These questions are thrown into stark relief when one evaluates the literature on probiotics in irritable bowel syndrome. To provide some guidance the current probiotic landscape is reviewed and some achievable steps to help bring light to a murky environment are proposed. The goal is to promote verifiable quality control and generate actionable evidence from well-conducted clinical trials of probiotic products in irritable bowel syndrome.

Prokinetics in the Management of Functional Gastrointestinal Disorders

A variety of common and some not common gastrointestinal syndromes are thought to be based on impaired gut motility. For some, the role of motility is well defined, for others and the functional gastrointestinal disorders, in particular, the role of hypo- or dysmotility remains unclear. Over the years pharmacological and physiological laboratories have developed drugs which stimulate gut motility; many have been evaluated in motility and functional disorders with what can best be described as mixed results. Lack of receptor specificity and resultant expected and unexpected adverse events have led to the demise of some of these agents. Newer, more selective agents offer promise but the heterogeneity of the clinical disorders they target continues to pose a formidable challenge to drug development in this area.

Factors Predictive of Treatment-Emergent Adverse Events of Prucalopride: An Integrated Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.

Factors Predictive of Treatment-Emergent Adverse Events of Prucalopride: An Integrated Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials

BACKGROUND/AIMS: This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. METHODS: Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. RESULTS: Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. CONCLUSIONS: Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.

Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non-Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies

BACKGROUND/AIMS: To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). METHODS: Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of > or = 3 spontaneous complete bowel movements (SCBMs)/week; average increases of > or = 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS: Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of > or = 3 SCBMs/week in Asian (34% vs. 11%, P or = 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. CONCLUSIONS: Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.

Microflora Modulation of Motility

That gastrointestinal motility can influence the gut microbiota has been known for decades and the clinical consequences of impaired motility, in terms of the bacterial population of the small intestine, amply illustrated by the syndrome of small intestinal bacterial overgrowth which so commonly accompanies diffuse intestinal motility disorders. As the importance of the microbiota to homeostasis in health and to a variety of disease states is increasingly appreciated and as the full diversity and biology of this "hidden organ" have been revealed by molecular methodologies, the true nature of the interaction between the microbiota and motility is being re-examined and the complexity of this relationship exposed. In health, as well as in disease states, this is a truly bi-directional relationship: not only can gut motor patterns influence the microbiota but changes in the microbiota can exert profound influences on gut sensori-motor function.