Effect of female sex hormone supplementation and withdrawal on gastrointestinal and colonic transit in postmenopausal women

Females are disproportionately affected by constipation, which is often aggravated during pregnancy. Bowel function also changes during the luteal phase of the menstrual cycle. The aim was to compare the effects of acute administration of female sex steroids on gastric emptying, small bowel transit and colonic transit in healthy postmenopausal subjects. A second aim was to determine whether withdrawal of the hormones was associated with a change in transit. Forty-nine postmenopausal females were randomized to receive for 7 days 400 mg day(-1) micronized progesterone, 0.2 mg day(-1) oestradiol, combination of the two, or placebo. Treatment groups were balanced on age. Participants underwent whole gut transit measurement by scintigraphy using a 99m-labeled technetium-egg meal and 111-labeled indium-charcoal via a delayed-release capsule. Transit measurement was repeated after withdrawal of the study medications. The primary endpoints were ascending colon (AC) emptying half-life time (t1/2) and colonic geometric centre (GC) at 24 h. Secondary analysis variables were GC at 4 and 48 h, gastric emptying t1/2 and colonic filling at 6 h. There was a significant overall effect of progesterone on colonic transit with shorter AC emptying t1/2 and significantly greater colonic GC at 48 h. No transit endpoints were altered by oestradiol or combined hormonal treatment relative to placebo. Oestradiol and progesterone resulted in looser stool consistency. Withdrawal of the hormone supplement was not associated with significant alteration in transit. Micronized progesterone does not retard colonic transit in postmenopausal females.     

Does co‐administration of a non‐selective opiate antagonist enhance acceleration of transit by a 5‐HT4 agonist in constipation‐predominant irritable bowel syndrome? A randomized controlled trial

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.     

Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study

Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans. In a double-blind, randomized study, 30 healthy volunteers were randomly assigned to DRO 5 mg b.i.d. or PLA for three doses. We measured GI functions noninvasively: day 0, Ensure satiation test to measure maximum tolerated volume (MTV) and 30-min post-Ensure symptoms; day 1, scintigraphic transit ((111)In-egg meal) and fasting and postprandial gastric volume ((99Tcm)-SPECT); day 2, 24-h colonic transit and repeat satiation test. ancova was used to compare treatment groups with gender, age, and, for the satiation test, the baseline MTV, as covariates. A log-rank test was used to assess treatment effects on gastric emptying. Planned sample size had 80% power to detect 25-30% differences in primary end points. There was an overall retardation of gastric emptying with DRO (P = 0.018); this was more pronounced in females (P = 0.011), than in males (P = 0.184). No significant treatment differences were detected for gastric volumes, MTV, post-Ensure(R) symptoms, small bowel and colonic transit. Fasting gastric volume was greater in males receiving DRO compared with PLA (238 +/- 17 vs 185 +/- 16, P = 0.04). DRO retards gastric emptying in humans; effects are gender-related. Dronabinol also increases fasting gastric volumes in males.     

Pharmacogenetics of low dose clonidine in irritable bowel syndrome

Abstract  Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (gastrointestinal, GI) sensorimotor functions. We aimed to determine whether candidate ADR-SER genes affect GI responses to low dose clonidine (CLO) in humans. Forty healthy and 120 irritable bowel syndrome (IBS) participants received CLO, 0.1 mg or 0.15 mg b.i.d., for 6 days. At baseline and post-CLO, we measured: gastric volume (GV); satiation volume; rectal compliance, sensation thresholds and ratings with distensions. Genetic variations tested were: α2A (C-1291G), α2C (Del 322-325), GNβ3 (C825T) and solute carrier family 6 ( neurotransmitter transporter, serotonin ) , member 4 ( SLC6A4 ) (serotonin transporter linked polymorphic region). CLO reduced volume to satiation ( P  = 0.002), postprandial GV ( P  < 0.001), sensation threshold for pain (<0.001); CLO increased rectal compliance ( P  = 0.024). There were significant associations between post-CLO responses and gene variations for ΔGV ( α2A and SLC6A4 ), rectal sensation of gas ( α2A , GNβ3 ), urgency ( α2A ); and pain ( GNβ3 and SLC6A4 ); and rectal compliance ( SLC6A4 ). α2A , GNβ3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.     

A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating

AIM: To evaluate the effects of a combination probiotic on symptoms and colonic transit in patients with irritable bowel syndrome (IBS) and significant bloating. METHODS: Forty-eight patients with Rome II IBS were randomized in a parallel group, double-blind design to placebo or VSL# 3 twice daily (31 patients received 4 weeks and 17 patients 8 weeks of treatment). Pre- and post-treatment colonic transit measurements were performed using scintigraphy with (111)In charcoal. Symptoms were summarized as an average daily score for the entire period of treatment and separately for the first 4 weeks of treatment. Weekly satisfactory relief of abdominal bloating was assessed. RESULTS: Treatment with VSL# 3 was associated with reduced flatulence over the entire treatment period (placebo 39.5 +/- 2.6 vs VSL# 3 29.7 +/- 2.6, P = 0.011); similarly, during the first 4 weeks of treatment, flatulence scores were reduced (placebo 40.1 +/- 2.5 vs VSL# 3 30.8 +/- 2.5, P = 0.014). Proportions of responders for satisfactory relief of bloating, stool-related symptoms, abdominal pain and bloating scores were not different. Colonic transit was retarded with VSL# 3 relative to placebo (colon geometric center 2.27 +/- 0.20 vs 2.83 +/- 0.19, P = 0.05 respectively). CONCLUSION: VSL# 3 reduces flatulence scores and retards colonic transit without altering bowel function in patients with IBS and bloating.     

Relationship of cytochrome P450 pharmacogenetics to the effects of yohimbine on gastrointestinal transit and catecholamines in healthy subjects

Abstract  Alpha-2 adrenergic receptors tonically inhibit colonic motility and the α₂-adrenergic antagonist yohimbine, given intravenously, increased colonic tone in humans. However, the effect of yohimbine on colonic transit in humans is unknown. In this study, 30 healthy volunteers were randomized to yohimbine 16.2 mg p.o. t.i.d. or identical placebo for 7 days. We evaluated gastric emptying, small intestinal, and colonic transit by scinitigraphy, bowel habits, haemodynamics and plasma catecholamines. As cytochrome P450 enzymes metabolize yohimbine, P450 genotypes ( CYP2D6 and CYP3A4 ) were determined in 25 of 30 subjects who consented to genetic studies. The relationship between drug metabolizer status predicted by CYP2D6 and CYP3A4 and effects of yohmibine were assessed. Compared to placebo, yohimbine increased ( P  ≤ 0.02) diastolic blood pressure, plasma noradrenaline concentrations and maximum tolerated volume during the satiation test [yohimbine (1241 ± 88, mean ± SEM) vs placebo (1015 ± 87), P  = 0.054]. However, yohimbine did not affect gastrointestinal transit. Based on CYP2D6 and CYP3A4 alleles, seven and 18 subjects were, respectively, extensive (EM) and poor (PM) metabolizers of yohimbine. Compared to EM, PM of yohimbine had a greater increase in plasma noradrenaline ( P  = 0.1 for PM vs EM), lower maximum tolerated volumes (1120 ± 95 vs 1484 + 131 mL, P  = 0.02), and faster colonic transit (i.e. GC₂₄ was 3.0 ± 0.4 vs 2.1 ± 0.5, P  = 0.1). These data suggest that CYP2D6 and CYP3A4 genotypes which determine the metabolism of yohimbine may influence its sympathetic and gastrointestinal effects.