Pharmacodynamic effects of a novel prokinetic 5-HT4 receptor agonist, ATI-7505, in humans

ATI-7505, an investigational 5-HT(4) receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T(1/2), colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T(1/2). Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T(1/2) (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T(1/2) (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.     

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation

Abstract  Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT₄ receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T _1/2 after first dose. Secondary endpoints included gastric emptying (GE) T _1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T _1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T _1/2 at 15–50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.     

Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo-controlled study

We studied effects of i.v. atilmotin (BAX-ACC-1638, a novel motilin agonist, circulating t(1/2) < 10 min) on gastrointestinal transit in humans using a randomized, parallel-group, dose-response double-blind study of i.v. atilmotin, 6, 30, 60 microg or vehicle (placebo) given 2 min after standardized breakfast, lunch and dinner. The breakfast meal contained (99m)Tc-eggs and (111)In-milk. Full gastrointestinal transit was measured by scintigraphy. Primary endpoints were % gastric emptying (GE) at 30 min, GE t(1/2), colonic filling (CF) at 6 h, and geometric centre of colonic transit at 24 h. Analysis included adjustment for age, gender and body mass index, with Bonferroni correction applied for multiple comparisons. A significant treatment effect of atilmotin was detected for GE (%) at 30 min for solids and liquids (P < 0.01 for both). There were no significant effects on CF or CT and no significant adverse clinical events. Thus, atilmotin accelerates GE of solids and liquids in healthy humans. These data suggest that, at the doses tested, atilmotin should be considered for treatment of stomach motility disorders.     

Effect of tegaserod on gut transit in male and female subjects

Tegaserod is a novel selective serotonin receptor type-4 (5-HT(4)) partial agonist that stimulates gastrointestinal (GI) motility. Tegaserod has proven efficacy in irritable bowel syndrome with constipation in women and in men and women with chronic idiopathic constipation. The effects on gastric emptying, small bowel transit and colonic transit have not been studied in detail in male and female subjects. This study aimed therefore to assess the effect of gender on GI transit with and without tegaserod. A randomized, placebo-controlled, double-blind, crossover study was performed in 40 healthy subjects (23 males, 17 females). Each treatment period involved three and a half days of bid treatment with either 6 mg tegaserod or an identical placebo. Transit parameters were assessed by a scintigraphy. Tegaserod significantly accelerated gastric emptying, small bowel and colonic transit times (P<0.05-0.0001). The effect was more apparent in male subjects than in females (P=0.044 to P<0.0001). The most striking prokinetic effects were observed in the upper GI tract (stomach and small intestine). In both healthy male and female subjects, tegaserod markedly accelerated small intestinal transit, and induced a significant increase in gastric emptying time and colonic transit. The results imply that tegaserod is a potent prokinetic agent throughout the GI in both sexes.     

Model of rapid gastrointestinal transit in dogs: effects of muscarinic antagonists and a nitric oxide synthase inhibitor

Our aims were to establish a canine model of rapid gastrointestinal transit, and to test the effects of muscarinic receptor antagonists (atropine, pirenzepine, AF-DX116, and darifenacin), and an NOS inhibitor, L-nitro-N-arginine (L-NNA) in this model. For gastric emptying and small bowel transit, 99mTc-labelled DTPA were added to a meal of skimmed milk (236 mL) that contained 2.4 g of magnesium hydroxide. Regional colonic transit was measured by111In-labelled beads placed in a capsule that released isotope in the proximal colon. Scintiscans were taken at regular intervals and indices of transit were calculated. Drugs were administrated intravenously. Gastric emptying, small bowel and colonic transit were rapid. Atropine and darifenacin (a selective M3 antagonist) delayed gastric emptying and colonic transit, the selective M1 and M2 muscarinic antagonists did not. The muscarinic blockers did not slow small bowel transit. L-NNA delayed small bowel and colonic transit but did not slow gastric emptying. A model suitable for the preclinical study of antidiarrhoeals was established. M3 receptors are important in the control of gastric emptying and colonic transit, and NOS inhibition slowed small bowel and colonic 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.     

Differential effects of selective and non‐selective muscarinic antagonists on gastrointestinal transit and bowel function in healthy women

Background The gastrointestinal effects of antimuscarinic drugs used to treat overactive bladder may be related to the selectivity of these agents for M₃‐muscarinic receptor subtypes. We compared the effects of non‐selective (fesoterodine) and M₃‐selective (solifenacin) antimuscarinics on gastrointestinal transit in healthy women. Methods Gastric emptying (GE), small‐intestinal transit (colonic filling at 6 h), colonic transit [geometric center at 24 h (GC24; primary endpoint) and 48 h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8 mg, solifenacin 10 mg, or placebo (2 : 2 : 1) for 14 days. An interim analysis to finalize sample size was conducted. Key Results After 60 subjects [placebo (n = 12), fesoterodine (n = 25), solifenacin (n = 23)] completed the study, the study was terminated due to a prespecified criterion (sample size ≥452.5 needed to provide ≥80% power to demonstrate superiority of fesoterodine over solifenacin in GC24). Compared with baseline, (i) placebo delayed small‐intestinal, but not colonic, transit, (ii) fesoterodine significantly increased GE t_1/2vs placebo (17.0 min; P = 0.027), and (iii) fesoterodine and solifenacin delayed small‐intestinal (?36.8% and ?21.8%, respectively, P < 0.001 vs placebo) and colonic transit (GC24: ?0.44 and ?0.49, respectively, P < 0.05 vs placebo; GC48: ?0.25 and ?0.65, respectively, P > 0.05 vs placebo). Solifenacin increased stool hardness from baseline (P = 0.010 for difference vs fesoterodine); stool frequency was comparable. Conclusions & Inferences In healthy women, fesoterodine had greater effects on small‐intestinal transit and solifenacin had greater effects on colonic transit; the latter finding may explain why solifenacin, but not fesoterodine, increased stool hardness. (ClinicalTrials.gov ID: NCT00892034).     

Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans

Background Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short‐term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6‐h infusion in humans. Methods Ghrelin (15 pmol kg^?1 min^?1) or saline was infused intravenously for 360 min after intake of radio‐opaque markers, acetaminophen, and lactulose after a standardized breakfast in 12 male volunteers. Gastric emptying, orocecal transit, colonic transit, postprandial plasma concentrations of glucose, insulin, glucagon‐like peptide‐1 (GLP‐1), and peptide YY were assessed. In vitro studies of gastrointestinal muscle contractility were performed. Key Results The gastric emptying rate was faster for ghrelin compared to saline (P = 0.002) with a shorter half‐emptying time (50.3 ± 3.9 vs 59.9 ± 4.4 min, P = 0.004). There was no effect of ghrelin on orocecal or colonic transit. Postprandial elevations of plasma glucose, insulin, and GLP‐1 occurred 15 min earlier and were higher with ghrelin. The insulinogenic index did not change during ghrelin infusion. Basal in vitro contractility was unaffected by ghrelin. Conclusions & Inferences The effect of a 6‐h ghrelin infusion on gastrointestinal motility is limited to the stomach without affecting orocecal or colonic transit. Plasma glucose, insulin, and GLP‐1 are elevated postprandially, probably as a result of the hastened gastric emptying. Changes in glucose homeostasis as a consequence of stimulated gastric emptying and hormone release, need to be taken into account in the use of pharmacological stimulants for the treatment of motility disorders.     

The influence of sacral nerve stimulation on gastrointestinal motor function in patients with fecal incontinence

Background Sacral nerve stimulation (SNS) is a well‐established treatment for fecal incontinence of various etiologies. However, the mechanism of action remains unclear. The aim of the present study was to determine whether SNS affects gastric emptying, small intestinal transit or colonic transit times. Methods Seven patients with a permanently implanted sacral nerve stimulator participated in a double‐blind randomized cross‐over study. The patients were allocated to stimulation ON or OFF for two 7‐day periods separated by at least 1 week. On days 4–7 of each 7‐day period, the patients were examined by gamma camera imaging to measure gastric emptying, small intestinal transit and colonic transit parameters of a radiolabeled, 1600 kJ mixed solid and liquid meal ingested on day 4. Key Results Sacral nerve stimulation did not change gastric retention at 15 min, gastric mean emptying time, gastric half emptying time, small intestinal mean transit time or colonic geometric center after 24, 48 and 72 h. Conclusions & Inferences Sacral nerve stimulation does not induce major changes in the propulsive capacity of the gastrointestinal tract in patients successfully treated for fecal incontinence with permanent sacral nerve stimulator.     

Effect of cyclooxygenase-2 inhibitors on gastric emptying and small intestinal transit in humans

Endogenous prostaglandins regulate smooth muscle activity; prostaglandins and cyclooxygenase (COX) inhibitors influence gastrointestinal motility in inflammatory states such as postoperative ileus in animal models. The objective of this study was to evaluate the effects of two COX-2 inhibitors on gastric emptying and intestinal transit in healthy humans. In a double-blind, placebo-controlled, parallel-group study, 66 healthy volunteers were randomized to one of two commercially available oral COX-2 inhibitors (celecoxib and rofecoxib), cisapride (positive control), or placebo. Following 7 days on therapy, study participants underwent a test of gastric emptying and small bowel transit of liquids and solids using scintigraphy. Data were analysed using Kruskal-Wallis (ANOVA on ranks)and Mann-Whitney rank sum tests. There were significant group effects on transit of solids: gastric emptying (ANOVA, P = 0.005) and small bowel transit (ANOVA, P = 0.056). However, neither COX-2 inhibitor significantly accelerated the liquid or solid gastric emptying or small bowel transit compared with placebo. The positive control, cisapride, accelerated gastric emptying of solids (post-lag slope of gastric emptying, P < 0.05), and small bowel transit of solids (t10%, P = 0.016). At maximum clinically approved dosages, celecoxib and rofecoxib have no significant effects on gastric emptying or small intestinal transit in healthy humans. Cisapride accelerates gastric emptying and small bowel transit in healthy humans.     

Glucagon like peptide-1 accelerates colonic transit via central CRF and peripheral vagal pathways in conscious rats

Glucagon like peptide-1 (7-36) (GLP-1), one of the gastrointestinal (GI) regulatory peptide, is known to act as a stress related brain neurotransmitter mediating GI function. Central administration of GLP-1 inhibits gastric emptying. However, little is known about the effect of central GLP-1 on colonic transit. Effects and mechanism of GLP-1 on colonic transit were investigated in conscious rats. Immediately after intracerebroventricular (icv)-injection of GLP-1, 51Cr was applied via the catheter positioned to the proximal colon. 90 min after 51Cr injection, rats were euthanized and the colon was removed and divided into 10 equal segments. The radioactivity of each segment was counted and the geometric center (GC) was calculated. Icv-injection of GLP-1 (0.3-3 nmol) dose-dependently accelerated colonic transit [(GC: 4.4+/-0.2 in controls, 7.8+/-0.5 in GLP-1 (3 nmol)]. In contrast, intraperitoneal (ip)-injection of GLP-1 (3 nmol) did not modify colonic transit. Icv-injection of GLP-1 (3 nmol)-induced acceleration of colonic transit was attenuated by vagotomy, atropine and hexamethonium, but not by guanethidine. Icv-injection of GLP-1 (3 nmol)-induced acceleration of colonic transit was abolished by corticotropin releasing factor (CRF) antagonist, astressin. Restraint stress-induced acceleration of colonic transit was abolished by a selective GLP-1 receptor antagonist, exendin. These results indicate that the endogenous GLP-1 is involved in mediating stress-induced alteration of colonic transit via a central CRF and peripheral cholinergic pathways in rats.     

Effect of tolterodine on gastrointestinal transit and bowel habits in healthy subjects

Abstract  Clinical trials and observations suggest that constipation is an uncommon side effect of treating overactive bladder with the muscarinic receptor antagonist tolterodine. Because muscarinic antagonism inhibits gastrointestinal motor activity, we evaluated the effects of tolterodine on bowel habits, gastrointestinal and colonic transit in healthy subjects. In this double-blind study, 36 healthy subjects were randomized to tolterodine extended release (ER, 4 mg daily) or placebo for 6 days. Gastric emptying (GE), small bowel and colonic transit were assessed on days 4–6 by scintigraphy. Bowel habits were recorded by diaries. Tolterodine did not significantly affect half-time for GE (GE t _half) [116 ± 6 min (mean ± SEM) for placebo vs 126 ± 7 min for tolterodine], small bowel transit measured by colonic filling at 6 h (45 ± 6% for placebo vs 36 ± 6% for tolterodine) or the geometric center of colonic transit at 24 h (2.9 ± 0.2 for placebo vs 2.6 ± 0.3 for tolterodine). Subjects who received tolterodine had slightly fewer bowel movements (i.e. 1.34 ± 0.1 stools per day for placebo vs 1.0 ± 0.1 for tolterodine; P  = 0.02 for treatment effect). Tolterodine did not significantly affect stool consistency or ease of defecation. At the therapeutic dose used to treat overactive bladder, tolterodine did not significantly affect gastrointestinal or colonic transit and had minor effects on bowel habits in healthy subjects. Further studies are necessary to elucidate whether these observations are explained by tolterodine effects at muscarinic receptors which stimulate and inhibit gastrointestinal motility.     

Performance characteristics of scintigraphic colon transit measurement in health and irritable bowel syndrome and relationship to bowel functions

Background The inter‐ and intra‐subject variations of scintigraphy, which are used to identify colonic transit disturbances in irritable bowel syndrome (IBS), are unclear. The relationship between colonic transit and bowel functions is incompletely understood. To assess inter‐ and intra‐subject variations of scintigraphic colonic transit measurements in 86 IBS patients and 17 healthy subjects and to quantify the relationship between colonic transit and bowel symptoms in 147 IBS patients and 46 healthy subjects. Methods Data from participants with multiple colonic transit measurements were analysed. Primary end points were colonic filling at 6 h (CF6h) and geometric center (GC) at 24 and 48 h for colonic transit. Bowel functions were assessed by daily stool diaries. Key Results Inter‐ and intra‐subject variations were greater for small intestinal than colonic transit. Overall, inter‐ and intra‐subject variations were relatively narrow for colonic transit (both GC24h and GC48h, with lower COV at 48 h); there was little intra‐subject variation in health and IBS‐constipation over a period of ≤3 weeks and over 2.0 years (median, range 0.1, 11.0 years). Significant intra‐individual differences in GC24h were observed only in IBS‐D patients. Colonic transit was significantly associated with stool form (accounting for 19–27% of the variance), frequency (19%), and ease of stool passage (12%). Conclusions & Inferences Despite inter‐subject variation in scintigraphic colonic transit results, the intra‐subject measurements are reproducible over time in healthy volunteers and patients with IBS; significant changes in colonic transit at 24 h were observed only in IBS‐D. Colonic transit is associated with stool form, frequency and ease of passage.     

A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers

Itopride, a dopamine D2 antagonist and acetylcholinesterase inhibitor, significantly improved symptoms in patients with functional dyspepsia in one phase II randomized trial. However, the mechanisms by which itopride may improve symptoms are unknown. We aimed to compare the effects of two doses of itopride and placebo on gastric volumes, gastric emptying, small bowel transit and satiation in female and male healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of itopride 100 mg (n = 16) or 200 mg (n = 15) or placebo (n = 15) t.i.d. Validated methods were used to study gastric accommodation (single photon emission computed tomography), gastric emptying and orocecal transit and satiation postnutrient challenge. The three arms were comparable with regard to age, gender and body mass index. There were no statistically significant effects of itopride on gastric emptying, orocecal transit, fasting gastric volume, maximum tolerated volume or aggregate symptom score with nutrient drink challenge. Postprandial (PP) change in gastric volume differed in the three groups (P = 0.019): 625[+/-28 (SEM)], 555(+/-26) and 512(+/-33) in placebo, itopride 100 and 200 mg groups, respectively. In healthy subjects, itopride reduced total PP gastric volume without accelerating gastric emptying or significantly altering gastric motor and sensory function in healthy individuals.     

Ameliorating effects of mirtazapine on visceral hypersensitivity in rats with neonatal colon sensitivity

Background The aim was to investigate the effects of mirtazapine on visceral hypersensitivity and gastric emptying in an established rodent model of colonic sensitization. Methods Twenty colonic sensitized rats and 20 matched controls were used. Visceral sensitivity during colorectal distension (CRD) was assessed by the measurement of abdominal electromyogram (EMG) with the pressures of 20, 40, and 60 mmHg. Mirtazapine with doses of 1, 5, and 10 mg kg⁻¹ were administered orally. Gastric emptying and small intestinal transit were performed in a separated experiment after gavage of 1.5 mL of phenol red solution. Key Results (i) Visceral hypersensitivity after neonatal colonic sensitization was confirmed. (ii) Mirtazapine dose‐dependently reduced visceral hypersensitivity in the colonic sensitized rats. The increases in EMG during CRD at 40, 60 mmHg were, 17.59 ± 6.49 and 26.04 ± 8.30, respectively, with saline session, and substantially reduced to 10.0 ± 5.95 (P = 0.02 vs corresponding saline) and 12.58 ± 7.43 (P < 0.001 vs saline) with mirtazapine at 10 mg kg⁻¹. Similar findings were noted at doses of 5 and 1 mg kg⁻¹ at a lesser degree. In the control rats, mirtazapine‐reduced visceral sensitivity only during CRD at 60 mmHg. (iii) Mirtazapine 10 mg kg⁻¹ significantly accelerated gastric emptying (P = 0.045) but slightly and marginally delayed intestinal transit (P = 0.058) the colonic sensitized rats. Conclusions & Inferences Mirtazapine dose‐dependently ameliorates visceral hypersensitivity in colonic sensitized rats. Mirtazapine at a high dose improves delayed gastric emptying in colonic sensitized rats but slightly and marginally delays small intestinal transit. Its roles in altering gastrointestinal motility need further investigation.     

Pilot study of pyridostigmine in constipated patients with autonomic neuropathy

BACKGROUND: The effects of cholinesterase inhibitors, which increase colonic motility in health, on chronic constipation are unknown. Our aims were to evaluate the efficacy of cholinesterase inhibitors for dysautonomia and chronic constipation and to assess whether acute effects could predict the long term response. METHODS: In this single-blind study, 10 patients with autonomic neuropathy and constipation were treated with placebo (2 weeks), followed by an escalating dose of pyridostigmine to the maximum tolerated dose (i.e., 180-540 mg daily) for 6 weeks. Symptoms and gastrointestinal transit were assessed at 2 and 8 weeks. The acute effects of neostigmine on colonic transit and motility were also assessed. RESULTS: At baseline, 4, 6, and 3 patients had delayed gastric, small intestinal, and colonic transit respectively. Pyridostigmine was well tolerated in most patients, improved symptoms in 4 patients, and accelerated the geometric center for colonic transit at 24 h by > or =0.7 unit in 3 patients. The effects of i.v. neostigmine on colonic transit and compliance predicted (P < 0.05) the effects of pyridostigmine on colonic transit. CONCLUSIONS: Pyridostigmine improves colonic transit and symptoms in some patients with autonomic neuropathy and constipation. The motor response to neostigmine predicted the response to oral pyridostigmine.     

Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice

Ghrelin is an orexigenic peptide with prokinetic effects in the rat. We investigated the effect of ghrelin and growth hormone-releasing hormone 6 (GHRP-6) on gastric emptying and transit in control and septic mice. Mice were injected i.p. with lipopolysaccharides (LPS) or saline (control). After 16-17 h mice were pretreated with saline, ghrelin or GHRP-6 1 h before intragastric administration of Evans blue. Fifteen minutes later, after assessment of the behaviour scale, mice were killed and gastric emptying, transit and rectal temperature were measured. In control mice, ghrelin (100 microg kg(-1)) and GHRP-6 (20-100 microg kg(-1)) accelerated gastric emptying, whereas ghrelin and GHRP-6 failed to increase transit significantly. Septic mice developed a delay in gastric emptying and transit, hypothermia and a deterioration of the behaviour scale. In septic mice, ghrelin (20 microg kg(-1)) accelerated gastric emptying without effect on transit while GHRP-6 significantly accelerated gastric emptying dose-dependently and failed to increase transit significantly. Ghrelin and GHRP-6 had no effect on the endotoxin-induced hypothermia or deterioration of behaviour scale. Therefore, the beneficial prokinetic effect of ghrelin but mainly of GHRP-6 offers potential therapeutic options in the treatment of septic gastric ileus.     

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.     

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.     

Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea

Background Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS‐D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO’s effects on colonic motility. Our aims were: (i) to compare dose‐related effects of DRO to placebo (PLA) on gut transit in IBS‐D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO’s transit effects. Methods Thirty‐six IBS‐D volunteers were randomized (double‐blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model. Key Results Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected. Conclusions & Inferences Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS‐D. There appears to be a treatment‐by‐genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS‐D patients most likely to benefit from CB agonist therapy.