Colonic transit time in patients with myelomeningocele

To evaluate colonic motility in patients with myelomeningocele, the transit time of radiopaque markers was studied in 22 patients with myelomeningocele and 22 age and sex matched controls. Mean colonic transit time was significantly longer in patients than in controls (103.2 ± 49 h versus 23.3 ± 13 h; P < 10⁻⁷). Thirteen of 22 patients with myelomeningocele were severely constipated. Six patients had constipation secondary to delayed colonic transit, particularly in the left colon, and seven had increased rectosigmoïd transit. The clinical questionnaire and particularly the frequency of bowel movements did not predict colonic transit. Among 13 patients with increased colonic transit, eight had more than five bowel movements per week and, thus, six of them did not use laxatives or enemas, despite the presence of faecal incontinence. There was no relationship between colonic transit time and the level of the spinal lesion or patient mobility in patients with myelomeningocele. Rectoanal dyssynergia was found in 14 of the 22 patients, but equally often in patients with delayed rectosigmoid transit (4/7) as in the other patients (10/15) (P = ns). Uninhibited detrusor contractions were observed more often in patients with increased colonic transit time than in others (8/12 versus 1/8, P = 0.05). In the absence of a correlation between colonic transit time, clinical symptoms, anorectal motility, level of spinal lesion, patient mobility, evaluation of colonic transit of radiopaque markers should be assessed routinely in all patients with myelomeningocele to plan the most appropriate treatment, mainly in case of unhibited detrusor contractions.     

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.     

Effects of an Intestinal Smooth Muscle Calcium Channel Blocker (Pinaverium Bromide) on Colonie Transit Time in Humans

Pinaverium bromide, a calcium channel blocker, is often used in the treatment of the irritable bowel syndrome. Colonie transit time (CTT) was evaluated by a simplified method using radiopaque markers in 19 healthy volunteers during 2 weeks of treatment with pinaverium bromide (50 mg three times a day) or placebo according to a double-blind crossover design. Pinaverium bromide significantly (p < .05) accelerated total CTT (30.2 ± 4.6 h, mean ± SE) compared with the placebo (38.2 ± 3.7 h). The decrease in CTT was related to accelerated transit in the descending and rectosigmoid areas of the colon (21 ± 4.5 vs. 30 ± 3.9 h, p < .05). CTT in the ascending colon was not significantly modified (9.2 ± 2.7 as compared with 9.5 ± 2.3 h). Stool frequency was not significantly increased by pinaverium bromide. These results suggest that pinaverium bromide might be effective in idiopathic constipation with slow CTT in the descending or rectosigmoid areas of the large bowel. The measurement of CTT is an easy and useful method for investigating the effects of drugs on colonie motility.     

Colonic transit time, sphincter EMG, and rectoanal videomanometry in multiple system atrophy.

Both constipation and fecal incontinence are prominent lower gastrointestinal tract (LGIT) dysfunctions that occur frequently in multiple system atrophy (MSA). We investigated the mechanism of constipation and fecal incontinence in MSA. Colonic transit time (CTT), sphincter electromyography (EMG), and rectoanal videomanometry were performed in 15 patients with MSA (10 men, 5 women; mean age, 63.5 years; mean duration of disease, 3 years; decreased bowel frequency [< 3 times a week] in 9; difficulty in expulsion in 11; fecal incontinence in 3) and 10 age-matched healthy control subjects (7 men and 3 women; mean age, 62 years; decreased bowel frequency in 2; mild difficulty in expulsion in 2; fecal incontinence in none). Compared to the control subjects, MSA patients had significantly prolonged CTT in the rectosigmoid segment and total colon. Sphincter EMG showed neurogenic motor unit potentials in none of control subjects but in 93% of MSA patients. At the resting state, MSA patients showed a lower anal squeeze pressure (external sphincter weakness) and a smaller increase in abdominal pressure on coughing. During rectal filling, MSA patients showed smaller amplitude in phasic rectal contraction, which was accompanied by an increase in anal pressure that normally decreased, together with leaking in 3 patients. During defecation, most MSA patients could not defecate completely and had larger postdefecation residuals. MSA patients had weak abdominal strain, smaller rectal contraction on defecation, and larger anal contraction on defecation (paradoxical sphincter contraction on defecation), although these differences were not statistically significant. These findings in MSA patients were similar to those in Parkinson's disease patients in our previous study, except for the sphincter denervation and weakness in MSA. Constipation in MSA most probably results from slow colonic transit, decreased phasic rectal contraction, and weak abdominal strain, and fecal incontinence results from weak anal sphincter due to denervation. The responsible sites for these dysfunctions seem to be both central and peripheral nervous systems that regulate the LGIT.     

Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort

Background Abnormalities of colonic motility were reported in relatively small studies of patients with lower functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). The influence of gender and body mass on the observed motor pathophysiology is unclear. We sought to compare colonic transit in patients within different lower FGID subgroups and healthy controls, controlling for gender and BMI, and to determine whether BMI independently influences colonic motility. Methods We evaluated a scintigraphic gastrointestinal and colonic transit database of 287 lower FGID patients associated with constipation (IBS‐C, or functional constipation, n = 118), diarrhoea (IBS‐D or functional diarrhoea, n = 139) or mixed bowel function (IBS‐M, n = 30) and 170 healthy controls. We measured colon filling at 6 h (CF 6 h), and overall colonic transit at 8, 24 and 48 h. Key Results Colon filling at 6 h did not differentiate health from FGID. Colonic transit was abnormal at 24 h (GC24 of <1.50 or >3.86) in 29.7% of all lower FGID patients. There was a significant overall association between colonic transit and subject group (healthy controls and FGID subgroups) at 8 (P = 0.01), 24 (P < 0.001) and 48 h (P < 0.001) in particular for those with diarrhoea or constipation at 24 and 48 h (P < 0.05), even after adjusting for age, gender and BMI. In addition, BMI was associated with colonic transit after adjusting for age, gender and subject group. Conclusions & Inferences Abnormal transit is documented non‐invasively with scintigraphy in 30% of lower FGID patients; transit measurement may help document pathophysiology and inform selection of therapy in lower FGID.     

Wireless pH‐motility capsule for colonic transit: prospective comparison with radiopaque markers in chronic constipation

Background Colon transit (CT) measurements are used in the management of significant constipation. The radiopaque marker (ROM) method provides limited information. Methods We proposed to validate wireless motility capsule (WMC), that measures pH, pressure and temperature, to ROM measurement of CT in patients with symptomatic constipation evaluated at multiple centers. Of 208 patients recruited, 158 eligible patients underwent simultaneous measurement of colonic transit time (CTT) using ROM (Metcalf method, cut off for delay >67 h), and WMC (cutoff for delay >59 h). The study was designed to demonstrate substantial equivalence, defined as diagnostic agreement >65% for patients who had normal or delayed ROM transit. Key Results Fifty‐nine of 157 patients had delayed ROM CT. Transit results by the two methods differed: ROM median 55.0 h [IQR 31.0–85.0] and WMC (43.5 h [21.7–70.3], P < 0.001. The positive percent agreement between WMC and ROM for delayed transit was ～80%; positive agreement in 47 by WMC/59 by ROM or 0.796 (95% CI = 0.67–0.98); agreement vs null hypothesis (65%) P = 0.01. The negative percent agreement (normal transit) was ～91%: 89 by WMC/98 by ROM or 0.908 (95% CI = 0.83–0.96); agreement vs null hypothesis (65%), P = 0.00001. Overall device agreement was 87%. There were significant correlations (P < 0.001) between ROM and WMC transit (CTT [r = 0.707] and between ROM and combined small and large bowel transit [r = 0.704]). There were no significant adverse events. Conclusions & Inferences The 87% overall agreement (positive and negative) validates WMC relative to ROM in differentiating slow vs normal CT in a multicenter clinical study of constipation.     

Non‐compliance does not impair qualitative evaluation of colonic transit time

Background Measurement of colonic transit time (CTT) by using radiopaque markers with the “Multiple ingestion‐Single film” technique is a simple, reproducible technique to measure total and segmental CTT. However, it requires good compliance of the patients, who must ingest the capsules containing radio‐opaque markers for 6 consecutive days. The purpose of this study was to estimate the error in CTT measurement if they fail to do this. Methods The protocol tested was to ingest 12 markers per day during 6 days and take a plain film of the abdomen on day 7. The study was done by simulation using a 3‐compartiment model (right colon, left colon, rectosigmoid area). There was a set of 67,525 possibilities with possible single or double failure of markers ingestion for 6 days either 238,266 combinations for one omission, or 312,375 combinations for two omissions; the absence of omission was the reference. The analysis focused on two complementary aspects of the evaluation of omission: quantitatively, the absolute and relative error on the CTT measured and qualitatively, the diagnostic error (a delayed transit is defined by a total CTT > 65 hours). Key Results Total and segmental CTT measured when omission occurred were greater than the reference time. The difference is particularly important, when omission occurs early during the study for all segments. Qualitative analysis showed that, for one omission of markers ingestion, a correct diagnosis of delayed colonic transit time and of the main site of delay could be obtained by the 3‐compartment model in 100% of cases. For two failures of markers ingestion, “delayed” colonic transit could be regarded as normal in only 9.59% of cases; furthermore, the site of delay was correctly recognized in 83% of the cases. Conclusions & Inferences Despite omission of markers ingestion for one or two days, measured CTT overestimates the absolute value of colonic transit time, the formulated diagnosis (delayed transit and site of delay) is perfectly acceptable clinically.     

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.     

Colonic transit time and rectoanal videomanometry in Parkinson's disease

BACKGROUND: Constipation is a prominent lower gastrointestinal tract dysfunction that occurs frequently in Parkinson's disease (PD). OBJECTIVE: To investigate colonic transport and dynamic rectoanal behaviour during filling and defecation in patients with PD. METHODS: Colonic transit time (CTT) and rectoanal videomanometry analyses were performed in 12 patients with PD (10 men and 2 women; mean age, 68 years, mean duration of disease, five years; mean Hoehn and Yahr grade, 3; decreased stool frequency (<3 times a week) in six, difficulty in stool expulsion in eight) and 10 age matched normal control subjects (7 men and 3 women; mean age, 62 years; decreased stool frequency in two, difficulty in stool expulsion in two). RESULTS: In the PD patients, CTT was significantly prolonged in the rectosigmoid segment (p<0.05) and total colon (p<0.01) compared with the control subjects. At the resting state, anal closure and squeeze pressures of PD patients were lower than those in control subjects, though not statistically significant. However, the PD patients showed a smaller increase in abdominal pressure on coughing (p<0.01) and straining (p<0.01). The sphincter motor unit potentials of the patients were normal. During filling, PD patients showed normal rectal volumes at first sensation and maximum desire to defecate, and normal rectal compliance. However, they showed smaller amplitude in phasic rectal contraction (p<0.05), which was accompanied by an increase in anal pressure that normally decreased, together with leaking in two patients. During defecation, most PD patients could not defecate completely with larger post-defecation residuals (p<0.01). PD patients had weak abdominal strain and smaller rectal contraction on defecation than those in control subjects, though these differences were not statistically significant. However, the PD patients had larger anal contraction on defecation (p<0.05), evidence of paradoxical sphincter contraction on defecation (PSD). CONCLUSIONS: Slow colonic transit, decreased phasic rectal contraction, weak abdominal strain, and PSD were all features in our PD patients with frequent constipation.     

Altered periodic rectal motor activity: a mechanism for slow transit constipation

The pathophysiology of slow transit constipation is poorly understood. Both decreased and increased distal colonic motility have been reported. In healthy humans, a 3 cycles per minute (cpm), periodic rectal motor activity (PRMA) has been described. Our aim was to investigate the characteristics of PRMA and to assess its role in the pathogenesis of constipation. A six-sensor solid-state probe was placed with the tip sensor in the mid-transverse colon, without sedation, and prolonged colonic motility was recorded in nine patients with slow transit constipation (1M, 8F) and in 11 healthy subjects (3M, 8F). Subjects were free to ambulate. We examined the frequency, nocturnal vs. diurnal variation, and characteristics of PRMA, and its relationship to proximal colonic motility. All subjects showed PRMA. The rhythm was similar (2.5-4 cpm) in both groups. However, constipated patients exhibited a greater (P < 0.001) number of PRMA cycles than controls. The duration of each cycle and amplitude of pressure waves during PRMA were also greater (P < 0.05) at night in patients compared with controls. In patients, 40% of PRMA cycles were associated with a proximal colonic motor event compared with 81% in controls (P < 0.02). The area under the curve of all colonic pressure waves and incidence of specialized propagating pressure waves was lower (P < 0.05) in patients during daytime. When compared with controls, constipated patients exhibited reduced daytime colonic pressure waves and a higher frequency of PRMA. Most of the PRMA was unrelated to proximal colonic activity in constipated patients in contrast with findings in control patients. In addition to decreased colonic motility, this excessive and unco-ordinated phasic rectal activity may further impede stool transport and contribute to the pathogenesis of slow transit constipation.     

Therapeutic effects of loxiglumide, a cholecystokinin antagonist, on chronic constipation in elderly patients: a prospective, randomized, double-blind, controlled trial

Severe chronic constipation is a common health problem, particularly among elderly nursing-home patients. Cholecystokinin (CCK) is involved in the regulation of colonic motility, and the blockade of CCK_A receptors with loxiglumide, a potent and highly specific CCK_A antagonist, dramatically accelerates colonic transit time in healthy human volunteers. The effect of loxiglumide on the bowel habits and colonic transit time in 21 chronically constipated nursing-home patients (mean age 83, range 71–89 years) was studied in a randomized, placebo-controlled, double-blind cross-over study. Loxiglumide 800 mg t.i.d. or identical-looking placebo tablets were given orally in sequence with a 7-day washout period in between for 21 days each. The number of spontaneous bowel movements and that of administered enemas was recorded for each 3-week phase. At the end of each treatment period colonic transit time was assessed using radio-opaque markers. Treatment with loxiglumide significantly (P < 0.005) accelerated colonic transit time from 113 ± 6 to 81 ± 10 h. The frequency of weekly bowel movements increased from 3.9 ± 0.5 (placebo) to 4.9 ± 0.5 (loxiglumide) (P < 0.006), while the number of enemas over the 3 weeks decreased from 2.7 ± 0.6 to 1.3 ± 0.4 for placebo and loxiglumide, respectively (P < 0.005). No serious side-effects were observed and there were no signs of exocrine pancreatic insufficiency induced by loxiglumide. The blockade of CCK_A receptors with loxiglumide significantly improves chronic constipation in geriatric patients. Loxiglumide may therefore constitute the prototype of a new class of potent therapeutic agents effective in the treatment of constipation.     

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.     

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.     

Results of 24-h manometric recording of colonic motor activity with endoluminal instillation of bisacodyl in patients with severe chronic slow transit constipation

The aims of this study were to assess the prevalence of manometric colonic abnormalities and to evaluate the motor effect of intraluminal bisacodyl in a cohort of refractory constipated patients. Twenty-four hour colonic motility recordings were performed in 40 patients referred for a severe intractable chronic constipation. At the end of each recording session the motor effects of the endoluminal instillation of 10 mg bisacodyl were assessed. These patients were compared with 20 healthy subjects. The number of high-amplitude propagating contractions (HAPC) was significantly decreased in patients with slow transit constipation (12 +/- 11.6 vs 1 +/- 8.6, P < 0.001). Based on manometric patterns four groups of patients were isolated. Ten patients had no spontaneous HAPC, no food-induced colonic motor response and significantly lower colonic activity in transverse colon (374 +/- 1220 vs 3249 +/- 3458, P < 0.05). Five patients had significantly increased sigmoid segmental motility (20298 +/- 6364 vs 88780 +/- 3643, P < 0.001) and eight patients had significantly lower number of HAPC without other manometric abnormalities while 17 patients had normal colonic motility recordings. Endoluminal bisacodyl was able to induce HAPCs in all groups of patients. Patients with severe slow transit refractory constipation represented a heterogeneous group and endoluminal bisacodyl was able to promote a propagated motor activity in a majority of patients even in those suspected of having an inert colon.     

Electrical colonic stimulation reduces mean transit time in a porcine model

Abstract  Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. The impact of stimulation and implanted material on the colonic wall was also assessed. Three pairs of electrodes were implanted into the caecal wall of 12 anaesthetized pigs. Reference colonic transit time was determined by radiopaque markers for each pig before implantation. It was repeated 4 weeks after implantation with sham stimulation and 5 weeks after implantation with electrical stimulation. Aboral sequential trains of 1-ms pulse width (10 V; 120 Hz) were applied twice daily for 6 days, using an external battery operated stimulator. For each course of markers, a mean value was computed from transit times obtained from individual pig. Microscopic examination of the caecum was routinely performed after animal sacrifice. A reduction of mean transit time was observed after electrical stimulation (19 ± 13 h; mean ± SD) when compared to reference (34 ± 7 h; P  = 0.045) and mean transit time after sham stimulation (36 ± 9 h; P  = 0.035). Histological examination revealed minimal chronic inflammation around the electrodes. Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.     

Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders

Background The membrane bound bile acid (BA) receptor, TGR5, is located on myenteric, cholinergic and nitrergic neurons in colon and proximal small intestine. Our aim was to assess the association of genetic variation in TGR5 and small bowel transit (SBT) and colonic transit. Methods In 230 healthy controls and 414 patients with lower functional GI disorders [FGID: irritable bowel syndrome (IBS)‐alternators (Alt) 84, IBS‐constipation (IBS‐C) 157, IBS‐diarrhea (IBS‐D) 173], we tested the association between TGR5 SNP rs11554825 (minor allele frequency 41%) with symptom phenotype (total cohort) and intermediate phenotype (SBT or colonic transit by radioscintigraphy) which was available in 213 people in this cohort. The association with symptom phenotype was assessed using logistic regression, while the association with colonic filling at 6 h (CF6), and colonic transit [geometric center (GC) at 24 h] was assessed using ancova , in each instance assuming a dominant genetic model. Key Results There was no significant association with symptom phenotype. We observed a potential association of SNP rs11554825 with overall transit: CF6 (P = 0.061) and GC24 (P = 0.083). The association of the SNP with CF6 in the IBS‐D subgroup (P = 0.017) indicated the TC/CC subgroup had an average 50% faster SBT compared with the TT subgroup. In IBS‐D patients, GC24 was not significantly associated with rs11554825 (TC/CC vs TT). Conclusions & Inferences Variation in TGR5 may contribute to altered SBT and colonic transit in lower FGID. Further studies are required to characterize the potential role of BA receptor, TGR5, in the mechanism and treatment of bowel dysfunction in lower FGID.     

Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients.

Mosapride citrate is a novel selective 5-HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K(+) channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrate's effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinson's disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre- and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Student's t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects.     

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.     

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.     

Constipation associated with chronic spinal cord injury: the effect of pelvic parasympathetic stimulation by the Brindley stimulator.

Ten subjects with severe constipation due to complete spinal cord injury (SCI) had prolonged oro-anal transit time (p less than 0.01), diminished faecal water content (p less than 0.05) and a reduced frequency of defaecation (p less than 0.01) compared to 10 non-SCI subjects. Paraplegics with an implanted Brindley S234 anterior sacral nerve root stimulator had a significant increase in frequency of defaecation (p less than 0.01), compared to the SCI group while the faecal water content was less although not significantly so. The Brindley stimulator group also showed a more rapid colonic transit than the SCI group but this did not reach statistical significance. SCI is associated with constipation which therefore appears to be favourably influenced by the Brindley S234 anterior nerve root stimulator. The effects produced are compatible with stimulation of left colonic motility, which facilitates the emptying of the distal colon, but also suggest that part of the response restricts transit in some areas of the colon or rectum. Since the motility changes induced by the Brindley stimulator do not affect the right colon a relatively greater residence time of the faecal bolus in this part of the large bowel would enhance water absorption.