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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Background:

Prucalopride is a selective and specific 5-hydroxytryptamine4 receptor agonist that is known to increase stool frequency and to accelerate colonic transit.

Aim:

To investigate the effect of prucalopride on high-amplitude propagated contractions and segmental pressure waves in healthy volunteers.

Methods:

After 1 week of dosing (prucalopride or placebo in a double-blind, randomized, crossover fashion), colonic pressures were recorded in 10 healthy subjects using a solid-state pressure catheter with six sensors spaced 10 cm apart. Subjects kept diary records of their bowel habits (frequency, consistency and straining). High-amplitude propagated contractions were analysed visually, comparing their total numbers and using 10-min time windows. Segmental pressure waves were analysed using computer algorithms, quantifying the incidence, amplitude, duration and area under the curve of all detected peaks.

Results:

When taking prucalopride, stool frequency increased, consistency decreased and subjects strained less. Prucalopride just failed to increase the total number of high-amplitude propagated contractions (P=0.055). The number of 10-min time windows containing high-amplitude propagated contractions was increased by prucalopride (P=0.019). Prucalopride increased the area under the curve per 24 h (P=0.026).

Conclusions:

The 5-hydroxytryptamine4 receptor agonist prucalopride stimulates high-amplitude propagated contractions and increases segmental contractions, which is likely to be the underlying mechanism of its effect on bowel habits in healthy volunteers.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Constipation is a common problem encountered by general practitioners and gastroenterologists, and is one of the most prevalent gastrointestinal symptoms. It is reported that between 12% and 30% of the population have consulted a doctor for this condition,1 and there may be an even larger number who have not consulted a physician.

Most currently used drugs for chronic idiopathic constipation are laxatives that act on the lumen of the colon. Bulking agents are used to increase luminal contents; other laxatives, such as osmotically active compounds, soften the stool and thus facilitate expulsion. Stimulant laxatives can stimulate the mucosa and induce secretion and mass movements. Another group of drugs, known to have effects in patients with constipation, are prokinetic agents. Benzofuran derivatives also have enterokinetic properties. Their mechanism of action is not entirely clear, but their stimulating properties on 5-hydroxytryptamine4 (5HT4) receptors may explain part of their motility effects.2, 3 Cisapride is used in delayed gastric emptying, but its effect on colonic motility is only moderate.

Prucalopride is a novel, potent, highly selective, specific, 5HT4 receptor agonist with enterokinetic properties,3, 4 which is being developed for the treatment of chronic constipation. In fasted awake dogs, it has been shown to dose-dependently shorten the time to the first giant migrating contraction. It also stimulates proximal colonic motility by specific and selective stimulation of 5HT4 receptors.5, 6 In humans, several studies have shown that prucalopride significantly increases the frequency of spontaneous complete bowel movements in both healthy subjects and patients with severe constipation.4, 7 Using a scintigraphic technique, Bouras et al. demonstrated that prucalopride accelerates colonic transit in healthy volunteers, partly by stimulating proximal colonic emptying, but does not alter gastric or small bowel transit.8 The functional effect on colonic transit has also been demonstrated in constipated patients.9 Recently, in vitro studies of the human colon have shown that prucalopride induces the relaxation of circular muscle solely through the activation of 5HT4 receptors.10

The exact mechanism of action of prucalopride and its effect on stool frequency in humans still remain unclear. Data on the colonic motility of healthy volunteers and patients with constipation are needed to achieve a better understanding of the mechanism of action of 5HT4 receptor agonists. Several studies on human colonic motility have shown that high-amplitude propagated contractions (HAPCs) are associated with defecation.11, 12 In a recent study, Cook et al. used a scintigraphic technique to demonstrate that the transport of bowel contents is related to both non-propagating activity and propagating sequences.13 The latter accounted for a greater extent of isotope movement.

We hypothesized that the effects of prucalopride on stool frequency and consistency are due to an increase in colonic motility. This could either implicate an increase in non-coordinated, non-propagating segmental motility or an increase in propagating pressure waves, or both.

The aim of this study was to investigate the effect of 4 mg prucalopride daily on colonic motility, as measured by prolonged ambulatory colonic manometry in healthy volunteers. The primary objectives were to investigate the influence of prucalopride on non-propagating segmental colonic motility and on HAPCs during 24 h. Furthermore, we evaluated the effect of prucalopride on bowel habits, and the relation between colonic motility and bowel habit.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Subjects

The study group comprised 10 healthy volunteers (five males, five females) aged 50 years (range, 28–72 years). None of the healthy subjects had a history of gastro-intestinal symptoms, use of medications or previous abdominal surgery. After the first screening, a run-in period of 2 weeks was used to check whether the subjects were eligible for inclusion depending on their bowel habits (thrice or less a day, and at least three times a week, normal consistency, no excessive straining and feeling of complete evacuation for at least 75% of the time), by recording these data in a diary.

To investigate these criteria, consistency was defined as follows: 0, watery; 1, loose; 2, normal; 3, hard; 4, very hard. Straining was scored as follows: 0, no straining; 1, slight straining; 2, moderate straining; 3, much straining; 4, severe straining. Finally, subjects had to write down whether or not they considered their evacuation to be complete after each bowel movement.

The study protocol was approved by the Ethics Committee of the University Medical Center, Utrecht, and all subjects gave their written informed consent to participate.

Study protocol

All subjects were studied twice using a double-blind, randomized, placebo-controlled, crossover design. The total time of the study was approximately 7 weeks per subject consisting of four periods: a 2-week run-in period, followed by the first treatment period (10 days); then a wash-out period (18 days) and, finally, the second treatment period (10 days).

After the run-in period, the first treatment period of 10 days was started. In both treatment periods, the volunteers were instructed to take the study medication (placebo or 4 mg prucalopride) before breakfast for 10 days. On the eighth day, they attended the motility unit for placement of the manometry catheter. Colonic motility was recorded from day 8 (afternoon) until day 10 (morning). All subjects were fully ambulant throughout the recording periods.

Usual diets were maintained for the duration of the study, except for the two manometry periods. Nutrient intake during these days was standardized and coffee or caffeine-containing foods were prohibited. Standardized meals consisted of a dinner (chicken and rice, 470 kcal; protein, 25 g; carbohydrate, 54 g; fat, 18 g) and dessert (170 kcal) on day 8, and breakfast (two slices of whole-wheat bread, one Dutch rusk, cheese and marmalade, 529 kcal), lunch (three slices of whole-wheat bread, one Dutch rusk, margarine, cheese, ham, marmalade and yoghurt, 707 kcal) and dinner (Chinese noodles, 405 kcal; protein, 23 g; carbohydrate, 60 g; fat, 9 g) plus dessert (170 kcal) on day 9. On day 10, a breakfast as on day 9 was taken.

Subjects kept diary records of bowel habits comparable with the run-in data (times at which defecation occurred, consistency, straining and complete evacuation) during the entire study. On manometry days, they also recorded the times of getting up, meals and micturition.

Colonic motility measurement

Colonic motility recordings were performed using a flexible catheter (total length, 230 cm; outer diameter, 3.3 mm) with six solid-state pressure transducers located at 2, 12, 22, 32, 42 and 52 cm from the tip (Millar Instruments, Inc., Houston, TX, USA). Pressure transducers were calibrated at pressures of 0 and 60 cmH2O using a vertical cylinder filled with water. Bowel cleansing was performed on day 8 of the treatment periods with 2 L of soap water enema, administered 3 h before catheter insertion, which took place in the afternoon. The catheter was placed colonoscopically without the use of premedication. This was performed by advancing the catheter together with the endoscope, its tip being fixed to the tip of the colonoscope. Once the transverse colon was reached, the tip of the catheter was released and the colonoscope was gently withdrawn, leaving the catheter in situ. During withdrawal, air was aspirated as completely as possible. Thereafter, the catheter position was checked by fluoroscopy. The position was checked again by fluoroscopy on day 9 and on day 10, before removing the catheter. The catheter was taped securely to the back, and connected to a portable datalogger (UPS 2020, Medical Measurement Systems, Enschede, The Netherlands) with a storage capacity of 4 MB. A sample frequency of 4 Hz was used. The manometric recordings were carried out over a 41-h period, starting on day 8 at approximately 16.00 h until day 10 at around 09.00 h.

After placement of the catheter, the subjects returned home. They were instructed to press the event button on the datalogger to indicate the time of getting up and going to bed, when they consumed their meals, when they felt the need to defecate and when they had specific abdominal sensations (cramps or pain). These times were also noted in a diary. Subjects refrained from strenuous exercise of all types during manometry periods.

After measurement, the data were transferred to a computer for further display and off-line analysis using commercially available software (Medical Measurement Systems, Enschede, The Netherlands) and locally developed computer algorithms.

DATA ANALYSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Visual analysis

Manometric tracings were analysed visually in a blind fashion by one of the authors (ADS). HAPCs were defined as pressure waves, propagated over at least three recording sites, with two amplitudes of at least 100 mmHg (= 13.3 kPa) and one of at least 75 mmHg (= 10.0 kPa).

For each HAPC, the mean peak amplitude (in mmHg), duration (in seconds) and propagation velocity (in centimetres per second) were measured. Velocity was considered to be the time between onset of the first (proximal) and the last (distal) propagated wave divided by the distance between the recording ports.

HAPCs were also analysed post hoc for clustered occurrence. An HAPC cluster was defined as the occurrence of two or more HAPCs in a 10-min window (Figure 1).

image

Figure 1. . Clustered high-amplitude propagated contractions (HAPCs) in the descending colon occurring within a 10-min period (HAPC episode).

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Computer analysis

Manometric data recorded during the 24-h period from 06.00 h on the ninth day until 06.00 h on the tenth day were analysed automatically by locally developed software.

Smoothing was carried out by averaging data points of the raw pressure curves over a moving window of 0.75 s. Using a sample frequency of 4 Hz, this implies averaging of three data points, resulting in reduction of vascular or cardiac noise.

Artefacts (recognized as simultaneous pressure increases in all six channels) caused by respiration and rises in abdominal pressure were eliminated by means of subtraction of a minimum curve, constructed by sample-by-sample determination of the lowest pressure in all six channels.

The colonic baseline curve was determined by calculation of the 10th percentile over a moving 60-s window of the smoothed pressure curve. Thereafter, the resulting curve was smoothed by calculation of the moving average over a 2.75-s window.

Peak detection was carried out on the subtracted data, using the calculated baseline curve as a reference. Pressure waves were detected and included in analysis when they reached a threshold of 1.5 kPa (= 11.5 mmHg). Rapidly successive peaks were detected as individual peaks when a minimum trough nadir of 25% of the maximum peak amplitude was reached; otherwise, they were counted as one contractile event.

The remaining segmental motility was automatically analysed as follows. While excluding HAPC episodes, the number of detected pressure waves, their amplitude, duration and area under the pressure curve (AUC) were calculated. Amplitudes were calculated by subtracting the baseline value from the maximum value of each contraction. The duration of each contraction was determined from the point where a contraction first passed the detection threshold value until the moment when it fell below this value again. The resulting motility variables were analysed over a 24-h period. In addition, in order to compare diurnal changes in colonic motility and to investigate periprandial motility, a number of 1-h periods were studied separately (at night, after waking up, before and after lunch and dinner).

Statistical analysis

Treatment effects on bowel habits and motility parameters were tested by paired Student's t-tests. All tests were two-tailed. Treatment effects on bowel movements and the 24-h AUC profile were also tested by analysis of variance (ANOVA) for repeated measures. P values of 0.05 or lower were considered to be statistically significant. Data are expressed as the mean ± S.E.M.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Study group

Twenty-two volunteers were randomized, 12 of whom failed to complete both treatment periods. In four subjects, the manometry catheter could not be positioned correctly and, in four others, the catheter was expelled during one of the recording periods. One subject stopped after the first day of the second treatment period because of diarrhoea immediately after taking the first tablet. One subject withdrew because she found the study to be too demanding. Two subjects withdrew after the first period because of personal problems.

As a result, 10 healthy subjects (five males, five females) were studied successfully with respect to colonic manometry, and these subjects define our study population for both the colonic manometry and stool frequency and consistency data.

Stool frequency and consistency

The number of bowel movements in the first week increased during treatment with prucalopride (15.5 ± 1.7) compared to placebo (8.9 ± 0.7) (P=0.0025). This effect was most prominent during the first day, but remained present during the rest of the treatment period. The mean number of bowel movements on days 2–9 with prucalopride was increased compared to placebo (P < 0.05) and there was no significant decrease in this effect with time (ANOVA, P=0.2, Figure 2). Furthermore, the stools became looser. The mean consistency value during prucalopride was 1.07 ± 0.1 compared to 1.51 ± 0.1 during placebo (P < 0.05). The subjects also had to strain less. The mean straining value was 0.64 ± 0.1 during prucalopride compared to 1.02 ± 0.1 during placebo (P < 0.01). However, these effects on consistency and straining decreased during the course of the study.

image

Figure 2. . Effect of prucalopride on bowel movements compared to placebo during the two treatment periods (P=0.0025).

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Colonic manometry

The tip of the catheter was in the transverse colon near the hepatic flexure in five subjects (50%) and near the splenic flexure in five subjects (50%). During the second treatment period, the catheter was placed at the same level as during the first colonoscopy, and no major displacements (of more than 10 cm) occurred, as checked by fluoroscopy.

HAPCs. These were observed only during the awake state: between midnight and 06.00 h of the studied period, no HAPCs were recorded. HAPCs preferentially occurred after waking up. In the first hour after waking up, 25% of all HAPCs took place (placebo vs. prucalopride, 22% vs. 27%; N.S.). In the first 2 h after waking up, 30% of all HAPCs were detected (placebo vs. prucalopride, 25% vs. 33%; P < 0.05).

Prucalopride tended to increase the total number of HAPCs per 24 h per subject compared to placebo (10.3 ± 2.0 vs. 6.0 ± 1.7; P=0.055) (Figure 3).

image

Figure 3. . Effect of prucalopride vs. placebo on the individual total numbers of high-amplitude propagated contractions (HAPCs) per 24 h (means 10.3 vs. 6.0; P=0.055).

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HAPC clusters were seen in 15 of the 20 recordings (75%). Both clustered and single HAPCs were often followed by a bowel movement. Prucalopride did not significantly increase the mean number of clusters in a 24-h period (placebo vs. prucalopride, 1.8 vs. 3.1; P=0.1). However, when clustered and single HAPCs were combined, the sum of these HAPC episodes was larger during prucalopride treatment compared to placebo (6.6 ± 1.3 vs. 3.9 ± 1.1; P=0.019) (Figure 4).

image

Figure 4. . Effect of prucalopride vs. placebo on the individual numbers of 10-min windows with one or more high-amplitude propagated contractions (HAPCs) per 24 h (means 6.6 vs. 3.9; P=0.0019).

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HAPC characteristics were not different during prucalopride treatment (Table 1). Overall, the mean peak amplitude of an HAPC was 137 ± 2.5 mmHg, the mean duration of one pressure wave was 13.8 ± 0.3 s and the mean propagation velocity was 1.40 ± 0.08 cm/s.

Table 1.  . Effects of prucalopride on incidence and characteristics of high-amplitude propagated contractions (HAPCs) Thumbnail image of

In the studied 24-h period, a total of seven bowel movements occurred in the placebo group, compared to 11 in the prucalopride group. During placebo treatment, all seven defecations were preceded by one or more HAPCs (100%); during prucalopride treatment, one or more HAPCs preceded 10 out of 11 defecations (91%). One bowel movement followed a propagated pressure wave of very low amplitude. Of all HAPCs, 12% and 11% were followed by defecation during placebo and prucalopride treatment, respectively.

Remaining segmental contractions. A trend towards an increase in the number of contractions per 24 h during prucalopride treatment was observed, but this failed to reach statistical significance (1272 vs. 1105). However, during the first hour after waking up, there was an increase in the number of contractions (101 vs. 68; P < 0.05; Table 2).

Table 2.  . Effects of prucalopride on the incidence, AUC (kPa s), amplitude (hPa) and duration (s) of the segmental colonic contractions Thumbnail image of

Prucalopride significantly increased the mean AUC during the complete 24-h recording period (23.418 vs. 15.725 kPa s; P < 0.05; Table 1). Similarly, the 24-h AUC profile also gives a clear view of the significant overall effect of prucalopride on AUC (P < 0.02 by repeated measures ANOVA; Figure 5).

image

Figure 5. . Twenty-four-hour profile of the area under the pressure curves (AUC), showing the effect of prucalopride compared to placebo (ANOVA for repeated measures: P < 0.02).

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The largest increase in AUC during prucalopride treatment was observed during the first hour after waking up (1.815 vs. 1.148 kPa s; P < 0.01; Table 2). Individual motor responses to standardized meals were not detected, nor did we find clear differences in AUC between the two treatment groups in response to a meal.

In the 24-h period, the mean amplitude of the detected contractions was not significantly increased by prucalopride (38.2 vs. 33.6 hPa; P=0.1). However, when different hours were studied separately, prucalopride appeared to significantly increase the amplitude of contractions during sleep (P < 0.05), in the first hour after waking up (P < 0.05) and in the first 2 h following a meal (P < 0.05).

There was a trend towards a longer mean duration of contractions per 24 h during prucalopride treatment (4.72 vs. 4.24 s; P=0.06; Table 2). During sleep, contraction durations were increased (4.92 vs. 3.68 s; P < 0.05), whereas these were not consistently affected on waking up or by a meal.

No relation was found between defecation frequency and colonic motility variables.

Adverse events

No serious adverse events were reported during the study. The most frequent adverse events in the healthy volunteers receiving oral prucalopride were transient diarrhoea, nausea and flatulence. Diarrhoea occurred in five subjects, mainly on the first day, varying from three to five defecations of loose consistency. Mild nausea occurred in five subjects and was only present on the first day of treatment. Three subjects noticed flatulence on the first two treatment days. All these events occurred mainly in the first two days of treatment and were not present during the manometry days. During treatment with placebo, one subject reported mild nausea and another had increased flatulence. Mild headache was present in two subjects during prucalopride treatment and in one subject while on placebo. No clinically relevant changes in blood pressure, pulse rate, QRS or QTc interval were noted.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Several studies have investigated the new colokinetic agent prucalopride and have shown an effect of this agent on bowel habit in dogs3, 5, 6 and cats.14 Furthermore, it has been tested in healthy volunteers4, 7, 15 and in patients with chronic constipation and post-operative ileus. The increased number of bowel movements when taking prucalopride compared to placebo has made it likely that prucalopride stimulates colonic motility.7 However, so far, no studies have been performed in vivo to show the direct effects of 5HT4 receptor agonists on colonic motility by using colonic manometry.

This is the first study to investigate various aspects of colonic motility in healthy volunteers receiving the 5HT4 receptor agonist prucalopride (4 mg) and placebo in a double-blind, randomized, crossover design.

As previously discussed, we prepared the colon using 2 L of soap water enema before inserting the catheter colonoscopically. Subjects did not change their diet in advance, nor did they receive oral cleansing solution because this would interfere with the normal physiology. A disadvantage of our method of bowel cleansing was that, in a number of cases, it was difficult to obtain a clear view during colonoscopy due to faecal material. This led to some subjects not completing the study because of a failure to position the catheter correctly. Dinoso et al. showed that contractile activity is greater after a cleansing enema than in the unprepared colon.16 We performed prolonged recordings for periods of at least 40 h and did not include the first day and night (excluding about 14 h) to avoid this preparation effect. This is in contrast with the majority of studies in which recordings were made for shorter periods and recording was started sooner after insertion of the probe.11, 17, 18 To avoid any sedative effects, no premedication was used.

We found that prucalopride increases the number of bowel movements. This is in agreement with other authors' experience,4 and is suggestive of a prokinetic effect of 5HT4 receptor agonists.

The increased number of bowel movements on days 2–9 indicates that the stimulating effect is not only due to the most prominent action on the first day of dosing.

In this study, we tested the hypothesis that the effect of prucalopride lies in its increased colonic motor activity and we specifically examined two major patterns: propagating high-amplitude colonic pressure waves and segmental motility. If this hypothesis is correct, it could be regarded as the underlying mechanism of the stimulating effects of prucalopride in healthy volunteers and patients with chronic constipation.

We assessed colonic motility using solid-state catheters. This has some important advantages over water perfusion manometry used in previous motility studies.11, 19 Most importantly, our volunteers were fully ambulant and were sent home during the measurement; some of them even went to work.

However, solid-state catheters also have certain shortcomings. Fragility may be regarded as one of the main technical limitations of this type of catheter. They very easily break down during and between measurements, possibly due to corrosive damage from irritant substances in faecal material. Other disadvantages are their high cost and the limited number of recording points available.

A problem with all types of catheter for colonic manometry is the difficulty in keeping them in the correct position. In this study, we used haemostatic clips to fix the catheter to the colonic mucosa and thus prevent it from bending or moving distally.20 This clearly provides a higher success rate of completed colonic manometry recordings.

During the measurement of both segmental and high-amplitude propagated colonic motility, we did not find any clear motor responses to meals. This could be due to the fact that the lunches and dinners provided contained fewer calories (≈ 700 kcal) than the standardized meals (1000 kcal) used by other investigators, who showed an increase in colonic motility.19, 21

Many different definitions have been used for HAPCs. Some studies have defined them as propagated contractions greater than 50 mmHg and migrating over more than 10 cm.22 By applying this definition, we would have found an unrealistically high number of HAPCs, sometimes even more than 50 per 24 h. Because there is no universally agreed definition, we used our own, based on our experience in previous manometry studies: we only classified contractions as HAPCs when they could be easily differentiated in terms of propagation, amplitude and duration.

Previous investigations have demonstrated that the incidence of HAPCs in patients with constipation is lower than that in healthy volunteers (2.6 per day vs. 6.1 per day).11, 23 We found a comparable number of HAPCs per day (6.0) in healthy volunteers during placebo treatment, but it should be noted that there was a substantial variation between subjects (range, 0–15). Prucalopride tended to increase the total number of HAPCs (P=0.055). We noticed that a large number of HAPCs occurred in clusters (mainly occurring within periods of 10 min or less). Therefore, we believe that it is more representative to use the number of 10-min windows with one or more HAPCs because this tells us more about the distribution of HAPCs during the day. Prucalopride significantly increased this number of 10-min windows.

When we analysed the segmental (non-propagating) motility, we excluded HAPCs from the calculations of all parameters to obtain a clearer view of segmental motility alone. The amplitudes during prucalopride treatment were not changed; however, there was a clear increase in the duration of the detected contractions. Therefore, we chose to use AUC as a parameter to quantify segmental motility instead of the motility index, because contraction durations are affected by the 5HT4 receptor agonist.

In conclusion, the present investigation shows that, in healthy volunteers, the 5HT4 receptor agonist prucalopride not only increases stool frequency and produces looser stools, but also significantly increases non-coordinated, segmental contractions. Furthermore, prucalopride significantly increases the number of HAPC episodes. This increase in colonic motor activity is likely to be one of the mechanisms underlying the prokinetic effect of 5HT4 receptor agonists.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References

Janssen Research Foundation provided support for this study.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. DATA ANALYSIS
  6. RESULTS
  7. DISCUSSION
  8. ACKNOWLEDGEMENTS
  9. References
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