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- DATA ANALYSIS
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.
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- DATA ANALYSIS
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.