Abstract
After many years of basic research we have now begun to learn how to manipulate the serotonergic mechanisms within the gut. This has lead to a number of significant advances including 5HT3 antagonists for the treatment of functional diarrhoea, 5HT4 agonists for the treatment of constipation and 5HT1 agonists for the treatment of impaired fundal relaxation. Initial enthusiasm has been somewhat dented by the withdrawal of alosetron because of ischaemic colitis, but it remains to be seen whether this adverse event will be seen with other 5HT3 antagonists. Finally it should be recognized that, in a substantial proportion of patients attending clinics complaining of functional symptoms, anxiety is a major component. The drugs so far described are by and large devoid of CNS effects. It remains possible therefore that a drug which combines both peripheral and central effects would likely to be beneficial.
Keywords: drugs, functional gastrointestinal disease, serotonin
It has been known for more than 25 years that there is a substantial amount of serotonin (5-hydroxytrypamine or 5HT) in the gut, distributed mainly in the enteroendocrine cells with a small amount in the enteric nervous system. Bulbring was the first to propose that 5HT played a key role in peristalsis [1] but it has taken over 40 years to clearly demonstrate the relevant pathways involved (see below). Initial difficulties in understanding its role was inevitable, given that it is now recognized that there are over 21 different receptor subtypes. As more specific agonists and antagonists have become available more discriminating studies have become possible to define these many separate and sometimes conflicting responses. However we are now entering an exciting era, as many new 5HT modulating drugs are becoming available for treating functional gastrointestinal (GI) disease. It is now becoming relevant therefore for clinicians to understand the role of serotonin in the normal gut function.
Serotonin and GI physiology
Distribution
Approximately 80% of total body serotonin is found in the GI tract, the remainder being divided between the platelets, which avidly take up free serotonin, and the central nervous system. Ninety five percent of GI 5HT is found within the granules of the enteroendocrine cells (ECs). These cells, which number about 1 per 100 epithelial cells, lie mainly at the base of the crypts. They have apical microvilli to detect luminal events, while the base of the cell rests on the basement membrane (Figure 1). Secretory granules are pleomorphic, with diameters ranging from 400 to 200 nm, contain 5HT and other peptides including CCK, neurotensin, GLP-1 and PYY [2]. ECs are found throughout the GI tract with greater density in the proximal duodenum and rectum. Throughout the gut, ECs containing 5HT granules are the most numerous subtype, followed by those containing CCK in the upper GI tract and PYY in the lower GI tract [3].
Figure 1.
Enteroendocrine cell from the rectal mucosa showing numerous secretory granules situated at the base adjacent to the basement membrane.
Factors modulating 5HT release from enteroendocrine cells
As shown in Figure 2 there are many factors which stimulates secretion from the granules by exocytosis. These include mechanical stimuli such as luminal pressure or mucosal stroking and bacterial toxins such as cholera toxin and cytotoxic drugs which nonspecifically damage the cells, such as cisplatinum [4].
Figure 2.
Cartoon illustrating the many stimuli and receptors which influence enteroendocrine cell granule exocytosis. Increase in intracellular Ca++ concentration appears to be the key final step. The precise pathways are not clearly defined in EC but depolarization by high K+ does lead to an increase intracellular calcium by opening L-type voltage-dependent calcium channels [89].
There is also classical receptor mediated stimulation via β-adrenergic, purinergic A2A/B and muscarinic receptors, together with inhibitory α2-adrenergic, histamine type 3 receptors and purinergic A1 receptors. These probably act through modulating intracellular Ca++, a surge in which is associated with 5HT release. Most of these mechanisms have been described in experimental animal models but there have been a number of studies of 5HT release in humans. Large mixed meals produce a rise in whole blood 5HT from around 220 to a peak of 300 ng ml−1 [5] though the precise mechanism is unclear and could include distension, luminal nutrients and neural reflexes.
Main receptors mediating GI effects of 5HT
5HT has many actions as illustrated in Figure 3. The numerous 5HT-receptor subtypes (21 at present and rising) allow for site-specific actions of the same molecule. The main effects relevant to gastrointestinal physiology are mediated via 5HT1a, 1p, 3, 4 receptors.
Figure 3.
Schematic illustration of multiple actions of 5HT-receptor modulating drugs. 5HT3 agonists inhibit gastric secretions, stimulate MMCs [15] and enhance intestinal secretions thereby accelerating small bowel transit [16]. They also stimulate antral contractions and vagal afferents inducing nausea [15]. 5HT3 antagonists are excellent antiemetics, counteracting the nauseating effects of opiates and 5HT released by chemo- and radiotherapy. 5HT4 agonists stimulate oesophageal peristalsis, gastric emptying and small bowel transit. Abbreviations: LOS=lower oesophageal sphincter, MMC=migrating motor complex.
5HT1 receptors are G-protein linked. There are however, many subtypes and they appear to be linked to different second messengers in different cells, some showing increase in adenyl cyclase and some showing the reverse with some acting independently of adenyl cyclase. In the gut 5HT1p agonists stimulate release of NO from inhibitory nerves supplying the gastric fundus and thus relax the fundus. 5HT2 receptors also exist in several forms (A, B and C), all G-protein linked to activation of phosphoinositide metabolism and hence elevation of intracellular calcium [6]. Most induce vascular smooth muscle contraction but in the rat they also mediate gastric fundal contraction. The 5HT3 receptor is quite different being a ligand-gated cation channel. 5HT binding opens the channels allowing entry of K+ and Ca++ leading to depolarization with an action potential similar to many neurotransmitters. It shows rapid desensitization and is suitable for transmitting rapidly changing information. By contrast the 5HT4 receptor is another G-protein linked receptor, ligand binding activating an increase in cAMP via adenyl cyclase. This increase activates a protein kinase, which inhibits K+ channels, preventing hyperpolarization, thereby enhancing excitability of the cell. Such an action is longer lasting than the 5HT3 effect and is well suited to a neuro-modulatory role. Both 5HT3 and 5HT4 agonists stimulate propulsion and secretion and excite afferent neurones.
5HT and sensation
As shown in Figure 4, 5HT3 receptors are found on vagal and mesenteric afferents. Recording from vagal afferents shows that 5HT increases the discharge acting via these receptors [7, 8]. One of the most striking effects of 5HT in the stomach is the induction of nausea and vomiting associated with chemotherapy. The more strongly emetogenic regimes which include cisplatinum, produce a marked increase in the plasma level and urine excretion of the metabolite 5-HIAA [9]. Agents with the strongest emetic effect are alkating agents, which kill cells at all stages of the cell cycle. It is likely therefore that the 5HT release is nonspecific, related to the damage to enteroendocrine cells, along with damage to the rest of the mucosa. Since vagotomy inhibits cisplatinum-induced vomiting [8] it is believed that most of the 5HT effect occurs locally on vagal afferents, though of course there are 5HT3 receptors in the chemoreceptor trigger zone in the nucleus tractus solitarus and the area postrema.
Figure 4.
Schematic illustration of selected neuronal and cellular sites where 5HT receptor modulators can act as discussed in the text. 5HT acting via 5HT1p receptors on the gastric inhibitory neurone causes the release of NO which relaxes the gastric fundus. 5HT3 antagonists inhibit splanchnic afferent nerve response to painful distension and inhibit vagal responses to chemotherapy induced 5HT release. They also inhibit discharge of secreto-motor nerves, which act via VIP, and NO. 5HT4 agonists induce peristaltic contractions by stimulating IPAN. These activate ascending excitatory pathways, mediated via acetylcholine and substance P, together with descending inhibitory pathways, mediated via NO and VIP release. Abbreviations: IPAN=intrinsic primary afferent neurone, VIP=Vasoactive intestinal peptide, SP=substance P, NO=nitric oxide.
When activation of enteric neurones has been studied histologically using the appearance of the early activation protein, c-fos, it has been shown that activation of submucosal neurones can be blocked by 5HT1p antagonists [10]. However the sensory limb of the peristaltic reflex appears to require activation of 5HT4 receptors, at least in man (see below).
Effect on GI motility (Figure 3)
During fasting a regular progression of quiescence (phase I) followed by increasing activity (phase II), culminating in intense regular phasic activity (phase III) migrates through the gut, the so-called ‘interdigestive housekeeper’. Intravenous 5HT increases the frequency of such migrating motor complexes (MMC) [11] as do 5HT reuptake inhibitors [12] which increase the effects of endogenously released 5HT. Serotonergic nerves appear to be critical in the MMC since their destruction in the rat disrupts the MMC [13] while ondansetron increases the migrating motor complex interval in man [14]. 5HT3 agonists stimulate human MMCs [15], antral contractions and excite vagal afferents, inducing nausea [16]. 5HT3 antagonists block gastric phase III motor activity (vital for emptying the fasting secretions and particulate debris from the stomach) [17]. In man, but not in dogs [18], this is also associated with an inhibition of the fluctuations in plasma motilin which normally precede a gastric MMC in man, raising the possibility that 5HT3 receptors may be involved in motilin secretion.
The role of 5HT in oesophageal function is less clear but cisapride, with 5HT4 agonist effects, stimulates oesophageal peristalsis, increasing the amplitude of contractions and increasing lower oesphageal sphincter pressure.
5HT may also be important in controlling gastric tone, inducing a relaxation of the guinea pig's stomach, acting via 5HT1 receptors, which stimulate nitrergic nerves to release NO [19]. This NO-mediated relaxation is important in the normal receptive relaxation associated with food ingestion [20]. Sumatriptan, a 5HT1P receptor agonist, induces gastric fundal relaxation in man and increases the volumes required to induce a sensation of discomfort [21]. Finally 5HT inhibits gastric secretion [22] probably acting through 5HT3[23] and 5HT1 receptors [22].
Importance of 5HT in peristalsis
The peristaltic reflex depends on the stimulation of primary sensory neurones by contact with a food bolus. This elicits, amongst other effects, an ascending stimulation of circular muscle contraction with a descending relaxation resulting in caudal propulsion. 5HT released from enteroendocrine cells by luminal pressure plays a key role in transducing the pressure stimulus into a nervous stimulus, the peristaltic reflex being abolished by either depleting mucosal 5HT stores or blocking both 5HT3 and 5HT4 receptors.
Mucosal stimulation by brushing produces a release of 5HT [24] which acts on 5HT4 receptors to stimulate the intrinsic primary afferent neurone (IPAN), one of whose neurotransmitter's is calcitonin gene-related peptide (CGRP). CGRP release is blocked by selective 5HT4 antagonists in the human jejunum [25] and rat colon [26] and by both selective 5HT4 and 5HT3 antagonists in the guinea pig colon.
Using a three-compartment model, in which the medium bathing stripped mucosa is separated into three compartments by glass slides, it is possible to locate where various mediators are released. Stroking produces a local release of CGRP, proximally substance P is released and circular muscle contraction occurs, while in the distal compartment VIP is released and circular muscle relaxation occurs [25]. The effect of this response can be assessed by placing an artificial pellet in the isolated gut, which results in it being propelled distally. This peristaltic movement in the guinea pig colon is the result of at least two redundant pathways, which are separately inhibited, either by 5HT3 or 5HT4 antagonists, which must both be used together to block peristalsis [27]. Both these pathways also involve cholinergic neurones and can be blocked by atropine. In addition to the contractile response associated with peristalsis there is also a secretory response.
5HT and intestinal secretion
Serotonin influences gastrointestinal secretions both directly via 5HT4 receptors on enterocytes and indirectly via 5HT3 receptors on secretory mucosal nerves and vagal afferents. The best studied example of 5HT-induced secretion is that induced by cholera toxin which induces secretion both by direct effects on the enterocyte and also indirectly by releasing 5HT from the enteroendocrine cell [28]. This 5HT-mediated secretion involves both stimulation of release of secretagogues such as VIP [29, 30] and NO [31] from secretory nerves as well as prostaglandin from macrophages acting via 5HT2 receptors. 5HT3 antagonists such as ondansetron and granisetron [28] as well as prostaglandin antagonists and 5HT2 and 5HT3 antagonists inhibit cholera toxin-induced secretion without affecting the release of 5HT3[32]. These data suggest a model whereby cholera toxin stimulates the release of 5HT from ECs, which then acts on submucosal and myenteric plexus neurones to stimulate secretion and on macrophages and fibroblasts, releasing prostaglandins, which in turn stimulate enterocyte secretion.
During normal digestion locally released 5HT stimulates vagal afferents. This is important in the pancreatic response to intraduodenal chow, maltose and hypertonic sodium chloride. Secretion induced by these stimuli is blocked by vagal afferent section and also by 5HT3 antagonists. In addition to inhibiting cholera toxin-induced secretion, the 5HT3 antagonist alosetron also enhances basal absorption. This implies that there is a basal tonic stimulation of intestinal secretion by 5HT [33], probably via 5HT3 receptors on mucosal secretory nerves as has been demonstrated in the rat colon [34]. In the human small intestine there are also 5HT4 receptors on the enterocytes, stimulation of which cause tetrodotoxin-resistant secretion [35].
Colonic response to feeding
Eating is one of the strongest stimuli to colonic motor activity, increasing both phasic contractions and tone, both of which can be blocked by 5HT3 antagonists. One of the early studies using granisetron (a 5HT3 antagonist) showed that 40 and 160 mg kg−1 intravenously reduced the increase in postprandial motility noted after a meal [36]. More recently in an important experimental study in healthy volunteers Bjornsson and colleagues [37] showed that granisetron 10 mg kg−1 i.v. blocked the colonic response to both balloon distension of the antrum as well as intraduodenal lipid perfusion. Granisetron did not however, alter the local colonic response to balloon distension within the colon. It seems likely that under these circumstances Granisetron is blocking 5HT3 receptors on the vagus thereby interrupting the afferent arm of the gastro-colonic reflex.
Intestinal transit
Ondansetron, one of the earlier 5HT receptor antagonists, delays colonic transit in normal volunteers [38], the main impact being on the left colon [39]. Ondansetron also inhibits the postprandial increase in tone in both healthy volunteers and patients with carcinoid diarrhoea [40, 41].
In addition to changes in GI transit, 5HT3 receptor antagonists also reduce visceral sensation in response to balloon distension [36], mainly by reducing colonic tone rather than any change in neural sensitivity [42].
Now that specific 5HT4 agonists have been developed for use in man it is possible to test the significance of the mechanisms demonstrated in experimental animals. Two 5HT4 agonists, tegaserod and prucalopride have both been shown to accelerate colonic transit. Prucalopride is significantly more selective for 5HT4 receptor and has no effect on gastric or small bowel transit [43, 44]. Tegaserod does accelerate both gastric emptying and small bowel transit [45] and may prove beneficial in upper GI dysmotility.
The sum of these effects implies that 5HT3 antagonists will slow intestinal transit, decrease intestinal secretions, decrease the water content of stool and diminish colonic pain. By contrast 5HT4 antagonists would be predicted to accelerate gastric emptying, small and large bowel transit and increase stool water content.
Clinical applications (Table 1)
Table 1.
Drugs acting via serotonergic mechanisms: sites of action and potential therapeutic areas.
Class and examples | Site | Action | Potential therapeutic areas |
---|---|---|---|
5HT1p agonists | Inhibitory gastric motor neurones | Fundal relaxation | Functional dyspepsia |
Buspirone | |||
Sumitriptam | |||
5HT3 antagonists | |||
Ondansetron | Vagal afferents | Inhibit nausea due to 5HT release | Chemotherapy induced nausea |
Granisetron | Enteric interneurones & secreto-motor neurones | Inhibit opiate induced nausea | Post operative nausea |
Alosetron | Mesenteric afferents | Inhibit sprial evoked responses to intestinal distension | Visceral hypersensitivity in IBS |
Cilansetron | |||
5HT4 antagonists | |||
Prucalopride | Cholinergic colonic motor nerves (enhances acetylcholine release) | Stimulates peristalsis | Constipation |
Accelerates colonic transit | |||
5HT4 partial agonist | |||
Tegaserod | Primary afferent enteric neurones | Stimulates peristalsis | Constipated IBS |
Enterocytes | Stimulates chloride secretion | ||
Extrinsic mesenteric afferents | Inhibits afferent firing in response to distension | ||
Combined 5HT4 agonist and 5HT3 antagonist | |||
Cisapride | Motor neurones | Stimulates increased amplitude of oesphageal peristalsis contractions and lower oesphageal sphineter pressure | Impaired oesphageal peristalsis |
Accelerating gastric emptying and small bowel transit | Gastroparesis | ||
Chronic intestinal pseudo-obstruction |
Note that this list of known sites of action is selective and certainly incomplete since the drugs have been studied in different models and in differing detail.
Gastro-oesophageal reflux
One of the earliest serotonergic-modulating drugs introduced into widespread clinical practice was cisapride, a drug that acts presynaptically via 5HT4 receptors [46], enhancing acetylcholine release in response to nerve stimulation [47]. Cisapride is a 5HT4 agonist with partial 5HT3 antagonist effects. It increases the amplitude of oesophageal contractions and lowers oesophageal sphincter pressure and accelerates gastric emptying and oro-caecal transit. The recent availability of 5HT4 antagonists suitable for use in man has made it possible to demonstrate that cisapride's acceleration of oro-caecal transit is mediated via 5HT4 receptors [48]. While relatively ineffective compared with proton pump inhibitors in severe erosive oesophagitis, cisapride is effective in less severe cases. However it has recently been withdrawn owing to the rare occurrence of cardiac arrhythmias, thought to be related to its effect of prolonging the QT interval acting via cardiac 5HT4 receptors.
Functional dyspepsia
This is a common condition in which patients suffer symptoms of upper gastric discomfort or pain in spite of normal endoscopy, ultrasound and other assessments. About one third of patients demonstrate delayed gastric emptying [49], another third demonstrate impaired gastric relaxation and about the same number demonstrate hypersensitivity to gastric distension [50, 51]. In general symptoms relate rather poorly to the abnormalities demonstrated, though Stanghellini et al. [49] found that severe vomiting and postprandial fullness together with female sex were predictive of delayed gastric emptying.
The demonstration of these abnormalities has encouraged the use of drugs to reverse them. In particular, initial interest focused on the role of cisapride, which had been shown to accelerate gastric emptying [52]. Cisapride also enhances postprandial gastric relaxation [53], whilst during fasting it increases fundal tone and perception of distension. These multiple actions may explain the somewhat confusing results in functional dyspepsia with some negative studies [54, 55], while others have shown significant benefit [56]. Meta-analysis suggests a modest overall positive treatment effect [57].
A common feature of functional dyspepsia is an abnormal distribution of test meals within the stomach immediately after ingestion, with an increased proportion in the antrum. This may relate both to impaired antral motility or impaired fundal relaxation. Cisapride does reduce the postprandial antral area [56] and enhance postprandial fundal relaxation, which may be helpful, however, its enhancement of visceral perception may aggravate symptoms. Interestingly, levosulpiride, a drug with both 5HT4 agonist effects as well as central D2 dopamine receptor antagonism, has been shown to be significantly better than cisapride at relieving symptoms in functional dyspepsia. The gastrokinetic effects of levosulpiride are similar [58], implying that drugs with combined peripheral and central effects may be more effective in this condition, in keeping with the fact than functional dyspeptic patients often show increased anxiety and depression.
Since impaired accommodation is found in 40% of patients with nonulcer dyspepsia [50] it would be logical to try a fundus-relaxing agent in functional dyspepsia. Sumatriptan, a 5HT1p agonist relaxes the gastric fundus [21] as does Buspirone, also a 5HT1p agonist, which showed some benefit in clinical trials [59].
Prevention of chemotherapy-induced nausea
The first successful clinical application for 5HT3 receptor antagonists was the use of ondansetron to prevent 5HT-induced nausea secondary to cancer chemotherapy. This class of drugs has also been shown to be efficacious in radiation-induced nausea, postoperative nausea, anorexia nervosa, nausea and vomiting in AIDS [60], and nausea due to acute viral gastro-enteritis [61].
Irritable bowel syndrome
IBS is a common chronic disorder affecting between 9 and 12% of the adult population, accounting for a substantial proportion of gastrointestinal outpatients. The symptoms of IBS are characterized by recurring abdominal pain or discomfort associated with disordered defaecation. This can take the form of either loose stools passed with urgency or hard stools associated with straining and a sense of incomplete evacuation. Cluster analysis indicates that about one third of patients fit the diarrhoea predominant IBS (D-IBS) category, one third constipation predominant (C-IBS) and a further third pass for the most part normal stools without urgency, their main complaint being abdominal pain [62]. It should be noted that these subgroups tend to have rather similar bowel frequencies and the main difference relates to stool consistency. Stool consistency is related to colonic transit and the time for water absorption, whereas defaecation frequency depends on many factors including rectal sensation, social circumstances and habit.
Delaying colonic transit and increasing water absorption would be predicted to help D-IBS. Furthermore IBS patients often experience worsening of pain after eating [63] and many studies have suggested an exaggerated colonic response to feeding so inhibiting this should be helpful. One other characteristic feature of patients with IBS is a reduced threshold for pain during gut distension, leading to much interest in drugs that alter visceral sensitivity.
5HT3 antagonists and IBS
Mechanistic studies
One of the earliest 5HT3 antagonists, granisetron, has been shown to reduce rectal sensitivity and postprandial motility in IBS [36]. The related 5HT3 antagonist, ondansetron has also been shown to increase stool consistency in both normals and IBS [64]. When used to specifically target D-IBS, ondansetron improves stool consistency and tends to delay colonic transit [65]. The more selective and potent 5HT3 antagonist, alosetron has also been shown to delay in colonic transit in both healthy volunteers [66] and patients with D-IBS [67]. Alosetron also increased the threshold for discomfort on balloon distension due to an increase in compliance, an effect which may well contribute to some of reduction in abdominal pain [42].
Clinical trials
Clinical trials with alosetron showed hardening of stool and a reduction of stool frequency in IBS patients [68, 69]. Sub-group analysis indicated that it was females who benefited most. A subsequent study [70] of females with D-IBS or alternating IBS reported that the proportion experiencing ‘adequate relief of pain and discomfort’ for all 3 months of treatment was significantly greater for the alosetron-treated patients at 41% vs 29% for placebo. Analysing by IBS subtypes shows that this significant difference was due to the effect on the D-IBS patients, the alternating IBS patients receiving no benefit compared with placebo. As expected from the pharmacology, alosetron significantly decreased stool frequency and improved stool consistency compared with placebo, effects that were seen within the first week of commencing treatment. Likewise the number of days with urgency again fell significantly. Thirty-three out of 342 patients treated with alosetron withdrew because of constipation compared with just one out 323 receiving placebo. On stopping the drug diarrhoeal symptoms returned within a week, supporting the idea that the improvement was pharmacologically specific.
Although there are 5HT3 receptors in the brain and 5HT antagonists have been shown to have anxiolytic properties in animal models, in IBS patients alosetron, at the dose effective clinically, did not produce any significant change in anxiety or depression [71]. When compared with mebeverine, the commonest drug prescribed for IBS in the UK alosetron was shown to be significantly more effective [72].
Adverse events
Regrettably alosetron has been withdrawn from the market after 446 000 prescription following reports of 49 cases of ischaemic colitis, a pharmacologically unexpected effect. The mechanism is obscure since alosetron does not alter intestinal blood flow in experimental animals. Whether this rare event is unique to alosetron is uncertain, but newer 5HT3 antagonists are also in development, so clinical studies are awaited with interest, since this class of drug is undoubtedly clinically effective. It does however, illustrate the fact that safety is all-important in a nonfatal disease such as IBS. The other expected adverse event experienced with alosetron was constipation, reported in 29% vs 5% placebo in the controlled trials. In most cases this was not sufficient to stop taking the drug but in 21 cases out of 435 000 out of trial prescriptions it was severe enough to require hospitalization. Ten of these went on to laparotomy, which in four cases demonstrated a perforated diverticulum. There were three deaths. It should be noted than the age of these cases ranged from 65 to 82 years suggesting that these were not in fact being given to patients with IBS but rather that their symptoms were due to diverticulitis.
5HT4 agonists and IBS
Cisapride
Cisapride's prokinetic effects probably depend on its 5HT4 agonist properties [73]. It accelerates gastric emptying, and mouth to caecum transit without altering stool weight or frequency [74]. Cisapride has been shown to be effective in chronic constipation [75]. However in IBS there are conflicting results with cisapride, some trials showing benefit, particularly in pain and distension [76] and ease of defecation [77], while others have shown no benefit [78]. The lack of effectiveness of cisapride may relate to the combination of a laxative effect from the 5HT4 agonist effects, counteracted by the constipated effect of the 5HT3 antagonist effects. With this in mind a selective 5HT4 agonist, tegaserod, has been developed.
Tegaserod
This drug stimulates motility in both the upper and lower GI tract in dog [79] and in the colon of rats [80]. It also accelerates colonic transit in man [81]. Physiological studies in IBS are as yet few in number. 2 mg twice daily of tegaserod accelerated oro-caecal transit and proximal colonic emptying, though overall colonic transit was not altered [82]. The dose here may have been insufficient, since in subsequent clinical trials using 6 mg twice daily it was shown to significantly decrease the number of hard stools and increase the number of bowel movements per 28 days from 22 to 35 [83]. The same study of 799 patients with constipated IBS showed a significant improvement in bloating [84], something which previous therapies have failed to do, in spite of its undoubted importance to patients. More recently, a study of 881 patients with C-IBS, receiving either 2 or 6 mg twice daily was reported with a significant improvement in ‘responder’ (defined as marked or moderate improvement for at least 2 out of 4 weeks, or somewhat improved for all 4 weeks) rates for females against placebo. This demonstrated an increment over the placebo response (27.5%) of 10 and 11% for the two doses, respectively [85]. This gain over placebo is small, giving a number needed to treat of eight to get one extra responder compared with placebo. However in a difficult condition like IBS, where there are few effective treatments, even this small effect is likely to be a welcomed addition to the therapeutic armamentarium.
Functional constipation
The enhancement of cholinergic neurotransmission in the colon suggested the use of cisapride in severe constipation [75, 86] and constipation associated with paraplegia [87], and in both conditions it has been shown to be beneficial. Prucalopride is another new 5HT4 agonists which is highly selective and probably a more potent laxative than tegaserod, though it very efficacy may cause abdominal cramps which may be undesirable in IBS. Several studies have demonstrated efficacy in severe constipation and constipated IBS [82, 88]. Prucalopride has been shown to be of benefit in patients with resistant constipation referred to a tertiary referral centre. 4 mg once daily increased stool frequency from a mean of 1.9 per week to 4.2. Fifteen out of 27 patients required a dose reduction mainly because of nausea and vomiting. Total gut transit decreased and stool consistency normalized. The commonest side-effects were headaches, nausea and abdominal cramps and four patients developed diarrhoea, in keeping with it secretory and prokinetic effect.
References
- 1.Bulbring E, Crema A. Thee release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa. J Physiol (Lond.) 1959;146:18–28. doi: 10.1113/jphysiol.1959.sp006175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Cristina ML, Lehy T, Zeitoun P, Dufougeray F. Fine structural classification and comparative distribution of endocrine cells in normal human large intestine. Gastroenterology. 1978;75:20–28. [PubMed] [Google Scholar]
- 3.Sjolund K, Sanden G, Hakanson R, Sundler F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology. 1983;85:1120–1130. [PubMed] [Google Scholar]
- 4.Schworer H, Racke K, Kilbinger H. Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: involvement of 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 1991;344:143–149. doi: 10.1007/BF00167211. [DOI] [PubMed] [Google Scholar]
- 5.Richter G, Stockmann F, Conlon JM, Creutzfeldt W. Serotonin release into blood after food and pentagastrin. Studies in healthy subjects and in patients with metastatic carcinoid tumors. Gastroenterology. 1986;91:612–618. doi: 10.1016/0016-5085(86)90630-x. [DOI] [PubMed] [Google Scholar]
- 6.Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin) Pharmacol Rev. 1994;46:157–203. [PubMed] [Google Scholar]
- 7.Blackshaw LA, Grundy D. Effects of 5-hydroxytryptamine (5-HT) on the discharge of vagal mechanoreceptors and motility in the upper gastrointestinal tract of the ferret. J Auton Nerv Syst. 1993;45:51–59. doi: 10.1016/0165-1838(93)90361-w. [DOI] [PubMed] [Google Scholar]
- 8.Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L. The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol. 1990;68:325–345. doi: 10.1139/y90-047. [DOI] [PubMed] [Google Scholar]
- 9.Cubeddu LX, Hoffmann IS, Fuenmayor NT, Malave JJ. Changes in serotonin metabolism in cancer patients. Its relationship to nausea and vomiting induced by chemotherapeutic drugs. Br J Cancer. 1992;66:198–203. doi: 10.1038/bjc.1992.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kirchgessner AL, Tamir H, Gershon MD. Identification and stimulation by serotonin of intrinsic sensory neurons of the submucosal plexus of the guinea pig gut: activity-induced expression of Fos immunoreactivity. J Neurosci. 1992;12:235–248. doi: 10.1523/JNEUROSCI.12-01-00235.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lordal M, Wallen H, Hjemdahl P, Beck O, Hellstrom PM. Concentration-dependent stimulation of intestinal phase III of migrating motor complex by circulating serotonin in humans. Clin Sci (Colch) 1998;94:663–670. doi: 10.1042/cs0940663. [DOI] [PubMed] [Google Scholar]
- 12.Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther. 1994;8:159–166. doi: 10.1111/j.1365-2036.1994.tb00273.x. [DOI] [PubMed] [Google Scholar]
- 13.Pineiro-Carrero VM, Clench MH, Davis RH, Andres JM, Franzini DA, Mathias JR. Intestinal motility changes in rats after enteric serotonergic neuron destruction. Am J Physiol. 1991;260:G232–G239. doi: 10.1152/ajpgi.1991.260.2.G232. [DOI] [PubMed] [Google Scholar]
- 14.Lordal M, Hellstrom PM. Serotonin stimulates migrating myoelectric complex via 5-HT3-receptors dependent on cholinergic pathways in rat small intestine. Neurogastroenterol Motil. 1999;11:1–10. doi: 10.1046/j.1365-2982.1999.00125.x. [DOI] [PubMed] [Google Scholar]
- 15.Coleman NS, Wright J, Parker M, Spiller RC. MKC-733, a selective 5-HT3 receptor agonist stimulates fasting human antral motility. Gastroenterology. 2001;120:A460–A461. [Google Scholar]
- 16.Coleman NS, Marciani L, Blackshaw PE, Gowland PA, Perkins AC, Spiller RC. MKC-733, a selective 5-HT3 receptor agonist stimulates small bowel transit and relaxes the gastric fundus in man. Gastroenterology. 2001;120:A71. [Google Scholar]
- 17.Wilmer A, Tack J, Coremans G, Janssens J, Peeters T, Vantrappen G. 5-hydroxytryptamine-3 receptors are involved in the initiation of gastric phase-3 motor activity in humans. Gastroenterology. 1993;105:773–780. doi: 10.1016/0016-5085(93)90895-j. [DOI] [PubMed] [Google Scholar]
- 18.Itoh Z, Mizumoto A, Iwanaga Y, Yoshida N, Torii K, Wakabayashi K. Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog. Gastroenterology. 1991;100:901–908. doi: 10.1016/0016-5085(91)90262-j. [DOI] [PubMed] [Google Scholar]
- 19.Meulemans AL, Helsen LF, Schuurkes JA. The role of nitric oxide (NO) in 5-HT-induced relaxations of the guinea-pig stomach. Naunyn Schmiedebergs Arch Pharmacol. 1993;348:424–430. doi: 10.1007/BF00171343. [DOI] [PubMed] [Google Scholar]
- 20.Desai KM, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature. 1991;351:477–479. doi: 10.1038/351477a0. [DOI] [PubMed] [Google Scholar]
- 21.Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J. Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut. 2000;46:468–473. doi: 10.1136/gut.46.4.468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lepard KJ, Chi J, Mohammed JR, Gidener S, Stephens RL., Jr Gastric antisecretory effect of serotonin: quantitation of release and site of action. Am J Physiol. 1996;271:E669–E677. doi: 10.1152/ajpendo.1996.271.4.E669. [DOI] [PubMed] [Google Scholar]
- 23.Johansen B, Bech K. BRL 24924, a 5-hydroxytryptamine type 3 antagonist, and gastric secretion of acid and pepsin in vivo. Digestion. 1991;48:121–127. doi: 10.1159/000200683. [DOI] [PubMed] [Google Scholar]
- 24.Foxx-Orenstein AE, Kuemmerle JF, Grider JR. Distinct 5-HT receptors mediate the peristaltic reflex induced by mucosal stimuli in human and guinea pig intestine. Gastroenterology. 1996;111:1281–1290. doi: 10.1053/gast.1996.v111.pm8898642. [DOI] [PubMed] [Google Scholar]
- 25.Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology. 1998;115:370–380. doi: 10.1016/s0016-5085(98)70203-3. [DOI] [PubMed] [Google Scholar]
- 26.Grider JR, Kuemmerle JF, Jin JG. 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons. Am J Physiol. 1996;270:G778–G782. doi: 10.1152/ajpgi.1996.270.5.G778. [DOI] [PubMed] [Google Scholar]
- 27.Kadowaki M, Wade PR, Gershon MD. Participation of 5-HT3, 5-HT4, and nicotinic receptors in the peristaltic reflex of guinea pig distal colon. Am J Physiol. 1996;271:G849–G857. doi: 10.1152/ajpgi.1996.271.5.G849. [DOI] [PubMed] [Google Scholar]
- 28.Turvill JL, Connor P, Farthing MJ. The inhibition of cholera toxin-induced 5-HT release by the 5-HT (3) receptor antagonist, granisetron, in the rat [In Process Citation] Br J Pharmacol. 2000;130:1031–1036. doi: 10.1038/sj.bjp.0703414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Mourad FH, Nassar CF. Effect of vasoactive intestinal polypeptide (VIP) antagonism on rat jejunal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. Gut. 2000;47:382–386. doi: 10.1136/gut.47.3.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Cooke HJ, Sidhu M, Wang YZ. Activation of 5-HT1P receptors on submucosal afferents subsequently triggers VIP neurons and chloride secretion in the guinea-pig colon. J Auton Nerv Syst. 1997;66:105–110. doi: 10.1016/s0165-1838(97)00075-1. [DOI] [PubMed] [Google Scholar]
- 31.Stoner MC, Scherr AM, Lee JA, Wolfe LG, Kellum JM. Nitric oxide is a neurotransmitter in the chloride secretory response to serotonin in rat colon. Surgery. 2000;128:240–245. doi: 10.1067/msy.2000.107608. [DOI] [PubMed] [Google Scholar]
- 32.Beubler E, Kollar G, Saria A, Bukhave K, Rask-Madsen J. Involvement of 5-hydroxytryptamine, prostaglandin E2, and cyclic adenosine monophosphate in cholera toxin-induced fluid secretion in the small intestine of the rat in vivo. Gastroenterology. 1989;96:368–376. doi: 10.1016/0016-5085(89)91560-6. [DOI] [PubMed] [Google Scholar]
- 33.Bearcroft CP, Andre EA, Farthing MJ. In vivo effects of the 5-HT3 antagonist alosetron on basal and cholera toxin-induced secretion in the human jejunum: a segmental perfusion study. Aliment Pharmacol Ther. 1997;11:1109–1114. doi: 10.1046/j.1365-2036.1997.d01-1389.x. [DOI] [PubMed] [Google Scholar]
- 34.Budhoo MR, Harris RP, Kellum JM. The role of the 5-HT4 receptor in Cl-secretion in human jejunal mucosa. Eur J Pharmacol. 1996;314:109–114. doi: 10.1016/s0014-2999(96)00474-8. [DOI] [PubMed] [Google Scholar]
- 35.Borman RA, Burleigh DE. Evidence for the involvement of a 5-HT4 receptor in the secretory response of human small intestine to 5-HT. Br J Pharmacol. 1993;110:927–928. doi: 10.1111/j.1476-5381.1993.tb13901.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Prior A, Read NW. Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 1993;7:175–180. doi: 10.1111/j.1365-2036.1993.tb00087.x. [DOI] [PubMed] [Google Scholar]
- 37.Bjornsson ES, Chey WD, Ladabaum U, et al. Differential 5-HT3 mediation of human gastrocolonic response and colonic peristaltic reflex. Am J Physiol. 1998;275:G498–G505. doi: 10.1152/ajpgi.1998.275.3.G498. [DOI] [PubMed] [Google Scholar]
- 38.Gore S, Gilmore IT, Haigh CG, Brownless SM, Stockdale H, Morris AI. Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Aliment Pharmacol Ther. 1990;4:139–144. doi: 10.1111/j.1365-2036.1990.tb00458.x. [DOI] [PubMed] [Google Scholar]
- 39.Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (Ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Digestive Dis Sci. 1990;35:477–480. doi: 10.1007/BF01536922. [DOI] [PubMed] [Google Scholar]
- 40.von O, Camilleri M, Kvols LK. A 5HT3 antagonist corrects the postprandial colonic hypertonic response in carcinoid diarrhea. Gastroenterology. 1994;106:1184–1189. doi: 10.1016/0016-5085(94)90008-6. [DOI] [PubMed] [Google Scholar]
- 41.Scolapio JS, Camilleri M, von der Ohe MR, Hanson RB. Ascending colon response to feeding. Evidence for a 5-hydroxytryptamine-3-mechanism. Scand J Gastroenterol. 1995;30:562–567. doi: 10.3109/00365529509089790. [DOI] [PubMed] [Google Scholar]
- 42.Delvaux M, Louvel D, Mamet JP, Campos-Oriola R, Frexinos J. Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 1998;12:849–855. doi: 10.1046/j.1365-2036.1998.00375.x. [DOI] [PubMed] [Google Scholar]
- 43.Poen AC, Felt-Bersma RJ, Van Dongen PA, Meuwissen SG. Effect of prucalopride, a new enterokinetic agent, on gastrointestinal transit and anorectal function in healthy volunteers. Aliment Pharmacol Ther. 1999;13:1493–1497. doi: 10.1046/j.1365-2036.1999.00629.x. [DOI] [PubMed] [Google Scholar]
- 44.Bouras EP, Camilleri M, Burton DD, McKinzie S. Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans. Gut. 1999;44:682–686. doi: 10.1136/gut.44.5.682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Degen L, Matzinger D, Merz M, et al. The 5-HT4 receptor partial agonist tegaserod (HTF919) accelerates upper and lower gastrointestinal (GI) transit. Gastroenterology. 2000;118:A845. [Google Scholar]
- 46.Goldhill J, Porquet MF, Angel I. Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae. Eur J Pharmacol. 1997;323:229–233. doi: 10.1016/s0014-2999(97)00046-0. [DOI] [PubMed] [Google Scholar]
- 47.Tonini M, Galligan JJ, North RA. Effects of cisapride on cholinergic neurotransmission and propulsive motility in the guinea pig ileum. Gastroenterology. 1989;96:1257–1264. doi: 10.1016/s0016-5085(89)80012-5. [DOI] [PubMed] [Google Scholar]
- 48.Bharucha AE, Camilleri M, Zinsmeister AR, Hanson RB. Adrenergic modulation of human colonic motor and sensory function. Am J Physiol. 1997;273:G997–G1006. doi: 10.1152/ajpgi.1997.273.5.G997. [DOI] [PubMed] [Google Scholar]
- 49.Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology. 1996;110:1036–1042. doi: 10.1053/gast.1996.v110.pm8612991. [DOI] [PubMed] [Google Scholar]
- 50.Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia [see comments] Gastroenterology. 1998;115:1346–1352. doi: 10.1016/s0016-5085(98)70012-5. [DOI] [PubMed] [Google Scholar]
- 51.Thumshirn M, Camilleri M, Saslow SB, Williams DE, Burton DD, Hanson RB. Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function. Gut. 1999;44:55–64. doi: 10.1136/gut.44.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Tvede M, RaskMadsen J. Bacteriotherapy for Clostridium difficile diarrhoea. Lancet. 1990;335:110. doi: 10.1016/0140-6736(90)90574-o. [DOI] [PubMed] [Google Scholar]
- 53.Tack J, Broeckaert D, Coulie B, Janssens J. The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther. 1998;12:761–766. doi: 10.1046/j.1365-2036.1998.00366.x. [DOI] [PubMed] [Google Scholar]
- 54.de Groot GH, de Both PS. Cisapride in functional dyspepsia in general practice. A placebo-controlled, randomized, double-blind study. Aliment Pharmacol Ther. 1997;11:193–199. doi: 10.1046/j.1365-2036.1997.117288000.x. [DOI] [PubMed] [Google Scholar]
- 55.Kellow JE, Cowan H, Shuter B, et al. Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther. 1995;9:153–160. doi: 10.1111/j.1365-2036.1995.tb00364.x. [DOI] [PubMed] [Google Scholar]
- 56.Eberl T, Barnert J, Dumitrascu DL, Fischer J, Wienbeck M. The effect of cisapride on dysmotility-like functional dyspepsia: reduction of the fasting and postprandial area, but not of the postprandial antral expansion. Eur J Gastroenterol Hepatol. 1998;10:991–995. doi: 10.1097/00042737-199812000-00002. [DOI] [PubMed] [Google Scholar]
- 57.Finney JS, Kinnersley N, Hughes M, O'Bryan-Tear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroenterol. 1998;26:312–320. doi: 10.1097/00004836-199806000-00022. [DOI] [PubMed] [Google Scholar]
- 58.Mansi C, Borro P, Giacomini M, et al. Comparative effects of levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia and gastroparesis. Aliment Pharmacol Ther. 2000;14:561–569. doi: 10.1046/j.1365-2036.2000.00742.x. [DOI] [PubMed] [Google Scholar]
- 59.Tack J. Functional dyspepsia. Impaired fundic accommodation. Curr Treat Options Gastroenterol. 2000;3:287–294. doi: 10.1007/s11938-000-0042-7. [DOI] [PubMed] [Google Scholar]
- 60.Hasler WL. Serotonin receptor physiology: relation to emesis. Dig Dis Sci. 1999;44:108S–13S. [PubMed] [Google Scholar]
- 61.Cubeddu LX, Trujillo LM, Talmaciu I, et al. Antiemetic activity of ondansetron in acute gastroenteritis. Aliment Pharmacol Ther. 1997;11:185–191. doi: 10.1046/j.1365-2036.1997.97269000.x. [DOI] [PubMed] [Google Scholar]
- 62.Ragnarsson G, Bodemar G. Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatients samples. Scand J Gastroenterol. 1999;34:993–1000. doi: 10.1080/003655299750025093. [DOI] [PubMed] [Google Scholar]
- 63.Ragnarsson G, Bodemar G. Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS). Patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study. Eur J Gastroenterol Hepatol. 1998;10:415–421. doi: 10.1097/00042737-199805000-00011. [DOI] [PubMed] [Google Scholar]
- 64.Goldberg PA, Kamm MA, Setti-Carraro P, Van den Sijp JR, Roth C. Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron) Digestion. 1996;57:478–483. doi: 10.1159/000201377. [DOI] [PubMed] [Google Scholar]
- 65.Steadman CJ, Talley NJ, Phillips SF, Zinsmeister AR. Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: A pilot study. Mayo Clinic Proceedings. 1992;67:732–738. doi: 10.1016/s0025-6196(12)60797-6. [DOI] [PubMed] [Google Scholar]
- 66.Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2000;14:775–782. doi: 10.1046/j.1365-2036.2000.00762.x. [DOI] [PubMed] [Google Scholar]
- 67.Viramontes B, McKinzie S, Pardi DS, Burton D, Thomforde GM, Camilleri M. Alosetron retards small bowel and overall colonic transit in diarrhea-predominant irritable bowel syndrome (DI-IBS) Gastroenterology. 2000;118:A848. doi: 10.1111/j.1572-0241.2001.04138.x. [DOI] [PubMed] [Google Scholar]
- 68.Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mills JG, et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2000;14:23–34. doi: 10.1046/j.1365-2036.2000.00684.x. [DOI] [PubMed] [Google Scholar]
- 69.Camilleri M, Mayer EA, Drossman DA, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther. 1999;13:1149–1159. doi: 10.1046/j.1365-2036.1999.00610.x. [DOI] [PubMed] [Google Scholar]
- 70.Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial [see comments] Lancet. 2000;355:1035–1040. doi: 10.1016/S0140-6736(00)02033-X. [DOI] [PubMed] [Google Scholar]
- 71.Heath MR, Drossman DA, Whitehead WE, et al. Alosetron does not improve anxiety in female IBS patients. Gastroenterology. 2000;118:A616. [Google Scholar]
- 72.Jones RH, Holtmann G, Rodrigo L, et al. Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients. Aliment Pharmacol Ther. 1999;13:1419–1427. doi: 10.1046/j.1365-2036.1999.00678.x. [DOI] [PubMed] [Google Scholar]
- 73.Bharucha AE, Camilleri M, Haydock S, et al. Effects of a serotonin 5-HT (4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans [In Process Citation] Gut. 2000;47:667–674. doi: 10.1136/gut.47.5.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Edwards CA, Holden S, Brown C, Read NW. Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects. Gut. 1987;28:13–16. doi: 10.1136/gut.28.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Muller-Lissner SA. Treatment of chronic constipation with cisapride and placebo. Gut. 1987;28:1033–1038. doi: 10.1136/gut.28.8.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Van Outryve M, Milo R, Toussaint J, Van Eeghem P. ‘Prokinetic’ treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49–57. doi: 10.1097/00004836-199102000-00012. [DOI] [PubMed] [Google Scholar]
- 77.Schutze K, Brandstatter G, Dragosics B, Judmaier G, Hentschel E. Double-blind study of the effect of cisapride on constipation and abdominal discomfort as components of the irritable bowel syndrome. Aliment Pharmacol Ther. 1997;11:387–394. doi: 10.1046/j.1365-2036.1997.133311000.x. [DOI] [PubMed] [Google Scholar]
- 78.Farup PG, Hovdenak N, Wetterhus S, Lange OJ, Hovde O, Trondstad R. The symptomatic effect of cisapride in patients with irritable bowel syndrome and constipation. Scand J Gastroenterol. 1998;33:128–131. doi: 10.1080/00365529850166833. [DOI] [PubMed] [Google Scholar]
- 79.Fioramonti J, Million M, Bueno L. Investigations on a 5HT4 agonistt (SDZ HTF 919) and its main metabolite in conscious dogs: effects on gastrointestinal motility and impaired gastric emptying. Gastroenterology. 2000;114:A752. [Google Scholar]
- 80.Huge A, Zittel TT, Kreis ME, Becker HD, Jehle EC. Effeects of tegaserod (HTF919) on gastrointtestinal motility and transit in awake rats. Gastroenterology. 2000;118:A403. [Google Scholar]
- 81.Appel S, Kumle A, Meier R. Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a model of slow colonic transit. Clin Pharmacol Ther. 1997;62:546–555. doi: 10.1016/S0009-9236(97)90050-3. [DOI] [PubMed] [Google Scholar]
- 82.Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology. 2000;118:463–468. doi: 10.1016/s0016-5085(00)70251-4. [DOI] [PubMed] [Google Scholar]
- 83.Schmitt C, Krumholz S, Tanghe J, Heggland J, Shi Y, Lefkowitz MP. Tegaserod, a partial 5-HT4 agonist improves abdominal discomfort/pain and altered bowel function in irritable bowel syndrome (IBS) Gut. 1999;45:A258. [Google Scholar]
- 84.Krumholz S, Tanghe J, Schmitt C, Heggland J, Shi Y, Ruegg P. The 5HT4 partial agonist, Tegaserod, improves abdominal bloating and altered stool consistency in irritable bowel syndrome (IBS) Gut. 1999;45:A260. [Google Scholar]
- 85.Mueller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther. 15:1655–1666. doi: 10.1046/j.1365-2036.2001.01094.x. [DOI] [PubMed] [Google Scholar]
- 86.Krevsky B, Maurer AH, Malmud LS, Fisher RS. Cisapride accelerates colonic transit in constipated patients with colonic inertia [see comments] Am J Gastroenterol. 1989;84:882–887. [PubMed] [Google Scholar]
- 87.Geders JM, Gaing A, Bauman WA, Korsten MA. The effect of cisapride on segmental colonic transit time in patients with spinal cord injury. Am J Gastroenterol. 1995;90:285–289. [PubMed] [Google Scholar]
- 88.Emmanuel AV, Nichols T, Roy AJ, Antonelli K, Kamm MA. Prucalopride (PRU) improves colonic transit and stool frequency in patients (PTS) with slow and normal transit constipation. Gastroenterology. 2000;118:A846. [Google Scholar]
- 89.Lomax RB, Gallego S, Novalbos J, Garcia AG, Warhurst G. L-Type calcium channels in enterochromaffin cells from guinea pig and human duodenal crypts: an in situ study. Gastroenterology. 1999;117:1363–1369. doi: 10.1016/s0016-5085(99)70286-6. [DOI] [PubMed] [Google Scholar]