drugs affecting serotonin receptors

5

Drugs affecting serotonin receptors

MICHAEL CAMILLERI MANFRED R. VON DER OHE

Serotonin (5hydroxytryptamine, 5-HT) has been recognized as a vasoconstrictor substance in serum since the turn of the century. It was isolated and identified chemically in 1948 (Rapport et al, 1948). Its effects on gastrointestinal motility and secretion have been difficult to ascertain; however, as predicted by Gershon and Erde (1981), the identification of multiple receptor subtypes and development of more or less specific agonists and antagonists have led to advances in the understanding of serotonergic mechanisms and may lead to further application of these drugs in clinical therapeutics. This chapter reviews current knowledge and the use of serotonergic compounds in gastroenterology.

SEROTONIN IN THE GASTROINTESTINAL TRACT: LOCATION AND GENERAL FUNCTIONS

It has been estimated that at least 95% of the serotonin in the gastrointestinal tract is located within enterochromaffin cells in the epithelial layer of the mucosa; the remainder is found predominantly within neurones in the myenteric plexus (Figure 1). Serotonergic neurones constitute about 2% of all myenteric neurones (Furness and Costa, 1987). Serotonin plays a role in intestinal secretion, modulating peristalsis and mediating visceral afferent function.

Enterochromaffin serotonergic cells may play a paracrine role, inducing enterocyte secretion, but there is little direct evidence for this. The release of serotonin from these cells is stimulated by serosal application of cholinergic agonists (muscarinic and nicotinic) and B-adrenergic agonists; release is inhibited by somatostatin, vasoactive intestinal peptide, az-adrenergic agonists, y-aminobutyric acid (through type A and B receptors) and histamine through H3 receptors (Forsberg and Miller, 1983; Racke and Schworer, 1991).

Enterochromaffin cells are also stimulated by chemotherapeutic agents (e.g. cisplatin) and radiotherapy; released serotonin then activates vagal afferents through type 3 serotonergic receptors (Figure 2). Stimulation of

Baillidre’s Clinical Gastroenterology- 301 Vol. 8, No. 2, June 1994 Copyright @ 1994, by Baillisre Tindall ISBN 0-7020-189~1 All rights of reproduction in any form reserved

302 M. CAMILLERI AND M. R. VON DER OHE

Serosa

Longitudinal muscle

Myentenc plexus

Circular muscle

Enterochromaffin cells Enterocytes

Submucosal plexus

Muscularis mucosae Lamina propria Epithelium

Neuronal cells 5-HT (, BsHT,~

Primary afferent

@ Cholinergic

0 Other

Figure 1. Paracrine and neurocrine functions of serotonin cells in the intestine. Note that 5-HT released from mucosal enterochromaffin cells alters enterocyte function but does not appear to influence myenteric neurones; there are no S-HT neurones in the submucosal plexus, but submucosal neurones have 5-HT receptors. Mventeric 5-HT neurones are involved in the

0 Afferent function via 5HTa receptors

5HTs receptors on vagal afferents and 5HTs receptors on vagal afferents and f----l vagal nuclei involved in chemotherapy- and vagal nuclei involved in chemotherapy- and

radiation-induced emesis

peristaltic reflex.

0 Peristaltic reflex

rema s neurones

Accelerates GE of liquids Faster or slower SB transit Stimulates SB myoelectric activity

motor dysfunction Carcinoid diarmoea < secretion

with 5-HTs receptors

00&00 b rEosa

5HTs component in colonic tone I

l 5-HT release from mucosal enterochrornaff in cells b

Figure 2. Schema showing the major roles of serotonin in the gastrointestinal tract and the major expression of these roles in disease states. Serotonin generally stimulates segmental gut motility and is a major putative mediator of carcinoid diarrhoea. Serotonin stimulates vagal afferents peripherally and nuclei centrally in the process of chemotherapy-induced emesis. GE, gastric emptying; SB, small bowel.

DRUGS AFFECTING SEROTONIN RECEPTORS 303

these vagal afferents triggers vomiting by virtue of their effect on the chemoreceptor trigger zone, area postrema and vagal nuclei.

It has long been believed that submucosal plexus neurones do not contain serotonin (Furness et al, 1981), but there are serotonin receptors on submucous neurones (Freiling et al, 1991), and recent data suggest this belief is wrong; intrinsic sensory neurones in the submucous plexus release several neurotransmitters. These transmitters include calbindin, substance P and serotonin (Kirchgessner and Gershon, 1988; Kirchgessner et al, 1992). Myenteric serotonergic neurones project to the submucous plexus and may thus affect enterocyte absorption and secretion, a neurocrine effect that is separate from the probably paracrine stimulation of enterocyte secretion by enterochromaffin cells. Gershon and Erde (1981) reviewed the compelling evidence for an ‘intra-enteric’ barrier preventing serotonin released by enterochromaffin cells from reaching the myenteric plexus. Release of serotonin from enterochromaffin cells in response to distension or pressure within the lumen activates intestinal propulsion, probably by stimulating intrinsic primary afferent neurones (Figure 1). Evidence from Kirchgessner and colleagues (1988, 1992) suggests that serotonergic submucosal plexus neurones may be involved in the transmission of afferent signals arising in the lumen (e.g. distension), release of serotonin from the enterochromaffin cells, and stimulation of myenteric serotonergic neurones.

Myenteric plexus serotonergic neurones are involved in peristalsis and other motor and secretory processes in the gut. The physiological responses of the gut to serotonin in studies performed in vivo and in vitro have been summarized by Gershon et al (1990) and are listed in Table 1 together with key observations since that review (the more recent observations are discussed below). Serotonin has the potential to affect both smooth muscle cells and neurones and, depending on the route of administration (e.g. mucosal or serosal) (Bulbring and Lin, 1958) and the subtype of receptor stimulated, serotonin either stimulates or inhibits peristalsis. Submucosal 5-HTir neurones are activated by mechanical stimulation on the luminal aspect of the intestine and appear to be important in mediating the afferent arm of the peristaltic reflex (Kirchgessner and Gershon, 1988). Serotonin is an important neurotransmitter in the interneurones involved in the

Table 1. Physiological responses of the gut postulated to involve serotonin.

Mediates pressure-induced triggering of peristaltic reflex Vagal relaxation of the stomach and lower oesophageal sphincter Post-train synaptic excitation of myenteric ganglion cells Modulation of the migrating motor complex Excitation of myoelectric activity in small bowel Ascending excitation in the colon Descending inhibition of vagal excitation in the colon Intestinal secretion Cholera toxin-induced enteric secretion Mediation of gastric vagal afferent function Modulation of the colon’s tonic response to meal ingestion

Adapted from Gershon et al (1990).


ascending contraction of the peristaltic reflex; however, it also causes presy- naptic inhibition of acetylcholine release from myenteric neurones and, hence, may be involved in the descending inhibition limb of the peristaltic reflex.

SEROTONIN RECEPTOR SUBTYPES

Table 2 summarizes the original classification of serotonin receptors as D (dibenzyline) and M (morphine) subtypes, as proposed by Gaddum and Picarelli (1957); the more complex table 3 summarizes the current classification and illustrates the complexity of the serotonergic system and the potential for the diverse actions of serotonin.

Table 2. Gaddum and Picarelli’s original classification.

Receptor Site of action Blocked by Current designation

D

M

Direct on smooth muscles

Depolarization of cholinergic neurones

Phenoxybenzamine

Morphine

Subtypes of 5-HT1 and 5-HT,

5-HT3

The 5-HTr receptor group can be subdivided into a number of types, all of which appear to be seven transmembrane domain receptors negatively coupled to adenylyl cyclase via regulatory G proteins. The 5-HTIA, 5-HTrn and several ~-HTID receptor types have been cloned, although the precise nature of the various so-called 5-HTr-like receptors remains to be determined.

The 5-HTro receptor is closely homologous with the 5-HT2 receptors, both being G protein-coupled and mediating their effects through the activation of phosphoinositide metabolism.

5-HTa receptors mediate the rapid neuronal depolarizing actions of serotonin in the brain and periphery, and appear to be important in controlling neurotransmitter release centrally and peripherally. This type of receptor is structurally intrinsic to a ligand-gated cationic channel (Derkach et al, 1989). Rapid depolarization by 5-HTs stimulation is followed by equally rapid desensitization. A subunit of the 5-HT3 receptor has been cloned (Maricq et al, 1991).

5-HT4 receptors activate adenylyl cyclase, and it has been suggested that they may be related to the 5-HTr group of receptors (Humphrey, 1992) which act through the same intracellular mediator.

PHYSIOLOGICAL MECHANISMS INVOLVING 5-HT RECEPTOR SUBTYPES

Serotonin’s relaxatory effect on smooth muscle is mediated either directly via a 5-HTr-like receptor, or indirectly by neuronal inhibition, as occurs in

Table

3.

Rece

nt c

lass

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Neur

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inhibi

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Corte

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Br

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Corte

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guinea-pig ileum. Recent data suggest that serotonin-induced relaxation in the ascending colon is partly mediated by nitric oxide (Briejer et al, 1992). In the whole animal, some data suggest that 5-HTi and 5-HTz antagonists have little effect on gut motility, and these receptors may not be critically involved in endogenous control of gut motility (Costa11 and Naylor, 1990). Other data suggest there may be a role for 5-HT2 receptors, which have been described in the rat fundus (Nelson et al, 1992), cat pylorus (Lidberg et al, 1984) and cat ileocaecal junction (Ouyang and Cohen, 1983). Thus, ketanserin (an antagonist of 5-HTz receptors) alters feline pyloric motility (Lidberg et al, 1984) and accelerates gastric emptying of liquids in an anaesthetized in-vivo rat model (Valdovinos et al, 1993). Ketanserin inhibited 5-HT-induced acceleration of fluid transit across the ileocolonic junction in the rat in vivo, but had no effect in the absence of the agonist (Oosterbosch et al, 1993). The mechanism for these effects of the 5-HT2 antagonist is unclear at this time. Uguru and Bamgbose (1986) showed that rat caecal relaxation is mediated by 5-HTZ mechanisms. It is therefore conceivable that future studies with more potent 5-HTi and 5-HTz agents will identify roles for these receptors in the control of gut motility, and such agents may still find a therapeutic role in gastroenterology, as was reported in a single report on patients with carcinoid diarrhoea (Gustafsen et al, 1986).

At present, 5-HTs receptors have a more clearly defined functional role. They are located on vagal afferents and myenteric cholinergic neurones, and are important in both arms of the peristaltic reflex: ascending contraction

e-methyl 5HT

4/ Litoxetine

Strong effect * Weak effect --IC

d Agonists (

Figure 3. Serotonergic agents acting through 5-HTs and 5-HT4 receptors in the gastrointestinal tract. Arrows indicate relative strength of effects of these agents on receptor subtypes.


and descending inhibition. The actions of 5-HTs antagonists to modify contraction responses in the gut appear to depend on the relative balance of an excitatory-inhibitory tone (Costa11 and Naylor, 1990), which varies between species and regions of the gut.

Serotonin type 3 receptors facilitate the induction of fast excitatory postsynaptic potentials (EPSPs) (Wood and Mayer, 1979). The receptor mediating slow EPSPs was designated the 5-HTiP receptor (Gershon et al, 1990). Serotonin type 4 receptors aer located on myenteric plexus neurones and appear to mediate the effects of substituted benzamides, which also have weak 5-HTs antagonist properties.

At present the serotonin receptors with the greatest potential for therapeutic manipulation are therefore the 5-HTs and 5-HT4 receptor subtypes. The relative agonist and antagonist properties of available drugs currently being used or tested in gastroenterological disorders are summarized in Figure 3.

PATHOPHYSIOLOGY OF SEROTONIN IN MODELS OF ALIMENTARY DISORDERS AND DISEASE

There is convincing evidence for the involvement of serotonin in the pathogenesis of two disease states: carcinoid diarrhoea and the emesis associated with chemotherapy and radiotherapy.

Serotonin is considered to be a potent intestinal secretugogue. Using in-vivo perfusion, Donowitz et al (1977) showed that chronic administration of subcutaneous serotonin to rabbits caused ileal secretion and reduced jejunal absorption of water and electrolytes. In transepithelial electrolyte transport studies of rabbit small and large bowel mucosa, serotonin inhibits neutral sodium chloride absorption (Donowitz et al, 1980); others have shown that stimulated electrogenic chloride secretion in rat colon (Zimmer- man and Binder, 1984). These secretory effects are partially mediated by neurones (Cooke and Carey, 1985; Siriwardena et al, 1991) and partially by non-neural serotonin receptors, such as 5-HT2 receptors in the mucosa or muscularis mucosae (Siriwardena et al, 1991). Beubler et al (1990) studied close intra-arterial injection of serotonin in a tied loop of rat jejunum and detected a reversal from absorption under control conditions to net secretion, an effect that was blocked by the 5-HTz antagonist ketanserin in a dose-dependent fashion. Using a non-absorbable marker perfusion tech- nique, we failed to show any net fluid or electrolyte secretion from rat ileum during intra-aortic infusion of serotonin at concentrations that accelerated gastric emptying and ileocolonic transit in the rat in vivo (Oosterbosch et al, 1993). Our data suggested that in the model studied motor effects of serotonin could be induced before altered net fluid fluxes could be elicited.

Thus, there appear to be regional and species differences in the secretory effects of serotonin. There is no consensus regarding the location of the serotonin receptors that regulate ion transport, and the fact that tetro- dotoxin and atropine inhibit the serotonin-induced increase in guinea-pig ileum short-circuit current suggests that serotonin acts via a cholinergic


neurone (Cooke and Carey, 1985). Serotonin and the myenteric plexus are involved in the mediation of other intestinal secretory disorders, such as cholera toxin-induced intestinal secretion (Cassuto et al, 1982; Jodel et al, 1993). The role of serotonin receptor subtypes in the mediation of cholera and other processes resulting in intestinal secretion must await further studies using specific pharmacological blockers.

The role of serotonin as a mediator of car&did diarrhoea is fairly convincing: the vast majority of patients have raised levels of plasma serotonin or urinary levels of its metabolite, 5-hydroxyindole acetic acid (5HIAA) (Emson et al, 1984; Feldman and O’Dorisio, 1986; von der Ohe et al, 1993); carcinoid tumours contain vast quantities of serotonin. Carcinoid diarrhoea has two important pathophysiological components that appear attributable to the effects of serotonin: Donowitz and Binder (1975) demonstrated a modest degree of jejunal secretion in patients with carcinoid diarrhoea, and von der Ohe et al (1993) recently showed alterations in small bowel and colonic motor functions in such patients. Drugs that inhibit serotonin receptors, such as methysergide and ketanserin, or serotonin synthesis, such as p-chlorophenylalanine, were effective in the short-term treatment of diarrhoea in carcinoid patients (Peart and Robertson, 1961; Gustafsen et al, 1986; Anderson et al, 1987; Sjoerdsma et al, 1970). There is also evidence that the 5-HTs antagonist ondansetron corrects the postprandial colonic hypertonicity associated with reduced colonic capacitance and accelerated colonic transit in these patients (von der Ohe et al, 1994b), and in two single patient studies ondansetron inhibited carcinoid diarrhoea and flushing (Buhl et al, 1992; Platt et al, 1992).

Paradoxically, patients with severe idiopathic constipation, who had undergone colonic resection, were reported to have increased serotonin-like fluorescence and indole content (5-HT and 5-HIAA) in the mucosa and increased indole content in the circular muscle layer of the sigmoid colon, compared with control samples taken from patients with colonic or rectal cancer (Lincoln et al, 1990). The role of increased indole levels in patients with this type of constipation are unclear, and this interesting observation requires further study; however, it may suggest that pharmacotherapy altering serotonin levels may be worthy of trial in the future. It is difficult to reconcile these data with the observation that 5-HT4 agonists may be helpful in colonic inertia (Krevsky et al, 1989).

The second disease state in which serotonin undoubtedly plays an important role is cancer chemotherapy-induced emesis (Figure 2). Serotonin is released from enterochromaffin cells during chemotherapy and radiotherapy (Tyers and Freeman, 1992). In patients with cancer, high-dose cisplatin increases plasma and urinary levels of 5-HIAA without changing platelet or free plasma serotonin concentrations; changes in 5-HIAA levels parallel the onset and development of vomiting (Cubeddu et al, 1990). Since antiemetics.do not affect the increased metabolism of serotonin induced by cisplatin, these drugs do not affect the amount of serotonin released, but appear to block serotonin receptors involved in the emetic response (Cubeddu, 1992). The emetic effects of serotonin are mediated through 5-HTs receptors, both centrally and peripherally. Centrally, the majority of


receptors are in the area postrema on the floor of the fourth ventricle, where they are associated with structures involved in emetic reflexes, such as the nucleus of the tractus solitarus; peripherally they are found on the vagus afferent terminals (Fukui et al, 1992) and enteric neurones (Costa11 and Naylor, 1992). Antagonists to 5-HT3 receptors have revolutionized the treatment of acute emesis during chemotherapy- and radiation-induced emesis .

Another author (Talley, 1992), reviewing the literature on the experimental or therapeutic use of serotonin agonists and antagonists, has suggested that serotonin may play a role in the pathogenesis or mediation or several other diseases, such as irritable bowel syndrome, dyspepsia, non- cardiac chest pain and gastro-oesophageal reflux. We believe that the current data do not conclusively support a role for serotonin in the aetio- pathogenesis of any of these disorders. Such drug studies merely demon- strate that serotonin may be involved at some point in the pathophysiology of the particular syndrome and may indeed be a target that can be modulated to alter the manifestations of that syndrome.

SEROTONERGIC DRUGS IN CLINICAL GASTROENTEROLOGY

Inhibition of serotonin synthesis, such as by para-chlorophenylalanine, may be effective in depleting the transmitter in disorders like carcinoid diarrhoea; however, the adverse effect profile including mental confusion, affective disorders, hallucinations and ataxia (Engelman et al, 1967) pre- clude its use in clinical practice. Thus, the major classes of serotonergic drugs that play an important role in the clinical practice of gastroenterology are the 5-HT3 antagonists and 5-HT4 agonists.

5HT1 and 5-HTz agents

Methysergide (a 5-HTi antagonist) is no longer used in modern therapeutics because of its tendency to cause retroperitoneal fibrosis. Ketanserin has been used in a few patients with carcinoid diarrhoea (Gustafsen et al, 1986) but its use is not widespread. Serotonin-uptake inhibitors have not generally been used for gut disorders. The clinical use of the majority of this class of antidepressants (e.g. fluoxetine, fluvoxamine) is associated with gastrointestinal side-effects such as nausea and vomiting. On the other hand, the new drug litoxetine is both a serotonin-uptake inhibitor and a 5-HTs antagonist, and it has antiemetic activity in the ferret (Angel et al, 1993). Suma- triptan, which is a 5-HTr receptor agonist, was developed specifically as an antimigraine drug on the assumption that 5-HTi receptors on the cranial vasculature play a critical part in the mechanisms of a migraine attack; sumatriptan is effective in the treatment of migraine and of the associated nausea and vomiting (Cady et al, 1991). It paradoxically slows the emptying of a liquid fat-containing meal in healthy subjects (Houghton et al, 1992) and has not been used for any primary gut disorder. Further studies of sumatriptan on gut motor function appear warranted, since its effects on the gastric


emptying of solids has not been evaluated and the clinical relevance of a prolongation in the lag time for the emptying of liquids without any change in the rate constant for liquid emptying (Houghton et al, 1992) is unclear.

5-HT3 antagonists

The 5-HTs antagonist drugs most widely used and studied to date are ondansetron, granisetron and tropisetron. Their main use in clinical therapeutics is in the control of cisplatin and other cytotoxic chemotherupy- and radiotherapy-induced emesis. Ondansetron is significantly more efficacious than metoclopramide during the first day following cisplatin treatment (Cubeddu et al, 1990; Marty et al, 1990) and radiation therapy (Priestman, 1989); however, evidence suggests that the therapeutic advantage is minimal to absent during the next 6 days (de Mulder et al, 1990). The usual recommended dose of ondansetron is 0.15 mg/kg for three doses on the day of chemotherapy (30 min before and 4 and 8 h afterwards). An alternative regimen in adults is a single dose of 32 mg intravenously before chemotherapy (Figg et al, 1993). Ondansetron may also be used with standard antiemetic therapy, such as corticosteroids, benzodiazepines and other neurotransmitter blockers (e.g. antidopaminergic agents) (Figg et al, 1993; Grunberg, 1993). Ondansetron is well tolerated with only a few adverse effects such as headache, sedation and constipation. Oral ondansetron, 4 mg four times daily is more efficacious than placebo in the control of delayed emesis, 2-5 days after high-dose cisplatin (Kris et al, 1992; Gandara et al, 1993), but the control of emesis is inadequate, with only 1 of the 4 days being significantly different between ondansetron and placebo. As stated above, a previous study showed no therapeutic advantage over metoclopramide in the control of delayed emesis. However, for multiple- day cisplatin-based chemotherapy, intravenous ondansetron is superior to intravenous metoclopramide (Sledge et al, 1991).

Ondansetron is also effective in the treatment ofpostoperutive nausea and vomiting (Dershwitz et al, 1992) and morphine-induced nausea (Koch et al, 1993). However, its efficacy in neuromuscular disorders causing nausea and vomiting remains unproven.

Granisetron is also an effective antiemetic when used as a prophylactic and as an intervention agent (Joss and Dott, 1993) and during multiple cycles of chemotherapy (Blijham, 1992). It is administered as a single 5-min infusion before chemotherapy and the only consistent side-effects are headache and constipation (Joss and Dott, 1993). It is also effective in total-body irradiation-induced emesis (Hunter et al, 1991). Tropisetron (single daily dose of 5 mg) is also an effective and well-tolerated antiemetic and remains effective during multiple chemotherapy courses (de Bruijn, 1992). Unlike the other two drugs, tropisetron also has 5-HT4 antagonist effects and could theoretically delay gut transit; however, Akkermans et al (1988) showed a slight acceleration of gastric emptying in healthy subjects.

In a cost analysis of the impact of these novel 5-HTs antagonists in the management of chemotherapy-induced emesis, it was concluded that sub- stantial clinical benefit is achieved for an increase of 3-10% of total


treatment costs. However, they appear to have no clinical advantage for delayed emesis (Jones et al, 1992).

On the grounds that 5-HT3 receptors are found on vagal afferents and can be effectively blocked with great clinical benefit in the setting of acute cisplatin-induced emesis, several studies have been performed infunctional gastrointestinal disorders to determine whether the abnormal motility or visceral hypersensitivity commonly found in all these disorders can be effectively reduced. While physiological and acute studies suggest they may be useful (e.g. in patients with non-cardiac chest pain (Stark et al, 1991) or in patients with irritable bowel syndrome and rectal hypersensitivity (Prior and Read, 1993)), there is no compelling evidence that this class of drug is effective in reducing visceral perception in the healthy stomach (Wilmer et al, 1993) or rectum (Goldberg et al, 1993), or in the rectum of patients with irritable bowel syndrome (Hammer et al, 1993). It is also unclear whether they are effective clinically in the medium or long term (Talley et al, 1989, 1990).

Ondansetron has been shown to delay orocaecal and colonic transit time (Talley et al, 1989; Gore et al, 1990) in healthy subjects, and tends to slow left-sided colonic transit in patients with diarrhoea-predominant irritable bowel syndrome (Steadman et al, 1992); approximately 10% of patients develop constipation while being administered 5-HT3 antagonists. In physiological studies intravenous ondansetron reduces the tonic gastrocolonic response to feeding (von der Ohe et al, 1994b) and the postcibal contraction of the proximal colon (Scolapio et al, 1993) in healthy subjects; intravenous ondansetron also reduces to normal values the tonic postprandial gastrocolonic response of patients with carcinoid diarrhoea (von der Ohe et al, 1994a). These data in healthy and carcinoid subjects provide the rationale for future clinical trials of 5-HT3 antagonists in carcinoid diarrhoea. Initial data suggest this approach is worth pursuing since, in the short term, tropisetron was shown to control the diarrhoea in five of six patients with carcinoid syndrome (Coupe et al, 1988), and two case reports suggest that ondansetron is also effective (Buhl et al, 1992; Platt et al, 1992).

In conclusion, the use of 5-HTs antagonists in patients with functional gastrointestinal disorders, emesis due to conditions other than chemotherapy or radiation, and carcinoid diarrhoea must still be considered experimental.

5HT4 agonists

Substituted benzamides are 5-HT4 agonists, and the prototype that has been studied must extensively, cisapride, is discussed in detail. The parent 5-HT4 agonist, metoclopramide, is also a dopamine D2 antagonist with antiemetic and prokinetic efficacy in the oesophagus and stomach. Metoclopramide is the only substituted benzamide generally available for parenteral use; hyperprolactinaemia, with galactorrhoea and menstrual irregularities, as well as the possibility of central (extrapyramidal, affective) disturbances have markedly reduced the use of metoclopramide in recent years, and the more selective agents such as cisapride are favoured.


Although there are several relatively selective 5-HT4 agonists in the substituted benzamide group (e.g. renzapride, zacopride, clebopride), most of the available clinical trials have evaluated cisapride, and this section is focused entirely on this drug. These 5-HT4 agonists promote gastrointestinal motor function, a property that led to the coining of the term ‘prokinetic agent’.

Cisapride indirectly stimulates cholinergic nerves to release acetylcholine through stimulation of 5-HT4 receptors on neurones in the myenteric plexus. Cisapride enhances contractile activity in the oesophagus, stomach, small bowel and colon in experimental models. Orally administered cisapride is almost completely absorbed from the digestive tract, but absolute bio-availability is around 45%, suggesting first-pass metabolism in the liver and/or gut wall. Steady-state plasma levels are achieved within 2-3 days. Cisapride is 98% bound to plasma proteins, chiefly albumin. Pharmaco- dynamics and pharmacokinetics have been reviewed in greater detail else- where (McCallum et al, 1988).

The approved clinical indication for cisapride in the USA is in the treatment of gastro-oesophageal reflux disease and, in other countries, gastroparesis and other motility disorders. The next section summarizes the vast literature dealing with the potential role of cisapride in the treatment of motility disorders of the gastrointestinal tract (Figure 4).

ACTIONS IN HEALTH OR DISEASE Stimulation of oesophageal body, LES

Gallbladder contraction Increased antral motility Accelerated gastric emptying ? Antroduodenal co-ordination

Stimulates small bowel contractility Accelerates small bowel transit of liquids and solids

Accelerates colonic transit of liquids

POSSIBLE CLINICAL INDICATIONS GERD

Gastroparesis Functional dyspepsia

Chronic intestinal pseudo-obstruction

Slow transit constipation

Reduces resting anal sphincter pressu

Figure 4. Effects of cisapride, a prototypic 5-HT4 agonist, on the human digestive tract and its potential use in disease. See text for further details. LES, lower oesophageal sphincter; GERD, gastro-oesophageal reflux disease.


There is evidence that cisapride would enhance oesophageal emptying in clinically significant neuropathic disorders of the oesophagus and stomach, and possibly also in myopathic disorders, as shown by scintigraphic studies of the oesophagus and stomach. Horowitz et al (1987a,b,c) showed that cisapride enhanced oesophageal transit and gastric emptying in patients with diabetes mellitus, scleroderma and dystrophia myotonica. Cisapride stimulates lower oesophageal sphincter tone (Gilbert et al, 1987; Ceccatelli et al, 1988) and European studies found it to be equal to cimetidine in promoting healing of reflux oesophagitis (Galmiche et al, 1990) and significantly better than placebo in the maintenance therapy of reflux oesophagitis after healing has been achieved with antisecretory therapy (Blum et al, 1993). Similarly, a multicentre study in the USA showed greater improvement in symptoms than with placebo in patients with grade 1 and 2 oesophagitis; two studies also suggested that cisapride improved healing of oesophagitis (Richter, 1993). In most centres, cisapride (10mg four times daily) is regarded as adjunctive to the treatment of oesophagitis and reflux symptoms with anti- acid secretory therapy. Its major role may be in the maintenance treatment of gastro-oesophageal reflux disease (10 mg twice daily or 20 mg at bedtime), for which treatment with a proton pump inhibitor indefinitely or with a histamine Hz-receptor blocker may be undesirable.

In idiopathic and secondary gastroparesis, as well as functional dyspepsia associated with impaired gastric emptying, cisapride (10-20 mg four times daily) significantly enhances gastric emptying (Corinaldesi et al, 1987; Horowitz et al, 1987a,b,c; Camilleri et al, 1989; Abel1 et al, 1991); this is associated, to a variable extent, with amelioration of symptoms (Corinaldesi et al, 1987; Jian et al, 1989; Richards et al, 1993). In chronic intestinal pseudo-obstruction, cisapride improves gastric and/or small bowel transit in acute, medium- and long-term studies (Camilleri et al, 1986, 1989; Abel1 et al, 1991). However, symptom improvement in 6- or 1Zweek studies is equivocal. Recent studies suggest that, in children, lack of migrating motor complexes (Hyman et al, 1993) and, in adults, association with extrinsic vagal denervation (Camilleri et al, 1994) are associated with poor symptomatic response to cisapride. Cisapride accelerates colonic transit (Krevsky et al, 1987,1989) and relieves simple constipation in adults (Mtiller-Lissner et al, 1987) and children (Staiano et al, 1991); other colonic motor dys- functions such as those associated with parkinsonism (Jost and Schimrigk, 1993) and paraplegia (Binnie et al, 1988) is also improved in the medium term. Cisapride may relieve abdominal pain and distension in patients with constipation-predominant irritable bowel syndrome (van Outryve et al, 1991). Cisapride reduces resting anal sphincter pressure and may thereby facilitate defaecation in patients with chronic constipation (Enck et al, 1989).

Adverse effects of cisapride are mild and relatively uncommon; they include headache, abdominal cramping and increased frequency of defaecation. Cisapride enhances the absorption of concomitantly administered histamine Hz-receptor antagonists, diazepam and alcohol. In patients receiving anticoagulants, prothrombin times tend to be increased and closer monitoring of anticoagulation is therefore warranted.

314 M. CAMILLEIU AND M. R. VON DER OHE

5-HT4 antagonists

GR125487 is a potent (pKi 10.4) 5-HT4 receptor antagonist with 10 OOO-fold selectivity over other receptor subtypes. This agent inhibited metoclopramide-induced acceleration of gastric emptying in a conscious rat model (Gale et al, 1993). Its duration of action (&) was greater than 4h, suggesting it is a potent and long-acting 5-HT4 receptor antagonist in vivo.

SDZ205-557 is a potent selective antagonist at 5-HT4 receptors in the isolated guinea-pig ileum; however, it also has some 5-HTs antagonist actions (Buchheit et al, 1992). SC53606 similarly antagonizes 2-methyl 5-HT-induced contractions in guinea-pig ileum, and is relatively selective for 5-HT4 receptors (Yang et al, 1992), which antagonizes serotonin- induced tachycardia in rats (Kaumann et al, 1992). Reports on any effects in the gastrointestinal tract are awaited before any potential therapeutic role can be explored.

SUMMARY

A greater understanding of the various serotonin receptor subtypes has led to a clearer appreciation of the role of serotonin in gastrointestinal motility, sensation and secretion. Serotonin is definitely involved in the aetiopatho- genesis of cisplatin-induced emesis and carcinoid diarrhoea. The application of serotonergic drugs in clinical therapeutics for gut disturbances is presently dominated by the use of 5-HTs antagonists for acute chemotherapy-induced nausea and vomiting, and the use of substituted benzamides which are 5-HT4 agonists stimulating gut motor function through 5-HT4 neuronal receptors. The best-studied 5-HT4 agonist is cisapride, which has been shown to stimulate motility at several levels of the gut. Cisapride is approved for healing and maintenance treatment of reflux oesophagitis and is used in several countries for the alleviation of symptoms consistent with regional stasis, from dyspepsia to constipation.

Carcinoid diarrhoea is a prototypic disease associated with deranged serotonin metabolism, and a rationale for using 5-HTs or 5-HT4 antagonists is based on the recent appreciation of the important role of impaired gut motor function in carcinoid diarrhoea. In the future, greater understanding of the serotonin receptor subtypes and their role in gut disorders may lead to novel approaches to alleviate increased visceral perception of functional gastrointestinal disorders, to correct changes in colonic capacitance, or to alter gastrointestinal motility that contributes to diarrhoea or constipation. However, at the present time, it must be stressed that these uses are still at an experimental stage and that careful validation and proper controlled studies are still required.

REFERENCES

Abel1 TL, Camilleri M, DiMagno EP et al (1991) Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility. Digestive Diseases and Sciences 36: 6X-620.


Akkermans LMA, Vos A, Hoekstra A et al (1988) Effect of ICS205-930 (a specific 5HTa receptor antagonist) on gastric emptying of a solid meal in normal subjects. Gut 29: 1249-1252.

Anderson JV, Coupe MO, Morris JA et al (1987) Remission of symptoms in carcinoid syndrome with a new S-hydroxytryptamine M receptor antagonist. British MedicalJournal 294: 1129.

Angel I, Schoemaker H, Prouteau M et al (1993) Litoxetine: a selective 5-HT uptake inhibitor with concomitant S-HT3 receptor antagonist and antiemetic properties. European Journal of Pharmacology 232: 139-145.

Beubler E, Coupar IM, Hardcastle J & Hardcastle PT (1990) Stimulatory effects of 5- hydroxytryptamine on fluid secretion and transmural potential difference in rat small intestine are mediated by different receptor subtypes. Journal of Pharmacy and Pharma- cology 42: 35-39.

Binnie NR, Creasey GH, Edmond P & Smith AN (1988) The action of cisapride on the chronic constipation of paraplegia. Paraplegia 26: 151-158.

Blijham GH (1992) Does granisetron remain effective over multiple cycles? European Journal of Cancer 28: S17-S21.

Blum AL, Adami B, Bouzo MH et al (1993) Effect of cisapride on relapse of esophagitis. A multinational, placebo-controlled trial in patients healed with an antisecretory drug. The Italian Eurocis Trialists. Digestive Diseases and Sciences 38: 551-560.

Briejer MR, Akkermans LMA, Meulemans AL et al (1992) Nitric oxide is involved in 5HT-induced relaxation of the guinea pig colon ascendens in vitro. British Journal of Pharmacology 107: 756761.

de Bruijn KM (1992) Tropisetron. A review of the clinical experience. Drugs 43: 11-22. Buchheit K-H. Gamse R & Pfannkuche H-J (1992) SDZ205-557. a selective. surmountable

antagonist for 5-HT4 receptors in the isolated guinea pig ileum. Naunyn-Schmiedeberg’s Archives of Pharmacology 345: 387-393.

Buhl C, Fibbe C & Frenzel H (1992) Ondansetron in carcinoid syndrome. Deutsche Medizinische Wochenschrift 117: 1821.

Btilbring E & Lin RCY (1958) The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis; the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity. Journal of Physiology 140: 381-407.

Cady RK, Wendt JK, Kirchner JR et al (1991) Treatment of acute migraine with subcutaneous sumatriptan. Journal of the American Medical Association 265: 2831-2835.

Camilleri M, Brown ML & Malagelada J-R (1986) Impaired transit of thyme in chronic intestinal pseudo-obstruction: correction by cisapride. Gastroenterology 91: 619-626.

Camilleri M, Malagelada J-R, Abel1 TL et al (1989) Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudo-obstruction. Gastroenterology 96: 704- 712.

Camilleri M, Balm RK & Zinsmeister AR (1994) Determinants of response to a prokinetic agent in neuropathic chronic intestinal motility disorder. GastroenteroZogy 106: 916923.

Cassuto J, Jodal M, Tuttle R & Lundgren 0 (1982) 5Hydroxytryptamine and cholera secretion: physiological and pharmacological studies in rats and cats. Scandinavian Journal of Gastroenterology 16: 377-384.

Ceccatelli P, Janssens J, Vantrappen G & Cucchiara S (1988) Cisapride restores the decreased lower esophageal sphincter pressure in reflux patients. Gut 29: 631-635.

Cooke HJ & Carey HV (1985) Pharmacological analysis of 5-hydroxytryptamine actions on guinea pig Seal mucosa. European Journal of Pharmacology 111: 329-337.

Corinaldesi R, Stanghellini V, Raiti C et al (1987) Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis. Gut 28: 300-305.

Costa11 B & Naylor RJ (1990) 5-Hydroxytryptamine: new receptors and novel drugs for gastrointestinal motor disorders. Scandinavian Journal of Gastroenterology 25: 769787.

Costall B & Naylor RJ (1992) Neuropharmacologv of emesis in relation to clinical response. British Journal of dance; supplement: SZ-SST-

Coupe MO, Anderson JO, Morris JA et al (1988) The effects of the 5-hydroxytryptamine (5HTs) receptor antagonist ICS205-930 in the carcinoid syndrome. Alimentary Pharma- cology and Therapeutics 2: 167-172.


Cubeddu LX (1992) Mechanisms by which cancer chemotherapeutic drugs induce emesis. Seminars in Oncology 19: 2-13.

Cubeddu LX, Hoffmann IS, Fuenmayor NT & Finn AL (1990) Efficacy of ondansetron (GR38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. New England Journal of Medicine 322: 810-816.

Derkach V, Surprenant A & North RA (1989) 5-HTs receptors are membrane ion channels. Nature 339: 706-709.

Dershwitz M, Rosow CE, DiBiase PM et al (1992) Ondansetron is effective in decreasing postoperative nausea and vomiting. Clinical Pharmacology and Therapeutics 52: 96-101.

Donowitz M & Binder HJ (1975) Jejunal fluid and electrolyte secretion in carcinoid syndrome. Digestive Diseases 20: 1115-1122.

Donowitz M, Charney AN & Heffernan JM (1977) Effect of serotonin treatment on intestinal transport in the rabbit. American Journal of Physiology 232: E85-94.

Donowitz M, Tai YH & Asarkof N (1980) Effect of serotonin on active electrolyte transport in rabbit ilium, gallbladder, and colon. American Journal of Physiology 239: G46sG472.

Emson PC, Gilbert RFT, Martensson H & Nobin A (1984) Elevated concentrations of substance P and 5-HT in plasma in patients with carcinoid tumors. Cancer 54: 715-718.

Enck P, Arping HG, Engel S et al (1989) Effect of cisapride on anorectal sphincter function. Alimentary Pharmacology and Therapeutics 3: 569645.

Engelman K, Lovenberg W & Sjoerdsma A (1967) Inhibition of serotonin synthesis by para-chlorophenylalanine in patients with the carcinoid syndrome. New England Journal of Medicine 277: 1103-1108.

Feldman JM & O’Dorisio TM (1986) Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. American Journal of Medicine 81: 41-48.

Figg WD, Graham CL, Hak LJ & Dukes GE (1993) Ondansetron: a novel antiemetic agent. Southern Medical Journal 86: 497-502.

Forsberg EJ & Miller RJ (1983) Regulation of serotonin release from rabbit intestinal enterochromaffin cells. Journal of Pharmacology and Experimental Therapeutics 227: 755-766.

Freiling T, Cooke HJ & Wood JD (1991) Serotonin receptors on submucous neurons in guinea pig colon. American Journal of Physiology 261: G1017-G1023.

Fukui H, Yamamoto M & Sato S (1992) Vagal afferent fibers and peripheral 5-HTs receptors mediate cisplatin-induced emesis in dogs. Japanes Journal of Pharmacology 59: 221-226.

Furness JB & Costa M (eds) (1987) Transmitter neurcochemistrv of enteric neurons. In The Enteric Nervous System, pp 55-89. Edinburgh: Churchill Li&gstone.

Furness JB. Costa M & Llewelvn-Smith IJ (1981) Branching natterns and uroiections of enteric neurons containing different putative‘trans’mitters. Pipkdes 2: 119. 1 *

Gaddum JH & Picarelli IP (1957) Two kinds of tryptamine receptors. British Journal of Pharmacology 12: 323-328.

Gale JD, Reeves JJ & Bunce KT (1993) Antagonism of the gastroprokinetic effect of metoclopramide by GR125487, a potent and selective 5HT4 receptor antagonist. Journal of Gastrointestinal Motility 5: 192 (abstract).

Galmiche JP, Freitag B, Filoche B et al (1990) Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Digestive Diseases and Sciences 35: 649-655.

Gandara DR, Harvey WH, Monaghan GG et al (1993) Delayed emesis following high-dose cisplatin: a double-blind randomised comparative trial of ondansetron (GR 38032F) versus placebo. European Journal of Cancer 29: S35-S38.

Gershon MD & Erde SM (1981) The nervous system of the gut. Gastroenterology 80: 1571- 1594.

Gershon MD, Wade PR, Kirchgessner AL & Tamir H (1990) 5-HT receptor subtypes outside the central nervous system. Roles in the physiology of the gut. Neuropsychopharmacology 3: 385-395.

Gilbert RJ, Dodds WJ, Kahrilas PJ et al (1987) Effect of cisapride, a new prokinetic agent, on esophageal motor function. Digestive Diseases and Sciences 32: 1331-1336.

Goldberg PA, Kamm MA, Setti-Carraro P et al (1993) 5HTa antagonism does not modify visceral sensation or compliance in healthy subjects. Gastroenterology 104: A512 (abstract).

Gore S, Gilmore IT, Haigh CG et al (1990) Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor (type 3) antagonist. Alimentary Pharmacology and Therapeutics 4: 139144.


Grunberg SM (1993) Potential for combination therapy with the new antiserotonergic agents. European Journal of Cancer 29: S39-S41.

Gustafsen J, Lendorf A, Raskov H & Boesby S (1986) Ketanserin versus placebo in carcinoid syndrome. A clinical controlled trial. Scandinavian Journal of Gastroenterology 21: 816- 818.

Hammer J, Phillips SF, Talley NJ & Camilleri M (1993) Effect of a 5-HTs antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome. Alimentary Pharmacology and Therapeutics 7: 543-551.

Horowitz M, Maddern GJ, Maddox A et al (1987a) Effects of cisapride on gastric and esophageal emptying in progressive systemic sclerosis. Journal of Gastroenterology 93: 311-315.

Horowitz M, Maddox A, Harding PE et al (1987b) Effect of cisapride on gastric and oesophageal emptying in insulin-dependent diabetes mellitus. Gastroenterology 93: 1899-1907.

Horowitz M, Maddox A, Wishart J et al (1987c) The effects of cisapride on gastric and oesophageal emptying in dystrophia myotonica. Journal of Gastroenterology and Hepatology 2: 285-293.

Houghton LA, Fowler P, Keene ON & Read NW (1992) The effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man. Alimentary Pharmacology and Therapeutics 6: 685-691.

Humphrey PPA (1992) Classijication of 5-hydroxytryptamine receptors. Proceedings of the Second International Symposium on Serotonin from Cell Biology to Pharmacology and Therapeutics, Houston, Texas, 1.5-18 September, p 2.

Hunter AE, Prentice HG, Pothecary K et al (1991) Granisetron, a selective 5HTa antagonist, for the prevention of radiation-induced emesis during total body irradiation. Bone Marrow Transplant 7: 439-441.

Hyman PE, DiLorenzo C, McAdams L et al (1993) Predicting the clinical response to cisapride in children with chronic intestinal pseudo-obstruction. American Journal of Gastro- enterology 88: 832-836.

Jian R, Ducrot F, Ruskone A et al (1989) Symptomatic, radionuclide and therapeutic assess- ment of chronic idiopathic dyspepsia: a double-blind placebo-controlled evaluation of cisapride. Digestive Diseases and Sciences 34: 657-664.

Jodal M, Holmgren S, Lundgren 0 & Sjiiqvist A (1993) Involvement of the myenteric plexus in the cholera toxin-induced net fluid secretion in the rat small intestine. Gastroenterology 105: 1286-1293.

Jones AL, Lee GJ & Bosanquet N (1992) The budgetary impact of .5+ITa receptor antagonists in the management of chemotherapy-induced emesis. European Journal of Cancer 29: 51-56.

Joss RA & Dott CS (1993) Clinical studies with granisetron, a new 5-HTs receptor antagonist, for the treatment of cancer chemotherapy-induced emesis. The Granisetron Study Group. European Journal of Cancer 29: S22-S29.

Jost WH & Schimrigk K (1993) Cisapride treatment of constipation in Parkinson’s disease. Movement Disorders 8: 339-343.

Kaumann AJ, Medhurst A, Boyland P et al (1992) SB203186, apotent selective 5HT4 receptor antagonist. Proceedings of the Second International Symposium on Serotonin from Cell Biology to Pharmacology and Therapeutics, Houston, Texas, September 15-18, 1992, p 44.

Kirchgessner AL & Gershon MD (1988) Projections of submucosal neurons to the myenteric plexus of the guinea pig intestine: in vitro tracing of microcircuits by retrograde and anterograde transport. Journal of Comparative Neurology 277: 487-498.

Kirchgessner AL, Tamir H & Gershon MD (1992) Identification and stimulation by serotonin of intrinsic sensory neurons of the submucosal plexus of the guinea pig gut: activity- induced expression of Fos immunoreactivity. Journal of Neuroscience 12: 235-248.

Koch KL, Xu L, Bingaman S et al (1993) Ondansetron, a 5HTa antagonist reduces nausea, restores normal gastric myoelectric activity and decreases plasma vasopression levels in healthy subjects with morphine-induced nausea. Journal of Gastrointestinal Motility 5: 198 (abstract).

Krevsky B, Malmud LS, Maurer AH et al (1987) The effect of oral cisapride on colonic transit. Alimentary Pharmacology and Therapeutics 1: 293-304.

Krevsky B , Maurer AH, Malmud LS & Fisher RS (1989) Cisapride accelerates colonic transit in


constipated patients with colonic inertia. American Journal of Gastroenferology 84: 882- 887.

Kris MG, Tyson LB, Clark RA & Gralla RJ (1992) Oral ondansetron for the control of delayed emesis after cisplatin. Report of a phase II study and a review of completed trials to manage delayed emesis. Cancer 70: 1012-1016.

Lidberg P, Dahlstrom A & Ahlman H (1984) Is 5HT a mediator in the motor control of the feline pylorus? Scandinavian Journal of Gasfroenterology 19: 321-328.

Lincoln J, Crowe R, Kamm MA et al (1990) Serotonin and 5-hydroxyindoleacetic acid are increased in the sigmoid colon in severe idiopathic constipation. Gastroenterology 98: 1219-1225.

McCallum RW, Prakash C, Campoli-Richards DM & Goa KL (1988) Cisapride. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use as a prokinetic agent in gastrointestinal motility disorders: Drugs 36: 652-681. -

Marica AV. Peterson AS, Brake AJ et al (1991) Primarv structure and functional exoression of the 5HTs receptor, a serotonin-gated ion channel:Science 254: 432-437. ’

Marty M, Pouillart P, Scholl S et al (1990) Comparisonof the 5-hydroxytryptamines (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. New England Journal of Medicine 322: 816-821.

De Mulder PH, Seynaeve C, Vermorken JB et al (1990) Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Annals of Internal Medicine 113: 834-840.

Miiller-Lissner SA and the Bavarian Constipation Study Group (1987) Treatment of chronic constipation with cisapride and placebo. Gut 28: 1033-1038.

Nelson DL, Wainscoft DB, Cohen ML et al (1992) P/z armacologic characterization of a novel serofonergic receptor (5HT2r) cloned from the rat stomach fundus. Proceedings of the Second International Symposium on Serotonin from Cell Biology to Pharmacology and Therapeutics, Houston, Texas, September 15-18, 1992, p 50.

von der Ohe M, Camilleri M, Kvols LK & Thomforde GM (1993) Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. New England Journal of Medicine 329: 1073-1078.

von der Ohe MR, Camilleri M & Kvols LK (1994a) A 5HTs antagonist corrects the postprandial colonic hypertonic response in carcinoid diarrhea. Gastroenferology 106: 1184- 1189.

von der Ohe MR, Hanson RB & Cemilleri M (1994b) Serotonergic mediation of postprandial colonic tonic and phasic responses in man. Gut 35: 536-541.

Oosterbosch L, von der Ohe M, Valdovinos MA et al (1993) Effects of serotonin on rat ileocolonic transit and fluid transfer in vivo: possible mechanisms of action. Gut 34: 794-798.

Ouyang A & Cohen S (1983) Multiple 5-hydroxytryptamine receptors on feline ileum and ileocecal sphincter. American Journal of Physiology 2441 (34266434.

Peart WS & Robertson JIS (1961) The effect of a serotonin antagonist (UML491) in carcinoid disease. Lancet ii: 1172-1174.

Platt AJ, Heddle RM, Rake MO & Smedley H (1992) Ondansetron in carcinoid syndrome. Lancet 339: 1416 (letter).

Priestman TJ (1989) Clinical studies with ondansetron in the control of radiation-induced emesis. European Journal of Cancer and Clinical Oncology 25: S2933.

Prior A & Read NW (1993) Reduction of rectal sensitivity and postpradial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome. Alimentary Pharmacology and Therapeutics 7: 175-180.

Racke K & Schworer H (1991) Regulation of serotonin release from the intestinal mucosa. Pharmacologic Research 23: 13-25.

Rapport MM, Green AA & Page IH (1948) Serum vasoconstrictor (serotonin). IV. Isolation and characterization. Journal of Biological Chemistry 176: 1243-1251.

Richards RD, Valenzuela GA, Davenport KG et al (1993) Objective and subjective results of a randomized, double-blind, placebo-controlled trial using cisapride to treat gastroparesis. Digestive Diseases and Sciences 38: 811-816.

Richter JE (1993) Chairperson’s Summary Report. Cisapride Clinical Investigators’ Confer- ence. Chicago, Illinois, 19 June (unpublished).


Scolapio JS, von der Ohe M, Hanson RB & Camilleri M (1993) Postprandial function of human ascending colon: a biphasic response involving a 5HTs mechanism. Gustroenterology 104: A519.

Siriwardena A, Booker C, Pratt J & Kellum JM (1991) Pathways of serotonin-induced electrolyte transport in rat distal colon. Surgery 110: 411-418.

Sjoerdsma A, Lovenberg W, Engelman Ket al (1970) NIH Conference: Serotoninnow: clinical implications of inhibiting its synthesis with para-chlorophenylalanine. Annuls ofInternal Medicine 73: 607-629.

Sledge GW Jr, Einhorn L, Nagy C & House K (1991) Phase 111 double-blind comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based chemotherapy.’ Cancer 70: 2524-2528.

Staiano A, Cucchiara S, Andreotti MR et al (1991) Effect of cisapride on chronic constipation in children. Digestive Diseases and Sciences 36: 733-736.

Stark M Jr, Maher K, Gupta P et al (1991) Visceral afferent blockade with ondansetron (Zofran) increases nociceptive thresholds in patients with chest pain of undertermined etiology (CPUE). American Journal of Gastroenterology 86: 1305 (abstract).

Steadman CJ, Talley NJ, Phillips SF & Zinsmeister AR (1992) Selective 5HTs receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome. A pilot study. Mayo Clinic Proceedings 67: 732-738.

Talley NJ (1992) 5-Hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Alimentary Pharmacology and Therapeutics 6: 273-289.

Talley NJ, Phillips SF, Haddad Aet al (1989) Effect of a selective 5HTs antagonist (GR38032F) on small intestinal transit and release of gastrointestinal peptides. Digestive Diseases and Sciences 34: 1511-1515.

Talley NJ, Phillips SF, Haddad A et al (1990) GR38032F (ondansetron), a selective 5HTs receptor antagonist, slows colonic transit in healthy man. Digestive Diseases and Sciences 35: 477-480.

Tyers MB & Freeman AJ (1992) Mechanism of the anti-emetic activity of 5-lXfs receptor antagonists. Oncology 49: 263-268.

Uguru MO & Bamgbose SO (1986) Mechanisms of the relaxations induced by 5-hydroxytryptamine on the rat isolated caecum. Journal of Pharmacy and Pharmacology 38: 140-143.

Valdovinos MA, Thomforde GM & Camilleri M (1993) Effect of putative carcinoid mediators on gastric and small bowel transit in rats and the role of 5-HT receptors. Alimentary Pharmacology and Therapeutics 7: 61-66.

Van Outryve M, Milo R, Toussaint J & Van Eeghen P (1991) ‘Prokinetic’ treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. Journal of Clinical Gastroenterology 13: 49-57.

Wilmer A, Tack J, Coremans G et al (1993) Effect of ondansetron, a SHTs-receptor agonist on perception of gastric distension and gastric compliance in healthy man. Gastroenterology 104: A603 (abstract).

Wood JD & Mayer CJ (1979) Serotonergic activation of tonic-type enteric neurons in guinea pig small bowel. Journal of Neurophysiology 422: 582-593.

Yang DC, Moormann AE, Flynn DL & Gullickson GW (1992) SC53606: a selective potent serotonin .5HT, receptor antagonist. Proceedings of the Second International Symposium on Serotonin from Cell Biology to Pharmacology and Therapeutics, Houston, Texas, September 15-l&1992, p 48.

Zimmerman TW & Binder HJ (1984) Serotonin induced alteration of colonic electrolyte transport in the rat. Gastroenterology 86: 310-317.

drugs affecting serotonin receptors

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