Gut 1999;45:713–718 713 EVect of diVerent prokinetic agents and a novel enterokinetic agent on postoperative in rats Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from

B Y De Winter, G E Boeckxstaens, J G De Man, T G Moreels, J A J Schuurkes, T L Peeters, A G Herman, P A Pelckmans

Abstract antagonists are able to accelerate gastric Background/Aim—The eVects of diVerent emptying in some species such as the rat.56 prokinetic agents, the motilide erythro- Their prokinetic activity mainly results from 1–4 mycin and the substituted 5-HT4 receptor agonism. The prokinetic and , were inves- benzamides probably enhance stomach motil- tigated in a rat model of postoperative ity in humans by enhancing cholinergic trans- ileus. These eVects were compared with mission possibly by stimulating neuronal

that of granisetron, a 5-hydroxytryptamine 5-HT4 receptors. In the human colon, the ben-

(5-HT3) receptor antagonist, and a novel zamides cause relaxation of the circular colonic

enterokinetic agent, , a 5-HT4 smooth muscles in vitro. Apparently in con- receptor . trast, cisapride mildly stimulates lower gut Methods—DiVerent degrees of inhibition motility and is moderately eVective in the of gastrointestinal transit, measured by treatment of . It is suggested that the migration of Evans blue, were additional mechanisms may explain the eVects achieved by skin incision, laparotomy, or of prokinetics on lower gut motility.2 laparotomy plus mechanical stimulation 5-HT4 receptor activation can cause relaxa- of the gut. tion or contraction depending on the region, Results—Metoclopramide decreased the cell type, and species under study. So far, our transit after laparotomy with or without knowledge on the distribution and exact locali- mechanical stimulation, whereas cisapride sation of the 5-HT4 receptors in humans is increased it after all three operations. limited. In human tissues, the eVects of Division of Granisetron had no eVect on the transit selective 5-HT4 receptor suggest that Gastroenterology and after the three operations when given these receptors are present on jejunal mucosa, Pharmacology, Faculty alone. Prucalopride tended to increase the ileal mucosa, gastric cholinergic neurones, and of Medical and circular colonic muscles.1–3 In general, in- Pharmaceutical transit after laparotomy with or without Sciences, University of mechanical stimulation when given alone. creased motor activity following 5-HT4 recep- http://gut.bmj.com/ Antwerp, Wilrijk, However, statistical significance was only tor activation results from increased release of Belgium reached when prucalopride was combined from cholinergic neurones, and B Y De Winter with granisetron. , a motilin relaxation results from activation of 5-HT4 JGDeMan 7 receptor agonist, did not improve postop- receptors on smooth muscle cells. In humans, T G Moreels mice, and dogs, selective 5-HT receptor A G Herman erative ileus in the rat. 4 P A Pelckmans Conclusions—Cisapride, but not metoclo- agonists have been shown to accelerate colonic transit.489 They initiate a peristaltic reflex in

pramide or erythromycin, is able to 710 on September 29, 2021 by guest. Protected copyright. Division of improve postoperative ileus in the rat. The humans and guinea pigs. In the rat gastro- Gastroenterology and intestinal tract, 5-HT receptor agonists stimu- results suggest that a combination of 4 Hepatology, Academic late gastric emptying.2311 Medical Centre, AZ 5-HT3 receptor antagonist and 5-HT4 Recently, a new 5-HT4 receptor agonist, Amsterdam, The receptor agonist properties may be re- 12 13 Netherlands quired to obtain a beneficial eVect on sur- prucalopride, was introduced. It is the first G E Boeckxstaens gery induced ileus in the rat. representative of the novel class of benzofurans, and is a highly specific and selective 5-HT Furthermore, they indirectly indicate that 4 Department of receptor agonist. It has been shown to accelerate Gastrointestinal stimulation of the excitatory mechanisms is not able to overcome the inhibitory delayed gastric emptying and to induce giant Pharmacology, Janssen migrating contractions in dogs.14 15 It has also Research Foundation, influence of the neural reflex pathways Beerse, Belgium been shown to shorten orocaecal and whole gut activated during abdominal surgery. 16 J A J Schuurkes (Gut 1999;45:713–718) transit time in humans. These enterokinetic properties may be of great importance for the Laboratory of Gut Keywords: ileus; motilin; cisapride; metoclopramide; treatment of motor disorders characterised by Hormones, University 5-HT3 receptor; 5-HT4 receptor decreased motility. of Leuven, Leuven, Postoperative ileus is a common complica- Belgium T L Peeters tion after abdominal surgery and is defined as Substituted benzamides, such as metoclopra- inhibition of the propulsive intestinal motility. Correspondence to: mide and cisapride, are prokinetics which are It is generally accepted to result from activation Professor P Pelckmans, often used to treat upper abdominal symptoms of inhibitory neural reflex pathways involving Division of Gastroenterology, 17 Faculty of Medicine, related to delayed gastric emptying. These inhibitory adrenergic neurones. We have pre- University of Antwerp, agents possess 5-hydroxytryptamine (5-HT3, viously shown the involvement of adrenergic Universiteitsplein 1, 2610 ) receptor antagonist and 5-HT4 and nitrergic neurones in the pathogenesis of Wilrijk, Belgium. receptor agonist properties.12Their antiemetic

Accepted for publication activity probably results from 5-HT3 receptor Abbreviation used in this paper: 5-HT, 1–4 11 May 1999 antagonism. In addition, 5-HT3 receptor 5-hydroxytryptamine. 714 De Winter, Boeckxstaens, De Man, et al

postoperative ileus in the rat: a combination of They then underwent a skin incision, the adrenergic neurone blocking reser- laparotomy, or laparotomy plus mechanical pine and the nitric oxide synthase inhibitor stimulation. The second group received an Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from L-nitroarginine was able to completely reverse intravenous injection of metoclopramide 30 the inhibition of the transit induced by a mg/kg one minute before the operation. The laparotomy plus mechanical stimulation of the third group received an intravenous injection of 18 gut. In this study, we investigated whether cisapride 1 mg/kg one minute before the stimulation of excitatory pathways could over- operation. The dose inducing 50% of the come these inhibitory reflex pathways and maximum eVect (ED50) for stimulation of gas- eventually resolve postoperative ileus. There- tric emptying in the rat has previously been fore we evaluated the eVect of the enterokinetic shown to be 1–1.5 mg/kg for cisapride and prucalopride and compared its action with that approximately eight times higher for of the clinically used prokinetics cisapride and metoclopramide.524 However, in preliminary metoclopramide. We also compared its eVect experiments, no prokinetic eVect of metoclo- with that of erythromycin, the model com- pramide 10 mg/kg could be demonstrated in pound for a new class of prokinetics, the moti- control rats (data not shown), therefore we lides, which are at present under development.1 Cisapride is a more potent increased the dose to 30 mg/kg. than metoclopramide and is devoid of anti- In a second series of experiments, we tested the e ect of the 5-HT receptor antagonist dopaminergic activity. They both increase the V 3 release of acetylcholine from the postgangli- granisetron. The rats were divided randomly onic nerve endings in the myenteric plexus by into three groups. Rats in the first group served 11920 as a control and were injected with vehicle one activation of a neural 5-HT4 receptor. Erythromycin, a macrolide antibiotic, has been minute before the operation. The second group shown to be a motilin receptor agonist.21 22 was injected intravenously with granisetron 10 Synthetic analogues of erythromycin, the moti- µg/kg and the third group with granisetron 50 lides, are devoid of antibacterial properties and µg/kg one minute before the operation. The 1 they represent a new class of prokinetic agents. ED50 value for stimulation of gastric emptying in rats for granisetron is 10 µg/kg.5 Materials and methods In a third series of experiments, we tested the

EXPERIMENTAL PROTOCOL eVect of the selective 5-HT4 receptor agonist, All procedures received approval from the prucalopride.12 13 Prucalopride (R093877/ commission for medical ethics at the University R108512) is a newly synthesised enterokinetic of Antwerp. Male Wistar rats (145–235 g) were agent and a benzofuran derivative with the fasted for 48 hours with free access to water. chemical structure 4-amino-5-chloro-2,3- The operation protocol has previously been dihydro-N-[1(3-methoxypropyl)-4-piperidinyl]- 18

described in detail. Briefly, the rats were ran- 7-benzofurancarboxamide monochloride. The http://gut.bmj.com/ domly divided into three groups and received rats were divided randomly into three groups. an abdominal operation under ether anaesthe- The first group received an intravenous injection sia. We have previously shown that ether of vehicle and served as a control. The second anaesthesia has no eVect on gastrointestinal group was injected intravenously with prucalo- 18 transit in our rat model of ileus. In the first pride 1 mg/kg and the third group with prucalo- group, an abdominal skin incision was made pride 5 mg/kg one minute before the operation. after the abdomen had been shaved and disin- The dose of prucalopride was based on gastric fected. The second group had a laparotomy emptying studies using a non-caloric meal in on September 29, 2021 by guest. Protected copyright. consisting of an incision through the abdomi- rats (data on file at Janssen Research Founda- nal skin, abdominal muscle layers, and perito- tion, Beerse, Belgium). neum. The third group had a laparotomy In a fourth series of experiments, we tested followed by evisceration and mechanical stimu- the eVect of a combination of the 5-HT recep- lation of the small intestine and caecum. After 3 tor antagonist and the 5-HT receptor agonist the operations, the rats were allowed to recover 4 on intestinal transit in rats. The rats were for one hour. They then received an intragas- divided randomly into two groups. Rats in the tric injection of 0.1 ml Evans blue (50 mg in 1 first group served as a control and were ml 0.9% NaCl)23 through a specially designed orogastric cannula introduced through the injected intravenously with vehicle. The second mouth. After 20 minutes, the rats were killed group received an intravenous injection of under ether anaesthesia and intestinal transit granisetron 50 µg/kg immediately followed by was measured as the migration of Evans blue an intravenous injection of prucalopride 1 from the pylorus to the most distal point of mg/kg one minute before the operation. migration and expressed as distance (cm) In a fifth series of experiments, the eVect of 21 migrated by the stain. erythromycin, a motilin receptor agonist, was In a first series of experiments, the eVect of tested on intestinal transit of Evans blue. The two prokinetic agents, metoclopramide and rats were randomly divided into two groups. cisapride, was tested on intestinal transit of Rats in the first group served as a control and Evans blue. The were injected before the received an intravenous injection of vehicle in a operation in an attempt to prevent develop- tail vein. They then had a skin incision, ment of postoperative ileus. The rats were ran- laparotomy, or laparotomy plus mechanical domly divided into three groups. The first stimulation. The second group received an group served as a control and received an intravenous injection of erythromycin 1 mg/kg intravenous injection of vehicle in a tail vein. one minute before the operation. This dose has Treatments for postoperative ileus 715

80 Control 80 Control * * Metoclopramide Granisetron 10 µg/kg 70 Cisapride 70 Granisetron 50 µg/kg Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from

60 † 60 * 50 50

40 † 40 * 30 30 * Migration (cm) Migration (cm) 20 20

10 * 10

0 0 SI LAP L + M SI LAP L + M Type of operation Type of operation Figure 1 EVect of skin incision (SI), laparotomy (LAP), Figure 2 EVect of skin incision (SI), laparotomy (LAP), or laparotomy plus mechanical stimulation of the small or laparotomy plus mechanical stimulation of the small intestine and caecum (L+M) on intestinal transit in control intestine and caecum (L+M) on intestinal transit in control rats (n = 9–10) and rats treated with metoclopramide (30 rats (n = 9–10) and rats treated with granisetron 10 µg/kg mg/kg; n = 9) or cisapride (1 mg/kg; n = 9–10). Results (n = 9) or 50 µg/kg (n = 9–10). Results are expressed as are expressed as cm migration of Evans blue and shown as cm migration of Evans blue and shown as mean (SEM). mean (SEM). *Significantly diVerent from the transit in One way analysis of variance could not detect any control rats with the same operation (p<0.05); significant diVerences between the treatment groups. †significantly diVerent from the transit in rats treated with metoclopramide with the same operation (p<0.05) (one way analysis of variance followed by the Bonferroni test). Results EFFECT OF METOCLOPRAMIDE AND CISAPRIDE ON INTESTINAL TRANSIT previously been shown to induce a prokinetic In control rats, transit after skin incision was eVect in dogs, rabbits, and humans.25–27 57.8 (2.1) cm (n = 10). It was significantly decreased by laparotomy to 34.6 (2.4) cm (n = 9). This inhibition of transit was even more CHEMICALS USED pronounced after laparotomy plus mechanical The following chemicals were used: diethyl stimulation (19.4 (2.4) cm, n = 9; fig 1). ether, L-ascorbic acid (Merck, Darmstadt, Metoclopramide 30 mg/kg significantly in- Germany), erythromycin lactobionate (Eryth- creased transit after skin incision from 57.8 rocine; S A Abbott, Saint-Remy, France), (2.1) cm (n = 10) in control rats to 71.3 (3.5) Evans blue (Sigma, St Louis, Missouri, USA), cm (n = 9) (fig 1). However, it further inhibited granisetron hydrochloride (Kytril; Smithkline transit after laparotomy with or without Beecham Pharma, Genval, Belgium), metoclo- mechanical stimulation: after laparotomy, tran- http://gut.bmj.com/ pramide hydrochloride (Alpha Pharma, Zw- sit was 20.8 (2.4) cm in rats treated with meto- evegem, Belgium), NaCl 0.9% (Plurule) and clopramide compared with 34.6 (2.4) cm in sterile water (Baxter, Lessines, Belgium). control rats, and after laparotomy plus me- Granisetron was kindly provided by Dr J Dier- chanical stimulation, transit was 7.6 (1.6) cm ckens (Smithkline Beecham Pharma). Cis- in rats treated with metoclopramide compared apride (R051619) and prucalopride with 19.4 (2.4) cm in control rats (n = 9, fig 1). Cisapride 1 mg/kg significantly increased on September 29, 2021 by guest. Protected copyright. (R093877/R108512) were kindly provided by J transit after the three operations. It was 71.4 S (Janssen Research Foundation). Prucalo- (2.6) cm (n = 9) after the skin incision, 51.6 pride was dissolved in sterile water, and (2.9) cm (n = 10) after laparotomy, and 28.9 cisapride was dissolved in 0.57 M ascorbic (3.1) cm (n = 10) after laparotomy plus acid. All other drugs were dissolved in 0.9% mechanical stimulation (fig 1). NaCl. The significant diVerences between the tran- sit after skin incision and that after laparotomy with or without mechanical stimulation re- PRESENTATION OF RESULTS AND STATISTICAL mained significant in the diVerent treatment ANALYSIS groups. Also the diVerence between transit The total length of the small intestine was not after laparotomy and that after laparotomy plus statistically diVerent between the groups (data mechanical stimulation remained significant in not shown). Therefore results are expressed as the three diVerent groups. distance (cm) migrated by Evans blue. The measurements were made from the pylorus to the most distal point of migration. Group EFFECT OF GRANISETRON ON INTESTINAL TRANSIT diVerences were assessed by simple factorial Granisetron had no eVect on transit after the analysis of variance followed by unpaired skin incision, laparotomy, or laparotomy plus Student’s t test or by one way analysis of mechanical stimulation. Transit after skin inci- variance followed by the Bonferroni test for sion tended to increase but statistical signifi- multiple comparisons. Values are shown as cance was not reached: transit was 61.4 (4.0) mean (SEM). p<0.05 was considered to be cm (n = 10) in control rats, 65.6 (4.3) cm (n = significant. All data were analysed with the 9) in rats treated with granisetron 10 µg/kg, and SPSS for windows software (SPSS Inc, Chi- 68.7 (4.0) cm (n = 10) in rats treated with cago, Illinois, USA). granisetron 50 µg/kg (fig 2). Granisetron at a 716 De Winter, Boeckxstaens, De Man, et al

80 Control 80 Control Prucalopride 1 mg/kg Granisetron 70 Prucalopride 5 mg/kg 70 + prucalopride Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from

60 60 * 50 50 *

40 40

30 30 * Migration (cm) Migration (cm) 20 20

10 10

0 0 SI LAP L + M SI LAP L + M Type of operation Type of operation Figure 3 EVect of skin incision (SI), laparotomy (LAP), Figure 4 EVect of skin incision (SI), laparotomy (LAP), or laparotomy plus mechanical stimulation of the small or laparotomy plus mechanical stimulation of the small intestine and caecum (L+M) on intestinal transit in control intestine and caecum (L+M) on intestinal transit in control rats (n = 9) and in rats treated with prucalopride 1 mg/kg rats (n = 10) and rats treated with a combination of (n = 9) or 5 mg/kg (n = 9). Results are expressed as cm granisetron (50 µg/kg) and prucalopride (1 mg/kg) (n = migration of Evans blue and shown as mean (SEM). 9–10). Results are expressed as cm migration of Evans blue *Significantly diVerent from the transit in control rats after and shown as mean (SEM). *Significantly diVerent from laparotomy (p<0.05) (one way analysis of variance the transit in control rats with the same operation (p<0.05) followed by the Bonferroni test). (unpaired Student’s t test). dose of either 10 or 50 µg/kg had no significant 80 Control eVect on transit after laparotomy or laparotomy Erythromycin plus mechanical stimulation (n = 9, fig 2). 70 The diVerences between transit after the skin 60 incision and that after laparotomy with or without mechanical stimulation, as well as the 50

diVerence between transit after laparotomy 40 alone and that after laparotomy plus mechani- cal stimulation remained significant in the dif- 30 Migration (cm) ferent treatment groups. 20

EFFECT OF PRUCALOPRIDE ON INTESTINAL 10 TRANSIT 0 SI LAP L + M

Prucalopride had no eVect on transit after the http://gut.bmj.com/ skin incision at either dose (1 and 5 mg/kg) Type of operation used. Transit was comparable with that (63.6 Figure 5 EVect of skin incision (SI), laparotomy (LAP), (3.7) cm) in control rats after skin incision (n = or laparotomy plus mechanical stimulation of the small 9, fig 3). Transit after laparotomy was signifi- intestine and caecum (L+M) on intestinal transit in control rats (n = 9) and rats treated with erythromycin (1 mg/kg; cantly increased by prucalopride 1 mg/kg from n = 9). Results are expressed as cm migration of Evans blue 37.4 (3.1) cm in control rats to 49.9 (2.8) cm and shown as mean (SEM). Unpaired Student’s t test (n = 9, fig 3). However, the increase produced could not detect any significant diVerences between the by the 5 mg/kg dose was not significantly treatment groups. on September 29, 2021 by guest. Protected copyright. diVerent: the transit was increased to 45.6 (3.4) 37.5 (2.8) cm in control rats to 45.5 (1.6) cm cm (n = 9, fig 3). The transit after laparotomy (n = 10, fig 4). Transit after laparotomy plus plus mechanical stimulation tended to increase mechanical stimulation was also significantly after treatment with prucalopride, but statisti- increased by this treatment from 17.4 (2.2) cm cal significance was not reached. The transit (n = 10) in control rats to 24.6 (1.8) cm (n = 9) was 17.9 (2.4) cm in control rats, 20.6 (1.7) cm (fig 4). after treatment with prucalopride 1 mg/kg, and In both groups, the diVerences between the 23.9 (2.5) cm after treatment with prucalo- transit after skin incision and that after pride 5 mg/kg (n = 9, fig 3). laparotomy with or without mechanical stimu- The diVerences between the transit after skin lation and the diVerence between the transit incision and that after laparotomy with or after laparotomy alone and that after without mechanical stimulation, as well as the laparotomy plus mechanical stimulation re- diVerence between the transit after laparotomy mained significant, indicating that the combi- alone and that after laparotomy plus mechani- nation treatment was not able completely to cal stimulation remained significant in the dif- reverse the transit inhibition caused by the ferent treatment groups. abdominal operations.

EFFECT OF A COMBINATION OF GRANISETRON EFFECT OF ERYTHROMYCIN ON INTESTINAL AND PRUCALOPRIDE ON INTESTINAL TRANSIT TRANSIT

The combination of the 5-HT3 receptor In control rats, transit after skin incision was antagonist granisetron (50 µg/kg) and the 59.9 (3.0) cm. That after laparotomy was

5-HT4 receptor agonist prucalopride (1 mg/kg) significantly decreased to 34.8 (3.9) cm. This had no eVect on the transit after skin incision transit inhibition was even more pronounced (n = 10, fig 4). However, the transit after when the laparotomy was associated with laparotomy was significantly increased from mechanical stimulation of the intestine (16.2 Treatments for postoperative ileus 717

(3.1) cm, n = 9; fig 5). Erythromycin 1 mg/kg prucalopride significantly increased transit had no eVect on the transit after the three after laparotomy with or without mechanical

operations (n = 9, fig 5). stimulation. Therefore we hypothesise that Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from

The transit after the skin incision was signifi- both 5-HT3 receptor antagonism and 5-HT4 cantly diVerent from that after laparotomy with receptor agonism are required to reduce or without mechanical stimulation in both experimental ileus in the rat. The eVect of cis- groups. Also the diVerence between the transit apride resembles that of the granisetron and after laparotomy and that after laparotomy plus prucalopride combination on transit after mechanical stimulation was significant in both laparotomy with or without mechanical stimu- groups. lation. As cisapride is known to possess both

5-HT3 receptor antagonist and 5-HT4 receptor Discussion agonist properties, this finding may confirm In our rat model of postoperative ileus, our hypothesis. Several clinical studies have diVerent degrees of inhibition of intestinal already shown a beneficial eVect of repeated transit were achieved by diVerent degrees of intravenous administration of cisapride on nociceptive stimulation. Skin incision had no postoperative ileus,29–31 while other studies eVect on the transit, whereas it was significantly could not confirm this eVect.32 33 Possibly, the delayed by laparotomy. This inhibition was eVectiveness of cisapride in the resolution of even more pronounced when the laparotomy postoperative ileus depends on the route of was associated with mechanical stimulation of administration.34 A recent study in humans the gut, confirming earlier data obtained by indicates that cisapride has prokinetic proper- Bueno et al.28 The role of inhibitory adrenergic ties only when administered after the reappear- neurones in the pathogenesis of postoperative ance of the migrating motor complexes.35 In ileus is generally accepted,17 but here we also this study, cisapride was administered after the show the involvement of inhibitory nitrergic operation through a nasointestinal tube and it neurones.18 In this study, we investigated the induced irregular spike bursts. eVect of prokinetic treatment on postoperative Interestingly, we found a diVerential eVect of

ileus in the rat. Although activation of 5-HT4 metoclopramide and cisapride on the abdomi- receptors is believed to be the mechanism of nal surgery induced decrease in transit: meto- action of substituted benzamides,12 the newly clopramide further inhibited, whereas cis-

synthesised 5-HT4 receptor agonist prucalo- apride ameliorated the inhibition of, transit pride did not improve recovery of postoperative after laparotomy with or without mechanical

ileus. Only combined 5-HT4 receptor agonism stimulation. In a clinical randomised double 36 and 5-HT3 receptor antagonism, provided by blind study, Jepsen et al also demonstrated either cisapride or a combination of graniset- this unexpected negative eVect of metoclopra- ron and prucalopride, increased transit signifi- mide on postoperative ileus; they proposed that

cantly after laparotomy with or without me- it was due to the generation of uncoordinated http://gut.bmj.com/ chanical stimulation. non-propulsive .36 The diVerence

The selective 5-HT4 receptor agonist, between metoclopramide and cisapride could 12 13 prucalopride, has been shown to induce be related to diVerent aYnities for the 5-HT3

giant migrating contractions and accelerate receptor and the 5-HT4 receptor or to the cen- gastric emptying in dogs, and to stimulate tral dopamine antagonistic activity of metoclo- gastrointestinal transit and bowel habits in pramide that is lacking for cisapride.19 20 On the healthy volunteers.14–16 However, in this study other hand, recent reports suggest that cis- in the rat, prucalopride only tended to increase apride enhanced gastroduodenal motility in the on September 29, 2021 by guest. Protected copyright. transit after laparotomy with or without interdigestive state by increasing the plasma mechanical stimulation, suggesting species dif- levels of motilin,37 suggesting that cisapride ferences. The eVect of prucalopride is not may enhance gastrointestinal motility by both clearly dose related, with only the lower dose serotonergic and non-serotonergic mecha- significantly increasing transit after nisms. The latter may also explain the different laparotomy. This lack of a dose related eVect eVect of cisapride and the combination of

was also shown with other selective 5-HT4 prucalopride and granisetron on the transit receptor agonists in a model of gastric after skin incision. emptying in the rat and dog11 and in a model of Erythromycin, a motilide, had no eVect on canine colonic transit.4 Hypothetically, the fact transit in either normal conditions or after that prucalopride is a partial agonist may abdominal surgery. Similarly, Plourde et al38 explain the diVerent eVects of cisapride and could not show any improvement in gastric prucalopride. However, the lack of a dose emptying in the rat after abdominal surgery related eVect of prucalopride does not support even if the rats were treated with a higher con-

this hypothesis. Granisetron, a 5-HT3 receptor centration (40 mg/kg) of erythromycin. Al- antagonist, was not able to increase intestinal though erythromycin induced an increase in transit after the three operations when given the motility index of the small intestine in the alone, although it was used at a concentration rat in one study,39 several other studies failed to

equal to the ED50 value for gastric emptying in show a prokinetic action of erythromycin in the 5 21 22 the rat. Whereas 5-HT3 receptor antagonists rat. These results may suggest that the rat is were previously shown to increase gastric emp- not an ideal species in which to study the tying in rats,56 in our study granisetron only eVects of motilides, although motilin immuno- tended to increase transit after skin incision, reactivity has been shown in the rat small but statistical significance was not reached. In intestine.22 In humans also, treatment with contrast, the combination of granisetron and erythromycin did not alter the clinical variables 718 De Winter, Boeckxstaens, De Man, et al

of gastrointestinal motility after abdominal 14 Briejer MR, Meulemans AL, Wellens A, et al. R093877 40 dose-dependently accelerates delayed gastric emptying in surgery, despite the acceleration of gastric conscious dogs [abstract]. Gastroenterology 1997;112:A705. emptying in healthy subjects41 and in patients 15 Briejer MR, Meulemans AL, Van Daele P, et al. R093877 Gut: first published as 10.1136/gut.45.5.713 on 1 November 1999. Downloaded from 42 43 induces giant migrating contractions (GMC) and alters with diabetic . Therefore the colonic motility patterns in awake dogs. Neurogastroenterol eYcacy of erythromycin or other motilides in Motil 1998;10:62. 16 Emmanuel AV, Kamm MA, Roy AJ, et al. EVect of a novel the treatment of postoperative ileus remains to prokinetic drug, R093877, on gastrointestinal transit in be proved. healthy voluntees. Gut 1998;42:511–16. In conclusion, of the prokinetics studied, 17 Livingston EH, Passaro EP. Postoperative ileus. Dig Dis Sci 1990;35:121–32. only cisapride is of use in the treatment of 18 De Winter BY, Boeckxstaens GE, De Man JG, et al. EVect postoperative ileus. Our study suggests that a of adrenergic and nitrergic blockade on experimental ileus in rats. Br J Pharmacol 1997;120:464–8. combination of 5-HT3 receptor antagonist and 19 Albibi R, McCallum RW. Metoclopramide: pharmacology 5-HT receptor agonist properties may be and clinical application. Ann Intern Med 1983;98:86–95. 4 20 Dowling PM. Prokinetic drugs: metoclopramide and required to obtain a beneficial eVect on surgery cisapride. Canadian Veterinary Journal 1995;36:115–16. induced ileus in the rat. Although prokinetics 21 Peeters T, Matthijs G, Depoortere I, et al. Erythromycin is a motilin receptor agonist. Am J Physiol 1989;257:G470–4. have a beneficial eVect in the treatment of gas- 22 Itoh Z. Motilin and clinical application. Peptides 1997;18: tric emptying disorders, they may be of limited 593–608. 23 Tanila H, Kauppila T, Taira T. Inhibition of intestinal motil- use in the treatment of postoperative ileus. ity and reversal of postlaparotomy ileus by selective alpha Their clinical relevance remains to be proved. 2-adrenergic drugs in the rat. Gastroenterology 1993;104: 819–24. Our results indirectly indicate that stimulation 24 Megens AAHP, Awouters FHL, Niemegeers CJE. General of excitatory neurones is not able to overcome pharmacology of the four gastrointestinal motility stimu- completely the inhibitory influence of the neu- lants bethanechol, metoclopramide, , and cisapride. Arzneimittelforschung 1991;41:631–4. ral reflex pathways activated by abdominal sur- 25 Peeters TL. Erythromycin and other macrolides as proki- gery. However, it is worth investigating further netic agents. Gastroenterology 1993;105:1886–99. 26 Peeters TL, Depoortere I. Motilin receptor: a model for the eVects of novel enterokinetics that have development of prokinetics. Dig Dis Sci 1994;39:76S–78S. profound eVects on colonic motility in hu- 27 Costa A, De Ponti F, Gibelli G, et al. In vivo characterization of the colonic prokinetic eVect of erythromycin in the rab- mans. bit. Pharmacology 1997;54:64–75. 28 Bueno L, Ferre JP, Ruckebusch Y. EVects of anesthesia and surgical procedures on intestinal myoelectric activity in B De W is a research assistant of the Fund for Scientific rats. Am J Dig Dis 1978;23:690–5. Research—Flanders (FWO), Belgium. This work was sup- 29 Boghaert A, Haesaert G, Mourisse P, et al. Placebo- ported by the FWO—Flanders, Belgium (grant no G.0220.96) controlled trial of cisapride in postoperative ileus. Acta and by the Interuniversity Pole of Attraction Programme (grant Anaesthesiol Belg 1987;38:195–9. no P4/16, Services of the Prime Minister—Federal Services for 30 Verlinden M, Michiels G, Boghaert A, et al. 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