Synergistic and antagonistic pharmacodynamic interaction between ranitidine and cisapride: a study on the isolated rabbit intestine

Pharmacological Research, Vol. 43, No. 4, 2001 doi:10.1006/phrs.2000.0785, available online at http://www.idealibrary.com on

SYNERGISTIC AND ANTAGONISTIC PHARMACODYNAMIC INTERACTION BETWEEN RANITIDINE AND CISAPRIDE: A STUDY ON THE ISOLATED RABBIT INTESTINE M. KOUTSOVITI-PAPADOPOULOU∗ , E. NIKOLAIDIS, G. C. BATZIAS and G. KOUNENIS Department of Pharmacology, Faculty of Veterinary Medicine, Aristotle University, Thessaloniki, Greece Accepted 14 November 2000

The present study examines the pharmacodynamic interaction between the H2 -receptor antagonist ranitidine and the prokinetic agent cisapride on the isolated rabbit intestine. Ranitidine produced a concentration-dependent contractile effect on the duodenal, ileal and ascending colon preparations, with EC50 values of 1.35×10−4 M for the duodenum, 1.2×10−4 M for the ileum and 1.15×10−4 M for the ascending colon. The effect of cisapride on the ranitidine contractile effect was dependent on the cisapride concentration used. Thus, cisapride, at concentrations from 10−10 up to 5 × 10−7 for the duodenum and the ascending colon and up to 10−6 M for the ileum, potentiated the contractile responses of the preparations to ranitidine. However, at higher concentrations cisapride produced a non-competitive inhibition of the intestinal contractile responses to ranitidine with IC50 values of 4.2 × 10−5 M for the duodenum, 1.65 × 10−5 M for the ileum and 3.2 × 10−6 M for the ascending colon. These data show that cisapride may modify the contractile responses of the isolated rabbit intestine to ranitidine, having a potentiating effect up to a certain concentration and an antagonistic one at higher concentrations. In conclusion, co-administration of the above drugs may lead to c 2001 Academic Press enhanced or reduced intestinal motility.

K EY WORDS : ranitidine, cisapride, rabbit intestine, pharmacodynamic interaction.

INTRODUCTION H2 -receptor antagonists, in addition to their well known gastric acid inhibitory effect, have prokinetic properties as well, thus stimulating gastrointestinal contractions and accelerating gastric emptying at gastric antisecretory doses [1, 2]. In fact, it has been suggested that some H2 -receptor antagonists are more effective than several prokinetics in improving dyspeptic symptoms, gastric emptying and distention [3]. The prokinetic activity of the above agents derives mainly from their anticholinesterase activity. Indeed, in vivo [4–7] and in vitro studies [4, 6, 8– 20] have shown that most H2 -receptor antagonists exhibit weak or strong anticholinesterase activity; ranitidine and nizatidine being the more potent among the H2 receptor antagonists with respect to acetylcholinesterase inhibition [10, 11, 18, 20]. Cisapride, a prokinetic agent, has been found to stimulate phasic motor activity from the oesophagus to the large intestine [21–26]. In agreement with comparative studies, cisapride has been found to be more ∗ Corresponding author. Department of Pharmacology, Faculty of Vet-

erinary Medicine, Aristotle University, Thessaloniki 540 06, Greece. E-mail: [email protected] 1043–6618/01/040329–06/$35.00/0

potent than other prokinetic agents in stimulating gastric emptying and in increasing gastroesophageal sphincter pressure [27–31]. Therefore, it has been suggested that cisapride presents important advantages over earlier prokinetic compounds for the alleviation of dysmotility symptoms and for the treatment of gastroesophageal reflux [32]. Anti-ulcerogenic properties of cisapride have been noted as well [33]. In addition, co-administration of cisapride with an H2 -receptor antagonist is often recommended, since from clinical studies it has been suggested that combination of the above agents may lead to increased symptomatic relief and prevent recurrent symptoms [34–45]. However, since several adverse effects, in which abdominal cramping and diarrhoea are included, have been reported in patients receiving therapy with either cisapride or an H2 -receptor antagonist alone [31, 46], it would be of importance to explore whether co-administration of the above agents would amplify these adverse effects. Therefore, the present study was undertaken in order to investigate whether a pharmacodynamic interaction between ranitidine and cisapride at the intestinal level exists and if co-administration of the above indirectly acting cholinomimetic agents influence the intestinal c 2001 Academic Press

330

motility in vitro. For this purpose, the effect of different concentrations of cisapride on the responses of the rabbit small and large intestine to ranitidine was studied.

MATERIALS AND METHODS

Preparations of the rabbit intestine Rabbits of either sex weighing approximately 2 kg were used. After the decapitation of the animals whole segments (1 cm long) of the duodenum, the terminal ileum and the ascending colon were rapidly excised and put into Tyrode solution (millimolar composition: NaCl 136.90, KCl 2.68, CaCl2 1.80, MgCl2 1.05, NaHCO3 11.90, NaH2 PO4 0.42 and glucose 5.55). The preparations were then suspended in 20 ml organ baths (Hugo Sachs Electronik KG, Germany) containing Tyrode solution which was bubbled constantly with a mixture of 95% O2 : 5% CO2 gas and maintained at a temperature of 37 ◦ C. The preparations were connected to isotonic myograph transducers (Narco Co., USA) under a resting tension of 0.5 g and the responses were recorded on a physiograph recorder (desk model type DMP-4A, Narco Co., USA). The preparations were allowed to equilibrate for 45 min (with intervening washings) before any compound addition.

Pharmacological Research, Vol. 43, No. 4, 2001

RESULTS

Responsiveness of the preparations to cisapride The response of the tissue to cisapride prior to the addition of ranitidine was dependent on the cisapride concentration used. Thus, at concentrations up to 10−6 M, either no response (in most cases) or a slight increase in the phasic contraction was observed. At cisapride concentrations higher than 10−5 M, a decrease in the phasic contraction was usually observed.

Responsiveness of the preparations to ranitidine before and after pretreatment with various concentrations of cisapride Duodenal preparations. Ranitidine, at concentrations from 10−5 to 10−3 M, produced a concentrationdependent contractile effect on the duodenal rabbit preparations with EC50 = 1.35 × 10−4 M. Cisapride, at concentrations from 10−10 to 5×10−7 M, shifted the ranitidine concentration–response curve to the left. However, this potentiation was not statistically significant except at the concentration of 10−5 M of ranitidine. The response of the duodenum to ranitidine at EC50 was potentiated by pretreatment with 5 × 10−7 M cisapride by 12% (no statistically significant potentiation). At concentrations from 10−6 to 7 × 10−6 M cisapride did not modify the concentration–response curve of ranitidine, while at concentrations equal or higher than 10−5 M it significantly antagonized it with IC50 = 4.2 × 10−5 M (Fig. 1).

Drugs The following compounds were used: ranitidine (Sigma Chemical Co., USA) and cisapride (Janssen Pharmaceutical, Beerse, Belgium).

Concentration–response curves After the 45 min equilibration period the duodenal, ileal and ascending colon preparations were exposed to cumulatively increasing concentrations of ranitidine (from 10−5 to 10−3 M) to obtain full concentration– response curves. The contact time of each cumulatively increasing concentration of ranitidine with the preparations was 1 min. In a second series of experiments the duodenal, ileal and ascending colon preparations were exposed to cumulatively increasing concentrations of ranitidine (from 10−5 to 10−3 M) in the presence of different concentrations of cisapride (from 10−10 to 2 × 10−5 M). Cisapride was added to the bath fluid 5 min prior to the addition of ranitidine.

Statistical analysis of results The responses obtained were expressed as a percentage of the maximum height attained in the control curve (ranitidine). Statistical evaluation of the data was performed using Student’s t-test for paired or unpaired data when appropriate. The data were expressed as mean ± SEM and P values of <0.05 were considered to be significant.

Ileal preparations. Ranitidine, at concentrations from 10−5 to 10−3 M, produced a concentration-dependent contractile effect on the ileal rabbit preparations with EC50 = 1.2 × 10−4 M. Cisapride, at concentrations from 10−10 to 10−6 M, potentiated the response of the preparations to ranitidine. The response of the ileum to ranitidine at EC50 was potentiated by pretreatment with 5 × 10−7 M cisapride by 44%. Cisapride, at the concentrations from 3 × 10−6 to 10−5 M, did not modify the concentration–response curve of ranitidine, while at concentrations equal or higher than 2 × 10−5 M it significantly antagonized it with IC50 = 1.65 × 10−5 M (Fig. 2). Ascending colon preparations. Ranitidine, at concentrations from 10−5 to 10−3 M, produced a concentrationdependent contractile effect on the ascending colon rabbit preparations with EC50 = 1.15 × 10−4 M. Cisapride, at concentrations from 10−10 to 5 × 10−7 M, potentiated the response of the preparations to ranitidine. The response of the ileum to ranitidine at EC50 was potentiated by pretreatment with 5 × 10−7 M cisapride by 36%. Cisapride, at the concentration of 10−6 M, did not modify the concentration–response curve of ranitidine, while at concentrations equal or higher than 3 × 10−6 M it significantly antagonized it with IC50 = 3.2 × 10−6 M (Fig. 3).

Pharmacological Research, Vol. 43, No. 4, 2001

331

130 130 110 % of maximum response

% of maximum response

110 90 70 50

90 70 50 30

30 10 10 − 10 5

− 10 5

4 3 Concentration (–log M)

Fig. 1. Concentration–response curves for the contractile response of the isolated rabbit duodenum to ranitidine in the absence ( , n = 24) and in the presence of cisapride at the concentrations of 10−10 M (, n = 5), 5 × 10−7 M ( , n = 12) and 10−5 M (N, n = 7). The ordinate is expressed as a percentage of the mean maximum response induced by ranitidine alone (control). Each point represents the mean ±SEM. ∗ or × indicate the significant values of ranitidine potentiation or antagonism caused by cisapride (P < 0.05).

•

◦

4 3 Concentration (–log M)

Fig. 3. Concentration–response curves for the contractile response of the isolated rabbit ascending colon to ranitidine in the absence ( , n = 32) and in the presence of cisapride at the concentrations of 10−10 M (, n = 8), 5 × 10−7 M ( , n = 8), 10−6 M (, n = 7) and 3 × 10−6 M (N, n = 8). The ordinate is expressed as a percentage of the mean maximum response induced by ranitidine alone (control). Each point represents the mean ±SEM. ∗ or × indicate the significant values of ranitidine potentiation or antagonism caused by cisapride (P < 0.05).

•

◦

DISCUSSION 150

% of maximum response

130 110 90 70 50 30 10 − 10

5

4 3 Concentration (–log M)

Fig. 2. Concentration–response curves for the contractile response of the isolated rabbit ileum to ranitidine in the absence ( , n = 23) and in the presence of cisapride at the concentrations of 10−10 M (, n = 7), 5 × 10−7 M ( , n = 6), 10−5 M (, n = 8) and 2 × 10−5 M (N, n = 7). The ordinate is expressed as a percentage of the mean maximum response induced by ranitidine alone (control). Each point represents the mean ±SEM. ∗ or × indicate the significant values of ranitidine potentiation or antagonism caused by cisapride (P < 0.05).

•

◦

Results of the present study have shown that ranitidine exerts a concentration-dependent contractile effect on the duodenum, ileum and ascending colon rabbit preparations. This effect was found to be strongest on the ascending colon and weakest on the ileum. Indeed, the maximum responses of the duodenum and the ileum to ranitidine were 90.49% and 64.77% of the maximum response of the ascending colon. The EC50 values were 1.15 × 10−4 M, 1.2 × 10−4 M and 1.35 × 10−4 M for the ascending colon, the duodenum and the ileum, respectively. These results are in agreement with previous studies concerning the contractile effect of ranitidine, since it has been shown from in vivo [4–6] and in vitro [4, 6, 8, 9, 11, 12, 15, 17, 20] studies that ranitidine elicits a marked contractile effect from the lower oesophageal sphincter to the colon of several animal species. This effect was attributed to the anticholinesterase activity of ranitidine. Indeed, it has been shown that most H2 receptor antagonists possess anticholinesterase activity; ranitidine and nizatidine being the more potent among the H2 -receptor antagonists with respect to acetylcholinesterase inhibition [10, 11, 17, 18, 20]. In addition, it has been previously shown that this effect of ranitidine is more pronounced on the duodenum and it becomes progressively less pronounced towards the ileum [9], an effect that was attributed to a difference in the distribution of cholinesterases along the intestine [47, 48].

332

According to the results of the present study cisapride modified the ranitidine’s contractile effect on the duodenal, ileal and ascending colon preparations. However, this influence was dependent on the cisapride concentration used. Thus, cisapride up to a certain concentration potentiated the contractile response of the preparations to ranitidine, producing a leftward shift of the concentration– response curve to ranitidine. This potentiating effect varied among the intestinal parts being more pronounced on the ileum, less pronounced on the ascending colon and even less pronounced on the duodenum. Furthermore, this effect became evident at different cisapride concentrations with respect to the intestinal region tested. More precisely, cisapride, at concentrations from 10−10 up to 5 × 10−7 M for the duodenum and the ascending colon and from 10−10 up to 10−6 M for the ileum, potentiated the contractile responses of the preparations to ranitidine. However, this potentiation was not statistically significant for the duodenum except at the concentration of 10−5 M of ranitidine. The response of the ileum to ranitidine at EC50 was potentiated by pretreatment with 5 × 10−7 M cisapride by 44%, the one of the ascending colon by 36% and the one of the duodenum by 12% (not statistically significant potentiation). That cisapride facilitates gastrointestinal motility both in vivo and in vitro from the oesophagus to the stomach, in small and large intestine, and in the gall bladder in several animal species, as well as in humans has already been shown in previous investigations. In accordance with results from in vitro studies it has been suggested that up to 10−6 M cisapride produces a stimulatory effect on both stimulated and unstimulated preparations [49–53]. This effect was attributed to the facilitation of cholinergic neurotransmission, as it has been suggested for the human gall bladder, oesophagus, stomach, small and large intestine [53], the guinea-pig ileum [50, 54], the feline oesophagus [52] and the canine antrum [55]. Results of the present study also showed that, at concentrations ranging from 10−6 M to 3 × 10−6 M for the duodenum, from 3 × 10−6 to 10−5 M for the ileum and at the concentration of 10−6 M for the ascending colon, cisapride did not modify the concentration–response curve of the preparations to ranitidine. However, at higher concentrations it produced a non-competitive inhibition of the intestinal contractile responses to ranitidine, causing a rightward shift with reduction of the maximum response of the intestinal preparations. More precisely, cisapride’s antagonistic effect on ranitidine’s contractile effect occurred from the concentrations of 3 × 10−6 M, 10−5 M and 2 × 10−5 M for the ascending colon, the duodenum and the ileum, respectively. These results show that the concentration of cisapride that reverses the contractile effect of ranitidine varies with respect to the intestinal region, being lower for the ascending colon, higher for the duodenum and even higher for the ileum. Thus, cisapride’s antagonistic effect on ranitidine’s contractile one appears at lower concentrations on the ascending colon and at higher ones on the ileum. This antagonistic effect is not surprising since results of previ-

Pharmacological Research, Vol. 43, No. 4, 2001

ous studies have shown that cisapride, at concentrations above 10−6 M, produces a less pronounced stimulatory effect or even an inhibitory one. In agreement with these findings cisapride, at micromolar concentrations, has a relaxing effect on the rabbit duodenum [51], reduces the contractions to electrical field stimulation in strips from human gall bladder and gastrointestinal tract [53] and suppresses or blocks both fast and slow excitatory postsynaptic potentials in the myenteric plexus of the guinea-pig ileum [54, 56]. This effect was attributed to an inhibitory action of cisapride on cholinergic neurotransmission [54, 56, 57]. Based on the above results there is evidence to suggest that a pharmacodynamic interaction between ranitidine and cisapride at the intestinal level exists and that the combination of the above indirect cholinomimetic agents may modify intestinal motility, their effect depending on the concentration scheme administered. Although our results should be critically extrapolated to humans, nevertheless, we could suggest that combination of the above agents may sometimes lead to enhancement of the intestinal motility and may probably intensify the adverse effects which either agent, when administered alone, might produce. On the other hand, it seems that somewhat higher concentrations of cisapride may counteract the prokinetic activity of ranitidine, so as to reduce the intestinal motility and thus diminish the adverse effects. In conclusion, cisapride up to a certain concentration potentiates ranitidine’s contractile effect on the isolated rabbit small and large intestine, while at somewhat higher concentrations it antagonizes ranitidine’s above effect. Thus, a pharmacodynamic interaction between cisapride and ranitidine at the rabbit intestinal level exists. This interaction may be either synergistic or antagonistic depending on the above drugs concentration scheme administered.

REFERENCES 1. Ueki S, Seiki M, Yoneta T, Aita H, Chaki K, Hori Y, Morita H, Tagashira E, Itoh Z. Gastroprokinetic activity of nizatidine, a new H2 -receptor antagonist, and its possible mechanism of action in dogs and rats. J Pharmacol Exp Ther 1993; 264: 152–7. 2. Kishibayashi N, Tomaru A, Ichikawa S, Kitazawa T, Shuto K, Ishii A, Karasawa A. Enhancement by KW-5092, a novel gastroprokinetic agent, of the gastrointestinal motor activity in dogs. Jpn J Pharmacol 1994; 65: 131–42. 3. Cucchiara S, Raia V, Minella R, Frezza T, De Vizia B, De Ritis G. Ultrasound measurement of gastric emptying time in patients with cystic fibrosis and effect of ranitidine on delayed gastric emptying. J Pediatr 1996; 128: 485–8. 4. Bertaccini G, Coruzzi G. Cholinergic-like effects of the new histamine H2 -receptor antagonist ranitidine. Agents Actions 1982; 12: 168–71. 5. Fioramonti J, Soldani G, Honde C, Bueno L. Effects of ranitidine and oxmetidine on gastrointestinal motility in conscious dog. Agents Actions 1984; 15: 260–3. 6. Bertaccini G, Coruzzi G, Poli E. Histamine H2 -receptor antagonists may modify dog intestinal motility independently of their primary action on the H2 -receptors. Pharmacol Res Commun 1985; 17: 241–54.

Pharmacological Research, Vol. 43, No. 4, 2001 7. Bortolotti M, Cucchiara S, Sarti P, Brunelli F, Mazza M, Bagnato F, Barbara L. Comparison between the effects of neostigmine and ranitidine on interdigestive gastroduodenal motility of patients with gastroparesis. Digestion 1995; 56: 96–9. 8. Bertaccini G, Poli E, Adami M, Coruzzi G. Effect of some new H2 -receptor antagonists on gastrointestinal motility. Agents Actions 1983; 13: 157–62. 9. Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou V. Cholinergic-like effect of the H2 -receptor antagonist ranitidine on the rabbit small intestine. Proceedings of 3r d European Association for Veterinary Pharmacology and Toxicology Congress. 1985: 143–51. 10. Lee HS, Cheah LS, Gwee MC. Inhibition of acetylcholinesterase by histamine agonists and antagonists. Clin Exp Pharmacol Physiol 1985; 12: 613–20. 11. Aono M, Moriga M, Mizuta K, Narusawa H. Cholinergic effects of histamine-H2 receptor antagonists partly through inhibition of acetylcholinesterase. Gastroenterol Jpn 1986; 21: 213–9. 12. Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou V. The inhibition of acetylcholinesterase by ranitidine: a study on the guinea pig ileum. J Pharmacobiodyn 1986; 9: 941–5. 13. Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou V. The excitatory effect of the new histamine H2 -receptor antagonist nizatidine (LY 139037) on the guinea pig ileum. J Pharmacobiodyn 1987; 10: 669–72. 14. Kounenis G, Voutsas D, Koutsoviti-Papadopoulou M, Elezoglou V. Inhibition of acetylcholinesterase by the H2 receptor antagonist nizatidine. J Pharmacobiodyn 1988; 11: 767–71. 15. Kounenis G, Voutsas D, Koutsoviti-Papadopoulou M, Elezoglou V. Effect of the histamine H2 -receptor antagonists nizatidine and ranitidine on the smooth muscle of rabbit colon. Hellenic J Gastroenterology 1988; 79: 185–93. 16. Kounenis G, Voutsas D, Koutsoviti-Papadopoulou M, Elezoglou V. Inhibition of acetylcholinesterase by the histamine H2 -receptor antagonist cimetidine; comparison with ranitidine. Hellenic J Gastroenterol 1989; 2: 296–300. 17. Gwee MC, Shoon ML, Cheah LS. Dual action of ranitidine at cholinergic sites in the rat isolated anococcygeus muscle. J Auton Pharmacol 1993; 13: 211–8. 18. Laine-Cessac P, Turcant A, Premel-Cabic A, Boyer J, Allain P. Inhibition of cholinesterases by histamine2 -receptor antagonist drugs. Res Commun Chem Pathol Pharmacol 1993; 79: 185–93. 19. Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou V. The anticholinesterase activity of the H2 -receptor antagonist famotidine. Proceedings of the 6th European Association for Veterinary Pharmacology and Toxicology Congress. 1994; 281–2. 20. Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou A, Voutsas A. Comparative study of the H2 -receptor antagonists cimetidine, ranitidine, famotidine and nizatidine on the rabbit stomach fundus and sigmoid colon. J Pharmacobiodyn 1995; 15: 561–5. 21. Chey WY, Lee KY, You CH, Shah AN, Hamilton DL. Effect of cisapride on colonic transit in dogs and humans. Dig Dis Sci 1984; 29: 562. 22. Suzuki T, Nakaya M, Nakamura T, Itoh Z. Effect of cisapride on the contractile activity of the gastrointestinal tract. Jpn Smooth Muscle Res 1985; 21: 139–49. 23. Schemann M, Ehrlein H-J. 5-Hydroxytryptophan and cisapride stimulate propulsive jejunal motility and transit of chyme in dogs. Digestion 1986; 34: 229–35. 24. Fujii K, Okajima M, Kawahori K. Effect of cisapride on the cholinergic control mechanisms of gastrointestinal motility in dogs. Nippon Heikatsukin Gakkai Zasshi 1988; 24: 1–12. 25. Strombeck DR, Turner WD, Harold D. Eructation of gas through the gastroesophageal sphincter before and after gastric fundectomy in dogs. Am J Vet Res 1988; 49: 87–9. 26. Schuurkes JAJ, van Nueten JM. Pharmacological modulation of gastroduodenal coordination. In: Gastropyloroduodenal coordination. van Nueten JM, Schuurkes JAJ, Akkermans LMA, eds. Petersfield: Wrightson Biomedical Publishing Ltd, 1990: 155–66. 27. Fitzpatrick LR, Lambert RM, Pendley CE, Martin GE, Bostwick JS, Gessner GW, Airey JE, Youssefyeh RD, Pendleton RG,

333

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40. 41. 42. 43. 44. 45. 46. 47.

48.

49.

50.

Decktor DL. RG 12915: a potent 5-hydroxytryptamine-3 antagonist that is an orally effective inhibitor of cytotoxic druginduced emesis in the ferret and dog. J Pharmacol Exp Ther 1990; 254: 450–5. Gullikson GW, Loeffler RF, Virina MA. Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. J Pharmacol Exp Ther 1991; 258: 103–10. Yoshida N, Ito T, Karasawa T, Itoh Z. AS-4370, a new gastrokinetic agent, enhances upper gastrointestinal motor activity in conscious dogs. J Pharmacol Exp Ther 1991; 257: 781–7. Gullikson GW, Virina MA, Loeffler RF, Yang DC, Goldstin B, Wang SX, Moummi C, Flynn DL, Zabrowski DL. SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism. J Pharmacol Exp Ther 1993; 264: 240–8. Wiseman LR, Faulds D. Cisapride: An updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders. Drugs 1994; 47: 116–52. Hatlebakk JG, Berstad A. Pharmacokinetic optimisation in the treatment of gastroesophageal reflux disease. Clin Pharmacokinet 1996; 31: 386–406. Alarcon de la Lastra C, Martin MJ, La Casa M, Lopez A, Motilva V. Effects of cisapride on ulcer formation and gastric secretion in rats: comparison with ranitidine and omeprazole. Gen Pharmacol 1996; 27: 1415–20. McKenna CJ, Mills JG, Goodwin C, Wood JR. Combination of ranitidine and cisapride in the treatment of reflux oesophagitis. Eur J Gastroenterol Hepatol 1995; 7: 817–22. Tytgat GN. The clinical use of cisapride in gastro-oesophageal reflux disease, with particular focus on the long-term treatment aspects. Scand J Gastroenterol Suppl 1995; 211: 39–43. Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino V, di Mario F, Battaglia G, Mela GS, Pilotto A. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995; 333: 1106–10. Brady WM, Ogorek CP. Gastroesophageal reflux disease. The long and the short of therapeutic options. Postgrad Med 1996; 100: 76–80. Corrado G, Cavaliere M, Frandina G, Rea P, Pachiarotti C, Capocaccia P, Cardi E. Primary gastro-oesophageal reflux disease and irritable oesophagus syndrome as causes of recurrent abdominal pain in children. Ital J Gastroenterol 1996; 28: 462–9. Heine RG, Gatto-Smith AG, Reddihough DS. Effect of antireflux medication on salivary drooling in children with cerebral palsy. Dev Med Child Neurol 1996; 38: 1030–6. Johnson DA. Medical therapy of GERD: current state of the art. Hosp Pract 1996; 31: 135–9. Champion MC. Prokinetic therapy in gastroesophageal reflux disease. Can J Gastroenterol 1997; (Suppl. B): 55B–65B. de Carle DJ. Gastro-oesophageal reflux disease. Med J Aust 1998; 169: 549–54. Hetzel D. Acid pump inhibitors. The treatment of gastroesophageal reflux. Aust Fam Physician 1998; 27: 487–91. Williams CN. Gastroesophageal reflux disease. Can J Gastroenterol 1998; 12: 107–8. Tytgat GN. Possibilities and shortcomings of maintenance therapy in gastroesophageal reflux disease. Dig Surg 1999; 16: 1–6. Bertaccini G, Coruzzi G. H2 -receptor antagonists: side effects and adverse effects. Ital J Gastroenterol 1984; 10: 119–25. Colas B, Sine JP, Ferrand R. Human intestinal mucosal cell cholinesterases (abstract). Proceedings of 3rd International Meeting on Cholinesterases. France: La Grande Motte, 1990: 90. Sine JP, Ferrand R, Colas B. Identification and characterization of cholinesterases in the intestine mucosal cells (abstract). Proceedings of 3rd International Meeting on Cholinesterases. France: La Grande Motte, 1990: 91. Nakayama S, Neya T, Yamasato T, Takaki M, Itano N. Effects of cisapride on the motility of digestive tract in dogs and guinea pigs. Jpn J Smooth Muscle Res 1985; 21: 1–9. Schuurkes JAJ, van Nueten JM, van Daele PGH, Reyntjens AJ, Janssen PAJ. Motor-stimulating properties of cisapride on iso-

334

51.

52.

53.

54.

Pharmacological Research, Vol. 43, No. 4, 2001 lated gastrointestinal preparations of the guinea pig. J Pharmacol Exp Ther 1985; 234: 775–83. Matthijs G, Peeters TL, Bormans V, Vantrappen G. In vitro relaxation of rabbit duodenum induced by high concentrations of cisapride. Gastroenterology 1987; 92: 1315. Schuurkes JAJ, van Bergen PJE, van Nueten JM. Cholinergic innervation of the feline esophagus (abstract). Br J Pharmacol 1989; 96: 50P. McKirdy HC, McKirdy ML, Marshall RW. Effects of cisapride on isolated muscle strips from human digestive tract. J Physiol 1990; 422: 88P. Tonini M, Galligan JJ, North RA. Effects of cisapride on

cholinergic neurotransmission and propulsive motility in the guinea pig ileum. Gastroenterology 1989; 96: 1257–64. 55. de Ridder WJE, Schuurkes JAJ. Cisapride and 5hydroxytryptamine enhance motility in the canine antrum via separate pathways, not involving 5-hydroxytryptamine1,2,3,4 receptors. J Pharmacol Exp Ther 1993; 264: 79–88. 56. Nemeth PR, Ort CS, Zafirov DH, Wood JD. Interaction between serotonin and cisapride on myenteric neurons. Eur J Pharmacol 1985; 108: 77–83. 57. Nemeth PR, Gullikson GW. Gastrointestinal motility stimulating drugs and 5-HT receptors on myenteric neurons. Eur J Pharmacol 1989; 166: 387–91.