Cisapride

Cisapride(R 51619) is a nonselective 5-HT4 receptor agonist, it is also a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor.

Cisapride, a selective serotonin 5-HT4-receptor agonist, inhibits voltage-dependent K(+) channels in rabbit coronary arterial smooth muscle cells.[Pubmed:27569285]

Biochem Biophys Res Commun. 2016 Sep 23;478(3):1423-8.

We investigated the effect of Cisapride, a selective serotonin 5-HT4-receptor agonist, on voltage-dependent K(+) (Kv) channels using freshly isolated smooth muscle cells from the coronary arteries of rabbits. The amplitude of Kv currents was reduced by Cisapride in a concentration-dependent manner, with an IC50 value of 6.77 +/- 6.01 muM and a Hill coefficient of 0.51 +/- 0.18. The application of Cisapride shifted the steady-state inactivation curve toward a more negative potential, but had no significant effect on the steady-state activation curve. This suggested that Cisapride inhibited the Kv channel in a closed state by changing the voltage sensitivity of Kv channels. The application of another selective serotonin 5-HT4-receptor agonist, prucalopride, did not affect the basal Kv current and did not alter the inhibitory effect of Cisapride on Kv channels. From these results, we concluded that Cisapride inhibited vascular Kv current in a concentration-dependent manner by shifting the steady-state inactivation curve, independent of its own function as a selective serotonin 5-HT4-receptor agonist.

Prokinetics prescribing in paediatrics: evidence on cisapride, domperidone, and metoclopramide.[Pubmed:25825854]

J Pediatr Gastroenterol Nutr. 2015 Apr;60(4):508-14.

OBJECTIVES: Domperidone and metoclopramide are prokinetics commonly prescribed off-label to infants and younger children in an attempt to treat gastro-oesophageal reflux symptoms. Another prokinetic drug, Cisapride, was used but withdrawn in 2000 in the United Kingdom because of serious arrhythmic adverse events. Medicines and Healthcare Products Regulatory Agency issued safety warnings for domperidone in May 2012 and restricted its indications. We report here national primary care prescribing trends and safety signals of these drugs in children. METHODS: We used data from the General Practice Research Database between 1990 and 2006 for children <18 years. Descriptive statistics and Poisson regressions were performed to characterise prescribing trends. We examined safety signals in nested case-control studies. RESULTS: The proportion of children <2 years old being prescribed one of the medications doubled during the study period. Prescriptions of domperidone increased 10-fold, mainly following the withdrawal of Cisapride in 2000. Prescriptions of metoclopramide did not change significantly. Despite the increase in prescriptions of domperidone, no new safety signals were identified. CONCLUSIONS: These data showed dramatic changes in prescribing of Cisapride and domperidone despite the lack of good-quality supporting evidence. It is possible that these prescribing trends were influenced by published guidelines. Even if produced without robust efficacy and safety evidence, published guidelines can influence clinicians and consequently affect prescribing. Therefore, improving the evidence base on prokinetics to inform future guidelines is vital. The lack of new safety signals during this period would support the development of suitable powered clinical studies.

Electroacupuncture at ST25 Inhibits Cisapride-Induced Gastric Motility in an Intensity-Dependent Manner.[Pubmed:26997963]

Evid Based Complement Alternat Med. 2016;2016:3457025.

Background. Previous studies have demonstrated the efficacy of frequency-specific EAS. However, evaluation of intensity-response effects is challenging and has yet to be addressed. Aims. Using Cisapride to promote gastric emptying, we measured the intensity-response relationship of EA at ST25 on gastric motility. Methods. We determined the effects of EA at ST25 using intensities (0.5, 1, 3, 5, 7, and 9 mA) on gastric motility in rats injected with Cisapride (0.2, 0.02, and 0.002 mg/kg). Results. Utilizing three concentrations of Cisapride yielded significantly differing levels of gastric motility. Furthermore, log IC50 values for EAS were different within each group. Given the same EA intensity, Cisapride antagonism decreased progressively in each group as a function of drug concentration. The relative amount of Cisapride antagonized by EAS did not change in a linear fashion. Finally, EAS at different intensities within the three groups induced a similar pattern of Cisapride antagonism. Conclusions. The ability of EAS to elicit a decrease in Cisapride-induced gastric motility pressure was demonstrated in this study. The study encompasses construct validity to mirror individualized treatment being based on patients' subjective feelings, not on a set fixed EA intensity. Clinically utilizing EAS at the smallest intensity can achieve the desired therapeutic effect.

High-resolution manometric evaluation of the effects of cisapride on the esophagus during administration of solid and liquid boluses in awake healthy dogs.[Pubmed:27463544]

Am J Vet Res. 2016 Aug;77(8):818-27.

OBJECTIVE To validate the use of high-resolution manometry (HRM) in awake, healthy dogs and compare the effects of bolus type (liquid vs solid) and drug treatment (saline [0.9% NaCl] solution [SS] vs Cisapride) on esophageal pressure profiles. ANIMALS 8 healthy dogs. PROCEDURES In a crossover study, each dog received SS (10 mL) IV, and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of SS) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of SS and water and food boluses in 4 dogs. Pressure profile data were obtained for all swallows, and 11 outcome variables were statistically analyzed. RESULTS After SS administration, predicted means for the esophageal contractile integral were 850.4 cm/mm Hg/s for food boluses and 660.3 cm/mm Hg/s for water boluses. Predicted means for esophageal contraction front velocity were 6.2 cm/s for water boluses and 5.6 cm/s for food boluses after SS administration. Predicted means for residual LES pressure were significantly higher following Cisapride administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM was feasible and repeatable in awake healthy dogs of various breeds and sizes. Stronger esophageal contractions and faster esophageal contraction velocity occurred during solid bolus and liquid bolus swallows, respectively. Lower esophageal sphincter pressure increased significantly following Cisapride administration. Esophageal contractions and bolus transit latency should be further evaluated by HRM in clinically dysphagic dogs.

Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens.[Pubmed:8321323]

Naunyn Schmiedebergs Arch Pharmacol. 1993 May;347(5):464-70.

UNLABELLED: The purpose of this study was to investigate whether the effects of Cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both Cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (Cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to Cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to Cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to Cisapride, and abolished those to R 76,186. The contractions to Cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves. CONCLUSIONS: Both Cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though Cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist.

Cisapride stimulates motility of the intestine via the 5-hydroxytryptamine receptors.[Pubmed:1890614]

J Pharmacol Exp Ther. 1991 Sep;258(3):1098-104.

The effects of Cisapride on intestinal contractility and on release of acetylcholine (ACh) were examined using the longitudinal muscle with the myenteric plexus preparation from the guinea pig ileum, as related to the 5-hydoxytryptamine (5-HT) receptor. 5-HT exerted a dual effect, transient increase in ACh release (EC50 = 2 X 10(-6)M) via the 5-HT3 receptor, followed by inhibition (EC50 = 5 X 10(-9)M) via the 5-HT1 receptor. Cisapride at low concentrations (10(-9)M to 10(-8)M) enhanced electrical stimulation -evoked contraction and ACh release. The effect of Cisapride was mimicked by methysergide and was not altered by ICS 205-930. Cisapride antagonized the 5-HT (5 X 10(-9) M)-induced inhibitory effect and the IC50 of Cisapride was 1.5 X 10(-9) M. These findings indicate that enhancement by low concentrations of Cisapride may be due to a block of the inhibitory 5-HT1 receptor. Cisapride at medium concentrations (10(-8) M to 3 X 10(-7) M) induced enhancement of electrical stimulation-evoked twitch contractions and ACh release evoked by electrical stimulation which were antagonized by 10(-6) M ICS 205-930, while this compound antagonized the 5-HT (2 X 10(-6) M)-and 2-methyl-5-HT-induced excitatory effects, and the IC50 of Cisapride was 5.2 X 10(-8) M. Thus, Cisapride acts on the putative 5-HT4 receptor as an agonist and the 5-HT3 receptor as an antagonist. Cisapride at high concentrations (10(-6) M to 10(-5) M) evoked contraction and the release of ACh, and these effects were antagonized by ICS 205-930 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Motor-stimulating properties of cisapride on isolated gastrointestinal preparations of the guinea pig.[Pubmed:3897516]

J Pharmacol Exp Ther. 1985 Sep;234(3):775-83.

The effects of Cisapride (R 51619), a new non-dopamine-blocking gastrokinetic drug, on gastrointestinal contractility have been determined on isolated preparations of the guinea pig. On the intact gastroduodenal preparation, Cisapride enhanced contractile amplitude (3.4 X 10(-7) M), improved antroduodenal coordination (EC50 = 1.9 X 10(-7) M) and antagonized gastric relaxation induced by phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine (in the presence of atropine) and periarterial nerve stimulation (IC50 range, 9.1 X 10(-7)-2.4 X 10(-6) M). Experiments with metoclopramide yielded similar results on amplitude, coordination and dopamine-induced relaxation at 5 X 10(-5), 2.2 X 10(-5) and 1.7 X 10(-5) M, respectively. On the ileum, Cisapride enhanced the contractile response to electrical stimulation at low concentrations (EC50 = 9.2 X 10(-9) M) as compared with metoclopramide (EC50 = 3.3 X 10(-6) M). On this preparation, Cisapride showed no direct cholinergic or nicotine-like effects and did not enhance the response to methacholine (indicative of a lack of inhibition of acetylcholinesterase-activity and of sensitization of the muscarine receptor). On the colon ascendens, Cisapride induced contractions (EC50 = 3.5 X 10(-8) M) (metoclopramide, 3.5 X 10(-6) M), insensitive to atropine and only marginally inhibited by tetrodotoxin. In conclusion, Cisapride effectively improves spontaneous or electrically evoked contractions of isolated preparations of the guinea pig, most likely via facilitation of the release of acetylcholine. However, the inhibition of gastric relaxation and the induction of colonic contractions in the presence of atropine indicate that, besides cholinergic neuronal pathways, other mechanisms are involved in the motor-stimulating properties of Cisapride.