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Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT₄ receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. It has been sold under the trade names Prepulsid (Janssen-Ortho) and Propulsid (in the U.S.). It was discovered by Janssen Pharmaceutica in 1980. In many countries, it has been either withdrawn from the market or had its indications limited because of side-effects.

The commercial preparations of this drug are the racemic mixture of both enantiomers of the compound. The (+) enantiomer itself has the major pharmacologic effects and does not induce many of the detrimental side-effects of the mixture.^[1]

Medical uses

Cisapride has been used for the treatment of gastroesophageal reflux disease (GERD). There is no evidence it is effective for this use in children.^[2] It also increases gastric emptying in people with diabetic gastroparesis. Evidence for its use in constipation is not clear.^[3]

In many countries, it has been either withdrawn or had its indications limited because of reports of the side-effect long QT syndrome, which may cause arrhythmias. The U.S. Food and Drug Administration (FDA) issued a warning letter to doctors,^[4] and cisapride was voluntarily removed from the U.S. market on July 14, 2000. Its use in Europe has also been limited.^[2] It was banned in India and in the Philippines on 2011.^[5]

Veterinary uses

Cisapride is still available in the United States and Canada for use in animals, and is commonly prescribed by veterinarians to treat megacolon in cats.

Cisapride is also commonly used to treat GI stasis in rabbits, sometimes in conjunction with metoclopramide (Reglan).

Kinetics

Oral bioavailability of cisapride is approximately 33%. It is inactivated primarily by hepatic metabolism by CYP3A4 with a half-life of 10 hours. The dose of the drug should be reduced in case of liver diseases.^[6]

Pharmacology and mechanism of action

As a prokinetic agent that increases gastrointestinal motility, cisapride acts as a selective serotonin agonist in the 5-HT 4 receptor subtype. Cisapride also relieves constipation-like symptoms by indirectly stimulating the release of acetylcholine in the muscarinic receptors.

References

^ US patent 5955478, Nancy M. Gray, N. M.; Young, J. W, "Methods for treating gastrointestinal motility dysfunction using optically pre (+) cisapride", issued 1999-Sep-21
^ ^a ^b Maclennan, S; Augood, C; Cash-Gibson, L; Logan, S; Gilbert, RE (Apr 14, 2010). "Cisapride treatment for gastro-oesophageal reflux in children.". The Cochrane database of systematic reviews (4): CD002300. doi:10.1002/14651858.CD002300.pub2. PMID 20393933.
^ Aboumarzouk, OM; Agarwal, T; Antakia, R; Shariff, U; Nelson, RL (Jan 19, 2011). "Cisapride for intestinal constipation.". The Cochrane database of systematic reviews (1): CD007780. doi:10.1002/14651858.CD007780.pub2. PMID 21249695.
^ "Propulsid (cisapride) Safety Information". Retrieved 2011-07-14.
^ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Retrieved 2013-09-17.
^ "Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers" European Journal of Clinical Pharmacology T Hedner et al. Volume 38, Number 6, 629-631, doi:10.1007/BF00278595

Sources

Brenner, G. M. (2000). Pharmacology. Philadelphia, PA: W.B. Saunders Company. ISBN 0-7216-7757-6
Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and Specialties (25th ed.). Toronto, ON: Webcom. ISBN 0-919115-76-4
Medline Plus

External links

Archived Drug Label

UpToDate Contents

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1. 胃不全麻痺の治療 treatment of gastroparesis
2. 慢性偽性腸閉塞 chronic intestinal pseudo obstruction
3. 後天性ＱＴ延長症候群 acquired long qt syndrome
4. 全身性硬化症（強皮症）における消化管疾患の治療 treatment of gastrointestinal disease in systemic sclerosis scleroderma
5. 悪性腫瘍関連胃不全麻痺：病態生理およびマネージメント malignancy associated gastroparesis pathophysiology and management

English Journal

Impact of safety-related regulatory action on clinical practice: a systematic review.

Piening S, Haaijer-Ruskamp FM, de Vries JT, van der Elst ME, de Graeff PA, Straus SM, Mol PG.SourceDepartment of Clinical Pharmacology, University Medical Center Groningen, Groningen, the Netherlands. s.piening@umcg.nl
Drug safety : an international journal of medical toxicology and drug experience.Drug Saf.2012 May 1;35(5):373-85. doi: 10.2165/11599100-000000000-00000.
BACKGROUND: After market approval, new serious safety issues are regularly identified for drugs that lead to regulatory action to inform healthcare professionals. However, the effectiveness of these safety-related regulatory actions is under question. We currently lack a comprehensive overview of th
PMID 22480319

Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG.

Jonsson MK, Vos MA, Mirams GR, Duker G, Sartipy P, de Boer TP, van Veen TA.SourceDepartment of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. m.k.b.jonsson@umcutrecht.nl
Journal of molecular and cellular cardiology.J Mol Cell Cardiol.2012 May;52(5):998-1008. Epub 2012 Feb 14.
Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing, and mechanistic explanations, of their overall pro-arrhythmic ability is lacking. Under standar
PMID 22353256

Japanese Journal

Decreased Motility of the Lower Esophageal Sphincter in a Rat Model of Gastroesophageal Reflux Disease May Be Mediated by Reductions of Serotonin and Acetylcholine Signaling

Saegusa Yayoi,Takeda Hiroshi,Muto Shuichi,Oridate Nobuhiko,Nakagawa Koji,Sadakane Chiharu,Nahata Miwa,Harada Yumi,Iizuka Mizuki,Hattori Tomohisa,Asaka Masahiro
Biological & Pharmaceutical Bulletin 34(5), 704-711, 2011
… The in vivo motility proximal to LES (% motility index) in conscious rats was decreased by atropine treatment and increased by cisapride (5-HT4 receptor agonist) treatment. … Intraperitoneal administration of cisapride improves the erosive damage in the esophagus in GERD rats. …
NAID 130000657784

Cisapride

佐藤嗣道,久保田潔
臨床薬理 = Japanese journal of clinical pharmacology 40(1), 47-52, 2009-01-31
NAID 10026157493

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「シサプリド」

Cisapride
Systematic (IUPAC) name
	(±)-cis-4-amino-5-chloro-N-(1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl)-2-methoxybenzamide
Clinical data
Trade names	Prepulsid, Propulsid
AHFS/Drugs.com	FDA Professional Drug Information
MedlinePlus	a694006
Pregnancy; category	AU: B1;
Legal status	AU: Prescription Only (S4); UK: POM; US: Withdrawn;
Routes	oral (tablets), suspension
Pharmacokinetic data
Bioavailability	30-40%
Protein binding	97.5%
Metabolism	hepatic CYP3A4, intestinal
Half-life	10 hours
Excretion	renal, biliary
Identifiers
CAS number	81098-60-4
ATC code	A03FA02
PubChem	CID 2769
IUPHAR ligand	240
DrugBank	DB00604
ChemSpider	2667
UNII	UVL329170W
KEGG	D00274
ChEMBL	CHEMBL1729
Chemical data
Formula	C23H29ClFN3O4
Molecular mass	465.945 g/mol
	SMILES Clc1cc(c(OC)cc1N)C(=O)NC3CCN(CCCOc2ccc(F)cc2)CC3OC;
	InChI InChI=1S/C23H29ClFN3O4/c1-30-21-13-19(26)18(24)12-17(21)23(29)27-20-8-10-28(14-22(20)31-2)9-3-11-32-16-6-4-15(25)5-7-16/h4-7,12-13,20,22H,3,8-11,14,26H2,1-2H3,(H,27,29) ; Key:DCSUBABJRXZOMT-UHFFFAOYSA-N ;
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英: cisapride
商: アセナリン、リサモール、Propulsid

副作用により販売停止となっている

CYP3A4で代謝を受けるために、これを阻害する薬物との併用でQT延長を引き起こしうる

[1] US patent 5955478, Nancy M. Gray, N. M.; Young, J. W, "Methods for treating gastrointestinal motility dysfunction using optically pre (+) cisapride", issued 1999-Sep-21

[GERD2010-2] Maclennan, S; Augood, C; Cash-Gibson, L; Logan, S; Gilbert, RE (Apr 14, 2010). "Cisapride treatment for gastro-oesophageal reflux in children.". The Cochrane database of systematic reviews (4): CD002300. doi:10.1002/14651858.CD002300.pub2. PMID 20393933.

[Cochrane2011-3] Aboumarzouk, OM; Agarwal, T; Antakia, R; Shariff, U; Nelson, RL (Jan 19, 2011). "Cisapride for intestinal constipation.". The Cochrane database of systematic reviews (1): CD007780. doi:10.1002/14651858.CD007780.pub2. PMID 21249695.

[urlFDA_UPDATES_WARNINGS_FOR_CISAPRIDE-4] "Propulsid (cisapride) Safety Information". Retrieved 2011-07-14.

[ban-5] "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Retrieved 2013-09-17.

[6] "Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers" European Journal of Clinical Pharmacology T Hedner et al. Volume 38, Number 6, 629-631, doi:10.1007/BF00278595

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cisapride