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Journal of Digestive Diseases 2011; 12; 147–156 doi: 10.1111/j.1751-2980.2011.00491.x

Leading article
Cisapride: What can we learn from the rise and fall of
a prokinetic?
Eamonn MM QUIGLEY

Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

Cisapride, the prototype serotonergic agent, evolved leading to its widespread withdrawal from markets.
from a body of research that defined the key roles of What lessons can we learn from the story of cisapride?
serotonergic receptors in gastrointestinal motor and How can its brief but spectacular rise and equally
sensory function. Impressed by its in vitro properties sensational demise inform the development of new
and encouraged by clinical trial data, cisapride became drugs which are so sorely needed in the management
the drug of choice for the treatment of a wide range of of motility and functional gastrointestinal disorders?
motility disorders and clinicians appeared impressed This review explores the background to the develop-
by its efficacy and comfortable with its side-effect ment of cisapride, its history in clinical trials and the
profile. Once serious cardiac events began to be experience with adverse events and, in so doing,
reported in association with cisapride therapy, dark attempts to identify lessons for the future in the thera-
clouds rapidly gathered and soon enveloped the drug, peutics of enteric neuromodulatory drugs.

KEY WORDS: cisapride, gastroesophageal reflux, gastrointestinal motility, gastroparesis, prokinetic, serotonin.

Cisapride, introduced worldwide in the 1990s, is system and hyperprolactinemia-related side effects
a serotonin 5-HT4 agonist with 5-HT3 antagonist activ- of metoclopramide, the latter avoiding the bladder
ity that stimulates the release of acetylcholine from and other side effects of traditional cholinergics, such
postsynaptic neurons in the enteric nervous system. as bethanechol. Though ultimately employed in a
It therefore had quite widespread prokinetic effects wide range of motility disorders from gastroparesis
throughout the gastrointestinal tract: stimulating and pseudo-obstruction to colonic inertia, cisapride
salivary secretion, increasing esophageal peristaltic was actually approved by the Food and Drug Admin-
amplitude, augmenting lower esophageal sphincter istration (FDA) in the USA for nocturnal heartburn
pressure, enhancing gastric emptying and stimulating based on the results of pivotal clinical trials. In primary
small bowel and colonic transit. It was, however, care, cisapride soon came to be prescribed, either on its
devoid of antidopaminergic and direct cholinomi- own or in combination with a histamine H2 receptor
metic effects; the former avoiding the central nervous antagonist or a proton pump inhibitor, for a range of
upper gastrointestinal symptoms including heartburn
and dyspepsia. Its use was especially advocated for
Correspondence to: Eamonn MM QUIGLEY, Department of Medicine, children with gastroesophageal reflux disease (GERD)
Cork University Hospital, Clinical Sciences Building, Cork, Ireland.
Email: e.quigley@ucc.ie based on the premise that dysmotility was predomi-
© 2011 The Author nant in the etiology of reflux in this patient popula-
Journal of Digestive Diseases © 2011 Chinese Medical Association tion. Though trials in gastroparesis did not always
Shanghai Branch, Chinese Society of Gastroenterology, Renji
Hospital Affiliated to Shanghai Jiaotong University School of show a consistent relationship between symptom
Medicine and Blackwell Publishing Asia Pty Ltd. improvement and an enhanced gastric emptying rate,

147
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148 EMM Quigley Journal of Digestive Diseases 2011; 12; 147–156

cisapride came to be regarded as the drug of choice for metabolism of cisapride, albeit to a much lesser
the treatment of this problem among both diabetics extent.6 In human liver microsomes, cisapride was
and non-diabetics. Encouraging results from trials N-dealkylated to norcisapride and hydroxylated
in chronic idiopathic intestinal pseudo-obstruction to 3-fluoro-4-hydroxycisapride and to 4-fluoro-2-
(CIIP), a most severe form of motility disorder, rapidly hydroxycisapride. The formation of norcisapride was
led to its advocacy in this challenging condition also. 3.9-fold to 5.9-fold higher than that of the two
Indeed, with the advent of proton pump inhibitors hydroxylated metabolites.7
and the recognition of their superiority over all other
agents, including cisapride, in the management of Since cisapride is metabolized by the cytochrome
GERD, cisapride use in non-GERD areas and in dys- P450 enzyme system, it is susceptible to drug interac-
pepsia, in particular, grew as its GERD market waned. tions with drugs that are known inhibitors of this
In short, cisapride rapidly came to be regarded as the system. In one in vitro study the inhibitory effects of 44
prototype promotility or prokinetic agent. drugs were tested for any effect on cisapride biotrans-
formation; 10 were shown to inhibit the metabolism
PHARMACOKINETICS of cisapride to an extent that was likely to be of clinical
relevance: the antidepressant nefazodone, the mac-
Structurally, cisapride is a substituted piperidinyl rolide antibiotic troleandomycin, the HIV-1 protease
benzamide that interacts with 5-hydroxytryptamine-4 inhibitors ritonavir and indinavir and the calcium
receptors and that is largely without central depres- channel blocker mibefradil. It was also concluded
sant, direct cholinergic or antidopaminergic effects.1 that the antimycotics ketoconazole, miconazole,
Instead, cisapride promotes acetylcholine release from hydroxy-itraconazole, itraconazole and fluconazole,
postganglionic nerve endings in the enteric nervous when administered orally or i.v., would inhibit
system, thereby, indirectly stimulating gastrointestinal cisapride metabolism.7 On the other hand, such
motility. Animal studies revealed that cisapride was an studies suggested that it was unlikely that cisapride
agonist at type 4 serotonin (5-HT4) receptors and was would inhibit the metabolism of co-administered
an antagonist at type 3 serotonin (5-HT3) receptors; it drugs.6 Subsequent studies in humans demonstrated
is thought that the prokinetic effects of cisapride are that the repeated consumption of grapefruit juice,
due to its actions on the former. another CYP inhibitor8 could increase plasma levels of
cisapride to a clinically relevant degree.9
Following oral administration, the absolute bioavail-
ability of cisapride is about 40–50%. Peak plasma
levels occur 1–2 h after administration. Protein PHARMACODYNAMICS
binding is approximately 98%, primarily to albumin, a
Studies on gastrointestinal function in health
factor that may have contributed to the relatively low
and disease
rate of serious adverse events with cisapride. Steady
state concentrations following the administration of Over the years the effects of cisapride on many param-
20 mg b.i.d. and 10 mg q.i.d. were similar.2 The elimi- eters of gastrointestinal physiology, especially, those
nation half-life of cisapride is about 10 h in healthy relevant to motor and sensory function, were evalu-
volunteers and may be prolonged in patients with ated in both health and disease. In reviewing this
hepatic impairment or in the elderly.3 Cisapride phar- literature it is evident that, for many of these func-
macokinetics are not altered in patients with renal tions, the results were not always consistent, an obser-
impairment or in patients receiving hemodialysis.4 vation that may be explained, at least in part, by
differences in dose, duration of exposure, route of
Metabolism is extensive with no active metabolites. administration, study protocol and study population
The major in vitro metabolite of cisapride is formed (healthy volunteer vs disease, fasting vs postprandial,
by oxidative N-dealkylation at the piperidine nitro- child vs adult) between studies.
gen, leading to the production of norcisapride. This
pathway and the aromatic hydroxylation of the
4-fluorophenyl ring are the major metabolic path- Saliva
ways. In humans, 41–45% of the administered dose is
excreted in the form of norcisapride.5 Cytochrome Given the role of saliva in the final neutralization
P450 (CYP) 3A4 is the major cytochrome enzyme of refluxed acid, it should come as no surprise that
involved, though CYP2A6 also contributes to the two studies10,11 examined the effects of cisapride on

© 2011 The Author

Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to
Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.
 17512980, 2011, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2980.2011.00491.x by INASP/HINARI - INDONESIA, Wiley Online Library on [07/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Journal of Digestive Diseases 2011; 12; 147–156 Cisapride; a look back 149

salivary flow and, indeed, demonstrated increased preprandial hunger and a reduction in postprandial
flow among patients with GERD. fullness.32 In disease states, cisapride was shown to
accelerate gastric emptying in FD,35,36 postsurgical,35
diabetic19,30,35,37–40 and idiopathic gastroparesis,33,40–42
Esophageal peristalsis and clearance as well as gastric emptying delay related to anorexia
Studies in human volunteers provide conflicting nervosa,43 CIIP,36,41 critical illness44 and GERD.45 Not
results with two showing no effect12,13 and two others all studies were positive46,47 and correlations between
demonstrating an augmentation of peristaltic ampli- its effects on liquid and solid emptying or between
tude;14,15 although in one of these studies, this effect improvements in emptying rate and symptoms were
was observed with i.v., but not oral, dosing.15 Among far from perfect. Indeed, in one study in preterm
patients with GERD the impact of cisapride was again infants, cisapride was shown to delay gastric emptying
variable. Some studies demonstrated it had positive and whole gut transit.48
effects on peristalsis,14,16–18 esophageal emptying19 and
acid clearance,16,18,20–23 while others could not demon- Antroduodenal motility
strate any effect.24–26 Interestingly, in one study,
In healthy volunteers cisapride inhibited isolated
cisapride was shown to inhibit meal-stimulated acid
pyloric pressure waves,33 decreased duodenal acid
secretion and postprandial gastric acidity in GERD
exposure49 and inhibited the antral response to
patients.23
intraduodenal lipid and acid instillation.29 In FD,
cisapride was shown to increase the antral motility
LES index,50,51 decrease duodenogastric reflux50 and
enhance phase III activity;51 similar effects were seen
In healthy volunteers cisapride consistently augmented in anorexia nervosa43 and among children with CIIP
LES pressure.12–15 Most14,16,17 but not all22,25 studies in where duodenal motility was stimulated.46 Cisapride
GERD patients revealed a similar effect, with basal LES reduced duodenogastric reflux and related symptoms
pressure doubling in one study.14 Two studies exam- among post-gastrectomy52 but not Barrett’s esopha-
ined transient LES relaxations (TLESR); one noted a gus26 patients, but its effects in diabetic gastroparesis
reduction in TLESR and acid exposure during sleep,27 were inconsistent, with one study revealing no effect30
the other saw no effect of cisapride on TLESR.25 while, in another, the prevalence of antral waves
propagating over 6 cm or more was increased.33
Function of the proximal stomach
Electrogastrography
The demonstration of abnormalities in gastric tone,
compliance, accommodation and sensation among An improvement,53 or a normalization54 in abnormal
patients with functional dyspepsia (FD) led to the baseline electrogastrographic patterns was demon-
exploration of the effects of cisapride on these param- strated in two studies in FD.
eters. In one such study, cisapride was shown to
enhance accommodation and the perception of gastric Small intestinal motility and transit
distension in healthy volunteers;28 in another, no effect
In healthy volunteers,55–58 as well as in diarrhea-
on proximal gastric motor function or gastric sensation
predominant irritable bowel syndrome (IBS)
was evident.29 In one study on patients with diabetic
patients,58,59 cisapride enhanced phase II activity,
gastroparesis, cisapride was shown to increase gastric
inducing intense propagating contractions in the
tone.30
jejunum while either not affecting,12 or reducing the
frequency of activity fronts.55 In health, cisapride
Gastric emptying had no effect on the transit of liquid through the small
intestine31 but normalized transit in patients with
In healthy volunteers cisapride accelerated gastric CIIP.60
emptying of liquids31,32 and solids33 and was also
capable of reversing the delay in emptying induced by Colonic motility and transit
fat instillation into the duodenum.34 In one study
in healthy volunteers, cisapride acceleration of the In one healthy volunteer study, cisapride was shown to
oil and aqueous components of a mixed olive oil accelerate cecal emptying and enhance transit through
and soup meal was associated with an increase in the ascending and transverse, but not the descending

© 2011 The Author

Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to
Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.
 17512980, 2011, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2980.2011.00491.x by INASP/HINARI - INDONESIA, Wiley Online Library on [07/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
150 EMM Quigley Journal of Digestive Diseases 2011; 12; 147–156

colon; the net effect being an acceleration of total colon Gastroparesis

transit.61 In disease, cisapride was shown to accelerate
colon transit in idiopathic slow transit constipation62,63 1. Diabetes-related
as well as in patients with constipation related to As described in the previous section, despite many
Parkinson’s disease64 and spinal cord injury.65 While studies demonstrating the ability of cisapride to accel-
cisapride was shown to increase the motility index in erate gastric emptying, clinical responses, in terms of
the remaining colon following a left colon resection either symptoms or glycemic control, were less impres-
and anastomosis, this effect did not confer any clinical sive, emphasizing both the complexity of symptom
benefit.66 pathogenesis in diabetic gastroenteropathy and the
poor correlations that exist between the gastric empty-
Gall-bladder motility ing rate and several of the symptoms that were thought
to be indicators of gastroparesis. Thus, only some
In healthy volunteers, cisapride accelerated gall- studies of symptoms showed an improvement19,41
bladder emptying;67,68 an effect that seemed indepen- while others failed to demonstrate a response;40,90 and
dent of both a stimulation of gall bladder contractions none showed an impact on glycemic control.19,47
and levels of cholecystokinin.68
2. Idiopathic and other non-diabetic causes of
Results of clinical trials gastroparesis
Here, results were even more disappointing with two
GERD
studies failing to identify any benefit.38,40
In adults, initial studies were encouraging. Cisapride
was found to heal and produce symptomatic improve- Chronic idiopathic pseudo-obstruction and other
ment among patients with esophagitis69–73 as well as chronic intestinal dysmotility syndromes
improve symptoms among those with symptomatic
Though cisapride came to be widely used for these
heartburn,74,75 prevent the provocation of heartburn
severe motility syndromes and was regarded by
by a fatty meal in susceptible individuals76 and reduce
clinicians as a valuable addition to their therapeutic
relapse rates among those with healed esophagitis.77
armamentarium, evidence from clinical trials was less
In comparative studies, healing rates and symptomatic
convincing. In a short-term study36 and a long-term
responses were shown to be similar to cimetidine70
follow up41 among patients with CIIP, cisapride
and ranitidine71,72 and to be equivalent for cisapride in
showed little effect apart from some short-term
dosing schedules of 10 mg q.i.d. and 20 mg b.i.d.73
improvement in pain.36 In one of the larger series
Not all results were consistent, either between differ-
among 42 patients with neuropathic chronic dysmo-
ent dosing regimens or in terms of their relative
tility, the total symptom score was lower at 1 year
impact on daytime and nocturnal heartburn. The fact
among those treated with cisapride; an effect that was
that the latter was more reproducible in the pivotal US
even more obvious in patients who did not have a
studies led to the rather unusual and restrictive label-
vagal neuropathy.91,92
ing for nocturnal heartburn. Furthermore, other
studies examining both the induction of remission78
Feeding intolerance in neonates
and prevention of relapse79–81 showed unimpressive
benefits for cisapride as a monotherapy, especially Though a systematic review of three open-label studies
when compared to omeprazole.81 In children, in suggested a positive effect of cisapride on gastric
contrast to, and despite its advocacy in this patient residuals, vomiting frequency and reflux, permitting
group,16 there was no evidence of benefit when all an increase in food volume and promoting weight
studies were critically evaluated.82–85 The Cochrane gain,93 a subsequent randomized controlled trial,
reviews, indeed, drew attention to significant publica- though confirming the effect on gastric residuals and
tion bias in the reporting of trials of cisapride among regurgitation, failed to demonstrate any benefit in
children with GERD.84,85 terms of feeding tolerance.94

FD Ileus
FD has proven to be an evasive target for prokinetics, Two studies in adults failed to demonstrate a clinically
cisapride being no exception, with three out of four significant benefit;66,95 rectal administration to neo-
studies demonstrating no significant benefit.86–89 nates accelerated bowel recovery following surgery.96

© 2011 The Author

Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to
Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.
 17512980, 2011, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2980.2011.00491.x by INASP/HINARI - INDONESIA, Wiley Online Library on [07/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Journal of Digestive Diseases 2011; 12; 147–156 Cisapride; a look back 151

IBS piratory failure, renal failure, hypokalemia or hypo-

magnesemia. Other instances were associated with
Reflecting its effects on small intestinal and colonic the co-administration of drugs or foods, such as grape-
motility described above, cisapride was found to fruit juice,104 that either inhibited hepatic CYP3A4
improve constipation-related symptoms in those with (such as fluconazole, itraconozole, ketoconazole,
constipation-predominant IBS but exacerbated pain erythromycin, clarithromycin, ritonavir, indinavir and
in those with the diarrhea-predominant variety.59 nefazodone) and thus resulted in high plasma levels
of cisapride or that also resulted in QT prolongation,
Chronic constipation as listed above.

Though relatively few studies are available to assess Subsequently, the cellular and molecular basis for
the response to cisapride in constipation, two studies cisapride’s arrhythmogenic potential was revealed. In
among adults63,97 and one in children98 did demon- in vitro studies cisapride was found to be a potent and
strate symptomatic responses. For example, in one dose-dependent blocker of the human ether-a-go-go-
study of adults, a 48% overall response rate was related gene (HERG) channel,105 which is the main
documented.63 channel responsible for the repolarization phase of
the cardiac action potential.106 HERG blockade pro-
SAFETY longs the duration of the action potential by delaying
the repolarization phase; mutations in HERG result in
Initial experience with cisapride, including post- the congenital prolongation of the QT interval.107
marketing data from two study groups totaling over Other studies suggested that it was not QT prolonga-
23 000 patients, suggested that the drug was remark- tion per se but rather the increase in dispersion
ably safe with diarrhea (incidence 4.1%), abdominal of repolarization, which usually accompanies QT
pain (1.6%), nausea or vomiting (1.5%), headache prolongation, that provides the arrhythmogenic
(1.4%) and constipation (1.2%) being the most fre- substrate.108
quently reported adverse events.99 In a review of
almost 37 000 patients who were prescribed cisapride Though some studies suggested that cisapride had
in the UK and Canada, serious cardiac rhythm disor- a low arrhythmogenic potential among neonates
ders were not found to be inordinately associated regardless of gestational age,109 others drew attention
with cisapride use.100 In children without underlying to the low levels of CYP3A4 in the neonatal liver110
cardiac disease or electrolyte imbalance, cisapride was and the consequent effects of this on cisapride
found to have no significant effect on cardiac electrical metabolism. The clinical implications of the latter
function101 and a meta-analysis of randomized con- were confirmed in a pharmacokinetic study in prema-
trolled clinical trials among children with GERD ture infants that demonstrated increased serum con-
also failed to reveal a problem with serious adverse centrations of cisapride and parallel prolongations of
events.83 the QT interval in premature infants.111

However, reports of cardiac events began to accumu- Unfortunately, around the same time, the prokinetic
late, beginning with a report of palpitations102 and properties of erythromycin had begun to be widely
culminating in instances of an unusual tachyarrhyth- appreciated and its co-administration with cisapride,
mia, torsades de pointes, ventricular fibrillation and or the sequential use of i.v. erythromycin and oral
sudden death.103 It soon came to be recognized that cisapride, was not uncommon. Others at risk were
cisapride use could result in the prolongation of those with a congenital prolongation of the QT inter-
the QT interval and, thereby, increase the risk of val, a family history of the long QT syndrome or those
arrhythmia, a phenomenon well described in associa- with significant bradycardia.
tion with a number of other drugs, most notably
quinidine, but including procainamide, sotalol, As large surveys in adults, children and neonates had
amiodarone, disopyramide, macrolide antibiotics, indicated that such events were rare80,96–99 and as it
astemizole, terfenadine, phenothiazines and tricyclic seemed that the risks could be managed by an appro-
antidepressants. It also became clear that the likeli- priate awareness program, the initial response to these
hood of arrhythmia in association with cisapride use reports was a risk management program emphasizing
was greater among those with serious underlying the identification of those at risk, as well as drugs
disease states such as heart disease, heart failure, res- that should not be co-administered with cisapride.

© 2011 The Author

Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to
Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.
 17512980, 2011, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2980.2011.00491.x by INASP/HINARI - INDONESIA, Wiley Online Library on [07/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
152 EMM Quigley Journal of Digestive Diseases 2011; 12; 147–156

Accordingly, in 1995, a black box warning contraindi- hindsight it is easy to see that the wrong indication
cating the use of cisapride among those taking drugs was chosen as the initial therapeutic target and studies
that affected its metabolism was issued by the FDA; in clinical conditions where the drug could have
at that time 34 cases of torsades de pointes, 23 of proven more valuable, though encouraging, never
prolonged QT interval and four deaths had been achieved the level of quality that would, nowadays, be
reported.103 A further warning was issued in 1996 in demanded prior to acceptance.
relation to its use with medications that also pro-
longed the QT interval and in conditions that predis- While the true prevalence of serious and fatal adverse
posed to cardiac arrhythmias and the black box was effects directly attributable to cisapride will never be
expanded in 1998. However, the subsequent realiza- known and will remain the province of lawyers rather
tion that serious adverse cardiac events could occur than clinicians or scientists, the experience with
among low-risk groups, including children, coupled cisapride does illustrate the problems that can arise
with the documentation of continued cisapride use in with less than ‘squeaky clean’ drugs when used widely
contraindicated situations112 led to the withdrawal of among a very diverse patient group. As the knowledge
the drug worldwide in July 2000. of the metabolism and interactions of this drug
became more widely appreciated and as the genomics
WHAT ARE THE LESSONS? of the QT interval were revealed, new and important
pharmacological principles to be applied henceforth
There is much to be learned from this story of with this class of drugs (that is, prokinetics) emerged
cisapride and, indeed, drug development in this and have come to be enshrined in regulatory pro-
area has been substantially altered in response. For cesses. For those of us who were in clinical practice
example, extensive testing, both in vitro and in vivo, for at the time and were involved in the management
the potential to induce QT prolongation is now a of these challenging patients, the cisapride episode,
fundamental prerequisite. which swung so dramatically from real hope to pro-
found despair, was a painful one. While some might
The cisapride episode illustrates vividly a number of argue that the legal and regulatory fallout from
challenges that characterize the fields of motility and cisapride has generated an atmosphere of overzealous
functional gastrointestinal disorders. Most of these caution, some important lessons have been learned:
disorders are heterogeneous and encompass a broad
spectrum of ailments across a range of patient charac- 1. Choose indications based on science and consis-
teristics: ‘clean’ patient groups are difficult to come tent, high-quality preclinical and Phase I and II
by. Some of these disorders (such as GERD) are data, not on market potential. In parallel, identify
very common; others, such as idiopathic pseudo- real clinical needs that may be uniquely addressed
obstruction, very rare; thus the attractiveness, both in by a new compound. A niche may not be so bad
terms of feasibility of study and the market potential, in the long term.
of studying the former rather than the latter. In retro-
spect, it is clear that cisapride had limited appeal in 2. Be wary of heterogeneous populations, as typified
the GERD arena, especially following the widespread by functional disorders such as dyspepsia. Choose
availability of proton pump inhibitors. Not only were a well-defined clinical entity (or subgroup);
the latter more effective than cisapride in GERD but, ideally one that possesses a validated biomarker:
once reports of serious side effects allegedly related to nocturnal heartburn scarcely fulfilled these
cisapride began to emerge, its risk benefit ratio was criteria.
consequently and dramatically skewed in the wrong
direction. Pseudo-obstruction, in contrast, represents 3. The threshold for rejection of a new compound
a potentially life-threatening and seriously incapaci- in the treatment of what are perceived to be non-
tating illness with few therapeutic alternatives. Here, life threatening gastrointestinal disorders (for
if the drug had been shown unequivocally to be example, FD and IBS) on the basis of any but the
beneficial, a greater risk might have been acceptable. mildest adverse events is now set very low indeed.
Once one strayed into more ‘organic’ diseases such Success or failure is here, as elsewhere, a benefit–
as the aforementioned pseudo-obstruction or diabetic risk equation: in a life-threatening situation, con-
gastroenteropathy, however, rates of comorbidity siderable risk may be acceptable and accepted
(including cardiac disease) and polypharmacy even if the benefits are modest; in benign,
increased and, accordingly, toxicity was more likely. In functional disorders, in contrast, one needs

© 2011 The Author

Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to
Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.
 17512980, 2011, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2980.2011.00491.x by INASP/HINARI - INDONESIA, Wiley Online Library on [07/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Journal of Digestive Diseases 2011; 12; 147–156 Cisapride; a look back 153

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are prescribed to all and sundry. It is the obliga-
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Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.