Download Effects on upper gastrointestinal motility

DRUGS OF TODAY Vol. 25, No. 2, 1989, pp. 101-113
DRUGS FOR UPPER DIGESTIVE MOTILITY DISORDERS
M. Guslandi
Gastrointestinal Unit, Institute of Internal Medicine, University of Milan, Via Pace 9, 20122 Milan, Italy
CONTENTS
Introduction ...............................................................................................
Metoclopramide ........................................................................................
Clebopride .................................................................................................
Domperidone .............................................................................................
Cisapride ...................................................................................................
References ................................................................................................
Introduction
Motor abnormalities are responsible for various
disorders of the upper digestive tract. Gastroesophageal reflux and consequent reflux esophagitis
are related to incompetence of the lower esophageal
sphincter, impaired esophageal clearance of acid due
to defective esophageal contractions and delayed
emptying of gastric juice from the stomach. Gastric
stasis, either secondary to diabetes or idiopathic,
causes painful and disturbed digestion, feeling of fullness, anorexia, etc., and can promote, in the long
run development of chronic gastritis and/or gastric
ulcer. Functional dyspepsia is a very common form
of non-ulcer dyspepsia where mucosal alterations
cannot be detected during endoscopy, while a
reduced gastric emptying rate plays a major pathogenetic role. Duodenogastric bile reflux may occur
because of impaired antroduodenal coordination and
pyloric incompetence. Hence, dyspeptic symptoms
can develop even before reflux gastritis becomes
microscopically evident. The pharmacological treatment of the motor disorders of the upper gastrointestinal tract is carried out by means of centrally
or peripherally acting drugs which are generally
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known to physicians more for their concomitant
anti-emetic properties than for their basic prokinetic
effects.
Metoclopramide
Metoclopramide (or methoxychloroprocainamide)
[I] is a substituted benzamide (or orthopramide) with
antidopaminergic and cholinergic effects. The drug
is known to exert anti-ometic activity against nausea
and vomiting induced by apomorphine, hydergine,
reserpine, copper sulfate, tetrodotoxin, digitalis, antibiotics, narcotics, analgesics, anesthetics and antineoplastic agents (e.g. cisplatin), as well as against
vomiting associated with radiation therapy or pregnancy (1,2). The anti-emetic properties of metoclopramide appear to be mainly related to a blockade
102
of dcpamine (D2) receptors in the chemoreceptor
trigger zone at the CNS level, but its gastrokinetic
activity also contributes to suppress nausea and
vomiting.
Effects on upper gastrointestinal motility
Metoclopramide influences various aspects of the
motility of the upper digestive tract. The pressure in
the lower esophageal sphincter is increased after
intravenous or oral administration of the drug (3,4),
the magnitude of the effect being dose-dependent,
directly proportional to the basal pressure levels and
more marked by the intravenous route (3-5). Conflicting results are reported on the influence of
metoclopramide on the peristaltic contractions in the
bodv of the esophagus (6,7). Metoclopramide stimulates gastric contractions, especially in the antrum,
both in normal subjects and in patients with reflux
esophagitis (8), vagotomy or other gastrointestinal
surgery (9,10), and in diabetics without clinical signs
ot delayed gastric emptying (11). No significant effects on antral contractions were observed in patients with clinically evident diabetic gastroparesis
(10,11). On the other hand, in diabetic gastroparesis, as well as in vagotomized patients and in
subjects with anorexia nervosa or other causes of
gastric stasis, metoclopramide (either oral or
parenteral) was found to increase the rate of gastric
emptying of both solids and liquids (9,12-17).
The drug is also thought to synchronize antroduodenal contractile activity and to induce pyloric
relaxation (18), but the latter effect is still controversial. The above properties of metoclopramide are
partially to be ascribed to its antagonist activity
against dopamine, which in the gastrointestinal tract
acts as an inhibitory neurotransmitter. In fact,
levodopa suppresses metoclcpramide-induced stimulation of the lower esophagoal sphincter (3,19),
while metoclopramide antagonizes the delaying effect of levodopa and apomorphine on gastric emptying (20,21). The effects of the drug on gastrointestinal motility, however, cannot be merely explained by its antidopaminergic properties, but also
rely upon a cholinergic activity.
The influence of metoclopramide on gastric emptying is not abolished by vagotomy (10,22), but is suppressed by atropine (11,23), suggesting that the activity of this prokinetic agent depends on intramural
cholinergic neurons and requires intrinsic stores of
acetylcholine (18,24). Metoclopramide can induce
acetylcholine release, sensitize muscarinic receptors
of gastrointestinal smooth muscle to acetylcholine
or facilitate cholinergic activity by means of other,
unidentified mechanisms (24,25).
MEDICAMENTOSA DE ACTUALIDAD
Clinical use
When orally administered to adults, metoclopnmide io usually employed in doses of 10 mg 3 or
4 times daily (before meals and at bedtime). In
children the dosage is 0.1 mg/kg per dose, the total
daily amount not to exceed 0.5 mg/kg. Absorption
after oral administration is rapid, with peak plasma
concentrations within 40-120 minutes, and the halflife in humans is about 4 hours. About 80% of the
dose is excreted in the urine unchanged or conjugated to sulfate or glucuronide. Parenteral administration of metoclopramide 10-20 mg can be
employed to treat upper digestive motility disorders.
Higher doses are required for other indications (e.g.
prevention and treatment of vomiting associatad
with anticancer chemotherapy).
1. Reflux esophagitis
When compared to placebo, metoclopramide 3040 mg daily for 6-8 weeks provided inconsistent
results as regards relief of symptoms of gastroesophageal reflux (Table I). Endoscopic assessment
of drug efficacy was performed only in one study
(26). Metoclopramide was found to be not significantly better than placebo in improving endoscopic
esophagitis, but the same applied to cimetidine
which also was included in this comparative trial.
The two drugs, however, were significantly (and
equally) superior to placebo in inducing symptomatic
relief.
In a randomized, single-blind study including 45
patients metoclopramide 10 mg t.i.d. was compared
with ranitidine 150 mg b.i.d. (27). After 6 weeks
of therapy, a significant (p < 0.01) and statistically similar improvement of dyspeptic symptoms was
observed. The severity of endoscop:c features was
significantly reduced (p < 0.01) by both drugs, but
ranitidine proved to be more effective (p < 0.05).
Histological improvement was achieved with ranitidine (p < 0.01), whereas non-significant changes
were found with metoclopramide.
In a recent double blind trial (28) metoclopramide plus Gaviscon® (alginate + artacid) or ranitidine was administered for 6 weeks to 53 patients
with reflux esophagitis. No significant differences
between the two treatments were observed as for
clinical, endoscopic and histological results.
2. Functional dyspepsia
Early trials versus placebo indicated that
metoclopramide can be effective in alleviating
dyspeptic symptoms in subjects with no evidence
of organic gastroduodenal disorders (1).
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DRUGS OF TODAY Vol. 25, No. 2, 1989
Table I: Prokinetic drugs in the treatment of reflux esophagitis. Studies versus placebo.
* = Randomized, not double-blind
NS = Statistically not significant
More recently, a multicenter, randomized, crossover trial carried out in the UK by general practitioners compared the symptomatic effect of a
4 week course with either metoclopramide (10 mg
t.i.d.) or two different antacid preparations (29). In
the 69 patients who completed the study a significant improvement was found both with metoclopramide and with antacids as regards most of the
dyspeptic symptoms (heartburn, belching, epigastric
pain, etc.). As expected, symptoms such as vomiting and inability to finish meals were significantly
suppressed by meclopramide (p < 0.01), but not
by antacids.
Direct comparisons with other, more recent prokinetic agents showed a substantial equivalence between metoclopramide and clebopride and between
metoclqpramide and cisapride (Table II). When compared with domperidone, the clinical efficacy of
metoclopramide was superior, equal or inferior according to the different investigators (Table II).
3. Delayed gastric emptying
As already mentioned, metoclopramide has been
employed to accelerate gastric emptying and reduce
symptoms of gastric stasis (early satiety, bloating,
nausea, vomiting and anorexia) in patients with
Table //: Prokinetic drugs in the treatment of fur,ctional dyspepsia. Double-blind comparative trials.
MET = Metoclopramide; DOM = domperidone; CLE = clebopride; CIS = Cisapride
Significantly superior; < significantly inferior
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gastroparesis of various nature. Most studies included insufficient number of subjects to permit accurate
evaluation of the data or have appeared only in
abstract form. However, double-blind trials versus
placebo showed a significantly greater improvement
of symptoms with metoclopramide both in diabetic
gastroparesis and in idiopathic or postsurgical gastric
stasis (15, 30-33). A concomitant improvement in
gastric emptying time was observed in postoperative conditions (15,30,32,33), whereas in diabetic
subjects some studies failed to detect any changes
in the rate of gastric evacuation (30,33).
Safety and side-effects
When metoclopramide is given in the usual
therapeutic doses (30-40 mg daily), adverse effects
occur in about 10-20% of cases (1,30). Drowsiness
has been reported in 10% or so of treated patients,
and for this reason concomitant administration of
sedative drugs is to be avoided.
Motor restlessness (akathisia), as well as other extrapyramidal reactions (trismus, facial spasms,
ophistthotone, etc.) can occur in up to 9% of cases,
especially in young subjects and in children, and
generally shortly after the beginning of therapy.
These reactions disappear within 24 hours after the
drug is discontinued. On the other hand, long-term
treatment with metoclopramide in older patients
may occassionally induce transient parkinsonism or,
more rarely, tardive and potentially irreversible
dyskinesia (34).
Metoclopramide stimulates prolactin release both
in females and rn males, with the consequent possible occurrence of breast tenderness, galactorrhea,
amenorrhea and gynecomastia (1,24,33). Arrhythmias and hypotension have been rarely reported,
mostly after parenteral administration. In contrast,
the drug may cause hypertensive crises in patients
with pheochromocytoma, possibly by inducing
Catecholamine release from the tumor (33).
Metoclopramide increases aldosterone secretion
and release (35), but the effect disappears after a
few days of continuous treatment and the risk of
hyperaldosteronism is negligible.
The drug should not be administered to parkinsonian subjects, in patients with pheochromocytoma, or in combination with phenothiazines, butyrophenones or orthiazanthines to avoid potentiation
of extrapyramidal effects. Likewise, in subjects taking monoamine oxidase inhibitors, tricyclic antidepressants or sympathomimetics the use of metoclopramide is not advisable.
In patients with severe renal failure a reduction
MEDICAMENTOSA DE ACTUALIDAD
in dosage (50% at least) is recommended (36). The drug
should not be employed during pregnancy or
breast-feeding. It must be remembered that, due to
the enhanced gastric emptying induced by
metoclopramide, absorption and time of peak
plasma concentration of drugs such as aspirin,
paracetamol, diazepam and antibiotic are also accelerated (1).
Clebopride
Clebopride [II] is another orthopi amide with antidopaminergic activity and a marked stimulatory effect on serotoninergic transmission (37). On a molar
basis clebopride appears to be more potent than
metoclopramide
in
antagonizing
apomorphinoinduced vomiting and in enhancing gastric emptying in animals (37,38).
In humans the drug has been shown to significantly counteract the gastric stasis induced by i.v.
glucagon (39) and to be significantly more effective
than domporidone in accelerating gastric evacuation
of barium in subjects with radiological signs of
gastric stasis (40). Moreover, in a double-blind study
clebopride proved to be significantly superior to
placebo in the prevention of vomiting associated
with cancer chemotherapy (41).
Clinical use
Uncontrolled studies were performed with
clebopride in patients with dyspepsia associated
with the use of non-steroidal anti-inflammatory
drugs. Clebopride at a dose of 0.5 mg t.i.d for 4
weeks was found to be effective in preventing and
counteracting the occurrence of dyspeptic symptoms in rheumatic patients treated with various antiinflammatory agents (42,43).
In the only available double-blind trial clebopride
0.5 mg t.i.d. and metoclopramide 10mg t.i.d. were
compared for 4 weeks in patients with functional
dyspepsia and delayed gastric emptying (44). Both
drugs significantly accelerated emptying rate (p <
0.01) and improved dyspeptic symptoms (p <
0.05). No differences were observed between the
two treatments (Table II).
Clebopride has been reported to be significantly
DRUGS OF TODAY Vol. 25, No. 2, 1989
better than placebo in increasing the pressure of the
lower esophagel sphincter (46), but, to date,
clinical studies on the treatment of gastroesophageal
reflux are not available.
Side-effects
Drowsiness (45) and hyperprolactinemia (47)
have been reported also with clebopride and, on the
whole, the tolerability profile appears to be quite
similar to that of metoclopramide.
Domperidone
Domperidone [45] is a peripheral dopamine antagonist, related to butyrophenones, which poorly
penetrates the blood-brain barrier and therefore
seldom causes adverse effects on the central nervous system (48). In fact, in animal studies the drug
proved to be effective against emesis by apomorphine, hydergine or levodopa, but not against centrally induced vomiting such as emesis by copper
suifate (49). Studies in humans confirmed the good
anti-emetic properties of domperidone in various
clinical conditions such as migraine, dysmenorrhea,
radiotherapy, surgical procedures and chemotherapeutic treatment (50-54).
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paresis a single oral dose of domperidone 40 mg
significantly stimulated gastric emptying of both liquids and solids (65). After long-term administration (35-51 days) of 20 mg t.i.d. by the oral route,
the drug was still significantly effective or liquid
emptying, but no longer capable of enhancing gastric
emptying of solids (65).
According to some authors, domperidone-induced
acceleration of gastric evacuation of liquids wood
actually be due to a decreased adaptive relaxation
of the stomach wall rather than to a change in the
half-time of gastric emptying (66). Indeed, domperidone is known to reduce botn dopamine-induced
(67) and adaptive (68) gastric relaxation and this
property may contribute to the overall effect of the
drug on gastric mctility. Manometric studies showed that single i.v. doses of domperidone 8 mg increase the duration (but not the frequency and
amplitude) of antral contractions (69) In experiments employing barium meals oral domperidone
20 mg or more (but not 10 mg) significantly stimulated antral peristalsis (64). Furthermore, domperidone was found to improve antroduodenal motor
coordination in vitro and in vivo (70), both in animals
and in man (70,71). Pyloric relaxation after intravenous domperidone has been reported in uncontrolled observations in man (72), but a double-blind
study failed to confirm this finding (71).
Clinical use
Motor effects on the upper gastrointestinal tract
Domperidone 10 mg i.v. increases the lower
esophageal sphincter pressure in normal subjects
(55,56), but the effect in patients with reflux
esophagitis is uncertain (57). The influence of oral
domperidone on the lower esophageal sphincter is
also controversial (58,59).
In dogs intravenous domperidone (0.4 mg/kg) accelerates gastric emptying of a radiolabeled solid
meal (60). Observations in humans showed that i.v.
domperidone (5-20 mg) antagonizes the inhibitory
effect of apomorphine and dopamine on gastric
emptying (61,62). A double-blind study in dyspep-tic
patients demonstrated that domperidone 20 mg i.v.
accelerates gastric emptying of liquids and solids to a
significantly greater extent than placebo (63).
When given by the oral route, the drug appears to
enhance gastric evacuation of a barium meal (40,
64), but to be ineffective against glucagon-ihduced
gastric stasis (39). In patients with diabetic gastro-
In adults oral domperidone is usually administered
at an oral dose of 10-20 mg t.i.d. (about 30 minutes
before meals) and, if necessary, also at bedtime. In
children the recomended dose is 0.3 mg/kg 3 or 4
times daily. Peak plasma levels are achieved within
30 minutes after oral administration (73). Increased values of intragastric pH induced by previous administration of antacids or H2-receptor antagonists
reduce domperidone absorption. After a single dose,
31% of the drug is excreted in the urine and 66%
in the feces over a 4-day period (74), mostly as inactive metabolites. Parenteral administration of
domperidone (1 mg/kg daily) has been discontinued
(see "safety and side-effects")
Rectal administration can be employed in case of
acute nausea or vomiting. The dosage in adults is
60 mg 2-4 times daily. In children doses from 20
to 120 mg daily can be used in relation to their age.
Peak plasma levels with suppositories are reached
within 60 minutes or so (73).
1. Reflux esophagitis When compared to placebo,
domperidone show-
106
ed good results as for disappearance of reflux symptoms, but was found to be ineffective in improving
endoscopic and histological signs of esophagitis
(Table I). In a comparative trial, however, domperidone 20 mg t.i.d., ranitidine 150 mg b.i.d. and the
combination of the above treatments were found
significantly (p < 0.01) and equally effective
in inducing both disappearance of dyspeptic symptoms and improvement of endoscopic and histological esophagitis (75).
2. Functional dyspepsia
With a few exceptions, the studies employing
domperidone 10-20 mg t.i.d. for periods of 2-4
weeks demonstrated that the drug promotes symptomatic relief in patients with functional dyspepsia,
significantly better than placebo (Table III).
When compared to metoclopramide, domperidone
was found to be statistically equivalent, superior or
inferior according to the various studies (Table II).
A recent small double-blind trial versus cisapride
yielded similar significant therapeutic results with
the two drugs (76).
Preliminary observations suggest that domperidone may also be effective in dyspeptic subjects
with duodenogastric bile reflux (77).
3. Gastric stasis
Symptomatic improvement in patients with diabetic gastroparesis has been occasionally reported
in small uncontrolled studies (65,78,79), but comparative, controlled trials versus placebo or other
prokinetic agents are still lacking.
Safety ana side-effects
Domperidone is usually well tolerated and, due to
MEDICAMENTOS DE ACTUALIDAD
its pheripherai action, extrapyramidal reactions have
been very seldom observed (80,81).
Although, like metoclopramide and clebopride,
domperidone stimulates prolactin release in males
and females, reports of clinical manifestations of
hyperprolactinemia are only anecdotal.
A report of ventricular arrhythmias in 4 women
treated with a. 24-hour i.v. infusion of domperidone
10 mg/kg to counteract cisplatin-induced emesis
(82) prompted the marketing companies to
withdraw parenteral formulations of the drug.
However, the possible cardiotoxicity of intravenous domperidone has been excluded by others (83), and the
adverse cardiac effects reported above can be
explained in view of the very high doses employed
(83,84), which were 10 times greater than the
recommended dosage and about 5 times greater
than the maximum daily amount that can be
reasonably administered (83).
Cisapride
Cisapride [IV] is a novel prokinetic compound
which stimulates gastrointestinal motility by promoting acetylcholine release from the myenteric
nerves (85) and by blocking serotonin S 2-receptors
(86). The drug has no antidopaminergic properties
nor, unlike cholinergic substances, does it influence
gastrointestinal secretions (87).
DRUGS OF TODAY Vol. 25, No. 2, 1989
Effects on upper gastrointestinal motility
Cisapride 4-10 mg i.v. was found to significantly
stimulate the amplitude of esophageal peristalsis
(87-90) and to markedly increase the pressure of
the lower esophageal sphincter (87-91), both in normal subjects and in patients with gastroesophageal
reflux. The effect on the esophageal sphincter
seems to be absent only in the early postprandial
period (91). Consistent results were reported after
a single oral dose of 20 mg in normal subjects (90),
whereas 10 mg t.i.d. for 3 days by the oral route
was found to be not significantly better than placebo
In patients with gastrdesophageal reflux (92).
Double-blind comparative studies versus metoclopramide showed equivalent effects of the two
drugs on esophageal motility after single i.v. administration (cisapride 4 mg vs. metoclopramide 10
mg) (93,94), the effect of cisapride being longer
lasting (94). In healthy volunteers oral doses of
either drug (10 mg t.i.d.) were equally effective in
reducing the number and duration of reflux episodes,
as assessed by 24-hour esophagea! pH monitoring
(94).
Gastric emptying of liquid in normal subjects is
accelerated by a single oral dose of cisapride 10-20
mg (88,95). Similarly, gastric stasis by dopamine
was abolished in healthy volunteers by either
cisapride or metoclopramide 10 mg i.v. (96). When
cisapride was given without dopamine, gastric emptying was only moderately enhanced. Dopamineinduced (but not spontaneous) duodenogastric bile
reflux was significantly decreased By both prokinetic
agents (96).
In dyspeptic subjects with delayed gastric emptying cisapride 8 mg i.v. proved significantly superior
to placebo in increasing gastric evacuation of liquids
and solids (97). Oral treatment with cisapride 10 mg
t.i.d. for 2 weeks was also found to be superior to
placebo (98) and as effective as metoclopramide
199) in accelerating gastric emptying of solids in
dyspeptic subjects with gastroparesis.
In patients with diabetic gastroparesis cisapride
5 mg i.v. significantly stimulated gastric evacuation
of radiopaque markers, while the prokinetic effect
of metoclopramide 10 mg failed to reach statistical
significance compared with baseline emptying time
(100). By the oral route cisapride both as a single
20-mg dose and after repeated administration (10
mg q.i.d. for 4 weeks) enhanced gastric emptying
of liquids and solids in diabetic subjects to a
significantly greater extent than placebo (101).
Similar findings were reported in idiopathic and
postsurgical gastric stasis (102), as well as in
107
delayed gastric emptying in cases of primary anorexia nervosa (103).
Moreover, cisapride was shown to stimulate antroduodenal motor activity and coordination
(104,105), and to increase interdigestive jejunal
motility (106).
It is worth adding that, unlike metoclopramide and
domperidone, cisapride exerts a potent stimulatorv
action also on colonic motility and transit time
(107,108), thus proving effective also in the treatment of chronic constipation (87,109).
Clinical use
The drug is not yet commercially available. In pilot
clinical studies oral doses of 4-20 mg have been
employed so far. Following oral intake, peak plasma
concentrations are reached within 2 hours. The absolute bioavailability is estimated to be 40-50% and
not influenced by gastric pH. The usual parenteral
dose of cisapride in adults is 10 mg. The drug is excreted in the urine and feces (about 50% of the dose
for each route) mostly as metabolic products.
1. Reflux esophagitis
In patients with hiatal hernia and gastroesophageal reflux cisapride 4-8 mg t.i.d was found to be
significantly superior to placebo (p < 0.05) in improving regurgitation and heartburn (110). Studies
in patients with reflux esophagitis showed that
cisapride promotes symptom relief and, possibly, endoscopic improvement significantly better than
placebo (Table I). Preliminary observations suggest
that cisapride may enhance the therapeutic efficacv
of ranitidine in reflux esophagitis ( 111) .
2. Functional dyspepsia
The majority of clinical trials comparing cisapride
and placebo in the treatment of functional dyspepsia indicate a significantly superior effect of the prokinetic agent (Table IV).
In double-blind studies versus domperidone or
metoclopramide cisapride displayed a similar ability to reduce the severity of dyspeptic symptoms
(Table II). Also, in diabetic gastroparesis dyspeptic
symptoms were significantly relieved by cisapride,
but not by placebo (101).
Safety and side-effects
In most of the clinical studies available to date no
relevant side-effects nave been reported even after
long-term (up to 12 months) continuous therapy
with cisapride. Abdominal grumbling has been
observed after i.v. administration (112), but this ef-
MEDICAMENTOS DE ACTUALIOAO
108
Table IV: Cisapride versus placebo in the treatment of functional dyspepsia.
CIS = Cisapride; P = placebo
> Significantly superior
fect was negligible aftsr oral doses of the drug
(106). On the Other hand, slight but significant
elevations of systolic blood pressure and heart rate
have been detected after 3 days of treatment with
cisapride 5-10 mg orally t.i.d. (106). This phenomenon warrants further investigation.
It has been reported that cisapride can reduce the
bioavailability of cimetidine and slightly increase the
anticoagulant affect of coumarinic agents, but these
effects seem to be clinically irrelevant (113).
8.
9.
10.
References
1. Pinder, R.M., Brogden, R.N., Sawyer, P.R.,
Speight, T.M. and Avery, G.S. Metoclopramide: A review of its pharmacological properties and clinica 1 use. Drugs 1976; 12: 81.
2. Gralla, R.J..Metoclopramide. A review of antiemetic. trials. Drugs 1983; 25(Suppl. 1): 63.
3. Baumann, H.W., Sturdevant, R.A.L. and
McCallum, R.W. L-Dopa inhibits metoclopramide stimulation of the lower esophageal
sphincter in man. Am J Digest Dis 1979; 24:
289.
4. Cohen, S., Morris, D.W., Schoen, H.J. and Di
Marino, A.J. The effect of oral and intravenous metoclopramide on human lower
esophageal sphincter pressure. Gastroenterol
1976; 70: 484.
5. McCallum, R.W., Kline, M.M., Curry, N. and
Sturdevant, R.A.L. Comparative effects of
metoclopramide and bethanecol on lower
esophageal sphincter pressure in reflux patients. Gastroenterol 1975; 68: 1114.
6. Wallin, L, Boesby, S. and Madsen, T. Effect
of metoclopramide on esophageal peristalsis
and gastroesophageal sphincter pressure.
Scand J Gastroenterol 1975; 14: 923.
7. Stanciu, C. and Bennett, J.R. Metoclopramide
11.
12.
13.
14.
15.
16.
17.
in gastro-esophageal reflux. Gut 1973; 14:
275.
Behar, J. and Ramsby, G. Gastric emptying
and antral motility in reflux esophagitis. Effect
of oral metoclopramide. Gastroenterol 1978;
74: 253.
Davidson, E.D., Hersch, T., llaun, C. and
Brooks, W.S. Use of metoclopramide in patients with delayed gas'tric emptying following gastric surgery. Am Surg 1977; 41: 40.
Malagelada, J.R., Rees, W.D.W., Mazzotta,
L.J. and Go, V.L.W. Gastric motor abnormalities in diabetic and postvagotomy gastroparesis. Effect of metoclopramide and betha
necol. Gastroenterol 1980; 78: 286.
Fox, S. and Behar, J. Pathogenesis of diabetic
gastroparesis: A pharmacological study.
Gastroenterol 1980; 78: 757.
Campbell, I.W., Heading, R.C., Tothill, R.,
Buist, A.S., Ewing, D.J. and Clarke, B.F.
Gastric emptying in diabetic autonomic
neuropathy. Gut 1977; 18: 462.
Perkel, M.S., Moore, C., Hersch, T. and Davidson, E.D. Metoclopramide therapy in patients
with delayed gastnc emptying - A randomized, double-blind study. Digest. Dis Sci 1979;
24: 662.
Longstreth, d.F., Maiagelada, J.R. and Kelly,
K.A. Metoclcpramide stimulation of gastric
motility and emptying in diabetic gastroparesis. Ann Intern Med 1977; 86: 195.
Meltzger, W.H., Cano, R. and Sturdevant,
R.A.L. Effect of metoclopramide in chronic
gastric retention after gastric surgery. Gastroenterol 1976; 71: 30.
Wright, R.A. and MacGregor, I.L. Effect of
metoclopramide on gastric stasis after reversed jejunal loop for postvagotomy diarrhea. Am
J Gastraenterol 1979; 72? 441.
Saleh, J.W. and Lebwohl, T. Metoclopramioe-
DRUGS OF TODAY Vol. 25, No. 2, 1989
induced gastric emptying in patients with
anorexia nervosa. Am J Gastioenterol 1980;
74: 127.
18. Johnson, A.G. Gastroduodenal motility and
synchronization. Postgrad Med J 1973;
Suppl. 4: 29.
19. Lanfranchi, G.A., Marzio, L., Cortinic, C.,
Trento, L. and Labo, G. Effect of dopamine
in gastric motility in man: Evidence for specific
receptors. In: Gastrointestinal Motility in
Health and Disease. MTP Publishers: Lancaster 1977; 161.
20. Berkowitz, D.M. and McCallum, R.W. Interaction of levodopa and metoclopramide on
gastric emptying. Clin Pharmacol Ther 1980;
27:414.
21. Ramsbottom, N. and Hunt, J.N. Studies on
the effect of metoclopram:de and spomorphine on gastric emptying and secretion in
man. Gut 1970; 11: 989.
22. Stadaas, J. and Aune, S The effect of
metoclopramide on gastric motility before and
after vagotomy in man. Scand J Gastroenterol
1971; 6: 17.
23. Kowalewski, K. and Kalodej, A. Effect of
metoclopramide on myoelectrical and
mechanical activity of the isolated canine
stomach perfused extracorporeally. Pharmacol 1975; 13: 549.
24. Schulze-Delrieu, K. Metoclopramide. N Engl J
Med 1981; 305: 28.
25. Zar, M.A., Ebong, 0.0. and Bateman, D.N. Effect of metoclopramide in guinea pig ileum
longitudinal muscle: Evidence against
dopamine-mediation. Gut 1982; 23: 66.
26. Bright-Asare, P. and EI-Bassoussi, M.
Cimetidine, metoclopramids or placebo in the
treatment of symptomatic gastroesophageal
reflux. J Clin Gastroenterol 1980; 2: 149.
27. Guslandi, M., Testoni, P.A., Passaretti, S.,
Masci, E., Ballarin, E., Comin, U., Marchi, R.,
Ronchi, G. and Tittetoeltb, A. Ranitidine vs
metoclopramide in the medical treatment of
reflux esophagit-is. Hepato-Gastroenterol
1983; 30: 96.
28. Tonnesen, H., Andersen, J.R., Christoffersen,
P. and Kaas-Claesson, N. Reflux esophagitis
in heavy drinkers. Effect of ranitidine and
alginate/metoclopramide. Digest 1987; 38:
69.
29. De Almeida, D.J.W., Cameron, W.R., Condie,
R., Deering, R.B., Fitzgetald, R.B., Joannou,
P., Johnston, E.M., Mnro, D.F., Smith, A.G.L.
109
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
and Valle-Jones, J.C. The treatment of
dyspepsia in general practice. Practitioner
1980; 224: 105.
Perkel, M.S., Hersch, T., Moore, C. and Davidson, P.O. Metoclopramide therapy in fifty-five
patients with delayed gastric emptying. Am
J Gastroenterol 1980; 74: 231.
Snape, W.J., Battle, W.M., Schwartz, S.S.,
Braunstein, S.N., Goldstein, H.A. and Alavi,
A. Metoclopramide to treat gastroparesis due
to diabetes mellitus. A double-blind controlled trial. Ann Intern Med 1982; 96: 444.
McClelland, R.N. and Horton, J.W. Relief of
acute, persistent postvagotomy atony by
metoclopramide. Ann Surg 1978; 188: 439.
Albibi, R. and McCallum, R.W. Metociopramide: Pharmacology and clinics! application.
Ann Intern Med 1983; 98: 86.
Grimes, J.D., Hassan, M.N. and Preston, D.N
Adverse neurologic effects of metoclopramide. Can Med Assoc J 1982; 126. 23.
Carey, R.M., Thorner, M.O. and Ortt, E.M
Dopaminergic inhibition of metoclopramide induced aldosterone secret'on in man.
Dissociation of responses tc dopamine an
bromocriptine. J Clin Inv/est 1980; 66: 10.
Bateman, D.N., Gokal, R., Dodd, T.R.P. and
Blain, P.G. The pharmacokinetics of single
doses c~ metoclopramide in renal failure. Eur
J Clin Pharmacol 1981; 19: 43/7
Roberts, D.J. The pharmacological basis of
the therapeutic activity of clebopride and
related substituted benzamides. Curr Ther Res
1982; 31 (Suppl. 1): S1.
Masso, J.L. and Roberts, D.J. Comparison of
potencies of clebopride and other substituted
benzamide drugs on isolated gastrointestinal
tract of the guinea-pig and rat. J Pharm Pharmacol 1980; 32: 727.
Saez, J.E.M. and Cirera, A.C. Double-blind
parallel comparison of the gastrokinetic effects of clebopride, domperidone and placebo
in human volunteers with gastric stasis induced
by
glucagon.
Curr
Ther
Res
1982; 31 (Suppl. 1): S58.
Nieto Calvet, M. Single-blind crossover comparison of the gastrokinetic effects of
clebopride and domperidone in patients with
retarded gastric evacuation. Curr Ther Res
1982; 31 (Suppl. 1): S69.
Murillo Capitan, E. and Sanchez Romero, J.A.
Double-blind crossover study comparing
clebopride and placebo in the prevention of
MEDICAMENTOS DE ACTUALIDAD
110
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
nausea and vomiting in patients undergoing
cancer chemotherapy. Curr Ther Res 1982;
31{Suppl. 1): S61.
Moller Parera, I., Molina Sota, J J. and Poal
Sallarin, J.M. Clinical experience with
ctebopride in rheumatic patients with nonsteroidal anti-inflammatory drug-induced
dyspepsia. Acta Ther 1985; 11: 13.
Alegre, C., Obach, J. and Barcelo, P. Clinical
experience with clebopride in dyspepsia
associated with the use of anti-inflammatory
drugs. Curr Ther Res 1985; 37: 289.
Borrachero, D.C.J. Efficacy of clebopride in
reducing dyspeptic symptoms in rheumatic
patients undergoing longterm treatment with
aspirin. Adv Ther 1984; 1: 427.
Corinaldesi, R., Stanghellini, V., Raiti, C.,
Zarabini, G.E., Rea, E.. Paparo, G.F. and Barbara, L. Effects of chronic oral administration
of clebopride and metoclopramide on gastric
emptying of solids in patients with functional
dyspepsia. Curr Ther Res 1985; 38: 790.
Vantrappen, G., Kortan, P. and Janssens, J.
The effect of clebopride on lower esophageal
sphincter pressure in normal subjects. Curr
Ther Res 1985; 37: 284.
Perez-Lopez, F.R., Legido, A., Sisskin, M. and
Abos, M.D. Stimulatory effect of clebopride
on human prolactin secretion. Fertil Steril
1980; 34: 452.
Reyntjens, A.J., Niemegeers, C.J.E., Van
Nueten, J.M., Laduron, P., Heykants, J.,
Scheliekens, K.H.L., Marsboom, R.,
Jageneau, A., Broekaert, A. and Janssen,
P.A.J. Domperidone, a novel and safe
gastrokinetic antinauseant for the treatment
of dyspepsia and vomiting. Arzneim-Forsch
1978; 28: 1194.
Niemegeers, C.J.E., Scheliekens, K.H.L. and
Janssen, P.A.J. The antiemetic effects of
domperidone, a novel potent gastrokinetic.
Arch Intl Pharmacodyn Ther 1980; 244: 130.
Reyntjens, A. Domperidone as an anti-emetic:
Summary of research reports. Postgrad Med
J 1979; 55(Suppl. 1): 50.
Boghaert, A., Carron, D., Gallant, J. and
Stockman, A. Postoperative vomiting treated
with domperidone. A double-blind comparison
with metoclopramide and a placebo. Acta
Anaesth Belg 1980; 31: 129.
Cooke, R.D., Comyn, D.J. and Ball, R.W.
Prevention of post-operative nausea and
vomiting by domperidone. A double-blind ran-
domised study using domperidone, motochpramide and a placebo. S Afr Med J 1979;
56: 827.
53. Swann, l.L, Thompson, E.N. and Qureski, K.
Domperidone or metoclopramide in preventing
chemotherapcuticaliy induced nausea and
vomiting. Brit Med J 1979; 2: 1188.
54. D'Souza, D.?., Reyntjens, A. and Thornes,
R.D. Domperidone in the prevention of nausea
and vomiting induced by antineoplastic
agents. A three-fold evaluation. Curr Ther Res
1980; 27: 384.
55. Bron, B. and Massih, L. Domperidone, a
neuroleptic with powerful action on the lower
oesophageal sphincter pressure. Digest 1980;
20: 375.
56. Lux, G., Engel, H. and Rosch, W. The stimulation of oesophageal motility with bromopride,
domperidone and metoclopramide. In: Progress with Domperidone. Royal Society of
Medicine International Congress and Symposium Series, No. 36 1981; 29.
57. Valenzuela, J.E., Defilippi, C. and Gutierrez,
F. Effect of domperidone on patients with
symptomatic gastro-esophageal reflux. Digest
Dis Sci 1980; 25: 716.
58. Weihrauch, T.R., Forster, C.R.F. and Krieglstein, J. Evaluation of the effect of domperidone on human oesophageal and gastroduodenal motility by intraluminal manometry.
Postgrad Med J 1979; 55(Suppl. 1): 7.
59. Bleckwell, J.N., Heading, R.C. and Fsttes,
M.R. Effects of domperidone on lower
oesophageal sphincter pressure and gastrcesophageal reflux in patients with peptic
oesophagitis. In: Progress with Domperidone.
Royal Society of Medicine International Congress and Symposium Series, No. 36 1981;
57.
60. Jacobs, F., Akkermans, L.M.A., Yo!, O.H. and
Witfeboi, P. Effects of domperidone on gastric
emptying of semi-solid and solid food. In: Progress with Domperidone. Royal Society of
Medicine International Congress and Symposium Series, No. 36 1981; 11.
61. Broekaert, A. Effect of domperidone on gastric
emptying and secretion. Postgrad Med J
1979; 55(Suppl. 1): 11.
62. Proctor, J.D., Fratkin, M.J., Evans, E.F. and
Wasserman, AJ. Effect of domperidone on
apomorphine-retarded gastric emptying. In:
Progress with Domperidone.'Royal Society of
Medicine. International Congress and Sym-
DRUGS OF TODAY Vol. 25, No. 2, 1989
posium Series, No. 36 1981; 37.
63. Corinaldesi, R., Stanghellini, V., Zarebini, G.E.,
Calamelli, R., Raiti, C., Paternico, A. and Barbara, L. The effect of domperidone on the
gastric emptying of solid and liquid phase of
a mixed meal in patients with dyspepsia. Curr
Ther Res 1983; 34: 982.
64. De Schepper, A., Wollaert, F. and Reyntjens, A.
Effects of oral domperidone on gastric
emptying and motility. Arzneim-Forsch 1978; 28:
1196.
65. Horowitz, M., Harding, P.E., Chatterton, B.E.,
Collins, P.J. and Shearman, D.J.C. Acute and
chronic effects of domperidone on gastric
emptying in diabetic autonomic neuropathy.
Digest Dis Sci 1985; 30: 1.
66. Beteman, D.N., Gooptu, D. and Whittingham,
T.A. The effects of domperidone on gastric
emptying of liquid in man. Brit J Clin Pharmacol 1982; 13: 675.
67. Van Nueten, J.M. and Janssen, P.A.J. Effect
of domperidone on gastric relaxation caused
by dopamine, secretion, 5-hydroxytryptaminef
substance P and adenosine triphosphate. In:
Gastrointestinal Motility. A. Christensen (Ed.).
Raven Press: New York 1980; 225.
68. Sinnett,
H.D.
and
Leathard,
H.L.
Domperidone: Its effect on human gastricadaptive relaxation. In: Progress with Domperidone. Royal Society of Medicine. International Congress and Symposium Series, No.
36 1981; 43.
69 Weirauch, T.R. and Ehl, W. Effect of
domperidone on the motility of antrum,
pylorus and duodenum in man. Scand J
Gastroenterol 1981; 16(Suppl. 67): 195.
70. Schuurkes, J.A.I, and Van Nueten, J.M.
Domperidone improves myogenically transmitted antroduodenal coordination by blocking dopaminergic receptor sites. Scand J
Gastroenterol 1984; 19(Suppl. 96): 101.
71. Eyre-Brook, I.A., Smallwood, R. and Johnson,
A.G. Human antroduodenal motility, pyloric
closure and domperidone. Scand J Gastroenterol 1984; 19(Suppl. 92): 4.
72. Platterborse, R., Hermans, C., Loots, W., Van
oon, J., Van Gorp, A., Smet, F. and
Jagenauu, A. The effect of domperidone on
pyloric activity in dog and man. Postgrad Med
J 1979; 55{Suppl. 1): 15.
73. Heykants, J., Hendriks, R., Meuldermans, W.,
Michiels, M., Scheygrofid, H. and Reyntjens,
H. On the pharmacokinetics of domperidone
111
in animals and man. IV. The pharmacokinetics of
intravenous domperidone and its bioavaila-bility
in man following intramuscularf oral and rectal
administration. Eur J Drug Metab Pharmacokinet 1981; 6: 61.
74. Meuldermans, W., Hurkmans, R., Swysen, E.,
Hendriks, J., Michiels, M., l.auwens, W. and
Heykants, J. On the pharmacokinetics of
domperidone in animals and man. III. Comparative study on the secretion and
metabolism of domperidone in ratsf dogs and
man. Eur J Drug Metab Pharmacokinet 1981;
6: 49.
75. Masci, E., Testoni, P.A., Passaretti, S.,
Guslandi, M. and Tittobello, A. Comparison of
ranitidine, domperidone maleate and ranitidine
+ domperidone maleate in the short-term
treatment of reflux oesophagitis. Drugs Exp
Clin Res 1985; 11: 687.
76. Verhaegen, H. Treatment of chrcnic dyspepsia with cisapride and domperidone. Digest
1986; 34: 151.
77. Hordijk, M.L., Van Roon, F.W., Scopman, W.
and Silberbush, J. The effect of domperidone
on duodenogastric biliary reflux in patients
with chronic dyspeptic complaints. Nederl Tijidsch Geneesk 1982; 126: 2319.
78. Nagler, J. and Miskovitz, P. Clinical evaluation of domperidone in the treatment of
chronic postprandial idiopathic upper gastrointestinal distress. Am J Gastroenterol 1 981;
76: 495.
79. Heer, M., Pirovino, M., Japp, H., Buhler, H.
and Schmid, M. Diabetic gastroparesis and
colonic dilatation treated with dcmperidone.
Lancet 1980; 2: 1145.
80. Sol, P., Pelet, B. and Guignard, J.P. Extrapyramidal reactions due to domperidone.
Lancet 1980; 2: 802.
81. Debontridder, 0. Extrapyramidal reactions de
to domperidone. Lancet 1980; 1: 802.
82. Osborne, R.J., Slevin, M.L., Hunter, R.W. and
Hamer, J. Cardiutoxicity oc intravenous
domperidone. Lancet 1985; 2: 385.
83. Love, E.M., Yin Liu, J.A. and Delamcre, T.
Cardiotoxicity of domperidone. Lancet 1885;
2: 676.
84. Quinn, N., Parkes, D., Jackson, G. and Upward, J. Cardiotoxicity of domperidone
Lancet 1985; 2: 724.
85. Schuurkes, J.A.J., Akkermans, L.M.A. and
Van Nueten
J.M. Stimulating effect of
cisapride on antroduodenal motility in con-
112
scious dogs. In: Gastrointestinal Motility. C.
Roman (Ed.). MTP Press: Lancaster 1984; 95.
86. Moriarty, K.J., Higgs, N.B., Woodford, M.,
Warhurst, G. and Turnberg, L.A. Inhibition of
the effect of serotonin on rat Heal transport
by cisapride: Evidence in favour of the involvement of 5-HT2 receptors. Gut 1987; 28: 844.
87. Reyntjens, A., Verlinden, M., Schuurkes, J.,
Van Nueten, J. and Janssen, P.A.J. New approach to gastrointestinal motor disfunction:
Non-antidopaminergic, non-cholinergic stimulation with cisapride. An introductory survery.
Curr Ther Res 1984; 36: 1029.
88. Corazziari, E., Scopinaro, F., Bontempo, I.,
Gatti, V., Liberatore, M^Biliotti, D., Del Buono,
G., Vignoni, A. and Torsoli, A. Effect of R 51
619 on distal oesophageal motor activity and
gestric emptying. Ital J Gastroenterol 1983;
15: 185.
89. Gilbert, R.J., Dodds, W.J., Kahrilas, P.J.,
Hogan, W.J. and Lipman, S. Double-blinded
assessment of the effect of intravenous and
oral cisapride on esophageal motor function.
Digest 1986; 34: 139.
90. Janssens, J., Ceccatelli, P. and Vantrappen,
G. Cisapride restores the decreased lower
esophageal sphincter pressure in reflux patients. Digest 1986; 34: 139.
91. Smout, A.J.P.M., Bogaard, J.W., Grade, A.C.,
Ten Thije, O.J., Akkermans, I.M.A. and Wittebol, P. Effects of cisapride, a new
gastrointestinal prokinetic substance, on interaigestive and postprandial motor activity of
the distal oesophagus in man. Gut 1985; 26:
246.
92. Holloway, R.H., Dent, J., Downton, J. and
Mitchell, B. Effects of cisapride on postprandial gastroesophageal reflux. Digest
1986; 34: 141.
93. Wienbeck, M., Cuder-Wiesenger, E. and
Bergos, W. Comparative study of cisapride's
versus metoclopramide's effect on esophageal motility. Digest 1986; 34: 141.
94. Weiser, H., Holscher, A. and Zimmermann, T.
Effects of cisapride anc' metoclopramide on
the lower esophageal motility. A pressure and
pH-metric study. Digest 1986; 34: 142.
95. Lazzaroni, M., Sangaletti, 0. and Bianchi
Porro, G. Effect of cisapride on gastric emptying and Heal transit time of balanced liquid
meal in healthy subjects. Digest 1987; 37:
110.
96. Muller-Lissner, S., Fraas, C. and Hartl, A.
MEDICAMENTOS DE ACTUALIDAD
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
Cisapride offsets dopamine-induced slowing
of fasting gastric emptying. Digest Dis Sci
1986; 31: 807.
Jian, R., Ducrot, F., Piedeloup, C., Mary, J.Y.,
Najean, Y. and Bernier, J J. Measurement of
gastric emptying in dyspeptic patients: Effect
of a new gastrokinetic agent (cisapride). Gut
1985; 26: 352.
Corinaldesi, R., Stangheilini, V., Raiti, C., Rea,
E., Salgemini, R. and Barbara, L. Effect of
chronic administration of cisapride on gastric
emptying of a solid meal and on dyspeptic
symptoms in patients with idiopathic gastrpparesis. Gut 1987; 28: 300.
Corinaldesi, R., Raiti, C., Stangheilini, V.,
Monetti, N., Rea, E., Salgemini, R., Paparo,
G.F. and Barbara, L. Comparative effects of
oral cisapride and metoclopramide on gastric
emptying of solids and symptoms in patients
with functional dyspepsia and gastroparesis.
Curr Ther Res 1987; 42: 428.
Feldman, M. and Smith, H.J. Effect of
disapride on gastric emptying of indigestible
solids in patients with gastroparesis diabeticorum. A comparison with metoclopramide
and placebo. Gastroenterol 1987; 92: 171.
Horowitz, M., Maddox, A., Harding, P.E.,
Maddern, G J., Chatterton, B.E. and Shearman, D.J.C. Acute and chronic effects of
cisapride on gastric and oesophageal emptying in insulin-dependent diabetes mellitus.
Digest 1986; 34: 149.
McCallum, R.W. Results of cisapride's effects
on gastric emptying of solids and liquids and
the symptom stats of patients with gastric
stasis. Digest 1986; 34: 148.
Stacher, G., Bergmann, H., Wiesnagrotzki, S.,
Kiss, A., Schneider, C., Mittelbach, G., Gaupmann, G. and Hobart, J. Intravenous cisapride
accelerates delayed gastric emptying and increases antral contraction amplitude in patients with primary anorexia nervosa. Gastroenterol 1987; 92: 1000.
Reboa, G.,' Arnulfo, G., Di Somma, C.,
Frascio, M., Arzillo, G., Berti-Riboli, E. and
Lucchetti, G. Prokinetic effects of cisapride on
normal and reduced antroduodenal motility
and reflexes. Curr Ther Res 1984; 36: 18,
Luz, G., Lederer, P.C-, Ellermann, A. and Ludwig, S. Effects of cisapride and metoclopramide on antroduodenal motor activity in man
Digest 1986; 34: 152.
Stacher, G., Gaupmann, G., Mittelbach, G.,
DRUGS QF TODAY Vol. 25, No. 2, 1989
Schneider, C., Steinringer, H. and Langer, B.
Effects of oral cisapride on interdigestive jejunal motor activity, osychomotor function
and side-effect profile in healthy man. Digest
Dis Sci 1987; 32: 1223.
107. Leaerer, P.C., Ellermann, A., Schmidt, H.,
Ernst, V. and Lux, G. Effect of cisapride on
sigmoid motility in healthy subjects and in
diabetic enteropathy with constipation. Digest
1986; 34: 155.
108. Krevski, B., Malmud, L, Mauer, A., Siegel, J.
and Fisher, R.S. Effects of cisapride on colcnic transit in man. Digest 1985; 34: 156.
109. Creytens, G., Verlinden, M. and Reyntjens, A.
Double-blind study of cisapride in the treatment of chronic, functional nonspastic constipation. Digest 1986; 34: 158.
113
1 10. Creytens, G. Effect of cisapride on gastroesophageal reflux symptoms in hiatal-hernia
patients. Digest 1986; 34: 145.
111. Wienbeck, M. Does cisapride added to
H2-receptor blocking treatment improve healing rates in patients with esophagitis? Digest
1986; 34: 144.
112. Stacher, G., Steinringer, H., Schneider, C.,
Winklehner, S., Mittelbach, G. and Gaupmann, G. Effects of cisapride on jejunal motor
activity in fasting healthy humans. Gastro
enterol 1986; 90: 1210.
113. Verlinden, M., Van Peer, A., Woestenborghs,
R., Heykants, J. and Reyntjens, A. Bioavailability of cisapride and concomitant drugs
in therapeutic conditions. Digest 1986; 34:
138.