Neurogastroenterol Motil (2011) 23, e32–e39
Influence of tegaserod on proximal gastric tone and on the
perception of gastric distention in functional dyspepsia
J. TACK ,* P. JANSSEN ,* R. BISSCHOPS ,* R. VOS ,* T. PHILLIPS   &
*Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
 Novartis Pharmaceuticals, Basel, Switzerland
Abstract
Background Abnormalities in gastric sensorimotor
function (hypersensitivity to distention and impaired
meal accommodation) have been implicated in the
pathophysiology of functional dyspepsia (FD). To
study the effect of the 5-HT4 agonist tegaserod on
sensitivity to gastric distention and gastric accom-
modation in FD. Methods Thirty FD patients (7 males,
mean age 42 ± 2 years) underwent a gastric barostat
study on two separate occasions, 2 weeks apart, after
5 days of pretreatment with placebo or tegaserod 6 mg
b.i.d. in a double-blind randomized order. After
introduction of the barostat bag, graded isobaric
distentions (2 mmHg increments/2 min) were per-
formed to determine gastric compliance and sensitiv-
ity to distention. Subsequently, the pressure level was
set at intra-abdominal pressure [minimal distending
pressure (MDP)] + 2 mmHg for 90 min, with admin-
istration of a liquid meal (200 mL; 300 kcal) after
30 min. Key Results Tegaserod had no influence on
MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric
compliance (44 ± 10 vs 61 ± 6 mL mmHg)1) and on
fasting thresholds for first perception (3.6 ± 0.4 vs
4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7
vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not
alter intra-balloon volumes before and after the meal
[respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs
283 ± 29 mL, not significant (NS)], or the amplitude
of the meal-induced gastric relaxation (151 ± 23 vs
162 ± 23 mL, NS). In the subgroup with normal
gastric emptying (n = 22), tegaserod significantly
enhanced meal-induced accommodation (126 ± 23 vs
Address for Correspondence
Jan Tack, Department of Internal Medicine, Division of Gas-
troenterology University Hospital Gasthuisberg, Herestraat
49, B-3000 Leuven, Belgium.
Tel: +32 16 34 42 25; fax: +32 16 34 44 19;
e-mail: jan.tack@med.kuleuven.ac.be
Received: 18 August 2010
Accepted for publication: 3 September 2010
e32
doi: 10.1111/j.1365-2982.2010.01613.
G. TOUGAS  
175 ± 29 mL, ANOVA P < 0.001). Conclusions & Infer-
ences Tegaserod does not alter gastric sensorimotor
function in FD patients as a group. In the subgroup
with normal gastric emptying, tegaserod 6 mg b.i.d
enhanced gastric accommodation.
Keywords functional dyspepsia, gastric accommo-
dation, gastric barostat, gastric sensitivity, tegaserod.
Abbreviations: MDP, Minimal distending pressure; 5-HT,
5-hydroxytryptamine; b.i.d., bis in diem/twice per day.
INTRODUCTION
Functional dyspepsia (FD) is a clinical syndrome
defined according to Rome III by the presence of early
satiation, postprandial fullness, epigastric pain or
burning, without identifiable cause by conventional
diagnostic means.1 The pathophysiology of FD is not
fully established, but a number of possible mecha-
nisms have been suggested.2 Delayed gastric emptying
can be found in up to one-third of the patients, but the
correlation with symptom pattern or severity has been
inconsistent.2–6 Barostat studies of the proximal stom-
ach have demonstrated hypersensitivity to gastric
distention and impaired accommodation to a meal as
possible pathophysiological abnormalities, present in
up to 40% of patients with FD.2,7–12
Tegaserod, a selective 5-HT4 receptor partial agonist,
was developed for the treatment of irritable bowel
syndrome with constipation13 and chronic constipa-
tion.14 A phase 2 and phase 3 study program evaluating
the efficacy of tegaserod in FD indicated potential
symptomatic benefit in a subset of the patients.15,16 In
healthy subjects, tegaserod has been shown to enhance
gastric emptying of solids,17 and to enhance meal-
induced gastric accommodation measured with the
gastric barostat.18 The aim of the present study was to
evaluate the influence of tegaserod on gastric sensori-
motor function in FD.
 2010 Blackwell Publishing Ltd
Volume 23, Number 2, February 2011
MATERIALS AND METHODS
Study subjects
Thirty four consecutive FD patients were screened for participa-
tion in this study. The patients presented to the motility
outpatient clinic because of pain or discomfort in the upper
abdomen, and all underwent careful history taking and clinical
examination, upper gastrointestinal endoscopy, routine biochem-
istry, upper abdominal ultrasound and a gastric emptying breath
test. Inclusion criteria were the presence of dyspeptic symptoms
according to the Rome II definition,19 in the absence of organic,
systemic or metabolic disease. Dyspeptic symptoms had to be
present at least 3 days per week, with 2 or more symptoms scored
as relevant or severe on the symptom questionnaire (see below).
Exclusion criteria were the presence of esophagitis, gastric
atrophy or erosive gastroduodenal lesions on endoscopy, heart-
burn as a predominant symptom, a history of peptic ulcer, major
abdominal surgery, underlying psychiatric illness, and the use of
nonsteroidal anti-inflammatory drugs, steroids or drugs affecting
gastric acid secretion. In order to exclude patients in which
dyspeptic symptoms are induced by Helicobacter pylori infec-
tion,20 biopsies were taken from the antrum and the corpus during
upper gastrointestinal endoscopy; and stained with cresyl violet
for the presence of H. pylori. A psychiatrist ruled out anorexia
nervosa in patients with weight loss in excess of 5% of the initial
body weight. All drugs potentially affecting gastrointestinal
motility or sensitivity were discontinued at least 1 week prior
to the barostat and gastric emptying studies. Informed consent
was obtained from each participant. The protocol had been
previously approved by the Ethics Committee of the University
Hospital.
Study design
This study (CHTF 919 D2206) used a randomized, placebo-
controlled, double-blind, double-dummy, crossover design to
evaluate the effect of tegaserod on gastric sensorimotor function.
Participating patients underwent a gastric barostat study on two
separate occasions, after treatment for 7 ± 2 days with placebo or
tegaserod 6 mg b.i.d. The order of placebo and tegaserod treatment
was equally allocated and randomized by Novartis Drug Supply
Management group, using a validated system that automates the
random assignment of treatment groups to randomization num-
bers. The study medication and identical looking placebo was
provided by Novartis. Patients were asked to take one tablet in the
morning and in the evening within 30 min prior to their meal. On
the morning of the barostat visits, study medication was admin-
istered by study staff at the site of the investigator.
Gastric emptying study
All patients underwent an octanoic acid gastric emptying breath
test prior to the start of the study. The test meal consisted of 60 g
of white bread, an egg, the yolk of which was doped with 74 kBq of
13
C octanoid acid sodium salt (DuPont, NEN Research, Boston,
MA, USA) and 300 mL of water. All meals were consumed within
a 5-min period. The total caloric value of the test meal was
250 kcal. At each sampling point, the subject exhaled into a tube
for measuring exhaled 13C. The 13C breath content was deter-
mined by on-line gas chromatographic purification-isotope ratio
mass spectrometry (ABCA, Europe Scientific, Crewe, UK). Gastric
half emptying time (t1/2) was calculated from the 13CO2 content of
breath samples as previously described.21
 2010 Blackwell Publishing Ltd
Tegaserod and proximal stomach function in functional dyspepsia.
Barostat recording technique
Patients presented to the motility unit following an overnight
fast.A double lumen polyvinyl tube (Salem sump tube 14 Ch.,
Sherwood Medical, Petit Rechain, Belgium) with an adherent
plastic bag (1200 mL capacity; 17 cm maximal diameter) finely
folded, was introduced through the mouth and secured to the
patient’s chin with adhesive tape. The position of the bag in the
gastric fundus was checked fluoroscopically.
With the patient in a recumbent position on a bed, the
polyvinyl tube was connected to a computer-driven programmable
barostat device (Synectics Visceral Stimulator, Stockholm, Swe-
den). To initially unfold the gastric balloon, it was inflated with a
fixed-volume of 500 mL of air for 2 min and then deflated
completely. After a 10 min equilibration period, the patients were
then positioned in a comfortable sitting position with the knees
slightly bent (80) by folding segments of the bed.
Barostat study protocol
After deflation of the bag, the subjects ingested the morning dose
of the drug followed by a 30 min equilibration period. To
determine the minimal intra-balloon distending pressure (MDP),
the intra-balloon pressure was increased by 1 mmHg every
minute until an intra-balloon volume of 30 mL or more was
reached.10,11 This intra-balloon pressure level equilibrates the
intra-abdominal pressure. Subsequently, stepwise distentions
were performed from MDP in increments of 2 mmHg every
2 min, while the corresponding intra-balloon volume was being
recorded. Patients scored the intensity of upper abdominal
sensations at the end of every distending step, by means of a
graphic rating scale which combines verbal and numerical
descriptors on a scale graded from 0 to 6.10,11 The sequence of
distentions was ended when the patients reported discomfort or
pain or when an intra-balloon volume of 1000 mL was reached.
After another 30 min equilibration period, the intra-balloon
pressure level was set at MDP + 2 mmHg for 90 min. After
30 min, a mixed liquid meal (200 mL; 300 kcal; 13% proteins,
48% carbohydrates, 39% lipids; Nutridrink, Nutricia, Bornem,
Belgium) was administered orally. At the end of the 60-min
postprandial period, a second series of stepwise gastric distentions
starting from MDP, as previously described, was performed.
Statistical analysis
Data were analyzed for all completed patients on a per-protocol
basis. The MDP was defined as the lowest intra-balloon pressure
which provides an intra-balloon volume of 30 mL or more. Based
on previous studies, gastric compliance was calculated as the
slope of the pressure–volume curve obtained after linear interpo-
lation of the stepwise ramp distension series (mL mmHg)1).22–24
Perception threshold was defined as the first level of intra-balloon
pressure that evoked a perception score of ‡1. Discomfort
threshold was defined as the first level of intra-balloon pressure
that provoked a perception score of ‡5.10
To evaluate gastric tone before and after the meal, the mean
intra-balloon volume was calculated over consecutive 5-min
intervals. Meal-induced gastric accommodation was quantified
by calculating the difference between the average intra-balloon
volume during the 30 min before and the 60 min after the
administration of the meal.11 The maximum postprandial
intra-balloon volume increase and the time needed to reach
the maximum postprandial intra-balloon volume were also
calculated.11
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J. Tack et al. Neurogastroenterology and Motility

The primary outcome variable was the magnitude of the meal- and belching (66%) were also frequently reported.
induced gastric relaxation. Based on previous studies, the study Vomiting and epigastric burning sensation were pres-
was estimated to have an 85% power to detect a 30% increase in
gastric accommodation at a 0.05 significance level. Gastric ent in respectively 43% and 67% of the patients.
compliance, sensitivity to gastric distention before and after the Weight loss in excess of 5% was present in 15 patients
meal, the maximum postprandial volume increase and the time (50%), and the mean weight loss was 5.8 ± 1.4 kg.
to maximum postprandial volume were secondary outcome
None of the patients had H. pylori infection on gastric
variables.
Data are presented as the mean ± SEM, unless specified biopsies.
otherwise. All efficacy endpoints were analyzed in the same The mean half emptying time for solids was
way using a two-way ANOVA including terms for period treatment 108 ± 13 min. Solid emptying was delayed in eight
and subject within sequence group. Differences were considered
patients (27%).
to be significant at the 5% level.
Retrospective data-driven analysis was performed on different
subsets of patients. Patients were subdivided into those with or
without delayed gastric emptying, into those with or without Fasting gastric distentions
hypersensitivity to gastric distention on the gastric barostat study
during placebo treatment, and into those with or without
The values for MDP and gastric compliance are
impaired gastric accommodation on the gastric barostat study summarized in Table 2. In all treatment arms, disten-
during placebo treatment. The influence of tegaserod on gastric tions of the stomach with progressively higher set
barostat results was compared to placebo in all of these subgroups. intra-balloon pressures produced progressively larger
intra-balloon volumes. Tegaserod had no significant
RESULTS influence on the MDP or on the slopes of the fasting
pressure–volume curves (Table 2). Intra-balloon vol-
Conduct of the study umes at different distending pressures did not differ
significantly (Fig. 1A).
Thirty four FD patients (27 females) were recruited for At the same distending pressures, similar perception
the study. Four subjects discontinued from the study scores were obtained in all treatment arms (Fig. 1B).
due to intolerance to the gastric balloon distention Treatment with tegaserod had no effect on intra-
(n = 2) or because they were lost to follow-up (n = 2). balloon pressures or volumes inducing first perception
Thirty patients (23 females, mean age 41.8 ± 2.3 years) (Table 2). Similarly, treatment with tegaserod had no
completed the study as planned. The analysis of effect on intra-balloon pressures or volumes inducing
variance revealed that the sequence in which a subject discomfort (Table 2).
underwent both treatments had no significant influ-
ence on the variables measured.
Pre and postprandial gastric volumes and
accommodation to a meal
Patient characteristics
Preprandial intra-balloon volumes did not differ
Table 1 summarizes the grading of dyspeptic symp- between placebo and tegaserod treatment [147 ± 14
toms in the patient group. Postprandial fullness and
bloating were the most prevalent symptoms, both
present in 93% of the patients. Epigastric discomfort Table 2 Summary of gastric compliance to stepwise distention in the
fasting state
(93%) or pain (90%), early satiety (80%), nausea (87%)
Tegaserod
Placebo 6 mg b.i.d.
Table 1 Summary of the symptom profile in patients enrolled for the
study. Numbers between brackets represent row percentages
No. of patients randomized 30 30
MDP (mmHg) 7.9 ± 0.4 7.4 ± 0.4
Symptom Absent Mild Moderate Severe Gastric compliance (mL mmHg)1) 52.5 ± 5.8 64.3 ± 5.1
based on all data points
Fullness 1 (3) 6 (20) 17 (57) 6 (20) Gastric compliance (mL mmHg)1) 44.4 ± 9.8 61.3 ± 6.1
Bloating 1 (3) 5 (17) 19 (63) 5 (17) based on data points representing
Discomfort 2 (7) 6 (20) 18 (60) 4 (13) >75% of subjects
Pain 3 (10) 9 (30) 16 (53) 2 (7) Pressure inducing first perception 3.6 ± 0.4 4.2 ± 0.4
Nausea 4 (13) 11 (37) 12 (40) 3 (10) (mmHg above MDP)
Satiety 6 (20) 5 (17) 14 (47) 5 (17) Pressure inducing discomfort 6.4 ± 0.7 6.3 ± 0.4
Belching 10 (33) 11 (37) 7 (23) 2 (7) (mmHg above MDP)
Epigastric burning 10 (33) 11 (37) 9 (30) 0 (0) Volume inducing first 222 ± 28 206 ± 23
Heartburn 14 (47) 8 (27) 8 (27) 0 (0) perception (mL)
Vomiting 17 (57) 8 (27) 4 (13) 1 (30) Volume inducing discomfort (mL) 550 ± 37 609 ± 32

e34  2010 Blackwell Publishing Ltd

Volume 23, Number 2, February 2011
Figure 1 (A) Fasting pressure–volume relationship obtained by step-
wise ramp distensions after treatment with placebo or tegaserod 6 mg
b.i.d. Only those levels of distention for which in at least 75% of the
subjects data were available are shown. Tegaserod did not significantly
alter fasting gastric compliance compared to placebo. (B) Fasting
pressure-sensitivity score relationship obtained by stepwise ramp dis-
tensions after treatment with placebo or tegaserod 6 mg b.i.d. Only
those levels of distention for which in at least 75% of the subjects data
were available are shown. Tegaserod did not significantly alter fasting
sensitivity to gastric distention compared to placebo.
vs 120 ± 11 mL, not significant (NS)]. In both groups,
administration of the meal caused an immediate
relaxation of the proximal stomach, reflected by an
increase in intra-balloon volume (Fig. 2). Five minutes
after the meal, the intra-balloon volume was signifi-
cantly greater than the average preprandial volume and
it remained significantly elevated until 60 min postp-
randially. Postprandial intra-balloon volumes (297 ± 28
vs 283 ± 29 mL, NS) and gastric accommodation to a
meal (151 ± 23 vs 162 ± 23 mL, NS) did not differ
between both treatments. The increase in intra-balloon
volume over time after the meal did not differ between
both treatment arms. The maximum postprandial
Figure 2 Influence of treatment with placebo or tegaserod 6 mg b.i.d.
on intra-balloon volumes before and after the meal. Both before and
after the meal, intra-balloon volumes did not differ significantly be-
tween both treatments. Meal-induced gastric accommodation also did
not differ significantly.
 2010 Blackwell Publishing Ltd
Tegaserod and proximal stomach function in functional dyspepsia.
volume increase (248 ± 30 vs 263 ± 26 mL, NS) and
the time to the maximum postprandial volume
(22.8 ± 2.8 vs 19.7 ± 2.1 min, NS) did not differ signif-
icantly.
Postprandial gastric distentions
During postprandial distentions, 60 min after ingestion
of the meal, the slopes of the postprandial pressure–
volume curves did not differ between both treatment
groups (Table 3). Intra-balloon volumes at different
distending pressures did not differ significantly
(Fig. 3A).
At the same distending pressures, similar perception
scores were obtained in all treatment arms (Fig. 3B).
Treatment with tegaserod had no effect on intra-
balloon pressures or volumes inducing first perception
(Table 3). Similarly, treatment with tegaserod had no
effect on intra-balloon pressures or volumes inducing
discomfort (Table 3).
Safety
The safety information collected included all adverse
events throughout the study period. The results of
physical examinations, data on vital signs and data from
laboratory evaluations (including pregnancy screening)
were recorded during the screening period only. No
serious adverse events occurred. The incidence of
adverse events was similar in both treatment groups,
and no difference between treatments was observed.
Adverse event with occurrence >1 in the tegaserod
group are summarized in Table 4. Gastrointestinal
events were most common and accounted for most of
the treatment difference between tegaserod and pla-
cebo during the double-blind treatment period. One
Table 3 Summary of gastric compliance to stepwise distention in the
postprandial state
Tegaserod
Placebo 6 mg b.i.d.
No. of patients randomized 29 27
Gastric compliance (mL mmHg)1) based on 68.6 ± 5.5 66.0 ± 4.7
all data points
Gastric compliance (mL mmHg)1) based on 70.9 ± 5.4 66.9 ± 4.8
data points representing >75% of subjects
Pressure inducing first perception (mmHg 3.2 ± 0.4 3.4 ± 0.3
above MDP)
Pressure inducing discomfort (mmHg 4.4 ± 0.7 4.4 ± 0.7
above MDP)
Volume inducing first perception (mL) 340 ± 35 293 ± 34
Volume inducing discomfort (mL) 624 ± 41 627 ± 41
MDP; minimal distending pressure.
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J. Tack et al. Neurogastroenterology and Motility

tegaserod did not affect gastric compliance or sensitiv-

ity to gastric distention in either group, both in the
fasting and in the postprandial period. In the subset
of patients with normal gastric emptying, gastric
accommodation tended to be greater after tegaserod
pretreatment (Fig. 4A). The postprandial increase in
intragastric volume was significantly greater after
tegaserod pretreatment, both for the first 30 min and
for the first 60 min after the meal (both P < 0.001,
2-way ANOVA with repeated measures). In those with
delayed emptying, tegaserod had no significant influ-
ence on pre- or postprandial volumes, on gastric
accommodation or on postprandial volume increase
(Fig. 4B).

Figure 3 (A) Postprandial pressure–volume relationship obtained by

stepwise ramp distensions after treatment with placebo or tegaserod
6 mg b.i.d. Only those levels of distention for which in at least 75% of
the subjects data were available are shown. Tegaserod did not signifi-
cantly alter postprandial gastric compliance compared to placebo. (B)
Postprandial pressure-sensitivity score relationship obtained by step-
wise ramp distensions after treatment with placebo or tegaserod 6 mg
b.i.d. Only those levels of distention for which in at least 75% of the
subjects data were available are shown. Tegaserod did not significantly
alter postprandial sensitivity to gastric distention compared to placebo.

Table 4 Summary of adverse events, shown as number (%)

Tegaserod 6 mg b.i.d. Placebo

Patients studied 33 33
Patients with AE(s) 28 (84.8) 16 (48.5)
Adverse event n (%) n (%)
Diarrhea 15 (45.5) 5 (15.2)
Nausea 4 (12.1) 1 (3.0)
Flatulence 4 (12.1) 0 (0.0)
Loose stools 3 (9.1) 1 (3.0)
Headache 2 (6.1) 2 (6.1)
Dyspepsia 2 (6.1) 0 (0.0)
Musculoskeletal and 2 (6.1) 1 (3.0)
connective tissue disorders
Musculoskeletal and 2 (6.1) 1 (3.0)
connective tissue disorders
Respiratory, thoracic and 2 (6.1) 2 (6.1)
mediastinal disorders

Serious Adverse Event (pharyngolaryngeal pain result-

ing in hospitalization) was reported in a patient during
double-blind treatment with tegaserod 6 mg b.i.d. The
etiology of the throat ache remains unclear, but was
considered unrelated to the study drug.
Analysis of the role of gastric emptying rate
When patients were subdivided into those with delayed
(n = 8) and with normal (n = 22) solid gastric emptying,
Figure 4 (A) Influence of treatment with placebo or tegaserod 6 mg
b.i.d. on the postprandial increase in intra-balloon volume in func-
tional dyspepsia (FD) patients with normal gastric emptying. The
postprandial increase in intragastric volume was significantly greater
after tegaserod pretreatment, both for the first 30 min and for the first
60 min after the meal (both P < 0.001, 2-way ANOVA with repeated
measures). (B) Influence of treatment with placebo or tegaserod 6 mg
b.i.d. on the postprandial increase in intra-balloon volume in FD
patients with delayed gastric emptying. No significant difference could
be detected.

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Volume 23, Number 2, February 2011
Subgroup analysis in the patients with normal
sensitivity or with hypersensitivity to gastric disten-
tion during placebo treatment did not show a differen-
tial effect of tegaserod on accommodation, but
tegaserod increased the threshold for discomfort during
fasting distentions in those with hypersensitivity to
gastric distention (4.9 ± 0.6 vs 8.0 ± 0.8 mmHg above
MDP, P < 0.05). Subgroup analysis in the patients with
normal accommodation or with impaired accommoda-
tion during placebo treatment did not demonstrate any
differential effects of tegaserod.
DISCUSSION
Functional Dyspepsia is considered a heterogeneous
disorder, in which different pathophysiological mecha-
nisms underlie a heterogeneous symptom pattern.1,2
The available options for the treatment of FD are of
limited efficacy, which probably reflects the incomplete
understanding of the nature of this disorder. It has been
proposed that treatment in FD should preferably be
directed towards the underlying pathophysiological
disorder,25 but these are not readily identifiable in
clinical practice. A meta-analysis of randomized
controlled studies suggests that FD patients with
co-existing heartburn, or with predominant epigastric
pain may respond to proton pump inhibitor (PPI) ther-
apy, while those with motility-like symptoms do not
respond to PPIs.26 Based on a meta-analysis, it can be
presumed that FD patients with motility-like symptoms
may respond to prokinetic drugs,27 but this conclusion is
hampered by the low quality of the available trials,
a potential reporting bias towards positive studies, and
limited availability of the drugs that were studied.
Tegaserod is a selective 5-HT4 receptor partial
agonist which enhances solid gastric emptying in
man.17 This prokinetic effect may provide a rationale
for its use in FD patients with delayed emptying, but
does not take into account potential effects of the drug
on other pathophysiological mechanisms like hyper-
sensitivity to gastric distention or impaired accommo-
dation. Effects on proximal stomach function are
potentially relevant, as they have been implicated in
the failure of the gastroprokinetic motilin agonist
ABT-229 to provide symptomatic benefit in FD.28–33
In the present study, we therefore investigated the
effects of tegaserod on gastric accommodation to a
meal and sensitivity to gastric distention in FD
patients. We observed that pretreatment with tegas-
erod did not alter sensitivity to gastric distention and
did not affect meal-induced gastric accommodation in
FD patients as a group. The lack of a significant effect
of tegaserod on these functions suggests that tegaserod
 2010 Blackwell Publishing Ltd
Tegaserod and proximal stomach function in functional dyspepsia.
may be less likely to induce worsening of symptoms
through unfavorable effects on these putative patho-
physiological mechanisms. On the other hand, these
findings are at variance with a study in healthy
volunteers, where tegaserod pretreatment enhanced
pre- and postprandial gastric volumes.18 They are also
at variance with a study which showed an enhanced
relaxatory response to duodenal nutrient infusion in
healthy volunteers and FD patients after tegaserod
treatment34 and they fail to explain the tendency for
symptomatic benefit observed in women with FD and
normal gastric emptying during treatment with tegas-
erod 6 mg b.i.d. in phase 2 studies.15
For this reason, post-hoc analyses were performed
according to baseline pathophysiological abnormali-
ties. No differences in effects of tegaserod on proximal
stomach function were observed according to baseline
gastric sensitivity or gastric accommodation status. In
patients with normal gastric emptying, tegaserod was
found to significantly enhance gastric accommodation,
and such effect might be relevant with regards to
symptomatic outcomes.34,35 This effect is in line with
previous studies investigating the effects of cisapride or
tegaserod on gastric accommodation in healthy sub-
jects, which also showed that these 5-HT4 agonists
enhanced accommodation.18,23 Impaired gastric
accommodation is considered a major pathophysiolog-
ical mechanism in FD, and an improvement of this
abnormality could be relevant to symptom improve-
ment in FD patients with normal gastric emptying.35
In the subgroup of patients with delayed emptying, no
such effect was found and, in fact, the tendency was
towards a decrease in accommodation. The mechanis-
tic basis for a differential effect on gastric accommo-
dation depending on gastric emptying rate is unclear.
One hypothesis could be that a neuromuscular abnor-
mality underlying delayed gastric emptying (such as for
instance abnormal nitric oxide synthesis36) leads to a
decreased or altered responsiveness to 5-HT4 receptor
stimulation. Alterations in gastro-gastric reflexes have
also been implicated in the pathogenesis of symptoms
in FD patients, who display impaired fundic relaxation
in response to antral distention.37 It is conceivable that
5-HT4 receptor stimulation overcomes this dysfunc-
tion in the subgroup of patients with normal emptying,
while improvement of antral contractility and gastric
emptying by tegaserod17 in those with delayed empty-
ing may actually lead to decrease in fundic relaxation.
Further studies will be required to further clarify the
effects of tegaserod or other on proximal and distal
gastric motor function in patients with gastroparesis.
The current Rome III definition of FD proposes a
subdivision into diagnostic categories of meal induced
e37
J. Tack et al. Neurogastroenterology and Motility

dyspeptic symptoms [postprandial distress syndrome
(PDS), characterized by postprandial fullness and early
satiation] and epigastric pain syndrome (EPS), charac-
terized by epigastric pain and burning.1 It remains to be
studied whether the Rome III subdivision would
identify subgroups of patients with a more homoge-
neous effect of tegaserod, or other 5-HT4 receptor
agonists, on proximal stomach sensorimotor function.
Meanwhile, phase 3 studies have been conducted
comparing tegaserod 6 mg b.i.d. to placebo in FD,
without stratification according to gastric emptying
status.16 Statistically significant benefit was obtained
in one study, but not in the other, and overall
therapeutic gain seemed small, although it was larger
in the patients with higher baseline symptom sever-
ity.16 The drug was well tolerated in this FD program,
but was withdrawn in 2007 for increased incidence of
cardiovascular ischemic events.
Currently, a number of other 5-HT4 receptor agon-
ists are being developed, which may be devoid of
cardiovascular effects38 and which are potential candi-
dates for the treatment of dysmotility-like FD, which
remains an unmet clinical need for the majority of
affected patients. In healthy controls, cisapride and
tegaserod, two 5-HT4 receptor agonists of a different
chemical class, enhanced postprandial gastric volumes,
suggesting that there is a consistent effect of 5-HT4
receptor agonists on gastric accommodation.18,23 The
present study suggests that the effects of 5-HT4-
receptor agonists on gastric sensorimotor function in
FD may differ, depending on the underlying patho-
physiology. Whether this differential mechanistic
effect has implications for the symptomatic outcome
of tegaserod, or other 5-HT4 receptor agonists under
development, in the treatment in FD remains to be
established.
In summary, we observed that tegaserod 6 mg b.i.d.
does not alter gastric compliance, sensitivity to gastric
distention and meal-induced gastric accommodation in
FD patients as a group. Tegaserod was well tolerated
and had no major side effects. In the subgroup of
patients with normal gastric emptying, tegaserod
enhanced meal-induced gastric accommodation. Fur-
thermore, in patients with hypersensitivity to gastric
distention tegaserod increased the threshold for dis-
comfort. This study warrants further research on the
role 5-HT4 receptor agonists can play to alleviate
symptoms in FD patients.
FUNDING
This work was funded by Novartis Pharmaceuticals.
DISCLOSURES
Todd Phillips and Gervais Tougas are employees of Novartis
Pharmaceuticals.
AUTHOR CONTRIBUTIONS
Design of the study: JT, GT, TP; Patient selection: JT, RB; Study
procedures: RV, JT; Data analysis: JT, TP; Interpretation: JT, PJ;
Manuscript writing and editing, figures and tables: JT, PJ.

dyspepsia. Am J Gastroenterol 2003; 10 Tack J, Caenepeel P, Fischler B,

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