1 Centre for Human Drug Research, 2333 CL Leiden, The Netherlands, 2 Department of Gastroenterology, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands; and 3 Johnson and Johnson Pharmaceutical Research and Development, HP14 GT High Wycombe, United Kingdom
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ABSTRACT |
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This study investigates motilin
effects on the proximal stomach in patients with functional dyspepsia
(FD) and healthy volunteers. Eight healthy volunteers and 12 patients
with FD were infused with synthetic motilin or placebo. Proximal
gastric volume was measured with a barostat at constant pressure and
during isobaric distensions. Abdominal symptoms were scored by visual
analog scales. Plasma motilin concentrations were measured by
radioimmunoassay. Motilin concentrations and baseline gastric volumes
were similar for patients and healthy volunteers. Motilin, compared
with placebo, reduced gastric volume by 112 ml
[F(29,195); confidence interval (CI)
95%] in patients and by 96 ml [F(7,200); CI
95%] in healthy volunteers. In patients, motilin decreased compliance
by 76 ml/mmHg [F(9,143); CI 95%] compared
with placebo, which was similar in volunteers [66 ml/mmHg;
F(11,120); CI 95%]. Patients were more nauseous during motilin compared with placebo (P = 0.04), whereas healthy volunteers did not experience nausea. We
conclude that in a fasted condition, FD patients have a similar
proximal gastric motor response to motilin as healthy volunteers, but
experience an exaggerated sensation of nausea.
barostat; gastric volume; gastric volume waves
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INTRODUCTION |
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MOTILIN IS A GASTROINTESTINAL (GI) peptide hormone synthesized and released by enterochromaffin cells in the proximal small intestine (17). Endogenous motilin is involved in the regulation of interdigestive motility (16, 24). Exogenous motilin increases the number of antrum contractions (7, 9), reduces gastric fundus volume (3), and accelerates gastric emptying (15). These findings suggest a role for motilin in the regulation of upper GI motility.
Functional dyspepsia (FD) is a syndrome defined by chronic or recurrent upper abdominal symptoms without any organic or biochemical abnormality (22). The symptoms are usually related to feeding and include early satiety, epigastric pain, bloating, fullness, nausea, belching, and vomiting (21, 22). The pathogenesis of FD is unknown, but it is reported that impaired relaxation of the stomach is present in 40% of the patients. (5, 20).
Whether motilin plays a role in the pathogenesis of FD is unclear. However, motilin reduces postprandial gastric volume in healthy volunteers (6), and impaired relaxation is present in a high proportion of patients (20) In addition, the motilin agonist ABT-229 induced symptom deterioration in FD patients (23).
Therefore, it may be hypothesized that disturbances in the regulatory function of motilin may play a role in the pathogenesis of FD. Hence, interference with this regulatory mechanism may provide new treatment opportunities for FD. In light of potential future therapeutic applications of motilin agonists or antagonists, a study was performed to obtain insight into the effects of exogenous motilin on the proximal stomach in FD patients and healthy volunteers.
Gastric volume and compliance were measured by using a barostat device. As most of the knowledge on motilin is derived from manometry, knowledge of the effects of motilin in humans with regard to GI-tract compliance and tonic variations is scarce. In addition, abdominal symptoms were scored by using visual analog scales (VAS).
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METHODS |
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Experimental Design
The study was carried out by using a double-blind, randomized, placebo-controlled, two-way, crossover design. The Medical Ethics Committee of Leiden University Medical Center (LUMC) approved the study protocol. The study was performed according to Good Clinical Practice and International Conference of Harmonisation guidelines.Subjects
Thirteen FD patients (9 female/4 male; mean age 40 yr; range, 22-59 yr) and eight healthy volunteers (5 female/3 male, mean age 31 yr, range 24-40 yr) participated in two separate studies after giving written informed consent. The study with the healthy volunteers also had other objectives. The use of these subjects as controls for the present study was prospectively determined.Healthy volunteers were eligible if they were healthy as assessed by medical screening. The main exclusion criteria were a history of gastrointestinal symptoms, abdominal surgery and the use of medication.
Patients underwent a medical screening and were eligible if they had
FD, defined as persistent or recurrent upper abdominal pain or
discomfort of at least 12 wk within the last 12 mo, which did not need
to be consecutive, according to the Rome II criteria (22).
All patients had symptoms of epigastric fullness or distension after a
meal (early satiety) (Table 1). They were
excluded if there was evidence for organic disease verified by recent
(1 yr) endoscopy or a history of gastrointestinal disease or surgery that was likely to explain the symptoms. They were also excluded if
dyspepsia was relieved by defecation exclusively or was associated with
the onset of a change in stool frequency or stool form, or if they used
medication other than medication for FD. Medication for FD had to be
stopped 1 wk before the first study day.
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Barostat
An electronic barostat device (visceral stimulator; Synectic Medical, Stockholm, Sweden) was used to measure volume changes in the proximal stomach. A polyethylene bag (maximum, 1,000 ml) was tied to the end of a 16-Fr multi-lumen catheter. This catheter was connected to a barostat device (25). Pressure (mmHg) and volume (ml) were constantly monitored and recorded on a computer equipped with dedicated software that corrects volume for air compressibility and temperature (Polygram for Windows, SVS module; Synectic Medical).Study Days
Each subject participated on two study days, separated by at least 7 days, during which motilin (4 pmol · kgAfter an overnight fast of at least 10 h, subjects reported to the
LUMC in the morning of each study day. Two cannulas were inserted in
contralateral forearm veins, one for blood sampling and one for the
administration of motilin or placebo. Then the barostat catheter was
positioned through the mouth in the fundus of the stomach. Correct
position was checked by fluoroscopy. Subjects were studied in a
semirecumbent position with the lower extremities just above abdominal
level. After determination of the minimal distending pressure (MDP;
pressure level needed to overcome intra-abdominal pressure)
(13), a constant pressure procedure was started, at a
pressure of 3 mmHg above MDP. During this procedure, motilin or placebo
infusion was started for a period of 90 min, after a 20-min baseline
recording. This procedure with constant pressure continued until 45 min
after the start of the infusion. In addition, during this procedure,
the number of cyclic variations in bag volume (the so-called "volume
waves") was calculated for 10-min periods (t = 10-0 min, 0-10 min, 10-20 min, and 30-40 min).
These gastric volume waves were defined as volume changes >30 ml that revert within 2 min by at least 50% (1, 10). After
completion of the constant pressure procedure, a resting period of 20 min was scheduled. Thereafter, a stepwise pressure distension procedure was performed; isobaric distensions were performed in 1 mmHg steps, every 90 s from 0 mmHg to a maximum of 14 mmHg. The procedure was
stopped if a bag volume of 800 ml was reached or if the subject could
not tolerate further distension.
During the constant pressure procedure, predose (t = 15, 0 min) and at every 15 min (t = 15, 30, and 45 min), perception of abdominal symptoms, such as fullness, nausea, upper
abdominal pain, wish to eat, and hunger, was scored on 100 mm VAS
(19). During the distension procedure, perception of these
abdominal sensations was scored every second pressure distension. In
healthy volunteers, abdominal symptoms were scored during the
distension procedure only. After ~4 h, subjects were offered lunch
and discharged from the unit.
Sample Handling and Motilin Assay
In FD patients, blood sampling for motilin assay (5 ml; Na/EDTA-coated tubes) was performed predose and at t = 10, 20, 30, 60, 90, 95, 100, 105, 110, and 120 min, and in healthy volunteers was performed predose and at t = 10, 20, 60, and 90 min. Blood samples were collected on ice and centrifuged for 10 min at 4°C (2,000 g). The separated plasma was stored atData Analysis
Motilin pharmacokinetics. Motilin pharmacokinetic parameters for exogenous motilin were assessed, taking into account endogenous motilin levels, as described previously (7). A continuous endogenous motilin production was assumed, and the rate of production was estimated in a one-compartment model. The modeling was done by using NONMEM V software that provided individual nonlinear regression estimates for pharmacokinetic parameters (NONMEM Project Group; University of California, San Francisco, CA).
Proximal gastric volume during constant pressure procedure.
Proximal gastric volume was measured continuously, and average values
over 5-min epochs were analyzed. Baseline gastric volume was calculated
as the average volume during the 15-min period (t = 10,
5, and 0 min) preceding the start of the infusion. Subsequent
gastric volumes were calculated as the average and maximum of the
values at t = 5, 10, 15, 20, 25, 30, 35, 40, and 45 min. Treatment effects were assessed by calculating the average (0-45 min) and maximum absolute volume change from baseline
(Emax).
Proximal gastric volume during distension procedure. Proximal gastric volume was measured continuously and average values over the last 30 s of each pressure level were analyzed. Volume at the highest pressure level was analyzed.
Compliance of the proximal stomach was quantified from the distension data, by smoothing the distension volume/pressure curve (Fig. 1) by using a sigmoid Emax model. The maximum slope was used as a measure of compliance. Sigmoid Emax modeling was performed by using PROC NLIN version 8.1 (SAS Institute, Cary, NC).
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Abdominal sensation.
Perception scores on 100 mm VAS were calculated in millimeters. During
the constant pressure procedure, baseline was characterized as the
average of the VAS scores at t = 15 and 0 min.
Subsequent VAS response was calculated as the average of the values at
t = 15, 30, and 45 min. Treatment effect was
characterized by the absolute change from baseline.
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RESULTS |
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Safety
The procedure was well tolerated by all healthy volunteers and FD patients, except for one patient, who dropped out due to difficulties in swallowing the barostat catheter. A total of 12 FD patients and eight healthy volunteers completed the study.Motilin Pharmacokinetics
On the placebo and motilin study days, baseline plasma motilin concentrations were similar: 72 ± 50 and 65 ± 41 pM in FD patients and 74 ± 15 and 67 ± 19 pM in healthy volunteers, respectively. Motilin kinetics was similar between the patient and healthy volunteer group (Table 2).
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Proximal Gastric Volume During Constant Pressure Procedure
MDPs and baseline proximal gastric volumes were similar between treatments, as well as between patients and volunteers (Table 3). Motilin decreased average (0-45 min) gastric volume by 112 ml [F(29,195); CI 95%] in FD patients and by 96 ml [F(
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Proximal Gastric Volume During Distension Procedure
In one FD patient, the distension procedure was not performed because the patient was not able to tolerate the barostat catheter for longer than the 45-min constant pressure procedure.Distension of the stomach with increasing pressure levels resulted in increasing proximal gastric volumes during both treatments (Fig. 1). However, during motilin infusion the proximal stomach was not able to distend as much as during placebo, which was reflected by a reduced increase in both gastric volume and compliance (Table 3).
Motilin significantly reduced gastric volume at the highest pressure level by 129 ml [F(36,222); CI 95%] in FD patients and by 130 ml [F(21,238); CI 95%] in volunteers compared with placebo.
Gastric compliance was significantly reduced by motilin by 76 ml/mmHg [F(9,143); CI 95%] in FD patients and by 66 ml/mmHg [F(11,120); CI 95%] in healthy volunteers, compared with placebo.
No significant differences in proximal gastric volume at the highest pressure level and in gastric compliance were observed between dyspeptic patients and healthy volunteers.
Abdominal Sensation
During the constant pressure procedure, increased nauseous feelings on the start of motilin infusion, and not after placebo, were reported in dyspeptic patients. Dyspeptic patients were significantly more nauseous during motilin than during placebo treatment (P = 0.04) (Table 4). No significant differences between treatments were observed for other abdominal sensations. Although no VAS lists were filled out during the constant pressure procedure by healthy volunteers, they did not experience nausea or other abdominal symptoms during either treatment.
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During the distension procedure, during motilin infusion, the perception scores for nausea and pain were higher in dyspeptic patients (25.1 ± 25.0 and 13.2 ± 22.5 mm, respectively) than in healthy volunteers (6.3 ± 8.8 and 1.8 ± 2.0 mm, respectively), but no significant differences were observed (P = 0.059 and P = 0.172, respectively).
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DISCUSSION |
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The present study investigated the effects of motilin on the proximal stomach in dyspeptic patients and healthy volunteers, to obtain more insight in the postulated role of motilin in the pathophysiology of FD. In contrast to most studies on motilin, in which the effects are derived from manometry, the present study focused on motilin effects on gastric compliance and tonic variations by using a barostat.
In both dyspeptic patients and healthy volunteers, motilin significantly reduced proximal gastric volume and compliance and increased the number of gastric volume waves. This observation corresponds well with the findings of Coulie et al. (3). It also agrees with the observation that the motilin agonist erythromycin reduces gastric fundus volume in healthy volunteers (2).
The mechanism of action of motilin cannot be deduced from the present study. However, it is likely that motilin interacts directly with the motilin receptor, inducing smooth muscle contraction, because motilin receptors are present on the smooth muscle and nerve cells in the stomach (4, 12, 14). Increased muscle activity by motilin was also shown by the increased number of gastric volume waves, which may be the result of the stimulating effect of motilin on antrum contraction frequency reported previously (7, 9).
The present study may be considered not to provide information about the role of motilin in regulating gastric tone under physiological conditions, because the infusion resulted in systemic motilin concentrations ~10-fold higher than baseline motilin concentrations. However, because motilin is synthesized and released in the proximal GI tract and because it is likely that motilin is metabolized hepatically, it is conceivable that peripheral motilin levels do not represent the concentration at the site of action. Thus the attained high peripheral motilin concentrations can be of physiological relevance at the site of action (in the gut). This is supported further by the fact that contractions in the distal stomach were attained by these concentrations and the number of contractions was well within a physiological range (7).
Baseline gastric volume in dyspeptic patients was not different from that in healthy volunteers. Although there was an apparent difference in baseline gastric volume between treatments, this difference was not statistically significant. Also, the study was performed in a randomized, crossover and double-blind fashion, which would preclude a biased study outcome. It thus seems that interdigestive gastric volume is rather variable.
No significant difference in proximal gastric motor response to motilin between dyspeptics and healthy volunteers was observed. Also no differences between patients and volunteers could be detected for basal motilin levels and motilin pharmacokinetics. In general, it is apparently difficult to identify gastric motor differences between dyspeptics and healthy volunteers on the basis of data obtained in the fasted state, which is in line with previous reports (8, 11). This may be explained by the fact that in most dyspeptic patients symptoms are directly related to food intake (22). This complicates the establishment of a relationship between motilin and the pathogenesis of FD. In the present study, patients with the symptom "early satiety" were selected because the presence of this symptom may often be explained by impaired postprandial relaxation of the stomach (20). Because motilin impairs postprandial gastric relaxation and induces negative abdominal symptoms (6), these patients were expected to be the most sensitive for exogenous motilin administration.
The present observations do not prove the hypothesis that motilin is involved in the pathogenesis of FD. However, the role of motilin in FD cannot be excluded, because we have recently demonstrated that motilin reduced postprandial volumes in healthy volunteers (6), a feature present in 40% of dyspeptic patients (20). Also, the finding of the present study that motilin induced nauseous feelings in dyspeptic patients, whereas motilin was well tolerated by fasted healthy volunteers, suggests a role for motilin. Hence, it must be noted that no symptoms were scored during the constant pressure procedure in healthy volunteers, because in previous studies it was already shown that motilin did not induce symptoms in fasted healthy volunteers (7, 9).
It may be appropriate to study the effect of motilin on gastric accommodation and symptoms in the postprandial state in FD patients to better define a role for motilin in the pathogenesis of FD.
In conclusion, in the fasted state, dyspeptic patients have a similar proximal gastric motor response to motilin as healthy volunteers but experience an exaggerated abdominal sensation of nausea.
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ACKNOWLEDGEMENTS |
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This study was financially supported by Johnson & Johnson Pharmaceutical Research and Development (Raritan, New Jersey).
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FOOTNOTES |
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Address for reprint requests and other correspondence: I. M. C. Kamerling, Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands (E-mail: Ikamerli{at}CHDR.NL).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 2, 2003;10.1152/ajpgi.00456.2002
Received 23 October 2002; accepted in final form 18 December 2002.
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