DOI: 10.1111/eci.12367

ORIGINAL ARTICLE Effect of acotiamide on gastric emptying in healthy adult humans Hiroaki Zai*, Kei Matsueda†, Motoyasu Kusano‡, Yoshihisa Urita*, Youichi Saito§ and Hiroki Kato§ *

Department of General Medicine and Emergency Care, Faculty of Medicine, School of Medicine, Toho University, Tokyo, Japan, †Sakura Life Clinic, Tokyo, Japan, ‡Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Maebashi, Japan, §Zeria Pharmaceutical Co., Ltd, R&D, Tokyo, Japan

ABSTRACT Background Acotiamide is a first-in-class drug that is used to treat functional dyspepsia (FD). It is considered that acotiamide acts as an antagonist on muscarinic autoreceptors in the enteric nervous system and inhibits acetylcholinesterase activity. We examined the effect of acotiamide on gastric emptying in healthy adult humans. Materials and methods Twelve healthy adult males were enrolled in this double-blind crossover study. Acotiamide or placebo was administered orally in the 12 subjects 30 min before ingestion of a nutritional liquid meal (400 Kcal/400 mL). Six of the 12 participants took 100 mg of acotiamide or placebo, and six of the 12 participants took 300 mg of acotiamide or placebo in a double-blind crossover fashion. All subjects underwent measurement of gastric emptying by the 13C breath test. Results After the meal with placebo was ingested, the %dose/h curve ascended. The %dose/h curve after a meal with 100 or 300 mg of acotiamide ascended in an identical manner compared with the results with placebo. No significant differences were observed at any studied time point, and there were no significant changes in gastric emptying parameters (gastric emptying coefficient, t-1/2ex and t-lag ex). Conclusions A single administration of 100 or 300 mg of acotiamide did not affect gastric emptying after a liquid meal in healthy adult humans. Acotiamide has profound effects on restoring delayed gastric emptying and impaired accommodation in patients with FD but may have no effect on gastric emptying in healthy subjects. Such pharmacological actions have not been observed in previous gastroprokinetic studies. Keywords

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C breath test, acotiamide, gastric emptying.

Eur J Clin Invest 2014; 44 (12): 1215–1221

Introduction Acotiamide (Zeria Pharmaceutical Co., Ltd. and Astellas Pharma Inc., Tokyo, Japan) is a first-in-class drug that is used for the treatment of functional dyspepsia (FD) and was released in June 2013 in Japan. Clinical trials indicated that acotiamide has potency to improve symptoms such as postprandial fullness, upper abdominal bloating and early satiation [1–5]. Acotiamide is effective in the treatment of patients with FDpostprandial distress syndrome (PDS) according to the Rome III diagnostic criteria. It is considered that the beneficial effects of acotiamide for the treatment of FD were based on improvement of impaired gastric accommodation and acceleration of gastric emptying rate [6,7]. However, it has not been completely elucidated how acotiamide improves the symptoms of FD-PDS. Several recent studies suggested that the pharmacological potency of acotiamide was based on inhibition of acetylcho-

linesterase (AChE), regulation of muscarinic autoreceptors and regulation of gene expression of c-aminobutyric acid (GABA) transporters in the medulla oblongata [6,8–12]. Akaike et al. [10] reported that the excitatory or inhibitory effects of acotiamide on the firing rates of neurons or actions of nicotine and GABA on area postrema (AP) neurons may explain postmeal relaxation in rats. Seto et al. [12] reported that acotiamide significantly improved both delayed gastric emptying and feeding inhibition in a restraint stress-induced model, but it did not affect basal gastric emptying nor feeding in intact rats. These results suggest that acotiamide normalises stressinduced gastric dysfunctions. That is to say, there is a high possibility that acotiamide acts as a stress modulator, and its potency as a stress modulator is probably one of the most important mechanisms of action in FD treatment. However, those studies were conducted by using animal models. More data based on clinical studies are required.

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Adam et al. [7] reported that gastric emptying in patients with FD tended to be faster on 100 mg of acotiamide treatment than when patients took a placebo, whilst no change was apparent in healthy adults. Those results are similar to the results of experiments in animals, and it is supposed that the mechanisms of action of acotiamide in humans are the same as those in animals. However, not enough data to support the estimation have been reported. The effect of acotiamide on gastric emptying in healthy subjects has not been fully studied. It was suggested that FD symptoms are caused not only by the gastric empting time, but also by the velocity of gastric emptying [13]. Therefore, we studied the effect of acotiamide on gastric emptying by administering different doses of acotiamide and by comparing the %dose/h curves (velocity of gastric emptying) over time in healthy adult humans.

Methods Design overview In this double-blind crossover study, we enrolled 12 healthy adult males. To avoid the change in gastrointestinal contractile activities induced by the ovarian cycle, female subjects were excluded from this study. This study was a phase I trial conducted at Oosaki Clinic, Shinagawa, Tokyo, Japan. The study flow chart is shown in Fig. 1. All participants underwent blood test examination, electrocardiogram, upper abdominal endoscopy and 13C-urea breath test for Helicobacter pylori examination during the 1-week screening period before the start of the study. Then, the subjects took 100 or 300 mg of acotiamide, or placebo, and gastric emptying was measured by means of the 13 C acetic breath test using a nutritional liquid meal. The agents of acotiamide and the placebo were identical in appearance,

Figure 1 Trial design. All participants underwent blood test examination, electrocardiography, upper abdominal endoscopy and 13C-urea breath test for Helicobacter pylori examination during the screening period. Test dose: Placebo, or 100 or 300 mg of acotiamide was administered orally before taking the test meal. GEBT, gastric emptying breath test.

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and acotiamide and placebo were given 7 days apart in random order to the subjects. The trial was conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, the Declaration of Helsinki and local laws and regulations. The protocol for this study was approved by the ethics committee of Oosaki Clinic. All participants provided informed consent before the study.

Eligibility of participants We recruited healthy Japanese adult males aged between 20 and 29 years (mean age 22
1  1
4 year  SD). No subjects had previously undergone gastrointestinal surgery. No subject was taking any medication that may have affected gastric motility at the time of the study. Heavy smokers who smoked more than 20 cigarettes a day were excluded from this study. Smoking was prohibited during the duration of the study. Helicobacter pylori (HP) status was assessed by the 13C urea breath test, and HP-positive individuals were excluded from this study. All subjects underwent upper abdominal endoscopy during the observation period prior to taking acotiamide and the placebo. No subjects had certain organic diseases in the oesophagus, stomach and duodenum.

Measurement of gastric emptying After overnight fasting, acotiamide (Zeria Pharmaceutical Co., Ltd.) or the placebo was administered orally in the 12 subjects 30 min before ingestion of the test meal. The subject sat in an armchair and was instructed to remain seated during the examination. In a preliminary study in adult males, we had found that after a single dose of 100 mg of acotiamide before a meal, the time at which the concentration of acotiamide in blood plasma was maximal (Tmax) was 0
96  0
34 (SD) hour after administration of acotiamide and the maximal concentration, Cmax, of acotiamide was 69
24  30
56 (SD) ng/mL (n = 29). The biological half-life (T1/2) of acotiamide was 36
5  21
2 (SD) hour (n = 6). When oral administration of 100 mg of acotiamide was carried out three times per day before every meal for 9 days, both Cmax and Tmax did not significantly change (n = 6). In addition, when 10 mg/kg of 14C-labelled acotiamide was administered orally in rats, the radioactivity in the stomach and the small intestine reached a peak at 30 min after the beginning of the test. Therefore, all subjects took the test agent 30 min before ingestion of the test meal. Six of the 12 participants took 100 mg of acotiamide or the placebo, and six of the 12 participants took 300 mg of acotiamide or the placebo in a double-blind crossover fashion. Then, the subject ingested a total of 400 mL of the liquid test meal over approximately 4 min. The subject was asked to ingest 100 mL of the liquid test meal using a straw within 1 min, and

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EFFECT OF ACOTIAMIDE ON GASTRIC EMPTYING

this was repeated three times continuously. The liquid test meal (400 kcal in 400 mL K3-S; Kewpie Corporation, Tokyo, Japan), consisting of 64
4% carbohydrate, 17
6% fat and 18% protein, was labelled with 100 mg of 1-13C sodium acetate (Cambridge Isotope Laboratories Inc., Tewksbury, MA, USA). During the 4-h period after ingestion of the test meal, a 13C breath test was performed on breath samples obtained using an exclusive nasal cannula connected to an infrared spectrometer (Breath ID System; Exalenz Bioscience Ltd., Modiin, Israel) that analyses the ratio of 13CO2 to 12CO2 in each breath sample. This system, which is mechanically identical to Microstream capnography (Covidien, Dublin, Ireland) for monitoring end-tidal CO2, collects each subject’s breath automatically under continuous suction, with virtually no cooperation from the subject. Collected breath samples were stored in intermediate cells with a built-in capnography to regulate the CO2 concentrations in the breath collections, which were subsequently passed on continuously and in sequence to an analysis chamber. The total number of breath samples after administration of acotiamide or the placebo ranged from 90 to 100 per subject. Ratio data obtained from breath tests were expressed as the rate of 13CO2 recovery (ratio of 13CO2 to 12CO2) per hour of each initially administered 13C-substrate (%dose/h). By plotting %dose/h values, the slope of the resulting curve corresponds to the velocity of gastric emptying between data time points. Values for %dose/h were determined by calculating the ratio of 13CO2 to 12CO2 in the breath samples.

carried out using PASW Statistics 18 for Windows (SPSS Inc., Chicago, IL, USA). Results are expressed as mean  SD, and statistical significance was set at a P-value of < 0
05.

Results Effect of acotiamide on gastric emptying in healthy adult humans after ingesting a liquid meal The time course of 13CO2 excretion (%dose/h curves) in the subjects who were used to estimate the gastric emptying rate after a meal is shown in Fig. 2 and Table 1. After the placebo followed by the liquid meal was ingested, the %dose/h curve ascended, reaching a plateau of 12
52  1
18 (SD) %dose/h at 79
75  16
70 (SD) min. The %dose/h curve after a meal with 100 or 300 mg of acotiamide, ascended in an identical manner compared with the results with placebo. No significant differences in %dose/h were observed at any of the studied time points (10, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 135, 150, 180, 210, 240 min, Table 1). There were no significant corresponding changes in GEC, t-1/2ex and t-lag ex after taking 100 or 300 mg of acotiamide (Table 2). On the basis of these data, we concluded that administration of 100 and 300 mg of acotiamide does not affect normal gastric emptying after a liquid meal in healthy adult humans.

Data analysis Gastric emptying was evaluated by using three parameters: gastric emptying coefficient (GEC), half-excretion time (t-1/ 2ex) and excretory ‘lag phase’ (t-lag ex) as defined by Ghoos et al. [14–18]. The t-1/2ex indicates the time at which half of the 13 CO2 dose, in relation to cumulative 13CO2 excretion when time is infinite, is excreted. For the reasons stated above, the t-1/2ex and scintigraphic half-emptying time are not identical; however, there is a linear correlation between t-1/2ex in the 13C breath test and scintigraphic half-emptying time. There is a linear correlation between t-lag ex and the time at which the peak of the %dose/h curve in the 13C breath test is attained.

Statistical analysis The effects of acotiamide on GEC, half-excretion time (t-1/2ex) and lag phase (t-lag ex) were compared, with subject as the variable, in analysis of variance (ANOVA). Repeated-measures two-factor ANOVA with interactions was used to analyse treatment and time effects among the six participants taking 100 mg of acotiamide, and among the six participants taking 300 mg of acotiamide. If a significant interaction between treatment and time was indicated (P < 0
05), pairwise comparisons were performed after Bonferroni correction. Statistical analyses were

Figure 2 Effect of acotiamide on gastric emptying curves (%dose/h curves). Curves of 13CO2 excretion (%dose/h) after ingestion of a liquid test meal with placebo, 100 mg of acotiamide and 300 mg of acotiamide. There was no significant interaction between time and treatment. Values with placebo are mean  SD of excretion measured in 12 subjects, and values with 100 or 300 mg of acotiamide are mean  SD of excretion measured in six subjects each.

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Table 1 Effect of acotiamide on gastric emptying; changes in the gastric emptying rate over time 0

10

20

30

40

50

60

70

80 min

%dose/h Placebo ( SD)

0

3
15 (1
50)

5
82 (1
98)

8
50 (2
15) 10
03 (2
04) 11
10 (1
82) 11
78 (1
56) 12
13 (1
32) 12
23 (1
12)

100 mg ( SD)

0

2
78 (1
07)

5
50 (1
56)

8
02 (1
81)

300 mg ( SD)

0

3
36 (0
46)

6
14 (0
98)

8
76 (1
27) 10
17 (1
37) 11
10 (1
37) 11
63 (1
33) 11
86 (1
25) 11
83 (1
16)

Placebo vs. 100 mg

–

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

Placebo vs. 300 mg

–

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

100 vs. 300 mg

–

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

9
53 (1
79) 10
62 (1
64) 11
30 (1
53) 11
66 (1
43) 11
77 (1
37)

P-value

90

105

120

135

150

165

180

210

240 min

%dose/h Placebo ( SD)

12
11 (1
03) 11
58 (1
03) 10
86 (1
15) 10
03 (1
28)

9
14 (1
38)

8
24 (1
45)

7
26 (1
52)

5
69 (1
45)

4
32 (1
30)

100 mg ( SD)

11
67 (1
36) 11
26 (1
39) 10
56 (1
48)

9
77 (1
50)

8
91 (1
58)

8
09 (1
57)

7
25 (1
60)

5
72 (1
62)

4
36 (1
33)

300 mg ( SD)

11
63 (1
08) 10
98 (0
96) 10
20 (1
00)

9
35 (1
05)

8
46 (1
12)

7
60 (1
18)

6
65 (1
25)

5
15 (1
27)

3
94 (1
23)

P-value Placebo vs. 100 mg

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

Placebo vs. 300 mg

1
000

0
901

0
854

0
901

1
000

1
000

1
000

1
000

1
000

100 vs. 300 mg

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

1
000

All %dose/h values are shown as mean  SD. Repeated-measures two-factor ANOVA (time and treatment) with interaction could not detect significant differences in %dose/h curves between placebo (n = 12), 100 mg (n = 6) and 300 mg (n = 6) of acotiamide treatment.

Table 2 Effect of acotiamide on gastric emptying parameters Placebo (n = 12) GEC ( SD) P-value t-1/2ex min ( SD) P-value t-lag ex min ( SD) P-value

3
35  0
22 †

0
82*, 0
95

130
40  21
73 †

0
96*, 0
94

78
90  16
33 †

0
97*, 0
83

Acotiamide 100 mg (n = 6)

Acotiamide 300 mg (n = 6)

3
28  0
25 ‡

0
96

133
27  22
45 ‡

0
87

3
32  0
24 – 126
71  22
42 –

80
82  15
21 ‡

0
75

74
49  12
16 –

GEC, gastric emptying coefficient. Analysis of variance (ANOVA) was used to compare the effects of acotiamide on GEC, half-excretion time (t-1/2ex) and lag-phase (t-lag ex). Acotiamide did not increase GEC, did not reduce t-1/2ex and did not change t-lag ex significantly, indicating that acotiamide has no potency to change gastric emptying in healthy adult males. *Placebo vs. 100 mg. † Placebo vs. 300 mg. ‡ 100 vs. 300 mg.

Discussion The development of acotiamide had begun in the early 1990s. In those days, several prokinetic agents such as dopamine2

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receptor antagonist and 5HT4 receptor agonist were developed, and after elucidation of the mechanism of their effect on gastrointestinal regulatory systems, the clinical use of these agents was permitted. The investigators had originally obtained the

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idea for developing acotiamide from the AChE inhibition effect of nizatidine (H2-receptor antagonist) [19–22]. The chemical structure of acotiamide actually resembles that of nizatidine in part. Many studies on the pathophysiology of FD have been carried out, and it had been considered that delayed gastric emptying induced the dysmotility-like symptoms in patients with FD. In this background, the pharmacological potency of acotiamide was assumed to be a prokinetic effect involving AChE inhibition. However, around that time, a study on the effect of ABT229 (motilide) suggested that the strong stimulation of gastric motility in patients with FD was unphysiological and might give a clue to normal gastrointestinal functions [23]. Thereafter, it has been considered that prokinetic agents that have strong potency cannot improve the symptoms of FD in many cases. In this study, we examined the effect of 100 or 300 mg of acotiamide on gastric emptying in healthy adult humans. According to the results of all evaluated factors (time-dependent gastric emptying rate, %dose/h, and the gastric emptying parameters, GEC, t-1/2ex and t-lag ex), a single administration of 100 or 300 mg of acotiamide had no effect on gastric emptying in healthy adult males. Kusunoki et al. [6] reported that acotiamide improved the impaired gastric accommodation and accelerated the gastric emptying rate in patients with FD. It is difficult to compare their results with our results, because their test meal was different from ours. They used 400 mL (13
1 kcal) of consomme soup. Energy substrates slow both gastric emptying and changes in gut contractility [24]. In addition, we do not consider that our results are contrary to their results, because the participants in our study were healthy subjects who had no gastrointestinal symptoms. Acotiamide improves gastric accommodation and antral contraction, and there may be no effect of ingesting a large liquid meal on net gastric emptying in healthy humans. That may be a very important clue to understanding the effect of acotiamide. The effect of acotiamide might be different between patients with FD and healthy adults. This estimation must be very important for understanding the mechanisms of action of acotiamide. Interestingly, previous reports indicated that it took about 2 weeks for improvement of FD symptoms after beginning treatment with acotiamide [3,5]. What is the lag time for this drug to have an effect? As reported by Akaike and Seto et al. [10,12], acotiamide probably affects the part of the central nervous system involved in the stress response. The normalisation of dysfunction in the brain–gut axis caused by stress may improve the impaired gastric motility in patients with FD. As a result, it is thought that gastric emptying is restored. That is to say, the gastrokinetic effect of acotiamide may be provided via the central nervous system. We think that such an action mechanism of acotiamide is related to the lag time.

As another interesting characteristic of the effect of acotiamide, dose-dependent efficacy has not been observed. The optimal dose of acotiamide is only 100 mg. According to a previous report [5], taking 100 mg of acotiamide was the most effective in improving the symptoms of FD compared with taking other doses (50 or 300 mg). This result also might indicate that the ameliorating effect of acotiamide was not based on accelerated gastric emptying. As for gastric accommodation, nitric oxide-induced smooth muscle relaxation is closely related to gastric accommodation. However, in studies using a barostat in healthy subjects, administration of a nitric oxide synthase inhibitor showed that nitric oxide did not play a major role in the control of sensitivity to gastric distension [25–27], and sildenafil (phosphodiesterase5 inhibitor) had no significant influence on the pressure levels inducing first perception [28]. Furthermore, stimulating gastric contractile activity did not relieve symptoms in patients with FD [23,29]. The drugs used in those studies have potency to affect gastric motility or gastric emptying in healthy adults. However, acotiamide had no potency to change gastric emptying in healthy adult males. The pathophysiology of FD is very complicated. Gastrointestinal motility, gastric accommodation, visceral perception, psychological stress and the brain–gut axis per se affect the symptoms of FD [30–35]. The difficulty in treating patients with FD is related to the heterogeneity of the aetiology of FD. It is supposed that the mechanisms of action of acotiamide may involve both peripheral and central mechanisms. Peripheral effects include inhibition of presynaptic muscarinic cholinergic autoreceptors and AChE inhibition, both leading to increased availability of acetylcholine (ACh) in the synaptic cleft which probably enhances signal transduction to enteric motor neurons. The central effects on AP neurons and on afferent vagal fibres, affect motility and counteract some stress-mediated changes in the brainstem. These multiple mechanisms of action on different levels of FD pathogenesis make it a promising therapeutic option in FD patients. In healthy subjects, those integrated gastrointestinal regulatory systems act normally. Under normal conditions, acotiamide has no potency to increase the availability of acetylcholine that can accelerate gastric emptying. The mechanism of action of acotiamide is crucially different from that of existing prokinetics such as dopmamine2 receptor antagonist or 5HT4 receptor agonist for the treatment of patients with FD. In conclusion, a single administration of 100 or 300 mg of acotiamide did not affect normal gastric emptying in healthy adult humans. Our results showed that acotiamide has no effect on gastric emptying in healthy subjects, and this may indicate that the beneficial effect of acotiamide in patients with FD results from restoring stress-induced impairment of gastric motility. Further investigations on the origin of the clinical

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benefit of acotiamide are expected and will elucidate various pathologic conditions in patients with FD.

Acknowledgements This study was supported by a grant from Zeria Pharmaceutical Co., Ltd. The authors especially thank the late Zen Itoh (Professor Emeritus of Gunma University) for his general supervision.

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Conflict of interest The authors declare that they have no conflict of interests. Address Department of General Medicine and Emergency Care, Faculty of Medicine, School of Medicine, Toho University, Omori Medical Center, 6-11-1, Omori-Nishi, Ota, Tokyo 143-8541, Japan (H. Zai, Y. Urita); Sakura Life Clinic, 1-14-7-2F, Kinshi, Sumida, Tokyo 130-0013, Japan (K. Matsueda); Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, 3-39-15, Showa, Maebashi 371-8511, Japan (M. Kusano); Zeria Pharmaceutical Co., Ltd, R&D, 10-1, Nihonbashi Kobuna, Chuo, Tokyo 103-8351, Japan (Y. Saito, H. Kato). Correspondence to: Hiroaki Zai, Department of General Medicine and Emergency Care, Toho University Omori Medical Center, 6-11-1, Omori-Nishi, Ota, Tokyo 143-8541, Japan. Tel.: +81-3-5763-6624; fax: +81-3-3765-6518; e-mail: [email protected]

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Received 17 June 2014; accepted 31 October 2014 15

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EFFECT OF ACOTIAMIDE ON GASTRIC EMPTYING

22 Ueki S, Seiki M, Yoneta T, Aita H, Chaki K, Hori Y et al. Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats. J Pharmacol Exp Ther 1993;264:152–7. 23 Talley NJ, Verlinden M, Snape W, Beker JA, Ducrotte P, Dettmer A et al. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebocontrolled trial. Aliment Pharmacol Ther 2000;14:1653–61. 24 Teramoto H, Shimizu T, Yogo H, Nishimiya Y, Hori S, Kosugi T et al. Assessment of gastric emptying and duodenal motility upon ingestion of a liquid meal using rapid magnetic resonance imaging. Exp Physiol 2012;97:516–24. 25 Kuiken SD, Tytgat GN, Boeckxstaens GE. Role of endogenous nitric oxide in regulating antropyloroduodenal motility in humans. Am J Gastroenterol 2002;97:1661–7. 26 Kuiken SD, Vergeer M, Heisterkamp SH, Tytgat GN, Boeckxstaens GE. Role of nitric oxide in gastric motor and sensory functions in healthy subjects. Gut 2002;51:212–8. 27 Boeckxstaens GE, Hirsch DP, Kuiken SD, Heisterkamp SH, Tytgat GN. The proximal stomach and postprandial symptoms in functional dyspeptics. Am J Gastroenterol 2002;97:40–8. 28 Sarnelli G, Sifrim D, Janssens J, Tack J. Influence of sildenafil on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2004;287:G988–92.

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