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Keywords:

  • colonic motility;
  • irritable bowel syndrome;
  • mosapride;
  • serotonin (5-hydroxytryptamine);
  • visceral perception

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

Background  The 5-HT4 receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS).

Methods  Thirty-seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (= 19) or placebo (= 18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10-min period.

Key Results  The pain threshold in the patients was significantly lower than that in controls (< 0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (< 0.01; group × period interaction by two-way anova) and increased the mean number of contractions (< 0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea-predominant subjects), mosapride (= 13) increased rectosigmoid tone (< 0.01) and contractions (< 0.05) more than placebo (= 14).

Conclusions & Inferences  Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.


Abbreviations:
5-HTTLPR

5-hydroxytryptamine (serotonin) transporter linked promoter region

AML

ascending method of limits

PVEs

phasic volume events

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder that is characterized by recurrent abdominal pain/discomfort and abnormal bowel function.1 Although it has been reported that IBS symptoms are associated with disturbances in GI motility and enhanced visceral sensitivity,1,2 the pathophysiology of IBS is not fully understood. Serotonin [5-hydroxytryptamine (5-HT)] is a pivotal regulatory monoamine of GI motility 3,4 and dysfunction of serotonergic signaling is considered important in the pathogenesis of IBS and may represent a therapeutic target.4 [Correction added after online publication 25 May 2011: serotonin has been corrected to monoamine from peptide]

Studies have shown that serotonergic agents, acting primarily through 5-HT3 and 5-HT4 receptors, provide clinical benefit to patients with functional GI disorders including IBS.5 Mosapride citrate is a selective 5-HT4 receptor agonist with no affinity for 5-HT1, 5-HT2, adrenaline α1/2, or dopamine D2 receptors.6 The principal metabolite (M1) of mosapride is a weak serotonin 5-HT3 antagonist. Mosapride enhances gastric emptying and motility-facilitating acetylcholine release from enteric cholinergic neurons.6 Its clinical use includes functional dyspepsia and diabetic gastroparesis.6,7 It has also been shown to increase bowel frequency in patients with constipation related to Parkinsonism8 and diabetic neuropathy.9 Mosapride is widely used in patients with dyspepsia symptoms in Japan, South Korea, and China6 and has no serious side effects unlike tegaserod which was withdrawn from the US market due to cardiotoxicity.

The human 5-HT transporter (5-HTT) gene, SLC6A4 (solute carrier family 6 member 4), is located on chromosome 17q12, and a variant in its upstream promoter region has been identified.10 The 5-HTT linked promoter region (5-HTTLPR) polymorphism with long (l, 528 bp) and short (s, 484 bp) forms affect the expression and function of 5-HTT. This allele is associated with lower promoter transcriptional efficacy, leading to lowered 5-HTT expression and reduced cellular uptake of serotonin in the presynaptic nerve terminals of serotonergic neurons. Thus, 5-HTT dysfunction may contribute to behavioral and functional gut disorder. However, a recent meta-analysis study11 concluded that 5-HTTLPR genotypes are not risk factors for IBS. Nevertheless, some studies have explored possible correlations between genotypes and the therapeutic responses of IBS patients to serotonergic agents. A recent pharmacogenomic study12 reported that IBS patients with constipation who express the long homozygous genotype (l/l) responded poorly to treatment with the 5-HT4 receptor agonist, tegaserod. Thus, the polymorphism may influence acceleration of colonic transit during the serotonergic treatment for IBS.

Although modulations of 5-HT and its receptors are considered to play an important role in IBS treatment, no studies have reported the effect of mosapride on colonic function in IBS patients. The primary aim of the present study, therefore, was to investigate whether mosapride changes rectosigmoid motility and perception in patients with IBS. The secondary aim of the study was to confirm whether 5-HTTLPR genotypes influence the effect of mosapride.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

Subjects

Thirty-seven patients with IBS meeting Rome II criteria13 (24 female patients; mean age, 23 ± 1 years) were recruited by advertisement at Tohoku University Campus in Sendai, Japan. Inclusion criteria also included abdominal pain/discomfort with two of the following characteristics for at least 12 weeks (not necessarily consecutive) in the previous 12 months: (i) relief of symptoms with defecation; (ii) onset associated with a change in stool frequency; and (iii) onset associated with a change in stool form. Each participant underwent a medical interview and physical examination so that subjects with organic disease could be excluded. Subtyping of predominant bowel habit (stool consistency and frequency) classified patients as constipation-predominant (IBS-C) or diarrhea-predominant (IBS-D) according to Rome II diagnostic classification.13 The remaining subtype was classified as alternating IBS (IBS-A). Eighteen healthy subjects without any significant or recurring GI symptoms (10 female subjects; mean age, 24 ± 1 years) participated in this study as controls. Subjects were excluded if they had undergone abdominal surgery other than appendectomy or had suffered serious physical or psychiatric complications, and they were not pregnant at the time of study. The study was approved by Tohoku University Ethics Committee, and written informed consent to participate was obtained from all participants. This clinical trial is registered in JMACCT (ID: JMA-IIA00040).

Assessment of GI symptoms, psychological symptoms, and quality of life

Gastrointestinal symptoms, negative emotion, and quality of life (QOL) were assessed by validated questionnaires. Gastrointestinal symptoms were evaluated by the IBS Severity Index (IBSSI),14,15 disease-specific QOL was examined by the IBS-QOL,16,17 and psychological tendencies were evaluated by the Self-rating Depression Scale (SDS)18 and State-Trait Anxiety Inventory (STAI).19 All questionnaires were validated in Japanese.

Colonic sensory and motility testing

Patients were requested to fast for at least 12 h prior to sensory and motility testing. The barostat is a computer-controlled pump (Distender II model; G&J Electronics, Willodale, ON, Canada) used for testing perception thresholds and smooth muscle tone in the lumen of the bowel.20 It inflates a plastic bag to a predefined pressure and maintains this pressure for a fixed period of time by adding or subtracting air. Volumes and pressures are recorded 16 times per s and are displayed graphically in real time. The rate of inflation and deflation was 38 mL s−1. Controlling the pump by means of a computer program made it possible to present complex sequences of distentions. At approximately 9:00 am, the barostat catheter was placed in the rectum prior to testing. All sensory and motility testing was performed with the subject lying in a left-lateral position to minimize pressure caused by the weight of overlying body tissues compressing the bowel.

First of all, sample distentions were performed by inflating the barostat bag in a stepwise fashion by increasing bag pressure by 2 mmHg every 15 s until the subject reported moderate pain. This served three purposes: (i) to insure that the barostat bag was unfolded; (ii) to teach the subject how to use the rating scale to describe the intensity of colonic sensations; and (iii) to decrease anticipatory anxiety.2 The individual operating pressure (IOP) during measurement of smooth muscle tone was determined as the minimum distending pressure required to overcome mechanical forces plus 2 mmHg.20

Perception thresholds in the rectosigmoid colon were assessed using the ascending method of limits (AML).20 Phasic distentions were 30 s in duration and were separated by 30-s rest intervals, starting at 4 mmHg and increasing by 4-mmHg steps until either the subject requested the protocol be stopped or a pressure of 40 mmHg was reached. Subjects were instructed to report their definite pain and urgency to defecate experienced at the end of each distention.2 The pain or urge threshold was defined as the pressure at which the subject first reported definite pain or urge to defecate.2,20 If the subject reached a pressure of 40 mmHg without reporting definite pain, then the pain threshold was defined as 40 mmHg. The pain or urge threshold was confirmed by applying pressure around the thresholds randomly in 2-mmHg steps every 30 s. Patients rested for 10 min after the sensory testing, then the resting barostat bag volume at IOP was measured for 20 min in all participants.

Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (= 19) or placebo (= 18) orally with 200 mL water. Randomization was performed by a generator (S.F.) using a table of random numbers and concealed from patients and investigators. The rectosigmoid bag volume at IOP was measured again for 60 min following dosing. After motility testing, the AML and random sequence were performed again to measure the perception thresholds. The current protocol for colonic sensory and motility testing completed within 3 h.

Rectosigmoid smooth muscle tone and contractility at IOP were evaluated during the final 10 min at baseline (IBS and healthy subjects) and within each 10-min period during the final 30 min postadministration (IBS patients only). Average barostat bag volume at IOP was recorded as a measure of smooth muscle tone.2,20 Phasic volume events (PVEs) served as a measure of phasic contractions.21,22 To control for occasional, minor changes in muscle tone, the bag volume had to differ more than 10% from the baseline tone occurring at a frequency of 1–4 min−1 to be characterized as a change.21 Movement artifacts were defined as sudden changes in bag volume that did not continue for more than 15 s and/or did not differ more than 10% from baseline; these artifacts were excluded from data analysis.

Genotyping

Peripheral blood DNA samples were obtained from 34 subjects with IBS and 17 healthy subjects. Genotyping was performed using previously described methods.23 In brief, DNA was extracted from lymphocytes and genotyped by polymerase chain reaction (PCR). Polymerase chain reaction-amplification of the polymorphism in the regulatory region of the 5-HTT gene was carried out using primer pairs reported by Lesch et al.10 The amplification products were separated on 2% agarose gel by electrophoresis and classified as long and short alleles.

To insure genotype accuracy, sequence analysis of 5-HTTLPR genes was performed on amplified PCR products purified from an agarose gel using the QIAquick Gel Extraction kit (QIAGEN, Hilden, Germany). Amplimers were sequenced directly using the ABI PRISM dRodamine™ Terminator Cycle Sequencing Ready Reaction kit (PE Applied Biosystems, Foster City, CA, USA), and excess dye terminators were removed using Centri-sep Columns (Princeton Separations, Adelphia, NJ, USA). Automated sequencing was performed on an ABI 310 Genetic Analyzer (PE Applied Biosystems). All procedures were performed according to the previous reports from our laboratory.23,24 Forward and reverse primers were used to sequence the PCR products.

Statistical analyses

Numerical values are expressed as the mean ± SEM. After checking the normal distribution, Student’s t-test was used to compare IBS patients with controls. For non-normal distributions, the Mann–Whitney U-test was used. Two-way analysis of variance (two-way anova) or three-way anova was used to compare changes in the perception thresholds, bag volume, and number of PVEs between mosapride and placebo groups in patients with IBS. Additional analyses were performed within IBS patients with constipation. For all analyses, a P-value of 0.05 defined statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

Subject characteristics are shown in Table 1. The mosapride and placebo groups of IBS patients showed significantly higher scores of IBS symptom severity and psychological symptoms (with the exception of the state anxiety score on the STAI for the mosapride group), and lower IBS-QOL scores compared with those of healthy control subjects. There was no difference in age, gender, or scores on the IBSSI, STAI, SDS, or IBS-QOL between the mosapride and placebo groups. No difference in the proportion of 5-HTTLPR polymorphisms was detected among the patient groups and controls.

Table 1.   Characteristics of IBS patient groups and healthy controls
 Healthy controlsIBS placeboIBS mosapride
  1. IBS, irritable bowel syndrome. Data were expressed as mean ± SEM. *< 0.05, **< 0.01 vs controls.

Number (female)18 (10)18 (11)19 (13)
Age (years)24 ± 124 ± 123 ± 1
Subtypes of bowel habit
 Diarrhea-predominant46
 Constipation-predominant89
 Alternating64
IBS symptom severity (overall)39 ± 9227 ± 22**257 ± 25**
IBS-QOL score99 ± 083 ± 3**77 ± 4**
Trait anxiety score (STAI)41 ± 351 ± 3*51 ± 3*
State anxiety score (STAI)39 ± 348 ± 3*44 ± 2
Depressive score (SDS)34 ± 245 ± 2**42 ± 2**
5-HTTLPR genotype (number)
 Short homozygous101312
 Short/long heterozygous535
 Long homozygous210
 Uninvestigated112

There were no differences between the mosapride and placebo groups in the smooth muscle tone, number of PVEs, or perception threshold at baseline (Tables 2 and 3). Pain thresholds of both patient groups at baseline were significantly lower than those of controls (mosapride, < 0.01; placebo, < 0.05), but urge thresholds did not reach a significant level (mosapride, = 0.08; placebo, = 0.06). There was no difference in the pain or urge threshold, mean bag volume (i.e., smooth muscle tone), or number of PVEs among patients with IBS-C, IBS-D, and IBS-A.

Table 2.   Changes in rectosigmoid motility pre- and postadministration of mosapride in IBS
 Healthy controls (= 18)IBS placebo (= 18)IBS mosapride (= 19)
  1. IBS, irritable bowel syndrome; IOP, individual operating pressure; PVEs, phasic volume events. Data were expressed as mean ± SEM. *< 0.05, **< 0.01 vs placebo group. < 0.01, group × period interaction between mosapride and placebo groups by two-way anova.

IOP (mmHg)9 ± 09 ± 09 ± 0
Mean bag volume (mL)
 Baseline preadministration149 ± 10145 ± 10153 ± 12
 30–40 min postadministration147 ± 11147 ± 13
 40–50 min postadministration146 ± 12126 ± 11
 50–60 min postadministration153 ± 12119 ± 11*
Number of PVEs (times per 10 min)
 Baseline preadministration0.8 ± 0.30.8 ± 0.21.0 ± 0.3
 30–40 min postadministration1.3 ± 0.43.1 ± 0.7*
 40–50 min postadministration1.3 ± 0.43.6 ± 0.8*
 50–60 min postadministration1.5 ± 0.54.2 ± 0.9**
Table 3.   Changes in visceral perception thresholds during the rectosigmoid distention
 Healthy controls (= 18)IBS placebo (= 18)IBS mosapride (= 19)
  1. IBS, irritable bowel syndrome. Data were expressed as mean ± SEM. *< 0.05, **< 0.01 vs controls.

Pain threshold at baseline (mmHg)38 ± 134 ± 2*31 ± 2**
Pain threshold after administration (mmHg)32 ± 228 ± 2
Urge threshold at baseline (mmHg)32 ± 127 ± 227 ± 2
Urge threshold after administration (mmHg)27 ± 227 ± 2

Samples of traces for barostat bag volume at IOP after administration of mosapride or placebo are shown in Figure 1. In IBS patients, administration of mosapride citrate significantly decreased the mean bag volume compared with placebo (< 0.01; group × period interaction by two-way anova, Table 2) and increased the mean number of contractions (< 0.01; Table 2) compared with placebo, but did not affect pain or urge perception (Table 3). To adjust for any baseline difference in smooth muscle tone for each subject, comparison of the percentage of bag volume postadministration was performed. The analysis showed again that mosapride significantly decreased bag volume compared with placebo (< 0.01; group × period interaction by two-way anova; Figure 2). When the predominant bowel habit (i.e., constipation, alternator, or diarrhea) was considered to be a covariate factor for the further analyses, the subtypes did not significantly influence any findings of the colonic motility or perception.

image

Figure 1.  Samples of barostat bag volume at individual operating pressure in response to administration of mosapride (A) or placebo (B) from each patient group. Traces were obtained 40–60 min postadministration. Low bag volume indicates elevated smooth muscle tone in the rectosigmoid colon.

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image

Figure 2.  Changes in rectosigmoid smooth muscle tone postadministration of mosapride (closed bars, = 19) or placebo (open bars, = 18) in patients with irritable bowel syndrome. Smooth muscle tone was measured as mean bag volume in 10-min time periods from 30 min postadministration (i.e., post 30–40, 40–50, and 50–60 min). Bars show percentage of baseline value for the groups. Data are expressed as mean + SEM. *< 0.05 vs placebo group.

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In the patients with constipation (i.e., excluding diarrhea-predominant subjects), mosapride (= 13) significantly decreased bag volume (< 0.01; group × period interaction) and increased number of contractions (< 0.05) compared with placebo (= 14; Table 4). There was no gender difference in the effect of mosapride on the rectosigmoid motility and perception (data were not shown). No adverse effects were observed during the study.

Table 4.   Changes in rectosigmoid motility pre- and postadministration of mosapride in IBS patients with constipation
 IBS-C placebo (= 14)IBS-C mosapride (= 13)
  1. IBS, irritable bowel syndrome; PVEs, phasic volume events. Data were expressed as mean ± SEM. #= 0.05, *= 0.01, **< 0.01 vs placebo group. < 0.05, < 0.01, group × period interaction between mosapride and placebo groups by two-way anova.

Mean bag volume (mL)
 Baseline preadministration143 ± 8155 ± 13
 30–40 min postadministration143 ± 10142 ± 16
 40–50 min postadministration137 ± 12117 ± 12
 50–60 min postadministration143 ± 12109 ± 13#
Number of PVEs (times per 10 min)
 Baseline preadministration0.5 ± 0.21.2 ± 0.4
 30–40 min postadministration1.1 ± 0.43.8 ± 0.9*
 40–50 min postadministration1.1 ± 0.44.1 ± 0.9**
 50–60 min postadministration1.2 ± 0.44.2 ± 0.9**

The 5-HTTLPR polymorphisms were not associated with a dominant bowel habit or any symptom severity in IBS patients. In mosapride group, patients with the short homozygous (s/s) genotype showed more increase in phasic contractions during 50- to 60-min period compared with patients with the long (l/s merged with l/l) genotype (5.3 ± 1.1 vs 1.6 ± 0.8 times, < 0.05). Three-way anova interaction analysis (with group, genotype, and period as main effects) revealed a significant interaction effect on the number of PVEs between group and genotype (< 0.01), but not on bag volume or perception threshold.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

This is the first study to be conducted on the effects of mosapride citrate, a 5-HT4 receptor agonist with a partial 5-HT3-receptor antagonized affiliation, on IBS. The findings reveal that a single administration of 15 mg mosapride citrate significantly increases rectosigmoid smooth muscle motility in IBS patients, regardless of the dominant bowel habit or gender. Perception threshold to rectosigmoid distention was not affected by a 15-mg administration of this agent. Our study also demonstrates that the short allele of the 5-HTTLPR polymorphism may be associated with more increase in smooth muscle contractility to mosapride compared with the long allele genotype.

These observations suggest that the role of 5-HT4 may predominate in the control of colonic tonic and phasic motor activity with respect to the effect of mosapride. 5-HT4 activity is associated with the peristaltic contraction of the GI tract.25 However, the effect of mosapride on colonic function has not been well investigated. Mosapride was shown to augment not only upper but also lower GI motility in animal models.26,27 Previously, the upper GI prokinetic effect of mosapride in health and diseases has been investigated.7,28 In patients with Parkinson’s disease who have constipation, mosapride significantly shortened the total colonic transit time and facilitated defecation.8 Other 5-HT4 agonistic agents (e.g., cisapride, tegaserod, and prucalopride) have also been shown to accelerate colonic transit time.29–31 Recently, it was reported that treatment of IBS-C patients with tegaserod improved postprandial modification of rectosigmoid tone.32 However, administration of this agent failed to increase fasting rectosigmoid tone in patients with IBS-C.32

Management of visceral pain hypersensitivity is thought to play an important role in treatment strategy of IBS.1 It has not been determined whether 5-HT4 receptor activation modifies visceral perception, even though it might be expected to increase afferent excitability via adenylate cyclase coupling.33 However, another 5-HT4 agonist tegaserod (0.3 mg kg−1) was found to inhibit the heightened visceromotor response to nociceptive colorectal distentions (40 mmHg or more) in a rat model.34 Recently, Seto et al. found that higher dose of mosapride (3 and 10 mg kg−1) and its major metabolite M1 (1 mg kg−1) significantly inhibited pain-related abdominal muscle contractions induced by gastric balloon distention in rats.35 On the other hand, in patients with IBS-C, tegaserod (6 mg b.i.d. for 7 days) failed to decrease the maximal volume of rectal distension tolerated.36 In the present study, a single administration of mosapride (15 mg) did not change perception threshold to colonic distention in IBS patients. Therefore, a higher dose of mosapride might have significant effects on decrease in visceral pain sensitivity.

Li et al.12 investigated the association between 5-HTTLPR polymorphisms and the clinical efficacy of a 4-week treatment period with tegaserod in 41 Chinese IBS patients with constipation. They reported that the responder rate to tegaserod was significantly higher in the short homozygous and heterozygous genotype than in the long homozygous genotype, but did not assess any physiological findings. The long genotype may be associated with insufficient endogenous 5-HT release at the enteric neurons. Thus, this may affect the attenuated effect of the 5-HT4 receptor agonists in colonic motility.

No complications were observed after administration of mosapride in the present study. Previously, a small number of IBS patients treated with other serotonergic agents experienced serious adverse events. Alosetron was associated with ischemic colitis, while patients receiving tegaserod experienced a small excess number of cerebrovascular and cardiovascular ischemic events.5 These adverse sequelae led to both agents being withdrawn from the US market. Both drugs have now been reintroduced with some restrictions. Fortunately, mosapride was well-tolerated in clinical trials and no life-threatening adverse events were associated with it in human or animal studies.6

The present study has some limitations. Firstly, a single administration was performed to observe changes in the rectosigmoid motility or perception in patients with IBS. Changes in clinical symptom severity or disease-specific QOL were not able to be assessed during such a short observation period (within 3 h) in the current protocol. Secondly, we did not assess colonic mucosal inflammation or cytokines in the present study. It has been reported that intestinal immune activation in proximity to nerve terminals was associated with severity of abdominal pain in IBS patients.37 Mosapride citrate may have mucosal anti-inflammatory effect together with prokinetic action in a postoperative ileus rat model.38 In this model, a number of macrophages and neutrophils significantly increased in the intestinal smooth muscle, resulting in induction of inflammatory mediators after administration of mosapride (0.3 and 1 mg kg−1). Lastly, only a small number of participants carried the long allele of the 5-HTTLPR polymorphism. It has been reported that the long allele genotype is significantly more prevalent in Caucasian subjects than those of Asian subjects.10,11,24 This might result in misleading the pharmacogenomic conclusions. However, selection bias was unlikely in this randomized control study as the proportion of genotypes in each group was almost in accordance with that of a previous study undertaken in the Eastern countries.11,23,24 Additional long-term multicenter clinical trials from both Western and Eastern countries are required to explore the precise effect of mosapride.

From the present preliminary study, mosapride citrate was observed to stimulate colonic motility in IBS patients without any adverse effect. These findings suggest that mosapride may act dominantly on 5-HT4 receptors in the gut, and have the potential to be a novel, safe agent for the treatment of IBS with constipation and/or functional constipation. Furthermore, 5-HTT pharmacogenomics may influence the colonic motility response to a 5-HT4 receptor agonist. Further clinical trials are warranted to confirm the efficacy of mosapride.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

This study was supported by Grants-in-Aid from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan and Research Grant from Dainippon Sumitomo Pharma Co. Ltd., Japan.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

The authors have no conflict of interest except Shin Fukudo. Shin Fukudo received Grant/Research support from Dainippon Sumitomo Pharma Co. Ltd.

Author Contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References

MK prepared the study concept and design, performed data collection, data analysis and drafting of the manuscript; SW and CT carried out subject recruitment and data collection; HK and MA carried out the data analysis; SF prepared the study concept and design, and carried out critical revision of the manuscript.

References

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. Author Contribution
  10. References
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