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A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia

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A Correction to this article was published on 25 January 2021

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Abstract

Background

Acotiamide is widely used to improve symptoms in patients with functional dyspepsia (FD) in multiple large-scale clinical studies, but there are few reports about the drug’s mechanism of action. The aim of this study was to assess the effects of acotiamide on gastric accommodation and gastric emptying, gastrointestinal symptoms, and health-related quality of life (HR-QOL) in a placebo-controlled study.

Methods

We conducted a randomized, double-blind placebo-controlled study. Fifty Japanese FD patients were randomly assigned to either placebo (n = 25) or acotiamide 100 mg × 3/day for 2 weeks (n = 25). At baseline and at 2 weeks of treatment, we evaluated the patients’ gastric motility using scintigraphy to determine the accommodation and emptying values, gastrointestinal symptom rating scale (GSRS), HR-QOL (SF-8), and anxiety and depression scale (HADS).

Results

Four patients failed to complete the medication regimen and were omitted from analysis; data from 24 placebo patients and 22 acotiamide patients were analyzed. Acotiamide significantly increased gastric accommodation compared to the placebo (p = 0.04 vs. p = 0.08; respectively). Acotiamide significantly accelerated gastric emptying (50 % half-emptying time) (p = 0.02 vs. p = 0.59). Acotiamide significantly improved the total GSRS scores compared to placebo (p = 0.0007 vs. p = 0.14). HR-QOL did not differ significantly between the two groups, but acotiamide significantly improved the HADS anxiety score compared to placebo (p = 0.04 vs. p = 0.20).

Conclusions

Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients’ dyspeptic symptoms and anxiety score.

Clinical Trials Registry no: UMIN000013544.

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Abbreviations

FD:

Functional dyspepsia

HR-QOL:

Health-related quality of life

GSRS:

Gastrointestinal symptom rating scale

HADS:

Anxiety and depression scale

PDS:

Postprandial distress syndrome

PF:

Physical functioning

RP:

Role physical

BP:

Bodily pain

GH:

General health

VT:

Vitality

SF:

Social functioning

RE:

Role emotional

MH:

Mental health

PCS:

Physical component summary

MCS:

Mental component summary

AchE:

Acetylcholinesterase

Ach:

Acethlcholine

US:

Ultrasonography

References

  1. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;130:1466–79.

    Article  PubMed  Google Scholar 

  2. Mimidis K, Tack J. Pathogenesis of dyspepsia. Dig Dis. 2008;26:194–202.

    Article  PubMed  Google Scholar 

  3. Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology. 2005;129:1756–80.

    Article  PubMed  Google Scholar 

  4. Hammer J, Führer M, Pipal L, et al. Hypersensitivity for capsaicin in patients with functional dyspepsia. Neurogastroenterol Motil. 2008;20:125–33.

    CAS  PubMed  Google Scholar 

  5. Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528–33.

    Article  PubMed  Google Scholar 

  6. Aro P, Talley NJ, Ronkainen J, et al. Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study. Gastroenterology. 2009;137:94–100.

    Article  PubMed  Google Scholar 

  7. Kusunoki H, Haruma K, Manabe N, et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil. 2012;24:540–e251.

    Article  Google Scholar 

  8. Tack J, Masclee A, Heading R, et al. A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia. Neurogastroenterol Motil. 2009;21:272–80.

    Article  CAS  PubMed  Google Scholar 

  9. Matsueda K, Hongo M, Tack J, et al. A placebo-controlled trial of acotiamide for meal-related symptoms of functional dyspepsia. Gut. 2012;61:821–8.

    Article  CAS  PubMed  Google Scholar 

  10. Ueda M, Iwasaki E, Suzuki H. Profile of acotiamide in the treatment of functional dyspepsia. Clin Exp Gastroenterol. 2016;9:83–8.

    PubMed  PubMed Central  Google Scholar 

  11. Matsushita M, Masaoka T, Suzuki H. Emerging treatments in neurogastroenterology: acotiamade, a novel treatment option for functional dyspepsia. Neurogastroenterol Motil. 2016;28:631–8.

    Article  CAS  PubMed  Google Scholar 

  12. Matsueda K, Hongo M, Ushijima S, et al. A long-term study of acotiamide in patients with functional dyspepsia: results from an open-label phase III trial in Japan on efficacy, safety and pattern of administration. Digestion. 2011;84:261–8.

    Article  CAS  PubMed  Google Scholar 

  13. Xiao G, Xie X, Fan J, et al. Efficacy and safety of acotiamide for the treatment of functional dyspepsia: systematic review and meta-analysis. Sci World J. 2014;2014:541950.

    Google Scholar 

  14. Altan E, Masaoka T, Farré R, et al. Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome. Expert Rev Gastroenterol Hepatol. 2012;6:533–44.

    Article  CAS  PubMed  Google Scholar 

  15. Matsueda K, Hongo M, Tack J, et al. Clinical trial: dose-dependent therapeutic efficacy of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia—100 mg t.i.d. is an optimal dosage. Neurogastroenterol Motil. 2010;22:618–e173.

    Article  PubMed  Google Scholar 

  16. Tack J, Janssen P. Acotiamide (Z-338, YM443), a new drug for the treatment of functional dyspepsia. Expert Opin Investig Drugs. 2011;20:701–12.

    Article  CAS  PubMed  Google Scholar 

  17. Suzuki H, Hibi T. Acotiamide (Z-338) as a possible candidate for the treatment of functional dyspepsia. Neurogastroenterol Motil. 2010;22:595–9.

    Article  CAS  PubMed  Google Scholar 

  18. Abell TL, Camilleri M, Donohoe K, et al. American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol. 2008;103:753–63.

    Article  PubMed  Google Scholar 

  19. Dimenäs E, Glise H, Hallerbäck B, et al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol. 1993;28:681–7.

    Article  PubMed  Google Scholar 

  20. Turner-Bowker DM, Bayliss MS, Ware JE Jr, et al. Usefulness of the SF-8 health survey for comparing the impact of migraine and other conditions. Qual Life Res. 2003;12:1003–12.

    Article  PubMed  Google Scholar 

  21. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.

    Article  CAS  PubMed  Google Scholar 

  22. Zai H, Kusano M. Investigation of gastric emptying disorders in patients with functional dyspepsia reveals impaired inhibitory gastric emptying regulation in the early postcibal period. Digestion. 2009;79(Suppl 1):13–8.

    Article  PubMed  Google Scholar 

  23. Azpiroz F, Feinle-Bisset C, Grundy D, et al. Gastric sensitivity and reflexes: basic mechanisms underlying clinical problems. J Gastroenterol. 2014;49:206–18.

    Article  PubMed  Google Scholar 

  24. Farré R, Vanheel H, Vanuytsel T, et al. In functional dyspepsia, hypersensitivity to postprandial distention correlates with meal-related symptom severity. Gastroenterology. 2013;145:566–73.

    Article  PubMed  Google Scholar 

  25. Vanheel H, Farré R. Changes in gastrointestinal tract function and structure in functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2013;10:142–9.

    Article  PubMed  Google Scholar 

  26. Kindt S, Tack J. Impaired gastric accommodation and its role in dyspepsia. Gut. 2006;55:1685–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee KJ, Kindt S, Tack J. Pathophysiology of functional dyspepsia. Best Pract Res Clin Gastroenterol. 2004;18:707–16.

    Article  CAS  PubMed  Google Scholar 

  28. Tominaga K, Higuchi K, Ochi M, et al. Concurrent assessment of reservoir and emptying of the stomach for dyspepsia patients. Hepatogastroenterology. 2008;55:744–9.

    PubMed  Google Scholar 

  29. Tack J, Bisschops R. Mechanisms underlying meal-induced symptoms in functional dyspepsia. Gastroenterology. 2004;127:1844–7.

    Article  PubMed  Google Scholar 

  30. Quartero AO, de Wit NJ, Lodder AC, et al. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci. 1998;43:2028–33.

    Article  CAS  PubMed  Google Scholar 

  31. Ahluwalia NK, Thompson DG, Mamtora H, et al. Evaluation of gastric antral motor performance in patients with dysmotility-like dyspepsia using real-time high-resolution ultrasound. Neurogastroenterol Motil. 1996;8:333–8.

    Article  CAS  PubMed  Google Scholar 

  32. Gilja OH, Hausken T, Wilhelmsen I, Berstad A. Impaired accommodation of proximal stomach to a meal in functional dyspepsia. Dig Dis Sci. 1996;41:689–96.

    Article  CAS  PubMed  Google Scholar 

  33. Guo WJ, Yao SK, Zhang YL, Yan J, Yin LJ, Li HL. Relationship between symptoms and gastric emptying of solids in functional dyspepsia. J Int Med Res. 2012;40:1725–34.

    Article  PubMed  Google Scholar 

  34. Tack J, Talley NJ. Functional dyspepsia–symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol. 2013;10:134–41.

    Article  CAS  PubMed  Google Scholar 

  35. Matsunaga Y, Tanaka T, Saito Y. et al [Pharmacological and clinical profile of acotiamide hydrochloride hydrate (Acofide(®) Tablets 100 mg), a novel therapeutic agent for functional dyspepsia (FD)]. Nihon Yakurigaku Zasshi. 2014;143:84–94.

    Article  CAS  PubMed  Google Scholar 

  36. Kawachi M, Matsunaga Y, Tanaka T, et al. Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats. Eur J Pharmacol. 2011;666:218–25.

    Article  CAS  PubMed  Google Scholar 

  37. Nagahama K, Matsunaga Y, Kawachi M, et al. Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. Neurogastroenterol Motil. 2012;24:566–74.

    Article  CAS  PubMed  Google Scholar 

  38. Matsunaga Y, Tanaka T, Yoshinaga K, et al. Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride. J Pharmacol Exp Ther. 2011;336:791–800.

    Article  CAS  PubMed  Google Scholar 

  39. Seto K, Sasaki T, Katsunuma K, et al. Acotiamide hydrochloride (Z-338), a novel prokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats. Neurogastroenterol Motil. 2008;20:1051–9.

    Article  CAS  PubMed  Google Scholar 

  40. Tomita T, Okugawa T, Yamasaki T, et al. Use of scintigraphy to evaluate gastric accommodation and emptying: comparison with barostat. J Gastroenterol Hepatol. 2013;28:106–11.

    Article  CAS  PubMed  Google Scholar 

  41. Akaike H, Jang II, Hori N, et al. Effects of Z-338, a novel gastroprokinetic agent, on the actions of excitatory and inhibitory neurotransmitters on neurons in area postrema. J Smooth Muscle Res. 2010;46:31–47.

    Article  PubMed  Google Scholar 

  42. Kaji M, Fujiwara Y, Shiba M, et al. Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life. J Gastroenterol Hepatol. 2010;25:1151–6.

    Article  PubMed  Google Scholar 

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Acknowledgments

Toshihiko Tomita and Hiroto Miwa contributed to the concept and design of the study. Kumiko Nakamura and Toshihiko Tomita were involved in data acquisition and analysis. All authors contributed to data interpretation and critically reviewed the manuscript for important intellectual contents. All authors approved the final version of the manuscript. Tadayuki Oshima provided statistical design. Jiro Watari and Hiroto Miwa coordinated acquisition of data and trial supervision. This study was funded by Astellas Pharma Inc. and Zeria Pharmaceutical Co., Ltd. Tokyo, Japan.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Kumiko Nakamura, Toshihiko Tomita, Tadayuki Oshima, Haruki Asano, Takahisa Yamasaki, Takuya Okugawa, Takashi Kondo, Tomoaki Kono, Katsuyuki Tozawa, Yoshio Ohda, Hirokazu Fukui, Jiro Watari & Hiroto Miwa

  2. Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Fukushima Kazuhito & Shozo Hirota

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  1. Kumiko Nakamura
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Correspondence to Hiroto Miwa.

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Nakamura, K., Tomita, T., Oshima, T. et al. A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia. J Gastroenterol 52, 602–610 (2017). https://doi.org/10.1007/s00535-016-1260-7

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  • DOI: https://doi.org/10.1007/s00535-016-1260-7

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