Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito

BMC Gastroenterology

Tetsuo Arakawa⁴  Motoyasu Kusano⁸  Kazuma Fujimoto^1,15  Kazuhide Higuchi⁶  Sumio Watanabe⁵  Shin’ichi Takahashi^1,17  Ken Haruma^1,10  Yoshikazu Kinoshita⁹  Hiroto Miwa^1,12  Kazunari Murakami^1,13  Takahisa Furuta¹  Katsuhiko Iwakiri^1,11  Akihito Nagahara⁵  Hiroaki Kusunoki^1,10  Takeo Odaka⁷  Kouichi Sakurai²  Kenji Furuta⁹  Ryuichi Iwakiri^1,16  Toshihisa Takeuchi⁶  Yasuyuki Shimoyama⁸  Hiroshi Takeda^1,14  Mototsugu Kato³  Kazunari Tominaga⁴  Yasuhisa Sakata^1,15 

[1] Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan;Department of Gastroenterology, Kumamoto University Graduate School of Medicine, Kumamoto, Japan;Division of Endoscopy, Hokkaido University Hospital, Hokkaido, Japan;Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka City, Japan;Department of Gastroenterology, Juntendo University School of Medicine, Juntendo, Japan;Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan;Department of Gastroenterology, Chiba University Graduate School of Medicine, Chiba, Japan;Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Gunma, Japan;Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Shimane, Japan;Department of Gastroenterology, Kawasaki Medical School, Kawasaki, Japan;Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Nippon, Japan;Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan;Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan;Department of Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, Hokkaido, Japan;Department of Internal Medicine and Gastroenterology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan;Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan;Third Department of Internal Medicine, Kyorin Medical College, Kyorin, Japan

关键词: Elderly patient;    Herbal medicine;    Postprandial;    Acid-related dysmotility;    Gastroesophageal reflux;   

Others  :  854690
DOI  :  10.1186/1471-230X-14-116

 received in 2014-04-03, accepted in 2014-06-26,  发布年份 2014

【 摘 要 】

Background

The incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT.

Methods

Two hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups.

Results

There were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain.

Conclusions

RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals).

Trial registration

(UMIN000005880)

【 授权许可】

   
2014 Sakata et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group: The Montreal definition and classification of gastroesophageal reflux disease: a global evidence based consensus. Am J Gastroenterol 2006, 101:1900-1920.
• [2]Coté GA, Howden CW: Potential adverse effects of proton pump inhibitors. Curr Gastroenterol Rep 2008, 10:208-214.
• [3]Fass R: Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure. Drugs 2007, 67:1521-1530.
• [4]Fass R, Shapiro M, Dekel R, Sewell J: Systematic review: proton pump inhibitor failure in gastro-oesophageal reflux disease. Where next? Aliment Pharmacol Ther 2005, 22:79-94.
• [5]Fujimoto K: Review article: prevalence and epidemiology of gastro-oesophageal reflux disease in Japan. Aliment Pharmacol Ther 2004, 20(Suppl 8):5-8.
• [6]Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K: Strategy for treatment of nonerosive reflux disease in Asia. World J Gastroenterol 2008, 14:3123-3128.
• [7]Bacak BS, Patel M, Tweed E, Danis P: What is the best way to manage GERD symptoms in the elderly? J Fam Pract 2006, 55:251-254. 258
• [8]Fujimoto K, Iwakiri R, Okamoto K, Oda K, Tanaka A, Tsunada S, Sakata H, Kikkawa A, Shimoda R, Matsunaga K, Watanabe K, Wu B, Nakahara S, Ootani H, Ootani A: Characteristics of gastroesophageal reflux disease in Japan: increased prevalence in elderly women. J Gastroenterol 2003, 38(Suppl 15):3-6.
• [9]Fujimoto K, Hongo M: Risk factors for relapse of erosive GERD during long-term maintenance treatment with proton pump inhibitor: a prospective multicenter study in Japan. J Gastroenterol 2010, 45:1193-1200.
• [10]Furuta T, Shimatani T, Sugimoto M, Ishihara S, Fujiwara Y, Kusano M, Koike T, Hongo M, Chiba T, Kinoshita Y, Acid-Related Symptom Research Group: Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan. J Gastroenterol 2011, 46:1273-1283.
• [11]Furuta K, Kushiyama Y, Kawashima K, Shibagaki K, Komazawa Y, Fujishiro H, Kitajima N, Adachi K, Kinoshita Y: Comparisons of symptoms reported by elderly and non-elderly patients with GERD. J Gastroenterol 2012, 47:144-149.
• [12]Tominaga K, Arakawa T: Kampo medicines for gastrointestinal tract disorders: a review of basic science and clinical evidence and their future application. J Gastroenterol 2013, 48:452-462.
• [13]Tatsuta M, Iishi H: Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther 1993, 7:459-462.
• [14]Kusunoki H, Haruma K, Hata J, Ishii M, Kamada T, Yamashita N, Honda K, Inoue K, Imamura H, Manabe N, Shiotani A, Tsunoda T: Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med 2010, 49:2195-2202.
• [15]Tominaga K, Iwakiri R, Fujimoto K, Fujiwara Y, Tanaka M, Shimoyama Y, Umegaki E, Higuchi K, Kusano M, Arakawa T, GERD 4 Study Group: Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized, multicenter trial in Japan. J Gastroenterol 2012, 47:284-292.
• [16]Tominaga K, Kato M, Takeda H, Shimoyama Y, Umegaki E, Iwakiri R, Furuta K, Sakurai K, Odaka T, Kusunoki H, Nagahara A, Iwakiri K, Furuta T, Murakami K, Miwa H, Kinoshita Y, Haruma K, Takahashi S, Watanabe S, Higuchi K, Kusano M, Fujimoto K, Arakawa T, G-PRIDE Study Group: A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study. J Gastroenterol 2014. in press
• [17]Tominaga K, Kido T, Ochi M, Sadakane C, Mase A, Okazaki H, Yamagami H, Tanigawa T, Watanabe K, Watanabe T, Fujiwara Y, Oshitani N, Arakawa T: The traditional Japanese medicine rikkunshito promotes gastric emptying via the antagonistic action of the 5-HT3 receptor pathway in rats. Evid Based Complement Alternat Med 2011, 2011:248481. doi:10.1093/ecam/nep173
• [18]Fass R: Symptom assessment tools for gastroesophageal reflux disease (GERD) treatment. J Clin Gastroenterol 2007, 41:437-444.
• [19]Kusano M, Shimoyama Y, Sugimoto S, Kawamura O, Maeda M, Minashi K, Kuribayashi S, Higuchi T, Zai H, Ino K, Horikoshi T, Sugiyama T, Toki M, Ohwada T, Mori M: Development and evaluation of FSSG; frequency scale for the symptoms of GERD. J Gastroenterol 2004, 39:888-891.
• [20]Revicki DA, Wood M, Wiklund I, Crawley J: Reliability and validity of the gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. Qual Life Res 1998, 7:75-83.
• [21]Kindt S, Dubois D, Van Oudenhove L, Caenepeel P, Arts J, Bisschops R, Tack J: Relationship between symptom pattern, assessed by the PAGI-SYM questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia. Neurogastroenterol Motil 2009, 21:1183. e105
• [22]Tieerdsma HC, Smout AJ, Akkermans LM: Voluntary suppression of defecation delays gastric emptying. Dig Dis Sci 1993, 38:832-836.
• [23]Araki Y, Mukaisho KI, Fujiyama Y, Hattori T, Sugihara H: The herbal medicine rikkunshito exhibits strong and differential adsorption properties for bile salts. Exp Ther Med 2012, 3:645-649.
• [24]Miwa H, Koseki J, Oshima T, Kondo T, Tomita T, Watari J, Matsumoto T, Hattori T, Kubota K, Iizuka S: Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa. J Gastroenterol 2010, 45:478-487.
• [25]Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, Asaka M: Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 2008, 134:2004-2013.
• [26]Matsumura T, Arai M, Yonemitsu Y, Maruoka D, Tanaka T, Suzuki T, Yoshikawa M, Imazeki F, Yokosuka O: The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J Gastroenterol 2010, 45:300-307.
• [27]Fujitsuka N, Asakawa A, Uezono Y, Minami K, Yamaguchi T, Niijima A, Yada T, Maejima Y, Sedbazar U, Sakai T: Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl Psychiatr 2011, 26:e23.
• [28]van der Lely AJ, Tschop M, Heiman ML, Ghigo E: Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004, 25:426-457.
• [29]Konturek PC, Brzozowski T, Pajdo R, Nikiforuk A, Kwiecien S, Harsch I, Drozdowicz D, Hahn EG, Konturek SJ: Ghrelin-a new gastroprotective factor in gastric mucosa. J Physiol Pharmacol 2004, 55:325-336.
• [30]Utumi Y, Iseki E, Murayama N, Nozawa M, Kumagai R, Matsubara Y, Ichimiya Y, Arai H: Effect of Rikkunshi-to on appetite loss found in elderly dementia patients: a preliminary study. Psychogeriatrics 2011, 11:34-39.
• [31]Takeda H, Muto S, Hattori T, Sadakane C, Tsuchiya K, Katsurada T, Ohkawara T, Oridate N, Asaka M: Rikkunshito ameliorates the aging-associated decrease in ghrelin receptor reactivity via phosphodiesterase III inhibition. Endocrinology 2010, 151:244-252.
• [32]Pilotto A, Franceschi M, Paris F: Recent advances in the treatment of GERD in the elderly: focus on proton pump inhibitors. Int J Clin Pract 2005, 59:1204-1209.
• [33]Cremonini F, Ziogas DC, Chang HY, Kokkotou E, Kelley JM, Conboy L, Kaptchuk TJ, Lembo AJ: Meta-analysis: the effects of placebo treatment on gastrooesophageal reflux disease. Aliment Pharmacol Ther 2010, 32:29-42.
• [34]Hongo M: Epidemiology of FGID symptoms in Japanese general population with reference to life style. J Gastroenterol Hepatol 2011, 26(Suppl 3):19-22.
• [35]Tack J, Fried M, Houghton LA, Spicak J, Fisher G: Systematic review: the efficacy of treatments for irritable bowel syndrome–a European perspective. Aliment Pharmacol Ther 2006, 24:183-205.
• [36]Talley NJ, Locke GR, Lahr BD, Zinsmeister AR, Cohard-Radice M, D'Elia TV, Tack J, Earnest DL: Predictors of the placebo response in functional dyspepsia. Aliment Pharmacol Ther 2006, 23:923-936.