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Pediatrics International (2015) 57, 67 3–676
doi: 10.1111/ped.12582
Original Article
Efficacy of the Japanese herbal medicine rikkunshito in infants with gastroesophageal reflux disease Kohei Otake,1 Keiichi Uchida,1 Koichiro Mori,1 Shozo Ide,1 Yuhki Koike,1 Mitsuyuki Takamura,2 Mikihiro Inoue1 and Masato Kusunoki1 1 Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine and 2Kampo Medicine Outpatient Department, Mie University Hospital, Mie, Japan Abstract
Background: Gastroesophageal reflux disease (GERD) in infants is among the most common reason for physician consultation worldwide. A traditional Japanese medicine, rikkunshito (RKT), is effective for GERD in adult and pediatric patients. The aim of this study was to evaluate the efficacy and safety of RKT in infants with GERD. Methods: Fifty-four infants were referred to between July 2004 and December 2012 for evaluation and treatment of GERD. All infants had failure to thrive. We excluded nine patients with cow’s milk protein allergy, neurological impairment or surgical indications. We retrospectively reviewed the clinical records of 45 infants with GERD. Twentynine infants were treated with RKT (TJ-43; 0.3 g/kg/day; RKT group), and 16 infants were treated with mosapride citrate at 0.5 mg/kg/day (mosapride group). The primary endpoint was RKT-induced relief of clinical symptoms and bodyweight gain in infants with GERD. Results: After 3 months of treatment, the frequency of vomiting per day was significantly lower in the RKT group than in the mosapride group (P = 0.0146) and the weight Z-score was significantly higher in the RKT group than in the mosapride group (RKT group, −2.5 ± 1.5 vs mosapride group, −5.0 ± 2.0; P = 0.0386). No adverse effects were noted in either group. Conclusions: RKT may be safe and effective for relief of GER symptoms and for bodyweight gain in infants with GERD.
Key words gastroesophageal reflux, infant, mosapride, prokinetics, rikkunshito.
Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, and GER disease (GERD), defined as symptoms or complications of GER, are common pediatric problems. Clinical manifestations of GERD in children include vomiting, poor weight gain, dysphagia, abdominal or substernal pain, esophagitis, and respiratory disorders.1 Investigations used for the diagnosis of GER in newborn infants include 24 h pH monitoring, impedance monitoring, upper gastrointestinal contrast studies, and esophagoscopy. Thorough history and physical examination with attention to warning signals, however, is generally sufficient to allow the clinician to establish a diagnosis of uncomplicated GER in infants.2 Antacid medications currently available to treat reflux are effective in raising the pH of the gastric refluxate and may therefore improve the signs and symptoms of pain and discomfort from acidic reflux, but they do not alter transient lower esophageal sphincter relaxation and are therefore not effective in treating the actual underlying cause of reflux. The mechanism of
action of prokinetic agents should allow for a reduced refluxate volume; nevertheless, the literature has not supported any significant proven benefits in the treatment of reflux in neonates and infants.3 Rikkunshito (RKT) is widely prescribed in Japan for patients with a variety of gastrointestinal symptoms, including anorexia, nausea, and vomiting.4 The effects of RKT on gastrointestinal function include stimulation of gastrointestinal motility, facilitation of gastric emptying, improvement of GER, improvement of functional dyspepsia symptoms, stimulation of ghrelin secretion, and improvement of cisplatin-induced anorexia and vomiting. Studies have shown that RKT is effective for GER in adult and pediatric patients,5,6 but there are no reports on the efficacy of RKT in infants with GER. The aim of the present study was therefore to evaluate the efficacy and safety of RKT compared with the prokinetic agent mosapride citrate in infants with GER.
Correspondence: Keiichi Uchida, MD, Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Email: kohei815 @clin.medic.mie-u.ac.jp Received 26 November 2013; revised 25 November 2014; accepted 11 December 2014.
This retrospective, open-label study evaluated the efficacy and safety of RKT (TJ-43; Tsumura, Tokyo, Japan) for relieving symptoms of GER in infants. Fifty-four infants aged ≤1 year were referred to the pediatric surgery unit at Mie University Hospital between July 2004 and December 2012 for evaluation
© 2015 Japan Pediatric Society
Methods
674
K Otake et al.
and treatment of GER symptoms. All infants were referred to treat regurgitation and failure to thrive with or without troublesome symptoms such as crying, fussing or arching of the back, refusal to feed and hematemesis. We excluded nine patients with cow’s milk protein allergy, neurological impairment, or surgical indications. Thus, 45 infants were evaluated in this study. Each infant underwent radiography of the upper gastrointestinal tract to exclude mechanical obstruction as a cause of symptoms, and no infant was found to have hiatal hernia. To compare the efficacy between the prokinetics, patients were divided into two subgroups: 29 patients were treated with RKT (TJ-43; RKT group), and 16 patients were treated with mosapride citrate (mosapride group). RKT (TJ-43) or mosapride citrate (Gasmotin; Dainippon Sumitomo Pharma, Osaka, Japan) was administered via nasogastric tube or orally (RKT group: nasogastric tube, n = 4; oral, n = 25; mosapride group: nasogastric tube, n = 3; oral, n = 19) in three divided doses. RKT (TJ-43) was administered before meals at a dose of 0.3 g/kg/day based on previously published reports.5,7,8 Mosapride citrate was administered at a dose of 0.5 mg/kg/day after meals. In this study, the dose for infants aged ≤1 year was calculated according to the conversion table of von Harnack, because the dose for pediatric patients has not been established yet. If there was no clinical improvement in the GER symptoms ≥2 weeks after the medication was started, famotidine at 0.6 mg/kg was combined with these prokinetics. The improvement was estimated on periodic questioning for the GER symptoms. Response to treatment was assessed at the clinical visits after the initiation of RKT (TJ-43) or mosapride citrate therapy. In this study, we analyzed frequency of vomiting and bodyweight, which could be quantified. The frequency of vomiting per day was retrieved from medical records before and 1, 2, and 3 months after beginning treatment. Bodyweight data were retrieved from medical records before and 1, 2 and 3 months after beginning treatment. We used changes in the weight Z-score to assess infant weight gain (Z-score = [individual weight – standardized weight]/standard deviation). Safety was assessed by recording adverse events. An adverse event was defined as any unfavorable or unintended sign (constipation, diarrhea, bad temper, edema [due to kanzo], unknown fever, etc.), whether or not it was considered to be causally related to the study drug. Parametric data are presented as mean ± SD. Non-parametric data are presented as median (interquartile range; 25th–75th percentile, IQR). Statistical analysis was performed using chisquared test with Fischer’s probability test, Mann–Whitney U-test and Wilcoxon signed-rank test. P < 0.05 was considered statistically significant. Statistical analysis was performed using STATVIEW version 5.0J (SAS Institute Japan, Tokyo, Japan).
Results The subject clinical characteristics are listed in Table 1. The clinical characteristics were not significantly different between the RKT and mosapride groups, with the exception of patients who received the combination therapy. In the mosapride group, famotidine was combined with mosapride citrate in 10 patients (62.5%). This rate was significantly higher than in the RKT group © 2015 Japan Pediatric Society
Table 1 Subject clinical characteristics
Sex, n Male Female Gestational age (weeks) Birthweight (kg) At start of therapy Age (months) Bodyweight (kg) Combination therapy, n Famotidine None
RKT group (n = 29)
Mosapride group (n = 16)
P-value
18 11 34.6 ± 5.0
8 8 37.1 ± 3.2
0.145
2.075 ± 0.860
2.384 ± 0.704
0.205
3.4 ± 2.9 2.8 ± 1.5
4.0 ± 2.4 3.2 ± 1.4
0.319 0.177 0.001
4 25
10 6
0.433
RKT, rikkunshito.
(13.8%; P = 0.002). Apparent life-threatening events were not observed in either group during this study period. No adverse effects were noted in either group. The frequency of vomiting per day in each group is presented in Figure 1(a). In both groups, the daily frequency of vomiting was significantly decreased after 1 month of treatment (RKT group: 0 months, 3 episodes/day of vomiting [IQR, 2–5] vs 1 month, 0 episodes/day [IQR, 0–2], P < 0.0001; mosapride group: 0 months, 2.5 episodes/day [IQR, 2–5] vs 1 month, 1 episode/day [IQR, 0–2], P = 0.001). The daily frequency of vomiting was significantly lower after 3 months of treatment in the RKT group than in the mosapride group (RKT group, 0 episodes/day [IQR, 0–0] vs mosapride group, 1 episode/day [IQR, 0.75–1.25], P = 0.015). With regard to weight Z-score (Fig. 1b), there was an increasing trend in the RKT group and a decreasing trend for the 3 months of treatment in the mosapride group. The weight Z-score was significantly higher after 3 months of treatment in the RKT group than in the mosapride group (RKT group, −2.5 ± 1.5 vs mosapride group, −5.0 ± 2.0; P = 0.039).
Discussion The present study has demonstrated the safety and efficacy of RKT in infants with GER. After 3 months of treatment, the daily frequency of vomiting was significantly lower and the weight Z-score was significantly higher in the RKT group than in the mosapride group. Hence, RKT was superior to mosapride citrate in terms of relief of symptoms and bodyweight gain in infants with GER. Mosapride citrate is a 5-HT4 agonist and analog of cisapride that lacks the cardiac side-effects associated with cisapride.9 It is available in Japan as well as in some other Asian countries, but not in the USA or European countries.10 Mosapride citrate may improve the symptoms of non-erosive reflux disease by various mechanisms: (i) modulation of esophageal motor function, which may result in reduction of reflux;11 and (ii) acceleration of gastric emptying.12 It is known that gastric motility is impaired in some patients with non-erosive reflux disease, and mosapride citrate has been shown to improve the symptoms in such patients.12
Efficacy of RKT in infant GERD (a)
*
*
(b)
*
*
Fig. 1 Changes in (a) median daily frequency of vomiting and (b) bodyweight Z-score after 3 months of treatment. (a) Daily frequency of vomiting was significantly lower in the ( ) rikkunshito (RKT) group than in the ( ) mosapride group (*P = 0.02), and (b) Z-score was significantly higher in the ( ) RKT group than in the ( ) mosapride group (*P = 0.04), after the 3 month treatment.
In Japan, the traditional medication RKT has been approved for medicinal use in the form of extract granules for ethical use (TJ-43; Tsumura) by the Japanese Ministry of Health and Welfare, and it is widely prescribed for patients with upper gastrointestinal symptoms.6 RKT decreases the acid exposure time in the esophagus and enhances esophageal clearance in patients with GERD.5 Several previous studies have demonstrated that RKT also has a pharmacological action similar to that of prokinetic agents, as shown by its attenuation of the gastric dysmotility caused by a nitric oxide-synthesizing enzyme inhibitor and exogenous serotonin.13–15 In addition, a double-blind trial demonstrated the efficacy of RKT in the attenuation of upper gastrointestinal symptoms such as postprandial fullness, abdominal distension, and gastric discomfort in patients with functional dyspepsia as diagnosed on the Rome II criteria, which frequently overlap with those of non-erosive reflux disease.16 These findings
675
suggest the possible efficacy of RKT in infants with GER via its pharmacological action, which is similar to that of prokinetic agents. Rikkunshito increased plasma acylated ghrelin, but the level of plasma deacylated ghrelin did not change in healthy human volunteers.17 This effect was maintained for at least 4 weeks after the end of RKT treatment. mRNA expression of ghrelin in gastric tissue was upregulated after 2 weeks of RKT treatment in mice.17 RKT stimulates endogenous ghrelin secretion from the stomach via 5-HT2B and 5-HT2C receptor antagonism.18,19 The 5-HT system in the gastrointestinal tract has an important role in the regulation of gastrointestinal motor activities. Selective serotonin re-uptake inhibitors changed the phase III-like contractions to fed-like motor activities.19 The effect of ghrelin could be one of the reasons why RKT is useful in treating infants with GER. Rikkunshito had no adverse effect in the present cohort. It has, however, been established that several potential side-effects, such as allergic reactions or impairment of liver, may occur during RKT treatment.20 Allergic reactions included skin rash, redness, and itching. The impairment of liver included fever, jaundice, brown urine, and fatigue. The most troublesome problem of Kampo medicines for pediatric physicians is its bad taste, but the taste of RKT is better than other Kampo medicines. This study has some important limitations. The most significant limitation is its retrospective and open-label design, which allowed for the possibility of placebo responses. But the fact that RKT was more effective than mosapride citrate in the present study makes a placebo effect less likely. The fact that RKT has been shown to be effective in other adult GER studies makes the effect of RKT more plausible.5,7 RKT is readily available in Japan, and its good safety profile makes it an attractive therapeutic option. The other significant limitation is that tests before and after treatment, such as esophageal pH monitoring, were not evaluated. Large prospective studies are needed to evaluate the specific effects of RKT on combined multiple esophageal impedance-pH recording in infants with GER. Finally, the feeding frequency and amount of feeding were not analyzed in the present study. Prospective studies are needed to evaluate them. Conclusion
Rikkunshito is useful in treating infants with GER via not only its prokinetic action but also its appetite-enhancing effect. To establish the efficacy of RKT therapy in infants with GER, further studies, such as prospective randomized trials, are warranted.
Acknowledgments The authors report no conflicts of interest in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication.
References 1 Rudolph CD, Mazur LJ, Liptak GS et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2001; 32 (Suppl. 2): S1–31.
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2 Vandenplas Y, Salvatore S, Hauser B. The diagnosis and management of gastro-oesophageal reflux in infants. Early Hum. Dev. 2005; 81: 1011–24. 3 Schurr P, Findlater CK. Neonatal mythbusters: Evaluating the evidence for and against pharmacologic and nonpharmacologic management of gastroesophageal reflux. Neonatal Netw. 2012; 31: 229–41. 4 Suzuki H, Inadomi JM, Hibi T. Japanese herbal medicine in functional gastrointestinal disorders. Neurogastroenterol. Motil. 2009; 21: 688–96. 5 Kawahara H, Kubota A, Hasegawa T et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr. Surg. Int. 2007; 23: 1001–5. 6 Tominaga K, Iwakiri R, Fujimoto K et al. Rikkunshito improves symptoms in PPI-refractory GERD patients: A prospective, randomized, multicenter trial in Japan. J. Gastroenterol. 2012; 47: 284–92. 7 Kawahara H, Mitani Y, Nomura M et al. Impact of rikkunshito, an herbal medicine, on delayed gastric emptying in profoundly handicapped patients. Pediatr. Surg. Int. 2009; 25: 987–90. 8 Kawahara H, Tazuke Y, Soh H et al. Physiological analysis of the effects of rikkunshito on acid and non-acid gastroesophageal reflux using pH-multichannel intraluminal impedance monitoring. Pediatr. Surg. Int. 2014; 30: 927–31. 9 Madan K, Ahuja V, Kashyap PC et al. Comparison of efficacy of pantoprazole alone versus pantoprazole plus mosapride in therapy of gastroesophageal reflux disease: A randomized trial. Dis. Esophagus 2004; 17: 274–8. 10 Miwa H, Inoue K, Ashida K et al. Randomised clinical trial: Efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease – a double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 2011; 33: 323–32. 11 Ruth M, Finizia C, Cange L et al. The effect of mosapride on oesophageal motor function and acid reflux in patients with
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12
13
14
15
16
17
18
19
20
gastro-oesophageal reflux disease. Eur. J. Gastroenterol. Hepatol. 2003; 15: 1115–21. Kamiya T, Adachi H, Hirako M et al. Impaired gastric motility and its relationship to reflux symptoms in patients with nonerosive gastroesophageal reflux disease. J. Gastroenterol. 2009; 44: 183–9. Hayakawa T, Arakawa T, Kase Y et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp. Clin. Res. 1999; 25: 211–18. Kido T, Nakai Y, Kase Y et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-L-arginine. J. Pharmacol. Sci. 2005; 98: 161–7. Tominaga K, Kido T, Ochi M et al. The traditional Japanese medicine rikkunshito promotes gastric emptying via the antagonistic action of the 5-HT(3) receptor pathway in rats. Evid. Based Complement. Alternat. Med. 2011; 2011: 248481. Hattori T, Fujitsuka N, Asakawa A et al. A new strategy using Rikkunshito (Liu-Jun-Zi-Tang), a Japanese traditional medicine, to treat gastrointestinal disease. In: Satoh H (ed). Basics of EvidenceBased Herbal Medicine. Research Signpost, Kerala, 2010; 149– 60. Matsumura T, Arai M, Yonemitsu Y et al. The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J. Gastroenterol. 2010; 45: 300–7. Takeda H, Sadakane C, Hattori T et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 2008; 134: 2004–13. Fujitsuka N, Asakawa A, Hayashi M et al. Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin. Biol. Psychiatry 2009; 65: 748–59. Gunji S, Ueda S, Yoshida M et al. Effects of rikkunshito, a kampo medicine, on quality of life after proximal gastrectomy. J. Surg. Res. 2013; 185: 575–80.
Pediatrics International (2015) 57, 67 3–676
doi: 10.1111/ped.12582
Original Article
Efficacy of the Japanese herbal medicine rikkunshito in infants with gastroesophageal reflux disease Kohei Otake,1 Keiichi Uchida,1 Koichiro Mori,1 Shozo Ide,1 Yuhki Koike,1 Mitsuyuki Takamura,2 Mikihiro Inoue1 and Masato Kusunoki1 1 Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine and 2Kampo Medicine Outpatient Department, Mie University Hospital, Mie, Japan Abstract
Background: Gastroesophageal reflux disease (GERD) in infants is among the most common reason for physician consultation worldwide. A traditional Japanese medicine, rikkunshito (RKT), is effective for GERD in adult and pediatric patients. The aim of this study was to evaluate the efficacy and safety of RKT in infants with GERD. Methods: Fifty-four infants were referred to between July 2004 and December 2012 for evaluation and treatment of GERD. All infants had failure to thrive. We excluded nine patients with cow’s milk protein allergy, neurological impairment or surgical indications. We retrospectively reviewed the clinical records of 45 infants with GERD. Twentynine infants were treated with RKT (TJ-43; 0.3 g/kg/day; RKT group), and 16 infants were treated with mosapride citrate at 0.5 mg/kg/day (mosapride group). The primary endpoint was RKT-induced relief of clinical symptoms and bodyweight gain in infants with GERD. Results: After 3 months of treatment, the frequency of vomiting per day was significantly lower in the RKT group than in the mosapride group (P = 0.0146) and the weight Z-score was significantly higher in the RKT group than in the mosapride group (RKT group, −2.5 ± 1.5 vs mosapride group, −5.0 ± 2.0; P = 0.0386). No adverse effects were noted in either group. Conclusions: RKT may be safe and effective for relief of GER symptoms and for bodyweight gain in infants with GERD.
Key words gastroesophageal reflux, infant, mosapride, prokinetics, rikkunshito.
Gastroesophageal reflux (GER), defined as the passage of gastric contents into the esophagus, and GER disease (GERD), defined as symptoms or complications of GER, are common pediatric problems. Clinical manifestations of GERD in children include vomiting, poor weight gain, dysphagia, abdominal or substernal pain, esophagitis, and respiratory disorders.1 Investigations used for the diagnosis of GER in newborn infants include 24 h pH monitoring, impedance monitoring, upper gastrointestinal contrast studies, and esophagoscopy. Thorough history and physical examination with attention to warning signals, however, is generally sufficient to allow the clinician to establish a diagnosis of uncomplicated GER in infants.2 Antacid medications currently available to treat reflux are effective in raising the pH of the gastric refluxate and may therefore improve the signs and symptoms of pain and discomfort from acidic reflux, but they do not alter transient lower esophageal sphincter relaxation and are therefore not effective in treating the actual underlying cause of reflux. The mechanism of
action of prokinetic agents should allow for a reduced refluxate volume; nevertheless, the literature has not supported any significant proven benefits in the treatment of reflux in neonates and infants.3 Rikkunshito (RKT) is widely prescribed in Japan for patients with a variety of gastrointestinal symptoms, including anorexia, nausea, and vomiting.4 The effects of RKT on gastrointestinal function include stimulation of gastrointestinal motility, facilitation of gastric emptying, improvement of GER, improvement of functional dyspepsia symptoms, stimulation of ghrelin secretion, and improvement of cisplatin-induced anorexia and vomiting. Studies have shown that RKT is effective for GER in adult and pediatric patients,5,6 but there are no reports on the efficacy of RKT in infants with GER. The aim of the present study was therefore to evaluate the efficacy and safety of RKT compared with the prokinetic agent mosapride citrate in infants with GER.
Correspondence: Keiichi Uchida, MD, Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Email: kohei815 @clin.medic.mie-u.ac.jp Received 26 November 2013; revised 25 November 2014; accepted 11 December 2014.
This retrospective, open-label study evaluated the efficacy and safety of RKT (TJ-43; Tsumura, Tokyo, Japan) for relieving symptoms of GER in infants. Fifty-four infants aged ≤1 year were referred to the pediatric surgery unit at Mie University Hospital between July 2004 and December 2012 for evaluation
© 2015 Japan Pediatric Society
Methods
674
K Otake et al.
and treatment of GER symptoms. All infants were referred to treat regurgitation and failure to thrive with or without troublesome symptoms such as crying, fussing or arching of the back, refusal to feed and hematemesis. We excluded nine patients with cow’s milk protein allergy, neurological impairment, or surgical indications. Thus, 45 infants were evaluated in this study. Each infant underwent radiography of the upper gastrointestinal tract to exclude mechanical obstruction as a cause of symptoms, and no infant was found to have hiatal hernia. To compare the efficacy between the prokinetics, patients were divided into two subgroups: 29 patients were treated with RKT (TJ-43; RKT group), and 16 patients were treated with mosapride citrate (mosapride group). RKT (TJ-43) or mosapride citrate (Gasmotin; Dainippon Sumitomo Pharma, Osaka, Japan) was administered via nasogastric tube or orally (RKT group: nasogastric tube, n = 4; oral, n = 25; mosapride group: nasogastric tube, n = 3; oral, n = 19) in three divided doses. RKT (TJ-43) was administered before meals at a dose of 0.3 g/kg/day based on previously published reports.5,7,8 Mosapride citrate was administered at a dose of 0.5 mg/kg/day after meals. In this study, the dose for infants aged ≤1 year was calculated according to the conversion table of von Harnack, because the dose for pediatric patients has not been established yet. If there was no clinical improvement in the GER symptoms ≥2 weeks after the medication was started, famotidine at 0.6 mg/kg was combined with these prokinetics. The improvement was estimated on periodic questioning for the GER symptoms. Response to treatment was assessed at the clinical visits after the initiation of RKT (TJ-43) or mosapride citrate therapy. In this study, we analyzed frequency of vomiting and bodyweight, which could be quantified. The frequency of vomiting per day was retrieved from medical records before and 1, 2, and 3 months after beginning treatment. Bodyweight data were retrieved from medical records before and 1, 2 and 3 months after beginning treatment. We used changes in the weight Z-score to assess infant weight gain (Z-score = [individual weight – standardized weight]/standard deviation). Safety was assessed by recording adverse events. An adverse event was defined as any unfavorable or unintended sign (constipation, diarrhea, bad temper, edema [due to kanzo], unknown fever, etc.), whether or not it was considered to be causally related to the study drug. Parametric data are presented as mean ± SD. Non-parametric data are presented as median (interquartile range; 25th–75th percentile, IQR). Statistical analysis was performed using chisquared test with Fischer’s probability test, Mann–Whitney U-test and Wilcoxon signed-rank test. P < 0.05 was considered statistically significant. Statistical analysis was performed using STATVIEW version 5.0J (SAS Institute Japan, Tokyo, Japan).
Results The subject clinical characteristics are listed in Table 1. The clinical characteristics were not significantly different between the RKT and mosapride groups, with the exception of patients who received the combination therapy. In the mosapride group, famotidine was combined with mosapride citrate in 10 patients (62.5%). This rate was significantly higher than in the RKT group © 2015 Japan Pediatric Society
Table 1 Subject clinical characteristics
Sex, n Male Female Gestational age (weeks) Birthweight (kg) At start of therapy Age (months) Bodyweight (kg) Combination therapy, n Famotidine None
RKT group (n = 29)
Mosapride group (n = 16)
P-value
18 11 34.6 ± 5.0
8 8 37.1 ± 3.2
0.145
2.075 ± 0.860
2.384 ± 0.704
0.205
3.4 ± 2.9 2.8 ± 1.5
4.0 ± 2.4 3.2 ± 1.4
0.319 0.177 0.001
4 25
10 6
0.433
RKT, rikkunshito.
(13.8%; P = 0.002). Apparent life-threatening events were not observed in either group during this study period. No adverse effects were noted in either group. The frequency of vomiting per day in each group is presented in Figure 1(a). In both groups, the daily frequency of vomiting was significantly decreased after 1 month of treatment (RKT group: 0 months, 3 episodes/day of vomiting [IQR, 2–5] vs 1 month, 0 episodes/day [IQR, 0–2], P < 0.0001; mosapride group: 0 months, 2.5 episodes/day [IQR, 2–5] vs 1 month, 1 episode/day [IQR, 0–2], P = 0.001). The daily frequency of vomiting was significantly lower after 3 months of treatment in the RKT group than in the mosapride group (RKT group, 0 episodes/day [IQR, 0–0] vs mosapride group, 1 episode/day [IQR, 0.75–1.25], P = 0.015). With regard to weight Z-score (Fig. 1b), there was an increasing trend in the RKT group and a decreasing trend for the 3 months of treatment in the mosapride group. The weight Z-score was significantly higher after 3 months of treatment in the RKT group than in the mosapride group (RKT group, −2.5 ± 1.5 vs mosapride group, −5.0 ± 2.0; P = 0.039).
Discussion The present study has demonstrated the safety and efficacy of RKT in infants with GER. After 3 months of treatment, the daily frequency of vomiting was significantly lower and the weight Z-score was significantly higher in the RKT group than in the mosapride group. Hence, RKT was superior to mosapride citrate in terms of relief of symptoms and bodyweight gain in infants with GER. Mosapride citrate is a 5-HT4 agonist and analog of cisapride that lacks the cardiac side-effects associated with cisapride.9 It is available in Japan as well as in some other Asian countries, but not in the USA or European countries.10 Mosapride citrate may improve the symptoms of non-erosive reflux disease by various mechanisms: (i) modulation of esophageal motor function, which may result in reduction of reflux;11 and (ii) acceleration of gastric emptying.12 It is known that gastric motility is impaired in some patients with non-erosive reflux disease, and mosapride citrate has been shown to improve the symptoms in such patients.12
Efficacy of RKT in infant GERD (a)
*
*
(b)
*
*
Fig. 1 Changes in (a) median daily frequency of vomiting and (b) bodyweight Z-score after 3 months of treatment. (a) Daily frequency of vomiting was significantly lower in the ( ) rikkunshito (RKT) group than in the ( ) mosapride group (*P = 0.02), and (b) Z-score was significantly higher in the ( ) RKT group than in the ( ) mosapride group (*P = 0.04), after the 3 month treatment.
In Japan, the traditional medication RKT has been approved for medicinal use in the form of extract granules for ethical use (TJ-43; Tsumura) by the Japanese Ministry of Health and Welfare, and it is widely prescribed for patients with upper gastrointestinal symptoms.6 RKT decreases the acid exposure time in the esophagus and enhances esophageal clearance in patients with GERD.5 Several previous studies have demonstrated that RKT also has a pharmacological action similar to that of prokinetic agents, as shown by its attenuation of the gastric dysmotility caused by a nitric oxide-synthesizing enzyme inhibitor and exogenous serotonin.13–15 In addition, a double-blind trial demonstrated the efficacy of RKT in the attenuation of upper gastrointestinal symptoms such as postprandial fullness, abdominal distension, and gastric discomfort in patients with functional dyspepsia as diagnosed on the Rome II criteria, which frequently overlap with those of non-erosive reflux disease.16 These findings
675
suggest the possible efficacy of RKT in infants with GER via its pharmacological action, which is similar to that of prokinetic agents. Rikkunshito increased plasma acylated ghrelin, but the level of plasma deacylated ghrelin did not change in healthy human volunteers.17 This effect was maintained for at least 4 weeks after the end of RKT treatment. mRNA expression of ghrelin in gastric tissue was upregulated after 2 weeks of RKT treatment in mice.17 RKT stimulates endogenous ghrelin secretion from the stomach via 5-HT2B and 5-HT2C receptor antagonism.18,19 The 5-HT system in the gastrointestinal tract has an important role in the regulation of gastrointestinal motor activities. Selective serotonin re-uptake inhibitors changed the phase III-like contractions to fed-like motor activities.19 The effect of ghrelin could be one of the reasons why RKT is useful in treating infants with GER. Rikkunshito had no adverse effect in the present cohort. It has, however, been established that several potential side-effects, such as allergic reactions or impairment of liver, may occur during RKT treatment.20 Allergic reactions included skin rash, redness, and itching. The impairment of liver included fever, jaundice, brown urine, and fatigue. The most troublesome problem of Kampo medicines for pediatric physicians is its bad taste, but the taste of RKT is better than other Kampo medicines. This study has some important limitations. The most significant limitation is its retrospective and open-label design, which allowed for the possibility of placebo responses. But the fact that RKT was more effective than mosapride citrate in the present study makes a placebo effect less likely. The fact that RKT has been shown to be effective in other adult GER studies makes the effect of RKT more plausible.5,7 RKT is readily available in Japan, and its good safety profile makes it an attractive therapeutic option. The other significant limitation is that tests before and after treatment, such as esophageal pH monitoring, were not evaluated. Large prospective studies are needed to evaluate the specific effects of RKT on combined multiple esophageal impedance-pH recording in infants with GER. Finally, the feeding frequency and amount of feeding were not analyzed in the present study. Prospective studies are needed to evaluate them. Conclusion
Rikkunshito is useful in treating infants with GER via not only its prokinetic action but also its appetite-enhancing effect. To establish the efficacy of RKT therapy in infants with GER, further studies, such as prospective randomized trials, are warranted.
Acknowledgments The authors report no conflicts of interest in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication.
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