Review Article Beneficial Effects of Rikkunshito, a ...downloads.hindawi.com/journals/ecam/2014/519035.pdf · Kampo medicines are traditional herbal medicines which have been approved

Review ArticleBeneficial Effects of Rikkunshito a Japanese Kampo Medicineon Gastrointestinal Dysfunction and Anorexia in Combinationwith Western Drug A Systematic Review

Sachiko Mogami and Tomohisa Hattori

Tsumura Research Laboratories Tsumura amp Co 3586 Yoshiwara Ami-Machi Inashiki-Gun Ibaraki 300-1192 Japan

Correspondence should be addressed to Tomohisa Hattori hattori tomohisamailtsumuracojp

Received 15 November 2013 Accepted 17 February 2014 Published 20 March 2014

Academic Editor Isadore Kanfer

Copyright copy 2014 S Mogami and T Hattori This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Background Kampo medicines are traditional herbal medicines which have been approved for medicinal use by the JapaneseMinistry of Health and Welfare and are currently being used more and more often in combination with Western drugs Thusthe need for investigation of interactions between Kampo medicines and Western drugs is now widely recognized Aim Tosummarize the effects and drug interactions of rikkunshito a Kampomedicine often prescribed for upper gastrointestinal disordersand anorexia Methods Animal and human studies were systematically reviewed to identify published data on rikkunshitoResults describing its effects were abstracted with an emphasis on drug interactions Results and Discussion Rikkunshitoameliorates anorexia induced by anticancer drugs improves quality of life scores and can even prolong survival compared withmonotherapy Rikkunshito combined with proton pump inhibitor therapy is shown to be useful in the treatment of PPI-refractorygastroesophageal reflux disease patients and patients with gastrointestinal symptoms after endoscopic submucosal dissectionRikkunshito reduces antidepressant-induced adverse events and improves quality of life without influencing antidepressant effectsConclusions Rikkunshito shows ameliorative effects on adverse reactions induced by variousWestern drugs and can achieve betterresults (eg anticancer drugs and proton pump inhibitor) without influencing the efficacy and bioavailability of Western drugs

1 Introduction

Herbal therapy has been used in Asia and other parts ofthe world for thousands of years and is currently manufac-tured in Japan as ldquoJapanese Traditional (herbal) or Kampomedicinesrdquo These medicines are standardized with regardto quality and quantity of its ingredients and have beenapproved by the Japanese Ministry of Health and WelfareAt present almost 90 of physicians in Japan use Kampomedicines in daily practice sometimes as the first choiceBecause Kampo medicines are now being used more andmore often in combination with Western drugs the needfor investigation of interactions between Kampo medicinesand Western drugs is now widely recognized An emergingtherapeutic target for Kampomedicines in clinical practice isgastrointestinal functional disorders in which conventionalpharmacotherapy is either only partly effective or associated

with adverse events Rikkunshito a Kampo medicine isoften prescribed for upper gastrointestinal disorders suchas functional dyspepsia (FD) gastroesophageal reflux andanorexia [1ndash3] and is prepared by compounding eight of thefollowing crude drugs Atractylodis lanceae rhizoma Ginsengradix Pinellia tuber Hoelen Zizyphi fructus Aurantii nobilispericarpium Glycyrrhizae radix and Zingiberis rhizome Thepresent paper reviews the physiology and clinical benefits ofrikkunshito with special focus on rikkunshito-Western drugcombination therapies

2 Methods

A literature search was performed on PubMed using thekeywords rdquorikkunshitordquo rdquorikkunshi-tordquo rdquoTJ-43rdquo (productID) and rdquoLiu-Jun-Zi-Tangrdquo (Chinese pronunciation) After

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2014 Article ID 519035 7 pageshttpdxdoiorg1011552014519035

2 Evidence-Based Complementary and Alternative Medicine

Table 1 Administration of rikkunshito in combination with Western drugs in human studies

Reference Western drugs Patients Outcome[4] Docetaxel5-FUcisplatin Esophageal cancer Improved QOL[5] S-1cisplatin Unresectable or relapsed gastric cancer Improved anorexia[6] Gemcitabine Stage IIIIV pancreatic cancer with ascites Prolonged median survival[7] Rabeprazole PPI-refractory GERD Improved GERD score[8] Lansoprazole PPI-refractory LPR Improved global sensation VAS scores[9] Rabeprazole Gastrointestinal symptoms after ESD Improved GSRS score[10] Fluvoxamine Depressive disorder Improved GSRS scores[11] Antidepressants or antipsychotics Elderly patients with dementia Increase in food intake[12] Anti-Parkinson drugs Parkinsonrsquos disease Ameliorated gastroparesis[13] Ofloxacin Healthy volunteers No effects on bioavailability[14] Levofloxacin Healthy volunteers No effects on bioavailabilityESD endoscopic submucosal dissection GERD gastroesophageal reflux disease LPR laryngopharyngeal reflux PPI proton-pump inhibitor QOL quality oflife GSRS Gastrointestinal Symptom Rating Scale VAS visual analog scale

accumulating a combined list of studies publications notexamining the use of rikkunshito and those not writtenin English were excluded Data abstraction was performedto characterize physiological and clinical effects and druginteractions of rikkunshito Because a formal meta-analysiswas not possible based on variations in study populationsdisorders and study protocols retrieved data are presenteddescriptively with regard to the physiological and clinicaleffects of rikkunshito

3 Results and Discussion

The initial search terms yielded 2 books 14 reviews and 66original manuscripts related to rikkunshito of which 30 werehuman studies and 36 were animal and in vitro studies Ofthese 30 human studies 10 concerned the use of Westerndrugs in combination with rikkunshito (Table 1) of the 36animal and in vitro studies 6 concerned the use of Westerndrugs in combination with rikkunshito (1 of these included ahuman study) and 1 investigated the effects of rikkunshito onhuman drug metabolic enzymes

31 Clinical Applications of Rikkunshito A double-blindedrandomized placebo-controlled trial on rikkunshito wasconducted by Tatsuta and Iishi in 42 patients with chronicidiopathic dyspepsia [15] Gastric emptying was significantlyaccelerated and gastrointestinal symptoms were significantlyreduced in patients treated with rikkunshito for 7 daysindicating that rikkunshito has a prokinetic action on gastricemptying and may be useful in treating FD Arai et alconducted a parallel randomized controlled trial to inves-tigate the effects of rikkunshito on upper gastrointestinalsymptoms and ghrelin levels in 27 patients with FD treatedwith either rikkunshito or domperidone for 4 weeks [16]Gastrointestinal SymptomRating Scale (GSRS) questionnairescores significantly improved in both groups but plasmaghrelin levels significantly increased only in the rikkunshitogroup and good correlation was found for improvementsin reflux and indigestion symptoms A study on the effects

of rikkunshito on gastric accommodation reflex and duo-denogastric motility was conducted in 16 patients with FDusing extracorporeal ultrasonography before and after 14days of treatment [17] GSRS scores for abdominal painsheartburn and abdominal distension significantly decreasedand the expansion rate of the proximal stomach was sig-nificantly greater after treatment A study on the effectsof 4-week treatment with rikkunshito in 19 patients withgastric cancer who had undergone proximal gastrectomymore than 6 months previously was conducted by Gunjiet al [18] Patientsrsquo body weight significantly increasedafter the treatment course and in a subgroup analysis ofpatients showing a GSRS score of ge2 before treatment themean total GSRS score significantly improved after treatmentbecause of significant improvements in the subscale scoresfor abdominal pain acid reflux diarrhea and constipationSignificant attenuation of post-gastrectomy gastrointestinalsymptoms and increase in the ratio of acyl-total ghrelinconcentration by rikkunshito treatment for 4 weeks were alsoreported by Takiguchi et al in 25 patients who had undergonedistal gastrectomy or total gastrectomy [19] Takahashi etal in a crossover study examined the clinical effects ofrikkunshito in 11 patients who were to undergo pylorus-preserving gastrectomy for early gastric cancer [20] Rikkun-shito significantly improved emptying of solid meals fromthe remnant stomach according to (99m)Tc-labeled solidscintigraphy and stasis-related symptoms were significantlyreduced during the treatment Yagi et al evaluated theeffect of rikkunshito on symptoms and gastric myoelectricactivity in 8 dyspeptic pediatric patients whose symptomshad persisted for over 1 year after gastrointestinal surgeryFollowing rikkunshito therapy all patients exhibited symp-tomatic relief and a significant decrease in the mean symp-tom scores along with increased gastric contractile activityaccording to electrogastrography [21] Symptomatic relief andimproved gastric emptying by rikkunshito administrationwere reported by Kawahara et al in 9 handicapped patientsusing the 13C-acetate breath test and the BreathID system[22] Kawahara et al also investigated the effects of rikkun-shito on clinical symptoms and esophageal acid exposure in

Evidence-Based Complementary and Alternative Medicine 3

8 children with symptomatic gastroesophageal reflux disease(GERD) before and after 7 days of therapy [23] Treatmentrelieved symptoms and reduced the distal esophageal acidexposure through improvement in esophageal acid clearanceThe largest and most comprehensive clinical study wasconducted by Harasawa et al in 1998 in 235 patients withdysmotility-like dyspepsia although it is reported in Japaneseand not found in the PubMed search but outlined in Englishelsewhere [24ndash26]

32 Effects of Rikkunshito in Nonclinical Studies

321 Effects on Upper Gastrointestinal Function The effectsof rikkunshito on gastric adaptive relaxation have beenreported in isolated guinea pig stomachs [27] consciousdogs [28] and isolated fundus smooth muscle from diabeticneuropathic rats with gastric dysmotility [29] Rikkunshitonot only increased gastric adaptive relaxation at the basallevel but also ameliorated inhibited relaxation by the nitricoxide synthase inhibitor [27] Improvement in gastric accom-modation was also reported in virtual reality stress-imposedhealthy humans [30] Rikkunshito was reported to stimulategastrointestinal contractions in the interdigestive state andgastric emptying in conscious dogs through cholinergic neu-rons and serotonin type-3 receptors [31] The enhancementeffect of rikkunshito was also reported in delayed gastricemptying induced by either nitric oxide synthase inhibitor(active components hesperidin (derived fromAurantii nobilispericarpium) and L-arginine (derivation not determined))[32] or serotonin [33] Rikkunshito was reported to amelio-rate the reduced voluntary movement in reflux esophagitismodel rats and improve barrier function of the esophagealmucosa by restoring tight junction protein expression [34]and also reported to show great capacity to absorb bile salts[35] Preventive effects of rikkunshito were also reported ongastric mucosal injury induced by either repeated electricalstimulation of the gastric artery or ethanol treatment viamodulating platelet-activating factor production and oxida-tive granulocyte activation [36] in a nitric oxide-dependentmanner [37] and by increasing surface mucin content [38]

322 Effects on Ghrelin Ghrelin a 28-residue octanoylatedpeptide is an endogenous ligand of the growth hormonesecretagogue receptor (GHS-R) [39] Ghrelin is known toplay a role in both growth hormone release and stimulationof gastric motility and food intake [40ndash42] Various studiesare reported with regard to investigating the effects ofrikkunshito on ghrelin secretion and signaling Rikkunshitowas reported to increase plasma ghrelin levels in humans andmice [43] and dogs [31] and was also reported to restore thedecreased plasma ghrelin levels induced by serotonin releasein rats This rikkunshito effect is mediated by the serotonin2B2C receptor (5-HT

2BR5-HT2CR) antagonistic effect the

active components of rikkunshito including 331015840410158405678-heptamethoxyflavone and hesperidin (Aurantii nobilis peri-carpium) and isoliquiritigenin (Glycyrrhizae radix) [44 45]Rikkunshito hesperidin and isoliquiritigenin amelioratedreduced hypothalamic ghrelin secretion and reduction in

GHS-R signal transduction in the hypothalamus via 5-HT2CR

antagonism [46 47] The potentiating effects on ghrelin sig-naling in vitro were also demonstrated in GHS-R-expressingcells showing significantly sustained increase in intracellularCa2+ levels induced by ghrelin mediated by the increasedbinding ability of ghrelin to its receptor following pretreat-ment by rikkunshito or its one of the active componentsatractylodin (Atractylodis lanceae rhizoma) The inhibitoryeffects on activities of ghrelin metabolizing enzymes whichinactivate ghrelin to deacylated form were investigated bySadakane et al [48] Several components of rikkunshito suchas glycycoumarin (Glycyrrhizae radix) and pachymic acid(Hoelen) were reported to show inhibitory activity againsthuman ghrelin-deacylating enzyme butyrylcholinesteraseIn surgically induced GERD model rats the ameliorativeeffects of exogenous ghrelin on reduced antral motility wereobserved only after pretreatment with rikkunshito indicatingthat this medicine had restored gastrointestinal motility byreversing impaired ghrelin signaling [49]

323 Effects on Other Hormones Rikkunshito is reportedto induce significant increases in plasma somatostatin andgastrin levels compared with a placebo group in healthysubjects but not in motilin vasoactive intestinal peptidecalcitonin gene-related peptide and substance P levels [5051] It is also reported that rikkunshito suppresses increasesin plasma adrenocorticotropic hormone levels cortisol levelsand neuropeptide Y levels compared with the response to aplacebo under stress conditions by repetitive blood samplingin health volunteers [52 53]

324 Effects in Anorexia Models Rikkunshito and itscomponents nobiletin (Aurantii nobilis pericarpium) hep-tamethoxyflavone and isoliquiritigenin reportedly amelio-rated compromised ghrelin reactivity in the hypothalamusand regulation of its secretion in mice with aging-associatedanorexia via inhibition of phosphodiesterase type 3 [54]These effects are considered to be mediated by suppressionof leptin signaling in the hypothalamus by increased levels ofcyclic adenosine monophosphate Rikkunshito amelioratedreduced feeding behavior in an urocortin-1-induced anorexiamodel and its effect was abolished by GHS-R antagonistcoadministration [55] Rikkunshito also attenuated anorexiainduced by novel environmental change by increasingplasma ghrelin levels via antagonism to 5-HT

1B2CR [56] and5-HT2BR [57] Effects of rikkunshito in a cancer anorexia-

cachexia model were reported by Fujitsuka et al [6] whereamelioration in anorexia gastrointestinal dysmotility musclewasting and anxiety-related behavior as well as prolongedsurvival were recorded These effects were mediated byrikkunshitorsquos active components hesperidin and atracty-lodin which led to potentiated ghrelin secretion and receptorsignaling respectively Ameliorative effects of rikkunshito onanorexia and body composition change is also reported innovel stomach cancer cachexia model by Terawaki et al [58]On the other hand Tsubouchi et al recently reported theprotective effects of rikkunshito against acute lung injury by


protecting the alveolar epithelial cells and regulating lunginflammation independently of the ghrelin system [59]

33 Rikkunshito and Western Drug Interactions

331 Rikkunshito and Anticancer Drugs Adverse reactionssuch as chemotherapy-induced nausea and vomiting ofteninterfere with continuation of chemotherapy The effectsof rikkunshito on such adverse reactions were investigatedin docetaxel5-FUcisplatin therapy which is useful in thetreatment of advanced esophageal cancer as a prospec-tive randomized study [4] Nineteen patients who were toundergo docetaxel5-FUcisplatin therapy were randomlyassigned to rikkunshito-treated and nontreated groups Inci-dence of symptoms nausea score mood score and activityof daily living score in quality of life (QOL) scoring weresignificantly lower in the rikkunshito-treated group than inthe control group The effects of rikkunshito on S-1cisplatinchemotherapy-induced anorexia and ghrelin secretion werealso investigated in a crossover design [5] Ten unresectable orrelapsed patients with gastric cancer were randomly dividedbetween two groups In the rikkunshito-on period nocisplatin-induced decrease was observed for plasma ghrelinlevels average oral intake was significantly higher and thegrade of anorexia was significantly lower compared to thosein the rikkunshito-off period The effects of rikkunshitowere also investigated as a retrospective study in 39 patientstreated with gemcitabine who had pathologically provenstage IIIIV pancreatic cancerwith ascitesMedian survival inpatients treated with rikkunshito was significantly prolongedcompared with that in patients treated with gemcitabinealone [6]

Combined administration of rikkunshito (1000mgkg)and cisplatin (2 or 4mgkg) was also reported in animalstudies In a cisplatin-induced anorexia model rikkunshitowas reported to ameliorate reduced food intake by reversingreduced plasma ghrelin levels reduced hypothalamic ghrelinsecretion and decreased GHS-R signal transduction [44 46ndash48] It was also reported that combined administration ofrikkunshito (500mgkg) and cisplatin (1mgkg) significantlyprolonged survival in tumor-bearing rats compared withcisplatin monotherapy [6]

332 Rikkunshito and Proton-Pump Inhibitors (PPI) Therelative efficacy of rikkunshito in combination with PPIrabeprazole and a double dose of rabeprazole was com-pared by Tominaga et al in a prospective multicenterrandomized parallel comparative study in 104 PPI-refractoryGERD patients [7] After 4-week treatment with rabepra-zole patients were randomly assigned to either combinationtherapy (rikkunshito with a standard dose of rabeprazole)or a double dose of rabeprazole Both treatment regimenssignificantly decreased the frequency scale for the symptomsof GERD in both groups With regard to the therapeuticimprovement rate there were also significant effects in bothgroups However in the subgroup analysis based on refluxesophagitisnonerosive GERD (NERD) the improvementrate for male patients with NERD in the rikkunshito group

was significantly higher than that for male patients inthe other group These studies indicate that rikkunshitoin combination with PPI therapy may be a useful newstrategy for treatment of PPI-refractory patients The effectsof rikkunshito on laryngopharyngeal reflux (LPR) symptomsand gastric emptying in 22 patients with proton-pumpinhibitor PPI-refractory LPR were investigated by Tokashikiet al as a prospective randomized parallel comparative study[8] Following 2 weeks of treatment with PPI monotherapypatients were randomly divided between two treatmentgroups rikkunshito monotherapy and rikkunshito plus lan-soprazole Following 4 weeks of treatment in both groupsthe authors observed significantly decreased global sensationvisual analog scale (VAS) scores which showed significantpositive correlation with improvement in gastric empty-ing The VAS score for sore throat significantly decreasedfollowing treatment with rikkunshito plus PPI but not byrikkunshito alone Effects of rikkunshito on gastrointesti-nal symptoms following endoscopic submucosal dissection(ESD) were evaluated in combination with rabeprazole byUehara et al in a prospective randomized parallel compar-ative study [9] Patients who were scored ge3 more than theaverage GSRS score for abdominal pain or indigestion 6ndash8days after ESD were randomized to either of the two groups(PPI monotreatment group 119899 = 5 or a PPI + rikkunshitogroup 119899 = 8) Overall GSRS score and abdominal pain scorewere significantly improved only in PPI plus rikkunshitogroup

333 Rikkunshito and Antidepressant Agents Upper gas-trointestinal symptoms such as nausea and vomiting arecommon adverse events associated with the administrationof selective serotonin reuptake inhibitors (SSRIs) and mayresult in discontinuation of drug therapy in patients with adepressive disorder A study on the effects of rikkunshito ongastrointestinal symptoms and antidepressant effectswas per-formed byOka et al [10] in a randomized controlled study of50 patients with depressive disorder treated by fluvoxaminePatients were divided into two groups fluvoxamine andfluvoxamine plus rikkunshito with administration over 8weeks The numbers of patients complaining of adverseevents or nausea in the combination group were lower thanthose in the fluvoxamine group GSRS scores improved in thecombination group but not in the fluvoxamine group Self-RatingDepression Scale scoreswere not different between thetwo groups at all assessment points

Functional gastrointestinal symptoms are frequentlyfound in elderly patients with dementia and treated bythe administration of antidepressants or second-generationantipsychotics but with the risk of side effects Although onlyin a preliminary study the effects of rikkunshito on appetiteloss in elderly patients with dementia were investigated byUtumi et al [11] Rikkunshito was administered for 4 weeksin six elderly patients with dementia suffering from appetiteloss in combination with olanzapine + sulpiride donepezil +paroxetine trazodone quetiapine or donepezil + quetiapineor as monotherapy In one patient investigation was stoppedbecause of the development of cholecystitis (administration


of rikkunshito was ruled out as being of relevance becauseof the presence of gallstones and history of cholecystitis)Significant increases in food intake were observed followingadministration of rikkunshito with the side effect of mildlower limb edema occurring in two patients

The ameliorative effects of rikkunshito (1000mgkg) inrats administered SSRI (fenfluramine 2 or 5mgkg) that hadinduced gastrointestinal dysmotility were also reported byFujitsuka et al [45] Rikkunshito reversed the disruptionof Phase III-like contractions and decreased food intakeby restoring the reduced ghrelin secretion via 5-HT

2CRreceptor antagonism These studies suggest that rikkunshitoreduces SSRI-induced adverse events and improves QOLrelated to gastrointestinal symptoms without affecting theantidepressant effect of SSRI

334 Rikkunshito and Anti-Parkinson Drugs Effects ofrikkunshito on gastroparesis in Parkinsonrsquos disease patientswere reported by Doi et al [12] Twenty patients withmild gastrointestinal symptoms were enrolled 14 of the 20patients had constipation Sixteen patients were taking lev-odopacarbidopa 2 were taking dopamine agonists and theothers were not treated yet Twelve weeks after rikkunshitoadministration 67 of patients reported improvement oftheir gastrointestinal symptoms particularly appetite lossand bloating Rikkunshito significantly shortened the gastricemptying time in these patients measured by the 13C-sodiumacetate expiration breath test without any adverse effectsexcept for its bitter taste

335 Rikkunshito and Bioavailability of Antimicrobial AgentsThe effects of rikkunshito on the bioavailability of ofloxacinin seven healthy volunteers [13] and that of levofloxacinin eight healthy volunteers [14] were investigated in anopen random crossover study by Hasegawa et al Subjectswere administered a single oral dose of either ofloxacin orlevofloxacin alone or by coadministration of rikkunshito at1-week intervals No significant differences in any estimatedbioavailability parameters of ofloxacin or levofloxacin wereobserved between the two groups Urinary recovery ofofloxacin and levofloxacin was not significantly differentcompared with that after coadministration of rikkunshito

336 Rikkunshito and Human Metabolic Enzymes Theeffects of rikkunshito on the activity of cytochrome P450(CYP) a superfamily of drug-metabolizing enzymes and P-glycoprotein (P-gp) a major drug transporter were inves-tigated by Ito et al [60] The inhibition rate of rikkunshitoon human CYP3A4 2C9 2C19 2D6 and 2E1 was lessthan 50 at concentrations below 01mgmL Furthermorerikkunshito did not affect ATPase activity using human P-gp membranes at concentrations lower than 01mgmL ineither the presence or absence of P-gp substrate These find-ings indicate that rikkunshito is unlikely to cause clinicallyrelevant drug interactions involving the inhibition of majorCYP isozymes or P-gp

4 Conclusion

Rikkunshito administration has shown its effects with regardto improvement in the symptoms of GERD and in func-tional and drug-associated dyspepsia through its effectson upper gastrointestinal functions and ghrelin secretionand signaling Rikkunshito in combination with anticancerdrugs also appeared to ameliorate anorexia improve QOLand even prolong survival compared with Western drugmonotherapy Rikkunshito in combination with PPI ther-apy also showed beneficial effects in PPI-refractory GERDpatients and patients with gastrointestinal symptoms afterESD compared with monotherapy Rikkunshito reducedantidepressant-induced adverse events and improved QOLwithout affecting antidepressant effects Rikkunshito showedno significant effect on the bioavailability and renal excretionof antimicrobial agents

However because the studies described above were allperformed in Japan on account of the nonavailability ofstandardized rikkunshito outside Japan the basic and clinicaleffects of rikkunshito in other countries may not be con-sistent with these data In addition to confirm the safetyand efficacy of rikkunshito multiple randomized placebo-controlled trials (preferably international) using commonendpoints are required On account of the increasing useof Kampo medicines accurate data on interactions betweenthese and Western drugs are required not only for patientsbut also by healthcare providers

In conclusion at present rikkunshito is considered tohave no influence on the efficacy and bioavailability ofWestern drugs More importantly it has shown ameliorativeeffects on adverse reactions induced by various Westerndrugs and sometimes yields better results in combinationwith for example anticancer drugs and PPIs than Westerndrug monotherapy

Abbreviations

CYP Cytochrome P450ESD Endoscopic submucosal dissectionFD Functional dyspepsiaGERD Gastroesophageal reflux diseaseGHS-R Growth hormone secretagogue receptorGSRS Gastrointestinal Symptom Rating ScaleLPR Laryngopharyngeal refluxP-gp P-glycoproteinPPI Proton-pump inhibitorQOL Quality of life5-HTR Serotonin receptorSSRIs Selective serotonin reuptake inhibitorsVAS Visual analog scale

Conflict of Interests

Sachiko Mogami and Tomohisa Hattori are employed byTsumura amp Co


References

[1] H Suzuki J M Inadomi and T Hibi ldquoJapanese herbalmedicine in functional gastrointestinal disordersrdquo Neurogas-troenterology and Motility vol 21 no 7 pp 688ndash696 2009

[2] K Tominaga and T Arakawa ldquoKampo medicines for gastroin-testinal tract disorders a review of basic science and clinical evi-dence and their future applicationrdquo Journal of Gastroenterologyvol 48 no 4 pp 452ndash462 2013

[3] T Oka H Okumi S Nishida et al ldquoEffects of Kampo onfunctional gastrointestinal disordersrdquoBiopsychosocialMedicinevol 8 article 5 2014

[4] J Seike T SawadaNKawakita et al ldquoAnew candidate support-ing drug Rikkunshito for the QOL in advanced esophagealcancer patients with chemotherapy using docetaxel5-FUCDDPrdquo International Journal of Surgical Oncology vol2011 Article ID 715623 7 pages 2011

[5] T Ohno M Yanai H Ando et al ldquoRikkunshito a traditionalJapanese medicine suppresses cisplatin-induced anorexia inhumansrdquoClinical and Experimental Gastroenterology vol 4 no1 pp 291ndash296 2011

[6] N Fujitsuka A Asakawa Y Uezono et al ldquoPotentiationof ghrelin signaling attenuates cancer anorexia-cachexia andprolongs survivalrdquo Translational Psychiatry vol 1 article e232011

[7] K Tominaga R Iwakiri K Fujimoto et al ldquoRikkunshitoimproves symptoms in PPI-refractory GERD patients aprospective randomized multicenter trial in Japanrdquo Journal ofGastroenterology vol 47 no 3 pp 284ndash292 2011

[8] R Tokashiki I Okamoto N Funato and M Suzuki ldquoRikkun-shito improves globus sensation in patients with proton-pumpinhibitor-refractory laryngopharyngeal refluxrdquoWorld Journal ofGastroenterology vol 19 no 31 pp 5118ndash5124 2013

[9] R Uehara H Isomoto H Minami et al ldquoCharacteristics ofgastrointestinal symptoms and function following endoscopicsubmucosal dissection and treatment of the gastrointestinalsymptoms using rikkunshitordquo Experimental and TherapeuticMedicine vol 6 no 5 pp 1083ndash1088 2013

[10] T Oka Y Tamagawa S Hayashida Y Kaneda N Kodamaand S Tsuji ldquoRikkunshi-to attenuates adverse gastrointestinalsymptoms induced by fluvoxaminerdquo Biopsychosocial Medicinevol 1 article 21 2007

[11] Y Utumi E Iseki N Murayama et al ldquoEffect of Rikkunshi-to on appetite loss found in elderly dementia patients apreliminary studyrdquo Psychogeriatrics vol 11 no 1 pp 34ndash392011

[12] H Doi R Sakakibara M Sato et al ldquoDietary herb extractrikkunshi-to ameliorates gastroparesis in Parkinsonrsquos disease apilot studyrdquo European Neurology vol 71 no 3-4 pp 193ndash1952014

[13] T Hasegawa K Yamaki M Nadai et al ldquoLack of effect ofChinese medicines on bioavailability of ofloxacin in healthyvolunteersrdquo International Journal of Clinical Pharmacology andTherapeutics vol 32 no 2 pp 57ndash61 1994

[14] T Hasegawa K Yamaki I Muraoka M Nadai K Takagiand T Nabeshima ldquoEffects of traditional Chinese medicineson pharmacokinetics of levofloxacinrdquo Antimicrobial Agents andChemotherapy vol 39 no 9 pp 2135ndash2137 1995

[15] M Tatsuta and H Iishi ldquoEffect of treatment with Liu-Jun-Zi-Tang (TJ-43) on gastric emptying and gastrointestinal symp-toms in dyspeptic patientsrdquo Alimentary Pharmacology andTherapeutics vol 7 no 4 pp 459ndash462 1993

[16] M Arai T Matsumura N Tsuchiya et al ldquoRikkunshitoimproves the symptoms in patients with functional dyspepsiaaccompanied by an increase in the level of plasma ghrelinrdquoHepato-Gastroenterology vol 59 no 113 pp 62ndash66 2012

[17] H Kusunoki K Haruma J Hata et al ldquoEfficacy of Rikkunshitoa traditional Japanesemedicine (Kampo) in treating functionaldyspepsiardquo Internal Medicine vol 49 no 20 pp 2195ndash22022010

[18] S Gunji S Ueda M Yoshida M Kanai H Terajima and ATakabayashi ldquoEffects of rikkunshito a kampo medicine onquality of life after proximal gastrectomyrdquo Journal of SurgicalResearch vol 185 no 2 pp 575ndash580 2013

[19] S Takiguchi Y Hiura T Takahashi et al ldquoEffect of rikkunshitoa Japanese herbal medicine on gastrointestinal symptoms andghrelin levels in gastric cancer patients after gastrectomyrdquoGastric Cancer vol 16 no 2 pp 167ndash174 2013

[20] T Takahashi S Endo K Nakajima Y Souma and T NishidaldquoEffect of rikkunshito a Chinese herbal medicine on stasis inpatients after pylorus-preserving gastrectomyrdquoWorld Journal ofSurgery vol 33 no 2 pp 296ndash302 2009

[21] M Yagi S Homma M Kubota et al ldquoThe herbal medicineRikkunshi-to stimulates and coordinates the gastricmyoelectricactivity in post-operative dyspeptic children after gastrointesti-nal surgeryrdquo Pediatric Surgery International vol 19 no 12 pp760ndash765 2004

[22] H Kawahara Y Mitani M Nomura et al ldquoImpact of rikkun-shito an herbal medicine on delayed gastric emptying in pro-foundly handicapped patientsrdquo Pediatric Surgery Internationalvol 25 no 11 pp 987ndash990 2009

[23] H Kawahara A Kubota T Hasegawa et al ldquoEffects of rikkun-shito on the clinical symptoms and esophageal acid exposure inchildren with symptomatic gastroesophageal refluxrdquo PediatricSurgery International vol 23 no 10 pp 1001ndash1005 2007

[24] T Hattori N Fujitsuka A Asakawa and A Inui ldquoA new strat-egy usingRikkunshito (Liu-Jun-Zi-Tang) a Japanese traditionalmedicine to treat gastrointestinal diseaserdquo Basics of Evidences-Based Herbal Medicine pp 149ndash160 2010

[25] T Hattori ldquoRikkunshito and ghrelinrdquo International Journal ofPeptides vol 2010 Article ID 283549 3 pages 2010

[26] K Watanabe K Matsuura P Gao et al ldquoTraditional JapaneseKampo medicine clinical research between modernity andtraditional medicinemdashthe state of research andmethodologicalsuggestions for the futurerdquo Evidence-Based Complementary andAlternativeMedicine vol 2011 Article ID 513842 19 pages 2011

[27] T Hayakawa T Arakawa Y Kase et al ldquoLiu-Jun-Zi-Tanga kampo medicine promotes adaptive relaxation in isolatedguinea pig stomachsrdquo Drugs under Experimental and ClinicalResearch vol 25 no 5 pp 211ndash218 1999

[28] N Furukawa NManabe Y Kase et al ldquoIntragastric infusion ofrikkunshito (kampo) induces proximal stomach relaxation inconscious dogsrdquo Autonomic Neuroscience vol 179 no 1-2 pp14ndash22 2013

[29] Y Kito and H Suzuki ldquoProperties of Rikkunshi-to (TJ-43)-induced relaxation of rat gastric fundus smooth musclesrdquoAmerican Journal of Physiology vol 298 no 5 pp G755ndashG7632010

[30] M Shiratori T Shoji M Kanazawa M Hongo and S FukudoldquoEffect of rikkunshito on gastric sensorimotor function underdistentionrdquo Neurogastroenterology and Motility vol 23 no 4pp 323ndash329 2011

[31] M Yanai E Mochiki A Ogawa et al ldquoIntragastric adminis-tration of rikkunshito stimulates upper gastrointestinal motility


and gastric emptying in conscious dogsrdquo Journal of Gastroen-terology vol 48 no 5 pp 611ndash619 2013

[32] T Kido Y Nakai Y Kase et al ldquoEffects of Rikkunshi-to atraditional Japanese medicine on the delay of gastric emptyinginduced by 119873119866-nitro-L-argininerdquo Journal of PharmacologicalSciences vol 98 no 2 pp 161ndash167 2005

[33] K Tominaga T Kido M Ochi et al ldquoThe traditional japanesemedicine rikkunshito promotes gastric emptying via the antag-onistic action of the 5-HT

3receptor pathway in ratsrdquo Evidence-

based Complementary and Alternative Medicine vol 2011 Arti-cle ID 248481 8 pages 2011

[34] H Miwa J Koseki T Oshima et al ldquoRikkunshito a tradi-tional Japanese medicine may relieve abdominal symptoms inrats with experimental esophagitis by improving the barrierfunction of epithelial cells in esophageal mucosardquo Journal ofGastroenterology vol 45 no 5 pp 478ndash487 2010

[35] Y Araki K-I Mukaisho Y Fujiyama T Hattori and HSugihara ldquoThe herbal medicine rikkunshito exhibits strong anddifferential adsorption properties for bile saltsrdquo Experimentaland Therapeutic Medicine vol 3 no 4 pp 645ndash649 2012

[36] I Kurose S Miura D Fukumura H Suzuki M Tsuchiya andH Ishii ldquoInhibitions of platelet-activating factor productionand granulocyte oxidative activation by Rikkunshi-To in theprocess of gastric mucosal injuryrdquo Pathophysiology vol 2 no3 pp 153ndash159 1995

[37] T Arakawa K Higuchi Y Fujiwara et al ldquoGastroprotection byLiu-Jun-Zi-Tang (TJ-43) possible mediation of nitric oxide butnot prostaglandins or sulfhydrylsrdquo Drugs under Experimentaland Clinical Research vol 25 no 5 pp 207ndash210 1999

[38] Y Goso Y Ogata K Ishihara and K Hotta ldquoEffects oftraditional herbal medicine on gastric mucin against ethanol-induced gastric injury in ratsrdquo Comparative Biochemistry andPhysiology C vol 113 no 1 pp 17ndash21 1996

[39] M Kojima H Hosoda Y Date M Nakazato H Matsuo andK Kangawa ldquoGhrelin is a growth-hormone-releasing acylatedpeptide from stomachrdquoNature vol 402 no 6762 pp 656ndash6601999

[40] M Nakazato N Murakami Y Date et al ldquoA role for ghrelin inthe central regulation of feedingrdquo Nature vol 409 no 6817 pp194ndash198 2001

[41] A Asakawa A Inui T Kaga et al ldquoGhrelin is an appetite-stimulatory signal from stomach with structural resemblanceto motilinrdquo Gastroenterology vol 120 no 2 pp 337ndash345 2001

[42] A M Wren L J Seal M A Cohen et al ldquoGhrelin enhancesappetite and increases food intake in humansrdquo Journal ofClinical Endocrinology and Metabolism vol 86 no 12 ArticleID 5992 2001

[43] T Matsumura M Arai Y Yonemitsu et al ldquoThe traditionalJapanese medicine Rikkunshito increases the plasma level ofghrelin in humans and micerdquo Journal of Gastroenterology vol45 no 3 pp 300ndash307 2010

[44] H Takeda C Sadakane T Hattori et al ldquoRikkunshito anherbal medicine suppresses cisplatin-induced anorexia in ratsvia 5-HT2 receptor antagonismrdquo Gastroenterology vol 134 no7 pp 2004ndash2013 2008

[45] N Fujitsuka A AsakawaMHayashi et al ldquoSelective serotoninreuptake inhibitorsmodify physiological gastrointestinalmotoractivities via 5-HT2c receptor and acyl ghrelinrdquo BiologicalPsychiatry vol 65 no 9 pp 748ndash759 2009

[46] K Yakabi C Sadakane M Noguchi et al ldquoReduced ghrelinsecretion in the hypothalamus of rats due to cisplatin-inducedanorexiardquo Endocrinology vol 151 no 8 pp 3773ndash3782 2010

[47] K Yakabi S Kurosawa M Tamai et al ldquoRikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexiavia hypothalamic ghrelin interactionrdquo Regulatory Peptides vol161 no 1ndash3 pp 97ndash105 2010

[48] C Sadakane S Muto K Nakagawa et al ldquo10-Gingerol a com-ponent of rikkunshito improves cisplatin-induced anorexiaby inhibiting acylated ghrelin degradationrdquo Biochemical andBiophysical Research Communications vol 412 no 3 pp 506ndash511 2011

[49] M Nahata S Muto N Oridate et al ldquoImpaired ghrelinsignaling is associated with gastrointestinal dysmotility in ratswith gastroesophageal reflux diseaserdquo American Journal ofPhysiology vol 303 no 1 pp G42ndashG53 2012

[50] T Naito H Itoh F Yasunaga and M Takeyama ldquoRikkunshi-to raises levels of somatostatin and gastrin in human plasmardquoBiological and Pharmaceutical Bulletin vol 24 no 7 pp 841ndash843 2001

[51] T Naito H Itoh and M Takeyama ldquoComparison of the effectsof hange-shashin-to and Rikkunshi-to on human plasma cal-citonin gene-related peptide and substance P levelsrdquo Biologicaland Pharmaceutical Bulletin vol 26 no 8 pp 1104ndash1107 2003

[52] T Naito H Itoh and M Takeyama ldquoSome gastrointestinalfunction regulatory Kampo medicines have modulatory effectson human plasma adrenocorticotropic hormone and cortisollevels with continual stress exposurerdquo Biological and Pharma-ceutical Bulletin vol 26 no 1 pp 101ndash104 2003

[53] Y Sato F Katagiri H Itoh and M Takeyama ldquoEffects of somekampo medicines on plasma levels of neuropeptide Y undervenipuncture stressrdquo Biological and Pharmaceutical Bulletinvol 28 no 9 pp 1757ndash1761 2005

[54] H Takeda S Muto T Hattori et al ldquoRikkunshito amelioratesthe aging-associated decrease in ghrelin receptor reactivity viaphosphodiesterase III inhibitionrdquo Endocrinology vol 151 no 1pp 244ndash252 2010

[55] K Yakabi M Noguchi S Ohno et al ldquoUrocortin 1 reducesfood intake and ghrelin secretion via CRF

2receptorsrdquoAmerican

Journal of Physiology vol 301 no 1 pp E72ndashE82 2011[56] Y Saegusa H Takeda SMuto et al ldquoDecreased plasma ghrelin

contributes to anorexia following novelty stressrdquo AmericanJournal of Physiology vol 301 no 4 pp E685ndashE696 2011

[57] C Yamada Y Saegusa K Nakagawa et al ldquoRikkunshitoa Japanese Kampo medicine ameliorates decreased feedingbehavior via ghrelin and serotonin 2B receptor signaling in anovelty stress murine modelrdquo BioMed Research Internationalvol 2013 Article ID 792940 9 pages 2013

[58] K Terawaki Y Sawada Y Kashiwase et al ldquoNew cancercachexia rat model generated by implantation of a peritonealdissemination-derived human stomach cancer cell linerdquo Amer-ican Journal of Physiology vol 306 no 4 pp E373ndashE387 2014

[59] H Tsubouchi S Yanagi A Miura et al ldquoRikkunshito ame-liorates bleomycin-induced acute lung injury in a ghrelin-independent mannerrdquo American Journal of Physiology vol 306no 3 pp L233ndashL245 2014

[60] K Ito T Satoh YWatanabe et al ldquoEffects of Kampomedicineson CYP and P-gp activity in vitrordquo Biological and Pharmaceuti-cal Bulletin vol 31 no 5 pp 893ndash896 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Administration of rikkunshito in combination with Western drugs in human studies

Reference Western drugs Patients Outcome[4] Docetaxel5-FUcisplatin Esophageal cancer Improved QOL[5] S-1cisplatin Unresectable or relapsed gastric cancer Improved anorexia[6] Gemcitabine Stage IIIIV pancreatic cancer with ascites Prolonged median survival[7] Rabeprazole PPI-refractory GERD Improved GERD score[8] Lansoprazole PPI-refractory LPR Improved global sensation VAS scores[9] Rabeprazole Gastrointestinal symptoms after ESD Improved GSRS score[10] Fluvoxamine Depressive disorder Improved GSRS scores[11] Antidepressants or antipsychotics Elderly patients with dementia Increase in food intake[12] Anti-Parkinson drugs Parkinsonrsquos disease Ameliorated gastroparesis[13] Ofloxacin Healthy volunteers No effects on bioavailability[14] Levofloxacin Healthy volunteers No effects on bioavailabilityESD endoscopic submucosal dissection GERD gastroesophageal reflux disease LPR laryngopharyngeal reflux PPI proton-pump inhibitor QOL quality oflife GSRS Gastrointestinal Symptom Rating Scale VAS visual analog scale

accumulating a combined list of studies publications notexamining the use of rikkunshito and those not writtenin English were excluded Data abstraction was performedto characterize physiological and clinical effects and druginteractions of rikkunshito Because a formal meta-analysiswas not possible based on variations in study populationsdisorders and study protocols retrieved data are presenteddescriptively with regard to the physiological and clinicaleffects of rikkunshito

3 Results and Discussion

The initial search terms yielded 2 books 14 reviews and 66original manuscripts related to rikkunshito of which 30 werehuman studies and 36 were animal and in vitro studies Ofthese 30 human studies 10 concerned the use of Westerndrugs in combination with rikkunshito (Table 1) of the 36animal and in vitro studies 6 concerned the use of Westerndrugs in combination with rikkunshito (1 of these included ahuman study) and 1 investigated the effects of rikkunshito onhuman drug metabolic enzymes

31 Clinical Applications of Rikkunshito A double-blindedrandomized placebo-controlled trial on rikkunshito wasconducted by Tatsuta and Iishi in 42 patients with chronicidiopathic dyspepsia [15] Gastric emptying was significantlyaccelerated and gastrointestinal symptoms were significantlyreduced in patients treated with rikkunshito for 7 daysindicating that rikkunshito has a prokinetic action on gastricemptying and may be useful in treating FD Arai et alconducted a parallel randomized controlled trial to inves-tigate the effects of rikkunshito on upper gastrointestinalsymptoms and ghrelin levels in 27 patients with FD treatedwith either rikkunshito or domperidone for 4 weeks [16]Gastrointestinal SymptomRating Scale (GSRS) questionnairescores significantly improved in both groups but plasmaghrelin levels significantly increased only in the rikkunshitogroup and good correlation was found for improvementsin reflux and indigestion symptoms A study on the effects

of rikkunshito on gastric accommodation reflex and duo-denogastric motility was conducted in 16 patients with FDusing extracorporeal ultrasonography before and after 14days of treatment [17] GSRS scores for abdominal painsheartburn and abdominal distension significantly decreasedand the expansion rate of the proximal stomach was sig-nificantly greater after treatment A study on the effectsof 4-week treatment with rikkunshito in 19 patients withgastric cancer who had undergone proximal gastrectomymore than 6 months previously was conducted by Gunjiet al [18] Patientsrsquo body weight significantly increasedafter the treatment course and in a subgroup analysis ofpatients showing a GSRS score of ge2 before treatment themean total GSRS score significantly improved after treatmentbecause of significant improvements in the subscale scoresfor abdominal pain acid reflux diarrhea and constipationSignificant attenuation of post-gastrectomy gastrointestinalsymptoms and increase in the ratio of acyl-total ghrelinconcentration by rikkunshito treatment for 4 weeks were alsoreported by Takiguchi et al in 25 patients who had undergonedistal gastrectomy or total gastrectomy [19] Takahashi etal in a crossover study examined the clinical effects ofrikkunshito in 11 patients who were to undergo pylorus-preserving gastrectomy for early gastric cancer [20] Rikkun-shito significantly improved emptying of solid meals fromthe remnant stomach according to (99m)Tc-labeled solidscintigraphy and stasis-related symptoms were significantlyreduced during the treatment Yagi et al evaluated theeffect of rikkunshito on symptoms and gastric myoelectricactivity in 8 dyspeptic pediatric patients whose symptomshad persisted for over 1 year after gastrointestinal surgeryFollowing rikkunshito therapy all patients exhibited symp-tomatic relief and a significant decrease in the mean symp-tom scores along with increased gastric contractile activityaccording to electrogastrography [21] Symptomatic relief andimproved gastric emptying by rikkunshito administrationwere reported by Kawahara et al in 9 handicapped patientsusing the 13C-acetate breath test and the BreathID system[22] Kawahara et al also investigated the effects of rikkun-shito on clinical symptoms and esophageal acid exposure in






























4 Conclusion




Abbreviations





References








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































4 Conclusion




Abbreviations





References








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































4 Conclusion




Abbreviations





References








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























4 Conclusion




Abbreviations





References








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References








































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Beneficial Effects of Rikkunshito, a ...downloads.hindawi.com/journals/ecam/2014/519035.pdf · Kampo medicines are traditional herbal medicines which have been approved