原著論文

The eﬀectiveness of the herbal medicine, rikkunshito (TJ43), on the absorption of levodopa and in the treatment ofgastrointestinal symptoms in Parkinson's disease*
Yasuhiro Suzuki1, Takashi Kimura1, Kohei Kano1, Hideaki Kishi1, Kenta Nomura1,Kosuke Yoshida1, Yoko Aburakawa1, Kenji Kuroda1, Chisato Murakami2,
Sachiko Okuno3 and Osamu Yahara1
1

Department of Neurology, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan2

Department of Clinical Research, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan3Department of Hospital Pharmacy, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan

Abstract
Object The aim of this prospective study was to assess the effectiveness of rikkunshito on the absorptionof administrated levodopa and in the treatment of gastrointestinal symptoms in Parkinson’s disease
patients.
Materials and Methods: Eight participants with Parkinson’s disease were enrolled. The serum levodopa
concentration, maximum concentration, and area under the plasma concentration-time curve of levodopa
before and after treatment were measured in all patients taking rikkunshito in conjunction with levodopa
for 4 weeks. Gastrointestinal manifestations were evaluated by the Gastrointestinal Symptom Rating
Scale (GSRS).
Results: After administration of rikkunshito, the maximum concentration of levodopa improved in 5
Parkinson’s disease patients, while the area under the plasma concentration-time curve of levodopa
increased in 4 Parkinson’s disease patients. The GSRS showed amelioration of the symptoms in theupper gastrointestinal tract in 3 of the patients, one of whom exhibited a normalized levodopa absorption
pattern. In contrast, the GSRS showed the symptoms improved in the lower gastrointestinal tract in 6 of
the Parkinson’s disease patients.
Conclusion: Rikkunshito treatments improved lower gastrointestinal symptoms such as constipation anddefecatory dysfunction in Parkinson’s disease patients.
Key words: Parkinson’s disease, rikkunshito, levodopa, GSRS, ghrelin

Yasuhiro Suzuki, MD, PhD

Department of Neurology, Asahikawa Medical Center, National Hospital Organization
7. HanasakiChiyo, Asahikawa, Hokkaido, 070-8644, Japan
Phone: +81-166-51-3161; Fax: +81-166-53-9184 E mail: ysuzuki@asahikawa.hosp.go.jp―3―PD\EHEHQH¿FLDOLQWUHDWLQJIXQFWLRQDOG\VSHSVLDSDWLHQWVIntroduction

who have impaired gastric motility by extracorporeal

Non-motor manifestations of Parkinson’s disease

ultrasonography. 11) Hiyama et al. further demonstrated(PD) are recognized as derangements of behavior, sleep,that rikkunshito administered with levodopa improved

sensation, and autonomic function. The most common

erratic gastric emptying and stabilized the plasma levodopa

non-motor feature of PD is gastrointestinal dysfunction.

levels, thereby resulting in an improvement in the motor

Gastrointestinal motility is regulated by both the extrinsic

fluctuations in Parkinsonian patients.12) However, there

inputs from the dorsal motor nucleus of the vagus (DMV)

have been few reports on whether rikkunshito can improveand the paravertebral sympathetic ganglia, and by the local

the lower gastrointestinal dysmotility.

reflexes mediated by the intrinsic neurons of the enteric

Therefore, this study was designed to investigate

nervous system (ENS), which consists of the myentericif rikkunshito could improve the pharmacologicalplexus (of Auerbach) and the submucosal plexus (ofmanifestations for levodopa absorption, and to examineMeissner).

1,2)Well known characteristics of PD include an

accumulation of alpha-synuclein, which is commonly seen
as Lewy bodies and Lewy neuritis. Moreover, during theearly stages of PD, both DMV and EMS have been shown
to be affected by Lewy body pathology, resulting to provide
3,4,5)

whether rikkunshito could ameliorate the known pre-motor
gastrointestinal dysfunctions associated with PD.

Materials and Methods
Patients
Eight patients (5 men and 3 women) with idiopathic

the gastrointestinal dysmotility.

Impaired gastric emptying and accommodation in PD canPD were enrolled in this prospective study. Age, sex,

potentially have profound pharmacokinetic implications.

clinical stage, evolution, and treatment course are listed

Delayed gastric emptying and delayed levodopa arrival atin Table 1. Mean age of the patients was 72 ± 2 years

intestinal absorptive sites can result in erratic responses

old and mean disease duration was 8.75 ± 3.46 years.

to these medications. Moreover, absorptive variations canPatient AMC5 received anticholinergic medication, while

also lead to activation of one of the mechanisms of motor

patients AMC3, 5, 7, and 8 were given medications for6)ÀXFWXDWLRQWKDWDUHIRXQGLQ3'

constipation and defecatory dysfunction. None of the

Several approaches to the treatment of gastrointestinal

patients suffered from any gastrointestinal disease or had

dysmotility in PD have been investigated. Domperidone,

any history of gastrointestinal surgery. Diagnosis of PD

which blocks dopamine receptors but does not pass throughwas made according to the United Kingdom Parkinson’s

the blood-brain barrier, can be used in PD and improves

Disease Society Brain Bank Diagnostic Criteria.13) This

both the gastric emptying and gastrointestinal symptoms.7)

study was approved by the Ethics Committee of Asahikawa

The prevalence of gastrointestinal symptoms reported tooccur before the onset of motor symptoms of PD include
constipation (87%), and defecatory dysfunction (58.9%).8) It
has also been proposed that the onset of the PD pathology
is non-motor, with the non-motor symptoms beginning

Table 1.
Clinical characteristic of 8 Parkinson s disease patientstreated with rikkunshito. mH & Y; modified Hoehn andYahr staging scale, yr; year.

as early as 10 to 20 years before the actual onset of themotor symptoms.9) A previous report has confirmed thatdaikenchuto improves constipation in PD patients.10) The
prokinetic effect of daikenchuto on colonic motility was
shown to be mediated by an increase in the level of serum
motilin, vasoactive intestinal polypeptide (VIP), and 5-HT.
Recently Kusunoki et al. demonstrated that rikkunshito―4―Medical Center. Informed consent was obtained from eachparticipant prior to the study.

Results
Serum levodopa concentration results for the 8 patientsare shown in Figure 1. A single mean Cmax peak wasMethods
Eight PD patients received 2.5 g of rikkunshito 30

observed for rikkunshito at 0.5 hours after taking theminutes after each meal, (total 7.5 g per day), for 4 weeks

medication, after which the levels decreased duringin conjunction with levodopa/carbidopa (100 mg/10 mg).

fasting conditions. Delayed and incomplete absorption

If patients were taking other medications, these wereof levodopa were seen in patients AMC2, 6, and 8 priorFRQWLQXHGXQWLOWKHVWXG\ZDV¿QLVKHG

to taking the oral rikkunshito. Figure 2 shows the clinical

Blood samples for the single-time plasma levodopa

estimations for the Cmax, AUC and GSRS. Mean Cmax

concentration were collected immediately before and after

increased in patients AMC2, 3, 5, 6, and 8 after the 4-week

the levodopa/carbidopa morning dose and at the end of theadministration of rikkunshito. In addition, mean AUC

4-week rikkunshito administration. Depending upon theincreased in patients AMC2, 3, 6, and 8 under the same

protocol, patients took 1 tablet of levodopa/carbidopa (100conditions. Although the pattern of absorption of themg/10 mg) at 0.5 hour intervals for up to 1.0 hour, and thenlevodopa exhibited a single peak in patient AMC5 after

at 1.0 hour intervals for up to 4 hours. All patients fasted

taking rikkunshito for 4 weeks, there was no improvement

prior to the blood sampling.

observed in the AUC. The upper gastrointestinal tract

To estimate the concentration of the plasma levodopa,GSRS improved in patients AMC6, 7, and 8. Although theblood samples were promptly centrifuged at 4°C, withlower gastrointestinal tract GSRS in patients AMC2, 3, 5,

the plasma samples then frozen at -80°C. SRL Inc.,6, 7, and 8 showed amelioration of the symptoms, with the(Tokyo, Japan) performed all measurements of theexception of case AMC6, all of these patients required alevodopa concentration using HPLC-ECD. The maximum

prescription for constipation. The respective differences

concentration (Cmax) and the area under the plasma

noted for the lower gastrointestinal tract GSRS in eachconcentration-time curve of levodopa (AUC) wereSDWLHQWZHUHVWDWLVWLFDOO\VLJQL¿FDQW 3 1RDGYHUVH

calculated using the trapezoidal method in each patient.

effects were observed while taking rikkunshito during this

Gastrointestinal functions were estimated using theGSRS.

14)

GSRS is a disease-specific methodology that

LQFOXGHVLWHPVWKDWDUHWKHQFRPELQHGLQWR¿YHV\PSWRP

study.

Discussionclusters that address different gastrointestinal symptoms.

The present study demonstrated that rikkunshito

The five-symptom clusters depict reflux, abdominal pain,

treatment in PD patients led to an improvement in lower

indigestion, diarrhea and constipation. The GSRS uses agastrointestinal tract symptoms such as constipation andseven-level Likert-type graded scale where 1 represents thedefecatory dysfunction. Gastrointestinal symptoms suchabsence of bothersome symptoms and 7 represents veryas nausea, abdominal pain, and bloating are frequent

bothersome symptoms.

complaints of PD patients. Disturbance of levodopa
absorption due to delayed and erratic gastric emptying
contributes to the development of “delayed on” and “noStatistical analysis
GSRS differences with or without rikkunshito at 4on” motor fluctuations in PD. At the present time, partial

weeks after administration were estimated using a two-way

improvements in patients can sometimes be achieved

ANOVA. The Cmax and AUC were compared before andby combining oral levodopa with prokinetic drugs suchat 4 weeks after administration using a two-way ANOVA.

as domperidone, which accelerate gastric motility. 7)

All statistical calculations were two-side, and P < 0.05

Rikkunshito, an herbal medicine, contains 8 mixed raw

LQGLFDWHGVWDWLVWLFDOVLJQL¿FDQFH

herbs in the following ratios: JP (Japanese Pharmacopoeia)―5―Figure 1.
Concentration of plasma levodopa before and at 4 weeks after oral administration of rikkunshito. The efficacy oflevodopa absorption was improved in patients AMC2, 3, 5, 6, and 8, whose absorption of levodopa was unstable. Pre;
before treatment with rikkunshito. Post; 4 weeks after rikkunshito.

Atractylodes Lancea Rhizome 4.0 g, JP Ginseng 4.0 g,

to be effective for improving the symptoms of functional

JP Pinellia Tuber 4.0 g, JP Poria Sclerotium 4.0 g, JP

dyspepsia, gastroesophageal reflux disease, and cisplatin-Jujube 2.0 g, JP Citrus Unshiu Peel 2.0 g, JP Glycyrrhiza

induced anorexia. 11,15) Thus, this herbal medicine has

1.0 g, and JP Ginger 0.5 g. Rikkunshito has been shown

the potential to be successfully used in the treatment of―6―

Figure 2.
Comparison of clinical and pharmacokinetic data from Parkinson’s disease patients after 4 weeks of administration ofrikkunshito.
No statistical differences were seen for the Cmax, AUC, and GSRS (upper tract). In contrast, statistically significant
differences were seen for the GSRS (lower tract). P = 0.044.
Cmax; maximum concentration, AUC; area under the plasma concentration-time curve, GSRS; Gastrointestinal Symptom
Rating Scale, n.s.QRWVLJQL¿FDQW3UHEHIRUHWUHDWPHQWZLWKULNNXQVKLWR3RVWZHHNVDIWHUWUHDWPHQWZLWKULNNXQVKLWR

gastrointestinal disorders in Japan.

with autonomic dysfunction may occur via the NO or 5-HT3

Several previous studies have examined the mechanism ofreceptor pathways.

rikkunshito when used to treat gastrointestinal dysfunctions

Interestingly, we observed statistically significant

in animal models. Hayakawa et al. demonstrated that

improvements in the GSRS scores for the lower

rikkunshito in isolated guinea pig stomachs promoted

gastrointestinal tract in 6 of the participants after16)

Kido etrikkunshito treatment. Using the Sitzmarks radiopaqueal. proposed that rikkunshito ameliorated the effects of nitricmarker (Konsyl Inc., USA), Doi et al. were the first tooxide (NO)-mediated gastric functions including delayeddemonstrate that rikkunshito improved colonic transit

adaptive relaxation, i.e., gastric accommodation.

Hesperidin and L-arginine have beentime in 7 of 8 PD patients.19) However, it remained unclear

LGHQWL¿HGDVWZRRIWKHDFWLYHLQJUHGLHQWVWKDWFRQWULEXWHWR

as to how rikkunshito affected the lower gastrointestinal

the ability of rikkunshito to facilitate gastric emptying indysfunction in PD.

gastric emptying.

17)

rats. Furthermore, Tominaga et al. reported that rikkunshito*KUHOLQZKLFKZDVLGHQWL¿HGDVWKHQDWXUDOVHFUHWDJRJXH

appeared to improve the delay in gastric emptying via

for growth hormone in 1999,20) was shown to be abundantly

the antagonistic action of the 5-hydroxytryptaminesynthesized by specialized mucosal cells in the stomach.

(HT)3 receptor pathway in rats.

18)

Based on this previous

Matsumura et al. showed that rikkunshito increased theevidence, we speculate that improvement in the absorption

plasma acylated ghrelin level in healthy volunteers andof levodopa after rikkunshito administration in PD patientsnormal mice.21) In addition, Hirayama et al. demonstrated―7―

the ghrelin receptor existed in the lumbosacral defecation
control center (L6-S1 region of the spinal cord) and thatthe acylated ghrelin peptide was essential for promoting

2. Benarroch EE. Enteric nervous system: functional organizationand neurologic implications. Neurology. 2007;69:1953-1957
3. Braak H, Del Tredici KD, Rub U, et al. Staging of brain
pathology related to sporadic Parkinson’s disease. Neurobio

propulsive contractions of the colorectum in rats.22)

Aging. 2003;24:197-211

Although we did not examine patient ghrelin levels

4. Braak H, de Vos RA, Bohl J, Tredici K. Gastric alpha-synucleinin this study, we speculated that acylated ghrelin might

immunoreactive inclusions in Meissner’s and Auerbach’s
plexuses in cases staged for Parkinson’s disease-related brain

have modified the gastrointestinal function in 7 cases.

pathology. Neurosci Lett. 2006;396:67-72

Even though there has been little previous evidence that

5. Cersosimo MG, Benarroch EE. Neural control of therikkunshito can modify clinical symptoms, especiallygastrointestinal tract: implications for Parkinson disease. Movconstipation, our current study clearly indicated that

Disord. 2008;23:1065-1075

rikkunshito has a potent and special effect on lower

6. Djaldetti R, Barron J, Ziv I, Melamed E. Gastric emptying
in Parkinson’s disease: patients with and without response

intestinal dysfunction in PD. It is our belief that rikkunshitoÀXFWXDWLRQV1HXURORJ\

not only improves the function of the upper gastrointestinal

7. Soykan I, Sarosiek I, Shifflett J, et al. Effect of chronic oral

tract, but also has an effect on the lower gastrointestinal

domperidone therapy on gastrointestinal symptoms and gastric
emptying in patients with Parkinson’s disease. Mov Disord.

tract. This effect occurs via different mechanism thatfound for daikenchuto, and leads to an improvement in the1997;12:952-957
8. Cersosimo MG, Raina GB, Pecci C, et al. Gastrointestinal

GHIHFDWLRQG\VIXQFWLRQIRXQGLQ3',QRUGHUWRGH¿QLWLYHO\manifestations in Parkinson’s disease: prevalence and occurrence

elucidate how rikkunshito regulates the lower intestinal tract

before motor symptoms. J Neurol. 2013;260:1332-1338
9. Gaig C, Tolosa E. When does Parkinson’s disease begin? Movin PD patients, further studies will need to be undertaken.
In conclusion, we demonstrated that rikkunshito treatments

Disord. 2009;24:S656-S66410.Sakakibara R, Odaka T, Lui Z, et al. Dietary herb extract dai-improved the defecation dysfunction and constipation askenchu-to ameliorates constipation in parkinsonian patients

ZHOODVWKHJDVWULFG\VPRWLOLW\DQGWKXVZRXOGEHRIEHQH¿W

(Parkinson’s disease and multiple system atrophy). Mov Disord.

in PD patients. However, in order for this herbal medicine

2005;20:261-261

to gain wider acceptance in other countries, further studies

.XVXQRNL++DUXPD.+DWD-HWDO(I¿FDF\RI5LNNXQVKLWR
a traditional Japanese medicine (Kampo), in treating functional

RQWKHVSHFL¿FVRIWKHSK\VLRORJLFDODQGFOLQLFDOHIIHFWVZLOO
need to be performed.

dyspepsia. Intern Med. 2010;49:2195-2202
12.Hiyama Y, Tosa H, Terasawa K, et al. The effects of Rikkunshito on parkinsonian patients with unstable effect of levodopa/*An earlier version of this paper was read at the 54th Annual
Meeting of the Japanese Society of Neurology, May 29 tocarbidopa. J Trad Med. 1991;8:83-88
13.Fahn S, Elton RL, UPDRS Development Committee. The
8QL¿HG3DUNLQVRQ¶V'LVHDVH5DWLQJ6FDOH,Q)DKQ60DUVGHQJune 1, 2013.

CD, Calne DB, Goldstein M, eds. Recent developments inParkinson’s disease. Vol. 2. Florham Park, N.J.: Macmillan

The authors state that they have no conflict of interest(COI).

Healthcare Information. 1987; p153-163, p293-304
14.Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale
for gastrointestinal symptoms in patients with irritable bowel
syndrome and peptic ulcer disease. Dig Dis Sci. 1988;33:129-Acknowledgements134This study was supported in part by a grant-in-Aid for

15.Takeda H, Sadakane C, Hattori T, et al. Rikkunshito, an herbal
medicine, suppresses cisplatin-induced anorexia in rats via

Clinical Research from the National Hospital Organization.

5-HT2 receptor antagonism. Gastroenterology. 2008;134:20042013

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