EKAT Appendix 2014 漢方専門医認定機関、日本東洋医学会 | EBM特別委員会

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Evidence Reports of Kampo Treatment (EKAT)

Appendix 2014

漢方治療エビ

ンスレポー

(EKAT) Appendix 2014

6 June 2015

Task Force for Evidence Reports (ER-TF)

Committee for Evidence-based Medicine (EBM)

The Japan Society for Oriental Medicine (JSOM)

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History of version upgrades

6 Jun. 2015: Kampo Chiryo Ebidensu Repoto Appendix 2014 (Evidence Reports of Kampo Treatment Appendix 2012)

31 Dec. 2013: Kampo Chiryo Ebidensu Repoto 2013 – 402 no RCT (Evidence Reports of Kampo Treatment 2013: 402 Randomized Controlled Trials)

31 Dec. 2012: Kampo Chiryo Ebidensu Repoto Appendix 2012 (Evidence Reports of Kampo Treatment Appendix 2012)

1 Oct. 2011: Kampo Chiryo Ebidensu Repoto Appendix 2011 (Evidence Reports of Kampo Treatment Appendix 2011)

1 Jun. 2010: Kampo Chiryo Ebidensu Repoto 2010 – 345 no RCT (Evidence Reports of Kampo Treatment 2010: 345 Randomized Controlled Trials)

1 Jun. 2009: Kampo Chiryo Ebidensu Repoto 2009 – 320 no RCT (Evidence Reports of Kampo Treatment 2009: 320 Randomized Controlled Trials)

1 Apr. 2008: Kampo Chiryo Ebidensu Repoto Dai 2-han – RC T wo Shu ni Shite- Chukan Hokoku 2007 ver 1.1 (Evidence Reports of Kampo Treatment 2nd edition - Focusing on RCTs- Interim Report 2007 ver.1.1) 15 Jun. 2007: Kampo Chiryo Ebidensu Repoto Dai 2-han –RC T wo Shu ni Shite- Chukan Hokoku 2007 (Evidence

Reports of Kampo Treatment 2nd edition - Focusing on RCTs- Interim Report 2007)

20 Jul. 2005: Kampo Chiryo niokeru Ebidensu Repoto (Evidence Reports of Kampo Treatment) (Nihon Toyo Igaku Zasshi [Kampo Medicine] 2005: 56, EBM supplementary issue)

20 Sept. 2002: Kampo Chiryo niokeru EBM – 2002 nen Chukan Hokoku (EBM in Kampo 2002, Interim Report) (Nihon Toyo Igaku Zasshi [Japanese Journal of Oriental Medicine] 2002: 53 [5], supplementary issue)

Version/date Title Year of publication of target references

2015.6.6

Evidence Reports of Kampo Treatment, Appendix 2014

(EKAT appendix 2014)

From EKAT 2013

2013 (First half) 513

2)

4181), 2)

167

2013.12.31 Evidence Reports of Kampo Treatment, 2013

- 402 Randomized Controlled Trials 1986-2012 (First half) 494

3)

4031), 3)

159

2012.12.31

From EKAT 2011

2011 (First half) 457 379

1), 4)

1504)

2011.10.1

From EKAT 2010

2010 (First half) 432 360

1), 5)

-2010.6.1

Evidence Reports of Kampo Treatment, 2010 - 345 Randomized Controlled Trials

(EKAT 2010)

1986-2009 (First half) 416 3461)

132

2009.6.1

Evidence Reports of Kampo Treatment, 2009 - 320 Randomized Controlled Trials

(EKAT 2009)

1986-2008 (First half) 385 3211)

111

2008.4.1

Evidence Reports of Kampo Treatment, 2nd edition

- Focusing on RCTs - Interim Report 2007 ver1.1

1999-2005 116 98 32

2007.6.15

Evidence Reports of Kampo Treatment, 2nd edition

- Focusing on RCTs - Interim Report 2007

1999-2005 104 102 42

1) _{Including meta-analysis}

2) _{Total of all references added in EKAT 2013 and EKAT Appendix 2014.} 3)

4) _{Total of all references added or removed in EKAT 2010, EKAT Appendix 2011 and EKAT Appendix 2012.} 5) _{Total of all references added in EKAT 2010 and EKAT Appendix 2011.}

No. of references

No. of structured

abstracts (SAs)

No. of excluded references

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Notes on the current version

The Task Force for Evidence Reports (ER -TF) of the Japan Society for Oriental Medicine (JSOM), Committee for Evidence-based Medicine (EBM) gathers comprehensive data on randomized controlled trials (RCTs) of Kampo formulations in Japan, compiles structured abstracts (SAs), and then publishes them as Kampo Chiryo Ebidensu Repoto (Evidence Reports of Kampo Treatment: EKAT). The Task Force for Evidence Reports was amalgamated with the Task Force for Clinical Practice Guidelines in June 2009 because RCTs of Kampo prescriptions were used for preparation of Clinical Practice Guidelines and it was considered that the relation between the two was strong. Nevertheless, it was determined that the Task Force for Evidence Reports return to activity as a separate body in June 2014 for project management reasons.

As indicated in "History of version upgrades" on the previous page,Kampo Chiryo Ebidensu Repoto 2013 - 402 no RCT- (EKAT 2013) was published on December 31, 2013, and included 402 RCTs and 1 meta-analysis published between 1986, when the specifications for the quality of Kampo formulations for prescription came into current effect, and the first half of 2012. Of the RCTs published in EKAT 2014 Appendix over about one year there are an additional 17 SAs (16 RCTs and one meta-analysis) and three revised SAs. Additionally, although references by Hirayama et al in 1990 and 1992 had been treated as separate RCTs and had separate SAs, it became clear that they were based on the same study, so the SAs were combined into one. This resulted in a decrease in the number of SAs by one. Furthermore, another SA was removed for reasons detailed below. The previous page presents a summary of the figures to do with the references and SAs in this Appendix.

Although the website has not been updated since EKAT 2013, the Google search engine available on the EKAT website allows users to search all SAs in both EKAT β01γ and the EKAT Appendix β014. The society’s past practice has been to make broad selections of references for EKAT on the principle of inclusiveness so as not

to miss any RCT. This has meant that references were included in EKAT if they indicated the publisher’s name

and included content sufficient for an SA to be written, even if they were academic society articles or similar. But

since β010, the Novartis’ Diovan scandal and the STAP cell falsification scandal have prompted heightened

concerns about medical paper authorship and conflict of interest (COI). The society has found among Kampo prescription RCTs differences in the results and the numbers of patients in articles by journalists and the finished reference concerned, and in some cases it has not been possible to follow the link from the RCT in an article to the reference. In March this year, the Japanese Association of Medical Journal Editors, a part of the Japanese

Association of Medical Sciences, published its Medical Journal Editing Guidelines (http://jams.med.or.jp/guideline).

Therefore, from EKAT Appendix 2014 on, the society will not include reports that are in article form and whose authors are clearly journalists. In addition, past SAs that were based on reports in article form will be revised when the finished reference is gathered, and if a reference is added to a past SA, the past SA will be removed and a new SA will be written.

The society again plans to publish them as an Appendix in the next EKAT and has decided to conduct the reference search at a different time from then on. In the past, the reference search has been conducted in November, however, differences have emerged between the EKAT name and the time of publishing, causing confusion. For example, because the reference search for this Appendix was conducted in November 2013, it does

not include references in journals published in the latter half of 2013. Nevertheless, this Appendix is called EKAT Appendix 2014, which can be a cause for misunderstanding. To resolve this issue, the society plans to conduct the reference search for the next EKAT in April 2015, prepare SAs for references from most of the journals published

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Fourth Phase (June 2013 -)

Task Force for Evidence Reports (ER-TF)

Committee for Evidence-based Medicine (EBM)

The Japan Society for Oriental Medicine (JSOM)

Organization

Chair and chairperson of Committee for EBM

:

Kiichiro TSUTANI

Faculty of Health Sciences, Tokyo Ariake University of

Medical and Health Sciences

Department of Drug Policy and Management, Graduate

School of Pharmaceutical Sciences, the University of Tokyo

Members (12 persons, order of the Japanese syllabary):

Ichiro ARAI

Department

of

Pharmaceutical

Sciences,

Nihon

Pharmaceutical University

Takahisa

USHIROYAMA

Health Science Clinic, Osaka Medical College

Tetsuro OKABE

Okabe Kampo Medical Clinic

Toshiaki KOGURE

Department of Japanese Oriental Medicine, Gunma Central

General Hospital

Hirozo GOTO

Department of Kampo Medicine

,

Hokusei Hospital

Hiroki TAKUMA

Acupuncture and Physical Therapy Teacher Training School,

University of Tsukuba

Koki TSURUOKA

Graduate School of Social Service Management, Japan

College of Social Work

Hideyuki NAKATA

Kampo Internal Medicine/Health Medical Center, Nerima

General Hospital

Michio FUJISAWA

Division for Health Service Promotion, University of Tokyo

Etsuo HOSHINO

Division of Kampo Support, Cancer Institute Ariake Hospital

Miyuki MINARI

Sub Committee to Assess the Efficacy of Kampo

Formulations, Committee on Kampo Formulations for

Prescription,

Japan

Kampo

Medicines

Manufacturers

Association

Yoshiharu MOTOO

Department of Medical Oncology, Kanazawa Medical

University

Trustee in charge of Committee for EBM, Japan Society for Oriental Medicine (JSOM):

Shin-ichi

MURAMATSU

Division of Oriental Medicine, Center for Community

Medicine, Jichi Medical University (trustee in charge of

Committee for EBM, JSOM)

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Lists of Structured Abstracts

<<EKAT Appendix 2014: Structured Abstracts describing RCTs and the References Reporting Them>>

Note: Original English titles assigned by authors were used in these lists and the structured abstracts. When references had no English titles, the Task Force translated the original Japanese titles into English ones (*).

ICD-10 Research Question

Kampo

Formula References

Study Design Source

Page No.

C18.9

To evaluate the

anti-inflammatory effects of daikenchuto (大建中湯) on

patients with colorectal cancer following laparoscopic resection.

daikenchuto(大建中湯)

Yoshikawa K, Shimada M, Nishioka M, et al. The effects of the Kampo medicine (Japanese herbal medicine)

“Daikenchuto” on the surgical inflammatory response

following laparoscopic colorectal resection. Surgery Today 2012; 42: 646-51.

RCT I 10

C22.0

To evaluate the usefulness of daikenchuto (大建中湯) in

postoperative patients who underwent hepatectomy.

Nishi M, Shimada M, Uchiyama H, et al. The beneficial effects of Kampo medicine dai-ken-chu-to after hepatic resection: a prospective randomized control study. Hepato-Gastroenterology 2012; 59: 2290-4.

RCT N 11

C25.9

To evaluate the effect of juzentaihoto (十全大補湯) for

antigen-specific immunity and performance status of advanced pancreatic cancer patients receiving peptide vaccine therapy.

juzentaihoto (十全大補湯)

Yutani S, Komatsu N, Matsuda S, et al. Juzentaihoto failed to augment antigen-specific immunity, but prevented

deterioration of patients’ conditions in advanced pancreatic

cancer under personalized peptide vaccine. Evidence-based Complementary and Alternative Medicine 2013: 1-10.

RCT N 12

F03

To evaluate the efficacy and safety of

yokukansankachimpihange (抑肝散加陳皮半夏) on

cognitive function.

yokukansankachimpi hange (抑肝散加陳皮半夏)

Fujita H, Yoshida M, Yomoda S. Effects of Yokukansankachimpihange on cognitive ability, an open randomized controlled trial. Psychiatry 2013; 23: 130-8 (in Japanese with English abstract).

quasi-RC

T N 13

G47.3

To evaluate the lipid lowering and antihypertensive effects of bofutsushosan (防風通聖散) and daisaikoto (大柴胡湯) for patients with

obstructive sleep apnea as a complication of obesity and hypertension.

bofutsushosan (防風通聖散)

daisaikoto (大柴胡湯)

Murase K, Toyama Y, Harada Y, et al. Evaluation and comparison of the effect of two Chinese herbal medicines (Bofu-tsusho-san and Dai-saiko-to) on metabolic disorders in obstructive sleep apnea patients. American Journal of Respiratory and Critical Care Medicine 2013; 187: A5694.

RCT C 14

G62.9

To investigate the inhibitory effect of TSUMURA Goshajinkigan (牛車腎気丸)

Extract Granules(TJ-107) on oxaliplatin-induced peripheral neuropathy (OPN).

goshajinkigan (牛車腎気丸)

Kono T, Hata T, Morita S, et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent oxaliplatin-induced neuropathy. Cancer Chemotherapy and Pharmacology 2013; 72: 1283-90.

DB-RCT N 15

H93.1

To evaluate the effects of hangekobokuto (半夏厚朴湯)

on chronic tinnitus.

hangekobokuto (半夏厚朴湯)

Ino T, Odaguchi H, Wakasugi A, et al. A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of hangekobokuto in adult patients with chronic tinnitus. Journal of Traditional Medicines 2013; 30: 72-81.

DB-RCT I 16

K11.7

To evaluate the effects of daikenchuto (大建中湯) on

salivary secretion and salivary neuropeptide levels in humans after a single oral dose.

Suzuki Y, Itoh H, Yamamura R, et al. Significant increase in salivary substance P level after a single oral dose of Japanese herbal medicine Dai-kenchu-to in humans. Biomedicine & Aging Pathology 2012; 2: 81-4.

RCT- cross over

N 17

K59.0

To evaluate the efficacy and safety of daikenchuto (大建中湯) in the treatment of

functional constipation.

Iturrino J, Camilleri M, Wong BS, et al. Randomized clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit and anorectal and bowel function in female patients with functional constipation. Alimentary Pharmacology and Therapeutics 2013; 37: 776-85.

DB-RCT C 18

K59.8

To evaluate the effectiveness of daikenchuto (大建中湯)

for perioperative intestinal paralysis following laparoscopic colon cancer surgery.

Yaegashi M, Otsuka K, Itabashi T, et al. Applying a Kampo medication to lower gastrointestinal tract surgery.* Shokaki Geka (Gastroenterological Surgery) 2013; 36: 1315-24.

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Kampo

Formula References

Study Design Source

Page No.

K91.0

To verify the inhibitory effect of goreisan (五苓散) on

nausea and vomiting after surgery under general anesthetic.

goreisan (五苓散)

Kori K, Oikawa T, Odaguchi H, et al. Go-rei-san, a Kampo medicine, reduces postoperative nausea and vomiting: A prospective, single-blind, randomized trial. The Journal of Alternative and Complementary Medicine 2013; 19: 946-50.

RCT N 20

K91.9

To evaluate the effect of daikenchuto (大建中湯) on

abdominal bloating in patients who underwent hepatectomy for liver malignancies

daikenchuto (大建中湯)

Hanazaki K, Ichikawa K, Munekage M, et al. Effect of Daikenchuto (TJ-100) on abdominal bloating in hepatectomized patients. World Journal of Gastrointestinal Surgery 2013; 5: 115-22.

RCT N 21

N95.1

To verify the clinical efficacy of porcine placental extract on shoulder stiffness in climacteric women.

porcine placental extract

Koike K, Yamamoto Y, Suzuki N, et al. Efficacy of porcine placental extract on shoulder stiffness in climacteric women. Climacteric 2013; 16: 447-52. (in Japanese with English abstract)

RCT N 22

N95.1

To verify the clinical efficacy of porcine placental extract on shoulder stiffness in postmenopausal women taking hormone replacement therapy.

porcine placental extract

Koike K, Yamamoto Y, Suzuki N, et al. Efficacy of porcine placental extract on shoulder stiffness in climacteric women. Climacteric 2013; 16: 447-52. (in Japanese with English abstract)

RCT N 23

Z01.8

To analyze the blood kinetics of indicator ingredients in

daikenchuto (大建中湯).

Munekage M, Ichikawa K, Kitagawa H, et al. Population pharmacokinetic analysis of daikenchuto, a traditional Japanese medicine (Kampo) in Japanese and US health volunteers. Drug Metabolism and Disposition 2013; 41: 1256-63.

RCT- cross over

N 24

Meta-analysis

G30.1

To perform a systematic review of the efficacy and tolerability of yokukansan (抑

肝散) in the treatment of

behavioral and psychological symptoms of dementia

(BPSD).

yokukansan (抑肝散)

Matsuda Y, Kishi T, Shibayama H, et al. Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. Human Psychopharmacology 2013; 28: 80-6.

meta-

analysis N 25

Revisions of Already Included References

Kampo

Formula References

Study Design Source

Page No.

F05.9

To evaluate the efficacy of yokukansan (抑肝散) for

postoperative delirium after cardiovascular surgery in the elderly.

yokukansan (抑肝散)

Takase S. The efficacy of Yokukansan (抑肝散) on

postoperative delirium after cardiovascular surgery in the elderly*. Kampo Igaku (Science of Kampo Medicine) 2010; 34: 132–4 (in Japanese).

RCT- envelope

N

26 Takase S, Yokoyama H. Using a Kampo medication in the

perioperative period – The preventative effects of

yokukansan (抑肝散) on postoperative delirium after

cardiovascular surgery in the elderly*. Kampo to Saishin-chiryo (Kampo & the Newest Therapy) 2013; 22: 113–19 (in Japanese).

N

G62.9

To clarify the efficacy and adverse effects of

for peripheral neuropathy induced by oxaliplatin therapy for advanced or recurrent colorectal cancer.

Nishioka M, Shimada M, Kurita N, et al. The Kampo medicine, goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. International Journal of Clinical Oncology 2011; 16: 322–7.

RCT N

27 Nishioka M, Shimada M, Kurita N, et al. The significance of

Kampo as needed for cancer therapy – How to put it to use in clinical settings – Goshajinkigan alleviates FOLFOX-related peripheral neuropathy*. Sanfujinka Kanpo Kenkyu no Ayumi (Recent Progress of Kampo Medicine in Obstetrics and Gynecology) 2012; (29): 22–7 (in Japanese).

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K73.2

To evaluate the efficacy and safety of shosaikoto ( 柴胡湯) in the treatment of chronic

active hepatitis.

shosaikoto ( 柴胡湯)

Hirayama C, Okumura M, Tanikawa K, et al. A multicenter randomized controlled clinical trial of sho-saiko-to in chronic active hepatitis. Gastroenterologia Japonica 1989; 24: 715–9.

DB-RCT C&I

28 Hirayama C, Okumura M, Tanikawa K, et al. A multicenter

randomized controlled clinical trial of shosaiko-to in chronic active hepatitis. Kan-Tan-Sui 1990; 20: 751–9 (in Japanese).

I

Hirayama C, Okumura M, Tanikawa K, et al. A multicenter randomized controlled clinical trial of shosaiko-to in chronic active hepatitis – Variation in serum enzyme activity*. Kan-Tan-Sui 1992; 25: 551–8 (in Japanese).

I

L20.9

To evaluate the efficacy and safety of hochuekkito (補中益気湯) in patients with qikyo

( 気虚 , qi deficiency)

associated with atopic dermatitis (AD).

hochuekkito (補中益気湯)

Furue M, Tanaka Y, Kobayashi H, et al. Efficacy of Kanebo Hochuekkito in patients with atopic dermatitis with “qikyo” – a multicenter, double-blind trials*. Arerugi (Japanese Journal of Allergology). 2005; 54: 1020 (in Japanese).

DB-RCT N

29 Kobayashi H, Ishii M, Takeuchi S, et al. Efficacy and safety

of a traditional herbal medicine, Hochu-ekki-to in the long-term management of Kikyo (delicate constitution) in patients with atopic dermatitis: a 6-month, multicenter, double-blind, randomized, placebo-controlled study. Evidence-based Complementary and Alternative Medicine 2008 1-7 (2010; 7: 367-73).

N

Kobayashi H, Ishii M, Furue M. Efficacy of hochuekkito for skin symptoms in patients with atopic dermatitis associated with qikyo – An investigation by rash element –*. Nishinihon Hifuka (the Nishinihon Journal of Dermatology) 2012; 74: 642-7 (in Japanese).

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List of Excluded References

(Appendix 2014)

Note: Original English titles assigned by authors were used in this list and the structured abstracts.

When references had no English titles, the Task Force translated the original Japanese titles into

English ones (*).

Abbreviations: C, The Cochrane Library (CENTRAL); I, Igaku Chuo Zasshi (Japana Centra Revuo Medicana, Ichushi); N, Database Offered by Nikkankyo (the Japan Kampo Medicines Manufacturers Association)

Reasons for exclusion were classified as follows:

1) Clinical studies that were not RCTs or meta-analyses.

2) Studies using medicines that were not approved as Kampo preparations in Japan (Kampo tozai [decoctions], Chinese preparations, and others).

3) Studies using Kampo preparations manufactured before 1985 (their quality being different from that currently available).

4) Studies citing existing RCT papers.

5) Studies with unclear content.

6) Others (reasons are described in the list).

ICD-10 Research Question Kampo Formula References Reason for

Exclusion Source

C18.9

Evaluation of the anti-inflammatory effect and shortening of time until first flatus of daikenchuto (大建中湯) in colorectal cancer

patients following laparotomy

Yoshikawa K. Evaluation of anti-inflammatory efficacy of daikenchuto.*_{Dai 5 Kai Nippon Shokakan Gakkai} Sokai Gakujutsu Syukai (5th Annual Meeting of the JGA). 2009; 9-10 ( i n J a p a n e s e )

6) Although included as structured abstract in the

EKAT 2013, this study was excluded in the Appendix 2014 because it was reported in article form. N E88.9

Effect of bofutsushosan (防風通聖散) on metabolic

syndrome

bofutsushosan

防風通聖散

Wakasugi A. Kampo clinical research on metabolic syndrome*_. _{Uehara Kinen Seimei Kagaku Zaidan} Kenkyu Houkokusyu. 2012; 26: 105 ( i n J a p a n e s e )

5) I

G47.8 Evaluation of the efficacy _{and safety of yokukansan (}

抑肝散 ) on REM sleep

behavior disorder

yokukansan

(抑肝散)

S h i n o b e R . E ffi c a c y o f yo ku ka n s a n o n REM sleep behavior disorder (RBD) – comparison with clonazepam –*_._{Ka mp o I g a ku}₍_{Sc i e n c e o f Ka mp o} Me d i c i n e) . 2 0 1 3 ; 3 7 : 2 2 - 5 ( i n J a p a n e s e )

6) Reported

in article

form.

N

G47.9 Effect _{yokukansankachimpihange}of

(抑肝散加陳皮半夏) on

sleep in healthy adult males

yokukansankachimpihange

(抑肝散加陳皮半夏)

K a m b a y a s h i T, A i z a w a R , H a y a s h i Y, e t a l . E ffe c t o f yokukansankachimpihange on sleep in healthy adult males*_.

Ka mp o I g a ku (Sc i e n c e o f Ka mp o Me d i c i n e) . 2 0 1 3 ; 3 7 : 3 4 - 3 7 ( i n J a p a n e s e )

6) Reported

in article

form.

N

I25.9

Effect of Kampo medications on recovery of cerebrovascular function

keishibukuryogan ( 枝茯苓丸)

tokakujokito

核承気湯

tsudosan

通散

Yokoyama N, Hagiwara N, Yokoyama Y, et al. Use of kampo medicine to facilitate absorption of brain hemorrhage and functional recovery of patients. Cerebrovascular diseases. 2012; 34 Suppl 1: 36.

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ICD-10 Research Question Kampo Formula References Reason for

Exclusion Source

J20.0 Tolerability and effect of EPs

7630 on acute bronchitis EPs 7630

Kamin W, Ilyenko LI, Malek FA, et al. Treatment of acute bronchitis with EPs 7630: Randomized, controlled trial in children and adolescents. Pediatrics International 2012; 54: 219-26

2) I

K51.2

Remission effect of a herbal preparation on ulcerative proctitis

Xilei San suppository

Fukunaga K, Ohda Y, Hida N, et al. Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis. Journal of gastroenterology and hepatology. 2012; 27: 1808-15.

2) C

K91.3

Effectiveness of daikenchuto (大建中湯) on bowel

motility and on prevention of paralytic ileus after pancreaticoduodenectomy

Okada K, Kawai M, Uesaka K, et al. Effect of daikenchuto (TJ-100) on postoperative bowel motility and on prevention of paralytic ileus after pancreaticoduodenectomy： a multicenter, randomized

placebo-controlled phase Ⅱtrial (The JAPAN-PD

Study). Japanese Journal of Clinical Oncology 2013; 43: 436-8

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Evidence Reports of Kampo Treatment Appendix 2014 Task Force for Evidence Reports, the Japan Society for Oriental Medicine

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120012e 2. Cancer (Condition after Cancer Surgery and Unspecified Adverse Drug Reactions of Anti-cancer Drugs)

Reference

Yoshikawa K, Shimada M, Nishioka M, et al. The effects of the Kampo medicine (Japanese herbal medicine) “Daikenchuto” on the surgical inflammatory response following laparoscopic colorectal resection. Surgery Today 2012; 42: 646-51. Ichushi Web ID: 2013248005, Pubmed ID: 22202972

1. Objectives

To evaluate the anti-inflammatory effects of daikenchuto (大建中湯) on patients with colorectal cancer

following laparoscopic resection.

2. Design

Randomized controlled trial (RCT).

3. Setting

One center: Tokushima University Hospital, Japan.

4. Participants

Thirty patients with colorectal cancer following laparoscopic resection.

5. Intervention

Arm 1: TSUMURA Daikenchuto (大建中湯) Extract Granules (7.5 g/day) for seven days from the day

after surgery (n=15).

Arm 2: no administration of daikenchuto (大建中湯) (n=15).

6. Main outcome measures

Number of days to first flatus and number of days to discharge after surgery were recorded and measurements were taken before surgery and on days 1, 3, 5, and 7 after surgery for body temperature, heart rate, white blood cell count, lymphocyte count, C-reactive protein (CRP), -D-glucan, and Candida antigen.

7. Main results

Mean age was significantly lower in arm 1 than arm 2. The number of days to first flatus was significantly lower in arm 1 (1.8 ± 0.5) than arm 2 (2.7 ± 0.5). Only on the third day of hospitalization, CRP was significantly lower in arm 1 (4.6 ± 0.6) than arm 2 (8.3 ± 1.1). Body temperature was significantly lower in arm 1 (36.2 ± 0.4) than arm 2 (36.9 ± 0.6). There was no significant difference between arms for number of days to discharge after surgery, heart rate, white blood cell count, -D-glucan, and Candida antigen.

8. Conclusions

Administering daikenchuto for seven days from the day after laparoscopic colorectal cancer surgery is useful for inhibiting inflammation and promoting flatus.

9. From Kampo medicine perspective

None.

10. Safety assessment in the article

Not mentioned.

11. Abstractor’s comments

If it were possible to inhibit the inflammatory response (CRP) and shorten the period of intestinal paralysis through some form of intervention after colorectal surgery, there would be a decrease in hospitalization periods and in the need for treatment for complications, which would be useful from the point of view of controlling medical costs; however, hospitalization periods did not decrease in this study. The authors of this study chose patients who underwent laparoscopic surgery for their study with an aim to demonstrate that daikenchuto has an anti-inflammatory effect after surgery with low invasiveness. The inflammation inhibitory action mechanisms of daikenchuto soon after surgery that the authors listed include 1) promotion of intestinal motility through increased release of acetylcholine from cholinergic nerves mediated by Japanese Pepper (sansho), 2) the subsequent inhibition of enteric bacterial growth, 3) increase in dose-dependent intestinal tract blood flow mediated by Processed Ginger (kankyo), and 4) the inhibition of bacterial translocation and homeostasis maintenance in the intestinal epithelium mediated by inhibition of the production of inflammatory cytokines such as IFN- , IL-6, and TNF-α attributable to daikenchuto, observed in rats. While inhibiting inflammation after abdominal surgery might be useful for recovery from surgical invasion, it is liable to be disadvantageous from the point of view of defense. And the multifaceted effects of Kampo medications are a merit as well as a demerit. There needs to be careful verification of whether surgeons’ current habit of indiscriminately prescribing daikenchuto for long periods after abdominal surgery is valid or not. Furthermore, while the authors have published a study undertaken at the same time under the same protocols in conference proceedings (Proceedings of the 5th Annual Meeting of the Japanese Gastroenterological Association 2009: 9-10), the results of that paper differ from the results of this one. This appears to be due to differences in some of the cases enrolled in the study (for that reason, the structured abstract, which had been included in the previous version of Evidence Reports of Kampo Treatment [EKAT], was excluded from EKAT Appendix 2014 [added to the list of excluded abstracts]).

12. Abstractor and date

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11

Reference

Nishi M, Shimada M, Uchiyama H, et al. The beneficial effects of Kampo medicine dai-ken-chu-to after hepatic resection: a prospective randomized control study. Hepato-Gastroenterology 2012; 59: 2290-4. CENTRAL ID: CN-00912891, Pubmed ID: 23435143

1. Objectives

To evaluate the usefulness of daikenchuto (大建中湯) in postoperative patients who underwent

hepatectomy.

2. Design

3. Setting

One hospital (Tokushima University Hospital, Japan).

4. Participants

Thirty-two patients who underwent partial hepatectomy for primary/metastatic liver cancer or other liver diseases, except patients undergoing laparoscopic surgery, gastrointestinal resection, or splenectomy, etc.

5. Intervention

Arm 1: group receiving TSUMURA Daikenchuto (大建中湯) Extract Granules 2.5 g t.i.d. before meals via

a nasogastric tube or orally, starting from the day after operation (n=16).

Arm 2: control group receiving no TSUMURA Daikenchuto (大建中湯) Extract Granules 2.5 g (n=16).

Hematology of the following parameters on the day of and 1, 3, 5, and 7 days after operation: WBC, total bilirubin, ALT, total protein, prothrombin time (INR), ammonia, CRP, and -D-glucan. The numbers of days until the postoperative initial passage of flatus, initial defecation, initial intake of ordinary diet, and discharge, and complications.

7. Main results

There were no significant differences between groups in WBC, total bilirubin, ALT, total protein, prothrombin time (INR), or ammonia. On the third hospital day, CRP was significantly lower in arm 1 than in arm 2 (P<0.05). On the third hospital day, mean -D-glucan level was significantly lower in arm 1 than in arm 2 (P<0.05). There were no differences in postoperative complications between groups. The numbers of days until the postoperative initial passage of flatus, defecation, and intake of ordinary diet were smaller in arm 1 than in arm 2. In contrast, there was no significant difference in the number of days until discharge.

8. Conclusions

Daikenchuto can be safely used as a useful medication to suppress inflammation, promotes bowel motility, and stimulates appetite after hepatectomy.

None.

Daikenchuto is associated with no adverse reactions.

The study demonstrated that daikenchuto administered at a low dose (half the usual dose) early after partial hepatectomy significantly decreased blood CRP and -D glucan levels on postoperative day 3 and promoted postoperative improvement in bowel peristalsis. Daikenchuto has traditionally been used for relief of abdominal symptoms including abdominal pain, abdominal distension, Crohn’s disease, and irritable bowel syndrome. Mentioning recent studies that have shown the effects of daikenchuto to improve bowel motility and defecation and shorten the duration of hospitalization after colon cancer surgery, to exert efficacy for intestinal obstruction after abdominal surgery, and to reduce postoperative complications after total gastrectomy by improving bowel motility, etc. The authors explained that they conducted this study since there was only one previous study on daikenchuto administration after hepatectomy. The authors assumed the following possible mechanisms of action of daikenchuto: enhancement of gastrointestinal motility through stimulation of 5HT3 receptors and promotion of VIP and motilin secretions; increase in blood flow in gastrointestinal tract and portal vein mediated by calcitonin gene-related peptides; anti-inflammatory effect via inhibition of COX-2 activity; and suppression of bacterial translocation via suppression of proinflammatory cytokines. The authors did not explain the reason for reducing the dose of daikenchuto by half. Use of the usual dose may produce different results (effects and adverse reactions), necessitating investigation of the optimal dose.

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12

Reference

Yutani S, Komatsu N, Matsuda S, et al. Juzentaihoto failed to augment antigen-specific immunity, but prevented deterioration of patients’ conditions in advanced pancreatic cancer under personalized peptide vaccine. Evidence-Based Complementary and Alternative Medicine 2013: 1-10. doi: 10.1155/2013/981717. CENTRAL ID: CN-00919989, Pubmed ID: 23840274

1. Objectives

To evaluate the effect of juzentaihoto (十全大補湯) for antigen-specific immunity and performance status

of advanced pancreatic cancer patients receiving peptide vaccine therapy.

2. Design

3. Setting

Department of Immunology and Immunotherapy, Kurume University School of Medicine, Japan; Research Center for Innovative Cancer Therapy, Kurume University, Japan; Department of Surgery, Kurume University Hospital, Japan.

4. Participants

Fifty-seven patients with standard therapy-resistant advanced pancreatic cancer.

5. Intervention

Arm 1: cycles of 6 weeks of weekly subcutaneous injection of up to 4 kinds of peptide vaccines. administration of TSUMURA Juzentaihoto (十全大補湯) Extract Granules 2.5 g t.i.d. (7.5 g/day)

for 35 days from the first day of the first cycle (n=28). Arm 2: the above peptide vaccine therapy alone (n=29).

Cytokines such as interferon- as a measure of cellular immunity and peptide-specific IgG as a measure of humoral immunity. Performance status (PS) and laboratory values.

7. Main results

Five patients in the juzentaihoto group and 2 patients of the vaccine therapy group failed to complete the first cycle of the vaccine therapy and provided no post-vaccination data. After exclusion of these dropouts, remaining 50 were included in the analysis population. There were no significant differences between groups in the changes from baseline in antigen-specific T cell response (cellular immunity), antigen-specific IgG (humoral immunity), or overall survival after initiation of the vaccine therapy. However, after initiation of the vaccine therapy, PS was not significantly changed from baseline in the juzentaihoto combination group but was significantly decreased from baseline in the vaccine alone group (P=0.0156). After initiation of the vaccine therapy, significant decreases in hemoglobin concentration (P=0.0203), lymphocyte count (P=0.0351), and serum albumin level (P=0.0214) were noted in the vaccine alone therapy, but not in the juzentaihoto combination group.

8. Conclusions

Juzentaihoto does not potentiate antigen-specific immunity but prevents aggravation of general conditions and declines in hemoglobin concentration, lymphocyte count, and serum albumin level in pancreatic cancer patients receiving peptide vaccine therapy.

None.

The article describes that there were no significant differences in the incidence or severity of adverse events between groups and that the independent Safety Monitoring Committee judged all adverse events observed to be due to progression of pancreatic cancer or concomitant anticancer drugs, but not due to the peptide vaccine or juzentaihoto.

This is the first study to verify the clinical effect of juzentaihoto combined with the peptide vaccine therapy in advanced pancreatic cancer patients. Since the study population consisted of patients with chemotherapy-resistant, rapidly-progressive pancreatic cancer, the study period may have been too short for the authors to confirm the immunity-potentiating effect. Nevertheless, it should be appreciated that they demonstrated the benefits of juzentaihoto, including improvement in performance status and suppression of aggravation in hematological values, in an RCT. The authors are expected to conduct similar clinical research with postoperative adjuvant chemotherapy for cancer or in patients with slowly-progressive cancer in future. Readers can take the study results that peptide vaccine plus juzentaihoto combination has virtually no safety problem but inconclusive efficacy.

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13

130002e 5. Psychiatric/Behavioral Disorders

Reference

Fujita H, Yoshida M, Yomoda S. Effects of Yokukansankachimpihange on cognitive ability, an open randomized controlled trial. Psychiatry 2013; 23: 130-8 (in Japanese with English abstract).

1. Objectives

To evaluate the efficacy and safety of yokukansankachimpihange (抑肝散加陳皮半夏) on cognitive

function.

2. Design

Quasi-randomized controlled trial (quasi-RCT).

3. Setting

Residents or users and staff of 3 institutions in Toyama Prefecture, Japan.

4. Participants

Forty-one adult males and females aged 55 years or older with moderate strength, slightly weak gastrointestinal system, easy fatigability, aggressiveness, irritability, insomnia, and mild psychiatric symptoms

5. Intervention

Arm 1: Kracie Yokukansankachimpihange (抑肝散加陳皮半夏)Extract Granules 7.5 g/day (3.75 g b.i.d)

for 4 weeks (n=20)

Arm 2: no administration of yokukansankachimpihange (n=21)

Prior to and 4 weeks after the study, the Mini-Mental State Examination (MMSE), Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog.), and assessments of behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (neuropsychiatric inventory [NPI] and disability assessment for dementia [DAD]) were performed. In addition, changes in oxyhemoglobin concentration (ΔO2Hb) were measured using an infrared oxygen monitor to determine cerebral blood flow during execution of the following tasks: standard clinical assessment for attention, tapping span, memory updating test, digit span, and compound digit cancellation test.

7. Main results

Three subjects in arm 1 dropped out of the study. There was no significant between-group difference in MMSE score, NPI score, or DAD score The amount of change in ADAS-J cog. was –2.9 ± 3.5 in arm 1 and 0.22 ± 2.6 in arm 2, indicating a significant improvement in arm 1 compared to arm 2 (P<0.01). The ΔO2Hb value in the left hemisphere during task execution was significantly higher in arm 1 than in arm 2 (P<0.05). Of the tasks executed during measurement of cerebral blood flow, the standard clinical assessment for attention showed a significantly larger difference in total number of answers between the baseline and 4 weeks after the study in arm 1 than in arm 2 (P<0.05).

8. Conclusions

Yokukansankachimpihange improves ADAS-J cog. for core symptoms and oxygen metabolism in the brain during task execution.

The inclusion criteria for the study are the sho (証, pattern) for yokukansankachimpihange. 10. Safety assessment in the article

Treatment was discontinued in 2 subjects receiving yokukansankachimpihange due to increased blood pressure and vomiting. Changes in blood components were within the normal range in both groups.

This landmark clinical study has clarified the effects of yokukansankachimpihange on cognitive function, based on clinical symptoms (including core symptoms, BPSD and activities of daily living), and changes in cerebral blood flow in the frontal lobe. On the other hand, the authors state only that residents and staff of institutions were included in the study without providing detailed information on them; that is, effects in dementia patients and those in normal persons are mixed in study results. The authors also state that subjects were stratified and randomized by sex, age, and MMSE score, although the number of the subjects was small and other measurements may be biased. In fact, there was no between-group difference in mean baseline ADAS-J cog. score, but the yokukansankachimpihange group included many subjects with high ADAS-J cog. scores. For this reason, the amount of change in score may have been larger in the yokukansankachimpihange group. Moreover, as described in the Discussion section, the amount of change in oxyhemoglobin concentration (ΔO2Hb), which was measured to determine brain metabolism during task execution, was less in the control group than in the yokukansankachimpihange group after 4 weeks, thereby contributing to the significant difference between the two groups. However, these laborious investigations and evaluations of cerebral blood flow will play an important role in determining the effects of Kampo medicines on cognitive function. It is hoped that clinical studies in dementia patients will be continued.

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14

130003e 4. Metabolism and Endocrine Diseases

Reference

Murase K, Toyama Y, Harada Y, et al. Evaluation and comparison of the effect of two Chinese herbal medicines (Bofu-tsusho-san and Dai-saiko-to) on metabolic disorders in obstructive sleep apnea patients. American Journal of Respiratory and Critical Care Medicine 2013; 187: A5694. CENTRAL ID: CN-00870751

1. Objectives

To evaluate the lipid lowering and antihypertensive effects of bofutsushosan (防風通聖散) and daisaikoto

(大柴胡湯) for patients with obstructive sleep apnea as a complication of obesity and hypertension.

2. Design

3. Setting

Not mentioned (the corresponding author belongs to the Faculty of Medicine, Kyoto University, Japan).

4. Participants

One hundred and twenty-eight obstructive sleep apnea patients with hypertension and obesity remaining after at least six-month CPAP treatment.

5. Intervention

Arm 1: Bofutsushosan (防風通聖散) (manufacturer unknown) for six months (n=65).

Arm 2: Daisaikoto (大柴胡湯) (manufacturer unknown) for six months (n=63).

Body mass index (BMI), blood pressure.

7. Main results

The patients who completed the study were 44 in arm 1 and 41 in arm 2. BMI decreased significantly in arm 1 from 34.6±6.3 kg/m2 before treatment to 33.7±6.6 kg/m2 after six months of treatment, while in arm 2 the scores were 34.9±7.9 kg/m2 before administration and 34.9±8.1 kg/m2 after six months. Although in statistical terms no antihypertensive effect with a significant difference between groups was found, a decrease in morning systolic blood pressure was observed in home blood pressure measurements in arm 1 (from 143.3±13.4 mmHg to 138.7±13.9 mmHg, P=0.03) and a decrease in diastolic blood pressure was observed in arm 2 (from 84.3±10.4 mmHg to 80.2±11.1 mmHg, P<0.01). A decrease in sleep onset latency was observed.

8. Conclusions

The results suggest bofutsushosan (防風通聖散) and daisaikoto (大柴胡湯) have lipid lowering and

antihypertensive effects for patients with obstructive sleep apnea as a complication of obesity and hypertension.

None.

Not mentioned.

Having evaluated the lipid-lowering and antihypertensive effects of bofutsushosan and daisaikoto for patients with obstructive sleep apnea as a complication of obesity and hypertension, the authors’ interim report suggests that bofutsushosan has a BMI-lowering action. While no significant antihypertensive effect was observed between the two groups, blood pressure measurements taken in the morning with a home sphygmomanometer suggest a decrease in systolic blood pressure in the bofutsushosan group, and a decrease in diastolic blood pressure in the daisaikoto group. As this paper is an interim report, completion of the trial must be awaited for the final results.

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130004e 6. Nervous System Diseases (including Alzheimer’s Disease)

Reference

Kono T, Hata T, Morita S, et al. Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent

oxaliplatin-induced neuropathy. Cancer Chemotherapy and Pharmacology 2013; 72: 1283-90. CENTRAL ID: CN-00961704, Pubmed ID: 24121454

1. Objectives

To investigate the inhibitory effect of TSUMURA Goshajinkigan (牛車腎気丸) Extract Granules(TJ-107)

on oxaliplatin-induced peripheral neuropathy (OPN).

2. Design

Double-blind randomized controlled trial (DB-RCT).

3. Setting

Twenty centers including university hospitals, Japan.

4. Participants

Patients with pathologically confirmed colorectal cancer receiving a chemotherapy regimen including oxaliplatin (85 mg/m2 oxaliplatin every two weeks in FOLFOX4 or mFOLFOX6) (n=93).

5. Intervention

Arm 1: TSUMURA Goshajinkigan (牛車腎気丸) Extract Granules (2.5 g t.i.d.) administered before meals,

continued for 26 weeks after start of chemotherapy (n=47).

Arm 2: placebo administered under the same schedule as above (control group, n=46).

An investigating physician graded peripheral neuropathy and other adverse effects between 0 and 4 according to the National Cancer Institute Common Terminology Criteria for Adverse Events

(NCI-CTCAE) ver. 3 before the start of chemotherapy, then every 2 weeks (8 times), then every 4 weeks until the 26th week. The patients also graded themselves for degree of numbness before therapy and then before each chemotherapy treatment between grade 0 and 4 according to the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12 items questionnaire

(FACT/GOG-Ntx-12).

7. Main results

Three patients in arm 1 and one patient in arm 2 dropped out of the study. OPN appearing by the 8th anticancer drug administration and graded at least grade 2 occurred in 39% of arm 1 and in 51% of the placebo group, and of those, 7% in arm 1 and 13% in arm 2 had grade 3: arm 1 had the lower scores in both cases. TJ-107 inhibited the advance of OPN severity, with the median length of time to reach at least Gr. 2 being 5.5 months in arm 1 and 3.9 months in arm 2. The percentage of patients displaying OPN by the 26th week was 54.1% in arm 1 and 62.5% in arm 2. The degree of OPN as measured by the patients showed no significant difference between groups in the 8th and 26th weeks. There was no difference between the effects of TJ-107 for FOLFOX4 and mFOLFOX6. There was no difference between groups for other adverse effects, although there were fewer cases of vomiting in arm 1. There was no difference between groups for antitumor effects (percentages of complete response [CR] + partial response [PR] and CR+PR+ stable disease [SD]): TJ-107 had no adverse effect.

8. Conclusions

Goshajinkigan delays onset of peripheral neuropathy of Grade 2 or more induced by oxaliplatin.

None.

There was no difference in adverse drug reaction incidence for arms 1 and 2. There was no issue with the safety of goshajinkigan.

The results of chemotherapy for colorectal cancer have dramatically improved with the advent of oxaliplatin in recent years. However, overcoming OPN has been an issue as it is a dose-limiting toxicity. The authors used goshajinkigan for this study as it has previously been useful for diabetes-induced peripheral neuropathy. Starting with a retrospective trial, they conducted a multi-center RCT before this multi-center DB-RCT, which suggested the preventative effect of goshajinkigan for OPN. The authors consider that goshajinkigan’s main mechanism of action lies in the analgesic action of bushi, as well as the neuroprotection, neurotransmitter modification, bloodstream improvement mediated by the production of nitric oxide, and various actions of the other crude drugs. However, as the quantity of bushi in

goshajinkigan is no more than 1 g per day, increasing the quantity of bushi may increase its anti-OPN effect. Further investigation into the therapeutic effects of Kampo for OPN under a protocol including an increased quantity of powdered processed Aconite Root for ethical dispensing in the goshajinkigan is anticipated.

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130005e 8. Ear Diseases

Reference

Ino T, Odaguchi H, Wakasugi A, et al. A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of hangekobokuto in adult patients with chronic tinnitus. Journal of Traditional Medicines 2013; 30: 72-81. Ichushi Web ID: 2013310385 J-STAGE

1. Objectives

To evaluate the effects of hangekobokuto (半夏厚朴湯) on chronic tinnitus.

2. Design

Double-blind, placebo-controlled, randomized controlled trial (DB-RCT).

3. Setting

Department of Otorhinolaryngology, Kitasato University Hospital, Japan.

4. Participants

Seventy-six adults aged at least 20 years with tinnitus persisting for at least three months, the impairment rated at least 18 points on the Tinnitus Handicap Inventory score (THI score), or between mild and severe. The five exclusion criteria were: (1) objective tinnitus, intermittent tinnitus, or pulsatile tinnitus; (2) conductive hearing impairment; (3) acoustic nerve tumor confirmed by MRI or clinically related nerve impairment, psychiatric disorder, or systemic disease (e.g. cardiac disease, malignant tumor, renal failure, hepatic failure); (4) administration of a Kampo medication within 4 weeks before the trial; and (5) currently pregnant or breastfeeding.

5. Intervention

Arm 1: Kracie Hangekobokuto (半夏厚朴湯) Extract Tablets, 6 tablets b.i.d. for 12 weeks (n=38)

Arm 2: Placebo, 6 tablets b.i.d. for 12 weeks (n=38). The placebo tablets were made of cornstarch and lactose to resemble the Hangekobokuto (半夏厚朴湯) Extract Tablets in color, form, weight, smell

and taste.

The main outcome was the difference between baseline and final THI scores. Secondary outcomes: changes in the visual analog scale (VAS), Hospital Anxiety and Depression Scale (HADS), and Short-Form 36-Items Health Survey scores (SF36).

7. Main results

There was no significant difference between arms in THI scores (total: P =0.73, functional: P=0.99, emotional: P=0.78, catastrophic: P=0.59). There was no significant difference in the secondary outcome measures. There was no difference between arms in THI score among participants with no anxiety or depression. THI scores tended to improve in the hangekobokuto arm compared to the placebo arm among participants with dizziness (total: P=0.006). The authors did a hangekobokuto pattern subgroup analysis (16 participants in the hangekobokuto arm and 26 in the placebo arm), but there was no significant difference between groups.

8. Conclusions

While there were no significant differences between arms, hangekobokuto tended to improve THI scores for participants with dizziness more than the placebo.

As mentioned in the results, a hangekobokuto pattern subgroup analysis was carried out.

Itchiness and worsened tinnitus were observed in the placebo arm. Neither was sufficiently severe to discontinue the trial.

This is a well-designed RCT. The randomization, delineation between the inclusion and exclusion criteria, participant recruitment, flow diagram, and outcomes were clear and readily comprehensible. It is an exemplary paper with much to teach new learners of EBM. Although unfortunately the results did not demonstrate significant differences, as the authors mention in their considerations, they will take the next step forward by finding the definitive factors that lead to Kampo medication prescribing, and formulating a study design that fully reflects the particular features of Kampo. Further development of this research is anticipated.

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120014e 11. Gastrointestinal, Hepato-Biliary-Pancreatic Diseases

Reference

Suzuki Y, Itoh H, Yamamura R, et al. Significant increase in salivary substance P level after a single oral dose of Japanese herbal medicine Dai-kenchu-to in humans. Biomedicine & Aging Pathology 2012; 2: 81-4. Pubmed ID: 23589717

1. Objectives

To evaluate the effects of daikenchuto (大建中湯) on salivary secretion and salivary neuropeptide levels in

humans after a single oral dose.

2. Design

Randomized controlled trial (cross-over) (RCT-cross over).

3. Setting

Department of Pharmacy, Oita University Hospital, Japan.

4. Participants

Five nonsmoking healthy male volunteers aged 25 to 31 years.

5. Intervention

Since allocation of patients to treatment arms is not mentioned, the treatment arms are described in terms of treatment regimen.

Arm 1: Single dose of TSUMURA Daikenchuto (大建中湯) Extract Granules 15 g with 200 mL of water

Arm 2: Single dose of placebo (lactose; dosage not specified) with 200 mL of water Subjects were crossed over to the alternate arm after a 1-month interval.

The volume of saliva collected from subjects at rest in a relaxed state at 20, 40, 60, 90, 120, 180, and 240 minutes after administration, and salivary levels of substance P-like immunoreactive substances (SP-IS), calcitonin gene-related peptide (CGRP)-IS, and vasoactive intestinal polypeptide (VIP)-IS measured by enzyme immunoassays.

7. Main results

Although differences in salivary volume between arms 1 and 2 were not significant, the volume increased 1.2–1.5 times during the 20–120 minutes after administration. The salivary SP-IS level in arm 1 was significantly increased at 20, 40, and 60 minutes after administration, compared to that in arm 2 (P<0.05). The salivary volume was significantly positively correlated with the SP-IS level (r=0.42, P=0.0062). There were no significant differences in CGRP-IS and VIP-IS levels between arms 1 and 2.

8. Conclusions

Daikenchuto increases salivary secretion by increasing the level of substance P. Patients with xerostomia will benefit from treatment with daikenchuto.

None.

Not mentioned.

The relevant references show that the group to which the authors belong has studied the effect of daikenchuto on neuropeptides in human plasma, effect of pilocarpine on neuropeptides in human saliva, and effect of hangekobokuto (半夏厚朴湯) on neuropeptides in human plasma and saliva since around

year 2000. Therefore, this RCT is considered clinical verification of evidence from a series of their studies with an RCT design. Since the present study was conducted in healthy subjects, it is premature to conclude that daikenchuto is effective for xerostomia. This study, however, is a starting point for the verification of new beneficial effects of daikenchuto and hopefully will lead to further development of their research.

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130006e 11. Gastrointestinal, Hepato-Biliary-Pancreatic Diseases

Reference

Iturrino J, Camilleri M, Wong BS, et al. Randomized clinical trial: the effects of daikenchuto, TU-100, on gastrointestinal and colonic transit and anorectal and bowel function in female patients with functional constipation. Alimentary Pharmacology and Therapeutics 2013; 37: 776-85. CENTRAL ID: CN-00853558, Pubmed ID: 23451764

1. Objectives

To evaluate the efficacy and safety of daikenchuto (大建中湯) in the treatment of functional constipation.

2. Design

3. Setting

Mayo Clinic, U.S.A. (single institution).

4. Participants

Forty-five subjects with functional constipation recruited from October 2010 to November 2012.

5. Intervention

Arm 1: TSUMURA Daikenchuto (大建中湯) Extract Granules po 2.5 g t.i.d for 4 weeks (n=15).

Arm 2: TSUMURA Daikenchuto (大建中湯) Extract Granules po 5 g t.i.d for 4 weeks (n=15).

Arm 3: Placebo (n=15).

Gastrointestinal transit, rectal compliance, rectal sensation thresholds, gastrointestinal motility in response to anal sphincter pressures and bowel movement status, changes in psychosensory symptoms associated with constipation, and quality of daily life.

7. Main results

Gastrointestinal motility was not significantly increased by arm 1 and arm 2 compared to arm 3. There was no difference in main outcome measures between arm 1 and arm 2. In arm 2, daikenchuto lowered the rectal sensation thresholds for the first bowel movement and gas sensation (P = 0.045 and 0.024, respectively).

8. Conclusions

In women with functional constipation, daikenchuto may increase the rectal sensation threshold for bowel movement but has no therapeutic effect on gastrointestinal motility, stool softness, frequency of stools, psychosensory symptoms, or quality of life. The mechanism of action of daikenchuto remains to be elucidated in clinical settings.

None.

Although daikenchuto produced adverse reactions such as headache and abdominal pain, no differences in adverse reactions were noted among the groups and daikenchuto was safe and well tolerated.

This excellent study measured defecation sensation in the rectum associated with intestinal motility and defecation behavior in women with functional constipation by using various objective, physiological examination methods, in an attempt to elucidate the clinical efficacy of daikenchuto. The study revealed that 5 g/dose (15 g/day) of daikenchuto does not affect gastrointestinal motility or rectal sensation. However, it lowers the thresholds for bowel movement and gas sensation in the rectum, a finding which will contribute a great deal to the conduct of future clinical studies of daikenchuto. Daikenchuto is not widely used for the treatment of functional constipation, but has been shown to promote gastrointestinal motility in in vitro experiments. The present study may be the driving force for the elucidation of how daikenchuto-related sub-ileus can be prevented. I hope verification will be obtained from a different point of view or based on a study protocol that involves the sho (証, pattern) for daikenchuto.

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130007e 11. Gastrointestinal, Hepato-Biliary-Pancreatic Diseases

Reference

Yaegashi M, Otsuka K, Itabashi T, et al. Applying a Kampo medication to lower gastrointestinal tract surgery*. Shokaki Geka (Gastroenterological Surgery) 2013; 36: 1315-24.

1. Objectives

To evaluate the effectiveness of daikenchuto (大建中湯) for perioperative intestinal paralysis following

laparoscopic colon cancer surgery.

2. Design

3. Setting

One center: Department of Surgery, Iwate Medical University, Japan.

4. Participants

Fifty-four cases of laparoscopic colon cancer surgery (aged between 43 and 89 years).

5. Intervention

Arm 1: Daikenchuto (大建中湯) (manufacturer unknown) 7.5 g/day two days before surgery then from the

first day after surgery until discharge from hospital (n=27, aged 51 to 83 years).

Arm 2: Intestinal disorder medication two days before surgery then from the first day after surgery until discharge from hospital (n=27, aged 43 to 89 years).

Time until first flatus and until bowel movement.

7. Main results

Since 1 patient in arm 1 and 2 patients in arm 2 dropped out of the study, the efficacy analysis set included 26 and 25 patients in arm 1 and arm 2, respectively. Greater acceleration of first flatus and bowel movement from post-operative extubation was observed in arm 1 compared to arm 2 (P<0.05). White blood cell count and CRP showed no significant difference between arms.

8. Conclusions

Daikenchuto is effective for accelerating improvement of intestinal paralysis following laparoscopic surgery.

None.

No adverse drug reactions were observed.

This paper is a randomized controlled trial investigating the effectiveness of daikenchuto in improving intestinal paralysis after laparoscopic surgery. Previous papers have reported early administration of daikenchuto to be effective in improving gastrointestinal dysfunction, however, this paper suggests even greater efficacy by commencing administration before surgery. A future clinical trial involving the effectiveness of daikenchuto and its administration timing in the perioperative period is anticipated.

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130008e 11. Gastrointestinal, Hepato-Biliary-Pancreatic Diseases

Reference

Kori K, Oikawa T, Odaguchi H, et al. Go-rei-san, a Kampo medicine, reduces postoperative nausea and vomiting: A prospective, single-blind, randomized trial. The Journal of Alternative and Complementary Medicine 2013; 19: 946-50. CENTRAL ID: CN-00961902, Pubmed ID: 23837690

1. Objectives

To verify the inhibitory effect of goreisan (五苓散) on nausea and vomiting after surgery under general

anesthesia.

2. Design

3. Setting

One center: Department of Anesthesiology, Osaka Medical College Hospital, Japan.

4. Participants

Ninety-nine gynecological patients who underwent laparoscopic surgery under general anesthetic.

5. Intervention

Arm 1: TSUMURA Goreisan (五苓散) Extract Granules (2.5 g t.i.d.) administered before meals on the day

before surgery (GRS group) (n=49).

Arm 2: The above extract granules were not administered (control group) (n=50).

At 3 and 24 hours after surgery, an evaluator who did not know which patients belonged to which groups scored the intensity of nausea during 0 to 3 hours and 0 to 24 hours after surgery using a verbal rating scale (VRS) between 0 and 10, and recorded the frequency of vomiting over the respective periods.

7. Main results

Nausea intensity scores (VRS scores) up to 24 hours after surgery were significantly lower in arm 1 (2.16 ± 2.70) than arm 2 (4.08 ± 3.17), the percentage of patients who vomited up to 24 hours after surgery was significantly lower in arm 1 (15 patients, 30.6%) than arm 2 (26 patients, 52.0%), and the frequency of vomiting was also significantly lower in arm 1 (0.51 ± 0.89) than arm 2 (1.06 ± 1.16).

8. Conclusions

Administering goreisan on the day before gynecological laparoscopic surgery under general anesthesia is useful for reducing postoperative nausea and vomiting.

None.

No goreisan-related adverse events occurred.

This is a single blind randomized study into the clinical effects of goreisan aiming to verify its effectiveness for inhibiting nausea and vomiting after surgery under general anesthesia. It verified through a randomized controlled trial the previously known effectiveness of goreisan on nausea and vomiting. Being limited to gynecological laparoscopic surgery, the study did not elucidate the effects on males; however, the study does warrant certain appraisal. The results of future studies on whether or not it is effective for males, on administration for 5 to 7 days before surgery, and on the inhibitory effects on nausea and vomiting after non-gynecological surgery are therefore anticipated. The authors could not conduct a double blind trial using placebo because the extract manufacturer declined to provide a placebo, yet, hopefully in future it may be possible to use the extract in capsule form.