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Isogai T, Morita K, Okada A, Michihata N, Matsui H, Miyawaki A, Yasunaga H. Association Between Complementary Use of Daikenchuto (a Japanese Herbal Medicine) and Readmission in Older Patients With Heart Failure and Constipation. Circ Rep 2025; 7:86-96. [PMID: 39931709 PMCID: PMC11807698 DOI: 10.1253/circrep.cr-24-0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/25/2024] [Accepted: 11/04/2024] [Indexed: 02/13/2025] Open
Abstract
Background Constipation commonly coexists with heart failure (HF) and can increase blood pressure because of straining during defecation and accompanying mental stress. Daikenchuto, a Japanese herbal medicine to ameliorate gastrointestinal motility, may be effective as a complement to laxatives in improving outcomes in patients with HF and constipation. Methods and Results We used the Diagnosis Procedure Combination database to identify patients aged ≥65 years who were admitted for HF, had constipation, and were discharged alive between April 2016 and March 2022. We divided the 115,544 eligible patients into 2 groups according to the prescription of Daikenchuto in addition to laxatives at discharge and compared the incidence of 1-year HF readmission using 1 : 4 propensity score matching. Daikenchuto was prescribed at discharge in 3,315 (2.9%) patients. In the unmatched cohort, patients treated with Daikenchuto were more often male and had a higher prevalence of malignancy than those treated without Daikenchuto. In the 1 : 4 propensity score-matched cohort (3,311 and 13,243 patients with and without Daikenchuto, respectively), no significant difference was noted in 1-year HF readmission between the groups (22.2% vs. 21.9%; hazard ratio=1.02, 95% confidence interval=0.94-1.11). This result was consistent across clinically relevant subgroups except for renal disease. Conclusions Complementary use of Daikenchuto in combination with laxatives was not associated with a lower incidence of HF readmission in patients with HF and constipation.
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Affiliation(s)
- Toshiaki Isogai
- Department of Cardiology, Tokyo Metropolitan Tama Medical Center Tokyo Japan
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Kojiro Morita
- Department of Nursing Administration and Advanced Clinical Nursing, Division of Health Sciences and Nursing, Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Akira Okada
- Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Nobuaki Michihata
- Cancer Prevention Center, Chiba Cancer Center Research Institute Chiba Japan
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo Tokyo Japan
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo Tokyo Japan
| | - Atsushi Miyawaki
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo Tokyo Japan
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo Tokyo Japan
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo Tokyo Japan
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Isogai T, Michihata N, Okada A, Morita K, Matsui H, Miyawaki A, Jo T, Yasunaga H. Use of Japanese Herbal Kampo Medicine in Patients With Acute Cardiovascular Disease - A 12-Year Nationwide Cohort Analysis. Circ J 2024; 88:1322-1331. [PMID: 38583961 DOI: 10.1253/circj.cj-23-0770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
BACKGROUND Kampo, a Japanese herbal medicine, is approved for the treatment of various symptoms/conditions under national medical insurance coverage in Japan. However, the contemporary nationwide status of Kampo use among patients with acute cardiovascular diseases remains unknown. METHODS AND RESULTS Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified 2,547,559 patients hospitalized for acute cardiovascular disease (acute myocardial infarction, heart failure, pulmonary embolism, or aortic dissection) at 1,798 hospitals during the fiscal years 2010-2021. Kampo medicines were used in 227,008 (8.9%) patients, with a 3-fold increase from 2010 (4.3%) to 2021 (12.4%), regardless of age, sex, disease severity, and primary diagnosis. The top 5 medicines used were Daikenchuto (29.4%), Yokukansan (26.1%), Shakuyakukanzoto (15.8%), Rikkunshito (7.3%), and Goreisan (5.5%). From 2010 to 2021, Kampo medicines were initiated earlier during hospitalization (from a median of Day 7 to Day 3), and were used on a greater proportion of hospital days (median 16.7% vs. 21.4%). However, the percentage of patients continuing Kampo medicines after discharge declined from 57.9% in 2010 to 39.4% in 2021, indicating their temporary use. The frequency of Kampo use varied across hospitals, with the median percentage of patients prescribed Kampo medications increasing from 7.7% in 2010 to 11.5% in 2021. CONCLUSIONS This nationwide study demonstrates increasing Kampo use in the management of acute cardiovascular diseases, warranting further pharmacoepidemiological studies on its effectiveness.
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Affiliation(s)
- Toshiaki Isogai
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
- Department of Cardiology, Tokyo Metropolitan Tama Medical Center
| | - Nobuaki Michihata
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
- Cancer Prevention Center, Chiba Cancer Center Research Institute
| | - Akira Okada
- Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo
| | - Kojiro Morita
- Global Nursing Research Center, Graduate School of Medicine, The University of Tokyo
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
| | - Atsushi Miyawaki
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo
| | - Taisuke Jo
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo
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Kashihara H, Okikawa S, Morine Y, Yoshikawa K, Tokunaga T, Nishi M, Takasu C, Nishiyama M, Zushi M, Shimada M. Impact of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass. THE JOURNAL OF MEDICAL INVESTIGATION 2024; 71:210-218. [PMID: 39462554 DOI: 10.2152/jmi.71.210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
INTRODUCTION We investigated the effect of Daikenchuto (TU-100) on the early postoperative period in duodenal-jejunal bypass (DJB). METHODS Study 1:The effect of TU-100 on diabetic rats was investigated. Rats were sacrificed after receiving TU-100 for one week. Study 2:The effect of TU-100 on DJB was investigated. Rats in the DJB and TU-100 treated DJB groups were sacrificed 24 hours postoperation to evaluate blood glucose, cytokine expression, and gut microbiome. RESULTS Study 1:TU-100 did not affect glucose or body weight. TU-100 suppressed intestinal inflammation and modified the gut microbiome. Specifically, Bifidobacterium and Blautia were increased, and Turicibacter were decreased in this group. Study 2:Both DJB and TU-100 treated DJB rats showed lower blood glucose at 24 hours postoperation than at preoperation. Cytokine expression in the liver and small intestine of the TU-100 treated DJB group was significantly lower than that of the DJB group. The gut microbiome composition in TU-100 treated DJB rats was altered. In particular, Bifidobacterium and Blautia were increased in this group. CONCLUSION DJB suppressed blood glucose during the early postoperative period. TU-100 may enhance the anti-diabetic effect of metabolic surgery by changing the gut microbiome and suppressing inflammation in the early postoperative period. J. Med. Invest. 71 : 210-218, August, 2024.
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Affiliation(s)
| | - Shohei Okikawa
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Kozo Yoshikawa
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Takuya Tokunaga
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Masaaki Nishi
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Chie Takasu
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Mitsue Nishiyama
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Makoto Zushi
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
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Dickerson RN, Farrar JE, Byerly S, Filiberto DM. Enteral feeding tolerance during pharmacologic neuromuscular blockade. Nutr Clin Pract 2023; 38:1236-1246. [PMID: 37475530 DOI: 10.1002/ncp.11045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/22/2023] Open
Abstract
A common misperception is that critically ill patients who receive paralytic therapy will not tolerate enteral nutrition. As a result, some clinicians empirically withhold enteral feedings for critically ill patients who receive neuromuscular blocker pharmacotherapy (NMB). The intent of this review is to examine the evidence regarding enteral feeding tolerance for critically ill patients given NMB. Studies evaluating enteral feeding during paralytic therapy are provided and critiqued. Evidence examining enteral feeding tolerance during NMB is limited. Enteral feeding intolerance is more likely attributable to the underlying illnesses and concurrent opioid analgesia, sedation, and vasopressor therapies. Most critically ill patients can be successfully fed during NMB. Prokinetic pharmacotherapy may be warranted in some patients.
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Affiliation(s)
- Roland N Dickerson
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Julie E Farrar
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Saskya Byerly
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Dina M Filiberto
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Yoshikawa K, Shimada M, Tokunaga T, Nakao T, Nishi M, Takasu C, Kashihara H, Wada Y, Yoshimoto T. The application of enhanced recovery after surgery in total gastrectomy: a propensity score-matched analysis. World J Surg Oncol 2023; 21:148. [PMID: 37194033 DOI: 10.1186/s12957-023-03034-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/11/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND This study aimed to investigate the feasibility and safety of our enhanced recovery after surgery protocol including early oral intake and omitting nasogastric tube (NGT) placement after total gastrectomy. METHODS We analyzed 182 consecutive patients who underwent total gastrectomy. The clinical pathway was changed in 2015, and patients were divided into 2 groups (conventional group and modified group). Postoperative complications, bowel movement, and postoperative hospital stays were compared in the two groups in all cases and propensity score matching (PSM). RESULTS Flatus and defecation were significantly earlier in the modified group compared with those in the conventional group (flatus: 2 (1-5) days vs 3 (2-12) days, p = 0.03; defecation: 4 (1-14) days vs 6 (2-12) days p = 0.04). The postoperative hospital stay was 18 (6-90) days in the conventional group and 14 (7-74) days in the modified group (p = 0.009). Days until discharge criteria were met were earlier in the modified group compared with that in the conventional group (10 (7-69) days vs 14 (6-84) days p = 0.01). Overall and severe complications occurred in nine patients (12.6%) and three patients (4.2%) in the conventional group and twelve patients (10.8%) and four patients (3.6%) in the modified group, respectively (p = 0.70 and p = 0.83) in all cases. In PSM, there is no significant difference between the two groups concerning the postoperative complications (overall complication 6 (12.5%) vs 8 (16.7%) p = 0.56, severe complications 1 (2%) vs 2 (4.2%) p = 0.83). CONCLUSIONS Modified ERAS for total gastrectomy may be feasible and safe.
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Affiliation(s)
- Kozo Yoshikawa
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan.
| | - Mitsuo Shimada
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Takuya Tokunaga
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Toshihiro Nakao
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Masaaki Nishi
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Chie Takasu
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Hideya Kashihara
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Yuma Wada
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Toshiaki Yoshimoto
- The Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
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Dickerson RN, Corley CE, Holmes WL, Byerly S, Filiberto DM, Fischer PE. Gastric feeding intolerance in critically ill patients during sustained pharmacologic neuromuscular blockade. Nutr Clin Pract 2023; 38:350-359. [PMID: 36156827 DOI: 10.1002/ncp.10911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/23/2022] [Accepted: 08/28/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The purpose of this study was to assess gastric feeding intolerance for critically ill patients who received sustained neuromuscular blocker (NMB) pharmacotherapy. METHODS Adult patients (>17 years of age) admitted to the trauma intensive care unit who received continuous intravenous NMB pharmacotherapy (rocuronium, cisatracurium, vecuronium, or pancuronium) for ≥48 h during continuous intragastric enteral nutrition (EN) were retrospectively evaluated. Gastric feeding intolerance was defined by initiation of a prokinetic agent (metoclopramide, erythromycin, or both) for an elevated gastric residual volume (GRV) >300 ml and with distention of the abdomen by physical examination, observation of regurgitation or emesis, temporary discontinuation of EN with low intermittent gastric suctioning, or initiation of parenteral nutrition (PN). Patients were evaluated for gastric feeding intolerance for the first 3 days of combined EN and NMB pharmacotherapy. A P value < 0.05 was considered statistically significant. RESULTS Ten patients of the 47 patients (21%) were intolerant to EN during NMB pharmacotherapy. No statistically or clinically relevant differences in patient characteristics were found between patients who tolerated EN vs those who experienced gastric feeding intolerance, except for a higher median maximum GRV of 125 ml (28, 200) vs 300 (250, 400) ml, respectively (P < 0.001). Five patients responded to prokinetic therapy and five required PN. CONCLUSION Most patients tolerated intragastric EN during sustained NMB pharmacotherapy. Presence of NMB pharmacotherapy is not an absolute contraindication for EN.
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Affiliation(s)
- Roland N Dickerson
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | | | - Whitney L Holmes
- Department of Pharmacy, Regional One Health, Memphis, Tennessee, USA
| | - Saskya Byerly
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Dina M Filiberto
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Peter E Fischer
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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7
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Manabe N, Nakajima A, Odaka T, Haruma K. Daikenchuto significantly improves stool consistency and lower gastrointestinal symptoms in patients with chronic constipation. JGH Open 2023; 7:182-189. [PMID: 36968570 PMCID: PMC10037039 DOI: 10.1002/jgh3.12870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/12/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND AND AIM A number of basic and clinical studies have confirmed that the traditional Japanese herbal medicine, Daikenchutou (DKT) has a pharmacological effect on cholinergic and serotonergic mechanisms with a favorable safety profile and an improving effect on lower gastrointestinal (GI) symptoms including abdominal pain or bloating. The purpose of this study is to evaluate the efficacy and safety of DKT on chronic constipation. METHODS This multicenter, randomized, placebo-controlled, double-blinded clinical trial enrolled 67 patients with chronic constipation fulfilling Rome III criteria. After a 2-week observation period, 63 patients with persistent symptoms were finally randomized to a 4-week course of treatment with DKT or placebo. The primary endpoint consisted of a global assessment of overall treatment effect (OTE), while the secondary endpoints consisted of improvements in stool consistency, spontaneous bowel movements, lower GI symptoms related to constipation, and quality of life. Factors associated with OTE were also investigated. RESULTS After 4 weeks administration of DKT, OTE was significantly higher than placebo. No side effects were observed. Significant improvement in stool consistency and lower GI symptoms was observed in the DKT group. The improvements in lower GI symptoms as well as stool consistency were associated with OTE. OTE was higher in patients with greater improvement in lower GI symptoms with mental component summary scores close to normal before treatment. CONCLUSION DKT was effective and safe in treating chronic constipation, especially in patients having symptoms related to constipation with no impaired mental component summary score.
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Affiliation(s)
- Noriaki Manabe
- Division of Endoscopy and Ultrasonography, Department of Clinical Pathology and Laboratory MedicineKawasaki Medical SchoolOkayamaJapan
| | - Atsushi Nakajima
- Department of Gastroenterology and HepatologyYokohama City University Graduate School of MedicineYokohamaJapan
| | - Takeo Odaka
- Odaka Internal and Gastrointestinal ClinicChibaJapan
| | - Ken Haruma
- Division of Gastroenterology, Department of Internal Medicine 2Kawasaki Medical SchoolOkayamaJapan
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Kunitomi Y, Nakashima M, Takeuchi M, Kawakami K. Efficacy of Daikenchuto in the prevention of bowel obstruction in patients with colorectal cancer undergoing laparoscopic surgery: An observational study using a Japanese administrative claims database. Support Care Cancer 2023; 31:133. [PMID: 36697914 DOI: 10.1007/s00520-023-07599-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023]
Abstract
PURPOSE Daikenchuto is an herbal medicine widely used in Japan without clear evidence to prevent bowel obstruction after abdominal surgery. We evaluated the efficacy of Daikenchuto in laparoscopic surgery for colorectal cancer (CRC). METHODS We included patients from the medical claims databases diagnosed with CRC between January 2012 and December 2019 and treated with laparoscopic surgery. We compared the Daikenchuto and control groups to evaluate early bowel obstruction (EBO) events for 1 year. The Daikenchuto group included patients prescribed Daikenchuto on postoperative day (POD) 0 or 1. An EBO event was defined as the use of a nasogastric tube, transnasal ileus tube, endoscopic balloon dilatation, or the requirement of reoperation for bowel obstruction from PODs 1 to 364. RESULTS In total, 46,458 patients met the eligibility criteria; 2407 and 44,051 patients were included in the Daikenchuto and control groups, respectively. Some of the patient's characteristics were significantly different between the groups. The frequencies of EBO events in the Daikenchuto and control groups were 5.7% (95% confidence interval: 4.8-6.7) and 4.6% (4.4-4.8), respectively. The most frequent events were nasogastric tube (3.1%, 2.9%) and transnasal ileus tube insertions (1.4%, 0.8%) in the Daikenchuto and control groups, respectively. The hospital stay was significantly shorter in the Daikenchuto group than in the control; this trend was confirmed in the sensitivity analysis. CONCLUSIONS Daikenchuto did not demonstrate efficacy for EBO. It might be adequate for shortening patient's hospital stay. Further studies are warranted.
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Affiliation(s)
- Yuji Kunitomi
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto, 606-8501, Japan.,Department of Data Science, Taiho Pharmaceutical Co., Ltd., 1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo, 101-8444, Japan
| | - Masayuki Nakashima
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto, 606-8501, Japan
| | - Masato Takeuchi
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto, 606-8501, Japan
| | - Koji Kawakami
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto, 606-8501, Japan.
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Yamamoto M. KAMPOmics: A framework for multidisciplinary and comprehensive research on Japanese traditional medicine. Gene X 2022; 831:146555. [PMID: 35569769 DOI: 10.1016/j.gene.2022.146555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/18/2022] [Accepted: 05/06/2022] [Indexed: 11/04/2022] Open
Abstract
Traditional Japanese medicines, known as "Kampo medicines", are pharmaceutical-grade multi-herbal treatments that are integrated within the modern medical system in Japan. Although basic and clinical research including placebo-controlled double-blind trials is attempting to clarify their effectiveness and mechanisms of action, such studies are seriously limited due to the multi-targeted, multi-component "long-tail" properties of Kampo medicines, which are fundamentally different from modern western therapeutics. However, recent progress in high-throughput analytical technology, coupled with an exponential increase in biomedical information on various levels from molecular biology to clinical "big" data, is enabling us to commence a multidisciplinary and comprehensive investigation of Kampo medicines based on multi-omics, bio-informatics, and systems biology. In addition to deriving an inclusive understanding of the benefits and mechanisms of Kampo medicines, "KAMPOmics" may lead to the development of new principles to control and treat diseases in a systems-oriented manner. Furthermore, elucidation of "sho" and "mibyo" - classical concepts of Kampo, which loosely approximate to the notions of "precise medicine" and "pre-symptomatic aberration", respectively - may contribute to the development of patient-oriented medicine, an area attracting enormous growth and interest in contemporary medicine.
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Affiliation(s)
- Masahiro Yamamoto
- Tsumura Research Laboratories, Tsumura & Co., Yoshiwara 3586, Ami, Inashiki, Ibaraki 300-1192, Japan.
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Wada Y, Nishiyama M, Uehara H, Sato K, Hamamoto Y, Ogihara H, Nishi A, Asakawa T, Yamamoto M. Microbiome biomarkers associated with the gut contraction response elicited by the Japanese traditional medicine daikenchuto. Gene 2022; 826:146262. [PMID: 35257788 DOI: 10.1016/j.gene.2022.146262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/26/2021] [Accepted: 01/27/2022] [Indexed: 12/30/2022]
Abstract
Objective biomarkers are crucial in the development of personalized medicines, such as Japanese traditional medicine (Kampo). To date, some objective markers to predict the response of Kampo medicines have been reported, but the information is somewhat limited. The aim of this study was to search for objective markers and combinations thereof to estimate the effect of the Japanese traditional medicine daikenchuto (DKT) on colon contraction intensity in guinea pigs. Specifically, the microbiome biomarkers were employed as candidate, using the Fisher ratio and the nearest neighbor classifier for statistical pattern recognition. The combination of the ratio between gut microbes of family Ruminococcaceae/Rikenellaceae, Ruminococcaceae/Paraprevotellaceae, and genus Ruminococcus/unknown genus in family Rikenellaceae of guinea pig gut microbes was found to influence the activity of DKT with 0.8 accuracy for test samples. These findings suggest that statistical pattern recognition can contribute to identifying target markers of multi-target drugs such as Kampo.
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Affiliation(s)
- Yu Wada
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan.
| | - Mitsue Nishiyama
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
| | - Hideaki Uehara
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
| | - Kazuko Sato
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
| | - Yoshihiko Hamamoto
- Department of Biomolecular Engineering, Yamaguchi University Graduate School of Medicine, Tokiwadai 2-16-1, Ube, Yamaguchi 755-8611, Japan
| | - Hiroyuki Ogihara
- Department of Biomolecular Engineering, Yamaguchi University Graduate School of Medicine, Tokiwadai 2-16-1, Ube, Yamaguchi 755-8611, Japan
| | - Akinori Nishi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
| | - Takeshi Asakawa
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
| | - Masahiro Yamamoto
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ibaraki 300-1192, Japan
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Kono T, Maejima T, Ono Y, Ito T, Furukawa S, Nishiyama M, Yamamoto M, Sugitani A, Karasaki H, Mizukami Y, Maemoto A. Distinct effects of TU-100 (daikenchuto) on long-lasting dysbiosis in the small intestine in patients with colorectal cancer and inflammatory bowel disease. Gene 2022; 820:146266. [PMID: 35134471 DOI: 10.1016/j.gene.2022.146266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 01/27/2022] [Indexed: 11/04/2022]
Abstract
The profile of the human small intestinal microbiota remains to be uncovered primarily due to sampling difficulties. Ileostomy provides the intestinal luminal contents as ileostomy effluents (IE) that offer opportunity for performing extensive analyses of nutrients, gastrointestinal fluids, metabolites, and microbiome. In the present study, we evaluated changes in the microbiome, pH, and bacterial short-chain fatty acids (SCFAs) in IE obtained from patients who had undergone ileostomy following surgical resection of colon cancer and inflammatory bowel disease (IBD). We enrolled 11 patients who varied in the duration of ileostomy from 3 days to >5 years after surgery and had no inflammation in the small intestine. The analyses suggested that IE from patients previously having IBD had less diversity and greater intraday and interday fluctuations, and increased pH and decreased levels of propionic acid and acetic acid than those in IE from patients previously having cancer. Furthermore, correlation analysis suggested a possible effect of the intestinal microbiome on luminal pH, presumably via SCFA production. The present study suggested that inflammation in the colon may induce long-term dysbiosis in the small intestine even after removal of diseased parts of the colon. Moreover, pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) was found to have beneficial effects on postoperative bowel dysfunction and the human small intestinal microbiota. Taken together, these results suggest the necessity of a direct remedy for dysbiosis and the treatment of gastrointestinal lesions to achieve favorable outcomes for chronic gastrointestinal disorders.
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Affiliation(s)
- Toru Kono
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Taku Maejima
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Yusuke Ono
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Takahiro Ito
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Shigeru Furukawa
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Mitsue Nishiyama
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 300-1192, Japan
| | - Masahiro Yamamoto
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Inashiki, Ibaraki 300-1192, Japan
| | - Ayumu Sugitani
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Hidenori Karasaki
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Yusuke Mizukami
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan; Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan
| | - Atsuo Maemoto
- Institute of Biomedical Research, Sapporo-Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan.
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Shimazutsu K, Watadani Y, Ohge H. Efficacy and Safety of the Japanese Herbal Medicine Daikenchuto (DKT) in Elderly Fecal Incontinence Patients: A Prospective Study. J Anus Rectum Colon 2022; 6:32-39. [PMID: 35128135 PMCID: PMC8801247 DOI: 10.23922/jarc.2021-038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/19/2021] [Indexed: 11/30/2022] Open
Abstract
Objectives: Methods: Results: Conclusions:
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Affiliation(s)
| | - Yusuke Watadani
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital
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13
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Satoh K, Nakae H. Daijokito Administration in Critically Ill Patients Increasing the Stool Volume: A Retrospective Observational Study. Front Nutr 2021; 8:749570. [PMID: 34708065 PMCID: PMC8542686 DOI: 10.3389/fnut.2021.749570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/13/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: Daijokito, a traditional Japanese herbal medicine (Kampo), has been used to treat abdominal distention of the middle yang stage pattern. The use of Daijokito has not been thoroughly investigated in critical care. To investigate a new Kampo approach to defecation control in critically ill patients, our study aimed to assess the effects of Daijokito on fecal management. Methods: We analyzed 30 consecutive patients treated with Daijokito in the intensive care unit (ICU) between March 2017 and February 2021. The eligibility criteria were patients who were newly prescribed Daijokito in the ICU during the study period. Exclusion criteria were patients who were started on other laxatives within one day of beginning Daijokito. The study's primary outcome was defecation volume three days before and three days after starting Daijokito. We recorded the most dominant stool quality within three days after the start of Daijokito. Results: Twenty-one patients were included in the analysis. The median age was 69.0 years, and the median sequential organ failure assessment score on admission to the ICU was 6.0. Major diseases included trauma, pancreatitis, and burns. Administration of Daijokito resulted in defecation in 17 of twenty-one patients (81.0%). Comparison of defecation volume between 3 days before Daijokito administration and three days, including the day of Daijokito administration, showed that defecation volume increased significantly after Daijokito administration, with a median of 0 to 360 g (p < 0.001). At the three-day follow-up, six of 17 (35.3%) patients defecated on the day of Daijokito administration, and nine (52.9%) defecated on the day after administration. One patient was judged to have excessive defecation, and Daijokito administration was discontinued. Stool quality was normal in one (5.9%) of the 17 patients, soft-formed in two (11.8%), loose-unformed in 11 (64.7%), and liquid in three (17.6%). Discussion: Daijokito administration in critically ill patients caused defecation in 81% of the patients and significantly increased stool volume. The novelty of this study is that it sheds light on the Kampo treatment of defecation control in critically ill patients. In addition to the present report, further studies are warranted to quantify the therapeutic efficacy and safety of Daijokito.
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Affiliation(s)
- Kasumi Satoh
- Advanced Emergency and Critical Care Center, Akita University Hospital, Akita, Japan
| | - Hajime Nakae
- Advanced Emergency and Critical Care Center, Akita University Hospital, Akita, Japan
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14
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Takasu C, Miyazaki K, Yoshikawa K, Nishi M, Tokunaga T, Kashihara H, Yoshimoto T, Ogawa H, Morine Y, Shimada M. Effect of TU-100 on Peyer's patches in a bacterial translocation rat model. Ann Gastroenterol Surg 2021; 5:683-691. [PMID: 34585053 PMCID: PMC8452476 DOI: 10.1002/ags3.12460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 02/25/2021] [Accepted: 03/18/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Daikenchuto (TU-100), a Japanese herbal medicine, is widely used for various gastrointestinal diseases. We have previously reported that TU-100 suppresses CPT-11-induced bacterial translocation (BT) by maintaining the diversity of the microbiome. In this study we show that TU-100 modulates the immune response during BT by inducing PD-1 expression in Peyer's patches. METHODS Eighteen male Wistar rats were divided into four groups: a control group; a control + TU-100 group, given TU-100 1000 mg/kg orally for 5 d; a BT group, given CPT-11 250 mg/kg intra-peritoneal for 2 d; and a TU-100 group, given TU-100 1000 mg/kg orally for 5 d with CPT-11 250 mg/kg intra-peritoneal on days 4 and 5. RESULTS The size of Peyer's patch was significantly bigger in the BT group compared to the control group (9.0 × 104 µm2 vs 29.4 × 104 µm2, P < .05), but improved in the TU-100 group (15.4 × 104 µm2, P < .005). TU-100 significantly induced PD-1 expression in Peyer's patch compared to the control group and the BT group (control vs BT vs TU-100 = 4.3 ± 4.9 vs 5.1 ± 10.3 vs 17.9 ± 17.8). The CD4+ cells were increased in the BT group (P < .05) compared to the control group but decreased in the TU-100 group. The Foxp3+ cells were increased in the BT group compared to the control group (P < .05), and further increased in the TU-100 group compared to the BT group. CPT-11 significantly increased TLR4, NF-κβ, TNF-α mRNA expressions in the BT group. TU-100 cotreatment significantly reversed these mRNA expressions. CONCLUSION TU-100 may have a protective effect against BT through PD-1 expression in Peyer's patch.
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Affiliation(s)
- Chie Takasu
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Katsuki Miyazaki
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Kozo Yoshikawa
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Masaaki Nishi
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Takuya Tokunaga
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Hideya Kashihara
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Toshiaki Yoshimoto
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Hirohisa Ogawa
- Department of Pathology and Laboratory MedicineTokushima University Graduate SchoolTokushimaJapan
| | - Yuji Morine
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
| | - Mitsuo Shimada
- Department of SurgeryInstitute of Health BiosciencesTokushima UniversityTokushimaJapan
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15
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Ogawa K, Tashima A, Okazaki K, Morinaga O. Evaluation of the Amounts of Sennosides A and B in Rhubarb-containing Kampo Medicines to Create a Ranking of Kampo Medicines for Appropriate Selection of Laxatives. JOURNAL OF THE ANUS RECTUM AND COLON 2021; 5:229-236. [PMID: 34395934 PMCID: PMC8321582 DOI: 10.23922/jarc.2020-102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022]
Abstract
Objectives: To evaluate 20 Kampo medicines, which comprised 6 formulas, Otsujito, Junchoto, Tokakujokito, Bofutsushosan, Mashiningan, and Keishikashakuyakudaioto, from 7 brands, to create a ranking of Kampo medicines for appropriate selection of laxatives. Methods: The amounts of sennosides A and B, the important components showing laxative effects contained in Kampo medicines, were analysed using High Performance Liquid Chromatography. Results: We found that the amounts of sennosides A and B were different among brands, even when they had the same formula. Furthermore, the amounts of sennosides differed when the same amounts of rhubarb were used. Conclusions: These results suggest that the differences in amounts of sennosides are caused by the quality of the rhubarb used. Kampo medicines containing laxatives other than rhubarb, including disodium sulphate and hemp seed, had synergistic laxative effects. Thus, in the future, it may be possible to adjust laxative potency of Kampo medicines through further clinical tests.
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Affiliation(s)
- Kakuyou Ogawa
- Department of Natural Medicines, Faculty of Pharmaceutical Sciences, Daiichi University of Pharmacy, Fukuoka, Japan
| | - Ai Tashima
- Department of Natural Medicines, Faculty of Pharmaceutical Sciences, Daiichi University of Pharmacy, Fukuoka, Japan
| | - Keisuke Okazaki
- Okazaki Surgery, Clinic for Gastroenterology and Proctology, Himeji, Japan
| | - Osamu Morinaga
- Department of Natural Medicines, Faculty of Pharmaceutical Sciences, Daiichi University of Pharmacy, Fukuoka, Japan
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16
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Hanada K, Wada T, Kawada K, Hoshino N, Okamoto M, Hirata W, Mizuno R, Itatani Y, Inamoto S, Takahashi R, Yoshitomi M, Watanabe T, Hida K, Obama K, Sakai Y. Effect of herbal medicine daikenchuto on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: A prospective randomized study. Biomed Pharmacother 2021; 141:111887. [PMID: 34237597 DOI: 10.1016/j.biopha.2021.111887] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/06/2021] [Accepted: 06/28/2021] [Indexed: 12/22/2022] Open
Abstract
We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated.
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Affiliation(s)
- Keita Hanada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshiaki Wada
- Department of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Nobuaki Hoshino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Michio Okamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Wataru Hirata
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Rei Mizuno
- Department of Surgery, Uji Tokushukai Medical Center, Kyoto, Japan
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Inamoto
- Department of Surgery, Osaka Red Cross Hospital, Osaka, Japan
| | - Ryo Takahashi
- Department of Surgery, Kokura Memorial Hospital, Fukuoka Japan
| | - Mami Yoshitomi
- Department of Surgery, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
| | - Takeshi Watanabe
- Department of Surgery, Takashima Municipal Hospital, Shiga, Japan
| | - Koya Hida
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Osaka Red Cross Hospital, Osaka, Japan
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17
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Daikenchuto improves the post-surgical albumin level and prognostic nutritional index after aortic valve replacement. ADVANCES IN TRADITIONAL MEDICINE 2021. [DOI: 10.1007/s13596-020-00445-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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18
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Fukudo S, Okumura T, Inamori M, Okuyama Y, Kanazawa M, Kamiya T, Sato K, Shiotani A, Naito Y, Fujikawa Y, Hokari R, Masaoka T, Fujimoto K, Kaneko H, Torii A, Matsueda K, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for irritable bowel syndrome 2020. J Gastroenterol 2021; 56:193-217. [PMID: 33538894 PMCID: PMC7932982 DOI: 10.1007/s00535-020-01746-z] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
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Affiliation(s)
- Shin Fukudo
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Behavioral Medicine Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Toshikatsu Okumura
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahiko Inamori
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yusuke Okuyama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ken Sato
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akiko Shiotani
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yuji Naito
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiko Fujikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tastuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuma Fujimoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroshi Kaneko
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kei Matsueda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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Sasaki K, Sasaki D, Sasaki K, Nishidono Y, Yamamori A, Tanaka K, Kondo A. Growth stimulation of Bifidobacterium from human colon using daikenchuto in an in vitro model of human intestinal microbiota. Sci Rep 2021; 11:4580. [PMID: 33633259 PMCID: PMC7907203 DOI: 10.1038/s41598-021-84167-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/28/2020] [Indexed: 12/11/2022] Open
Abstract
Daikenchuto (DKT) is a Japanese traditional herbal (Kampo) medicine containing ginseng, processed ginger, and Japanese or Chinese pepper. We aimed to determine how DKT affects human colonic microbiota. An in vitro microbiota model was established using fecal inocula collected from nine healthy volunteers, and each model was found to retain operational taxonomic units similar to the ones in the original human fecal samples. DKT was added to the in vitro microbiota model culture at a concentration of 0.5% by weight. Next-generation sequencing of bacterial 16S rRNA gene revealed a significant increase in the relative abundance of bacteria related to the Bifidobacterium genus in the model after incubation with DKT. In pure cultures, DKT significantly promoted the growth of Bifidobacterium adolescentis, but not that of Fusobacterium nucleatum or Escherichia coli. Additionally, in pure cultures, B. adolescentis transformed ginsenoside Rc to Rd, which was then probably utilized for its growth. Our study reveals the in vitro bifidogenic effect of DKT that likely contributes to its beneficial effects on the human colon.
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Affiliation(s)
- Kengo Sasaki
- Graduate School of Science, Technology and Innovation, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan.
| | - Daisuke Sasaki
- Graduate School of Science, Technology and Innovation, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan
| | - Katsunori Sasaki
- Sumitomo Chemical, Co., Ltd., 27-1 Shinkawa 2-chome, Chuo-ku, Tokyo, 104-8260, Japan
| | - Yuto Nishidono
- College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Akihiro Yamamori
- Sumitomo Chemical, Co., Ltd., 27-1 Shinkawa 2-chome, Chuo-ku, Tokyo, 104-8260, Japan
| | - Ken Tanaka
- College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Akihiko Kondo
- Graduate School of Science, Technology and Innovation, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe, Hyogo, 657-8501, Japan.,RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
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20
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Arai I. Clinical studies of traditional Japanese herbal medicines (Kampo): Need for evidence by the modern scientific methodology. Integr Med Res 2021; 10:100722. [PMID: 34136346 PMCID: PMC8181179 DOI: 10.1016/j.imr.2021.100722] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 01/23/2023] Open
Abstract
Background Japanese Kampo medicine is a traditional medicine with roots in ancient Chinese medicine. Because traditional physicians had been abolished in Japan, the present mainstream of Kampo treatment is that physicians who learned modern Western medicine prescribe Kampo extract products based on Western medical diagnosis. This situation is different from that in other east Asian countries, and the physicians require scientific clinical evidence. Methods Clinical studies were searched from literature databases, clinical trial registry sites, and “Evidence Reports of Kampo Treatment (EKAT)” published by the Japan Society for Oriental Medicine. Results At the approval of Kampo products, scientific clinical evidence was not required because they have a long-period experience as a decoction. However, in the 1990s, Kampo products became a subject for national reevaluation; double-blind and placebo-controlled clinical trials. At the time, a methodological foundation for conducting clinical assessments of Kampo medicines was established. From 2000 onwards, with the evidence-based medicine era, the field of Kampo medicine also saw many randomized controlled trials, and their evidence was collected and published as EKAT. In the 2010s, post-marketing clinical trials of Kampo products also had to be conducted in this environment due to the need for ethical and scientific assurance. Currently, there are numerous clinical trials of Kampo products being conducted with high-grade trial designs. Conclusion The situation of Kampo clinical studies reflects the unique history and position of Kampo medical system and Kampo products in Japan.
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Affiliation(s)
- Ichiro Arai
- Department of Pharmaceutical Sciences, Nihon Pharmaceutical University
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21
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Qin Z, Xiang K, Su DF, Sun Y, Liu X. Activation of the Cholinergic Anti-Inflammatory Pathway as a Novel Therapeutic Strategy for COVID-19. Front Immunol 2021; 11:595342. [PMID: 33633726 PMCID: PMC7901247 DOI: 10.3389/fimmu.2020.595342] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action in vitro and in vivo. As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.
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Affiliation(s)
- Zhen Qin
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China.,Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
| | - Kefa Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ding-Feng Su
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Yang Sun
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Xia Liu
- Department of Clinical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
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Suzuki K, Takehara Y, Sakata M, Kawate M, Ohishi N, Sugiyama K, Akai T, Suzuki Y, Sugiyama M, Kawamura T, Morita Y, Kikuchi H, Hiramatsu Y, Yamamoto M, Nasu H, Johnson K, Wieben O, Kurachi K, Takeuchi H. Daikenchuto increases blood flow in the superior mesenteric artery in humans: A comparison study between four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction magnetic resonance imaging and Doppler ultrasound. PLoS One 2021; 16:e0245878. [PMID: 33503053 PMCID: PMC7840032 DOI: 10.1371/journal.pone.0245878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 01/07/2021] [Indexed: 11/18/2022] Open
Abstract
Respiratory-gated four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction (4D PC-VIPR) is magnetic resonance (MR) imaging technique that enables analysis of vascular morphology and hemodynamics in a single examination using cardiac phase resolved 3D phase-contrast magnetic resonance imaging. The present study aimed to assess the usefulness of 4D PC-VIPR for the superior mesenteric artery (SMA) flowmetry before and after flow increase was induced by the herbal medicine Daikenchuto (TJ-100) by comparing it with Doppler ultrasound (DUS) as a current standard. Twenty healthy volunteers were enrolled in this prospective single-arm study. The peak cross-sectionally averaged velocity was measured by 4D PC-VIPR, peak velocity was measured by DUS, and flow volume (FV) of SMA and aorta were measured by 4D PC-VIPR and DUS 25 min before and after the peroral administration of TJ-100. The peak cross-sectionally averaged velocity, peak velocity, and FV of SMA measured by 4D PC-VIPR and DUS significantly increased after administration of TJ-100 (4D PC-VIPR: the peak cross-sectionally averaged velocity; p = 0.004, FV; p = 0.035, DUS: the peak velocity; p = 0.003, FV; p = 0.010). Furthermore, 4D PC-VIPR can analyze multiple blood vessels simultaneously. The ratio of the SMA FV to the aorta, before and after oral administration on the 4D PC-VIPR test also increased (p = 0.015). The rate of change assessed by 4D PC-VIPR and DUS were significantly correlated (the peak cross-sectionally averaged velocity and peak velocity: r = 0.650; p = 0.005, FV: r = 0.659; p = 0.004). Retrospective 4D PC-VIPR was a useful modality for morphological and hemodynamic analysis of SMA.
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Affiliation(s)
- Katsunori Suzuki
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yasuo Takehara
- Department of Fundamental Development for Advanced Low Invasive Diagnostic Imaging, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Mayu Sakata
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masanori Kawate
- Department of Radiology, Hamamatsu University Hospital, Hamamatsu, Shizuoka, Japan
| | - Naoki Ohishi
- Department of Radiology, Hamamatsu University Hospital, Hamamatsu, Shizuoka, Japan
| | - Kosuke Sugiyama
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Toshiya Akai
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yuhi Suzuki
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masataka Sugiyama
- Department of Fundamental Development for Advanced Low Invasive Diagnostic Imaging, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takafumi Kawamura
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yoshifumi Morita
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hirotoshi Kikuchi
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yoshihiro Hiramatsu
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masayoshi Yamamoto
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hatsuko Nasu
- Department of Diagnostic Radiology & Nuclear Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kevin Johnson
- Department of Medical Physics, University of Wisconsin, Madison, WI, United States of America
- Department of Radiology, University of Wisconsin, Madison, WI, United States of America
| | - Oliver Wieben
- Department of Medical Physics, University of Wisconsin, Madison, WI, United States of America
- Department of Radiology, University of Wisconsin, Madison, WI, United States of America
| | - Kiyotaka Kurachi
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- * E-mail:
| | - Hiroya Takeuchi
- Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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Saegusa H, Nomura H, Takao M, Hamaguchi T, Yoshida M, Kodama Y. Development and validation of an analysis method for pesticide residues by gas chromatography-tandem mass spectrometry in Daikenchuto. J Nat Med 2021; 75:344-360. [PMID: 33389591 PMCID: PMC7902578 DOI: 10.1007/s11418-020-01473-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/24/2020] [Indexed: 11/24/2022]
Abstract
Daikenchuto (DKT) is one of the most widely used “Kampo” in Japan as a representative of herbal medicine. Because DKT is made from a natural product like food, it requires the management of pesticides; therefore, an analysis of residual pesticides in Kampo is required. The World Health Organization (WHO) indicates that pesticide residue analysis by the U.S. Pharmacopeia (USP) is required. USP defines 107 compounds containing organochlorine pesticides and organophosphorus pesticides and their metabolites, which have a high residual risk. Accordingly, to guarantee the safety of herbal medicines according to global standards is a very important issue. In this study, we developed an analytical method for 91 compounds, which are listed in USP, using DKT as the subject. The method could extract pesticides from DKT with acetone, elute pesticides with acetonitrile using a SepPak C18 column (5 g) and with ethyl acetate using a DSC-NH2 column (2 g), and perform simultaneous analyses by gas chromatography–tandem mass spectrometry (GC–MS/MS). This method, which could quantify 88 compounds, was validated according to USP. A pesticide residue analysis method that meets USP requirements enables the analysis of pesticide residues with a high residue risk and contributes to improving the safety of “Kampo” and other herbal medicines.
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Affiliation(s)
- Hirokazu Saegusa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. .,CMC Research and Development Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan.
| | - Hiroshi Nomura
- CMC Research and Development Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Masaki Takao
- CMC Research and Development Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Takashi Hamaguchi
- CMC Research and Development Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan
| | - Masaru Yoshida
- Division of Metabolomics Research, Department of Internal Medicine Related, Kobe University Graduate School Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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Kogure Y, Kanda H, Wang S, Hao Y, Li J, Yamamoto S, Noguchi K, Dai Y. Daikenchuto attenuates visceral pain and suppresses eosinophil infiltration in inflammatory bowel disease in murine models. JGH Open 2020; 4:1146-1154. [PMID: 33319050 PMCID: PMC7731802 DOI: 10.1002/jgh3.12410] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Daikenchuto (DKT), a traditional Japanese formula, comprises four herbal medicines and is used for abdominal pain. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD) and is characterized by colonic inflammation and chronic abdominal pain. The present study aimed to investigate whether DKT suppresses colonic hypersensitivity and inflammation associated with IBD in animal models. METHODS Sprague-Dawley rats were administered 4% sodium dextran sulfate (DSS) or trinitrobenzene sulfate (TNBS) in the colon to establish UC or CD models, respectively. DKT and 5-aminosalicylic acid (5-ASA) were administered orally once a day from Days 3 to 7 after induction of colitis. On Day 7, visceral pain and inflammation were evaluated by measuring the visceromotor response (VMR) to colorectal distention (CRD) and inflammatory indicators, including histological score, length of leukocyte infiltration, MPO activity, and eosinophil count. RESULTS DSS and TNBS increased VMR to CRD and the inflammation indicators. DKT, but not 5-ASA, suppressed the VMR to CRD in DSS- and TNBS-treated rats. DKT and 5-ASA decreased the eosinophil count in both IBD models. In DSS-treated rats, 5-ASA, but not DKT, suppressed the MPO activity. In TNBS-treated rats, neither 5-ASA nor DKT suppressed MPO activity. CONCLUSION These results suggest that DKT is beneficial for abdominal pain associated with IBD. The anti-inflammatory effect of DKT on IBD may involve inhibition of eosinophils. The mechanism of anti-inflammatory effect of DKT partially differs from that of 5-ASA. Coapplication of DKT and conventional medicine may produce a positive synergy effect for IBD treatment.
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Affiliation(s)
- Yoko Kogure
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Hirosato Kanda
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- Traditional Medicine Research CenterChinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM)KobeJapan
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
| | - Shenglan Wang
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- School of Acupuncture‐Moxibustion and TuinaBeijing University of Chinese Medicine (BUCM)BeijingChina
| | - Yongbiao Hao
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Junxiang Li
- Division of Gastroenterology, Department of Internal MedicineDongfang Hospital of BUCMBeijingChina
| | - Satoshi Yamamoto
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
| | - Koichi Noguchi
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
| | - Yi Dai
- Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan
- Traditional Medicine Research CenterChinese Medicine Confucius Institute at Hyogo College of Medicine (CMCIHCM)KobeJapan
- Department of Anatomy and NeuroscienceHyogo College of MedicineNishinomiyaJapan
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Maeda K, Katsuno H, Kono T. The Japanese Extracted Herbal Medicine Daikenchuto Increases the Contractile Activity of the Internal Anal Sphincter Muscle in Conscious Dogs. JOURNAL OF THE ANUS RECTUM AND COLON 2020; 4:193-200. [PMID: 33134601 PMCID: PMC7595681 DOI: 10.23922/jarc.2020-041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/01/2020] [Indexed: 11/30/2022]
Abstract
Objectives: This study aimed to elucidate the effect of the extract of daikenchuto (DKT), a Japanese Kampo medicine, on the contractile activity of the internal anal sphincter in conscious dogs. Methods: Force transducers were attached to the serosal surface of the rectum and the internal anal sphincter of male beagle dogs. In addition, the contractile activity of the rectum and the internal anal sphincter was continuously measured until 6 h after DKT administration via telemetry in the conscious state. The DKT dose was 1.5 g/body, and the administration route was intrarectal in the expectation of a direct effect on the rectoanal region. DKT was re-administered to the same animal after drug withdrawal, and the plasma concentrations of hydroxy-α-sanshool (HAS) and hydroxy-β-sanshool (HBS) before and after administration were measured. Results: After DKT administration, the contractile activity of the internal anal sphincter immediately increased, peaked at 10 min, continued for ≥1 h, and had almost disappeared after 4 h. Rectal contraction differed from that of the internal anal sphincter, with no significant contraction observed. HAS and HBS were found in the plasma of animals administered with DKT and persisted up to 2 h after the administration. Conclusions: This is the first report on in vivo telemetry demonstrating that DKT exhibited contractile effects on the dog's internal anal sphincter. The increased anal pressure and improvement of fecal incontinence symptoms observed in previous clinical studies may have been based on this sphincter contraction.
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Affiliation(s)
- Kotaro Maeda
- International Medical Center, Fujita Health University Hospital, Toyoake, Japan
| | - Hidetoshi Katsuno
- Department of Surgery, Fujita Health University Okazaki Medical Center, Okazaki, Japan
| | - Toru Kono
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
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Ueno M, Minagawa T, Saito T, Imamura T, Nagai T, Ogawa T, Ishizuka O. Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats. Low Urin Tract Symptoms 2020; 12:198-205. [PMID: 32017455 DOI: 10.1111/luts.12302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/23/2019] [Accepted: 01/08/2020] [Indexed: 01/20/2023]
Abstract
Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty-five female Sprague-Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia-inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.
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Affiliation(s)
- Manabu Ueno
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonori Minagawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tetsuichi Saito
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tetsuya Imamura
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takashi Nagai
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Teruyuki Ogawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Osamu Ishizuka
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
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Kubota K, Mase A, Matsushima H, Fujitsuka N, Yamamoto M, Morine Y, Taketomi A, Kono T, Shimada M. Daikenchuto, a traditional Japanese herbal medicine, promotes colonic transit by inducing a propulsive movement pattern. Neurogastroenterol Motil 2019; 31:e13689. [PMID: 31374154 PMCID: PMC6852043 DOI: 10.1111/nmo.13689] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 06/21/2019] [Accepted: 07/11/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The traditional Japanese herbal medicine, daikenchuto (DKT), has been used to treat constipation and postoperative ileus. However, the precise mechanisms involved in the pharmacological effects of DKT remain uncertain. The aim of this study was to clarify the effect of DKT on motor patterns and transit activity in the isolated rat colon. METHODS The entire colon or segments of the proximal colon in rats were isolated and placed in Krebs solution. The motility of the colon was evaluated by analyzing spatiotemporal maps of diameter derived from video imaging and measuring the intraluminal pressure in the anal end of the proximal colon, and the transit time of a plastic bead through the entire isolated colon. KEY RESULTS Several types of propagating contractions were observed in the isolated entire colon. When DKT was added to Krebs solution, the frequency of large-extent anal propagating contractions increased. DKT treatment increased the intraluminal pressure in the isolated proximal colon, which was related to the propagating contractions. This effect was abolished by treatment with the neural blocker tetrodotoxin. These findings suggest DKT induced peristaltic contractions in the isolated colon. DKT accelerated colonic transit activity, which was related to peristaltic contractions induction in the colon. These effects were also observed in the colons treated with bethanechol and the active ingredient of DKT, hydroxy-α-sanshool. CONCLUSIONS AND INFERENCES Daikenchuto could enhance colonic transit activity by inducing peristaltic contractions, which may be mediated by the activation of the enteric nervous system in the colon.
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Affiliation(s)
- Kunitsugu Kubota
- Tsumura Kampo Research LaboratoriesTsumura & Co.IbarakiJapan,Department of Digestive Surgery and TransplantationTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Akihito Mase
- Tsumura Kampo Research LaboratoriesTsumura & Co.IbarakiJapan
| | | | - Naoki Fujitsuka
- Tsumura Kampo Research LaboratoriesTsumura & Co.IbarakiJapan
| | | | - Yuji Morine
- Department of Digestive Surgery and TransplantationTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Toru Kono
- Department of Digestive Surgery and TransplantationTokushima University Graduate School of Biomedical SciencesTokushimaJapan,Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan,Center for Clinical and Biomedical ResearchSapporo Higashi Tokushukai HospitalSapporoJapan
| | - Mitsuo Shimada
- Department of Digestive Surgery and TransplantationTokushima University Graduate School of Biomedical SciencesTokushimaJapan
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Maeda H, Okada KI, Fujii T, Oba MS, Kawai M, Hirono S, Kodera Y, Sho M, Akahori T, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Sakamoto J, Yamaue H. Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD. Oncol Lett 2018; 16:6847-6853. [PMID: 30333892 DOI: 10.3892/ol.2018.9422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/22/2018] [Indexed: 02/04/2023] Open
Abstract
Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P<0.05). According to the results of the present study, TJ-100 has an effect on the change in serum cytokine levels from POD1 to POD3 following PD. However, the role of different transition pattern of cytokines in postoperative recovery following PD has to be investigated by further mechanical studies focusing on these extracted cytokines (ClinicalTrials.gov; no. NCT01607307; May 30, 2012).
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Affiliation(s)
- Hiromichi Maeda
- Cancer Treatment Center, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
| | - Ken-Ichi Okada
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8560, Japan
| | - Mari S Oba
- Department of Medical Statistics Faculty of Medicine, Toho University, Tokyo 143-8540, Japan
| | - Manabu Kawai
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Seiko Hirono
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8560, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takahiro Akahori
- Department of Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Yoshiyasu Ambo
- Department of Surgery, Teine-Keijinkai Hospital, Sapporo, Hokkaido 006-8555, Japan
| | - Naru Kondo
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553, Japan
| | - Yoshiaki Murakami
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553, Japan
| | - Jiro Ohuchida
- Department of Surgery, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Miyazaki 880-8510, Japan
| | - Hidetoshi Eguchi
- Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | | | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
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Kaido T, Shinoda M, Inomata Y, Yagi T, Akamatsu N, Takada Y, Ohdan H, Shimamura T, Ogura Y, Eguchi S, Eguchi H, Ogata S, Yoshizumi T, Ikegami T, Yamamoto M, Morita S, Uemoto S. Effect of herbal medicine daikenchuto on oral and enteral caloric intake after liver transplantation: A multicenter, randomized controlled trial. Nutrition 2018; 54:68-75. [PMID: 29747091 DOI: 10.1016/j.nut.2018.02.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/12/2018] [Accepted: 02/28/2018] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Postoperative early oral or enteral intake is a crucial element of the Enhanced Recovery After Surgery (ERAS) protocol. However, normal food intake or enteral feeding cannot be started early in the presence of coexisting bowel dysfunction in patients undergoing liver transplantation (LT). The aim of this multicenter, randomized, double-blinded, placebo-controlled trial was to determine the enhancement effects of the Japanese herbal medicine Daikenchuto (DKT) on oral/enteral caloric intake in patients undergoing LT. METHODS A total of 112 adult patients undergoing LT at 14 Japanese centers were enrolled. The patients were randomly assigned to receive either DKT or placebo from postoperative day (POD) 1 to 14. The primary endpoints were total oral/enteral caloric intake, abdominal distension, and pain on POD 7. The secondary endpoints included sequential changes in total oral/enteral caloric intake after LT, and portal venous flow volume and velocity in the graft. RESULTS A total of 104 patients (DKT, n = 55; placebo, n = 49) were included in the analyses. There were no significant differences between the two groups in terms of primary endpoints. However, postoperative total oral/enteral caloric intake was significantly accelerated in the DKT group compared with the placebo group (P = 0.023). Moreover, portal venous flow volume (POD 10, 14) and velocity (POD 14) were significantly higher in the DKT group than in the placebo group (P = 0.047, P = 0.025, P = 0.014, respectively). CONCLUSIONS Postoperative administration of DKT may enhance total oral/enteral caloric intake and portal venous flow volume and velocity after LT and favorably contribute to the performance of the ERAS protocol.
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Affiliation(s)
- Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yukihiro Inomata
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Medicine, Kumamoto University, Kumamoto, Japan
| | - Takahito Yagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yasutsugu Takada
- Department of Hepato-Pancreatic-Biliary and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan
| | - Yasuhiro Ogura
- Department of Transplantation Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Satoshi Ogata
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshihiko Ikegami
- First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michio Yamamoto
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Satoshi Morita
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Endo M, Hori M, Ozaki H, Oikawa T, Odaguchi H, Hanawa T. Possible anti-inflammatory role of Zingiberis processum rhizoma, one component of the Kampo formula daikenchuto, against neutrophil infiltration through muscarinic acetylcholine receptor activation. J Pharmacol Sci 2018; 137:379-386. [PMID: 30145033 DOI: 10.1016/j.jphs.2018.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/23/2018] [Accepted: 07/26/2018] [Indexed: 12/17/2022] Open
Abstract
Zingiberis processum rhizoma (ZPR) is a major active component of daikenchuto (DKT), which induces anti-inflammatory action by inhibiting macrophage infiltration. However, it is unclear whether ZPR is related to DKT-induced anti-inflammatory action via a reduction of neutrophil infiltration against postoperative ileus (POI). In this study, we orally administered individual herbal components of DKT to mice four times before and after intestinal manipulation (IM). The anti-inflammatory action of each crude drug was evaluated by histochemical analysis of relevant molecules. The results showed that treatment with all herbal components of DKT significantly inhibits neutrophil infiltration. This inhibition of neutrophil infiltration by ZPR was significantly reduced in 5-hydroxytryptamine receptor 4 (5-HT4R) knockout (KO) mice but not in alpha-7 nicotinic acetylcholine receptor (α7nAChR) KO mice. Also, transient receptor potential ankyrin 1 (TRPA1) and muscarinic acetylcholine receptor (mAChR) antagonists partly and significantly inhibited the amelioration of neutrophil infiltration by ZPR. Therefore, DKT-induced anti-inflammatory action, mediated by inhibition of neutrophil infiltration in POI, depends, in part, on the effects of ZPR. ZPR activates TRPA1 channels, possibly in enterochromaffin (EC) cells, to release 5-HT. This 5-HT stimulates 5-HT4R in the myenteric plexus neurons to release acetylcholine, which, in turn, activates mAChR to inhibit inflammation in POI.
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Affiliation(s)
- Mari Endo
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Japan.
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
| | - Hiroshi Ozaki
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan
| | - Tetsuro Oikawa
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Japan
| | - Hiroshi Odaguchi
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Japan
| | - Toshihiko Hanawa
- Department of Clinical Research, Oriental Medicine Research Center, Kitasato University, Japan; Department of Oriental Medicine Research, Research and Development Center for Medical Education, Kitasato University School of Medicine, Japan; Department of Oriental Medicine, Doctoral Program of Medical Science, Kitasato University Graduate School, Japan
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31
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Nobutani K, Miyoshi J, Musch MW, Nishiyama M, Watanabe J, Kaneko A, Yamamoto M, Yoshida M, Kono T, Jeong H, Chang EB. Daikenchuto (TU-100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal. Pharmacol Res Perspect 2018; 5. [PMID: 28971602 PMCID: PMC5625165 DOI: 10.1002/prp2.361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/15/2017] [Accepted: 08/21/2017] [Indexed: 12/16/2022] Open
Abstract
Herbal medicines and natural products used for maintenance of health or treatment of diseases have many biological effects, including altering the pharmacokinetics and metabolism of other medications. Daikenchuto (TU‐100), an aqueous extract of ginger, ginseng, and Japanese green pepper fruit, is a commonly prescribed Kampo (Japanese herbal medicine) for postoperative ileus or bloating. The effects of TU‐100 on drug metabolism have not been investigated. In this study, we analyzed the effect of TU‐100 on expression of key drug‐metabolizing enzymes (DMEs) and drug transporters (DTs) in murine liver and gastrointestinal tract using a dietary model. Liver, jejunum, and proximal colon were analyzed for phase I and II DMEs and DT mRNA expression by reverse transcription (RT) first by nonquantitative and followed by quantitative polymerase chain reaction (PCR) and protein expression. Liver, jejunum, and proximal colon expressed some identical but also unique DMEs and DTs. TU‐100 increased the greatest changes in cytochrome (Cyp) 2b10 and Cyp3a11 and Mdr1a. Basal and TU‐100 stimulated levels of DME and DT expression were gender‐dependent, dose‐dependent and reversible after cessation of TU‐100 supplementation, except for some changes in the intestine. Quantitative Western blot analysis of protein extracts confirmed the quantitative PCR results.
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Affiliation(s)
- Kentaro Nobutani
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Jun Miyoshi
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Mark W Musch
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Mitsue Nishiyama
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Junko Watanabe
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Atsushi Kaneko
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | | | - Masaru Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan.,Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hyunyoung Jeong
- Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois
| | - Eugene B Chang
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
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Efficacy and Safety of Daikenchuto for Constipation and Dose-Dependent Differences in Clinical Effects. Int J Chronic Dis 2018; 2018:1296717. [PMID: 29693001 PMCID: PMC5859840 DOI: 10.1155/2018/1296717] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/23/2018] [Accepted: 01/31/2018] [Indexed: 12/20/2022] Open
Abstract
Background Daikenchuto (DKT) is a Kampo medicine used for the treatment of constipation. In this study, we evaluated the effectiveness of DKT against constipation. Patients and Methods Thirty-three patients administered DKT for constipation were selected and divided into low-dose (7.5 g DKT; n = 22) and high-dose (15 g DKT; n = 11) groups. We retrospectively evaluated weekly defaecation frequency, side effects, and clinical laboratory data. Results Median defaecation frequencies after DKT administration (5, 5.5, 5, and 8 for the first, second, third, and fourth weeks, resp.) were significantly higher than that before DKT administration (2) in all 33 cases (P < 0.01). One case (3%) of watery stool, one case of loose stools (3%), and no cases of abdominal pain (0%) were observed. Median defaecation frequencies in the high-dose group (7 and 9) were significantly higher than those in the low-dose group (4 and 3) in the first (P = 0.0133) and second (P = 0.0101) weeks, respectively. There was no significant change in clinical laboratory values. Conclusion We suggest that DKT increases defaecation frequency and is safe for treating constipation.
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Enhanced anastomotic healing by Daikenchuto (TJ-100) in rats. Sci Rep 2018; 8:1091. [PMID: 29348453 PMCID: PMC5773623 DOI: 10.1038/s41598-018-19550-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/03/2018] [Indexed: 02/08/2023] Open
Abstract
Daikenchuto (DKT), a traditional Japanese medicine, is widely used to treat various gastrointestinal disorders. This study aimed to investigate whether DKT could promote the anastomotic healing in a rat model. Pedicled colonic segments were made in left colon by ligation of the feeding arteries, and then intestinal continuity was restored. Colonic blood flow was analyzed by using ICG fluorescence imaging: Fmax, Tmax, T1/2, and Slope were calculated. Anastomotic leakage (AL) was found in 6 of 19 rats (31.6%) in the control group, whereas in 1 of 16 rats (6.2%) in the DKT group. The Fmax and Slope of DKT group were significantly higher than those of control group. DKT could promote the anastomotic healing, with the higher bursting pressure on postoperative day (POD) 2 and 5, the larger granulation thickness on POD 5, and neoangiogenesis on POD 5. Histological examination showed DKT exhibited a decreased inflammatory cell infiltration, enhanced fibroblast infiltration, and enhanced collagen density on POD 5. In the DKT group, the levels of TGFβ1 on POD 2 and VEGFα on POD5 were significantly higher, whereas the level of TNFα on POD 2 was significantly lower. Therefore, DKT could be effective for the prevention of AL following colorectal surgery.
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Inoue A, Furukawa A, Yamamoto H, Ohta S, Linh NDH, Syerikjan T, Kaida S, Yamaguchi T, Murata S, Obata T, Tani M, Murata K. Acceleration of small bowel motility after oral administration of dai-kenchu-to (TJ-100) assessed by cine magnetic resonance imaging. PLoS One 2018; 13:e0191044. [PMID: 29320574 PMCID: PMC5761958 DOI: 10.1371/journal.pone.0191044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 12/27/2017] [Indexed: 12/11/2022] Open
Abstract
Dai-kenchu-to (TJ-100) is an herbal medicine used to shorten the duration of intestinal transit by accelerating intestinal movement. However, intestinal movement in itself has not been evaluated in healthy volunteers using radiography, fluoroscopy, and radioisotopes because of exposure to ionizing radiation. The purpose of this study was to evaluate the effect of TJ-100 on intestinal motility using cinematic magnetic resonance imaging (cine MRI) with a steady-state free precession sequence. Ten healthy male volunteers received 5 g of either TJ-100 or lactose without disclosure of the identity of the substance. Each volunteer underwent two MRI examinations after taking the substances (TJ-100 and lactose) on separate days. They drank 1200 mL of tap water and underwent cine MRI after 10 min. A steady-state free precession sequence was used for imaging, which was performed thrice at 0, 10, 20, 30, 40, and 50 min. The bowel contraction frequency and distention score were assessed. Wilcoxon signed-rank test was used, and differences were considered significant at a P-value <0.05. The bowel contraction frequency tended to be greater in the TJ-100 group and was significantly different in the ileum at 20 (TJ-100, 8.95 ± 2.88; lactose, 4.80 ± 2.92; P < 0.05) and 50 min (TJ-100, 9.45 ± 4.49; lactose, 4.45 ± 2.65; P < 0.05) between the groups. No significant differences were observed in the bowel distention scores. Cine MRI demonstrated that TJ-100 activated intestinal motility without dependence on ileum distention.
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Affiliation(s)
- Akitoshi Inoue
- Department of Radiology, Shiga University of Medical Science, Otsu, Shiga, Japan
- * E-mail:
| | - Akira Furukawa
- Department of Radiological Science, Tokyo Metropolitan University, Arakawa, Tokyo, Japan
| | - Hiroshi Yamamoto
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Shinichi Ohta
- Department of Radiology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Nguyen Dai Hung Linh
- Department of Radiological Science, Tokyo Metropolitan University, Arakawa, Tokyo, Japan
| | - Tulyeubai Syerikjan
- Department of Radiological Science, Tokyo Metropolitan University, Arakawa, Tokyo, Japan
| | - Sachiko Kaida
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tsuyoshi Yamaguchi
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Satoshi Murata
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Toru Obata
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Kiyoshi Murata
- Department of Radiology, Shiga University of Medical Science, Otsu, Shiga, Japan
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Nishino T, Yoshida T, Goto M, Inoue S, Minato T, Fujiwara S, Yamamoto Y, Furukita Y, Yuasa Y, Yamai H, Takechi H, Toba H, Takizawa H, Yoshida M, Seike J, Miyoshi T, Tangoku A. The effects of the herbal medicine Daikenchuto (TJ-100) after esophageal cancer resection, open-label, randomized controlled trial. Esophagus 2018; 15:75-82. [PMID: 29892933 PMCID: PMC5884909 DOI: 10.1007/s10388-017-0601-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 12/11/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. METHODS Forty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. RESULTS We examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups. CONCLUSIONS TJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.
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Affiliation(s)
- Takeshi Nishino
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
| | - Takahiro Yoshida
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Masakazu Goto
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Seiya Inoue
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takuya Minato
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Satoshi Fujiwara
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yota Yamamoto
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yoshihito Furukita
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasuhiro Yuasa
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiromichi Yamai
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hirokazu Takechi
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiroaki Toba
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiromitsu Takizawa
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuteru Yoshida
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Junichi Seike
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takanori Miyoshi
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Akira Tangoku
- Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
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Sinagra E, Morreale GC, Mohammadian G, Fusco G, Guarnotta V, Tomasello G, Cappello F, Rossi F, Amvrosiadis G, Raimondo D. New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond. World J Gastroenterol 2017; 23:6593-6627. [PMID: 29085207 PMCID: PMC5643283 DOI: 10.3748/wjg.v23.i36.6593] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/15/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies.
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Affiliation(s)
- Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | | | - Ghazaleh Mohammadian
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden
| | - Giorgio Fusco
- Unit of Internal Medicine, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Valentina Guarnotta
- Section of Cardio-Respiratory and Endocrine-Metabolic Diseases, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo 90127, Italy
| | - Giovanni Tomasello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesco Cappello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesca Rossi
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
| | - Georgios Amvrosiadis
- Unit of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Dario Raimondo
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
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Takasu C, Yismaw WG, Kurita N, Yoshikawa K, Kashihara H, Kono T, Shimada M. TU-100 exerts a protective effect against bacterial translocation by maintaining the tight junction. Surg Today 2017; 47:1287-1294. [PMID: 28421347 DOI: 10.1007/s00595-017-1518-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 02/16/2017] [Indexed: 01/09/2023]
Abstract
PURPOSE We previously reported that TU-100 suppresses irinotecan hydrochloride (CPT-11)-induced inflammatory cytokines and apoptosis. However, the mechanism underlying this effect has not been fully elucidated. The aim of this study was to further clarify the mechanism of CPT-11-induced bacterial translocation (BT) and the effect of TU-100 on BT. METHODS Cell cytotoxicity was assessed in vitro by a WST-8 assay. For the in vivo experiments, rats were randomly divided into 3 groups: the control group, the CPT-11 group (250 mg/kg i.p. for 2 days), and the CPT-11 and TU-100 co-treated group (1000 mg/kg, p.o. for 5 days). All of the rats were sacrificed on day 6 and their tissues were collected. RESULTS CPT-11 and TU-100 co-treatment improved CPT-11 the related cytotoxicity in vitro. All CPT-11-treated rats developed different grades of diarrhea and BT was observed in 80% of the rats. CPT-11 caused a significant increase in the expression of TLR4, IL-6, TNF-α, IL-1β and caspase-3 mRNAs in the large intestine. The expression of tight junction (TJ) marker mRNAs (occludin, claudin-1 and 4, and ZO-1) was significantly decreased in comparison to the control group. TU-100 co-treatment significantly reversed diarrhea, BT, and the expression of TLR2, IL-6, TNF-α, IL-1β and caspase-3, and improved the expression of occludin, claudin-4 and ZO-1. CONCLUSIONS TU-100 can suppress the adverse effects associated with CPT-11 and improve the function of the TJ. It is possible that this occurs through the TLR pathway.
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Affiliation(s)
- Chie Takasu
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan.
| | - Wubetu Gizachew Yismaw
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan
| | - Nobuhiro Kurita
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan
| | - Kozo Yoshikawa
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan
| | - Hideya Kashihara
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan
| | - Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Hisgashi Tokushukai Hospital, Hokkaido, Japan
| | - Mitsuo Shimada
- Departments of Surgery, Institute of Health Biosciences, Tokushima University, Kuramoto 3-18-15, Tokushima, 770-8503, Japan
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Katahira H, Sunagawa M, Watanabe D, Kanada Y, Katayama A, Yamauchi R, Takashima M, Ishikawa S, Hisamitsu T. Antistress effects of Kampo medicine "Yokukansan" via regulation of orexin secretion. Neuropsychiatr Dis Treat 2017; 13:863-872. [PMID: 28360524 PMCID: PMC5365329 DOI: 10.2147/ndt.s129418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE Various stressors induce stress responses through the hypothalamic-pituitary-adrenal and the sympathetic-adrenal-medullary axes, which are regulated, in part, by orexin. For example, secretion of orexin in the hypothalamus is increased in rats exposed to the stress of social isolation for 1 week. In this study, the antistress effects of Kampo medicine Yokukansan (YKS) via the regulation of orexin secretion were investigated using a rat model. METHODS AND RESULTS The administration of 300 mg/kg per day of YKS to rats for 1 week significantly decreased the plasma orexin levels compared with non-treated rats, whereas the administration of 1,000 mg/kg of YKS had no effect on orexin levels. Therefore, 300 mg/kg of YKS was an effective dose for controlling orexin secretion. Subsequently, rats were divided into group-housed control (Con), individually housed stress (Stress), and individually housed YKS (300 mg/kg)-treated stress (Stress + YKS) groups. After 1 week, a resident-intruder aggression test was performed, and the plasma levels of orexin and corticosterone were measured. In the Stress group, aggressive behavior and the levels of corticosterone and orexin significantly increased compared with the Con group; however, these effects were inhibited in the Stress + YKS group. Further, an orexin receptor antagonist (TCS 1102; 10 mg/kg) was intraperitoneally administered to rats exposed to isolation stress to determine whether orexin was involved in stress responses. Under these conditions, aggressive behavior and the level of corticosterone significantly decreased compared with the Stress group. CONCLUSION These results suggest that orexin is involved in the control of stress response and that YKS exerts an antistress effect via the regulation of orexin secretion.
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Affiliation(s)
| | | | - Daishi Watanabe
- Department of Physiology
- Department of Neurology, School of Medicine, Showa University
| | - Yasuaki Kanada
- Department of Physiology
- Department of Surgery, Showa University Koto Toyosu Hospital, Tokyo
| | | | | | - Masashi Takashima
- Department of Orthopaedic Surgery, Showa University Fujigaoka Hospital, Kanagawa, Japan
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Hasebe T, Matsukawa J, Ringus D, Miyoshi J, Hart J, Kaneko A, Yamamoto M, Kono T, Fujiya M, Kohgo Y, Wang CZ, Yuan CS, Bissonnette M, Musch MW, Chang EB. Daikenchuto (TU-100) Suppresses Tumor Development in the Azoxymethane and APC min/+ Mouse Models of Experimental Colon Cancer. Phytother Res 2017; 31:90-99. [PMID: 27730672 PMCID: PMC5590753 DOI: 10.1002/ptr.5735] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/26/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023]
Abstract
Chemopreventative properties of traditional medicines and underlying mechanisms of action are incompletely investigated. This study demonstrates that dietary daikenchuto (TU-100), comprised of ginger, ginseng, and Japanese pepper effectively suppresses intestinal tumor development and progression in the azoxymethane (AOM) and APCmin/+ mouse models. For the AOM model, TU-100 was provided after the first of six biweekly AOM injections. Mice were sacrificed at 30 weeks. APCmin/+ mice were fed diet without or with TU-100 starting at 6 weeks, and sacrificed at 24 weeks. In both models, dietary TU-100 decreased tumor size. In APC min/+ mice, the number of small intestinal tumors was significantly decreased. In the AOM model, both TU-100 and Japanese ginseng decreased colon tumor numbers. Decreased Ki-67 and β-catenin immunostaining and activation of numerous transduction pathways involved in tumor initiation and progression were observed. EGF receptor expression and stimulation/phosphorylation in vitro were investigated in C2BBe1 cells. TU-100, ginger, and 6-gingerol suppressed EGF receptor induced Akt activation. TU-100 and ginseng and to a lesser extent ginger or 6-gingerol inhibited EGF ERK1/2 activation. TU-100 and some of its components and metabolites of these components inhibit tumor progression in two mouse models of colon cancer by blocking downstream pathways of EGF receptor activation. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Takumu Hasebe
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Jun Matsukawa
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Daina Ringus
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Jun Miyoshi
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - John Hart
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Atsushi Kaneko
- Tsumura Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
| | | | - Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan
- Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yutaka Kohgo
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Chong-Zi Wang
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA
| | - Chun-Su Yuan
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA
| | - Marc Bissonnette
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Mark W. Musch
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Eugene B. Chang
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
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Kim H, Kim HJ, Yang D, Jung MH, Kim BJ. Depolarizing Effects of Daikenchuto on Interstitial Cells of Cajal from Mouse Small Intestine. Pharmacogn Mag 2017; 13:141-147. [PMID: 28216898 PMCID: PMC5307899 DOI: 10.4103/0973-1296.196312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 01/21/2016] [Accepted: 01/06/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Daikenchuto (DKT; TJ-100, TU-100), a traditional herbal medicineis used in modern medicine to treat gastrointestinal (GI) functional disorders. Interstitial cells of Cajal (ICCs) are the pacemaker cells of the GI tract and play important roles in the regulation of GI motility. OBJECTIVE The objective of this study was to investigate the effects of DKT on the pacemaker potentials (PPs) of cultured ICCs from murine small intestine. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from mouse small intestine tissues. All experiments on ICCs were performed after 12 h of culture. The whole-cell patch-clamp configuration was used to record ICC PPs (current clamp mode). All experiments were performed at 30-32°C. RESULTS In current-clamp modeDKT depolarized and concentration-dependently decreased the amplitudes of PPs. Y25130 (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist) did not block DKT-induced PP depolarization, but RS39604 (a 5-HT4 receptor antagonist) did. Methoctramine (a muscarinic M2 receptor antagonist) failed to block DKT-induced PP depolarization, but pretreating 4-diphenylacetoxy-N-methylpiperidine methiodide (a muscarinic M3 receptor antagonist) facilitated blockade of DKT-induced PP depolarization. Pretreatment with an external Ca2+-free solution or thapsigargin abolished PPsand under these conditions, DKT did not induce PP depolarization. Furthermore Ginseng radix and Zingiberis rhizomes depolarized PPs, whereas Zanthoxyli fructus fruit (the third component of DKT) hyperpolarized PPs. CONCLUSION These results suggest that DKT depolarizes ICC PPs in an internal or external Ca2+-dependent manner by stimulating 5-HT4 and M3 receptors. Furthermore, the authors suspect that the component in DKT largely responsible for depolarization is probably also a component of Ginseng radix and Zingiberis rhizomes. SUMMARY Daikenchuto (DKT) depolarized and concentration-dependently decreased the amplitudes of pacemaker potentials (PPs)Y25130 (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist) did not block DKT-induced PP depolarization, but RS39604 (a 5-HT4 receptor antagonist) didMethoctramine (a muscarinic M2 receptor antagonist) failed to block DKT-induced PP depolarization, but pretreating 4-DAMP (a muscarinic M3 receptor antagonist) facilitated blockade of DKT-induced PP depolarizationGinseng radix and Zingiberis rhizomes depolarized PPswhereas Zanthoxyli fructus fruit (the third component of DKT) hyperpolarized PPs. Abbreviation used: DKT: Daikenchuto, GI: Gastrointestinal, ICCs: Interstitial cells of Cajal, PPs: Pacemaker Potentials.
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Affiliation(s)
- Hyungwoo Kim
- Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Hyun Jung Kim
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Dongki Yang
- Department of Physiology, College of Medicine, Gachon University, Incheon, Republic of Korea
| | - Myeong Ho Jung
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
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Tsuchiya K, Kubota K, Ohbuchi K, Kaneko A, Ohno N, Mase A, Matsushima H, Yamamoto M, Miyano K, Uezono Y, Kono T. Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus. Neurogastroenterol Motil 2016; 28:1792-1805. [PMID: 27284001 DOI: 10.1111/nmo.12877] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 05/10/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Stimulation of transient receptor potential ankyrin 1 (TRPA1), which abundantly expressed in enterochromaffin cells (ECC), has been reported to exert apparently contradictory results in in vitro contractility and in vivo gastrointestinal (GI) transit evaluations. The pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) has been reported to be beneficial for postoperative ileus (POI) and accelerate GI transit in animals and humans. TU-100 was recently shown to increase intestinal blood flow via stimulation of TRPA1 in the epithelial cells of the small intestine (SI). METHODS The effects of various TRPA1 agonists on motility were examined in a manipulation-induced murine POI model, in vitro culture of SI segments and an ECC model cell line, RIN-14B. KEY RESULTS Orally administered TRPA1 agonists, aryl isothiocyanate (AITC) and cinnamaldehyde (CA), TU-100 ingredients, [6]-shogaol (6S) and γ-sanshool (GS), improved SI transit in a POI model. The effects of AITC, 6S and GS but not CA were abrogated in TRPA1-deficient mice. SI segments show periodic peristaltic motor activity whose periodicity disappeared in TRPA1-deficient mice. TU-100 augmented the motility. AITC, CA and 6S increased 5-HT release from isolated SI segments and the effects of all these compounds except for CA were lost in TRPA1-deficient mice. 6S and GS induced a release of 5-HT from RIN-14B cells in a dose- and TRPA1-dependent manner. CONCLUSIONS & INFERENCES Intraluminal TRPA1 stimulation is a potential therapeutic strategy for GI motility disorders. Further investigation is required to determine whether 5-HT and/or ECC are involved in the effect of TRPA1 on motility.
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Affiliation(s)
- K Tsuchiya
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - K Kubota
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - K Ohbuchi
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - A Kaneko
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - N Ohno
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - A Mase
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - H Matsushima
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - M Yamamoto
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - K Miyano
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan
| | - Y Uezono
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan
| | - T Kono
- Laboratory of Pathophysiology & Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.,Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
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Yamada T, Matsumoto S, Matsuda MKA, Shinji S, Yokoyama Y, Takahashi G, Iwai T, Takeda K, Ohta K, Uchida E. The effect of Daikenchuto on postoperative intestinal motility in patients with right-side colon cancer. Surg Today 2016; 47:865-871. [PMID: 27873059 DOI: 10.1007/s00595-016-1449-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 11/03/2016] [Indexed: 12/20/2022]
Abstract
PURPOSE Daikenchuto (DKT) has a stimulant effect on intestinal motility and reportedly has a positive effect on postoperative intestinal motility in patients with sigmoid colon cancer. In this study, we investigated the effects of DKT in patients with right-side colon cancer. METHODS This retrospective study included 88 patients with right-side colon cancer. We orally administered 7.5 g of DKT in the DKT group and did not administer any DKT to patients in the no-DKT group. All patients ingested radiopaque markers 2 h before surgery, which were used to assess intestinal motility. The postoperative intestinal motility was radiologically assessed by counting the numbers of residual markers in the large and small intestines. RESULTS The DKT and no-DKT groups showed no marked differences in the total number of residual markers or number of residual markers in the small intestine. However, in the elderly subgroup, the total number of residual markers in the DKT group was significantly less than in the no-DKT group. CONCLUSION Although DKT had some small effect on the postoperative intestinal motility for most patients, it may have positive effects in elderly patients.
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Affiliation(s)
- Takeshi Yamada
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Satoshi Matsumoto
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | | | - Seiichi Shinji
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Yasuyuki Yokoyama
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Goro Takahashi
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Takuma Iwai
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Kouki Takeda
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Keiichiro Ohta
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Eiji Uchida
- Department of Digestive Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
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Kimata Y, Ogawa K, Okamoto H, Chino A, Namiki T. Efficacy of Japanese traditional (Kampo) medicine for treating chemotherapy-induced peripheral neuropathy: A retrospective case series study. World J Clin Cases 2016; 4:310-317. [PMID: 27803912 PMCID: PMC5067493 DOI: 10.12998/wjcc.v4.i10.310] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 07/14/2016] [Accepted: 08/08/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate Japanese traditional (Kampo) medicine’s effectiveness on cancer chemotherapy-induced peripheral neuropathy (CIPN), we carried out this retrospective study.
METHODS By searching our outpatient database of 3154 patients who consulted our outpatient clinic of Japanese-Oriental (Kampo) Medicine at Chiba University Hospital from November 2005 to December 2010, a total of 281 patients diagnosed with cancer were identified. Twenty-four patients out of the 281 patients identified met the following three conditions and were eligible for further investigation of the effectiveness of Kampo treatment: At least one course of cancer chemotherapy had been administered; numbness and pain appeared after the chemotherapy; and CIPN was diagnosed before they were given Kampo treatment.
RESULTS The 24 patients included 6 males and 18 females and ranged in age from 39 to 86 (mean 61.2 ± 11.5) years old. Kampo formulas were individually chosen by Kampo expert doctors based on Kampo-specific diagnostics. Beneficial outcomes were obtained by Kampo treatment in 20 out of the 24 cases (83.3%). Nine out 20 cases had a major response (the numbness and pain showed improvement or reduction by 50% or more), with 7 of 9 cases showing a more than 70% symptom reduction. Eleven out of 20 cases showed a minor response (less than 50% symptom reduction), and 4 out of the 24 cases had no beneficial response. The most frequently used formula was goshajinkigan (GJG), followed by hachimijiogan (HJG) and keishibukuryogan. Thirteen of the 24 cases (54.2%) were prescribed aconite root-containing formulas including GJG and HJG. Aconite root has “warming” effects and ameliorates pain and numbness; 21 out of 24 cases (87.5%) in total used warming formulas such as aconite root-containing formulas to reduce CIPN.
CONCLUSION Our current study suggested that Kampo formulas chosen based on Kampo-specific diagnostics could be for treating CIPN that is refractory to conventional medicine.
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Yada K, Ishibashi H, Mori H, Morine Y, Zhu C, Feng R, Kono T, Shimada M. The Kampo medicine "Daikenchuto (TU-100)" prevents bacterial translocation and hepatic fibrosis in a rat model of biliary atresia. Surgery 2016; 159:1600-1611. [PMID: 26994485 DOI: 10.1016/j.surg.2016.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 01/03/2016] [Accepted: 02/03/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Biliary atresia is the most common cause of end-stage liver disease in children. It is known that bile duct ligation contributes to liver fibrosis via bacterial translocation (BT) and toll-like receptor 4 (TLR4) signaling of hepatic stellate cells (HSCs). We have reported previously that the traditional Japanese medicine, "Dai-kenchu-to (TU-100)," a form of "Kampo medicine" prevents BT in rats exposed to the stress of fasting. The aim of this study was to clarify the effect of TU-100 on a rat model of biliary atresia using bile duct ligation. METHODS Bile duct ligation and subsequent daily oral administration of TU-100 was performed in 6-week-old rats. The rats were killed at 3, 7, or 14 days after bile duct ligation to evaluate the liver injury, occurrence of BT, and hepatic fibrosis. As an in vitro experiment, we isolated fresh HSCs from the rats undergoing bile duct ligation. After cell attachment, TU-100 and its 3 component herbs (eg, processed ginger, ginseng radix, and Japanese pepper) were added, and the expressions of Alpha actin2 (acta2), Alpha-1 type I collagen (colIa1), and tissue inhibitor of metalloproteinase 1 (timp1) were analyzed. RESULTS In vivo experiments demonstrated that oral administration of TU-100 decreased liver injury and atrophy of intestinal mucosa BT, hepatic fibrosis, and hepatic expression of alpha smooth muscle actin (αSMA) and TLR4, compared with rats that underwent bile duct ligation only. In vitro experiments showed that administration of TU-100 or the component herbs inhibited the expressions of acta2, colIa1, and timp1 in the HSCs. CONCLUSION TU-100 prevented BT, activation of HSCs, and subsequent hepatic fibrosis. TU-100 may prevent progression of hepatic fibrosis in children with biliary atresia and improve prognosis.
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Affiliation(s)
- Keigo Yada
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan; Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima, Japan.
| | - Hiroki Ishibashi
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan
| | - Hiroki Mori
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan
| | - Chengzhan Zhu
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan; Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima, Japan
| | - Rui Feng
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan
| | - Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Hokkaido, Japan
| | - Mitsuo Shimada
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan
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Katsuno H, Maeda K, Ohya M, Yoshioka K, Tsunoda A, Koda K, Matsuoka H, Ohge H, Morita S, Saji S, Kanematsu T, Kitajima M. Clinical pharmacology of daikenchuto assessed by transit analysis using radiopaque markers in patients with colon cancer undergoing open surgery: a multicenter double-blind randomized placebo-controlled study (JFMC39-0902 additional study). J Gastroenterol 2016; 51:222-9. [PMID: 26162646 DOI: 10.1007/s00535-015-1100-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 06/21/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND This exploratory trial was conducted to investigate whether daikenchuto accelerates the recovery of gastrointestinal function in patients undergoing open surgery for sigmoid or rectosigmoid cancer. METHODS Eighty-eight patients who underwent colectomy at one of the 11 clinical trial sites in Japan from January 2009 to June 2011 were registered in the study. Patients received either placebo or daikenchuto (15.0 g/day, 5 g three times a day) from postoperative day 2 to postoperative day 8. The study end points included the gastrointestinal tract transit time evaluated with radiopaque markers and the time to first flatus. The safety profile of daikenchuto was also evaluated until postoperative day 8. RESULTS Seventy-one patients (daikenchuto, n = 38; placebo, n = 33) were statistically analyzed. Although the number of radiopaque markers in the anal side of the small intestine at 6 h was significantly greater in the daikenchuto group than in the placebo group (15.19 vs 10.06, p = 0.008), the total transit analysis results and the mean time to first flatus did not differ significantly between the two groups. CONCLUSIONS Daikenchuto has a positive effect on the resolution of delayed gastric emptying, but has a limited effect on the resolution of postoperative paralytic ileus after open surgery in patients with sigmoid or rectosigmoid cancer. Daikenchuto may contribute to early oral intake in the postoperative course.
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Affiliation(s)
- Hidetoshi Katsuno
- Department of Surgery, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake, Toyoake, Aichi, 470-1192, Japan.
| | - Koutarou Maeda
- Department of Surgery, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake, Toyoake, Aichi, 470-1192, Japan
| | - Masatoshi Ohya
- Department of Surgery, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan
| | - Kazuhiko Yoshioka
- Department of Surgery, Kansai Medical University Takii Hospital, Moriguchi, Japan
| | - Akira Tsunoda
- Department of Surgery, Kameda Medical Center, Kamogawa, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Japan
| | | | - Hiroki Ohge
- Department of Surgery, Hiroshima University School of Medicine, Hiroshima, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shigetoyo Saji
- Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan
| | | | - Masaki Kitajima
- International University of Health and Welfare, Otawara, Japan
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Nam Y, Lee JM, Wang Y, Ha HS, Sohn UD. The effect of Flos Lonicerae Japonicae extract on gastro-intestinal motility function. JOURNAL OF ETHNOPHARMACOLOGY 2016; 179:280-290. [PMID: 26743226 DOI: 10.1016/j.jep.2015.12.056] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 12/23/2015] [Accepted: 12/29/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Flos Lonicerae Japonicae is a well-known herb of traditional Chinese medicine that has been used for heat-clearing, detoxification, anti-inflammation, throat pain and gastro-intestinal (GI) disorder. In order to verify the effect of Flos Lonicerae Japonicae on GI disorder, we investigated the prokinetic effect of GC-7101 on GI motility function. MATERIALS AND METHODS GC-7101 is the standardized extract of Flos Lonicerae Japonicae. The contractile action of GC-7101 on feline esophageal smooth muscle cell (ESMC) was evaluated by measuring dispersed cell length. The isometric tension study was performed to investigate the effect of GC-7101 on feline lower esophageal sphincther (LES). The prokinetic effect of GC-7101 was investigated by gastric emptying (GE) and gastro-intestinal transit (GIT) in rats. RESULTS GC-7101 produced concentration-dependent contractions in ESMCs. Pretreatment with 5-HT3 and 5-HT4 receptor blocker (ondansetron and GR113808) inhibited the contractile responses of the GC-7101-induced ESMCs. In isometric tension study, GC-7101 recovered the HCl-induced decreased tone of LES muscle strips. The treatment of GC-7101 enhanced the carbachol-induced contractile responses and the electric field stimulation (EFS)-induced on-contraction. The oral administration of GC-7101 not only significantly accelerated GE and GIT in normal rats but also recovered the delayed GE and GIT, and its effect was more potent than that of conventional prokinetics (e.g., domperidone, a dopamine-receptor antagonist, and mosapride, a 5-HT4-receptor agonist). CONCLUSION GC-7101 revealed a prokinetic effect through enhancing the contractile responses of ESMCs, tone increases, enhancing the carbarchol- or EFS-induced contractile responses of LES muscle strips, and the acceleration of GE and GIT. We have identified the significant potential of GC-7101 for the development of new prokinetic drugs through this study.
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Affiliation(s)
- Yoonjin Nam
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-784, Republic of Korea.
| | - Jong Mi Lee
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-784, Republic of Korea.
| | - Yiyi Wang
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-784, Republic of Korea.
| | - Hyun Su Ha
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-784, Republic of Korea.
| | - Uy Dong Sohn
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-784, Republic of Korea.
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Hasebe T, Ueno N, Musch MW, Nadimpalli A, Kaneko A, Kaifuchi N, Watanabe J, Yamamoto M, Kono T, Inaba Y, Fujiya M, Kohgo Y, Chang EB. Daikenchuto (TU-100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K. Pharmacol Res Perspect 2016; 4:e00215. [PMID: 26977303 PMCID: PMC4777267 DOI: 10.1002/prp2.215] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 01/05/2016] [Accepted: 01/08/2016] [Indexed: 12/29/2022] Open
Abstract
Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long‐term of these agents. Daikenchuto, TU‐100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet‐incorporated TU‐100 was administered to mice over a period of several weeks. T‐RFLP and 454 pyrosequencing were performed to analyze the time‐dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU‐100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU‐100 components in plasma and in stool samples were measured by LC‐MS/MS. Cecal and stool short‐chain fatty acids were measured by GC‐MS. Dietary administration of TU‐100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU‐100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU‐100 promotes changes in gut microbiota enhancing metabolic capacity of TU‐100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.
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Affiliation(s)
- Takumu Hasebe
- Department of Medicine Inflammatory Bowel Disease Center The University of Chicago Chicago Illinois; Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Hokkaido Japan
| | - Nobuhiro Ueno
- Department of Medicine Inflammatory Bowel Disease Center The University of Chicago Chicago Illinois; Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Hokkaido Japan
| | - Mark W Musch
- Department of Medicine Inflammatory Bowel Disease Center The University of Chicago Chicago Illinois
| | - Anuradha Nadimpalli
- Department of Medicine Inflammatory Bowel Disease Center The University of Chicago Chicago Illinois
| | - Atsushi Kaneko
- Tsumura Research Laboratories Tsumura & Co., Ami Ibaraki Japan
| | - Noriko Kaifuchi
- Tsumura Research Laboratories Tsumura & Co., Ami Ibaraki Japan
| | - Junko Watanabe
- Tsumura Research Laboratories Tsumura & Co., Ami Ibaraki Japan
| | | | - Toru Kono
- Faculty of Pharmaceutical Sciences Hokkaido University Sapporo Hokkaido Japan; Center for Clinical and Biomedical Research Sapporo Higashi Tokushukai Hospital Sapporo Hokkaido Japan
| | - Yuhei Inaba
- Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Hokkaido Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Hokkaido Japan
| | - Yutaka Kohgo
- Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Hokkaido Japan
| | - Eugene B Chang
- Department of Medicine Inflammatory Bowel Disease Center The University of Chicago Chicago Illinois
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Matsushita A, Fujita T, Ohtsubo S, Kumamoto E. Traditional Japanese medicines inhibit compound action potentials in the frog sciatic nerve. JOURNAL OF ETHNOPHARMACOLOGY 2016; 178:272-80. [PMID: 26707752 DOI: 10.1016/j.jep.2015.12.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/08/2015] [Accepted: 12/14/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Japanese (Kampo) medicines have a variety of clinical effects including pain alleviation, but evidence for a mechanism for their pain relief has not yet been elucidated fully. Considering that Kampo medicine contains many plant-derived chemicals having an ability to inhibit nerve action potential conduction, it is possible that this medicine inhibits nerve conduction. The purpose of the present study was to know how various Kampo medicines affect nerve conduction. MATERIALS AND METHODS We examined the effects of Kampo and crude medicines on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. RESULTS Daikenchuto, rikkosan, kikyoto, rikkunshito, shakuyakukanzoto and kakkonto concentration-dependently reduced the peak amplitude of the CAP. Among the Kampo medicines, daikenchuto was the most effective in inhibiting CAPs. Daikenchuto is composed of three kinds of crude medicine, Japanese pepper, processed ginger and ginseng radix. When the crude medicines were tested, Japanese pepper and processed ginger reduced CAP peak amplitudes, while ginseng radix hardly affected CAPs. Moreover, there was an interaction between the Japanese pepper and processed ginger activities in such that one medicine at low but not high concentrations increased the extent of the inhibition by the other one that was co-applied. CONCLUSIONS Kampo medicines have an ability to inhibit nerve conduction. This action of daikenchuto is due to Japanese pepper and processed ginger but not ginseng radix, probably through an interaction between Japanese pepper and processed ginger in a manner dependent on their concentrations. Nerve conduction inhibition could contribute to at least a part of Kampo medicine's clinical effects such as pain alleviation.
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Affiliation(s)
| | - Tsugumi Fujita
- Department of Physiology, Saga Medical School, Saga, Japan.
| | - Sena Ohtsubo
- Department of Physiology, Saga Medical School, Saga, Japan.
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Tsuda H, Kotani T, Sumigama S, Mano Y, Hayakawa H, Kikkawa F. Efficacy and safety of daikenchuto (TJ-100) in pregnant women with constipation. Taiwan J Obstet Gynecol 2016; 55:26-9. [DOI: 10.1016/j.tjog.2015.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2014] [Indexed: 11/25/2022] Open
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50
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Japanese Guidelines for Nutrition Support Therapy in the Adult and Pediatric Critically Ill Patients. ACTA ACUST UNITED AC 2016. [DOI: 10.3918/jsicm.23.185] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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