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Lu IC, Hu PY, Lin CH, Chang LL, Wang HC, Cheng KI, Gau TP, Lin KW. Alkamides in Zanthoxylum Species: Phytochemical Profiles and Local Anesthetic Activities. Int J Mol Sci 2024; 25:12228. [PMID: 39596294 PMCID: PMC11595231 DOI: 10.3390/ijms252212228] [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: 10/05/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Zanthoxylum species have long been utilized in traditional medicine; among their various properties, they provide an analgesic effect. Central to this medicinal application are alkamides, a class of alkaloids characterized by their unsaturated fatty acid chains. These compounds are particularly noted for their distinctive alleviation of tingling and numbing effects, which are beneficial in dental pain management and local anesthesia. This review synthesizes the existing phytochemical research on alkamides derived from 11 Z. species, focusing on their chemical properties, pharmacodynamics and clinical implications. The analysis includes an examination of the structure-activity relationships (SARs), pharmacokinetics and mechanisms by which these compounds modulate sensations such as pungency and numbness, contributing to their analgesic and local anesthetic efficacy. This systemic review identifies significant research gaps, including the need for comprehensive evaluations of alkamide efficacy, detailed explorations of their pharmacological mechanisms and expanded clinical applications. These areas represent key opportunities for future investigations to enhance the understanding and utilization of alkamides in medical treatments.
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Affiliation(s)
- I-Cheng Lu
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Pin-Yang Hu
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
| | - Chia-Heng Lin
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
| | - Lin-Li Chang
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan
| | - Hung-Chen Wang
- Department of Neurosurgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833253, Taiwan;
| | - Kuang-I Cheng
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Tz-Ping Gau
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
| | - Kai-Wei Lin
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan; (I.-C.L.); (P.-Y.H.); (C.-H.L.); (K.-I.C.)
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Liang Q, Wang JW, Bai YR, Li RL, Wu CJ, Peng W. Targeting TRPV1 and TRPA1: A feasible strategy for natural herbal medicines to combat postoperative ileus. Pharmacol Res 2023; 196:106923. [PMID: 37709183 DOI: 10.1016/j.phrs.2023.106923] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/16/2023]
Abstract
Under physiological or pathological conditions, transient receptor potential (TRP) channel vanilloid type 1 (TRPV1) and TRP ankyrin 1 (TRPA1) possess the ability to detect a vast array of stimuli and execute diverse functions. Interestingly, increasing works have reported that activation of TRPV1 and TRPA1 could also be beneficial for ameliorating postoperative ileus (POI). Increasing research has revealed that the gastrointestinal (GI) tract is rich in TRPV1/TRPA1, which can be stimulated by capsaicin, allicin and other compounds. This activation stimulates a variety of neurotransmitters, leading to increased intestinal motility and providing protective effects against GI injury. POI is the most common emergent complication following abdominal and pelvic surgery, and is characterized by postoperative bowel dysfunction, pain, and inflammatory responses. It is noteworthy that natural herbs are gradually gaining recognition as a potential therapeutic option for POI due to the lack of effective pharmacological interventions. Therefore, the focus of this paper is on the TRPV1/TRPA1 channel, and an analysis and summary of the processes and mechanism by which natural herbs activate TRPV1/TRPA1 to enhance GI motility and relieve pain are provided, which will lay the foundation for the development of natural herb treatments for this disease.
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Affiliation(s)
- Qi Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Jing-Wen Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Yu-Ru Bai
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Ruo-Lan Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Chun-Jie Wu
- Institute of Innovation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Wei Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
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Tan F, Li H, Zhang K, Xu L, Zhang D, Han Y, Han J. Sodium Alginate/Chitosan-Coated Liposomes for Oral Delivery of Hydroxy-α-Sanshool: In Vitro and In Vivo Evaluation. Pharmaceutics 2023; 15:2010. [PMID: 37514196 PMCID: PMC10383520 DOI: 10.3390/pharmaceutics15072010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Hydroxy-α-Sanshool (HAS) possesses various pharmacological properties, such as analgesia and regulating gastrointestinal function. However, the low oral bioavailability of HAS has limited its oral delivery in clinical application. METHODS AND RESULTS To enhance its oral bioavailability, a nanocomposite delivery system based on chitosan (CH, as the polycation) and sodium alginate (SA, as the polyanion) was prepared using a layer-by-layer coating technique. The morphology, thermal behavior and Fourier transform infrared spectrum (FTIR) showed that the obtained sodium alginate/chitosan-coated HAS-loaded liposomes (SA/CH-HAS-LIP) with core-shell structures have been successfully covered with polymers. When compared with HAS-loaded liposomes (HAS-LIP), SA/CH-HAS-LIP displayed obvious pH sensitivity and a sustained-release behavior in in vitro studies, which fitted well to Weibull model. In vivo, the half-life of HAS from SA/CH-HAS-LIP remarkably extended after oral administration compared to the free drug. Additionally, it allowed a 4.6-fold and 4.2-fold increase in oral bioavailability, respectively, compared with free HAS and HAS-LIP. CONCLUSIONS SA/CH-HAS-LIP could be a promising release vehicle for the oral delivery of HAS to increase its oral bioavailability.
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Affiliation(s)
- Fengming Tan
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Huan Li
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Kai Zhang
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Lulu Xu
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Dahan Zhang
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Yang Han
- School of Chinese Materia Medica, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Jing Han
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
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Clinical efficacy of Daikenchuto (DKT: TJ-100) for gastrointestinal symptoms in patients with a history of colon and rectosigmoid cancer surgery: a randomized crossover study. Surg Today 2023:10.1007/s00595-022-02640-2. [PMID: 36662306 DOI: 10.1007/s00595-022-02640-2] [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: 06/02/2022] [Accepted: 11/16/2022] [Indexed: 01/21/2023]
Abstract
PURPOSE This randomized crossover trial investigated the effects of Daikenchuto (DKT: TJ-100) on gastrointestinal symptoms of patients after colon and rectosigmoid cancer surgery. METHODS Among patients who had completed surgery for colon cancer, including rectosigmoid cancer, over 6 months ago, 20 who complained of gastrointestinal symptoms were enrolled. Subjects were randomly assigned to two sequences: sequences: A and B. In period 1, sequence A subjects were orally administered DKT, whereas sequence B subjects were untreated for 28 days. After a 5-day interval, in period 2, sequences A and B were reversed. Quality-of-life markers (GSRS and VAS), the Sitzmark transit study, the orocecal transit time (lactulose hydrogen breath test) and Gas volume score were evaluated before and after each period with findings compared between the presence of absence of DKT administration. RESULTS Between sequences, there were no significant differences in clinicopathological characters or any evaluations before randomization. There was no carryover effect in this crossover trial. The administration of DKT significantly ameliorated the GSRS in total, indigestion, and diarrhea, although the planned number of subjects for inclusion in this trial was not reached. CONCLUSIONS DKT may ameliorate subjective symptoms for postoperative patients who complain of gastrointestinal symptoms.
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Tomita T, Kawano Y, Kassai M, Onda H, Nakajima Y, Miyazaki K. Hydroxy-β-sanshool isolated from Zanthoxylum piperitum (Japanese pepper) shortens the period of the circadian clock. Food Funct 2022; 13:9407-9418. [PMID: 35960176 DOI: 10.1039/d2fo01036d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We showed that an ethanol extract from Zanthoxylum piperitum can shorten the circadian rhythm at the cellular level and that this activity was due to hydroxy-β-sanshool, a secondary metabolite in this plant. An ethanol extract of Z. piperitum was repeatedly fractionated using solid phase extraction and reverse-phase HPLC, then the circadian rhythms of cells to which the fractions were loaded were monitored using real-time reporter gene assays. We purified one HPLC peak and identified it as hydroxy-β-sanshool using liquid chromatography (LC)-precision-mass spectrometry (MS). This compound shortened the period of Bmal1 and Per2 at the cellular level. Incubation cells for 24 h with hydroxy-β-sanshool resulted in upregulated Per2 promoter activity. Hydroxy-β-sanshool also dose-dependently upregulated expression of the clock genes Bmal1, Per1, Per2 and Cry1 and the clock-controlled oxidative stress responsive genes Gpx1and Sod2.
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Affiliation(s)
- Tatsunosuke Tomita
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Higashi 1-1-1, Tsukuba 305-8566, Japan.
| | - Yasuhiro Kawano
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Higashi 1-1-1, Tsukuba 305-8566, Japan.
| | - Masahiro Kassai
- S&B Foods Inc., #605 MITSUI LINK-Lab Shinkiba1 Shinkiba 2-3-8, Koto-ku, Tokyo 136-0082, Japan
| | - Hiroyuki Onda
- S&B Foods Inc., #605 MITSUI LINK-Lab Shinkiba1 Shinkiba 2-3-8, Koto-ku, Tokyo 136-0082, Japan
| | - Yoshihiro Nakajima
- Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Hayashicho 2217-14, Takamatsu, 761-0395, Japan
| | - Koyomi Miyazaki
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Higashi 1-1-1, Tsukuba 305-8566, Japan.
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Tan F, Xu L, Liu Y, Li H, Zhang D, Qin C, Han Y, Han J. Design of hydroxy-α-sanshool loaded nanostructured lipid carriers as a potential local anesthetic. Drug Deliv 2022; 29:743-753. [PMID: 35244508 PMCID: PMC8903781 DOI: 10.1080/10717544.2022.2039808] [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] [Indexed: 11/05/2022] Open
Abstract
Hydroxy-α-sanshool (HAS), extracted from Zanthoxylum piperitum, is commonly used in oral surgery to relief pain. However, the application of HAS is limited in clinical practice due to its poor stability. This study focuses on the design of a novel nano-formulation delivery system for HAS to improve its stability and local anesthetic effect. Hydroxy-α-sanshool loaded nanostructured lipid carriers (HAS-NLCs) were prepared by melting emulsification and ultra-sonication using monostearate (GMS) and oleic acid (OA) as lipid carriers, and poloxamer-188 (F68) as a stabilizer. Besides, the formulation was optimized by response surface methodology (RSM). Then, the best formulation was characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), drug loading (DL%), differential scanning calorimetry (DSC), and morphology (transmission electron microscopy, TEM). The obtained HAS-NLCs were homogeneous, near spherical particles with high DL% capacity. The stability of HAS-NLCs against oxygen, light, and heat was greatly improved over 10.79 times, 3.25 times, and 2.09 times, respectively, compared to free HAS. In addition, HAS-NLCs could exhibit sustained release in 24 h following a double-phase kinetics model in vitro release study. Finally, HAS-NLCs had excellent anesthetic effect at low dose in formalin test compared with free HAS and lidocaine, which indicated HAS-NLCs were a potential local anesthesia formulation in practice.
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Affiliation(s)
- Fengming Tan
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
| | - Lulu Xu
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
| | - Yanling Liu
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
| | - Huan Li
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
| | - Dahan Zhang
- Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China
| | - Cuiying Qin
- Department Center for Medical Science and Technology, Nation Health Commission of the People's Republic of China, Beijing, China
| | - Yang Han
- School of Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Han
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
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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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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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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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The Acute and Chronic Cognitive and Cerebral Blood-Flow Effects of Nepalese Pepper ( Zanthoxylum armatum DC.) Extract-A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Humans. Nutrients 2019; 11:nu11123022. [PMID: 31835620 PMCID: PMC6950039 DOI: 10.3390/nu11123022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/19/2019] [Accepted: 12/03/2019] [Indexed: 02/07/2023] Open
Abstract
Background: Zanthoxylum armatum DC. (ZA) is a traditional Asian culinary spice and medicinal compound, which is rich in monoterpenes and hydroxy α-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. Objectives: To investigate the effects of a single dose and 56-days supplementation with a lipid extract of ZA on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. Design: Double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years. Assessments were undertaken pre-dose and at 1, 3 and 5 hours post-dose on the first (Day 1) and last (Day 56) days of supplementation. Results: A single dose of ZA (Day 1) resulted in acute improvements on a 'Speed of Attention' factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. However, following ZA participants were less accurate on the name-to-face recall task. After 56 days of ZA consumption (Day 56), speed was enhanced on a global 'Speed of Performance' measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 hours assessment and were less mentally fatigued throughout the day than participants consuming placebo. These effects were complemented on both Day 1 and Day 56 by modulation of CBF parameters, as assessed by Near Infrared Spectroscopy (NIRS). The primary finding here was a reduced hemodynamic response during the RVIP task. Conclusion: ZA improves aspects of cognitive performance, in particular the speed of performing tasks, in healthy humans and results in concomitant reductions in hemodynamic responses in the frontal cortex during task performance. The findings suggest an increase in neural efficiency following ZA.
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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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12
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Kitagawa H, Ohbuchi K, Munekage M, Fujisawa K, Kawanishi Y, Namikawa T, Kushida H, Matsumoto T, Shimobori C, Nishi A, Sadakane C, Watanabe J, Yamamoto M, Hanazaki K. Phenotyping analysis of the Japanese Kampo medicine maoto in healthy human subjects using wide-targeted plasma metabolomics. J Pharm Biomed Anal 2019; 164:119-127. [PMID: 30368117 DOI: 10.1016/j.jpba.2018.10.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/05/2023]
Abstract
Traditional herbal medicine (THM) consists of a vast number of compounds that exert pharmacological effects throughout the body. Comprehensive phenotyping analysis using omics is essential for understanding the nature of THM in detail. We previously reported that the Japanese Kampo medicine maoto ameliorated flu-like symptoms in a rat infection model and dynamically changed plasma metabolites as indicated by metabolome analysis. The aim of this study was to apply wide-targeted plasma metabolomics with quantitative analysis of maoto compounds in a human clinical trial to evaluate the effect of maoto on plasma metabolites. Four healthy human subjects were recruited. Plasma samples were collected before and 0.25, 0.5, 1, 2, 4 and 8 h after maoto treatment. Wide-targeted metabolomics and quantitative analysis of the main chemical constituents of maoto were then performed. Plasma metabolome analysis revealed that maoto administration decreased essential amino acids including branched-chain amino acids (BCAAs) and increased various kinds of ω-3 fatty acids including eicosapentaenoic acid and docosahexaenoic acid, consistent with previous studies in rats. Fifteen of the major compounds in maoto were identified in the systemic circulation. Finally, the correlation between endogenous metabolites and maoto compounds in plasma was analyzed and the results indicated that the decrease in plasma BCAAs might be caused by ephedrines present in maoto. The present study demonstrated that plasma metabolomic studies of endogenous and exogenous metabolites are useful for elucidating the mechanism of action of THM.
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Affiliation(s)
- Hiroyuki Kitagawa
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Katsuya Ohbuchi
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan.
| | - Masaya Munekage
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Kazune Fujisawa
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Yasuhiro Kawanishi
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Tsutomu Namikawa
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Hirotaka Kushida
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan
| | | | - Chika Shimobori
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan
| | - Akinori Nishi
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan
| | - Chiharu Sadakane
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan
| | - Junko Watanabe
- Tsumura Kampo Research Laboratories, Tsumura & CO., Ibaraki, Japan
| | | | - Kazuhiro Hanazaki
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
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13
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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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Chruma JJ, Cullen DJ, Bowman L, Toy PH. Polyunsaturated fatty acid amides from the Zanthoxylum genus – from culinary curiosities to probes for chemical biology. Nat Prod Rep 2018; 35:54-74. [DOI: 10.1039/c7np00044h] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
A critical and comprehensive review of the discovery, synthesis, and biological activities of alkamides isolated from Zanthoxylum plants and synthetic derivatives thereof.
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Affiliation(s)
- Jason J. Chruma
- Key Laboratory of Green Chemistry & Technology (MOE)
- College of Chemistry
- Sino-British Materials Research Institute
- College of Physical Science & Technology
- Sichuan University
| | | | - Lydia Bowman
- Department of Chemistry
- The University of Hong Kong
- P. R. China
| | - Patrick H. Toy
- Department of Chemistry
- The University of Hong Kong
- P. R. China
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15
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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: 22] [Impact Index Per Article: 2.4] [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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16
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Gao S, Kushida H, Makino T. Ginsenosides, ingredients of the root of Panax ginseng, are not substrates but inhibitors of sodium-glucose transporter 1. J Nat Med 2016; 71:131-138. [DOI: 10.1007/s11418-016-1042-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 08/31/2016] [Indexed: 02/07/2023]
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17
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Rong R, Cui MY, Zhang QL, Zhang MY, Yu YM, Zhou XY, Yu ZG, Zhao YL. Anesthetic constituents ofZanthoxylum bungeanumMaxim.: A pharmacokinetic study. J Sep Sci 2016; 39:2728-35. [DOI: 10.1002/jssc.201600295] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Revised: 05/09/2016] [Accepted: 05/17/2016] [Indexed: 11/08/2022]
Affiliation(s)
- Rong Rong
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Mei-Yu Cui
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Qi-Li Zhang
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Mei-Yan Zhang
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Yu-Ming Yu
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Xian-Ying Zhou
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Zhi-Guo Yu
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
| | - Yun-Li Zhao
- Institute Department of Pharmaceutical Analysis, School of Pharmacy; Shenyang Pharmaceutical University; Shenyang China
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18
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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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Kitamura M, Nishino T, Obata Y, Oka S, Abe S, Muta K, Ozono Y, Koji T, Kohno S. The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice. Biol Pharm Bull 2015; 38:193-200. [PMID: 25747978 DOI: 10.1248/bpb.b14-00469] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.
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Affiliation(s)
- Mineaki Kitamura
- Second Department of Internal Medicine, Nagasaki University School of Medicine
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Watanabe J, Kaifuchi N, Kushida H, Matsumoto T, Fukutake M, Nishiyama M, Yamamoto M, Kono T. Intestinal, portal, and peripheral profiles of daikenchuto (TU-100)'s active ingredients after oral administration. Pharmacol Res Perspect 2015; 3:e00165. [PMID: 26516578 PMCID: PMC4618637 DOI: 10.1002/prp2.165] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 06/10/2015] [Accepted: 06/13/2015] [Indexed: 12/27/2022] Open
Abstract
A pharmaceutical grade Japanese traditional medicine, daikenchuto (TU-100), consisting of Japanese pepper, processed ginger, and ginseng, has been widely used for various intestinal disorders in Japan and now under development as a new therapeutic drug in the US. It is suggested that TU-100 ingredients exert pharmacological effects on intestines via two routes, from the luminal side before absorption and the peripheral blood stream after absorption. Therefore, in order to fully understand the pharmacological actions of TU-100, it is critically important to know the intraluminal amounts and forms of ingested TU-100 ingredients. In the present study, after administrating TU-100 to rats, the concentrations of TU-100 ingredients and their conjugates in the peripheral and portal blood and ileal contents were determined by LC-MS/MS. Next, TU-100 was administered to patients with ileostomy bags, but whose small intestines are diagnosed as healthy, and the ingredients/conjugates in the ileal effluent were analyzed. The results suggest that: (1) Pepper ingredients hydroxysanshools are rapidly absorbed and enter systemic circulation, (2) Ginseng ingredients ginsenosides are transported to the colon with the least absorption, (3) Ginger ingredients gingerols are absorbed and some conjugated in the small intestine and transported via the portal vein. While only a small amount of gingerols/gingerol conjugates enter systemic circulation, considerable amounts reappear in the small intestine. Thus, the effect of TU-100 on the intestines is believed to be a composite of multiple actions by multiple compounds supplied via multiple routes.
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Affiliation(s)
- Junko Watanabe
- Tsumura Research Laboratories, Tsumura & Co.Ami, Ibaraki, Japan
| | - Noriko Kaifuchi
- Tsumura Research Laboratories, Tsumura & Co.Ami, Ibaraki, Japan
| | | | | | - Miwako Fukutake
- Tsumura Research Laboratories, Tsumura & Co.Ami, Ibaraki, Japan
| | | | | | - Toru Kono
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Faculty of Pharmaceutical Sciences, Hokkaido UniversitySapporo, Hokkaido, Japan
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai HospitalSapporo, Hokkaido, Japan
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22
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Wang CZ, Moss J, Yuan CS. Commonly Used Dietary Supplements on Coagulation Function during Surgery. MEDICINES (BASEL, SWITZERLAND) 2015; 2:157-185. [PMID: 26949700 PMCID: PMC4777343 DOI: 10.3390/medicines2030157] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2023]
Abstract
BACKGROUND Patients who undergo surgery appear to use dietary supplements significantly more frequently than the general population. Because they contain pharmacologically active compounds, dietary supplements may affect coagulation and platelet function during the perioperative period through direct effects, pharmacodynamic interactions, and pharmacokinetic interactions. However, in this regard, limited studies have been conducted that address the pharmacological interactions of dietary supplements. To avoid possible bleeding risks during surgery, information of potential complications of dietary supplements during perioperative management is important for physicians. METHODS Through a systematic database search of all available years, articles were identified in this review if they included dietary supplements and coagulation/platelet function, while special attention was paid to studies published after 1990. RESULTS Safety concerns are reported in commercially available dietary supplements. Effects of the most commonly used natural products on blood coagulation and platelet function are systematically reviewed, including 11 herbal medicines (echinacea, ephedra, garlic, ginger, ginkgo, ginseng, green tea, kava, saw palmetto, St John's wort, and valerian) and 4 other dietary supplements (coenzyme Q10, glucosamine and chondroitin sulfate, fish oil, and vitamins). Bleeding risks of garlic, ginkgo, ginseng, green tea, saw palmetto, St John's wort, and fish oil are reported. Cardiovascular instability was observed with ephedra, ginseng, and kava. Pharmacodynamic and pharmacokinetic interactions between dietary supplements and drugs used in the perioperative period are discussed. CONCLUSIONS To prevent potential problems associated with the use of dietary supplements, physicians should be familiar with the perioperative effects of commonly used dietary supplements. Since the effects of dietary supplements on coagulation and platelet function are difficult to predict, it is prudent to advise their discontinuation before surgery.
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Affiliation(s)
- Chong-Zhi Wang
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-773-702-0166; Fax: +1-773-834-0601
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Kono T, Shimada M, Yamamoto M, Kaneko A, Oomiya Y, Kubota K, Kase Y, Lee K, Uezono Y. Complementary and synergistic therapeutic effects of compounds found in Kampo medicine: analysis of daikenchuto. Front Pharmacol 2015; 6:159. [PMID: 26300774 PMCID: PMC4523940 DOI: 10.3389/fphar.2015.00159] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 07/17/2015] [Indexed: 01/17/2023] Open
Abstract
Herbal medicines have been used in Japan for more than 1500 years and traditional Japanese medicines (Kampo medicines) are now fully integrated into the modern healthcare system. In total, 148 Kampo formulae are officially approved as prescription drugs and covered by the national health insurance system in Japan. However, despite their long track record of clinical use, the multi-targeted, multi-component properties of Kampo medicines, which are fundamentally different from Western medicines, have made it difficult to create a suitable framework for conducting well-designed, large-scale clinical trials. In turn, this has led to misconceptions among western trained physicians concerning the paucity of scientific evidence for the beneficial effects of Kampo medicines. Fortunately, there has been a recent surge in scientifically robust data from basic and clinical studies for some of the Kampo medicines, e.g., daikenchuto (TU-100). Numerous basic and clinical studies on TU-100, including placebo-controlled double-blind studies for various gastrointestinal disorders, and absorption, distribution, metabolism and excretion (ADME) studies, have been conducted or are in the process of being conducted in both Japan and the USA. Clinical studies suggest that TU-100 is beneficial for postoperative complications, especially ileus and abdominal bloating. ADME and basic studies indicate that the effect of TU-100 is a composite of numerous actions mediated by multiple compounds supplied via multiple routes. In addition to known mechanisms of action via enteric/sensory nerve stimulation, novel mechanisms via the TRPA1 channel and two pore domain potassium channels have recently been elucidated. TU-100 compounds target these channels with and without absorption, both before and after metabolic activation by enteric flora, with different timings and possibly with synergism.
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Affiliation(s)
- Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital Sapporo, Hokkaido, Japan ; Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University Sapporo, Japan ; Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, Tokushima University Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Institute of Health Biosciences, Graduate School of Medicine, Tokushima University Tokushima, Japan
| | - Masahiro Yamamoto
- Kampo Scientific Strategies Division, Tsumura Research Laboratories, Tsumura & CO. Ami, Japan
| | - Atushi Kaneko
- Kampo Scientific Strategies Division, Tsumura Research Laboratories, Tsumura & CO. Ami, Japan
| | - Yuji Oomiya
- Kampo Scientific Strategies Division, Tsumura Research Laboratories, Tsumura & CO. Ami, Japan
| | - Kunitsugu Kubota
- Kampo Scientific Strategies Division, Tsumura Research Laboratories, Tsumura & CO. Ami, Japan
| | - Yoshio Kase
- Kampo Scientific Strategies Division, Tsumura Research Laboratories, Tsumura & CO. Ami, Japan
| | - Keiko Lee
- Kampo Scientific Strategies Division, International Pharmaceutical Development Department, Tsumura & CO. Tokyo, Japan
| | - Yasuhito Uezono
- Division of Cancer Pathophysiology, National Cancer Center Research Institute Tokyo, Japan
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Kitagawa H, Munekage M, Matsumoto T, Sadakane C, Fukutake M, Aoki K, Watanabe J, Maemura K, Hattori T, Kase Y, Uezono Y, Inui A, Hanazaki K. Pharmacokinetic Profiles of Active Ingredients and Its Metabolites Derived from Rikkunshito, a Ghrelin Enhancer, in Healthy Japanese Volunteers: A Cross-Over, Randomized Study. PLoS One 2015; 10:e0133159. [PMID: 26186592 PMCID: PMC4506051 DOI: 10.1371/journal.pone.0133159] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/19/2015] [Indexed: 02/07/2023] Open
Abstract
Background Rikkunshito, a traditional Japanese (Kampo) medicine, has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux. This study investigated the exposure and pharmacokinetics of the ingredients of rikkunshito in healthy volunteers. Methods and Results First, an exploratory nonrandomized, open-label, one-period, noncrossover study using four healthy Japanese volunteers to detect 32 typical ingredients of rikkunshito in plasma and urine. As a result, 18 or 21 of 32 ingredients was detected in plasma or urine samples after oral administration of rikkunshito (7.5 g/day). Furthermore, a randomized, open-label, three-arm, three-period, crossover study using 21 subjects was conducted to determine the amounts of exposure and pharmacokinetic parameters of nine ingredients derived from rikkunshito (atractylodin, atractylodin carboxylic acid, pachymic acid, 3,3′,4′,5,6,7,8-heptamethoxyflavone, naringenin, nobiletin, liquiritigenin, isoliquiritigenin, and 18β-glycyrrhetinic acid) after oral administration of rikkunshito at three different doses (2.5, 5.0, or 7.5 g/day) during each period. The pharmacokinetic profiles of the nine ingredients in plasma were characterized. The geometric means (95% confidence interval) for the Cmax of the ingredients at a dose of 7.5 g were 1570 (1210–2040), 14,300 (12,200–16,800), 91.0 (71.8–115), 105 (75.6–144), 1150 (802–1650), 35.9 (24.6–52.5), 800 (672–952), 42.8 (30.4–60.3), and 55,600 (39,600–78,100) pg/mL, respectively, and for the AUC0–last were 1760 (1290–2390), 12700 (11,100–14,600), 1210 (882–1650), 225 (157–322), 4630 (2930–7320), 35.7 (20.4–62.7), 4040 (3260–5010), 122 (88.2–168), and 832,000 (628,000–1,100,000) pg·h/mL respectively. Conclusions We identified the ingredients of rikkunshito that are absorbed in humans. Furthermore, we determined the pharmacokinetics of nine ingredients derived from rikkunshito. This information will be useful for elucidating the pharmacological effects of rikkunshito. Trial Registration Japan Pharmaceutical Information Center #CTI-121801 and -142522
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Affiliation(s)
- Hiroyuki Kitagawa
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Masaya Munekage
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
| | - Takashi Matsumoto
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
- * E-mail:
| | - Chiharu Sadakane
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Miwako Fukutake
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Katsuyuki Aoki
- Kampo Formulations Development Center, Production Division, Tsumura & Co., Ibaraki, Japan
| | - Junko Watanabe
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Kazuya Maemura
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Tomohisa Hattori
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Yosio Kase
- Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan
| | - Yasuhito Uezono
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan
| | - Akio Inui
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kazuhiro Hanazaki
- Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
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Katsuno H, Maeda K, Kaiho T, Kunieda K, Funahashi K, Sakamoto J, Kono T, Hasegawa H, Furukawa Y, Imazu Y, Morita S, Watanabe M. Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study (JFMC39-0902). Jpn J Clin Oncol 2015; 45:650-6. [PMID: 25972515 PMCID: PMC4485603 DOI: 10.1093/jjco/hyv056] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/24/2015] [Indexed: 12/20/2022] Open
Abstract
Objective This exploratory trial was performed to determine whether Daikenchuto accelerates recovery of gastrointestinal function in patients undergoing open colectomy for colon cancer. Methods A total of 386 patients undergoing colectomy at 1 of the 51 clinical trial sites in Japan from January 2009 to June 2011 were registered for the study (JFMC39-0902). Patients received either placebo or Daikenchuto (15.0 g/day, t.i.d) between post-operative day 2 and post-operative day 8. Primary end-points included time to first bowel movement, frequency of bowel movement and stool form. The incidence of intestinal obstruction was evaluated post-operatively. The safety profile of Daikenchuto until post-operative day 8 was also evaluated. Results The results for 336 patients (Daikenchuto, n = 174; placebo, n = 162) were available for statistical analysis. The time to first bowel movement did not differ significantly between the two groups. All patients reported having diarrhea or soft stools immediately after surgery, and the time until stool normalization (50th percentile) in the Daikenchuto and placebo groups was 6 days and 7 days, respectively. The placebo group had a significantly greater number of hard stools at post-operative day 8 (P = 0.016), and bowel movement frequency continued to increase until post-operative day 8 as well. In contrast, bowel movement frequency in the Daikenchuto group increased until post-operative day 6, however decreased from post-operative day 7 and was significantly lower at post-operative day 8 compared with the placebo group (P = 0.024). Conclusion The moderate effects of Daikenchuto were observed ∼1 week after the operation. Although Daikenchuto had an effect on gastrointestinal function after open surgery in patients with colon cancer, this study did not show its clinical benefits adequately.
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Affiliation(s)
- Hidetoshi Katsuno
- Department of Surgery, Fujita Health University, School of Medicine, Toyoake
| | - Koutarou Maeda
- Department of Surgery, Fujita Health University, School of Medicine, Toyoake
| | - Takashi Kaiho
- Department of Surgery, Kimitsu Chuo Hospital, Kisarazu
| | - Katsuyuki Kunieda
- Department of Surgery, Gifu Prefectural General Medical Center, Gifu
| | - Kimihiko Funahashi
- Department of General and Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo
| | | | - Toru Kono
- Advanced Surgery Center, Sapporo Higashi Tokushukai Hospital, Sapporo
| | | | | | | | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan
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Kubota K, Ohtake N, Ohbuchi K, Mase A, Imamura S, Sudo Y, Miyano K, Yamamoto M, Kono T, Uezono Y. Hydroxy-α sanshool induces colonic motor activity in rat proximal colon: a possible involvement of KCNK9. Am J Physiol Gastrointest Liver Physiol 2015; 308:G579-90. [PMID: 25634809 PMCID: PMC4385894 DOI: 10.1152/ajpgi.00114.2014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 01/22/2015] [Indexed: 01/31/2023]
Abstract
Various colonic motor activities are thought to mediate propulsion and mixing/absorption of colonic content. The Japanese traditional medicine daikenchuto (TU-100), which is widely used for postoperative ileus in Japan, accelerates colonic emptying in healthy humans. Hydroxy-α sanshool (HAS), a readily absorbable active ingredient of TU-100 and a KCNK3/KCNK9/KCNK18 blocker as well as TRPV1/TRPA1 agonist, has been investigated for its effects on colonic motility. Motility was evaluated by intraluminal pressure and video imaging of rat proximal colons in an organ bath. Distribution of KCNKs was investigated by RT-PCR, in situ hybridization, and immunohistochemistry. Current and membrane potential were evaluated with use of recombinant KCNK3- or KCNK9-expressing Xenopus oocytes and Chinese hamster ovary cells. Defecation frequency in rats was measured. HAS dose dependently induced strong propulsive "squeezing" motility, presumably as long-distance contraction (LDC). TRPV1/TRPA1 agonists induced different motility patterns. The effect of HAS was unaltered by TRPV1/TRPA1 antagonists and desensitization. Lidocaine (a nonselective KCNK blocker) and hydroxy-β sanshool (a geometrical isomer of HAS and KCNK3 blocker) also induced colonic motility as a rhythmic propagating ripple (RPR) and a LDC-like motion, respectively. HAS-induced "LDC," but not lidocaine-induced "RPR," was abrogated by a neuroleptic agent tetrodotoxin. KCNK3 and KCNK9 were located mainly in longitudinal smooth muscle cells and in neural cells in the myenteric plexus, respectively. Administration of HAS or TU-100 increased defecation frequency in normal and laparotomy rats. HAS may evoke strong LDC possibly via blockage of the neural KCNK9 channel in the colonic myenteric plexus.
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Affiliation(s)
| | - Nobuhiro Ohtake
- 1Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan;
| | - Katsuya Ohbuchi
- 1Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan; ,2Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan;
| | - Akihito Mase
- 1Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan;
| | - Sachiko Imamura
- 1Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan;
| | - Yuka Sudo
- 2Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan;
| | - Kanako Miyano
- 2Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan;
| | | | - Toru Kono
- 3Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and ,4Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Yasuhito Uezono
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan;
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Contraction of gut smooth muscle cells assessed by fluorescence imaging. J Pharmacol Sci 2015; 127:344-51. [DOI: 10.1016/j.jphs.2015.02.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 01/14/2015] [Accepted: 02/02/2015] [Indexed: 11/20/2022] Open
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Oh JH, Lee YJ. Sample preparation for liquid chromatographic analysis of phytochemicals in biological fluids. PHYTOCHEMICAL ANALYSIS : PCA 2014; 25:314-330. [PMID: 24375623 DOI: 10.1002/pca.2484] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/04/2013] [Accepted: 10/04/2013] [Indexed: 06/03/2023]
Abstract
INTRODUCTION Natural products have been used traditionally for the treatment and prevention of diseases for thousands of years and are nowadays consumed as dietary supplements and herbal medicine. To ensure the safe and effective use of these herbal products, information about bioavailability of active compounds in plasma or target tissues should be provided via validated analytical methods combined with appropriate sampling methods. OBJECTIVE To provide comprehensive and abridged information about sample preparation methods for the quantification of phytochemicals in biological samples using liquid chromatography analysis. METHODS Sample pre-treatment procedures used in analytical methods for in vivo pharmacokinetic studies of natural compounds or herbal medicines were reviewed. These were categorised according to the biological matrices (plasma, bile, urine, faeces and tissues) and sample clean-up processes (protein precipitation, liquid-liquid extraction and solid-phase extraction). RESULTS Although various kinds of sample pre-treatment methods have been developed, liquid-liquid extraction is still widely used and solid-phase extraction is becoming increasingly popular because of its efficiency for extensive clean up of complex matrix samples. However, protein precipitation is still favoured due to its simplicity. CONCLUSION Sample treatment for phytochemical analysis in biological fluids is an indispensable and critical step to obtain high quality results. This step could dominate the overall analytical process because both the duration of the process as well as the reliability of the data depend in large part on its efficiency. Thus, special attention should be given to the choice of a proper sample treatment method that targets analytes and their biomatrix.
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Affiliation(s)
- Ju-Hee Oh
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
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Ueno N, Hasebe T, Kaneko A, Yamamoto M, Fujiya M, Kohgo Y, Kono T, Wang CZ, Yuan CS, Bissonnette M, Chang EB, Musch MW. TU-100 (Daikenchuto) and ginger ameliorate anti-CD3 antibody induced T cell-mediated murine enteritis: microbe-independent effects involving Akt and NF-κB suppression. PLoS One 2014; 9:e97456. [PMID: 24857966 PMCID: PMC4032249 DOI: 10.1371/journal.pone.0097456] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 04/14/2014] [Indexed: 01/09/2023] Open
Abstract
The Japanese traditional medicine daikenchuto (TU-100) has anti-inflammatory activities, but the mechanisms remain incompletely understood. TU-100 includes ginger, ginseng, and Japanese pepper, each component possessing bioactive properties. The effects of TU-100 and individual components were investigated in a model of intestinal T lymphocyte activation using anti-CD3 antibody. To determine contribution of intestinal bacteria, specific pathogen free (SPF) and germ free (GF) mice were used. TU-100 or its components were delivered by diet or by gavage. Anti-CD3 antibody increased jejunal accumulation of fluid, increased TNFα, and induced intestinal epithelial apoptosis in both SPF and GF mice, which was blocked by either TU-100 or ginger, but not by ginseng or Japanese pepper. TU-100 and ginger also blocked anti-CD3-stimulated Akt and NF-κB activation. A co-culture system of colonic Caco2BBE and Jurkat-1 cells was used to examine T-lymphocyte/epithelial cells interactions. Jurkat-1 cells were stimulated with anti-CD3 to produce TNFα that activates epithelial cell NF-κB. TU-100 and ginger blocked anti-CD3 antibody activation of Akt in Jurkat cells, decreasing their TNFα production. Additionally, TU-100 and ginger alone blocked direct TNFα stimulation of Caco2BBE cells and decreased activation of caspase-3 and polyADP ribose. The present studies demonstrate a new anti-inflammatory action of TU-100 that is microbe-independent and due to its ginger component.
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Affiliation(s)
- Nobuhiro Ueno
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois, United States of America
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Takumu Hasebe
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois, United States of America
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Atsushi Kaneko
- Tsumura Research Laboratories, Tsumura and Co., Ami, Ibaraki, 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
| | - 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
| | - Chong-Zhi Wang
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois, United States of America
| | - Chun-Su Yuan
- Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois, United States of America
| | - Marc Bissonnette
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois, United States of America
| | - Eugene B. Chang
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois, United States of America
| | - Mark W. Musch
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, Illinois, United States of America
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Yokoyama Y, Nagino M. Current scenario for the hepatoprotective effects of Inchinkoto, a traditional herbal medicine, and its clinical application in liver surgery: A review. Hepatol Res 2014; 44:384-94. [PMID: 24450947 DOI: 10.1111/hepr.12299] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 01/09/2014] [Accepted: 01/14/2014] [Indexed: 02/08/2023]
Abstract
Inchinkoto (ICKT) is one of the most commonly used herbal medicines as a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. Geniposide, after p.o. intake, is converted to the active metabolite genipin by intestinal bacteria and is absorbed in the portal circulation. The biological properties of ICKT and genipin have been studied in numerous experiments. Administration of ICKT or genipin exerts choleretic effects through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts an anti-apoptotic action through inhibition of transforming growth factor-β1- or tumor necrosis factor-α-dependent signaling pathways. The excessive inflammatory response induced by various hepatic stresses is also attenuated by ICKT pre-administration. Moreover, ICKT upregulates antioxidant enzymes in the liver under conditions of oxidative stress. These experimental results suggest potential benefit of ICKT in liver disease and particularly in hepatic surgery, which justify further well-designed controlled clinical study. To date, however, clinical data regarding the benefit of ICKT for liver surgery are rare. This review article summarized and discussed recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science.
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Affiliation(s)
- Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Munekage M, Ichikawa K, Kitagawa H, Ishihara K, Uehara H, Watanabe J, Kono T, Hanazaki K. Population pharmacokinetic analysis of daikenchuto, a traditional Japanese medicine (Kampo) in Japanese and US health volunteers. Drug Metab Dispos 2013; 41:1256-63. [PMID: 23545807 DOI: 10.1124/dmd.112.050112] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We constructed population pharmacokinetic (PK) models for the five constituents of daikenchuto (DKT), a traditional Japanese herbal medicine. Data were collected from two randomized PK studies conducted in Japan and the United States. Participants received single oral doses of 2.5 g, 5 g, and 10 g of DKT. The plasma concentrations of five DKT constituents--hydroxy-α-sanshool (HAS), hydroxyl-β-sanshool (HBS), 6-shogaol (6S), 10-shogaol (10S), and ginsenoside Rb1 (GRB1)--were determined by liquid chromatography-tandem mass spectrometry. A total of 1859 samples from 55 participants (US, n = 36; Japanese, n = 19) were included in the analysis. Population PK models of HAS, HBS, 6S, and 10S were best described by a one or two-compartment model with a bolus input. On the other hand, the model of GRB1 was best described by a one-compartment model with nonlinear extravascular input. Among the covariates evaluated, body mass index (BMI) and age were found to influence oral clearance (CL/F) and volume of distribution (Vd/F) for HAS and HBS, respectively. The influence of body weight on CL/F and Vd/F for 6S was demonstrated. Marked differences were observed in mean plasma concentrations of HAS and HBS between Japanese and US participants. However, the simulation results indicated that the difference in plasma concentrations may be attributed to the difference in demographic factors such as BMI, body weight, and age, whereas ethnic difference between the Japanese and US participants was considered minimal.
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Hanazaki K, Ichikawa K, Munekage M, Kitagawa H, Dabanaka K, Namikawa T. Effect of Daikenchuto (TJ-100) on abdominal bloating in hepatectomized patients. World J Gastrointest Surg 2013; 5:115-122. [PMID: 23671738 PMCID: PMC3646131 DOI: 10.4240/wjgs.v5.i4.115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Revised: 09/07/2012] [Accepted: 03/09/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the clinical usefulness of Daikenchuto (DKT) in hepatecomized patients.
METHODS: Twenty patients were enrolled with informed consent. Two patients were excluded because of cancelled operations. The remaining 18 patients were randomly chosen for treatment with DKT alone or combination therapy of DKT and lactulose (n = 9, each group). Data were prospectively collected. Primary end points were Visual Analogue Scale (VAS) score for abdominal bloating, total Gastrointestinal Symptoms Rating Scale (GSRS) score for abdominal symptoms, and GSRS score for abdominal bloating.
RESULTS: The VAS score for abdominal bloating and total GSRS score for abdominal symptoms recovered to levels that were not significantly different to preoperative levels by 10 d postoperation. Combination therapy of DKT and lactulose was associated with a significantly poorer outcome in terms of VAS and GSRS scores for abdominal bloating, total GSRS score, and total daily calorie intake, when compared with DKT alone therapy.
CONCLUSION: DKT is a potentially effective drug for postoperative management of hepatectomized patients, not only to ameliorate abdominal bloating, but also to promote nutritional support by increasing postoperative dietary intake.
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Kono T, Kaneko A, Omiya Y, Ohbuchi K, Ohno N, Yamamoto M. Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine. Am J Physiol Gastrointest Liver Physiol 2013; 304:G428-36. [PMID: 23275609 PMCID: PMC3566615 DOI: 10.1152/ajpgi.00356.2012] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161-170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.
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Affiliation(s)
- Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Hisgashi Tokushukai Hospital, Hokkaido, Japan.
| | - Atsushi Kaneko
- 2Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Hokkaido, Japan; and ,3Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan
| | - Yuji Omiya
- 2Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Hokkaido, Japan; and ,3Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan
| | - Katsuya Ohbuchi
- 3Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan
| | - Nagisa Ohno
- 3Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan
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Igarashi Y, Aoki K, Nishimura H, Morishita I, Usui K. Total synthesis of hydroxy-α- and hydroxy-β-sanshool using Suzuki-Miyaura coupling. Chem Pharm Bull (Tokyo) 2012; 60:1088-91. [PMID: 22863716 DOI: 10.1248/cpb.c12-00382] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Here, we describe the first total synthesis of hydroxyl-α- and hydroxyl-β-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-β-sanshool (2) was synthesized by regio- and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.
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Affiliation(s)
- Yasushi Igarashi
- Kampo Formulations Development Center, Tsumura & Co., 3586 Yoshiwara, Ami-mach, Inashiki-gun, Ibaraki 300-1192, Japan.
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Aoki K, Igarashi Y, Nishimura H, Morishita I, Usui K. Application of iron carbonyl complexation to the selective total synthesis of sanshools. Tetrahedron Lett 2012. [DOI: 10.1016/j.tetlet.2012.08.135] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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