Koji Takeuchi

Kyoto Pharmaceutical University, Kioto, Kyōto, Japan

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Publications (444)2365.12 Total impact

  • Koji Takeuchi · Hisayuki Uneyama
    YAKUGAKU ZASSHI 07/2015; 135(6):761-2. DOI:10.1248/yakushi.14-00250-F · 0.26 Impact Factor
  • Kikuko Amagase · Eiji Nakamura · Shinichi Kato · Koji Takeuchi
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    ABSTRACT: Monosodium glutamate (MSG) is known to provide the umami taste in the food. We have recently reported that glutamate has the potential to protect the small intestine against non-steroidal anti-inflammatory drugs (NSAIDs)-induced lesions in rats. In this paper, we examined this protective effect using sodium loxoprofen, one of the NSAIDs frequently used in Asian countries, to determine whether MSG accelerates the healing of loxoprofen-induced small intestinal lesions in rats. Loxoprofen at 60 mg/kg caused hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. These lesions spontaneously healed within 7 days, but this healing process was delayed by repeated administration of loxoprofen at low doses (10, 30 mg/kg) for 5 d after lesion induction. The healing-impairment action of loxoprofen was accompanied by the down-regulation of vascular endothelium-derived growth factor (VEGF) expression and an angiogenic response. The impaired healing caused by loxoprofen was significantly restored by co-treatment with a diet containing 5% MSG for 5 d, accompanied by the enhancement of VEGF expression and angiogenesis. We suggest that daily intake of MSG not only protects the small intestine against NSAIDs-induced damage but also exerts healing-promoting effects on these lesions.
    YAKUGAKU ZASSHI 06/2015; 135(6):779-82. DOI:10.1248/yakushi.14-00250-3 · 0.26 Impact Factor
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    ABSTRACT: We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wild-type mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin-sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE2 produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases.
    Current pharmaceutical design 05/2015; 21(21). DOI:10.2174/1381612821666150514105248 · 3.45 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-320-S-321. DOI:10.1016/S0016-5085(15)31060-X · 16.72 Impact Factor
  • Koji Takeuchi · Hiroshi Satoh
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    ABSTRACT: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. Studies were performed in experimental animals. Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE2, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs. © 2015 S. Karger AG, Basel.
    Digestion 03/2015; 91(3):218-232. DOI:10.1159/000374106 · 2.10 Impact Factor
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    ABSTRACT: We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats. Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L ASA at a rate of 0.4 mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30 mg/kg) was given p.o. 24 h before the perfusion. Rebamipide (3-30 mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion. Slight gastric bleeding or damage was observed with the perfusion of ASA under the stimulation of acid secretion, whereas these responses were significantly increased in the presence of clopidogrel. Both omeprazole and famotidine inhibited acid secretion and prevented these responses to ASA plus clopidogrel. Rebamipide had no effect on acid secretion, but dose-dependently prevented gastric bleeding in response to ASA plus clopidogrel, with the degree of inhibition being almost equivalent to that of the antisecretory drugs, and the same effects were obtained with the gastroprotective drugs, irsogladine and teprenone. These agents also reduced the severity of gastric lesions, although the effects were less than those of the antisecretory drugs. These results suggest that the antiplatelet drug, clopidogrel, increases gastric bleeding induced by ASA under the stimulation of acid secretion, and the gastroprotective drug, rebamipide, is effective in preventing the gastric bleeding induced under such conditions, similar to antisecretory drugs. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    Journal of Gastroenterology and Hepatology 12/2014; 29 Suppl S4(S4):37-46. DOI:10.1111/jgh.12774 · 3.50 Impact Factor
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    ABSTRACT: We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions. Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10°C for 90 min. CRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2 mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI2 analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE2 also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329. These results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI2 /IP receptors and partly by PGE2 /EP4 receptors. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    Journal of Gastroenterology and Hepatology 12/2014; 29 Suppl S4(S4):3-10. DOI:10.1111/jgh.12767 · 3.50 Impact Factor
  • Koji Takeuchi
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    ABSTRACT: Prostaglandin E2 not only prevents NSAID-generated small intestinal lesions, but also promotes their healing. The protective effects of prostaglandin E2 are mediated by the activation of EP4 receptors and functionally associated with the stimulation of mucus/fluid secretions and inhibition of intestinal hypermotility, resulting in the suppression of enterobacterial invasion and iNOS up-regulation, which consequently prevents intestinal lesions. Prostaglandin E2 also promotes the healing of intestinal damage by stimulating angiogenesis through the up-regulation of VEGF expression via the activation of EP4 receptors. These findings have contributed to a further understanding of the mechanisms responsible for ‘protective’ and ‘healing-promoting’ effects of prostaglandin E2 and the development of new strategies for the prophylactic treatment of NSAID-induced enteropathy.
    Current Opinion in Pharmacology 12/2014; 19:38–45. DOI:10.1016/j.coph.2014.07.005 · 4.60 Impact Factor
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    ABSTRACT: Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine γ-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose-dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. Copyright © 2014 Elsevier Inc. All rights reserved.
    Nitric Oxide 11/2014; 46. DOI:10.1016/j.niox.2014.11.001 · 3.52 Impact Factor
  • Koji Takeuchi · Jian-Ying Wang
    Current Opinion in Pharmacology 10/2014; 19. DOI:10.1016/j.coph.2014.09.014 · 4.60 Impact Factor
  • Koji Takeuchi · Eitaro Aihara
    Capsaicin - Sensitive Neural Afferentation and the Gastrointestinal Tract: from Bench to Bedside, Edited by Gyula Mozsik, Omar M. E. Abdel- Salam, Koji Takeuchi, 07/2014: chapter 6; InTech., ISBN: 978-953-51-1631-8
  • Koji Takeuchi · Shinichi Takayama · Chitose Izuhara
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    ABSTRACT: Aims: The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats. Main methods: The stomach was perfused with acidified ASA at a rate of 0.4 ml/min for 60 min under urethane anesthesia, and gastric bleeding was measured as the concentration of hemoglobin in the luminal perfusate, which was collected every 15 min. Clopidogrel (10-100mg/kg), ticlopidine (10-300 mg/kg), or cilostazol (3-30 mg/kg) was given p.o. 24h or 90 min before the perfusion of acidified ASA, respectively. Key findings: Perfusion of the stomach with acidified ASA alone led to slight bleeding and lesions in the stomach. The pretreatment with clopidogrel, even though it did not cause bleeding or damage by itself, dose-dependently increased the gastric bleeding and ulcerogenic responses induced by acidified ASA. Ticlopidine also aggravated the severity of damage by increasing gastric bleeding, and the effects of ticlopidine at 300 mg/kg were equivalent to those of clopidogrel at 100mg/kg. In contrast, cilostazol dose-dependently decreased gastric bleeding and damage in response to acidified ASA. Significance: These results demonstrated that clopidogrel and ticlopidine, P2Y12 receptor inhibitors, increased gastric bleeding and ulcerogenic responses to acidified ASA, to the same extent, while cilostazol, a phosphodiesterase III inhibitor, suppressed these responses. Therefore, cilostazol may be safely used in dual anti-platelet therapy combined with ASA, without increasing the risk of gastric bleeding.
    Life Sciences 06/2014; 37(8). DOI:10.1016/j.lfs.2014.06.017 · 2.70 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-508. DOI:10.1016/S0016-5085(14)61838-2 · 16.72 Impact Factor
  • Koji Takeuchi · Fumitake Ise · Eitaro Aihara · Shusaku Hayashi
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    ABSTRACT: We examined the effect of H2S on duodenal HCO3- secretion in rats and investigated the mechanism involved in this response. Animals were fasted overnight and anesthetized with urethane. A duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH stat-method. The loop was perfused at a rate of 0.2 mL/min with NaHS (H2S donor) for 5 min or 10 mM HCl for 10 min. Indomethacin or l-NAME was given s.c. 30 min or 3 h, respectively, before NaHS or acidification, while glibenclamide (KATP channel blocker) or propargylglycine (cystathionine-g-lyase inhibitor) was given i.p. 30 min before. Mucosal perfusion with NaHS dose-dependently increased the HCO3- secretion, and this effect was significantly attenuated by indomethacin and l-NAME as well as sensory deafferentation, but not by glibenclamide. Mucosal PGE2 and NO production were both increased by NaHS perfusion. Mucosal acidification stimulated HCO3- secretion concomitant with increase in PGE2 and NO production, and these responses were mitigated by propargylglycine. The duodenal damage induced by acid (100 mM HCl for 4 h) was aggravated by pretreatment with propargylglycine. These results suggest that H2S increases HCO3- secretion in the duodenum, and this action is partly mediated by PG and NO as well as by capsaicin-sensitive afferent neurons. It is assumed that endogenous H2S is involved in the regulatory mechanism of acid-induced HCO3- secretion and mucosal protection in the duodenum.
    Nitric Oxide; 05/2014
  • Koji Takeuchi · Kikuko Amagase · Hiroshi Satoh
    Gastroenterology 05/2014; 146(5):S-506. DOI:10.1016/S0016-5085(14)61830-8 · 16.72 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-699. DOI:10.1016/S0016-5085(14)62540-3 · 16.72 Impact Factor
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    ABSTRACT: Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of ClC-2/CFTR chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male SD rats were administered indomethacin (10 mg/kg) p.o. and killed 24 h later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1mg/kg) was administered p.o. in a single injection 30 min before the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of iNOS and TNFα mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the co-administration of AE3-208, a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggested that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/TNFα expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is unlikely to have contributed to the protective effects of lubiprostone.
    Journal of Pharmacology and Experimental Therapeutics 04/2014; 349(3). DOI:10.1124/jpet.114.213991 · 3.97 Impact Factor
  • Source
    Koji Takeuchi · Kenji Nagahama
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    ABSTRACT: Esophagitis was induced in rats within 3 h by ligating both the pylorus and transitional region between the forestomach and glandular portion under ether anesthesia. This esophageal injury was prevented by the administration of acid suppressants and antipepsin drug and aggravated by exogenous pepsin. Damage was also aggravated by pretreatment with indomethacin and the selective COX-1 but not COX-2 inhibitor, whereas PGE2 showed a biphasic effect depending on the dose; a protection at low doses, and an aggravation at high doses, with both being mediated by EP1 receptors. Various amino acids also affected this esophagitis in different ways; L-alanine and L-glutamine had a deleterious effect, while L-arginine and glycine were highly protective, both due to yet unidentified mechanisms. It is assumed that acid/pepsin plays a major pathogenic role in this model of esophagitis; PGs derived from COX-1 are involved in mucosal defense of the esophagus; and some amino acids are protective against esophagitis. These findings also suggest a novel therapeutic approach in the treatment of esophagitis, in addition to acid suppressant therapy. The model introduced may be useful to test the protective effects of drugs on esophagitis and investigate the mucosal defense mechanism in the esophagus.
    02/2014; 2014:532594. DOI:10.1155/2014/532594
  • Chapter: Organoid
    Eitaro Aihara · Marshall H. Montrose · Koji Takeuchi
    G.I. Research, 01/2014: pages 100-102; SENTAN IGAKU-SHA.
  • Source
    Hiroshi Satoh · Kikuko Amagase · Koji Takeuchi
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    ABSTRACT: Antisecretory drugs such as histamine H2-receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by NSAIDs. However, it has recently been reported that these drugs exacerbate NSAID-induced small intestinal lesions in rats. Unfortunately, there are few effective agents for the treatment of this complication. We examined the effects of mucosal protective agents (MPAs), misoprostol, irsogladine and rebamipide, and mucin of porcine stomach on diclofenac-induced intestinal lesions and the exacerbation of the lesions by ranitidine or omeprazole. The effects of the drugs on intestinal motility and mucus distribution/content were also examined. Male Wistar rats (180-220 g) were used. Each drug was administered orally under fed conditions. Diclofenac (1-10 mg/kg) produced multiple lesions in the small intestine dose-dependently. Both ranitidine (30) and omeprazole (100) significantly increased the intestinal lesions induced by low doses (3 and 6) of diclofenac. All of misoprostol (0.03-0.3), irsogladine (3-30) and rebamipide (30-300) as well as mucin (30-300) inhibited the formation of intestinal lesions caused by a high dose (10) of diclofenac alone and prevented the exacerbation of diclofenac-induced lesions by antisecretory drugs. Diclofenac (10) markedly increased the intestinal motility and decreased the mucosal mucus, and the decrease of mucus was significantly inhibited by the MPAs. These results indicate the usefulness of the MPAs for the treatment of intestinal lesions induced by NSAIDs alone or by co-administration with antisecretory drugs, and suggest that mucus plays an important role in the protection of intestinal mucosa by the MPAs.
    Journal of Pharmacology and Experimental Therapeutics 11/2013; 59(8). DOI:10.1124/jpet.113.208991 · 3.97 Impact Factor

Publication Stats

5k Citations
2,365.12 Total Impact Points


  • 1987–2015
    • Kyoto Pharmaceutical University
      • Laboratory of Pharmacology and Experimental Therapeutics
      Kioto, Kyōto, Japan
  • 2001–2002
    • Osaka City University
      • Department of Gastroenterology
      Ōsaka, Ōsaka, Japan
  • 2000–2001
    • Kyoto University
      Kioto, Kyōto, Japan
  • 1977
    • Bunkyo University
      Edo, Tōkyō, Japan
  • 1974–1977
    • The University of Tokyo
      • Department of Pharmaceutical Sciences
      Tōkyō, Japan