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Takeuchi K.,Kyoto Pharmaceutical University | Takeuchi K.,General Incorporated Association | Satoh H.,General Incorporated Association | Satoh H.,Doshisha Womens College of Liberal Arts
Digestion | Year: 2015

Background/Aims: 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. Methods: Studies were performed in experimental animals. Results: 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. Conclusion: 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.

Takeuchi K.,Kyoto Pharmaceutical University | Takeuchi K.,Doshisha Womens College of Liberal Arts | Takeuchi K.,General Incorporated Association
Journal of Physiology and Pharmacology | Year: 2014

Endogenous prostaglandins (PGs) play a role in modulating mucosal integrity and have various functions in the stomach, with E type PGs being the most effective. PGE2 provides gastric cytoprotection against damage induced in rats by HCl/ethanol, indomethacin, or acid back-diffusion after barrier disruption. These effects were mimicked by EP1 agonists and/or attenuated by an EP1 antagonist, and disappeared in EP1 (-/-) mice. Furthermore, the adaptive cytoprotection induced by a mild irritant was attenuated by the EP1 antagonist and indomethacin. Capsaicin also provides gastric protection against HCl/ethanol, and its action was mitigated by indomethacin and sensory deafferentation, but not by the EP1 antagonist. Similar results were obtained using mice lacking various EP receptor subtypes; i.e., PGE2 failed to provide both direct and adaptive cytoprotection in EP1 (-/-) mice, while capsaicin-induced protection was observed in EP1 (-/-) mice, but disappeared in IP (-/-) mice. The effects of PGE2 on various gastric functions are mediated by different EP receptor subtypes; inhibition of acid secretion (EP3) and motility (EP1), stimulation of mucus secretion (EP4) and HCO3- secretion (EP1), and an increase in mucosal blood flow (EP2/EP4). In conclusion, the presence of EP1 receptors is essential to the protective action of PGE2, either generated endogenously or administered exogenously, against HCl/ ethanol or indomethacin, and this action is functionally associated with the inhibition of gastric motility. Endogenous PGs also contribute to maintaining mucosal integrity after barrier disruption through an increase in mucosal blood flow, which occurs via sensory neurons influenced by activation of the EP1 receptor.

Takeuchi K.,Kyoto Pharmaceutical University | Takeuchi K.,General Incorporated Association
Current Opinion in Pharmacology | Year: 2014

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. © 2014 Elsevier Ltd.

Amagase K.,Kyoto Pharmaceutical University | Nakamura E.,Ajinomoto Co. | Kato S.,Kyoto Pharmaceutical University | Takeuchi K.,Kyoto Pharmaceutical University | Takeuchi K.,General Incorporated Association
Yakugaku Zasshi | Year: 2015

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. © 2015 The Pharmaceutical Society of Japan.

Tozuka Z.,Sekisui Medical Co. | Kusuhara H.,University of Tokyo | Nozawa K.,Sekisui Medical Co. | Hamabe Y.,Accelerator Centre | And 3 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

A study of the pharmacokinetics of 14 C-labeled acetaminophen (AAP) was performed in healthy Japanese subjects receiving an oral microdose of the drug. After separation by high-performance liquid chromatography (HPLC), the levels of AAP and its metabolites in the pooled plasma specimens were quantified using accelerator mass spectrometry (AMS). The total body clearance (CL tot)/bioavailability (F) of AAP was within the variation in the reported values at therapeutic doses, indicating the linearity of AAP pharmacokinetics. AAP-glucuronide (Glu) and AAP-4-O-sulfate satisfied the criteria of safety testing of drug metabolites. AMS could detect AAP-Cys, the active metabolite of AAP conjugated with cysteine, in the urine. Probenecid prolonged the systemic elimination of total radioactivity and caused a marked decrease in AAP-Glu levels in plasma. Probenecid likely inhibited the glucuronidation of AAP and the renal elimination of AAP-4-O-sulfate. Microdosing of 14 C-labeled drug followed by AMS is a powerful tool that can be used in the early phase of drug development for pharmacokinetic analysis of drugs and their metabolites and for detecting the formation of active metabolites in humans. © 2010 American Society for clinical Pharmacology and Therapeutics.

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