Shionogi Research Laboratories

Toyonaka, Japan

Shionogi Research Laboratories

Toyonaka, Japan
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Fukumori S.,Community Pharmacy | Tsuji Y.,University of Toyama | Mizoguchi A.,Sasebo Chuo Hospital | Kasai H.,University of Toyama | And 5 more authors.
Journal of Clinical Pharmacy and Therapeutics | Year: 2016

What is known and objective: The pharmacokinetic–pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24)/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24/MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the ‘area under the trough level’ (AUTL) and the ‘area above the trough level’ (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Methods: The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24. Results and discussion: Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24. The optimal cut-off value of AUTL was 331 μg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 μg/mL. What is new and conclusion: Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 μg/mL, this level should ideally not be exceeded. © 2016 John Wiley & Sons Ltd

Isobe Y.,University of Tokyo | Arita M.,University of Tokyo | Arita M.,Japan Science and Technology Agency | Iwamoto R.,University of Tokyo | And 6 more authors.
Journal of Biochemistry | Year: 2013

Uncontrolled inflammation is now considered to be a link between many widely occurring diseases. Thus, controlling the innate inflammatory response and its local chemical mediators has been receiving increasing attention. We recently identified a novel family of eicosapentaenoic acid (EPA)-derived mediators produced by eosinophils, denoted as resolvin E3 (RvE3), that possess potent anti-inflammatory actions both in vitro and in vivo. Carbons at 17 and 18 positions are asymmetric and thus the molecule has a total of four potential stereoisomers. Here, we assigned the stereochemistry of the conjugated double bonds and chirality of alcohols present in two natural isomers of RvE3 with four different stereoisomers prepared by total organic synthesis. The complete structures of two natural isomers of RvE3 were determined to be 17R,18S-and 17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-EPA, respectively. These natural isomers prepared by total organic synthesis displayed a potent anti-inflammatory action by limiting neutrophil infiltrations both in vitro and in vivo. The unnatural stereoisomers were much less active compared with the natural isomers, demonstrating the stereoselective action of RvE3. © 2012 The Authors.

Isobe Y.,University of Tokyo | Arita M.,University of Tokyo | Arita M.,Japan Science and Technology Agency | Matsueda S.,University of Tokyo | And 11 more authors.
Journal of Biological Chemistry | Year: 2012

Bioactive mediators derived from omega-3 eicosapentaenoic acid (EPA) elicit potent anti-inflammatory actions. Here, we identified novel EPA metabolites, including 8,18-dihydroxyeicosapentaenoic acid (8,18-diHEPE), 11,18-diHEPE, 12,18-di- HEPE, and 17,18-diHEPE from 18-HEPE. Unlike resolvins E1 and E2, both of which are biosynthesized by neutrophils via the 5-lipoxygenase pathway, these metabolites are biosynthesized by eosinophils via the 12/15-lipoxygenase pathway. Among them, two stereoisomers of 17,18-diHEPE, collectively termed resolvin E3 (RvE3), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The planar structure of RvE3 was unambiguously determined to be 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-EPE by high resolution NMR, and the two stereoisomers were assigned to have 17,18R- and 17,18S-dihydroxy groups, respectively, using chemically synthesized 18R- and 18S-HEPE as precursors. Both 18R- and 18S-RvE3 inhibited neutrophil chemotaxis in vitro at low nanomolar concentrations. These findings suggest that RvE3 contributes to the beneficial actions of EPA in controlling inflammation and related diseases. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Kubota T.,University of Tokyo | Arita M.,University of Tokyo | Arita M.,Japan Science and Technology Agency | Isobe Y.,University of Tokyo | And 8 more authors.
FASEB Journal | Year: 2014

Eicosapentaenoic acid (EPA) has beneficial effects in many inflammatory disorders. In this study, dietary EPA was converted to 17,18- epoxyeicosatetraenoic acid (17,18-EpETE) by ω-3 epoxygenation in the mouse peritoneal cavity. Mediator lipidomics revealed a series of novel oxygenated metabolites of 17,18-EpETE, and one of the major metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in murine zymosan-induced peritonitis. 12-OH-17,18-EpETE inhibited leukotriene B4-induced neutrophil chemotaxis and polarization in vitro in a low nanomolar range (EC50 0.6 nM). The complete structures of two natural isomers were assigned as 12S-OH-17R,18S-EpETE and 12S-OH-17S,18REpETE, using chemically synthesized stereoisomers. These natural isomers displayed potent anti-inflammatory action, whereas the unnatural stereoisomers were essentially devoid of activity. These results demonstrate that 17,18-EpETE derived from dietary EPA is converted to a potent bioactive metabolite 12-OH-17,18-EpETE, which may generate an endogenous anti-inflammatory metabolic pathway. © FASEB.

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