Fujii Y.,Kyoto University |
Fujii Y.,Daiichi University of Pharmacy |
Harada K.H.,Kyoto University |
Haraguchi K.,Daiichi University of Pharmacy |
Koizumi A.,Kyoto University
Chemosphere | Year: 2017
We investigated temporal changes of perfluoroalkyl carboxylic acids (PFCAs) with 8–14 carbon atoms (C8 to C14) in duplicate diet and serum samples in Japan. The sum dietary intakes of PFCAs (C8 to C13) in the Kansai and Tohoku region were highest in the 2010s (mean; 177 ng/day for Kansai, 107 ng/day for Tohoku) followed by the 2000s (77 ng/day for Kansai, 34 ng/day for Tohoku) and the 1990s (53 ng/day for Kansai, 58 ng/day for Tohoku), then the 1980s (19 ng/day for Kansai, 23 ng/day for Tohoku). The sum of the serum concentartions (C8 to C13) was also highest in the 2010s (mean; 17 ng/mL for Kansai, 7.4 ng/mL for Tohoku), followed by the 2000s (12 ng/mL for Kansai, 6.3 ng/mL for Tohoku), then the 1990s (6.8 ng/mL for Kansai, 5.5 mg/mL for Tohoku) and the 1980s (3.8 ng/mL for Kansai, 0.4 ng/mL for Tohoku). A positive correlation was observed between dietary intakes and serum concentration for C8 to C11 (r = 0.94, p < 0.05 for C8; r = 0.80, p < 0.05 for C9; r = 0.98, p < 0.05 for C10; and r = 0.84, p < 0.05 for C11). The levels of C8, C9 and C10 in serum and dietary intake in the 2010s were much higher in Kansai than those in Tohoku, although those of C11 did not show such differences. Kansai has a fluoropolymer manufacture known as a specific source of PFOA (C8), and is more urbanized than Tohoku, which may be attributed to the higher levels of PFCAs (C8 to C10). On the other hand, C11 is common to residents in Kansai and Tohoku. © 2017 Elsevier Ltd
Mori T.,Hoshi University |
Shimizu N.,Daiichi University of Pharmacy |
Shibasaki M.,Hoshi University |
Suzuki T.,Hoshi University
Biological and Pharmaceutical Bulletin | Year: 2012
The present study was designed to clarify whether the arachidonic acid cascade contributes to the decreased threshold for pentylenetetrazole-induced seizure under benzodiazepine withdrawal in mice. The seizure threshold for pentylenetetrazole was significantly decreased by the discontinuation of chronic treatment with diazepam. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was significantly suppressed by intracerebroventricular (i.c.v.) pretreatment with the phospholipase A 2 inhibitor quinacrine (30, 100 nmol) and the lipoxygenase inhibitor nordihydroguaiaretic acid (10, 30 nmol). In contrast, the decreased seizure threshold in the diazepam-withdrawal group was intensified by pretreatment with the cyclooxygenase inhibitor diclofenac (56 nmol). These compounds did not alter the threshold for seizure in a control group. These findings suggest that enhancement of the arachidonic acid cascade may contribute to the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. © 2012 The Pharmaceutical Society of Japan.
Wakai E.,Osaka University of Pharmaceutical Sciences |
Aritake K.,Daiichi University of Pharmacy |
Urade Y.,University of Tsukuba |
Fujimori K.,Osaka University of Pharmaceutical Sciences
Biochemical and Biophysical Research Communications | Year: 2017
Prostaglandin (PG) D2 enhanced lipid accumulation in adipocytes. However, its molecular mechanism remains unclear. In this study, we investigated the regulatory mechanisms of PGD2-elevated lipid accumulation in mouse adipocytic 3T3-L1 cells. The Gi-coupled DP2 (CRTH2) receptors (DP2R), one of the two-types of PGD2 receptors were dominantly expressed in adipocytes. A DP2R antagonist, CAY10595, but not DP1 receptor antagonist, BWA868C cleared the PGD2-elevated intracellular triglyceride level. While, a DP2R agonist, 15R-15-methyl PGD2 (15R) increased the mRNA levels of the adipogenic and lipogenic genes, and decreased the glycerol release level. In addition, the forskolin-mediated increase of cAMP-dependent protein kinase A (PKA) activity and phosphorylation of hormone-sensitive lipase (HSL) was repressed by the co-treatment with 15R. Moreover, the lipolysis was enhanced in the adipocyte-differentiated DP2R gene-knockout mouse embryonic fibroblasts. These results indicate that PGD2 suppressed the lipolysis by repression of the cAMP-PKA-HSL axis through DP2R in adipocytes. © 2017 Elsevier Inc.
Takeda S.,Daiichi University of Pharmacy
Yakugaku Zasshi | Year: 2013
Considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, and it has been reported to possess diverse biological activities. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), several studies have investigated whether CBDA itself is biologically active. In the present report, the author summarizes findings indicating that; 1) CBDA is a selective cyclooxygenase-2 (COX-2) inhibitor, and ii) CBDA possesses an anti-migrative potential for highly invasive cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. Further, the author introduces recent findings on the medicinal chemistry and pharmacology of the CBD derivative, CBD-2′,6′-dimethyl ether (CBDD), that exhibits inhibitory activity toward 15- lipoxygenase (15-LOX), an enzyme responsible for the production of oxidized low-density lipoprotein (LDL). These studies establish CBD as both an important experimental tool and as a lead compound for pharmaceutical development. In this review, the author further discusses the potential uses of CBD and its derivatives in future medicines. © 2013 The Pharmaceutical Society of Japan.
Yoshitake T.,Daiichi University of Pharmacy |
Yoshitake T.,Kyushu Central Hospital
Yakugaku Zasshi | Year: 2017
In Japan there are concerns that there will be a surge in social insurance costs such as medical and nursing care expenses as a result of the baby boom generation reaching the late stages of old age (75 years old and beyond) around 2025 (“The 2025 Problem”). In 2012, the “Outline on Social Insurance and Tax Reform” was approved by the Japanese cabinet and government, including “construction of regional comprehensive care”. To promote participation in home medical care by pharmacists, this article presents the roles demanded of pharmacists in regional comprehensive care from the standpoint of physicians, and the discussion of case studies bridging the gap from knowledge learned in lectures to practical applications. In the field of medical education, “The 2023 Problem”, regarding standards of education on a global level, caused medical schools across Japan to scramble for curriculum reform, specifically in the demand for increased time spent in clinical training and the expansion of community-based medical education. The current state of community-based medical education will be reviewed. In light of these developments, “the working group to create home clinical cases for education” was developed by clinical pharmacists in the field and university faculty members at Daiichi University of Pharmacy. © 2017 The Pharmaceutical Society of Japan.
Kobuke Y.,Daiichi University of Pharmacy
Yakugaku Zasshi | Year: 2017
In the pharmaceutical education model core curriculums revision, “basic qualities required as a pharmacist” are clearly shown, and “the method based on learning outcomes” has been adopted. One of the 10 qualities (No. 7. is “Practical ability of the health and medical care in the community”. In the large item “F. Pharmaceutical clinical” of the model core curriculums, “participation in the home (visit) medical care and nursing care” is written in “participation in the health, medical care, and welfare of the community”, and it is an important problem to offer opportunities of home medical care education at university. In our university, we launched a working group to create “home clinical cases for education” from the educational point of view to pharmacy students to learn home medical care, in collaboration with university faculty members and pharmacists, who are practitioners of home care. Through its working group activities, we would like to organize the present conditions and problems of home care education in pharmaceutical education and to examine the possibility of using “home clinical case studies” in home care education at university. © 2017 The Pharmaceutical Society of Japan.
Komatsu T.,Daiichi University of Pharmacy |
Komatsu T.,Duquesne University
Yakugaku Zasshi | Year: 2016
Morphine with its potent analgesic property has been widely used for the treatment of various types of pain. However, the intrathecal (i.t.) administration of morphine at doses far higher than those required for antinociception exhibited nociceptive-related behaviors consisting of scratching, biting and licking, hyperalgesia, and allodynia in mice. Morphine-3-glucuronide (M3G), one of the major metabolites of morphine, has been found to evoke nociceptive behaviors similar to those after high-dose i.t. morphine. It is plausible that M3G may be responsible for nociception seen after high-dose i.t. morphine treatment. This article reviews the potential mechanism of spinally mediated nociceptive behaviors evoked by i.t. M3G in mice. We discuss the possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, dynorphin, and Leu-enkephalin in the primary afferent fibers following i.t. M3G administration. It is possible to speculate that i.t. M3G could indirectly activate NK1, NMDA, and d2-opioid receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The major function of NO is the production of cGMP and the activation of protein kinase G (PKG). The NO-cGMP-PKG pathway plays an important role in M3G-induced nociceptive behavior. The phosphorylation of extracellular signal-related kinase (ERK) in the dorsal spinal cord was also evoked via the NO-cGMP-PKG pathway through the activation of δ2-opioid, NK1, and NMDA receptors, contributing to M3G-induced nociceptive behaviors. The demonstration of a neural mechanism underlying M3G-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses. © 2016 The Pharmaceutical Society of Japan.
Jiang R.,Hokuriku University |
Yamaori S.,Hokuriku University |
Takeda S.,Daiichi University of Pharmacy |
Yamamoto I.,Kyushu University of Health and Welfare |
Watanabe K.,Hokuriku University
Life Sciences | Year: 2011
Aims: Cannabidiol (CBD), one of the major constituents in marijuana, has been shown to be extensively metabolized by experimental animals and humans. However, human hepatic enzymes responsible for the CBD metabolism remain to be elucidated. In this study, we examined in vitro metabolism of CBD with human liver microsomes (HLMs) to clarify cytochrome P450 (CYP) isoforms involved in the CBD oxidations. Main methods: Oxidations of CBD in HLMs and recombinant human CYP enzymes were analyzed by gas chromatography/mass spectrometry. Key findings: CBD was metabolized by pooled HLMs to eightmonohydroxylated metabolites (6α-OH-, 6β-OH-, 7-OH-, 1″-OH-, 2″-OH-, 3″-OH-, 4″-OH-, and 5″-OH-CBDs). Among these metabolites, 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs were the major ones as estimated from the relative abundance of m/z 478, which was a predominant fragment ion of trimethylsilyl derivatives of the metabolites. Seven of 14 recombinant human CYP enzymes examined (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) were capable of metabolizing CBD. The correlations between CYP isoform-specific activities and CBD oxidative activities in 16 individual HLMs indicated that 6β-OH- and 4″-OH-CBDs were mainly formed by CYP3A4, which was supported by inhibition studies using ketoconazole and an anti-CYP3A4 antibody. The correlation and inhibition studies also showed that CBD 6α-hydroxylation was mainly catalyzed by CYP3A4 and CYP2C19, whereas CBD 7-hydroxylation was predominantly catalyzed by CYP2C19. Significance: This study indicated that CBD was extensively metabolized by HLMs. These results suggest that CYP3A4 and CYP2C19 may be major isoforms responsible for 6α-, 6β-, 7-, and/or 4″-hydroxylations of CBD in HLMs. © 2011 Elsevier Inc. All rights reserved.
Ishii Y.,Kyushu University |
Takeda S.,Kyushu University |
Takeda S.,Daiichi University of Pharmacy |
Yamada H.,Kyushu University
Drug Metabolism Reviews | Year: 2010
Drug oxidation and conjugation mediated by cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) have long been considered to take place separately. However, our recent studies have suggested that CYP3A4 specifically associates with UGT2B7 and alters the regioselectivity of morphine glucuronidation. This observation strongly supports the view that there is functional cooperation between P450 and UGT to facilitate multistep drug metabolism. In recent years, accumulating evidence has suggested an interaction between UGT isoforms or between P450 and UGTs and a change in UGT function by protein-protein association. In this review, we summarize these interactions and discuss their relevance to UGT function. © 2010 Informa UK Ltd.
Kuwano S.,Daiichi University of Pharmacy |
Masuda T.,Daiichi University of Pharmacy
Synthesis (Germany) | Year: 2016
The N-heterocyclic carbene (NHC)-catalyzed monoacylation of vicinal diols is described. Monoacylated compounds of 1,2-, 1,3-, and 1,4-diols are obtained in good yields and selectivity under mild reaction conditions at ambient temperature. © Georg Thieme Verlag Stuttgart, New York.