Okayama University Medical School Acta Medica Okayama 0386-300X 78 3 2024 Effect of Lipopolysaccharide on the Duration of Zolpidem-Induced Loss of Righting Reflex in Mice 227 235 EN Yudai Wada Department of Clinical Pharmacy, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soichiro Ushio Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshito Zamami Department of Clinical Pharmacy, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/67197 Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl− cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl− cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression. No potential conflict of interest relevant to this article was reported.

Frontiers Media S.A. Acta Medica Okayama 1663-9812 13 2022 Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition 890048 EN Soichiro Ushio Department of Pharmacy, Okayama University Hospital Yudai Wada Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuki Nakamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daiki Matsumoto Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Hoshika Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shoya Shiromizu Department of Pharmacy, Okayama University Hospital Naohiro Iwata Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Makoto Kajizono Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 mu g/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 76 2 2022 Retrospective Cohort Study of Clinical Efficacy and Safety of Cefozopran for Treating Febrile Neutropenia during Chemotherapy in Patients with Lung Cancer 167 172 EN Tsukasa Higashionna Department of Pharmacy, Okayama University Hospital Soichiro Ushio Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Kiminaka Murakawa Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Original Article 10.18926/AMO/63410 Febrile neutropenia (FN) is a serious side effect in patients undergoing cancer chemotherapy and frequently proves fatal. Since infection control is crucial in the management of FN, the antimicrobial agent cefozopran (CZOP) has been recommended but not approved for routine use in clinical care of FN in Japan. However, few studies of CZOP in the management of FN have used a thrice daily dose schedule. The aim of this study was to retrospectively compare the efficacy and safety of CZOP at a dose of 1 g three times daily to those of cefepime (CFPM) in the treatment of FN in our lung cancer patients. The response rates of the CZOP and CFPM groups were 89.5% (17/19 cases) and 83.0% (39/47 cases), respectively, with no significant difference between the two groups. The median duration of antimicrobial treatment was 6 days (4-10 days) in the CZOP group and 7 days (3-13 days) in the CFPM group, with no significant difference between groups. The incidence rates of adverse events were 21.1% (4/19 cases) in the CZOP group and 19.1% (9/47 cases) in the CFPM group. No adverse events of Grade 3 or higher were observed in either group. The findings of the present study suggest that CZOP administration at a dose of 1 g three times per day as an antimicrobial treatment alternative against FN. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 20 3 2019 Region-Specific Neuroprotective Features of Astrocytes against Oxidative Stress Induced by 6-Hydroxydopamine 598 EN Masato Asanuma Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences Nao Okumura-Torigoe Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences Ikuko Miyazaki Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences Shinki Murakami Department of Medical Neurobiology, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medical, Dental and Pharmaceutical Sciences In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes. No potential conflict of interest relevant to this article was reported.

Nature Research Acta Medica Okayama 2045-2322 10 1 2020 Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection 20698 EN Ryo Kikuoka Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ikuko Miyazaki Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Natsuki Kubota Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Megumi Maeda Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daiki Kagawa Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masaaki Moriyama Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Asuka Sato Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shinki Murakami Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masato Asanuma Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 6 2020 Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance 545 550 EN Yasuhisa Tatebe Department of Pharmacy, Okayama University Hospital Kiichiro Kanamitsu Department of pediatrics, Okayama University Hospital Hirotaka Kanzaki Department of Pharmacy, Okayama University Hospital Hisashi Ishida Department of pediatrics, Okayama University Hospital Kaori Fujiwara Department of pediatrics, Okayama University Hospital Kana Washio Department of pediatrics, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Akira Shimada Department of pediatrics, Okayama University Hospital Hirokazu Tsukahara Department of pediatrics, Okayama University Hospital Case Report 10.18926/AMO/61215 Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 4 2020 Immobility-reducing Effects of Ketamine during the Forced Swim Test on 5-HT1A Receptor Activity in the Medial Prefrontal Cortex in an Intractable Depression Model 301 306 EN Kei Takahashi Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soichiro Ushio Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/60368 Ketamine has been clinically proven to ameliorate depression, including treatment-resistant depression. The detailed mechanism of action of ketamine in treatment-resistant depression remains unclear. We examined the effects of ketamine on the immobility times of adrenocorticotropic hormone (ACTH)-treated rats during the forced swim test, and we explored the mechanism by which ketamine acts in this model. We investigated the neuroanatomical site of action by microinjecting ketamine into the medial prefrontal cortex of rats. A significant reduction of the rats’ immobility during the forced swim test was observed after the intraperitoneal injection of ketamine in both saline- and ACTH-treated rats. The microinjection of ketamine into the medial prefrontal cortex also decreased immobility during the forced swim test in both saline- and ACTH-treated rats. The immobility-decreasing effect of intraperitoneally injected ketamine was blocked by administering WAY100635, a 5-HT1A receptor antagonist, into the medial prefrontal cortex. These findings contribute to the evidence that ketamine can be useful against treatment-resistant depressive conditions. The immobility-reducing effects of ketamine might be mediated by 5-HT1A receptor activity in the medial prefrontal cortex. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 2055-0294 6 1 2020 Development of an appropriate simple suspension method for valganciclovir medication 16 EN Yasuyuki Masaoka Department of Pharmacy, Okayama University Hospital Yoichi Kawasaki Department of Pharmacy, Okayama University Hospital Ryo Kikuoka Department of Clinical Pharmacy,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Atsushi Ogawa Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Yudai Wada Department of Clinical Pharmacy,Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Soichiro Ushio Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Background</br> Valganciclovir (VGC) is essential for preventing cytomegalovirus infections after transplants in adult and pediatric patients. In pediatric patients, VGC tablets have to be pulverized so that they can be delivered via nasogastric tubes. The “simple suspension method” is usually used to suspend tablets in hot water in Japan. However, the optimal suspension conditions and metering methods for preparing VGC suspensions using the simple suspension method are unclear. The purpose of this study was to clarify these issues.</br> Methods</br> VGC tablets were suspended in water (initial water temperature: 25 °C or 55 °C) using the simple suspension method. The residual rate of VGC after it had been suspended in hot water was determined using HPLC. In addition, the suspended solution was passed through 6, 8, and 12 Fr. gavage tubes. The VGC concentrations of suspensions produced using different preparation methods were also determined using HPLC.</br> Results</br> Cracking the surfaces of VGC tablets and suspending them in water at an initial temperature of 55 °C was effective at dissolving the tablets. The VGC concentration of the suspension remained stable for at least 80 min. Furthermore, the VGC concentration remained stable for 48 h during cold dark storage. Cracking the surfaces of VGC tablets could be a more effective metering method than preparing powder from VGC tablets. In addition, little VGC remained in 6, 8, or 12 Fr. gavage tubes after VGC solution was passed through them.</br> Conclusion</br> The amount of VGC should be measured carefully when preparing VGC solutions using the simple suspension method. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 132 1 2020 薬物相互作用（47―全身麻酔薬の薬物相互作用） 29 33 EN Yusuke Igawa Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1347-9032 111 3 2019 YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers 849 856 EN Tatsuaki Takeda Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Hiromasa Yamamoto Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ken Suzawa Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shuta Tomida Center for Comprehensive Genomic Medicine, Okayama University Hospital Shunsaku Miyauchi Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kota Araki Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kentaro Nakata Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akihiro Miura Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kei Namba Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junichi Soh Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadahiko Shien Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Shinichi Toyooka Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 131 3 2019 薬物相互作用（46―注射薬の配合変化 : 注射薬の物理的・化学的な相互作用） 161 164 EN Yosuke Morishita Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Shigeki Nishihara Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

BMJ Publishing Group Acta Medica Okayama 2044-6055 9 12 2019 Fall-related mortality trends in older Japanese adults aged >= 65 years: a nationwide observational study e033462 EN Hideharu Hagiya Department of General Internal Medicine, Osaka University Hospital Toshihiro Koyama Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yoshito Zamami Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School Yasuhisa Tatebe Department of Pharmacy, Okayama University Hospital Tomoko Funahashi Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Kazuaki Shinomiya Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences Tokushima Bunri University Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Shiro Hinotsu Department of Biostatistics, Sapporo Medical University Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Hiromi Rakugi Department of General Internal Medicine, Osaka University Hospital Mitsunobu R. Kano Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University OBJECTIVES:<br/> Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016.<br/> DESIGN:<br/> We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare.<br/> RESULTS:<br/> The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change (APC). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average APC among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women.<br/> CONCLUSIONS:<br/> Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2045-2322 9 2019 Place of death trends among patients with dementia in Japan: a population-based observational study 20235 EN Toshihiro Koyama Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Misato Sasaki Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Hideharu Hagiya Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yoshito Zamami Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School Tomoko Funahashi Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Ayako Ohshima Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yasuhisa Tatebe Department of Pharmacy, Okayama University Hospital Naoko Mikami Division of Pharmacy, Chiba University Hospital Kazuaki Shinomiya Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital Shiro Hinotsu Department of Biostatistics, Sapporo Medical University Mitsunobu R. Kano Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Dementia is a major public health concern in ageing societies. Although the population of Japan is among the most aged worldwide, long-term trends in the place of death (PoD) among patients with dementia is unknown. In this Japanese nationwide observational study, we analysed trends in PoD using the data of patients with dementia who were aged >= 65 years and died during 1999-2016. Trends in the crude death rates and PoD frequencies were analysed using the Joinpoint regression model. Changes in these trends were assessed using the Joinpoint regression analysis in which significant change points, the annual percentage change (APC) and average APCs (AAPC) in hospitals, homes, or nursing homes were estimated. During 1999-2016, the number of deaths among patients with dementia increased from 3,235 to 23,757 (total: 182,000). A trend analysis revealed increased mortality rates, with an AAPC of 8.2% among men and 9.3% among women. Most patients with dementia died in the hospital, although the prevalence of hospital deaths decreased (AAPC: -1.0%). Moreover, the prevalence of nursing home deaths increased (AAPC: 5.6%), whereas the prevalence of home deaths decreased (AAPC: -5.8%). These findings support a reconsideration of the end-of-life care provided to patients with dementia. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 01970186 132 2020 Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes 104608 EN Nami Isooka Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ikuko Miyazaki Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryo Kikuoka Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kouichi Wada Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Erika Nakayama Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kotaro Shin Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daichi Yamamoto Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masato Asanuma Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 129 2 2017 薬物相互作用 (39―前立腺がん治療薬と薬物相互作用) 131 136 EN Hirotaka Kanzaki Department of Pharmacy, Okayama University Hospital Yuta Tanaka Department of Pharmacy, Okayama University Hospital Akinori Maruo Department of Pharmacy, Okayama University Hospital Shigeki Nishihara Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

Springer Acta Medica Okayama 2210-7703 37 6 2015 Exploring autistic-like traits relating to empathic attitude and psychological distress in hospital pharmacists 1258 1266 EN Yuji Higuchi Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yosuke Uchitomi Innovation Center for Supportive, Palliative and Psychosocial CareNational Cancer Center Maiko Fujimori Center for Suicide Prevention, National Institute of Mental HealthNational Center for Neurology and Psychiatry Toshihiro Koyama Department of Clinical PharmacyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hitomi Kataoka Department of Primary Care and Medical EducationOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yoshihisa Kitamura Department of Clinical PharmacyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toshiaki Sendo Department of Clinical PharmacyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Masatoshi Inagaki Department of NeuropsychiatryOkayama University Hospital BACKGROUND: Pharmacists are expected to play a key role in modern cancer care. Research suggests that an empathic approach and attitude in medical staff improves the quality of patient care. An empathic attitude and psychological distress are thought to be associated with autistic-like traits, but little is known about such traits. OBJECTIVE: In this study, we aimed to clarify the associations among autistic-like traits, empathic attitude in a medical context, and psychological health in hospital pharmacists. SETTING: Eligibility criteria for inclusion were certified pharmacists working at hospitals for patient care who returned their questionnaires. METHOD: Eight hundred and twenty-three hospital pharmacists completed a number of self-administered questionnaires anonymously by mail. MAIN OUTCOME MEASURES: Scores were obtained on the Autism-Spectrum Quotient, the Jefferson Scale of Empathy, the General Health Questionnaire-12, and subscales of the Interpersonal Reactivity Index (Perspective Taking, IRI-Empathic Concern, IRIPersonal Distress). We performed correlation and mediation analyses to confirm that the empathy and general health questionnaires were associated with autism-spectrum quotient scores, and with each IRI subscale. RESULTS: Complete responses were obtained from 379 pharmacists comprising 151 males (39.8 %) with a mean age of 37.7 ± 10.8 years (missing data, n = 13) and a median of 11 years after qualification as a pharmacist. Autism-Spectrum Quotient scores were inversely correlated with empathy (r = -0.22, p < 0.001) and positively correlated with general health scores (r = 0.40, p < 0.001). In the models with mediation, the inverse correlation between autism-spectrum quotient and empathy scores was mediated indirectly by IRI-Perspective Taking and IRI-Empathic Concern, and the positive correlation between autism-spectrum quotient and general health was mediated indirectly by IRI-Personal Distress. There were also direct effects, with significant effects of autism-spectrum quotient on empathy and general health scores. CONCLUSION: Our findings suggest that autistic-like traits affect both empathic attitude in a medical context and the psychological health of pharmacists. We recommend that to improve empathy in those with high levels of autistic-like traits, we may need to develop specialized interventions, such as improving communication skills training. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 129 1 2017 薬物相互作用 （ 38 - 新規睡眠薬 : ラメルテオン, スボレキサントの相互作用） 53 57 EN Kazuko Kubo Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 3 2016 薬物相互作用（37―新規Ｃ型肝炎治療薬の相互作用） 231 235 EN Masashi Miyamoto Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 2 2016 薬物相互作用（36―肺癌領域における経口分子標的治療薬） 141 146 EN Tsukasa Higashionna Department of Pharmacy, Okayama University Hospital Satoru Esumi Department of Pharmacy, Okayama University Hospital Yoshihisa Kitamura Department of Pharmacy, Okayama University Hospital Toshiaki Sendo Department of Pharmacy, Okayama University Hospital No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 128 1 2016 薬物相互作用 (35―オピオイド鎮痛薬の薬物相互作用） 53 59 EN Hikaru Sada Makoto Kajizono Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 3 2015 薬物相互作用 (34―食事と薬の薬物相互作用） 245 249 EN Hayato Hino Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 2 2015 薬物相互作用（33―抗菌薬の薬物相互作用） 151 154 EN Ken Tasaka Naoko Shiraishi Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

日本静脈経腸栄養学会 Acta Medica Okayama 1344-4980 29 4 2014 粉砕法による経管投与における薬剤量損失に対する簡易懸濁法の有用性についての検討 1027 1033 EN Yoshito Zamami Toshihiro Koyama Tetsuya Aiba Manabu Amano Tetsuaki Ando Naomi Kurata Hideki Nawa Hironori Nakura Yoshihisa Kitamura Toshiaki Sendo 【目的】従来の薬剤経管投与法である粉砕法は薬効の減少につながる薬剤量の損失が指摘されている。そこで粉砕法による薬剤量損失に対する簡易懸濁法の有用性について検討した。 【方法】頻繁に粉砕指示がなされる5種類の薬剤を用いて粉砕・分包による薬物含量減少、薬剤調製時の懸濁性および実際の経管投与を想定した薬物含量について2つの方法を比較した。 【結果】薬剤を粉砕・分包するとそれぞれの薬物含量は減少した。またワーファリン®錠を粉砕して水に溶解すると完全には懸濁せず、小さな塊が生じたが、簡易懸濁法では均一に懸濁した。ワーファリン®錠の経管投与を想定した実験において粉砕法では薬物含量が大幅に減少したが、簡易懸濁法では、ほとんど損失が認められなかった。【結論】簡易懸濁法は粉砕法に比べて薬剤損失の面で有用性が高いことが示唆され、ワーファリン®錠のように安定性が悪い薬剤では特に適正な薬物投与に貢献出来ると考えられる。 No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 1 2015 薬物相互作用 (32―新規経口抗凝固薬における薬物相互作用） 59 61 EN Hiromi Ida Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 3 2014 薬物相互作用 (31―乳がんホルモン療法における薬物相互作用） 245 248 EN Yasuyuki Masaoka Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 5 2014 Characteristics of the Runway Model of Intracranial Self-stimulation Behavior and Comparison with Other Motivated Behaviors 255 262 EN Satoru Esumi Yoichi Kawasaki Yutaka Gomita Yoshihisa Kitamura Toshiaki Sendo Review 10.18926/AMO/52893 Motivation incorporates several psychological aspects that produce reward-related and learning behaviors. Although reward-related behavior is reported to be mediated by the dopaminergic reward pathway, the involvement of dopaminergic systems in motivated behavior has not been fully clarified. Several experimental methodologies for motivational behavior have been reported, but pharmacological characteristics seem to vary among these methodologies. In this review, we attempt to summarize three main concepts:(1) the relationship of dopamine neuron physiology with motivated behavior, (2) the pharmacological characteristics of the runway intracranial self-stimulation model, and (3) the behavioral distinction of disparate motivated behaviors. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 2 2014 薬物相互作用 (30―慢性疼痛治療薬の相互作用） 159 163 EN Atsushi Ogawa Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 126 1 2014 薬物相互作用(29―ステロイドの薬物相互作用） 59 63 EN Youko Hayashi Hideki Nawa Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 3 2013 薬物相互作用 (28―過活動膀胱治療薬の薬物相互作用） 259 262 EN Yusuke Haruta Yoichi Kawasaki Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 67 5 2013 Preparation of Enteric-coated Capsules of Beclomethasone Dipropionate for Patients with Intestinal Graft-versus-Host Disease and a Case Study 319 324 EN Kiminaka Murakawa Tomoaki Sato Yoshinobu Maeda Yoshihisa Kitamura Mitsune Tanimoto Toshiaki Sendo Case Report 10.18926/AMO/51868 Graft-versus-host disease (GVHD) is a major concern in transplantation patients. Gut GVHD is accompanied by diarrhea, abdominal pain, and/or melena. Although oral treatment with corticosteroids (CSs) is effective in treating gut GVHD, it can cause adverse reactions that affect the entire body. Topical administration of CSs can be effective in treating diseases in which lesions are limited locally, because adverse reactions can then be alleviated. In this study, we examine and discuss an enteric-coated beclomethasone dipropionate (BDP) capsule (BDP-EC) formulated at Okayama University Hospital. The BDP-EC did not dissolve in solution 1 (pH1.2), and began disintegrating in solution 2 (pH6.8) after 5min, with a mean dissolution rate at 15min of 85%. We then used the capsule to treat a patient who developed gut GVHD after allogeneic hematopoietic stem cell transplantation. Clinically, the frequency of diarrhea decreased after BDP-EC administration. In addition, we were able to decrease the prednisolone equivalent dose. Symptoms associated with adverse reactions to BDP were not observed during the hospitalization period. These findings suggest that the administration of BDP-EC in the early stages of gut GVHD may allow a reduction in the initial doses of systemic CSs. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 2 2013 薬物相互作用（27―がん化学療法における制吐剤の薬物相互作用） 163 167 EN Yasuko Kurata Satoko Fujiwara Makoto Kajizono Megumu Aoyagi Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 1 2013 薬物相互作用(26―高尿酸血症治療薬の薬物相互作用） 73 75 EN Takashi Makita Yoshihisa Kitamura Toshiaki Sendo No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 64 4 2010 Effects of Imipramine and Lithium on the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in Adrenocorticotropic Hormone-treated Rats 219 223 EN Maho Doi Ikuko Miyazaki Tomoko Nagamachi Kazuaki Shinomiya Hisashi Matsunaga Toshiaki Sendo Hiromu Kawasaki Masato Asanuma Yutaka Gomita Yoshihisa Kitamura Original Article 10.18926/AMO/40129 We examined the influence of chronic adrenocorticotropic hormone (ACTH) treatment on the number of Ki-67-positive cells in the dentate gyrus of the hippocampus in rats. ACTH treatment for 14 days decreased the number of such cells. The administration of imipramine or lithium alone for 14 days had no effect in saline-treated rats. The effect of ACTH was blocked by the administration of imipramine. Furthermore, the coadministration of imipramine and lithium for 14 days significantly increased the number of Ki-67-positive cells in both the saline and ACTH-treated rats. The coadministration of imipramine and lithium normalized the cell proliferation in the dentate gyrus of the hippocampus in rats treated with ACTH. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 89 3 2008 Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment–resistant depression: Involvement of 5-HT 2A receptors? EN Yoshihisa Kitamura Kozue Akiyama Kouhei Kitagawa Kazuhiko Shibata Hiromu Kawasaki Katsuya Suemaru Hiroaki Araki Toshiaki Sendo Yutaka Gomita <p>The use of carbamazepine has been reported to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test (FST) are blocked by chronic treatment with adrenocorticotropic hormone (ACTH). In the present study, we examined the effect of the chronic administration of carbamazepine on the FST and the wet-dog shakes induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aiminopropane (DOI), a 5-HT2A receptor agonist, in ACTH-treated rats. Chronic administration of carbamazepine did not affect the duration of immobility in saline-treated and ACTH-treated rats. The reduction of immobility, induced by chronic administration of imipramine, was blocked by treatment with ACTH. When carbamazepine was administered concurrently with imipramine, we observed a significant decrease in immobility in rats treated with ACTH. Chronic ACTH treatment increased the number of the wet-dog shakes induced by DOI. This effect of ACTH was significantly increased by the coadministration of carbamazepine and imipramine. These results suggest that the use of carbamazepine together with tricyclic antidepressants had the effect of reducing immobility time in the FST in a tricyclic antidepressant-treatment-resistant depressive model induced by chronic ACTH treatment. </p> No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 150 3 2008 Angiotensin II type 2 receptors facilitate reinnervation of phenol-lesioned vascular calcitonin gene-related peptide (CGRP)-containing nerves in rat mesenteric arteries 730 741 EN Narumi Hobara Mitsuhiro Goda Namika Yoshida Shingo Takatori Yoshihisa Kitamura Mitsunobu Mio Hiromu Kawasaki <p>The present study was designed to investigate involvement of angiotensin (Ang) II type 2 receptors (AT2 receptors) in restoration of perivascular nerve innervation injured by topical phenol treatment. Male Wistar rats underwent in vivo topical application of 10% phenol around the superior mesenteric artery. After phenol treatment, animals were subjected to immunohistochemistry of the third branch of small arteries, Western blot analysis of AT2 receptor protein expression in dorsal root ganglia (DRG) and studies of mesenteric neurogenic vasoresponsiveness. Ang II (750 ng/kg/day), nerve growth factor (NGF; 20 μg/kg/day) and PD123,319 (AT2 receptor antagonist; 10 mg/kg/day) were intraperitoneally administered for 7 days using osmotic mini-pumps immediately after topical phenol treatment. Losartan (AT1 receptor antagonist) was administered in drinking water (0.025%). Phenol treatment markedly reduced densities of both calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI)- and neuropeptide Y (NPY)-LI-containing fibers. NGF restored densities of both nerve fibers to the Sham control level. Coadministration of Ang II and losartan significantly increased the density of CGRP-LI-fibers but not NPY-LI-fibers compared with saline control. The increase of the density of CGRP-LI-fibers by coadministration of Ang II and losartan was suppressed by adding PD123,319. Coadministration of Ang II and losartan ameliorated reduction of CGRP nerve-mediated vasodilation of perfused mesenteric arteries caused by phenol treatment. The AT2 receptor protein expression detected in DRG was markedly increased by NGF. These results suggest that selective stimulation of AT2 receptors by Ang II facilitates reinnervation of mesenteric perivascular CGRP-containing nerves injured by topical phenol application in the rat.</p> No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 61 6 2007 The Influence of Hyperactivity of the Hypothalamic-pituitary-adrenal Axis and Hyperglycemia on the 5-HT2A Receptor-mediated Wet-dog Shake Responses in Rats 311 317 EN Yuichi Umeda Manabu Amano Katsuya Suemaru Takumi Yamaguchi Yoshihisa Kitamura Yutaka Gomita Hiromu Kawasaki Hiroaki Araki Original Article 10.18926/AMO/32879 <p>Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induces hyperglycemia and serotonin (5-HT)2A receptor supersensitivity. In the present study, to investigate the effect of hyperglycemia on the function of 5-HT2A receptors, we compared the 5-HT2A receptor-mediated wet-dog shake responses in rats treated with adrenocorticotropic hormone (ACTH), dexamethasone and streptozotocin. ACTH (100 &#956;g/rat per day, s.c.), dexamethasone (1 mg/kg per day, s.c.) and streptozotocin (60 mg/kg, i.p.) produced significant hyperglycemia at 14 days after the start of these treatments, and the hyperglycemia was most pronounced in the streptozotocin-treated rats. The wet-dog shake responses induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, were significantly enhanced at 14 days after repeated treatment with ACTH and dexamethasone. However, streptozotocin-induced diabetes had no effect on the wet-dog shake responses. The results of the present study suggest that hyperglycemia is not strongly associated with the enhanced susceptibility of 5-HT2A receptors under the condition of hyperactivity of the HPA axis.</p> No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 58 6 2004 Influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. 271 274 EN Yoshihisa Kitamura Hiroaki Araki Tadashi Nagatani Katsuyuki Takao Kazuhiko Shibata Yutaka Gomita Article 10.18926/AMO/32092 <p>We studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing effect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened significantly. From the viewpoint of imipramine's effect, these findings suggest that chronic forced-swim stress testing in rats may be an effective animal model for depression.</p> No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 62 4 2008 Motivational Effects of Nicotine as Measured by the Runway Method Using Priming Stimulation of Intracranial Self-stimulation Behavior 227 233 EN Hidenori Sagara Yoshihisa Kitamura Satoru Esumi Toshiaki Sendo Hiroaki Araki Yutaka Gomita Original Article 10.18926/AMO/30940 <p>It is well known that priming stimulation promotes the motivational effects of intracranial self-stimulation(ICSS) behavior. An experimental methodology using the runway method could separately study the reward and motivational effects of ICSS behavior. In the present study, we examined the motivational effect of nicotine as measured by the runway method using priming stimulation of ICSS behavior. Electrodes were implanted chronically into the medial forebrain bundle (MFB) in rats. A lever for stimulation of the MFB was set on the opposite side of the start box in the apparatus, and rats were trained to get a reward stimulation (50-200 microA, 0.2 ms, 60 Hz) of MFB when the goal lever was pressed. After the rats were trained to press the lever, a priming stimulation of the MFB was performed. After receiving the priming stimulation, rats were placed at the start box of the runway apparatus, and the running time duration until the goal lever was pressed was measured. Subcutaneous injection of nicotine at a dose of 0.2mg/kg produced an increase in running speed to obtain the reward stimulation, and priming stimulation facilitated the motivational effect to obtain the electrical brain stimulation reward in the rats. These results suggest that nicotine significantly enhanced the motivational effect on ICSS behavior as determined using the runway method. The runway method using priming stimulation of ICSS behavior may become the new experimental methodology with which to measure the motivational effect of some drugs.</p> No potential conflict of interest relevant to this article was reported.

岡山大学医学部附属病院三朝医療センター Acta Medica Okayama 1348-1258 74 2004 気管支喘息患者におけるモンテルカストの有用性についての検討　－テオフイリンとモンテルカスト併用の影響を中心に－ 51 56 EN Fumihiro Mitsunobu Yoshiro Tanizaki 10.18926/14809 新規ロイコトリエン（LT）受容体桔抗薬であるモンテルカスト服用によるテオフイリン服用患者の処方動向，臨床検査値ならびに患者の服用に対する意識について検討を行った。 その結果，テオフイリン服用患者177名の内，51％がLT受容体抵抗薬を併用しており，併用率はモンテルカストが最も多く，プランルカスとザフィルルカストの順であった。また，プランルカストからモンテルカストに変更された症例が多かった。臨床検査値はモンテルカスト服用により血中好酸球数の減少作用が認められた。肝機能検査値（AST・ALT・ALP）は影響しなかった。テオフイリン服用量はモンテルカスト併用服用により減量され，それに伴い血中濃度も低下した。しかしながら，血中濃度／投与量比は影響しなかったことより，モンテルカストはテオフイリンクリアランスに影響しないと考えられる。モンテルカストヘの変更により，患者の服薬コンプライアンスは良好に維持され，自覚する副作用の発現は認められ なかった。以上の結果，テオフイリン服用患者へのモンテルカスト併用投与は良好な服薬コンプライアンスを維持させ，さらにテオフイリンの体内動態に影響を及ぼすことなく，テオフイリンの投与量を減少させ，患者のQOLの向上につながると考えられる。 No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 00301558 119 1 2007 薬物相互作用 (9―喫煙と薬の相互作用) 83 85 EN Hidenori Sagara Yoshihisa Kitamura Toshiaki Sendo Yutaka Gomita No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 00301558 120 1 2008 薬物相互作用(12―ベンゾジアゼピン系睡眠薬の薬物相互作用） 91 94 EN Kazuaki Shinomiya Yoshihisa Kitamura Satoshi Ueshima Tomoaki Satoh Toshiaki Sendo No potential conflict of interest relevant to this article was reported.