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Hideharu Hagiya,1 Ken Tasaka,2 Toshiaki Sendo,2 Fumio Otsuka11Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2Department of Pharmacy, Okayama University Hospital, Okayama, JapanObjectives: Stenotrophomonas maltophilia shows wide-spectrum resistance to antimicrobials and causes various infections in immunocompromised or critically ill patients with high mortality. In this era of antibiotics resistance, a revival of old antibiotics is now featured. We examined the clinical usefulness of latamoxef (LMOX) for the treatment of S. maltophilia infection.Patients and methods: The observational study was retrospectively performed at Okayama University Hospital (Okayama, Japan) from January 2011 to December 2013. LMOX was administered to 12 patients with S. maltophilia infection, with eleven of those patients being admitted to the intensive care unit.Results: Underlying conditions of the patients included postoperation, hematological transplantation, hepatic transplantation, and burn. Major infectious foci were surgical site infection (six cases), respiratory infection (four cases), blood stream infection (three cases), and burn site infection (one case). The doses of LMOX administered ranged from 1 g/d to 3 g/d for ten adult patients and from 40 mg/kg/d to 80 mg/kg/d for two pediatric patients. Microbiologic failure was seen in five (41.7%) of 12 cases, and 30-day and hospital mortality rates were 25% and 50%, respectively. Minimum inhibitory concentrations of LMOX were higher in the deceased group (4–64 µg/mL) than in the surviving group (1–4 µg/mL).Conclusion: LMOX treatment is not recommended for the treatment of S. maltophilia infection. Further investigation would be needed before its clinical use.Keywords: latamoxef, Stenotrophomonas maltophilia, intensive care unit, revival

Manabu Suno,1,* Yuriko Endo,1,* Hiroyuki Nishie,2 Makoto Kajizono,3 Toshiaki Sendo,3 Junji Matsuoka4 1Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 3Department of Pharmacy, Okayama University Hospital, 4Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan *These authors contributed equally to this work Background: An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients.Methods: Blood was collected from 21 Japanese cancer patients treated with a 24-hour transdermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations.Results: Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal–Wallis test and post hoc Mann–Whitney U-test, P

Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we aimed to examine the effects of chotosan, a traditional Japanese botanical drug, and its active component, Uncaria hook, on anxiety-like behaviors induced by systemic inflammation in mice., Methods: To induce systemic inflammation, the mice were treated with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS treatment, the mice were administered chotosan or Uncaria hook orally each day for 14 days. Anxiety-like behavior of the mice was evaluated using the light-dark test 24 h after LPS treatment., Results: Repeated administration of chotosan prevented anxiety-like behavior in both normal and LPS-treated mice. Similarly, administration of Uncaria hook suppressed LPS-induced anxiety-like behavior in mice. Furthermore, treatment with tandospirone, a 5-HT 1A receptor agonist, alleviated anxiety-like behavior in mice, whereas treatment with DOI, a 5-HT 2A receptor agonist, enhanced anxiety-like behavior in mice. LPS treatment significantly increased serotonin (5-HT) 2A receptor mRNA expression in the frontal cortex, whereas 5-HT 1A receptor mRNA expression remained unchanged in the hippocampus. Notably, chotosan significantly suppressed the mRNA expression of 5-HT 2A receptor., Discussion: These findings indicate that chotosan exerts anxiolytic-like effects in the context of inflammation-induced anxiety, potentially mediated by the inhibition of 5-HT 2A receptor hyperfunction in LPS-treated mice. Consequently, we postulate that chotosan may be effective in managing inflammation-induced anxiety-like behaviors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Okawa, Ushio, Izushi, Kitamura, Zamami and Sendo.)

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., Competing Interests: No potential conflict of interest relevant to this article was reported.

A complementary solid-state nuclear magnetic resonance and transmission electron microscopy (TEM) analysis was performed for LiBH 4 -ZrO 2 nanocomposites. As a result, amorphous LiBH 4 films with thicknesses of less than 30 nm were observed covering the ZrO 2 particles. Li imaging by energy-filtered TEM is useful for the real-space characterization of nanoscale LiBH 4 .

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 μg/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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ushio, Wada, Nakamura, Matsumoto, Hoshika, Shiromizu, Iwata, Esumi, Kajizono, Kitamura and Sendo.)

In recent years, medical staff including physicians and nurses have been participating in home health care, reflecting the needs of an aging society in Japan. Pharmacists are also asked to work on home health care teams to ensure the medical safety of patients. It currently remains unclear whether direct communication, i.e. a meeting, between home-visiting physicians and pharmacists contributes to the proper use of medications and continuous medical care. We retrospectively analyzed the medication management guidance records of home-visited patients who received their first home visit between April 2014 and March 2017. We collected data on pharmacist inquiries, the duration of visits, and details from a meeting between home-visiting physicians and pharmacists. Thirty-five patients were included. At the first visit, the inquiry rate by pharmacists was 65.7%. The prescription question rate was significantly lower in patients with a meeting than in those without (p=0.033). The average duration of visits was significantly shorter for home-visited patients whose health care providers had a meeting (p=0.007). These results suggest that pharmacists who held a meeting with the home-visiting physician before the first patient visit were able to resolve drug-related issues earlier, which increased the work efficiency of home-visiting pharmacists., Competing Interests: No potential conflict of interest relevant to this article was reported.

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., Competing Interests: No potential conflict of interest relevant to this article was reported.

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT) 2A receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light-dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2 weeks). 5-HT 2A receptor and 5-HT 2A receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT 2A receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT 2A receptor levels in the frontal cortex. However, chemotherapy increased 5-HT 2A receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT 2A receptor hyperactivity without an increase in 5-HT 2A receptor levels in rats., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aim: The current prevalence of hepatitis C virus infection and hepatitis C virus-associated mortality in Japan falls short of the World Health Organization goal of viral hepatitis elimination by 2030. We aimed to evaluate the trends in hepatitis C virus-associated mortality in Japan., Methods: This nationwide observational study used the Japanese Vital Statistics from 1998 to 2017 and included all Japanese hepatitis C virus-associated deaths (84 936) of adults aged ≥ 40 years. We calculated the crude and age-standardized mortality rates per 100 000 persons by age and sex. Joinpoint regression analysis was used to identify significant changing points in trends and to estimate the annual percentage changes and the average annual percentage changes for the entire study period., Results: The crude mortality rate per 100 000 persons (annual death number) increased from 5.5 (3548) in 1998 to 7.0 (4843) in 2005 and decreased to 4.0 (3095) in 2017. By 2017, the crude mortality rates per 100 000 persons among men and women had dropped to 3.6 and 4.3, respectively. The age-standardized mortality rate was higher in women than in men. The average annual percentage change was -3.8% (95% confidence interval: -5.0 to -2.5). The declining trend was more rapid in men (-4.5%, 95% confidence interval: -5.3 to -3.6) than in women (-2.7%, 95% confidence interval: -3.8 to -1.6)., Conclusions: Trends in hepatitis C virus-associated mortality rates have declined in an accelerating manner in Japan, especially among men., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Photoinitiators are utilized in the production of a wide range of commonly used products. However, some photoinitiators exert toxic effects. We previously demonstrated the endocrine-disrupting effects of photoinitiators in vitro . The present study investigated the estrogenic activities of three photoinitiators: 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP), which were subcutaneously injected into mouse xenografts with MCF-7 breast cancer cells. The results obtained showed that 1-HCHPK, MBB, and MTMP promoted breast tumor growth in these xenografts. A pretreatment with the estrogen receptor antagonist tamoxifen blocked the tumor growth-promoting effects of each photoinitiator. Collectively, the present results suggest that the three photoinitiators exhibit estrogenic agonist activities in vivo . Furthermore, as a factor for breast tumor growth, these photoinitiators potentially have estrogenic properties in vivo ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Benzodiazepine receptor agonists are widely prescribed therapeutic agents that alter gamma-aminobutyric acid (GABA) A receptor activity and have anxiolytic effects. Post-operative use of benzodiazepines is a risk factor of delirium. Inflammatory conditions alter the anxiolytic effects of benzodiazepine. We investigated the effect of diazepam, a typical benzodiazepine anxiolytic, on changes in the emotional behavior of mice in a hole-board test after lipopolysaccharide (LPS) treatment. Diazepam dose-dependently increased the number of head-dips at doses that did not alter locomotor activity; however, diazepam dose-dependently significantly decreased the number of head-dips at doses that did not alter locomotor activity in LPS-treated mice. Flumazenil, a benzodiazepine receptor antagonist, normalized the decrease in head-dipping behavior caused by diazepam treatment in normal and LPS-treated mice. The decrease of the head-dipping effect caused by diazepam was attenuated by minocycline in LPS-treated mice. We further found that the decrease in head-dipping behavior caused by diazepam was blocked by bumetanide, a Na + -K + -2Cl - cotransporter isoform 1 (NKCC1) antagonist, in LPS-treated mice. These findings suggest that diazepam induces the anxiety-like behavior under inflammation conditions, and may cause the GABA A receptor dysfunction associated with the chloride plasticity mediated by NKCC1, which contributes to benzodiazepine-induced delirium after surgery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Adverse drug events (ADEs) are a major cause of mortality., Objective: We examined long-term trends for ADE-related deaths in Japan., Methods: This observational study was conducted using the Japanese Vital Statistics from 1999 to 2016. Data for all ADE-related deaths were extracted using International Classification of Diseases, Tenth Revision codes. We analysed ADE-related deaths by age and sex and calculated crude and age-standardised mortality rates (ASMR) per 100,000 people. We used Joinpoint regression analysis to identify significant changing points in mortality trends and to estimate annual percentage change (APC)., Results: In total, 16,417 ADE-related deaths were identified. The crude mortality rate for individuals aged ≥ 65 years was higher than that of young individuals. The ASMR per 100,000 people increased from 0.44 in 1999 to 0.64 in 2016. The crude mortality rate increased from 0.44 in 1999 to 1.01 in 2016. The APC of ASMR increased at a rate of 2.8% (95% confidence interval [CI] 1.4-4.2) throughout the study period. In addition, crude mortality increased at a rate of 5.7% (95% CI 4.2-7.3) annually from 1999 to 2016. The ADE-related mortality rate was higher for men than for women during the study period., Conclusions: The number of and trend in ADE-related deaths increased in Japan from 1999 to 2016, particularly in the older population.

What Is Known and Objective: Recently, opportunities for pharmacists to have face-to-face conversations with cancer patients have increased in Japan. The aim of this study was to investigate the difficulties experienced by Japanese pharmacists when communicating with cancer patients., Methods: We interviewed 7 pharmacists at Okayama University Hospital (Japan), using the semi-structured interview method. The obtained data were qualitatively analysed. A questionnaire was also filled out by 50 Japanese pharmacists to determine the difficulties they faced when communicating with cancer patients., Results and Discussion: The difficulties experienced by pharmacists when communicating with cancer patients were classified into the following three domains: (a) coping with patients' negative emotions, (b) questions beyond the scope of pharmacists' expertise and (3) how to manage patients and their families. Factor analysis indicated that the main difficulties pharmacists experienced were coping with patients' negative emotions and questions that were beyond the scope of their expertise. However, pharmacists were unlikely to experience difficulties in communicating additional information regarding anticancer drugs. Hospital pharmacists in Japan had some difficulties in communicating with cancer patients. In particular, many pharmacists felt that they could not sufficiently manage patients' negative emotions and answer questions beyond the scope of their expertise, such as questions about life expectancy or prognosis., What Is New and Conclusions: The current study showed that pharmacists experienced three types of difficulties when communicating with cancer patients: coping with patients' negative emotions, questions beyond the scope of their expertise and how to manage patients and their families. These results might facilitate the development of interventions that aim to improve patient-pharmacist communications in Japan., (© 2020 John Wiley & Sons Ltd.)

Background: Cancer patients can suffer from psychological and cognitive disorders after chemotherapy, which influence quality of life., Objective: Oxidative stress may contribute to the psychological and cognitive disorders induced in rats by chemotherapy. In the present study, we examined the effects of N-acetylcysteine, an anti-oxidant, on anxiety-like behavior and cognitive impairment in rats treated with a combination of doxorubicin and cyclophosphamide., Methods: Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. The light-dark test and the novel location recognition test were used to assess anxiety-like behavior and spatial cognition, respectively. The rats' hippocampal levels of glutathione (GSH) and glutathione disulfide (GSSG) were measured using a GSSG/GSH quantification kit., Results: Combined treatment with doxorubicin and cyclophosphamide produced anxiety-like behavior and cognitive impairment in rats. N-acetylcysteine reversed the anxiety-like behavior and inhibition of novel location recognition induced by the combination treatment. Furthermore, the combination of doxorubicin and cyclophosphamide significantly reduced the rats' hippocampal GSH/GSSG ratios. N-acetylcysteine reversed the reduction in the GSH/GSSG ratio seen in the doxorubicin and cyclophosphamide-treated rats., Conclusion: These results suggest that N-acetylcysteine inhibits doxorubicin and cyclophosphamide-induced anxiety-like behavior and cognitive impairment by reducing oxidative stress in the hippocampus., (© 2020 S. Karger AG, Basel.)

Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are　highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: 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., Methods: 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., Results: 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., Conclusion: The amount of VGC should be measured carefully when preparing VGC solutions using the simple suspension method., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Globally, the number of deaths is estimated to increase to 74 million per year by 2030. Place of death (PoD) is increasingly being recognized as an important aspect of end-of-life care. However, recent trends in PoD in Japan, one of the super-aged societies, are unknown. Objective: To analyze trends in PoD in Japan over two decades. Design: Population-based retrospective observational study. Setting: All deaths reported in Japan, 1998-2017. PoD was defined as hospital, nursing home, or own home. Results: All Japanese decedents (∼22.6 million) over the past 20 years were analyzed. The proportion of hospital deaths was consistently high (>80%), with a significant decreasing trend from the mid-2000s. Although the proportion of deaths at home decreased in the first half of the study period, they later increased. There was a low proportion of deaths in nursing homes compared to other places of death; however, the proportion increased continually throughout the study period, particularly among women. In 2015, more women died in nursing homes than at home. Although the proportion of hospital deaths declined in the second half of the study period, their overall number continued to increase, reflecting an increase in total deaths in Japan. Conclusions: This study highlighted rapid changes in trends in PoD in Japan, and the need to consider affordable end-of-life care in Japan as well as other countries with aging populations. The findings from this long-term epidemiological study provide important insights on this issue.

Objectives: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs., Methods: We analysed health insurance claims data over 2013-2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes., Results: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians' offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4-991.7) and 532.4 (99% CI, 531.6-533.3), respectively. The visit rates for patients aged 0-17, 18-59, and 60-74 years were 2410.0 (99% CI, 2407.2-2412.9), 683.6 (99% CI, 682.7-684.6), and 682.1 (99% CI, 678.2-686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4-1095.2), 434.1 (99% CI, 433.4-434.9), and 353.4 (99% CI, 350.7-356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum., Conclusions: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

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., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Lubiprostone is an effective drug for various types of constipation in patients without cancer; however, there is no report on its efficacy and safety in patients with cancer. Our purpose was to evaluate the efficacy and safety of lubiprostone for constipation in cancer patients. We retrospectively studied 124 patients (cancer, N = 67) who were treated with lubiprostone for constipation in our hospital between June 2013 and May 2016. The number of bowel movements (BMs) increased in the both the cancer and non-cancer groups. The mean change in BM frequency did not differ between the two groups. Approximately 70% of patients in both groups had an initial BM within 24 h after administration of lubiprostone. The most common lubiprostone-related adverse events in both groups were diarrhea (38.8 vs. 14%), and nausea (22.4 vs. 8.8%). No lubiprostone-related serious adverse events occurred. Discontinuation due to the side effects of lubiprostone was more frequent in cancer patients (p = 0.023). Logistic regression analysis showed that the risk of discontinuation of lubiprostone in cancer patients was high in patients with a body-mass index (BMI) <22, and low in patients using opioids and magnesium oxide dosage ≥1000 mg/d. Our study showed that while lubiprostone was as effective in cancer patients as in non-cancer patients, in cancer patients it was associated with a high incidence of diarrhea and nausea side effects and warranted caution, especially in patients with a low BMI.

Introduction: Acute bacterial infectious diseases are major causes for outpatient visits for young children. Pivalate-conjugated antibiotics (PCAs) are frequently prescribed for these situations in Japan, while several literatures have shown a potential risk of hypoglycemia associated with PCAs. This study aimed to evaluate the incidence of PCA-induced hypoglycemia in children, compared with other oral beta-lactam antibiotics., Methods: This retrospective cohort study using a Japanese medical and pharmacy claims database was performed on children aged 1 month to 5 years old with at least once prescription of PCAs or other oral beta-lactam antibiotics from January 2011 to December 2013. Hypoglycemia was defined based on diagnostic codes or the prescription of 10% or 20% glucose injection. We examined the prevalence of hypoglycemic events and performed multivariate analysis to investigate the risk of hypoglycemia with PCAs compared with the control oral beta-lactam antibiotics., Results: We identified 179,594 eligible patients in this population. In the PCA and control groups, there were 454,153 and 417,287 prescriptions and 3356 (0.74%, 95% confidence intervals [CI] 0.71-0.76) and 2605 (0.62%, 95% CI 0.60-0.65) hypoglycemic events, respectively. Multivariate analysis revealed that PCAs were associated with hypoglycemia (adjusted odds ratios [OR] 1.18, 95% CI 1.12-1.24), and even a shorter duration of PCAs prescribing (≤7 days) was significantly associated with hypoglycemia (adjusted OR 1.17, 95% CI 1.11-1.24)., Conclusion: These results suggest that in young children PCA use, even for a short period, is a risk factor of hypoglycemia., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)