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We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio=11.67, 95% confidential interval=3.0644.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

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.

Adverse drug events (ADEs) are a major cause of mortality. We examined long-term trends for ADE-related deaths in Japan. 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). 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. The number of and trend in ADE-related deaths increased in Japan from 1999 to 2016, particularly in the older population. Adverse drug events (ADEs) are a public health issue, but descriptive data on ADEs in Japan are limited. Studies have shown that elderly people have a higher risk of dying from ADEs. Japan has one of the most rapidly aging populations and the highest percentage of older individuals worldwide. Clarifying long-term data trends in Japan is important in the aging world. Here, we aimed to clarify the trend in mortality related to ADEs in Japan. We selected 16,417 deaths that were assigned an underlying cause (i.e., ADEs) in vital statistics based on codes from the International Classification of Diseases, Tenth Revision (ICD-10). The crude mortality rate for both sexes increased from 0.44 per 100,000 in 1999 to 1.01 in 2016. The average annual percentage change (average APC), which numerically shows the change over time, was 5.7% throughout the study period. The age-standardised mortality rate, using the population in the first year, increased from 0.44 per 100,000 in 1999 to 0.64 in 2016. The average APC of the age-standardised mortality rate showed an increasing trend at 2.8%. Even after age standardisation, ADE-associated death showed an increasing trend. In particular, population groups aged ≥65 years showed a continuous increasing trend. These findings suggest that the ADE-related mortality rate in Japan is increasing, especially in elderly individuals.

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.We analysed health insurance claims data over 2013-2015 among Japanese patients aged75 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.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.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.

Patients who undergo multiple-day chemotherapy sessions experience hard-to-treat nausea and vomiting. Currently, there is no effective standard treatment for this condition. This study compared the preventive effect of first-generation 5-hydroxytryptamine 3 receptor antagonists (5-HT3 RAs) and second-generation 5-HT3 RAs palonosetron in multiple-day chemotherapy-induced nausea and vomiting. The design of this study was a retrospective case-control study of patients who received a five-day cisplatin-based chemotherapy and were treated with aprepitant, dexamethasone, granisetron, and ramosetron or palonosetron. The patients were divided into two groups: patients given granisetron and ramosetron (the first-generation group), and those given palonosetron (palonosetron group). The percentage of patients with a complete response or total control was assessed. They were divided into three phases: 0-216 h (overall phase), 0-120 h (remedial phase), and 120-216 h (after phase). The remedial phase was further divided into 0-24 h (early phase) and 24-120 h (later phase). Moreover, the nutritional status of each patient was assessed by noting the patients' total calorie-intake per day and total parenteral nutrition. First-generation 5-HT3 RAs and palonosetron were used for treatment in 18 and 28 patients, respectively. The complete response rate and caloric oral intake of the later phase were higher in the palonosetron group than in the first-generation group. We conclude that palonosetron treatment was more effective than first-generation 5-HT3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.

Background In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. Purpose Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. Methods We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. Results Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. Conclusions According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

Objectives To describe CT usage in Japan by age, gender, and region and to clarify the relationship between aging and CT examination rate. Materials and methods We conducted a cross-sectional study using openly accessible data from the National Database, which includes all Japanese health insurance claim data from 2014. These data are anonymized and publicly available as spreadsheets. Therefore, this study did not require institutional review board approval. We calculated the rate of CT examinations per 1000 population by age, sex, and region with 99% confidence intervals. Pearson correlation coefficients were calculated between CT rate and aging in each region. Results We analyzed 28.1 million CT scans, and the rate per 1000 population was 221.5 (99% CI, 221.4–221.6). By age, the corresponding rate for age 0–9 years was 28.9, that for age 10–9 years was 48.6, that for 20–29 years was 52.2, that for 30–39 years was 69.0, that for 40–49 years was 105.9, that for 50–59 years was 177.6, that for 60–69 years was 303.3, that for 70–79 years was 532.5 and that for ≥80 years was 801.5. The rate for male individuals was 233.6 and that for females was 210.0. The CT examination rate was 171.7 and 296.0 in the lowest- and highest-frequency regions, respectively. The average correlation coefficient between the aging rate in each region and the CT examination rate was 0.58 (0.35–0.74, p = 0.00002). Conclusion In Japan, the CT examination rate per 1000 population was high (third highest in the world). Age may be a factor that increases CT use. Furthermore, because variation in CT examination rates by age, gender, and region were observed, it is necessary to standardize CT utilization.

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....

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.

ObjectivesFall-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.DesignWe analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare.ResultsThe 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.ConclusionsAlthough 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.

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.

Objectives To describe and examine trends in polypharmacy according to age in Japan from 2010 to 2016. Design Retrospective observational study. Setting Outpatient settings. Participants Japanese individuals aged 20 and older. Measurements We analyzed pharmacy claims data that the Japanese Ministry of Health, Labor, and Welfare provided in the Survey of Medical Care Activities in Public Health Insurance from 2010 to 2016. The use of 5 or more oral prescription medications per month was defined as polypharmacy and of 10 or more as excessive polypharmacy. Regression analysis was used to estimate trends in polypharmacy with annual percentage changes. Using number of medications (polypharmacy vs excessive polypharmacy), trends in polypharmacy and crude and age‐adjusted rates of polypharmacy per 1,000 persons were calculated according to year and age group (20–34, 35–49, 50–64, 65–79, ≥ 80). Results We analyzed 240 million pharmacy claims data. The age‐adjusted monthly prevalence rate of polypharmacy increased from 85.2 to 93.8 per 1,000 persons per month and of excessive polypharmacy from 13.6 to 14.0 per 1,000 persons per month from 2010 to 2016 in the entire study population. The highest rate of polypharmacy (per 1,000 persons) was observed in 2016 in those aged 80 and older (326.8), followed by those aged 65 to 79 (167.3). The polypharmacy rate increased by 6.3% (95% confidence interval (CI)=4.0–8.7) per year from 2010 to 2012, then decreased by 0.7% (95% CI=–1.3–0.0) per year from 2012 to 2016. The rate of excessive polypharmacy increased by 4.5% (95% CI=1.1–8.0) per year from 2010 to 2013 and then decreased by 3.7% (95% CI=–6.7 to –0.6) per year from 2013 to 2016. Conclusion The overall trend of polypharmacy in Japan increased during the study period, although the increase ceased in 2013 and then declined from 2013 to 2016. Policy changes in Japan might be responsible for some of the changes. J Am Geriatr Soc 66:2267–2273, 2018.

The application and clinical impact of rapid antigen detection test (RADT) in the treatment of acute pharyngitis is unknown in Japan. We aimed to examine the proportions of RADT usage to identify Group A β-hemolytic Streptococcus (GAS) in outpatients with acute pharyngitis and evaluate the association between RADT and antibiotic treatment. We analyzed health insurance claims data from 2013 to 2015. Logistic regression models were used to analyze associated factors with RADT, overall antibiotic prescription, or penicillin use. We analyzed 1.27 million outpatient visits with acute pharyngitis, in which antibiotics were prescribed in 59.3% of visits. Of the total visits, 5.6% of patients received RADT, and 10.8% of the antibiotics were penicillin. Penicillin selection rates were higher in cases with RADT (25.4%) than those without RADT (9.7%). Compared to large-scale facilities, antibiotic prescription rates were higher in physicians' offices. For factor analysis, age (3-15 years), diagnosis code (streptococcal pharyngitis), size of the medical facility (large-scale hospitals), and physician's specialty (pediatrics) were associated with RADT use. Penicillin selection rate increased with RADT implementation (25.4% vs. 9.7%: adjusted odds ratio 1.55; 95% CI, 1.50-1.60). At 63% of the facilities, the RADT implementation rate was

The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH)-induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 µg/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long-term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective.

Background The trends in medication reviews made by community pharmacies in Japan are currently unknown. Objective We aimed to comprehensively describe the national trends in medication reviews in Japan's community pharmacies in the backdrop of the country's ageing population. Setting Community pharmacies in Japan. Methods We analysed national health insurance claims data for 2010-2015. These data were provided by the Ministry of Health, Labour and Welfare as part of the Survey of Medical Care Activities in Public Health Insurance. Main outcome measures The national trends in community pharmacy visits involving medicine dispensing and medication reviews that involve consultations with a physician. Results Among the 365 million pharmacy visits for 2010-2015, we identified 373,429 medication reviews accompanied by consultations with a physician. The pharmacy visit rate per 1000 population increased from 427.2 in 2010 to 483.7 in 2015. Medication reviews also increased from 407 per million pharmacy visits in 2010 to 1445 in 2015. Among the 373,429 medication reviews during the study period, the prescription was changed through collaboration with a physician 338,982 times (90.4%). The proportion of medication review acceptance increased from 80.6% in 2010 to 94.8% in 2015. The prescription change rate was higher among older patients than among younger ones. Conclusions Medication reviews by community pharmacists involving consultations with a physician increased in Japan from 2010 to 2015, as did prescription changes following these reviews.

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

Adult hippocampal neurogenesis is reported to change in animal models of depression and antidepressants. We have used the mitotic marker 5-bromo-2'-deoxyyridine to address the effects of imipramine and lithium on cell proliferation and survival following chronic treatment with adrenocorticotropic hormone (ACTH) in the subgranular zone of the hippocampal dentate gyrus. ACTH treatment for 14 d decreased adult hippocampal cell proliferation and survival. Coadministration of imipramine and lithium for 14 d blocked the loss of cell proliferation but not cell survival resulting from the chronic treatment with ACTH. The coadministration of imipramine and lithium may have treatment-resistant antidepressive properties, which may be attributed, in part, to a normalization of hippocampal cell proliferation.

The present study was performed to investigate the effects of kavain on the sleep-wake cycle in comparison with that of rilmazafone and diphenhydramine using sleep-disturbed rats. Electrodes for the electroencephalogram (EEG) and electromyogram (EMG) were implanted into Wistar rats. Total awake time, non-rapid eye movement (non-REM) sleep and rapid eye movement (REM) sleep were measured for 6 h. Kavain and rilmazafone showed a significant shortening in sleep latency, decreased awake time, and increased non-REM sleep time. On the other hand, significant shortening of the sleep latency was observed following the administration of diphenhydramine, while no effects were observed on the awake and non-REM sleep time. Moreover, kavain showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with rilmazafone. These results clearly indicate that kavain is a compound with not only hypnotic effects, but also sleep quality–enhancement effects. Keywords:: kavain, hypnotic effect, kava-kava, sleep

うつ病の治療は抗うつ薬を中心とした薬物療法が中心である．多くの患者は抗うつ薬の服用により自覚症状が改善し社会生活への復帰が可能となっている．しかしながら，十分な治療を行っても，うつ症状の改善を見ない治療抵抗性うつ病の存在が問題とされている．これまで，うつ病の動物モデルおよび抗うつ薬のスクリーニングモデルが報告され，新規抗うつ薬の開発に寄与している．その一方，治療抵抗性うつ病を反映した動物モデルはその病態像が明確でないこともあわせて報告がなかった．そこで，我々は治療抵抗性うつ病の病態像の解明および次世代の抗うつ薬の創薬研究に応用させるため，治療抵抗性うつ病の動物モデルの作製を行った．これまで，うつ病は中枢神経系の機能異常のみならず，視床下部-下垂体-副腎皮質（hypothalamic-pituitary-adrenal axis：HPA）系の機能異常を含む中枢神経系-内分泌系の機能異常が関与していることが知られていた．特に，既存の抗うつ薬に反応しない患者に対してグルココルチコイド受容体拮抗薬の有効性も明らかにされている．そこで，我々はHPA系の過活動モデルが治療抵抗性うつ病の病態像の一部を反映していると仮定し，adrenocorticotropic hormone（ACTH）反復投与によるHPA系過活動モデルの作製を試みた．治療抵抗性うつ病の動物モデルとしての有用性については抗うつ薬のスクリーニング系であるラット強制水泳法の不動時間を指標として検討を行った．その結果，ACTH反復投与ラットではいくつかの既存の抗うつ薬の抗うつ効果が消失し，薬物反応性の側面より治療抵抗性うつ病を反映していると考えられた．この抵抗性には自殺者の死後脳で増加が報告されている5-HT2A受容体の過活動の関与を認めている．さらに，ACTH反復投与ラットでは海馬歯状回における神経細胞の新生作用が抑制されていることより，この抑制作用が治療抵抗性の病態の一部とも考えられる．本稿ではこれらACTH反復投与によるHPA系過活動モデルの治療抵抗性うつ病の動物モデルとしての有効性を紹介する．

The present study was performed to examine the effect of tandospirone on sleep latency in a new insomnia animal model by placing rats on a grid suspended over water. For investigating the mechanism of tandospirone, the effect of tandospirone on sleep latency was also studied using rats that were depleted with neuronal serotonin (5-HT) after p-chlorophenylalanine administration. Tandospirone caused a shortening of sleep latency dose-dependently, and a significant effect was observed at 20 mg/kg, p.o. or more. A shortening of sleep latency was observed by administration of p-chlorophenylalanine (300 mg/kg, i.p.) for 2 days. On the other hand, tandospirone exerted no potentiating effect on the shortening of sleep latency induced by p-chlorophenylalanine. From these findings, a shortening of sleep latency induced by tandospirone may occur through the pre-synaptic 5-HT1A receptors in rats. Keywords:: tandospirone, sleep latency, sleep disturbed model, antianxiety, 5-HT1A receptor

The present study was undertaken to investigate the effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats in comparison with those of nitrazepam. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscle of rats for the electroencephalogram (EEG) and electromyogram (EMG), respectively. EEG and EMG were recorded with an electroencephalograph. SleepSign ver. 2.0 was used for EEG and EMG analysis. The total times of waking, non-rapid eye movement (non-REM), and rapid eye movement (REM) sleep were measured from 10:00 to 16:00. Nitrazepam showed a significant decrease in sleep latency, total waking time, and delta activity and an increase in the total non-REM sleep time. A significant decrease in the sleep latency was observed with diphenhydramine, chlorpheniramine, and cyproheptadine. Cyproheptadine also caused a significant decrease in the total waking time and increases in total non-REM sleep time, REM sleep time, slow wave sleep, and delta activity, although no remarkable effects were observed with diphenhydramine and chlorpheniramine. In conclusion, cyproheptadine can be useful as a hypnotic, having not only sleep inducing-effects, but also sleep quantity- and quality-increasing effects. Keywords:: sleep-disturbed rat, H1-antagonist, benzodiazepine hypnotic, sleep-wake cycle, delta activity

Six-year pharmacy education curriculums started in Japan in April 2006 and universities have been conducting early exposure to hospital work programs.We conducted such a program at Okayama University hospital for 45 first-year undergraduate pharmacy students at Okayama University.In the hospital the students visited a pharmacy,clinical trial center,hospital ward,rehabilitation division and an integrated support center for patients,led by hospital pharmacists and teachers of the faculty of pharmacy.In the pharmacy,they experienced the dispensing of a simulated prescription.In the present program,we obtained the help of not only pharmacists but also other medical staff including physicians,nurses,clinical research coordinators,physical therapists,social workers,and arranged it so that students could feel the importance of the medical care team.A questionnaire survey conducted before and after the early exposure to hospital work program indicated that all of students were satisfied with it,and many students were more aware of the roles of hospital pharmacists and their skills.In addition,comments made by students showed that they had greater motivation for learning,were more aware of the importance of the medical care team and communication skills.These results suggest that it would be useful to introduce such early exposure to hospital work programs into primary education for pharmacy students.

Signal transducer and activator of transcription (STAT) 3 is a key factor in multiple tyrosine kinase inhibitor (mTKI)-induced growth inhibition and apoptosis of renal cell carcinoma (RCC) cells. This study aimed to identify associations between single-nucleotide polymorphisms (SNPs) in the STAT3 gene and tumor response to mTKIs in patients with metastatic RCC (mRCC). Seventy-one patients with clear cell RCC treated with any mTKI were retrospectively genotyped to elucidate a potential association between STAT3 SNPs and overall best response to drugs. Of 50 patients included for analysis, a partial or complete response was observed in 17. A significant association was found between rs4796793 alleles and tumor response [G vs. C, odds ratio (OR) 3.25, 95 % confidence interval (CI) 1.30–8.07]. There were a higher percentage of responders with the C/C genotype at rs4796793 than with the G/C + G/G genotypes (OR 4.46, 95 % CI 1.31–15.28). Time-to-event analysis demonstrated a statistically significant difference between patients with the CC genotype and those with G/C + G/G genotypes in time-to-treatment response, but not in progression-free survival or time-to-treatment failure. The rs4796793 genotype is a novel predictive factor of the response to mTKIs in patients with mRCC. However, prospective translational trials with larger patient cohorts are required to confirm these results.

Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity. Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs). Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development. The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80–10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38–48.07; P = 0.001). In a time-to-event Kaplan–Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009). The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.

The aim of this study was to compare the effect of the serotonin (5-HT)1A receptor agonist tandospirone versus that of the benzodiazepine hypnotic flunitrazepam in a rat model of long-term adrenocorticotropic hormone (ACTH)-induced sleep disturbance. Rats implanted with electrodes for recording electroencephalogram and electromyogram were injected with ACTH once daily at a dose of 100 µg/rat. Administration of ACTH for 10 d caused a significant increase in sleep latency, decrease in non-rapid eye movement (non-REM) sleep time, and increase in wake time. Tandospirone caused a significant decrease in sleep latency and increase in non-REM sleep time in rats treated with ACTH. The effect of tandospirone on sleep patterns was antagonized by the 5-HT1A receptor antagonist WAY-100635. In contrast, flunitrazepam had no significant effect on sleep parameters in ACTH-treated rats. These results clearly indicate that long-term administration of ACTH causes sleep disturbance, and stimulating the 5-HT1A receptor by tandospirone may be efficacious for improving sleep in cases in which benzodiazepine hypnotics are ineffective.

The present study was performed to investigate the effects of valerian extract on the sleep-wake cycle using sleep-disturbed model rats. A significant shortening in sleep latency was observed with valerian extract at doses of 1000 and 3000 mg/kg. On the other hand, valerian extract had no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep, or REM sleep, even at a dose of 3000 mg/kg. Valerian extract at doses of 1000 and 3000 mg/kg showed a significant increase in the delta activity during non-REM sleep. In conclusion, valerian extract may be useful as an herbal medicine having not only sleep-inducing effects but also sleep quality-enhancement effects.

The effect of chlorogenic acid on the sleep-wakefulness cycle in rats was investigated in comparison with those of caffeic acid (the metabolite of chlorogenic acid) and dihydrocaffeic acid (the metabolite of caffeic acid). A significant prolongation of sleep latency was observed with chlorogenic acid and caffeic acid at a dose of 500 and 200 mg/kg, respectively. On the other hand, no remarkable effects were observed with dihydrocaffeic acid even at a dose of 500 mg/kg. Caffeine caused a significant increase in sleep latency and waking time and decrease in non-rapid eye movement sleep time at a dose of 10 mg/kg. In contrast, chlorogenic acid and its metabolites had no significant effects on each sleep state. From these results, it may be concluded that chrologenic acid caused a mild arousal effect compared with that of caffeine, and the effect of chlorogenic acid may have occurred through its metabolite caffeic acid.

New sleep disturbance model in rats is useful for estimating the characteristics of some hypnotics.The present study was undertaken to investigate the utility of a sleep disturbance model by placing rats on a grid suspended over water using three kinds of hypnotics, that is, short-acting benzodiazepine (triazolam), intermediate-acting benzodiazepine (flunitrazepam) and long-acting barbiturate (phenobarbital).Electrodes for measurement of EEG and EMG were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-REM and REM sleep were measured from 0900 to 1500 hours.In rats placed on the grid suspended over water up to 1 cm under the grid surface, not only triazolam but also flunitrazepam and phenobarbital caused a shortening of sleep latency. Both flunitrazepam and phenobarbital were effective in increasing of total non-REM sleep time in rats placed on sawdust or the grid, and the effects of both drugs in rats placed on the grid were larger than those in rats placed on sawdust. Measurement of the hourly non-REM sleep time was useful for investigating the peak time and duration of effect of the three hypnotics. Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect.The present insomnia model can be used as a sleep disturbance model for testing not only the sleep-inducing effects but also the sleep-maintaining effects including non-REM sleep and REM sleep of hypnotics.

The effect of histamine H 3 antagonist, iodophenpropit on amygdaloid kindled seizures in rats was studied in comparison with those of other H 3 antagonists. Under pentobarbital anesthesia, the rats were fixed to a stereotaxic apparatus and bipolar electrodes were implanted into the amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. To cause kindled seizures, electrical stimulation was applied to the amygdala bipolarly every day by a constant current stimulator, and electroencephalogram and convulsive behavior were observed. Drug effects were estimated in rats showing generalized kindled seizures. Intraperitoneal injection of H 3 antagonists, iodophenpropit, thioperamide, AQ0145 and clobenpropit, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of iodophenpropit on amygdaloid kindled seizures was more potent than those of thioperamide, AQ0145 and clobenpropit. In conclusion, iodophenpropit may be useful for the treatment of partial epilepsy and/or secondary generalized seizures in humans.

Background Delirium is an acute change in cognition and concentration that complicates the postoperative course. Patients who suffer delirium after surgery have an increased risk of persistent cognitive impairment, functional decline, and death. Postoperative delirium is also associated with an increased length of hospital stay and higher costs. With the goal of preventing delirium in postoperative patients, we organized a medical team from the Delirium Management and Assessment Center (D-mac) at Okayama University Hospital in January 2012. The team members consisted of physicians, pharmacists, nurses, and clinical psychologists. Methods We retrospectively reviewed the medical records of patients with delirium to examine risk factors related to the patients’ background. Results Fifty-nine postoperative patients with lung or esophageal cancer were investigated; 25% exhibited delirium during hospitalization. Multiple logistic regression analysis showed significant associations between the presence of delirium and a past history of delirium (odds ratio, 4.22; 95% CI, 1.10-16.2; p = 0.09) and use of benzodiazepine receptor agonists (odds ratio, 3.97; 95% CI, 1.09-14.5; p = 0.03). Intervention by the D-mac significantly reduced the rate of delirium episodes in lung cancer patients (p =0.01). Notably, prior to intervention, the incidence of delirium was 100% when three high-risk factors for delirium were present. In contrast, the incidence of delirium in patients with three high-risk factors decreased following implementation of the D-mac intervention. Conclusions These findings suggest that active participation by various staff in the medical team managing delirium had a marked therapeutic impact.

In the present study, we investigated the changes of sleep parameters in rats with chronic constriction injury (CCI) under aversive conditions. The electroencephalogram (EEG) in the frontal cortex of CCI rats and electromyogram (EMG) were measured over 6 h by placing rats on sandpaper as an aversive condition, to compare with rats placed on sawdust. Six days after CCI surgery, the rats exhibited significant mechanical allodynia, and also had neuropathic pain. When rats were placed on sawdust, no significant difference was observed between the CCI group and sham-operated control group in sleep latency, total waking time, total non-REM sleep time and total REM sleep time. On the other hand, when CCI rats were placed on sandpaper, a significant increase was observed in sleep latency and total waking time compared with the sham group; however, no significant difference was observed in the total non-REM sleep time and total REM sleep time between these two groups. These results indicate that an important factor of sleep disturbance in CCI rats is not only damage to the nerves but also being under aversive conditions. In addition, it was found that CCI rats placed on sandpaper as an aversive condition can serve as a new sleep disturbance model.

The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

Sandalwood oil is widely used in aromatherapy for alleviating various symptoms. Santalol, a major component of sandalwood oil, has been reported to have central nervous system depressant effects such as sedation. In the present study, we investigated the effect of santalol on the sleep-wake cycle in sleep-disturbed rats. When inhaled at a concentration of 5 X 10(-2) ppm, santalol caused a significant decrease in total waking time and an increase in total non-rapid eye movement (NREM) sleep time. In order to clarify the mechanism of action, olfactory hypofunction was caused in rats by intranasal application of 5% zinc sulfate solution, and thereafter the effects of inhalation of fragrances were evaluated. In this study, it was found that the impairment of the olfactory system showed no significant effect on the changes in sleep parameters induced by santalol. This result suggests that santalol may act via the circulatory system rather than the olfactory system. That is, santalol is thought to be absorbed into the blood through the respiratory mucosa, and then exert its action. From these results, it is concluded that santalol may be useful in patients having difficulty maintaining sleep without being affected by individual differences in perfume-related preference.

The effects of histamine H 1 receptor antagonists (promethazine, diphenhydramine, chlorphenilamine and triprolidine) on hippocampal theta rhythm during eight-arm radial maze performance were investigated using rats. Promethazine showed a significant increase in the number of total errors and working memory errors at doses of 10 and 20 mg/kg, and a significant increase was also observed in reference memory errors at a dose of 20 mg/kg. Diphenhydramine and chlorphenilamine at a dose of 20 mg/kg and triprolidine at a dose of 35 mg/kg also caused significant increases in the number of total, reference memory and working memory errors. Promethazine, diphenhydramine and chlorphenilamine, having potent anti-muscarinic receptor properties, increased hippocampal theta power during radial maze performance at a dose of 20 mg/kg. On the other hand, triprolidine, which has weak anti-muscarinic receptor properties compared with other histamine H 1 receptor antagonists, decreased theta power at a dose of 35 mg/kg. These results suggest that anti-muscarinic receptor properties rather than anti-histamine H 1 receptor properties may affect hippocampal theta power during spatial memory deficit induced by promethazine, diphenhydramine and chlorphenilamine.

In the present study, we studied the effect of valerian extract preparation (BIM) containing valerian extract, golden root (Rhodiola rosea L.) extract and L-theanine (gamma-glutamylethylamide) on the sleep-wake cycle using sleep-disturbed model rats in comparison with that of valerian extract. A significant shortening in sleep latency was observed with valerian extract and the BIM at a dose of 1000 mg/kg. On the other hand, valerian extract and the BIM caused no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Valerian extract and the BIM at a dose of 1000 mg/kg also had no significant effect on delta activity. In conclusion, it became clear that the BIM could be useful as a herbal medicine having a sleep-inducing effect without causing an alteration of the sleep-wakefulness cycle.

e15622 Background: Signal transducer and activator of transcription (STAT) 3 has been reported to be a mediator for keratinocyte toxicity induced by molecular-targeted drugs. Our purpose was to assess the association between single nucleotide polymorphisms (SNPs) in the STAT3 gene and hand-foot skin reaction (HFSR) in metastatic renal cell carcinoma (mRCC) patients treated with multi-kinase inhibitors (MKIs). Methods: Sixty-five mRCC patients treated with MKIs (sunitinib, sorafenib, or axitinib) were genotyped for rs4796793 in the 5′ region of the STAT3 gene. We retrospectively analyzed 60 patients whose first MKI therapy lasted for more than 4 months, regardless of the presence or absence of HFSR, and who developed HFSR within 4 months before treatment failure. Results: MKIs sunitinib, sorafenib, and axitinib were given to 35, 16, and 9 patients, respectively. HFSR was observed in 46 patients. Genotypes GG, GC, and CC at rs4796793 were found in 9, 27, and 24 patients, respectively. A significant associat...

Chlorogenic acid possessed a weak caffeine-like psychostimulant property when assessed for its effect on spontaneous locomotor activity in mice. In the evaluation of the effects for the major metabolites of chlorogenic acid which were detected upon incubation with rat feces and/or excreted in urine after oral administration to rats, caffeic and m-coumaric acids were found to be the principal active metabolites, while the others contributed little to this caffeine-like psychostimulant activity.

The present study was undertaken to investigate the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on marble-burying behavior in mice in comparison with those of fluvoxamine and clomipramine. Marble-burying test is extensively used as an animal model for ohsessive/compulsive disorder. A significant inhibition in marble-burying behavior was observed with paroxetine, at a dose of 10 mglkg. The earlier SSRI, fluvoxamine, also significantly inhibited marble-burying behavior at a dose of 30 mg/kg. Although clomipramine, a tricyclic antidepressant, caused an inhibition in marble-burying behavior, a high dose of 100 mglkg was needed to show a significant effect. On the other hand, all the drugs used in the present study showed no significant changes in spontaneous locomotor activity at doses inhibiting marble-burying behavior. In conclusion, it was confirmed that paroxetine has a potent inhibitory effect on marble-burying behavior in mice, and could have a similar antiobsessivel anticompulsive activity in human beings.

1. In the present study, we tested the effect of seed coat extract from black soybeans on eight-arm radial maze performance in rats. 2. Rats were fed a diet containing 5% seed coat extract from black soybeans or a normal diet for 40 days. 3. One week after the start of feeding, rats were tested for learning ability related to two types of memory, reference memory and working memory, with a partially (four of eight) baited eight-arm radial maze. 4. A significant decrease in the total number of errors was observed 30 (mean value of five trials of 26-30 days) and 35 days (30-35 days) after the intake of the diet containing seed coat extract compared with the control group. In addition, the mean number of days taken to reach this criterion was significantly decreased after the intake of the diet containing the seed coat extract. 5. The number of reference memory errors was significantly decreased 30 and 35 days after the intake of the diet containing seed coat extract. However, no significant decrease was observed in the number of working memory errors. 6. From these results, it is concluded that the intake of seed coat extract from black soybeans effectively enhances memory and learning ability, especially long-term memory, in rats.

The participation of histaminergic H(1) and noradrenergic alpha(1) receptors in orexin A-induced wakefulness was studied by examining the sleep-wakefulness cycle in rats. Intracerebroventricular infusion of orexin A (1 nmol) caused an increase in the wakefulness state, while non-rapid eye movement sleep (NREM sleep) and rapid eye movement sleep (REM sleep) states were decreased. Prazosin (150 nmol) showed no significant antagonistic effect on the orexin A-induced increase in the wakefulness state and decrease in NREM and REM sleep. On the contrary, pyrilamine (150 nmol) was effective in antagonizing orexin A-induced increase in wakefulness and decrease in NREM sleep. When prazosin (150 nmol) and pyrilamine (150 nmol) were simultaneously perfused into the lateral ventricle, an almost complete antagonistic effect was observed with the increase in the wakefulness state and decrease in NREM sleep. Orexin A (1 nmol) caused a significant decrease in the histamine contents of the cortex, hippocampus and hypothalamus, whereas noradrenaline contents were decreased only in the hypothalamus. From these results, we concluded that the arousal effect induced by orexin A occurs through histaminergic H(1) and noradrenergic alpha(1) receptors, although participation of the H(1) receptor was more important than the alpha(1) receptor.

The present study was performed to examine the sedative effects of second-generation histamine H(1) receptor antagonist using power spectrum analysis in the rat. Similar to ketotifen, olopatadine caused a decrease in sleep latency at a dose of 50 mg/kg, while epinastine and cetirizine showed no significant effect even at a dose of 50 mg/kg. On the other hand, no significant difference was observed in the total times of wakefulness, non-rapid eye movement sleep and rapid eye movement sleep by any drugs used in the experiments. The number of sleep phases and interval between sleep phases were also unchanged by these drugs. Ketotifen and olopatadine inhibited [(3)H]mepyramine binding to rat brain homogenates in parallel with a decrease in sleep latency. No significant effect was observed with epinastine and cetirizine on [(3)H]mepyramine binding. These findings suggest that the differences in the central nervous system (CNS) depressant effect observed in second generation H(1) receptor antagonists may be due to their liability to penetrate into the CNS.

The effects of [Arg(8)]-vasopressin (AVP) and related compounds on regional cerebral blood flow (rCBF) in the hippocampus were studied using conscious spontaneously hypertensive rats (SHR). rCBF in the hippocampus decreased gradually with age in proportion to an increase in mean blood pressure. Subcutaneous injection of AVP caused a dose-dependent increase in rCBF in the hippocampus. The effects of the metabolic fragments AVP4-9 and AVP4-8 on rCBF were relatively weak. OPC-31260, a vasopressin V(2) antagonist, antagonized the AVP-induced increase in rCBF in the hippocampus. Furthermore, subcutaneous injection of DDAVP, a V(2) agonist, increased rCBF in the hippocampus. On the other hand, the AVP-induced increase in rCBF in the hippocampus was not antagonized by OPC-21268, a vasopressin V(1) antagonist. Intracerebroventricular injection of AVP caused no significant changes in rCBF in the hippocampus, even at a dose of 10 ng/site.

To evaluate whether the elevated blood pressure induced by chronic treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) contributes to an impairment of endothelium-dependent relaxation (EDR), the effects of chronic treatment of Wistar rats with L-NAME on systolic blood pressure, pulmonary arterial blood pressure and EDR of the pulmonary arteries were studied and compared with those of stroke-prone spontaneously hypertensive rats (SHRSP). While the systolic blood pressure (SBP) of Wistar rats was increased above that of controls by chronic treatment with L-NAME, it was still significantly lower than that of SHRSP. Chronic treatment with L-NAME did not affect pulmonary arterial blood pressure. On the other hand, the pulmonary arterial blood pressure of SHRSP was slightly but significantly higher than that of the control normotensive Wistar Kyoto rats (WKY). EDR in response to acetylcholine in the pulmonary artery of L-NAME-treated rats was significantly smaller than that in control Wistar rats. The EDR markedly increased in the presence of L-arginine and completely disappeared in the presence of N(omega)-nitro-L-arginine. Indomethacin hardly affected EDR. In preparations from SHRSP, the EDR was not different from that in those from WKY. Relaxation induced by sodium nitroprusside was identical in all preparations. Elevation of SBP and the impairment of EDR observed in L-NAME-treated rats recovered two weeks following cessation of treatment. These results suggest that the impaired EDR in the pulmonary artery of L-NAME-treated rats is not due to an L-NAME-induced increase in blood pressure but due to the inhibition of nitric oxide synthase by the drug remaining in the endothelium.