Trends in Prescribing Antipsychotics for Children and Adolescents in Japan: A Descriptive Epidemiological Study Using a Large-Scale Pharmacy Dataset.

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17 years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17 years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17 years receiving an initial antipsychotic prescription.

Direct cell-cell interaction regulates division of stem cells from PC-3 human prostate cancer cell line.

Cancer stem cells (CSCs) are a subpopulation that can drive recurrence and metastasis. Therefore, therapies targeting CSCs are required. Although previous findings have suggested that non-CSCs regulate the proliferation and differentiation of CSCs in the tumor microenvironment, the precise molecular mechanism is largely unknown. In this study, we found that a direct interaction between CSCs and non-CSCs downregulated CSC division in the PC-3 human prostate cancer cell line. We found that the proliferation of PC-3-derived CSCs (PrSCs) was significantly decreased (∼47%) in the presence of non-CSC-rich parental PC-3 cells compared with that in a culture in which they were absent. We observed no differences in PrSC proliferation when we indirectly cocultured them with PC-3 cells across a Transwell insert, and PrSCs that were transiently bound to immobilized PC-3 cells proliferated more slowly than those bound to PrSCs. The frequency of cell division with prior PrSC-PrSC contact was 2.8 times higher in the PrSC monoculture compared with that in the coculture with PC-3 cells. We found that the PrSCs were approximately 1.3 times more closely associated in the monoculture compared with the coculture with PC-3 cells, as determined by a cell proximity assay. The frequency of asymmetric PrSC division was 6.5% in the monoculture compared with 1.0% in the coculture with PC-3 cells (P < 0.045). By analyzing our data, we determined the importance of PrSC-non-CSC contact in regulating the frequency and mode of PrSC division. This regulation might be a valuable target for treating cancer.

Association between antidepressant use during pregnancy and congenital anomalies in children: A retrospective cohort study based on Japanese claims data.

Certain studies previously pointed out that treating pregnant women with antidepressants may increase risks of congenital anomalies in their children. However, to date, the study results are not conclusive. Furthermore, most studies have been performed using data from Western countries; therefore, we examined this association using Japanese data. This retrospective cohort study was based on claims data of mothers and their children from January 2005 to July 2014, obtained from the JMDC Inc. Information on antidepressant prescriptions was extracted from the database. Children were followed up from birth through July 2014 or until their withdrawal from the database and were identified for obtaining information on their congenital anomalies. We used logistic regression analysis to evaluate the association between maternal antidepressant use during pregnancy and the children's congenital anomalies. Of 53 864 eligible pairs of mothers and children, 53 697 pairs met the study criteria. No increased risk of total congenital anomalies in children whose mothers used antidepressants of any type during the first trimester of pregnancy was found in the analysis (adjusted analysis with confounders, odds ratio: 0.86; 95% confidence interval: 0.52, 1.42). In addition, there was no increased risk of organ specific anomalies in the analysis by type of antidepressant. We found no increased risk of congenital anomalies in children whose mothers used antidepressants during the first trimester of pregnancy compared to that of non-users based on the Japanese claims data. Additional studies are necessary to further clarify the association between antidepressant use during pregnancy and congenital anomalies in children.

Palladium-Catalyzed Three-Component Coupling of Ynamides.

A palladium-catalyzed regioselective three-component coupling of ynamides was developed. The reaction proceeded smoothly to furnish the desired products when carried out at 70 °C in acetonitrile/water with potassium carbonate in the presence of 2.5 mol % Pd2(dba)3·CHCl3 without a ligand. Various iodides and boronic acids were used in this reaction, and a carbon-carbon bond was formed with satisfactory regioselectivity from the ynamides.

Association between antidepressant use during pregnancy and autism spectrum disorder in children: a retrospective cohort study based on Japanese claims data.

BACKGROUND: Studies using data from Western countries have raised concerns that treating pregnant women with antidepressants may increase the risk of autism spectrum disorders (ASDs) in their offspring. However, to date, the studies are inconclusive. We therefore examined the association between antidepressant use and ASD using claims data collected in Japan. METHODS: This retrospective cohort study was based on claims data from mothers and their children from January 2005 to July 2014, obtained from the Japan Medical Data Center. The information from mothers and children was linked using the family identification code. Information on antidepressant prescriptions during pregnancy was extracted from the database. To collect information on ASD, children for whom data were available 24 months or more after birth were followed up from birth through July 2014 or up until their withdrawal from the database. To ensure appropriate diagnosis of ASD, mother-child pairs where the children's data did not cover the 24 months after birth or pairs where children had a diagnosis of ASD within only 23 months after birth were excluded from the study cohort. We used logistic regression analyses to evaluate the association between antidepressant use during pregnancy and the children's ASD diagnosis. All statistical analyses were performed using IBM SPSS (Statistical Package for the Social Sciences) Statistics ver. 21.0. RESULTS: Of the 53,864 eligible mother-child pairs, 26,925 met the study criteria. Crude analysis showed that the ASD prevalence in children was significantly higher with any antidepressant use than with non-use (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.08, 4.95). However, when the analysis was adjusted for the confounding effect of maternal depression during pregnancy, statistical significance was lost (OR, 0.76; CI, 0.27, 2.18). CONCLUSIONS: After adjustment for confounders, we found no significant association between antidepressant use during pregnancy and ASD in children in Japan. This result provides additional evidence to support the idea that antidepressant use during pregnancy itself is not associated with an increase in ASD in children. In addition, this represents the first evidence based on Asian data.

Serum amyloid A and C-reactive protein positive nodule in alcoholic liver cirrhosis, hard to make definite diagnosis.

We describe a case of serum amyloid A (SAA) and C-reactive protein (CRP) positive nodule detected by immunohistochemical analysis in a 37-year-old woman with alcohol-related cirrhosis. Imaging studies at first admission pointed to hepatocellular carcinoma (HCC), a dysplastic nodule, an inflammatory pseudotumor or focal nodular hyperplasia (FNH). Ultrasonography-guided biopsy in Segment 2 showed minimal atypical changes, except for a slight increase in cell density and micronodular cirrhosis in the non-nodular portion. gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging carried out after a year and a half revealed hypervascularity in the arterial phase and isointensity in the hepatobiliary phase. Three years thereafter, however, the imaging displayed a change from isointensity to a defect in the hepatobiliary phase, and the nodule demonstrated minimal histological atypia. Immunohistochemical staining of the nodule was positive for SAA, CRP, liver fatty acid-binding protein and glutamine synthetase, but negative for ß-catenin, heat shock protein 70 and Glypican 3. Organic anion transporter (OATP)8 staining was weaker in the nodule than in the non-nodular portion of the alcohol-related micronodular cirrhosis. The nodule was diagnosed as an SAA and CRP positive nodule, and HCC was ruled out. Despite the change from isointensity to a defect in the hepatobiliary phase, no evidence of HCC was found in the biopsy specimen. The change may be explained more by the weak OATP8 staining compared with that of alcohol-related liver cirrhosis than by malignant transformation into HCC.

Good Laboratory Practice (GLP) status of Asian countries and its implementation in non-clinical safety studies in pharmaceutical drug development.

Non-clinical animal studies to assess the safety of compounds under development have to comply with Good Laboratory Practice (GLP). The Organization for Economic Co-operation and Development (OECD) has established the Mutual Acceptance of Data (MAD) system in OECD member countries for the mutual acceptance of non-clinical safety study data. Since 1997 non-OECD-member countries have also been able to participate in the MAD system, if the country meets the level of standardized compliance with OECD GLP. Thus, several Asian non-OECD countries are trying to develop their GLP standards in order to become official members of the MAD system. Pharmaceutical companies face significant expense in the drug-development process, including the cost of non-clinical safety studies; in response, companies in Asian countries are seeking to establish GLP facilities to provide cost-effective services for drug development. To assess the quality and cost of GLP performance in Asian countries, in this study we approached GLP facilities in a number of Asian countries to obtain price and quality information on a 'virtual compound' to be assessed in non-clinical safety studies. Also, the development status of GLP in Asian countries in terms of policy and infrastructure was analyzed. We found that, among Asian countries, India and Singapore may be candidates for participation in te MAD system in terms of their compliance with GLP, language, and costs. These findings will be beneficial to pharmaceutical companies planning GLP studies in Asian countries.

Effects of hypothyroidism induced by perinatal exposure to PTU on rat behavior and synaptic gene expression.

Hypothyroidism in the rat induced by perinatal exposure to propylthiouracil (PTU) is a useful animal model to study molecular changes underlying neurobehavioral defects associated with this condition. Understanding the developmental alterations in gene expression related to the neurobehavioral dysfunction should help to identify molecular markers for developmental neurotoxicity at an early stage of development. In the present study, we evaluate the effects of PTU on the expression of a set of genes implicated in neural network formation or synaptic function at a minimal dose of PTU causing behavioral alteration. Various doses of PTU were administered to dams from late pregnancy to the lactation period and the expression of selected genes in the hippocampus and the cerebral cortex of offspring was examined by quantitative RT-PCR. Behavioral performance of PTU-treated rats was also assessed. PTU-treated rats showed increased motor activity and impairment of E-maze learning at weaning and after maturation. At doses causing such behavioral alteration, expression of GAP-43 and M1 mRNAs was changed during neuronal network formation, suggesting that levels of these factors during development are important for accurate postnatal development and function.