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1.
World J Pediatr ; 15(1): 92-99, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30506238

ABSTRACT

BACKGROUND: Off-label use of psychotropic prescriptions for pediatric patients has been increasing in Japan. This study sought to clarify pediatric patients' off-label use of psychotropics approved only for adults in Japan. METHODS: This retrospective study on psychotropic utilization employed a pharmaceutical health insurance claims database supplied by a pharmacy for the fiscal year 2016. Seven psychotropic drugs were examined. For each drug, we calculated the proportion of patients aged < 16 years or who were under the approved age limit set in the United States out of all patients. The maximum daily dose of each drug within the study period was plotted by age. RESULTS: Data of 45,715 patients (female: 26,799, male: 18,916) with 331,920 prescriptions were examined in this study. For each drug, the proportion of pediatric patients aged < 16 years ranged from 0.15 to 1.1%, while the proportion of those under the approved age limit in the United States ranged from 0 to 0.27%. Olanzapine had the highest reported proportion. No drugs other than olanzapine were taken under the approved age limit in the United States. CONCLUSIONS: We identified the pediatric off-label use of psychotropics that were limited to adult use in Japan. The results indicated the possibility of referring to international guidelines or evidence in clinical practice, but these factors do not discount the existing problems with off-label use. More clinical trials within the pediatric population in Japan are needed to address the issue of off-label use and obtain useful and reliable information in the package inserts for rational use in future pediatric patients.


Subject(s)
Drug Prescriptions/statistics & numerical data , Off-Label Use/statistics & numerical data , Psychotropic Drugs/therapeutic use , Adolescent , Antidepressive Agents/therapeutic use , Databases, Pharmaceutical , Female , Humans , Japan , Male , Retrospective Studies , United States
2.
Am J Hum Genet ; 85(5): 569-80, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19853240

ABSTRACT

A modified alpha-N-acetylgalactosaminidase (NAGA) with alpha-galactosidase A (GLA)-like substrate specificity was designed on the basis of structural studies and was produced in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside. It retained the original NAGA's stability in plasma and N-glycans containing many mannose 6-phosphate (M6P) residues, which are advantageous for uptake by cells via M6P receptors. There was no immunological cross-reactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease recurrently treated with a recombinant GLA. The enzyme cleaved globotriaosylceramide (Gb3) accumulated in cultured fibroblasts from a patient with Fabry disease. Furthermore, like recombinant GLA proteins presently used for enzyme replacement therapy (ERT) for Fabry disease, the enzyme intravenously injected into Fabry model mice prevented Gb3 storage in the liver, kidneys, and heart and improved the pathological changes in these organs. Because this modified NAGA is hardly expected to cause an allergic reaction in Fabry disease patients, it is highly promising as a new and safe enzyme for ERT for Fabry disease.


Subject(s)
Enzyme Replacement Therapy/methods , Fabry Disease/drug therapy , alpha-N-Acetylgalactosaminidase/chemistry , alpha-N-Acetylgalactosaminidase/therapeutic use , Amino Acid Substitution , Animals , Binding Sites , CHO Cells , Catalysis , Cells, Cultured , Cricetinae , Cricetulus , Culture Media, Conditioned/chemistry , DNA, Complementary/metabolism , Disease Models, Animal , Drug Stability , Fabry Disease/enzymology , Fabry Disease/metabolism , Fibroblasts/drug effects , Fluorescent Dyes/metabolism , Galactosides/metabolism , Genetic Vectors , Humans , Hydrogen-Ion Concentration , Hymecromone/analogs & derivatives , Hymecromone/metabolism , Immunohistochemistry , Kidney/drug effects , Kidney/pathology , Kidney/ultrastructure , Liver/drug effects , Liver/pathology , Liver/ultrastructure , Mice , Mice, Knockout , Models, Molecular , Molecular Weight , Myocardium/pathology , Myocardium/ultrastructure , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Recombinant Proteins/therapeutic use , Retroviridae/genetics , Transfection , Trihexosylceramides/metabolism , alpha-N-Acetylgalactosaminidase/genetics , alpha-N-Acetylgalactosaminidase/isolation & purification
3.
Oncol Rep ; 14(3): 601-7, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16077962

ABSTRACT

The relationship between the expression level of putative drug resistance factors and sensitivity to anticancer drugs in human normal renal proximal tubule epithelial cells (RPTEC) and 3 kinds of renal cell carcinoma (RCC) cells, VMRC-RCW (RCW), OS-RC-2 (OS2), TUHR14TKB (14TKB), was examined. RPTEC exhibited high expression of P-glycoprotein (Pgp), gamma-glutamyl cysteine synthetase (gammaGCS) and cis-diamminedichloroplatinum (II) (CDDP) resistance-related gene 9 (CRR9), low expression of vacuolar ATPase (V-ATPase) and no expression of multidrug resistance-associated protein 1 (MRP1). 14TKB exhibited high expression of gammaGCS and CRR9, low expression of Pgp and V-ATPase, and no expression of MRP1. OS2 showed high expression of CRR9, low expression of Pgp, gammaGCS and MRP1, and no expression of V-ATPase. RCW exhibited high expression of Pgp, MRP1 and CRR9 and low expression of gammaGCS and V-ATPase. The level of expression of the resistance factors varied among the cells. GST activity and GST-pi expression level of each cell were correlated, and there were high levels in OS2 and RPTEC. When the cytotoxicity of anticancer drugs against each cell was measured at 96 h, the sensitivity to CDDP and Doxorubicin (DXR) in RPTEC and RCW was lower than that in the other cells. Sensitivity to DXR was enhanced by treatment with the Pgp inhibitor, Verapamil, in proportion to the Pgp expression level, and the sensitivity to CDDP was increased by the gammaGCS inhibitor, Buthionine sulfoximine, in proportion to the gammaGCS expression level (corresponding to GSH content). Although a significant increase in sensitivity to CDDP was not observed by treatment of RCC with the V-ATPase inhibitor, Bafilomycin, the sensitivity to DXR in Bafilomycin-treated cells increased about 2-fold. However, no relation between drug sensitivity and V-ATPase expression was observed. The features (such as degree of resistance) varied among the RCC cell lines manifesting many resistance factors or to the contrary, lacking or having lowered resistance factors in comparison with normal cells. Therefore, it is necessary in clinical cancer chemotherapy to determine and measure the level of expression of each resistance factor in respective tumor tissue.


Subject(s)
Carcinoma, Renal Cell/genetics , Epithelial Cells/metabolism , Kidney Neoplasms/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Antineoplastic Agents/pharmacology , Blotting, Western , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Drug Resistance/genetics , Epithelial Cells/cytology , Epithelial Cells/drug effects , Gene Expression/drug effects , Glutamate-Cysteine Ligase/genetics , Glutathione/metabolism , Glutathione Transferase/metabolism , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Kidney Tubules, Proximal/cytology , Membrane Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , Neoplasm Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Vacuolar Proton-Translocating ATPases/genetics
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