Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
Organoids/physiology* ; NAV1.2 Voltage-Gated Sodium Channel/genetics* ; Humans ; Anticonvulsants/pharmacology* ; Epilepsy/drug therapy* ; Mutation ; Cerebral Cortex/drug effects* ; Action Potentials/drug effects* ; Carbamazepine/pharmacology*

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS: We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS: HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION: HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.
Adult ; Aged ; *Alleles ; Allopurinol/adverse effects/*pharmacology ; Anticonvulsants/*adverse effects ; Asian Continental Ancestry Group/*genetics ; Carbamazepine/adverse effects/*pharmacology ; Case-Control Studies ; Drug-Related Side Effects and Adverse Reactions/*genetics/immunology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; HLA-B Antigens/*genetics ; Humans ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Stevens-Johnson Syndrome/ethnology/etiology/*genetics ; Triazines/adverse effects/*pharmacology

Psychopharmacology has developed over approximately the past five decades. The remarkable proliferation of information in this area has made it difficult for clinicians to understand the characteristics of various psychotropic agents. Atypical antipsychotics including amisulpride, asenapine, aripiprazole, blonanserin, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and zotepine cause fewer extrapyramidal problems and have many clinical applications, but they can cause metabolic disturbances. Mood stabilizers and lamotrigine are widely used for bipolar disorder. Other novel anticonvulsants such as topiramate, oxcarbazepine, gabapentin, tiagabine, pregabalin, vigabatrin, levetiracetam, and riulzole have also been tested with diverging or inconclusive results. Antidepressants are commonly used in the clinical treatment of depression and anxiety disorder. However, the mechanism of action of medications used in the treatment of psychiatric disorders remains unclear. Understanding the mechanisms of action and clarifying the diagnosis may enhance the treatment outcome in psychiatry. In this review, we analyzed clinical pharmacology data for each drug within a class and discussed clinical strategies for administering currently available antipsychotics, mood stabilizer/anticonvulsants, and antidepressants widely used for various psychiatric indications.
Aripiprazole ; Amines ; Anticonvulsants ; Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Benzodiazepines ; Bipolar Disorder ; Carbamazepine ; Clozapine ; Cyclohexanecarboxylic Acids ; Depression ; Dibenzothiazepines ; Dibenzothiepins ; Fructose ; gamma-Aminobutyric Acid ; Heterocyclic Compounds with 4 or More Rings ; Lurasidone Hydrochloride ; Isoindoles ; Isoxazoles ; Nipecotic Acids ; Quetiapine Fumarate ; Pharmacology, Clinical ; Pregabalin ; Piperazines ; Piperidines ; Piracetam ; Psychopharmacology ; Pyrimidines ; Quinolones ; Risperidone ; Sulpiride ; Thiazoles ; Treatment Outcome ; Triazines ; Vigabatrin

OBJECTIVETo investigate the anti-tumor effect and the mechanism of down-regulation of HER - 2 by cabamazepine in SKBR - 3 cells , a breast cancer cell line with HER - 2 over - expression.

METHODSWestern blotting was performed to evaluate the Her-2 expression level. The mRNA level of HER-2 was detected by RT-PCR. Immunoprecipitation was applied to detect the chaperon function and acetylation level of HSP90. The viability of cells was tested by MTT assay.

RESULTSCabamazepine treatment down-regulated HER-2 expression. Only HER-2 protein level decrease was observed with 10 micromol/L cabamazepine treatment, but both protein and mRNA expressions were inhibited by 100 micromol/L cabamazepine. Cabamazepine treatment could induce a higher acetylation level of HSP90 and destroy its chaperon function. Cabamazepine exerted synergism with Herceptin in promoting HER-2 protein degradation and synergism or potentiation with Herceptin or 17-AAG in inhibition of proliferation.

CONCLUSIONCabamazepine can reduce the expression of HER-2 and show a synergistic effect with Herceptin or 17-AAG. There may be potential benefits of carbamazepine for cancer therapy in future. HER-2;

Acetylation ; drug effects ; Antibodies, Monoclonal ; pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; pharmacology ; Benzoquinones ; pharmacology ; Blotting, Western ; Breast Neoplasms ; metabolism ; pathology ; Carbamazepine ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Down-Regulation ; drug effects ; Drug Synergism ; Female ; Gene Expression Regulation, Neoplastic ; drug effects ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; Humans ; Lactams, Macrocyclic ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Receptor, ErbB-2 ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trastuzumab

OBJECTIVE: This study was performed to investigate the prescribing patterns of antimanic agents in the treatment of acute bipolar disorder inpatients in Korea from 1990 through 2000. The results will serve as the basic data for the practice guideline for the pharmacotherapy of bipolar disorder patients in Korea. METHOD: Retrospective chart review of bipolar disorder inpatients of Soonchunhyang Medical Center in Seoul and Chun-An was conducted for each of the year 1990, 1995, and 2000. The following data are collected ; 1) demographic data, 2) history of bipolar disorder, 3) length of hospital stay, 4) detailed drug titration records of antimanic agents and antipsychotic agents. RESULTS: During the last decade, the frequency of lithium monotherapy was decreased obviously. Instead, more than half of the patients in 2000 were on combination therapy of lithium and anticonvulsants. Lithiumvalproate combination was the preferred strategy and the use rate of carbamazepine has been decreased. In addition, most of the patients were given antipsychotic agents during the last 10 years. And recently, atypical antipsychotics were increasingly prescribed. These changes in the field of pharmacology of bipolar disorder have resulted neither in shorter hospital stays nor lower dosages of concurrent neuroleptics. CONCLUSIONS: The results indicate the trends in the prescribing of antimanic agents for the treatment of bipolar disorder in Korea across the past 10 years. Mostly, the change seems to correspond to the international practice guideline. More systematic research is needed to find out the clinical benefits of the anticonvulsants in the real practice of treatment of bipolar disorder.
Anticonvulsants ; Antimanic Agents* ; Antipsychotic Agents ; Bipolar Disorder ; Carbamazepine ; Drug Therapy ; Humans ; Inpatients* ; Korea ; Length of Stay ; Lithium ; Pharmacology ; Retrospective Studies ; Seoul

No abstract available.
Acetic Acids/adverse effects/pharmacology ; Anticonvulsants/adverse effects/*pharmacology ; Carbamazepine/adverse effects/analogs & derivatives/pharmacology ; Clinical Trials ; Forecasting ; Fructose/adverse effects/analogs & derivatives/pharmacology ; Human ; Isoxazoles/adverse effects/pharmacology ; Propylene Glycols/adverse effects/pharmacology ; Triazines/adverse effects/pharmacology ; Vigabatrin ; gamma-Aminobutyric Acid/adverse effects/analogs & derivatives/pharmacology