Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

ADHD 中的羧酸酯酶 1 遗传变异和哌醋甲酯

基本信息

批准号：
9981428
负责人：
JOHN S MARKOWITZ
金额：
$ 57.54万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981428
关键词：
17 year old Adolescent Adult Adverse effects Adverse event Affect Age Attention deficit hyperactivity disorder Basic Science Behavior Biological Markers Blood Carboxylesterase 1 Child Childhood Chronic Clinical Clinical Research Clinical Trials Data Development Diagnosis Dose Drug Kinetics Enzymes Exhibits Frequencies Gene Frequency General Population Genes Genetic Markers Genetic Variation Genotype Hepatic Hyperactive behavior Impairment Impulsivity In Vitro Individual Lead Measures Metabolism Minor Molecular Genetics Neurodevelopmental Disorder Oral Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacogenomics Pharmacotherapy Proteomics Regimen Research Risk Ritalin Safety Testing Toxic effect Translating Variant Withdrawal adverse drug reaction aged clinical efficacy clinically relevant clinically significant dopamine transporter dosage drug response prediction evidence base expectation experience genetic variant healthy volunteer improved inattention individual patient individual variation inter-individual variation neuropsychiatric disorder novel pediatric patients pharmacokinetics and pharmacodynamics predictive marker protein expression psychostimulant response stimulant use sudden cardiac death therapy outcome treatment response

项目摘要

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder of childhood in the US. As of 2011, approximately 6.4 million children between the ages of 4 and 17 years of age have received a diagnosis of ADHD. Of these individuals, approximately 60% will be prescribed medication and the psychostimulant d,l-methylphenidate (MPH). In 2010, MPH was the most frequently prescribed medication of any type in adolescents aged 12-17 yrs. There is significant variability between individual patients in terms of blood concentrations measured (i.e. pharmacokinetics [PK]), clinical response, and adverse effects in individuals on the same dosage. Some severe adverse drug reactions (ADRs)-including sudden cardiac death--have been associated with MPH, although the precise reasons for these associations remain controversial. Up to 35% of AHDH patients do not respond satisfactorily to MPH therapy. Presently, there is no specific test or biomarker predictive of who will have a positive or negative response to or adverse effects from MPH treatment. The major hepatic enzyme carboxylesterase 1 (CES1) is responsible for MPH metabolism/deactivation. This project proposes to further identify and characterize genetic variants that affect CES1 expression and activity and reveal key associations between CES1 genotypes and the PK and pharmacodynamics (PD) of MPH in ADHD patients. This project will produce clinically relevant data, with great potential to improve the safety and clinical efficacy of MPH treatment in tens of thousands of patients annually. Study results can quickly be translated and adapted to clinical use in evidence-based strategies applied to drug selection and dosing in patients with ADHD and those medicated with other CES1 substrates.

注意缺陷/多动症（ADHD）是最常见的神经精神障碍在美国的童年。截至2011年，大约640万儿童在4岁至4岁之间 17岁的人已诊断为多动症。在这些人中，大约60％将被处方药和精神刺激剂D，L-甲基苯甲酯（MPH）。在2010年， MPH是12 - 17岁的青少年中最常开处方的药物。单个患者在血液浓度方面存在显着差异测量的（即药代动力学[PK]），临床反应和个体的不良影响相同的剂量。一些严重的不良药物反应（ADR） - 包括心脏突然死亡 - 与MPH相关，尽管这些关联的确切原因是保持争议。多达35％的AHDH患者对MPH疗法没有令人满意的反应。目前，没有特定的测试或生物标志物可以预测谁将具有正面或负面对MPH治疗的反应或不良影响。主要的肝酶羧酸酯酶1（CES1）负责MPH代谢/失活。这个项目提议进一步识别和表征影响CES1的遗传变异表达和活性并揭示了CES1基因型与PK和PK之间的关键关联 ADHD患者MPH的药效学（PD）。该项目将产生与临床相关的数据，具有提高安全性和 MPH治疗在每年数万患者中的临床疗效。研究结果可以快速翻译并适用于应用的基于证据的策略的临床用途在患有多动症患者和其他CES 1的患者中选择药物和给药。基材。