Pharmacogenetics of Opioid Agonist Therapy

阿片类激动剂治疗的药物遗传学

基本信息

批准号：
8628541
负责人：
Wade H Berrettini
金额：
$ 25.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628541
关键词：
Address Admission activity African American Age Agonist Alleles American Biological Markers Blood Brain Buprenorphine Chronic Clinical Clinical Trials Network DNA Data Disease Eligibility Determination Epidemic Equation Ethnic Origin European Evaluable Disease FDA approved Gender Gene Frequency Genes Genotype Hepatotoxicity Heroin Heroin Dependence Individual Interview Introns Lead Linkage Disequilibrium Measures Medical Records Medical center Medicine Methadone Methods Naloxone National Institute of Drug Abuse Opiate Addiction Opioid Opioid Receptor Outcome Measure Patients Persons Pharmaceutical Preparations Pharmacogenetics Phenotype Philadelphia Physicians Population Preclinical Drug Evaluation Preparation Probability Property Receptor Gene Relative Risks Research Sampling Screening Result Serum Single Nucleotide Polymorphism Structure System Testing Therapeutic Transaminases Treatment outcome United States Department of Veterans Affairs United States Substance Abuse and Mental Health Services Administration Urine Variant Venous blood sampling Woman arm design improved kappa opioid receptors liver function mu opioid receptors open label prescription opioid prescription opioid abuse public health relevance research study response substance abuse treatment treatment center

项目摘要

Abstract Methadone (MET) and buprenorphine/naloxone (BUP) are two distinct FDA-approved agonist medications for treatment of opioid addiction. There are prominent pharmacologic differences between BUP and MET. MET is a full mu agonist, while BUP is a partial mu agonist~ BUP has kappa antagonist properties, while MET is devoid of kappa antagonism. At present it is not possible to use clinical or biomarker predictors to determine who will most likely benefit from one medication versus the other. Recent research has suggested that a common variation in the delta opioid receptor gene (OPRD1), single nucleotide polymorphism (SNP) rs678849, may predict response (urine drug screen for illicit opioids) among African-Americans (AAs) to these medications. AA opioid addicts with a CC genotype at rs678849 have a greater probability of gaining substantial therapeutic benefit from MET, while those with alternative genotypes (C/T + TT) have a greater probability to responding well to BUP (relative risk = 2.8~ p = 2.2 x 10-5). The current project represents an attempt to confirm the original finding in an independent population. Individuals of AA ethnicity, age at least 18, being treated with methadone (n = 150) or buprenorphine/naloxone (n = 150) for opioid addiction at treatment centers in New Haven and the Philadelphia Veterans Administration Medical Center, will be invited to participate. Participation involves review of medical records (to determine eligibility and response to treatment), a brief semi-structured interview and a single small (5 ml) venous blood sample. Blood will be used for DNA extraction and the rs678849 SNP will be genotyped. Genotype x treatment interaction analysis is planned, including as co-variates age, gender, age-at-onset of opioid addiction, co-morbid disorders~ urine drug screen results for opioids during the most recent 20 weeks is the sole endpoint. This phenotype will be analyzed also using generalized estimating equation methods, with the urine drug screen results treated as repeated measures. If the original observation is confirmed, this research may lead to a simple and inexpensive test for optimal agonist treatment of opioid addiction among African- Americans.

抽象的美沙酮 (MET) 和丁丙诺啡/纳洛酮 (BUP) 是 FDA 批准的两种不同的激动剂用于治疗阿片类药物成瘾的药物。 BUP 与 BUP 之间存在显着的药理学差异和MET。 MET是完全mu激动剂，而BUP是部分mu激动剂~BUP具有kappa拮抗剂特性，而 MET 则缺乏 kappa 拮抗作用。目前不可能使用临床或生物标志物预测因子以确定谁最有可能从一种药物与另一种药物中受益。最近的研究有表明 δ 阿片受体基因 (OPRD1) 的一个常见变异，即单核苷酸多态性 (SNP) rs678849，可以预测非裔美国人 (AA) 的反应（尿液药物筛查非法阿片类药物）这些药物。 rs678849 具有 CC 基因型的 AA 阿片类药物成瘾者有更大的概率获得 MET 具有显着的治疗益处，而具有替代基因型 (C/T + TT) 的患者则具有更大的治疗益处对 BUP 反应良好的概率（相对风险 = 2.8~ p = 2.2 x 10-5）。当前的项目试图在独立人群中证实最初的发现。 AA 族裔、年龄至少 18 岁、正在接受美沙酮 (n = 150) 或丁丙诺啡/纳洛酮治疗的个体 (n = 150) 在纽黑文和费城退伍军人管理局治疗中心治疗阿片类药物成瘾医疗中心将受邀参加。参与涉及医疗记录审查（以确定资格和对治疗的反应）、简短的半结构化访谈和单次少量（5 毫升）静脉血样本。血液将用于提取 DNA，并对 rs678849 SNP 进行基因分型。基因型x 计划进行治疗相互作用分析，包括年龄、性别、阿片类药物的发病年龄作为协变量成瘾、共存疾病~ 最近 20 周内阿片类药物尿液药物筛查结果是唯一的终点。该表型也将使用广义估计方程方法进行分析，其中尿液药物筛查结果被视为重复测量。如果最初的观察得到证实，这项研究可能会导致一种简单且廉价的测试，用于非洲人阿片类药物成瘾的最佳激动剂治疗美国人。