Pharmacogenetics of Opioid Agonist Therapy

阿片类激动剂治疗的药物遗传学

• 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
• 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

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.

摘要 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之间存在显著的药理学差异， 和MET。 MET是一种完全的mu激动剂，而BUP是一种部分的mu激动剂，BUP具有κ拮抗剂特性， 而MET缺乏κ拮抗作用。 目前还不可能使用临床或生物标志物预测 以确定谁最有可能从一种药物和另一种药物中受益。 最近的研究 表明δ阿片受体基因（OPRD 1）的一种常见变异，即单核苷酸多态性， (SNP)rs678849可以预测非裔美国人（AAs）对阿片类药物的反应（尿液药物筛查非法阿片类药物） 这些药物。 在rs678849处具有CC基因型的AA阿片类成瘾者获得 MET具有显著的治疗益处，而具有替代基因型（C/T + TT）的患者具有更大的 对BUP反应良好的概率（相对危险度= 2.8~ p = 2.2 × 10-5）。 目前的项目代表了在独立人群中确认原始发现的尝试。 年龄至少18岁的AA种族个体，正在接受美沙酮（n = 150）或丁丙诺啡/纳洛酮治疗 （n = 150）在纽黑文和费城退伍军人管理局的治疗中心治疗阿片类药物成瘾 医疗中心，将被邀请参加。 参与包括审查医疗记录（以确定 合格性和对治疗的反应）、简短的半结构化访谈和单次少量（5 ml）静脉采血 sample. 将使用血液进行DNA提取，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，包括作为协变量的年龄、性别、阿片类药物开始使用时的年龄 成瘾，共病疾病-最近20周内阿片类药物的尿液药物筛查结果是 唯一的终点 还将使用广义估计方程方法分析该表型， 尿液药物筛查结果视为重复测量。如果最初的观察得到证实，这项研究 可能导致一种简单而廉价的测试，用于非洲阿片类药物成瘾的最佳激动剂治疗- 美国人