HAART Regimens in Substance Abusers

描述：高效抗逆转录病毒疗法的可用性 （HAART），包括HIV蛋白酶抑制剂（PI）和非核苷逆转录酶抑制剂 转录酶抑制剂（NNRTI），具有延长生存期和改善质量 对艾滋病病毒感染者和艾滋病患者来说，尽管如此， 艾滋病毒感染者的精神疾病和药物滥用共病， 由于药物与HAART组分的相互作用而变得非常复杂。许多HAART 药物是人细胞色素P450 3A（CYP3A）的抑制剂和/或诱导剂 亚型，负责许多精神药物的代谢， 滥用药物和药物滥用治疗。HAART药物也可抑制 和/或诱导P-糖蛋白（P-gp）的活性， 在胃肠道生物利用度和中枢神经系统进入的一些药物， 外国化学品HAART组分通过其对CYP3A或P-gp的作用， 可能：a）降低效力，增强毒性，或增强药物的可滥用性 合法处方的精神药物; B）增加非法药物的毒性 c）降低用于治疗的药剂的功效或增加其毒性 滥用药物我们提出了一系列协调的临床，实验， 体外和细胞培养研究，旨在开发一种范式， 这些相互作用的机制和后果可以迅速 评估，最终目标是制定基于 在实验和体外模型上。临床研究的目的是 开发和验证探针方法，用于同时定量 人体中的CYP3A（使用咪达唑仑）和P-gp活性（使用非索非那定） 受试者;随后该方法用于评估CYP3A和P-gp 初始和延长暴露于利托那韦的抑制和诱导， 地拉韦啶和奈韦拉平。细胞培养模型将评估P-gp介导的 运输各种精神药物、可能被滥用的药物，以及 药物滥用治疗，以及P-gp表达的调节 长期暴露于HAART成分和与物质相关的试剂 虐待这些模型的开发和验证应该会导致更多的 快速测试与HAART化合物的相互作用，最终更安全 更有效地治疗共病药物滥用障碍，或 艾滋病病毒感染者的精神疾病。

DESCRIPTION: The availability of highly active antiretroviral therapies (HAART), including the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), has prolonged survival and improved quality of life for individuals with HIV infection and AIDS. Nonetheless treatment of comorbid psychiatric illness and substance abuse in HIV-infected patients is greatly complicated by drug interactions with HAART components. Many HAART agents are inhibitors and/or inducers of human Cytochrome P450 3A (CYP3A) isoforms, responsible for metabolism of many psychotropic drugs, potentially abusable drugs, and substance abuse treatments. HAART agents may also inhibit and/or induce activity of P-glycoprotein (P-gp), a transport protein involved in gastrointestinal bioavailability and CNS entry of a number of drugs and foreign chemicals. HAART components, through their actions on CYP3A or P-gp, may: a) Reduce efficacy, enhance toxicity, or enhance abusability of legitimately prescribed psychotropic drugs; b) Increase toxicity of illegal drugs of abuse; c) Reduce efficacy or increase toxicity of agents used to treat substance abuse. We propose a coordinated series of clinical, experimental, in vitro and cell culture studies designed to develop a paradigm whereby the mechanisms and consequences of these interactions can be expeditiously evaluated, with the ultimate objective of developing predictive schemes based on experimental and in vitro models. Clinical studies have the objective of developing and validating a probe approach for simultaneous quantitation of CYP3A (using midazolam) and P-gp activity (using fexofenadine) in human subjects; subsequently the method is applied to assessing CYP3A and P-gp inhibition and induction with initial and extended exposure to ritonavir, delavirdine, and nevirapine. Cell culture models will assess P-gp mediated transport of various psychotropic drugs, potentially abusable drugs, and substance abuse treatments, as well as regulation of P-gp expression by extended exposure to HAART components, and to agents pertinent to substance abuse. The development and validation of these models should lead to more expeditious testing of interactions with HAART compounds, and ultimately safer and more effective treatment of comorbid substance abuse disorders or psychiatric illness in HIV-infected individuals.