ANTIRETROVIRAL THERAPIES AND SUBSTANCE ABUSE

描述：(改编自申请者摘要)患者滥用药物 感染人类免疫缺陷病毒(HIV)是一个主要的公众问题 健康问题。大约25%-30%的艾滋病毒感染者已经感染了 通过使用药物而得的疾病；一个主要的治疗目标是维持 禁欲，既是为了患者的健康，也是为了将患病风险降至最低 通过使用美沙酮或丁丙诺啡的维持方案进行传播。 对于这些和其他艾滋病毒感染患者来说，疾病的情感负担 会导致抑郁症、焦虑症和睡眠障碍的共病。 苯二氮卓类激动剂通常用于治疗焦虑和失眠，以及 有人对滥用这类药物表示关切。高度活跃 抗逆转录病毒疗法(HAART)，包括艾滋病毒蛋白酶抑制剂(PI) 和非核苷逆转录酶抑制物(NNRTI)，构成主要 艾滋病毒感染的治疗进展，但极大地复杂化了联系 艾滋病毒/艾滋病和药物滥用之间的关系。HIV PI和NNRT可能抑制和/或 诱导人细胞色素P4503A(CYP3A)酶的活性，负责 丁丙诺啡、美沙酮、许多苯二氮类药物的代谢 可卡因肝脏毒性代谢物的形成。抑制CYP3A可能 促进美沙酮毒性，或增加苯二氮卓类药物的滥用能力；细胞色素P3A 诱导可促进美沙酮的戒断和阿片类药物的复发，或增强 可卡因肝毒性。申请者建议申请在试管模型，使用 人肝微粒体制剂，以确定HIV PI的能力 (利托那韦、奈非那韦、依地那韦、沙奎那韦)和非那维定类药物， 奈韦拉平、依沙韦仑)抑制细胞色素P3A介导的美沙酮代谢， 丁丙诺啡、三唑仑、阿普唑仑、氟硝西潘和可卡因。在体外，在 活体标尺范例将被用于估计临床上 在活体互动中很重要。该模型的有效性将具有前瞻性。 经临床药代动力学-药效学对照研究 三唑仑与利托那韦或地拉韦定和美沙酮合用 与这两种相同的HMRT药物联合使用。时间-过程和程度 利托那韦诱导的细胞色素P3A，以及抑制和诱导的净平衡， 之前在三唑仑动力学和动力学的对照研究中进行了测试， 在长期接触利托那韦期间和之后。体外模型，如果 经过验证，具有提供临床重要信息的潜力 涉及艾滋病毒治疗和可滥用药物的相互作用相对较低 成本高，而且不会暴露于人类药物中。

DESCRIPTION: (Adapted from applicant's abstract) Substance abuse among patients with human immunodeficiency virus (HIV) infection is a matter of major public health concern. Some 25-30 percent of HIV-infected patients have acquired the disease through IV. drug-use; a principal therapeutic objective is to sustain abstinence, both for patients' health and to minimize risk of disease dissemination, through maintenance programs using methadone or buprenorphine. For these and other HIV-infected patients, the emotional burden of the disease produces comorbidity with depression, anxiety, and sleep disorders. Benzodiazepine agonists are commonly prescribe for anxiety and insomnia, and there is concern regarding abuse of this class of drugs. Highly active antiretroviral therapies (HAART), including the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), constitute major advances in the treatment of HIV infecffon, but greatly complicate the link between HIV/AID' and substance abuse. HIV PIs and NNRTls may inhibit and/or induce the activity of human Cytochrome P4503A (CYP3A) enzymes, responsible for the metabolism of buprenorphine, methadone, many benzodiazepines and for the formation of the hepatotoxic metabolite of cocaine. CYP3A inhibition could promote methadone toxicity, or enhance abusability of benzodiazopines; CYP3A induction could precipitate methadone withdrawal and opiate relapse, or enhance cocaine hepatotoxicity. The applicants propose to apply in vitromodels, using human liver microsomal preparations, to determine the capacity of HIV PIs (ritonavir, nelfinavir, indinavir, saquinavir) and of NNRTls tdelavirdine, nevirapine, efavirenz) to inhibit CYP3A-mediated metabolism of methadone, buprenorphine, triazolam, alprazolam, flunitrazepam, and cocaine. In vitro in vivoscaling paradigms will be used to estimate the probability of clinically important in vivointeractions. The validity of the model will be prospectively tested in controlled clinical pharmacokinetic-pharmacodynamic studies of triazolam coadministered with ritonavir or delavirdine, and of methadone coadministered with thes' same two HMRT drugs. The time-course and extent of CYP3A induction by ritonavir, and the net balance of inhibition and induction, are tested in a controlled study of triazolam kinetics and dynamics before, during, and after extended exposure to ritonavir. The in vitro model, if validated, has the potential to provide clinically important information on interactions involving HIV treatments and abusable drugs, at relatively low cost and with no human drug exposure.