ANTIRETROVIRAL THERAPIES AND SUBSTANCE ABUSE

描述：（改编自申请人摘要）患者中的药物滥用 人类免疫缺陷病毒（HIV）感染是一个主要的公众问题， 健康问题。大约25- 30%的艾滋病毒感染者获得了 疾病通过IV。药物使用;主要治疗目标是维持 禁欲，既为了病人的健康，也为了尽量减少疾病的风险 通过使用美沙酮或丁丙诺啡的维持方案传播。 对于这些和其他艾滋病毒感染者来说，这种疾病的情感负担 会导致抑郁焦虑和睡眠障碍 苯二氮卓激动剂通常用于治疗焦虑和失眠， 这类药物的滥用情况令人关注。高活性 抗逆转录病毒疗法（HAART），包括HIV蛋白酶抑制剂（PI） 和非核苷类逆转录酶抑制剂（NNRTI），构成了 艾滋病毒感染治疗的进展，但大大复杂的联系， 艾滋病和药物滥用之间的联系HIV PI和NNRT 1可抑制和/或 诱导人细胞色素P4503 A（CYP 3A）酶的活性， 丁丙诺啡、美沙酮、许多苯二氮卓类药物的代谢， 可卡因的肝毒性代谢物的形成。CYP 3A抑制可以 促进美沙酮毒性，或增强苯二氮卓类药物的滥用; CYP 3A 诱导可以加速美沙酮戒断和阿片类药物复吸，或增强 可卡因肝毒性申请人建议在体外模型中使用 人肝微粒体制剂，以确定HIV PI的能力 （利托那韦、奈非那韦、茚地那韦、沙奎那韦）和NNRT类地拉韦啶， 奈韦拉平，依法韦仑）抑制CYP 3A介导的美沙酮代谢， 丁丙诺啡、三唑仑、阿普唑仑、氟硝西泮和可卡因。体外 将使用活体定标范例来估计临床上 重要的是体内相互作用。该模型的有效性具有前瞻性 在对照临床药代动力学-药效学研究中进行了检测， 三唑仑与利托那韦或地拉韦啶联合给药，以及美沙酮 与同样的两种HMRT药物联合给药。时间进程和程度 利托那韦对CYP 3A的诱导，以及抑制和诱导的净平衡， 在三唑仑动力学和动力学的对照研究中进行了测试， 在长期暴露于利托那韦期间和之后。体外模型，如果 经验证，有可能提供临床重要信息， 涉及艾滋病毒治疗和可滥用药物的相互作用， 成本和没有人类药物暴露。

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.