DEVELOPMENTAL PHARMACOLOGY RESEARCH

调查人员表示，快速致命的感染和恶性肿瘤 在感染艾滋病毒的患者中，促使使用多种药物和 药物组合。其中许多药物还没有得到充分的评估， 在临床上出现的多种组合中，很少有人被评估过 练习一下。此应用程序描述了一种基于数据的方法 这些药物的临床药理及药理研究进展 组合。一般的做法是进行试验性研究，以 筛选药物相互作用或不良反应的预测因素。临床 然后将使用专门设计的药物进行药理学研究 方案在更多的患者中使用。 具体目标如下：(1)一是检测和量化 治疗药物之间的药代动力学和动力学相互作用 感染艾滋病毒的患者。(2)其次，申请者将评估 这些药物在特殊人群中的药代动力学， 包括少数民族、妇女以及营养不良、酗酒的人， 静脉吸毒、艾滋病胃肠病和艾滋病心肌病。(3) 接下来，申请者将尝试确定个人间的来源 对治疗的反应和坚持程度不同。由于遗传 基因多态是导致对大的 药物数量，所有在该ACTG网站登记的患者将被要求 志愿者用安全的原型药物进行简单的测试，以确定他们的 药物代谢多态的表型(例如，N-乙酰化、CYP2D6、 细胞色素P3A4、甲苯妥英P450)。对于在治疗期间不能戒毒的患者 基线测试，他们的CYP2D6基因将从0.5毫升 使用基于聚合酶链式反应(PCR)的分析方法采集血液样本。这个 这些多态中的每一个的预测能力都将通过 将它们在患者体内的常见分布进行比较 药品不良反应(ADRs)。这些研究的结果， 申请者声明，应使个人身份识别成为可能 增加不良反应或药物相互作用的风险。此外，生物的 将对这些因素进行分析，以检验它们可能影响 个人在决定接受调查性治疗或 遵守或遵守研究方案。 虽然要进行的确切研究只能在 由ACTU协调委员会、申请者进行协商和审查 在此建议进行一项具体研究，以评估 磷灰石(PFA)、血清电解质变化和心脏电生理。 也是评价药物-药物相互作用的一般方案 (特定目标#1)和特殊人群的药代动力学(特定目标 #2)进行了描述。来自这些研究的信息应该允许 医生为HIV感染患者提供护理为主的治疗 更好地了解其行动和不利影响的风险。

The investigators state that the rapid lethal infections and malignancies in patients with HIV infection prompts the use of many varied drugs and drug combinations. Many of these drugs have not been fully evaluated and few have been evaluated in the multiple combinations that occur in clinical practice. This application describes a data-based approach to the investigation of the clinical pharmacology of these drugs and their combinations. The general approach will be to conduct pilot studies to screen for drug interactions or predictors of adverse reactions. Clinical pharmacology studies will then be conducted using specifically designed protocols in larger numbers of patients. The specific aims are as follows: (1) The first is to detect and quantify pharmacokinetic and dynamic interactions between drugs used to treat patients with HIV infection. (2) Second, the applicants will evaluate the pharmacokinetics of these drugs in special populations of patients, including minorities, women, and those with malnutrition, alcoholism, intravenous drug use, AIDS gastroenteropathy and AIDS cardiomyopathy. (3) Next, the applicants will attempt to identify sources of inter-individual variation in response and adherence to therapy. Since genetic polymorphisms are responsible for adverse or aberrant responses to a large number of drugs, all patients enrolled at this ACTG site will be asked to volunteer for simple tests with safe prototypic drugs to identify their phenotype for polymorphic drug metabolism (e.g., N-acetylation, CYP2D6, CYP3A4, mephenytoin P450). For patients who cannot be drug free during baseline testing, their CYP2D6 genotype will be determined from a 0.5-ml blood sample using a polymerase chain reaction (PCR)-based assay. The predictive power of each of these polymorphisms will be examined by comparing their usual distributions to those in patients who develop adverse drug reactions (ADRs). The results of these studies, the applicants state, should make possible the identification of individuals at increased risk of ADRs or drug interactions. Additionally, the biological factors will be analyzed to test the hypothesis that they may influence the behavior of individuals in deciding to receive investigational therapy or to remain in, or comply with, a study protocol. Although the exact studies to be performed can only be determined after consultation and review by the ACTU coordinating committees, the applicants propose herein a specific study to evaluate the relationship between foscarnet (PFA), serum electrolyte changes and cardiac electrophysiology. Also general protocols for the evaluation of drug-drug interactions (specific aim #1) and pharmacokinetics in special populations (specific Aim #2) are described. The information from these studies should allow physicians caring for patients with HIV infection to provide therapy based on a greater understanding of its actions and risks for adverse effects.