CLINICAL PHARMACOLOGY

临床药理学

• 批准号: 3853240
• 负责人: D G POPLACK
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3853240
• 关键词: 2'3' dideoxynucleoside; 6 thiopurine; AIDS therapy; HIV infections; Primates; antiAIDS agent; antileukemic agent; antineoplastics; antiviral agents; brain neoplasms; central nervous system neoplasms; child (0-11); clinical trials; colony stimulating factor; cyclophosphamide; disease /disorder model; drug administration routes; drug adverse effect; drug delivery systems; drug metabolism; drug screening /evaluation; human subject; human therapy evaluation; human tissue; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neurotoxins; nucleotide analog; pediatric AIDS; pediatric neoplasm /cancer; pharmacokinetics; pyrimidine analog; pyrimidines; retinoate; thiotepa

The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies studied with emphasis on the role of pharmacologic monitoring and on both pre-clinical and clinical pharmacologic studies of Phase I agents. The clinical pharmacology of orally administered antileukemic agents has been evaluated and the limited bioavailability and variable drug levels of 6-MP achieved following oral administration has been documented. Studies are underway to determine the extent to which this phenomenon is the cause of treatment failure. Preclinical and clinical pharmacokinetic studies of a variety of new agents including Piritrexim, All-trans retinoic acid and Thiotepa plus GM-CSF are being completed. A major effort of this project is to investigate experimental approaches to the treatment of CNS malignancy. A unique primate model is utilized to study the CNS pharmacokinetics of various intrathecally and intravenously administered chemotherapeutic agents; to evaluate the neurotoxicities of various CNS treatments; and to evaluate and screen newer CNS treatment modalities and drug schedules. Information gained from the studies with this model is then applied to the design of clinical treatment protocols. Protocols evaluating strategies such as prolonged intravenous 6-MP infusions and intravenous Thiotepa for brain tumors are under way. Clinical studies of intrathecal AZQ, intrathecal 6-MP, and intrathecal mafosfamide, all approaches developed in this model, are in progress. A clinical study evaluating continuous intra-CSF drug infusion via a unique indwelling drug delivery device also is under way. As part of the Pediatric Branch AIDS research effort, the Leukemia Biology Section is studying the clinical pharmacology of antiretroviral agents in children. The study of these agents is a natural extension of our work on the clinical pharmacology of anticancer drugs, since most of the antiretroviral agents are nucleoside analogs, similar to the antimetabolites used in the treatment of ALL. The CNS pharmacology of antiretroviral therapies is being systematically evaluated in our non-human primate model, to determine which agents may be most effective against CNS HIV infection. We have also participated in the design of clinical trials of antiretroviral agents in children and performed detailed pharmacokinetic studies in the patients treated on these trials.

治疗中使用的抗肿瘤药物的临床药理学 儿科恶性肿瘤的研究重点是 药理学监测以及临床前和临床 I 期药物的药理学研究。临床药理学 口服抗白血病药物已被评估， 6-MP 的生物利用度有限且药物水平可变 口服给药后已被记录。 研究正在进行中 以确定这种现象在多大程度上是造成 治疗失败。一种药物的临床前和临床药代动力学研究 吡曲辛、全反式维甲酸等多种新药 噻替派加 GM-CSF 正在完成。 此次的一项重大努力 该项目旨在研究治疗的实验方法 中枢神经系统恶性肿瘤。 利用独特的灵长类动物模型来研究中枢神经系统 鞘内和静脉给药的各种药物的药代动力学 化疗剂；评估各种中枢神经系统的神经毒性 治疗；并评估和筛选新的中枢神经系统治疗方式 和药物时间表。 从该模型的研究中获得的信息 然后应用于临床治疗方案的设计。 评估长期静脉注射 6-MP 等策略的方案 用于治疗脑肿瘤的输注和静脉注射噻替哌正在进行中。 鞘内 AZQ、鞘内 6-MP 和鞘内注射的临床研究 mafosfamide，该模型中开发的所有方法都正在进行中。 一个 评估连续脑脊液内药物输注的临床研究 独特的留置给药装置也在研发中。 作为一部分 儿科艾滋病研究工作、白血病生物学科 正在研究抗逆转录病毒药物的临床药理学 孩子们。 对这些药物的研究是我们工作的自然延伸 抗癌药物的临床药理学研究，大多数 抗逆转录病毒药物是核苷类似物，类似于 用于治疗 ALL 的抗代谢药物。 中枢神经系统药理学 我们正在系统地评估抗逆转录病毒疗法 非人类灵长类动物模型，以确定哪些药物可能最有效 对抗中枢神经系统艾滋病毒感染。 我们也参与了设计 儿童抗逆转录病毒药物的临床试验 对接受这些治疗的患者进行详细的药代动力学研究 试验。