CLINICAL PHARMACOLOGY

临床药理学

• 批准号: 3896337
• 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/3896337
• 关键词: 6 thiopurine; CD4 molecule; antiAIDS agent; antileukemic agent; antineoplastics; antiviral agents; central nervous system neoplasms; child (0-11); combination chemotherapy; disease /disorder model; dosage; drug administration routes; drug adverse effect; drug metabolism; human subject; human therapy evaluation; injection /infusion; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nucleotide analog; pediatric neoplasm /cancer; pharmacokinetics; prodrugs; thiotepa

The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies is studied with emphasis on the role of pharmacologic monitoring and on both preclinical 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 Fazarabine, Piritrexim, and Thiotepa plus GM-CSF are in progress. A major effort of this project is to study 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 and continuous intrathecal 6-MP, approaches developed in this model, are in progress. Preclinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices 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. We have focused on several areas of research. An in vitro model utilizing a human CD4 positive cell line has been established to study the biochemical pharmacology of the dideoxynucleosides which are prodrugs that require intracellular activation to their corresponding triphosphorylated nucleotide. The CNS pharmacology of the antiretroviral is being systematically evaluated in our nonhuman primate model, to determine which agents may be most effective against the 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 children treated on these trials.

用于治疗肿瘤的抗肿瘤药物的临床药理学 对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药理学 I 期药物的研究。口服给药的临床药理学 抗白血病药物已被评估，但其生物利用度有限 口服给药后达到的 6-MP 的可变药物水平 已被记录。正在进行研究以确定这种情况的程度 现象是治疗失败的原因。临床前和临床 多种新药的药代动力学研究，包括法扎拉宾、 Piritrexim 和 Thiotepa 联合 GM-CSF 正在进行中。 一项重大努力 该项目旨在研究治疗中枢神经系统的实验方法 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 药物时间表。然后从该模型的研究中获得的信息 应用于临床治疗方案的设计。协议评估 策略，例如延长静脉内 6-MP 输注和静脉注射 噻替派治疗脑肿瘤的研究正在进行中。鞘内注射的临床研究 AZQ 和连续鞘内 6-MP，在此模型中开发的方法， 正在进行中。评估脑脊液内药物的临床前研究 通过留置给药装置进行给药正在进行中。作为一部分 儿科艾滋病研究工作的白血病生物学科 正在研究儿童抗逆转录病毒药物的临床药理学。 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，因为大多数抗逆转录病毒药物 药物是核苷类似物，类似于中使用的抗代谢药 ALL 的治疗。我们专注于几个研究领域。体外 已建立利用人类 CD4 阳性细胞系的模型 研究双脱氧核苷的生化药理学 需要细胞内激活其相应的前药 三磷酸化核苷酸。抗逆转录病毒药物的中枢神经系统药理学是 在我们的非人类灵长类动物模型中进行系统评估，以确定 哪些药物可能对中枢神经系统艾滋病毒感染最有效。我们有 还参与了抗逆转录病毒药物临床试验的设计 在儿童中进行了详细的药代动力学研究 在这些试验中接受治疗。