CLINICAL PHARMACOLOGY

临床药理学

• 批准号: 3916639
• 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/3916639
• 关键词: 6 thiopurine; antiAIDS agent; antileukemic agent; antineoplastics; azacitidine; central nervous system neoplasms; cerebrospinal fluid; child (0-11); combination cancer therapy; combination chemotherapy; cytolysis; cytosine arabinoside; diazo compound; disease /disorder model; dosage; drug administration routes; drug adverse effect; drug delivery systems; drug metabolism; drug screening /evaluation; fluorouracil; human subject; human therapy evaluation; injection /infusion; leukemia; meninges; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer radiation therapy; neuropharmacology; pediatric neoplasm /cancer; pharmacokinetics; thiotepa; trimetrexate

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 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. Additional efforts to optimize G-MP administration have been based on in vitro studies which have demonstrated a need for prolonged exposure to cytocidal concentrations of drug to maximize leukemic cell kill. Clinical Phase II protocols evaluating prolonged intravenous 6-MP infusions for acute leukemia, brain tumors and solid tumors are under way. Preclinical and clinical pharmacokinetic studies of a variety of new agents, such as Fazarabine and Piritrexim are in progress. A Phase I study of Thiotepa in pediatric patients has been completed which documents the excellent penetration of this agent into the CNS. 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. Clinical studies of intrathecal AZQ and continuous intrathecal 6MP are in progress. Pre-clinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices is under way. This model has also been used to assess the CNS penetration of a variety of new antiretroviral agents (used to treat AIDS). Clinical pharmacologic support for ongoing Phase I trials in children with AIDS is also pursued in this section.

抗肿瘤药物的临床药理学 儿童恶性肿瘤的治疗研究重点是 药理学监测的作用以及临床前和临床前的作用 I 期药物的临床药理学研究。 临床上 口服抗白血病药物的药理学 评估有限的生物利用度和可变的药物水平 口服给药后达到的 6-MP 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。 额外的努力 优化 G-MP 给药是基于体外研究 已证明需要长时间暴露于杀细胞剂 最大限度地杀死白血病细胞的药物浓度。 临床 评估长期静脉 6-MP 输注的 II 期方案 对于急性白血病、脑肿瘤和实体瘤的研究正在进行中。 多种药物的临床前和临床药代动力学研究 Fazarabine 和 Piritrexim 等新药物正在研发中。 一个 噻替派在儿科患者中的 I 期研究已经完成 这证明了该试剂具有出色的渗透性 中枢神经系统。 该项目的一个主要工作是研究实验 中枢神经系统恶性肿瘤的治疗方法。 独特的灵长类动物 模型用于研究各种中枢神经系统药代动力学 鞘内和静脉内给予化疗 代理；评估各种中枢神经系统治疗的神经毒性 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是 然后应用于临床治疗方案的设计。 鞘内AZQ和连续鞘内6MP的临床研究 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。 该模型还被用来评估中枢神经系统的渗透 多种新型抗逆转录病毒药物（用于治疗艾滋病）。 正在进行的 I 期试验的临床药理学支持 本节还关注患有艾滋病的儿童。