CONTINUOUS EXPOSURE ORAL PHENYLBUTYRATE 3 TIME DAILY SCHEDULE

每日连续口服苯丁酸 3 次

• 批准号: 6303298
• 负责人: JANE B ALAVI
• 金额: $ 2.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6303298
• 关键词: carboxylate; central nervous system neoplasms; clinical research; clinical trial phase I; drug administration rate /duration; drug adverse effect; drug screening /evaluation; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplastic process; oral administration; pharmacokinetics

Phenylbutyrate, a potential tumor differentiating agent and possible cytotoxic agent, can be given safely to children and adults with urea cycle disorders. Its safety and toxicity are being evaluated in patients with refractory solid tumors using varied schedules and routes of administration. Most clinical trials to date have excluded patients with primary CNS tumors or patients with CNS metastases because of potential side-effects of altering intracranial pressure. This CNS tumor exclusion is despite pre-clinical models suggesting significant anti-tumor activity of phenylbutyrate against malignant glioblastoma, and other solid tumors. Mechanism of action studies continue in the pre-clinical lab. This study is designed to evaluate the safety and toxicity of orally administered phenylbutyrate given three times daily to patients with refractory CNS tumors until evidence of tumor progression. Theoretically, a tumor-differentiating agent requires chronic administration. This schedule examines the tolerability of continued exposure phenylbutyrate. Attempts to excalate the dose of drug will be monitored by pharmacokinectics to achieve desired plasma levels of 2-6 mmol/L. To assist the laboratory with possible mechanisms of action of phenylbutyrate, various bioassays and tissue specimens will be evaluated to determine in vivo bioactivity of the drug. Purpose: 1) To determine maximum tolerated dose of phenylbutyrate taken 3 times a day in patients with relapsed gliomas. 2) To describe the pharmacokinetics of oral phenylbutyrate, attempting to achieve plasma levels of 2-6 mmole/L. 3) To evaluate therapeutic activity and correlate with bioassays.

苯丁酸是一种潜在的肿瘤分化剂和可能的细胞毒性剂，可以安全地用于患有尿素循环障碍的儿童和成人。 其安全性和毒性正在使用不同的时间表和给药途径在难治性实体瘤患者中进行评估。 迄今为止，大多数临床试验排除了原发性CNS肿瘤患者或CNS转移患者，因为改变颅内压的潜在副作用。 尽管临床前模型表明苯丁酸盐对恶性胶质母细胞瘤和其他实体瘤具有显著的抗肿瘤活性，但该CNS肿瘤排除。在临床前实验室中继续进行作用机制研究。本研究旨在评价难治性CNS肿瘤患者每日三次口服苯丁酸盐的安全性和毒性，直至出现肿瘤进展证据。理论上，肿瘤分化剂需要长期施用。 该时间表检查了持续暴露苯丁酸盐的耐受性。 将通过药代动力学监测增加药物剂量的尝试，以达到2-6 mmol/L的预期血浆水平。为了帮助实验室了解苯丁酸盐的可能作用机制，将对各种生物测定和组织标本进行评价，以确定药物的体内生物活性。目的：1）确定苯丁酸盐每日3次治疗复发性胶质瘤的最大耐受剂量。2)描述口服苯丁酸盐的药代动力学，试图达到2-6 mmole/L的血浆水平。3)评价治疗活性并与生物测定相关。