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，可以安全地给予患有尿素循环疾病的儿童和成人。 使用各种计划和给药途径在患有难治性实体瘤的患者中，正在评估其安全性和毒性。 迄今为止，大多数临床试验都排除了原发性中枢神经系统肿瘤或中枢神经系统转移患者，因为颅内压的潜在副作用。 尽管临床前模型表明苯丁酸对恶性胶质母细胞瘤和其他实体瘤的明显抗肿瘤活性，但该中枢神经系统肿瘤排除仍表明苯丁酸苯甲酸酯的显着抗肿瘤活性。行动研究机理在临床前实验室中继续进行。这项研究旨在评估口服苯丁酸苯甲酸苯甲酸苯甲酸苯胺生成酸酯的安全性和毒性，每天三次对难治性中枢神经系统肿瘤患者进行三次，直到肿瘤进展的证据。从理论上讲，肿瘤分化的剂需要长期给药。 该时间表检查了持续暴露苯丁酸的耐受性。 试图通过药代动力学监测药物剂量的尝试，以达到所需的血浆水平为2-6 mmol/L。为了协助实验室采用苯丁酸苯丁酯作用机制，将评估各种生物测定和组织标本以确定药物的体内生物活性。目的：1）确定复发性神经胶质瘤患者每天服用3次苯丁酸苯二甲酸苯甲酸酯的最大耐受剂量。 2）描述口服苯丁酸的药代动力学，试图达到2-6 mmole/L的血浆水平。 3）评估治疗活性并与生物测定相关。