CONTINUOUS EXPOSURE ORAL PHENYLBUTYRATE 3 TIME DAILY SCHEDULE

苯丁酸盐是一种潜在的肿瘤鉴别剂和可能的细胞毒性药物，可以安全地给予尿素循环障碍的儿童和成人。它的安全性和毒性正在对难治性实体瘤患者使用不同的时间表和给药途径进行评估。到目前为止，大多数临床试验都排除了原发性中枢神经系统肿瘤患者或中枢神经系统转移患者，因为改变颅内压的潜在副作用。尽管临床前模型显示苯基丁酸酯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，但中枢神经系统肿瘤排除。作用机制的研究继续在临床前实验室进行。本研究旨在评估难治性中枢神经系统肿瘤患者每日三次口服苯基丁酸酯的安全性和毒性，直至肿瘤进展。从理论上讲，肿瘤分化剂需要长期给药。本进度表检查持续接触苯丁酸盐的耐受性。计算药物剂量的尝试将通过药物动力学监测，以达到所需的血浆水平2-6毫摩尔/升。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估，以确定药物的体内生物活性。目的：1)确定复发胶质瘤患者每日服用3次苯基丁酸酯的最大耐受剂量。2)描述口服苯丁酸酯的药代动力学，试图达到2-6 mmol /L的血浆水平。3)评价治疗活性并与生物测定相关联。

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.