Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing - A surrogate marker of brain penetration
Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing - A surrogate marker of brain penetration
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DOI：
10.1002/cncr.10397
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发表时间：
2002-03-15
期刊：
影响因子：
6.2
通讯作者：
de Graaf, SSN
中科院分区：
文献类型：
--
作者：
Kellie, SJ;Barbaric, D;de Graaf, SSN
背景长春新碱（VCR）广泛用于肿瘤学实践，定期给药通常与感觉运动或自主神经病变的发生相关。然而，VCR相关中枢神经系统（CNS）毒性的发生率相对较低，表明血脑屏障可能限制药物渗透到脑实质中。本研究确定了在无原发性CNS病变的儿童中，静脉推注后是否可以在脑脊液（CSF）中检测到可测量浓度的VCR，作为脑实质渗透的替代标志物。方法。作者研究了17例年龄2.5-14.1岁（中位数6.8岁）的急性淋巴细胞白血病或非霍奇金淋巴瘤儿童患者，无软脑膜疾病证据。患者通过静脉推注接受VCR 1.5 mg/m2，然后在全身麻醉下以不同的时间间隔通过腰椎穿刺进行计划的鞘内甲氨蝶呤给药。在VCR注射后8分钟至146分钟的时间范围内，同时测量每例患者血浆和CSF中的成对VCR浓度。3例患者接受了两次研究。将配对样本储存在-40 ℃下，直至使用高效液相色谱法分析，CSF中的灵敏度为0.1 μ g/L，血浆中的灵敏度为0.4 μ g/L。血浆VCR浓度范围为2.2 mug/L至91.2 mug/L。在CSF样本中未检测到可测量的VCR浓度。VCR标准静脉推注给药后，CSF中VCR浓度无法测量。目前的观察结果与VCR相关CNS神经毒性相对罕见相一致，与通常观察到的感觉运动和自主神经病变相比。这些结果表明，VCR渗透到血脑屏障相对完整的患者的脑实质中的程度较低，VCR在这些患者的CNS导向治疗中的作用可能有限。(C)2002年美国癌症协会
BACKGROUND. Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology.METHODS. The authors studied 17 pediatric patients ages 2.5-14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m(2) by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at -40 degreesC until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 mug/L in CSF and 0.4 mug/L in plasma.RESULTS. Plasma VCR concentrations ranged from 2.2 mug/L to 91.2 mug/L. No measurable VCR concentrations were detected in the CSF samples.CONCLUSIONS. Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients. (C) 2002 American Cancer Society