Department of Neurological Surgery, University of Miami Miller School of Medicine and Miami Children's Hospital, Ambulatory Care Building Suite 3109, Miami, FL 33155, USA.
J Neurooncol. 2010 Mar;97(1):25-32. doi: 10.1007/s11060-009-9998-x. Epub 2009 Aug 18.
We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle potentially may play a role in treating malignant posterior fossa brain tumors. Accordingly, we used a piglet model developed in our laboratory to test the safety of etoposide infusions into the fourth ventricle and to study the pharmacokinetics associated with these infusions. In 5 piglets, closed-tip silicone catheters were inserted into the fourth ventricle and lumbar cistern. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. Serum and CSF from both catheters were sampled for measurement of etoposide level by reversed-phase high performance liquid chromatography (HPLC). For CSF samples, area under the concentration-time curve (AUC) was calculated. Piglets underwent daily neurological examinations, a 4.7 Tesla MRI scan, and then were sacrificed for post-mortem brain examination. No neurological deficits or signs of meningitis were caused by intraventricular chemotherapy infusions. MRI scans showed catheter placement within the fourth ventricle but no signal changes in the brain stem or cerebellum. In all piglets, the mean fourth ventricular CSF peak etoposide level exceeded the mean peak lumbar etoposide levels by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC were noted at peaks (DeltaAUC = 3384196 ng h/ml with 95%CI: 1758625, 5009767, P = 0.0044) and at all collection time points (DeltaAUC = 1422977 ng h/ml with 95%CI: 732188, 2113766, P = 0.0046) but not at troughs (DeltaAUC = -29546 ng h/ml (95%CI: -147526, 88434.2, P = 0.5251). Serum etoposide was absent at two and four hours after intraventricular infusions in all animals. Pathological analysis demonstrated meningitis, choroid plexitis, and ependymitis in the fourth and occasionally lateral ventricles. Etoposide can be infused directly into the fourth ventricle without clinical or radiographic evidence of damage. Autopsy examination revealed ventriculitis and meningitis which did not have a clinical correlate. Etoposide does not distribute evenly throughout CSF spaces after administration into the fourth ventricle, and higher peak CSF levels are observed in the fourth ventricle than in the lumbar cistern.
我们假设将化疗药物直接注入第四脑室可能在治疗恶性后颅窝脑肿瘤方面发挥作用。因此，我们使用我们实验室开发的小猪模型来测试顺铂脑室输注的安全性，并研究与这些输注相关的药代动力学。在 5 头小猪中，将封闭尖端硅酮导管插入第四脑室和腰池。通过第四脑室导管连续 5 天每天输注顺铂（0.5mg）。通过反相高效液相色谱法（HPLC）从两个导管的血清和 CSF 中取样以测量顺铂水平。对于 CSF 样本，计算浓度-时间曲线下面积（AUC）。小猪每天接受神经学检查、4.7T MRI 扫描，然后处死进行死后脑检查。脑室化疗输注未引起神经功能缺损或脑膜炎迹象。MRI 扫描显示导管位于第四脑室，但脑干或小脑无信号变化。在所有小猪中，第四脑室 CSF 顺铂峰浓度均高于腰池顺铂峰浓度 10 倍以上。在峰值时，第四脑室和腰池 AUC 之间存在统计学显著差异（DeltaAUC = 3384196ng h/ml，95%CI：1758625，5009767，P = 0.0044）和所有采集时间点（DeltaAUC = 1422977ng h/ml，95%CI：732188，2113766，P = 0.0046），但在低谷时没有差异（DeltaAUC = -29546ng h/ml（95%CI：-147526，88434.2，P = 0.5251）。所有动物在脑室输注后 2 小时和 4 小时时血清顺铂均不存在。组织病理学分析显示第四脑室和偶尔侧脑室有脑膜炎、脉络丛炎和室管膜炎。顺铂可以直接注入第四脑室，而没有临床或影像学损伤的证据。尸检显示脑室炎和脑膜炎，与临床无相关性。顺铂注入第四脑室后不会均匀分布于 CSF 间隙，第四脑室 CSF 峰浓度高于腰池。
