Zünkeler B, Carson R E, Olson J, Blasberg R G, DeVroom H, Lutz R J, Saris S C, Wright D C, Kammerer W, Patronas N J, Dedrick R L, Herscovitch P, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosurg. 1996 Dec;85(6):1056-65. doi: 10.3171/jns.1996.85.6.1056.
Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 +/- 1.4 and 34.1 +/- 22.1 microl/minute/ml (+/- standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 +/- 11.7 and 19.7 +/- 10.7 microl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 +/- 3.8 and 4.2 +/- 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 microM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.
通过向脑动脉输注甘露醇产生的高渗性血脑屏障破坏（HBBBD）已被用于治疗脑肿瘤，以增加药物向肿瘤及邻近脑组织的递送。然而，HBBBD在脑肿瘤治疗中的疗效一直存在争议。本研究的目的是测量恶性脑肿瘤患者HBBBD后血管通透性的变化。在HBBBD之前及之后以8至15分钟的间隔重复使用铷-82和正电子发射断层扫描测量肿瘤和正常脑血管的通透性（K1）。对13例患者进行了18项研究，其中8例为多形性胶质母细胞瘤，5例为间变性星形细胞瘤。HBBBD使所有患者的K1增加。脑和肿瘤的基线K1值分别为2.1±1.4和34.1±22.1微升/分钟/毫升（±标准差）。HBBBD后K1的绝对峰值增加在脑和肿瘤中分别为20.8±11.7和19.7±10.7微升/分钟/毫升，对应于脑内增加约1000%，肿瘤内增加约60%。脑和肿瘤的K1恢复至接近基线的半衰期分别为8.1±3.8分钟和4.2±1.2分钟。使用含有动脉内甲氨蝶呤的非常简单的模型对HBBBD的效果进行模拟，甲氨蝶呤是低通透性药物的典型代表，结果表明：1）通过甲氨蝶呤浓度-时间积分（或曲线下面积）测量，脑和肿瘤对甲氨蝶呤的总暴露量会随着输注持续时间的缩短而增加，与单独动脉内输注甲氨蝶呤相比，分别会增加130%至200%和7%至16%；2）在高于1微摩尔/升（甲氨蝶呤产生作用所需的最低浓度）的浓度下的暴露时间在肿瘤中不会增加，在脑中仅增加10%。高渗性血脑屏障破坏会短暂增加水溶性化合物向正常脑和脑肿瘤的递送。大部分暴露增强是由于药物被困在血脑屏障内，这是HBBBD对血脑屏障非常短暂改变的结果。在破坏后5至10分钟内给药时递送最有效。然而，甲氨蝶呤（其通透性在目前临床使用的药物中处于最低水平之一）出现的暴露增加和暴露时间增加是有限的，并且与肿瘤暴露相比，脑暴露的不成比例增加可能会改变许多药物的治疗指数。
