Blacklock J B, Wright D C, Dedrick R L, Blasberg R G, Lutz R J, Doppman J L, Oldfield E H
J Neurosurg. 1986 Feb;64(2):284-91. doi: 10.3171/jns.1986.64.2.0284.
Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo, the authors examined the distribution of drug delivery after internal carotid artery (ICA) infusion in rhesus monkeys. Carbon-14 (14C)-labeled iodoantipyrine was delivered into the ICA of eight monkeys at slow infusion rates (1% to 2% of ICA flow) or at fast infusion rates (20% of ICA flow) combined with additional techniques to promote mixing with ICA blood. Two monkeys received intravenous (IV) 14C-antipyrine. Uniformity of delivery was assessed by comparing high-to-low ratios of isotope concentration in four brain regions evaluated by quantitative autoradiography. There was striking non-uniformity of drug delivery in the slow IA infusion group, with as much as 13-fold differences in drug concentration in anatomically contiguous areas. The values of high-to-low concentration ratios (mean +/- standard deviation) in individual autoradiographic planes were: 1) frontoparietal cortex: slow IA infusion 4.54 +/- 2.07, fast IA infusion 1.71 +/- 0.31, IV infusion 1.30 +/- 0.174; 2) frontoparietal white matter: slow IA infusion 2.94 +/- 1.45, fast IA infusion 1.59 +/- 0.41, IV infusion 1.34 +/- 0.21; 3) temporal cortex: slow IA infusion 5.43 +/- 3.57, fast IA infusion 1.69 +/- 0.24, IV infusion 1.67 +/- 0.25; 4) basal ganglia: slow IA infusion 3.6 +/- 2.9, fast IA infusion 1.18 +/- 0.10, IV infusion 1.09 +/- 0.04. Differences between concentration ratios after slow IA and fast IA infusion are significant (p less than 0.01); those between fast IA and IV infusion are not significant. Intra-arterial drug administration at infusion rates analogous to those currently used clinically results in drug streaming with markedly heterogeneous drug deposition in the perfused hemisphere. This may cause suboptimal drug levels in the tumor, and toxic levels at sites within the perfused hemisphere. This effect can be abrogated by techniques that eliminate drug streaming.
通过动脉内（IA）化疗治疗脑肿瘤偶尔会因脑和视网膜中的局灶性毒性部位而变得复杂。局灶性毒性的一个可能原因是血管内药物流动导致药物递送不均匀。为了在体内研究这种现象，作者检查了恒河猴颈内动脉（ICA）输注后药物递送的分布情况。将碳 - 14（14C）标记的碘安替比林以缓慢输注速率（ICA血流的1%至2%）或快速输注速率（ICA血流的20%）注入八只猴子的ICA，并结合其他技术以促进与ICA血液混合。两只猴子接受静脉内（IV）14C - 安替比林。通过比较定量放射自显影评估的四个脑区中同位素浓度的高与低比率来评估递送的均匀性。在缓慢IA输注组中药物递送存在明显的不均匀性，在解剖学上相邻区域的药物浓度差异高达13倍。各个放射自显影平面中高与低浓度比率（平均值±标准差）的值为：1）额顶叶皮质：缓慢IA输注4.54±2.07，快速IA输注1.71±0.31，IV输注1.30±0.174；2）额顶叶白质：缓慢IA输注2.94±1.45，快速IA输注1.59±0.41，IV输注1.34±0.21；3）颞叶皮质：缓慢IA输注5.43±3.57，快速IA输注1.69±0.24，IV输注1.67±0.25；4）基底神经节：缓慢IA输注3.6±2.9，快速IA输注1.18±0.10，IV输注1.09±0.04。缓慢IA输注和快速IA输注后浓度比率之间的差异具有显著性（p小于0.01）；快速IA输注和IV输注之间的差异不具有显著性。以类似于目前临床使用的输注速率进行动脉内给药会导致药物流动，在灌注半球中药物沉积明显不均匀。这可能导致肿瘤内药物水平不理想，以及在灌注半球内的部位出现毒性水平。这种效应可以通过消除药物流动的技术来消除。
