DRUG TRANSPORT IN BRAIN

大流量微量脑内输注的理论模型 已经被开发出来，把大脑当作僵硬的或可变形的 流动时注入大分子溶液的弹性介质 费率为0.1%~6.0%L/分钟。之前的工作已经表明，这一点 技术允许缓慢降解的大分子获得治疗 体积至少在14到27立方厘米之间。这些计算有 被扩展到描述更多的活性分子，例如神经肽 和增长因素。穿透深度和相关的治疗量 基于药效学效应进行了计算，并表明 强烈依赖代谢率。预计治疗量会很大， 分别为2.7立方厘米(1.7厘米直径)和0.5立方厘米(直径0.98厘米) 对于1小时(例如，嵌合神经肽)和10分钟(例如， 生长因子)反应时间。这样的物质可以实现输液 0.5小时至3小时输液的稳态浓度分布， 与不反应的大分子不同，它具有S形轮廓，而不是 险峻的前线。尽管这些试剂的更大的反应性 降低预期的组织渗透率，但不会改变相对 这些药物的高流量微量输注提供的优势 竞争的低流量或聚合物溶解方法。在其他实验中 工作中，我们已经证实了这一预测，即 大分子白蛋白在灰质中呈球状向外运输 有一个移动的正面轮廓，直到它遇到灰白边界。

Theoretical transport models of high-flow microinfusion into brain tissue have been developed, treating the brain as either a rigid or a deformable elastic medium into which macromolecular solutions are infused at flow rates from 0.1 to 6.0 ~l/min. Previous work has shown that this technique allows slowly degraded macromolecules to access treatment volumes in the range of at least 14 to 27 cu cm. These computations have been extended to describe more reactive molecules, such as neuropeptides and growth factors. Penetration depths and associated treatment volumes based on pharmacodynamic effect have been calculated and shown to be strongly dependent on metabolic rate. Treatment volumes are expected, respectively, to be 2.7 cu cm (1.7 cm dia.) and 0.5 cu cm (0.98 cm dia.) for substances of 1-hr (e.g., a chimeric neuropeptide) and 10-min (e.g., a growth factor) reaction times. Such substances achieve infusion steady-state concentration profiles over 0.5-hr to 3-hr infusions and, unlike unreactive macromolecules, possess sigmoidal profiles that lack a precipitous front. Although the greater reactivity of these agents reduces expected tissue penetration, it does not alter the relative advantage that high-flow microinfusion of these agents provides over competing low-flow or polymer-dissolution methods. In other experimental work, we have confirmed the prediction that the slowly clearing macromolecule albumin is transported spherically outward in grey matter with a moving front profile until it encounters a grey-white boundary.