DRUG TRANSPORT IN BRAIN

高流量微输注脑组织的理论输运模型 已经发展起来，将大脑视为刚性或可变形的 大分子溶液在流动时注入的弹性介质 速率从0.1到6.0 ~l/min。以前的工作表明， 技术允许缓慢降解的大分子获得治疗 体积在至少14至27立方厘米的范围内。 这些计算具有 被扩展到描述更多的反应分子，如神经肽 和生长因子。 穿透深度和相关治疗体积 根据药效学效应计算， 强烈依赖于代谢率。治疗量是预期的， 分别为2.7立方厘米（1.7厘米直径）。和0.5立方厘米（0.98厘米直径） 对于1小时的物质（例如，嵌合神经肽）和10分钟（例如， 生长因子）反应时间。 这种物质实现输液 0.5小时至3小时输注期间的稳态浓度曲线， 与不反应的大分子不同，具有S形轮廓， 陡峭的前线 尽管这些药剂的反应性 减少预期的组织渗透，不会改变相对 这些试剂的高流量微输注提供的优点超过 竞争的低流动性或聚合物溶解方法。 在其他实验 工作，我们已经证实了预测，缓慢清除 大分子白蛋白在灰质中呈球形向外运输 移动的前轮廓直到它遇到灰白色的边界。

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.