PERIVASCULAR DRUG DELIVERY

然而，当地的药物输送被吹捧为一种令人兴奋的治疗方法 许多疾病的选择，包括心血管病理，这是 理论前景和初步动物研究的激动人心 没有在临床上实现。R01支持的第一阶段提供了帮助 美国认识到：1)地方行政不是地方的同义词 交付，2)我们还没有完全了解潜在的好处， 局部给药的局限性和机制，以及3)药理学 定义和描述系统管理的工具并不完全 描述将药物直接应用于特定节段的事件 脉管壁。 我们已经证明了药物在体内的沉积和分布 局部分娩后的动脉壁复杂且依赖于 壁内运输和绑定过程。我们开发了一种严格的 用于表征局部血管药代动力学的框架，以及 说明了我们预测药物沉积和分布的能力 高分辨率，使用一种模型血管治疗化合物，肝素。在… 与此同时，我们已经展示了监管的复杂性如何 生物靶点(如细胞周期癌基因和生长因子受体) 调节药物的生物效应。因此，任何一个地方的成功 给药策略取决于药物释放动力学与 药物在靶体内的沉积和分布机制 组织，以及靶病变病理的时间序列。 希望通过对其生物学特性的研究，提高其临床实用价值。 通过验证和扩展我们的局部血管来实现血管输送系统 高等动物物种的药代动力学分析，更复杂 动脉结构、状态改变和复杂的动脉病变，以及 具有不同物理化学性质的药物。了解在哪里 药品的分发和储存细节可能不仅确保 充分的药物动力学以实现生物效应，但也将使 研究特定主体在更适用、更完善的模型中的应用 疾病。因此，我们现在寻求： 。确定血管药代动力学模型是否可预测空间 药物在动脉壁内的分布。 。归因于运输和运输的结构和解剖基础 我们观察到的证词。 。药动学参数与溶质化学性质的相关性 对溶质运输至关重要，以及 。检查血管状态改变如何影响药代动力学、药物 沉积和生物效应。

While, local drug delivery has been touted as an exciting therapeutic option for many diseases, including cardiovascular pathologies, this theoretical promise and the excitement of preliminary animal studies has not been realized in the clinic. The first phase of R01 support helped us realize that: 1) local administration is not synonymous with local delivery, 2) we do not yet fully understand the potential benefits, limitations and mechanisms of local delivery, and 3) pharmacological tools that define and characterize systemic administration do not fully describe events when drugs are applied directly to specific segments of the vessel wall. We have shown that the deposition and distribution of drug in the arterial wall following local delivery to be complex and dependent upon intramural transport and binding processes. We developed a rigorous framework by which to characterize local vascular pharmacokinetics, and illustrated our ability to predict drug deposition and distribution with high resolution, using a model vasotherapeutic compound, heparin. At the same time, we have shown how the complexity of the regulation of the biologic target (e.g. cell cycle oncogenes and growth factor receptors) modulates a drug's biologic effect. Thus, the success of any local delivery strategy depends on matching the kinetics of drug release to the mechanisms of drug deposition and distribution in the target tissues, and the temporal sequence of target lesion pathology. We hope to examine the biology and enhance the clinical utility of local vascular delivery systems by validating and extending our local vascular pharmacokinetic analyses to higher animal species, more sophisticated arterial architectures, altered states and complex arterial lesions, and drugs of different physicochemical properties. Understanding where drugs distribute and are deposited in detail might not only ensure adequate drug kinetics to achieve biologic effect, but will also enable study of specific agents in more applicable and complete models of disease. We therefore now seek to: . determine if vascular pharmacokinetic models predict spatial distribution of drug within the arterial wall. . ascribe a structural and anatomic basis for the transport and deposition we have observed. . correlate pharmacokinetic parameters with solute chemical properties crucial to solute transport, and . examine how altered vascular states influence pharmacokinetics, drug deposition and biologic effects.