Factors of cerebrospinal drug transport

 描述：我们目前研究的总体目标是为目前无法治疗的、涉及中枢神经系统和脑膜的具有社会意义的疾病，如脑膜和脑膜癌、神经退行性疾病、创伤、感染和酶缺乏症开发新的治疗方法和药物输送方法。假设，脑脊液中最初的药物转运是由流体静力学控制的，而随后的溶质在脑脊液中的转运是 由活跃的生物力学混合(而不是定向流动或扩散)控制。因此，溶质被输送到液体管道的入口处，这些管道包裹着通往中枢神经系统(Virchow-Robin Spaces)的动脉和静脉。由于动脉的搏动，动脉周围的管道沿动脉轴线迅速混合。数据清楚地表明，动脉周围管道的边界对包括大分子在内的溶质是可穿透的。因此，进入脑脊液的溶质可以直接进入中枢神经系统实质的所有隔室。软脑膜药物转运的最终结果将取决于上述每个转运过程中的溶质(例如，药物)行为，这些过程都没有得到系统的研究。生理因素对脑脊液药物转运的影响可能取决于病理因素的存在，如炎症和肿瘤。针对每个运输过程中的特定行为优化药物分子或药物输送系统，有望使优先路由至所需的中枢神经系统或脑膜亚室。然而，缺乏关于脑脊液中流体静力和流体动力学溶质转运的定量机制知识，阻碍了优化通过脑脊液给药的新药的开发。这项拟议工作的目的是(A)研究静水推注转运和随后的流体动力驱动的溶质转运的机制，以及(B)建立和测试适用于药物开发的机械性药动学模型。这些研究将在啮齿动物和非人类灵长类动物身上进行。冲击力。这项研究将带来新的生理学知识和新的方法，促进目前无法治疗的涉及中枢神经系统和脑膜的疾病的药物开发。

 DESCRIPTION: The overall goal of our current research is to develop novel treatments and drug delivery methodologies for presently untreatable, socially significant conditions involving CNS and meninges, such as meningeal and brain cancer, neurodegenerative diseases, trauma, infections and enzyme deficiencies. Hypothetically, the initial bolus translocation in the CSF is hydrostatically controlled, and the subsequent solute transport in the cerebrospinal fluid (CSF) is governed by active biomechanical remixing (and not by directional flows or diffusion). Solutes are thus delivered to entrances of liquid conduits enveloping the arteries and veins leading into the CNS (Virchow-Robin spaces). The periarterial conduits are rapidly remixed along the arterial axes due to the pulsation of the arteries. The data clearly shows that the boundaries of the periarterial conduits are penetrable for solutes, including large molecules. Thus, solutes administered to the CSF have direct access to all compartments of CNS parenchyma. The final outcome of the leptomeningeal drug transport will depend on the solute (e.g., drug) behavior in each of the above transport processes, none of which has been studied systematically. The effects of physiological factors on drug transport in the CSF may depend on the presence of pathologies, such as inflammation and tumors. Optimization of a drug molecule or a drug delivery system for certain behavior in each of the transport processes is expected to enable preferential routing to a desirable subcompartment of either CNS or meninges. However, lack of quantitative mechanistic knowledge on the hydrostatic and hydrodynamic solute translocation in the CSF hinder the development of novel drugs optimized for delivery through the CSF. The objectives of the proposed work are (a) to investigate the mechanisms of hydrostatic bolus translocation and the subsequent hydrodynamically driven solute transport, and (b) to compose and test a mechanistic pharmacokinetic model suitable for drug development. The studies will be carried out in rodents and in non-human primates. Impact. The study will result in new physiological knowledge and novel approaches facilitating drug development for presently untreatable conditions involving CNS and meninges.