DIRECT NOSE/BRAIN DRUG/PEPTIDE TRANSPORT

描述(摘自《调查者摘要》)：鼻腔用药 给药已被证明是一种有效的非侵入性途径 全身性给药管理。有趣的是，个人 吸食非法毒品的人很早就采取了这条路线 行政管理。尽管有一些证据表明物质可能会进入 大脑直接从鼻腔进入，很少受到关注。 以解决鼻腔应用滥用物质的可能性 可以直接从鼻腔输送到中枢 神经系统(CNS)。目前还不清楚是否直接进入滥用 从鼻腔到大脑的物质可能会导致更多 强烈的(中枢神经系统)药物暴露和增加的滥用潜力 神经活性药物。此外，血脑屏障 代表了将神经肽用于 中枢神经疾病的药物治疗。有限 鼻-脑传输通路的使用已经引起了人们的注意 在中枢神经系统多肽递送中避免这一问题。总体目标 所建议的研究都是为了检查直接 鼻用药物/多肽的鼻-脑转运途径 确定局部血管收缩对血管收缩程度的影响 这样的交通工具。这项拟议的研究旨在检验两项 假设：首先，药物/多肽可以直接从 鼻腔到脑；第二，鼻脑用药的程度 当鼻腔中的血管被 收紧了。具体地说，拟议的研究将使用老鼠作为 动物模型。血浆和脑内药代动力学测定将 用来确定鼻腔注射的可卡因和 阿片类药物可以直接从鼻腔输送到大脑。 研究也被设计来确定局部的影响 血管紧张剂在鼻-脑药物/多肽中的作用 转座。这项研究的长期目标是确定 负责直接鼻-脑药物/肽转运的机制 确定这种物质的药理和毒理后果 运输，并检查这一新的脑通路的用途 神经活性多肽/蛋白质/基因治疗载体的输送 通过血脑屏障的能力有限。

DESCRIPTION (Adapted from Investigator's Abstract): Intranasal drug administration has been shown to be an effective non-invasive route of administration for systemic drug delivery. Interestingly, individuals who consume illicit drugs have long ago adopted this route of administration. Although some evidence exists that substances may enter the brain directly from the nasal cavity, little attention has been paid to addressing the possibility that nasally applied abuse substances could be transported directly from the nasal cavity to the central nervous system (CNS). It is not clear whether direct entry of abused substances from the nasal cavity to the brain could result in more intense (CNS) drug exposure and increase abuse potential of neurologically active drugs. Furthermore, the blood-brain barrier represents one of the essential obstacles for using neuropeptides for the pharmacological treatment of central nervous diseases. Limited attention has been paid to the use of a nose-brain transport pathway to circumvent this problem in CNS peptide delivery. The overall objectives of the proposed research are to examine the significance of the direct nose-brain transport pathway for nasally applied drugs/peptides and to determine the effects of localized vasoconstriction on the extent of such transport. The proposed research is designed to examine two hypotheses: first, drugs/peptides can be transported directly from the nasal cavity to the brain; second, the extent of nose-brain drug transport is improved when the blood vessels in the nasal cavity are constricted. Specifically, the proposed research will employ rats as the animal model. Plasma and brain pharmacokinetic determinations will be used as a tool to determine whether nasally applied cocaine and an opioid can be transported directly from the nasal cavity to the brain. Studies are also designed to determine the effect of local vasoconstricting agents on the extent of nose-brain drug/peptide transpost. The long-term goals of the research are to determine the mechanisms responsible for direct nose-brain drug/peptide transport, to determine the phamacological and toxicological consequences of such transport, and to examine the utility of this novel pathway for brain delivery of neuroactive peptides/proteins/gene therapy vectors which have limited passage through the blood brain barrier.