PILOT--PRECLINICAL SAFETY STUDIES FOR INTRATHECAL DPDPE

基于临床前工作的充分证据表明， 脊髓δ阿片受体可以改变 伤害性信息 少量数据， 选择性δ激动剂已经证实了这种可能性， 人类 开发高选择性的促肾上腺皮质激素受体激动剂， δ受体增加了最终证实 脊髓δ受体在人类中的作用 因此，化合物 DPDPE就是这样一种药剂，并评估其在人体中的作用 脊柱分娩后将是一个重要的理论和 临床相关进展。 本研究旨在 确定大鼠和犬鞘内注射DPDPE的安全性 模型 大鼠模型中的现有数据提供了一个初步的 DPDPE的安全性。 下一步之前， 转移到人类是为了进一步表征DPDPE的安全性 在评估其对人类的作用之前。 具体而言是 目前的研究将I）定义脊髓DPDPE对 大鼠的脊髓血流;以及ii）定义 溶剂28天脊髓输注的毒理学/组织病理学 或在明确定义的犬模型中给予两剂DEPDPE， 长期放置鞘内导管。 基于广泛的 有这些模型的经验，狗模型应该展示 安全性，随后应考虑 制定人体研究方案， 这种δ选择性激动剂的作用。

there is ample evidence based on preclinical work indicating that spinal delta opioid receptors can modify the processing of nociceptive information. Modest amounts of data with poorly selective delta agonists have confirmed this possibility in humans. The development of highly selective agonists for the delta receptor raises the possibility of finally confirming the role of spinal delta receptors in humans. Thus, the compound DPDPE is such an agent and assessment of its actions in humans after spinal delivery would be an important theoretical and clinically relevant advance. The present studies are aimed at defining the safety of DPDPE given intrathecally in rat and dog models. Existing data in a rat model has provided an initial confirmation of the safety of DPDPE. The next step prior to moving to humans is to further characterize the safety of DPDPE prior to assessing its action in humans. Specifically, the present studies will I) Define the effects of spinal DPDPE on spinal blood flow in the rat; and ii) Define the toxicology/histopathology of 28 day spinal infusion of vehicle or two doses of DEPDPE in a well defined dog model with chronically placed intrathecal catheters. Based on the extensive experience with these models, should the dog model display safety, it would be appropriate to subsequently consider the development of human studies protocols for examining the spinal effects of this delta selective agonist.