EICOSANOIDS--OCULAR PHYSIOLOGY AND PHARMACOLOGY

类二十烷酸--眼生理学和药理学

• 批准号: 3263186
• 负责人: LASZLO Z. BITO
• 金额: $ 19.57万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3263186
• 关键词: blood aqueous barrier; drug metabolism; eicosanoids; extraocular muscle; eye pharmacology; fluoroscopy; glaucoma; glaucoma test; intraocular pressure; isotope dilution method; ocular hypotensive; perfusion; pupil; pupillography; sign /symptom; slow release drug

Some eicosanoids (EDs), such as prostaglandins and their derivatives, have been shown to be effective ocular hypotensive agents in all animals studied as well as in normotensive human volunteers. However, EDs, like other drugs, have side effects which, unless they can be reduced or eliminated, may limit the usefulness of these substances in the long-term clinical management of chronic glaucomas. The goal of this project is to gain a clear understanding of the mechanisms of the ocular effects of EDs in order to provide the basic information required for the development of EDs as effective drugs for the long-term maintenance of IOP reduction with minimal ocular and systemic side effects. We shall undertake a thorough investigation of the following specific areas: 1) The ocular pharmacokinetics of EDs will be studied with special reference to an orthorectified slow-release system, using in vivo tracer techniques and in vitro flux studies; 2) studies on the mechanism of ED-induced IOP reduction will include secretion, pseudofacility, and conventional and uveoscleral outflow, using fluorophotometry, isotope dilution, tonography, and perfusion techniques. 3) The mechanism of other ocular effects will be studied, including miosis (pupillography, ED effects on isolated iridial muscles) and conjunctival hyperemia (tracer studies), as well as breakdown of the blood aqueous barrier (measurement of Tyndall effect and protein concentration) in species (cats, primates, and rabbits) in which flare develops to greatly different extents. A basic understanding of the pharmacokinetics, mechanisms of action, and side effects of EDs will provide the information essential for the effective use of ocular hypotensive EDs by ophthalmologists for the clinical management of glaucomas. Such understanding will also be essential for the consideration of EDs in other areas of ocular therapeutics and for the development of second and third generations of glaucoma drugs. The possibility still exists, however, that EDs, which effectively reduce IOP in normotensive human subjects, do not have the same effect on glaucomatous eyes. If this proves to be the case, our studies will make an important contribution to the understanding of glaucoma, since such lack of effect would imply that glaucoma is associated with a defect in some aspects of the ED system of the anterior segment. In short, this multipronged approach will make an important contribution to eye research in general and to glaucoma research in particular whether or not EDs do, as we believe that they will, provide a new approach to the medical management of glaucoma.

一些类二十烷酸 (ED)，例如前列腺素及其衍生物，具有 在所有研究的动物中均被证明是有效的降眼压剂 以及血压正常的人类志愿者。 然而，ED 和其他人一样 药物有副作用，除非可以减少或消除， 可能会限制这些物质在长期临床中的用途 慢性青光眼的治疗。 该项目的目标是获得 清楚了解 ED 的眼部影响机制，以便 提供开发 ED 所需的基本信息 长期维持眼压降低的有效药物 眼部和全身副作用。 我们将进行彻底的 研究以下特定领域： 1) 眼部 ED 的药代动力学将特别参考以下物质进行研究 正射校正缓释系统，使用体内示踪技术和 体外通量研究； 2）ED引起眼压降低的机制研究 将包括分泌、伪设施、常规和葡萄膜巩膜 流出，使用荧光光度法、同位素稀释、断层扫描和 灌注技术。 3）其他眼部效应的机制将是 研究包括瞳孔缩小（瞳孔造影、ED 对孤立虹膜的影响） 肌肉）和结膜充血（示踪剂研究），以及崩溃 血水屏障的测量（廷德尔效应和蛋白质的测量） 浓度）在物种（猫，灵长类动物和兔子）中耀斑 发展程度差异很大。 基本了解 ED 的药代动力学、作用机制和副作用 提供有效使用眼科设备所必需的信息 眼科医生进行低血压急诊室的临床管理 青光眼。 这种理解对于考虑也至关重要 眼科治疗其他领域的 ED 和开发 第二代、第三代青光眼药物。 可能性还是有的 然而，ED 可以有效降低血压正常患者的 IOP 人类受试者对青光眼没有同样的影响。 如果这个 事实证明确实如此，我们的研究将做出重要贡献 对青光眼的理解，因为缺乏效果意味着 青光眼与 ED 系统某些方面的缺陷有关 前段。 简而言之，这种多管齐下的方法将 对一般眼科研究和青光眼研究的重要贡献 特别是 ED 是否（我们相信他们会）提供 青光眼医疗管理的新方法。