EICOSANOIDS--OCULAR PHYSIOLOGY AND PHARMACOLOGY

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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.