Prostaglandins, nonsteroidal anti-inflammatory agents and eye disease.
The prostaglandins produce elevation of intraocular pressure and breakdown of the blood-aqueous barrier. They act via the secondary messenger system, cyclic AMP. Although the pathogenesis of many forms of ocular inflammation, both external and internal, is unclear, it is evident that some forms of ocular inflammation are prostaglandin-mediated, at least in part. Others may be totally mediated by prostaglandin synthesis. At present the corticosteroids are the mainstay of therapy of these conditions. However, the corticosteroids are poor inhibitors of prostaglandin synthesis and have many deleterious side effects such as induction of ocular hypertension, cataract, and infection. The search for new agents that will obviate these side effects and be more specific for the disease process is crucial. The discovery that the mode of action of many nonsteroidal anti-inflammatory agents is via inhibition of prostaglandin synthesis places a premium on elucidating which of these agents is most effective and least toxic in the eye and by which route of administration. The arachidonic acid screening model is ideal for initially choosing which agent has the greatest potential clinically. Arachidonic acid, a PGE2 precursor, when given topically also elevates intraocular pressure and aqueous humor protein, and these effects are blocked by the nonsteroidal anti-inflammatory drugs. This occurs if the arachidonic acid is injected into the vitreous humor, too, providing evidence that this in vivo model involves intraocular mechanisms. Utilizing the arachidonic acid system, a comparative study of nonsteroidal inhibitors of prostaglandin synthesis shows that the most effective of 14 agents were flurbiprofen solution and suspensions of polysorbate-dispersed indoxole, meclofenamic acid, indomethacin, and clonixin. Animal uveitis is not an ideal model for the human condition. Nevertheless, proving the superior efficacy of a screened drug in this system will identify those drugs to be tested in the human disease states. Only after the very few best drugs of this nature are identified should the ultimate steps of human testing be initiated.
D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005123:Eye / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects; D011339:Probenecid / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D011458:Prostaglandins E / Q000494:pharmacology; D011817:Rabbits
D001095:Arachidonic Acids; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D011458:Prostaglandins E; D000242:Cyclic AMP; D011339:Probenecid; D007213:Indomethacin