GLAUCOMA, LENS AND FLUID SECRETION PHARMACOLOGY

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The broad objectives of this research are to increase knowledge of secretory and carbonic anhydrase (CA)-dependent systems in the eye, brain, and inner ear, and apply this to certain medical problems, notably glaucoma, cataract, increased intracranial pressure, & Menieres disease. The physiological work will be done in parallel with enzyme studies on the appropriate tissues. EYE: a) Search will continue for an effective non-toxic carbonic anhydrase inhibitor for treatment of glaucoma by corneal instillation rather than systemically. Current work on principles of corneal penetration show this to be feasible. Studies are also planned on ion-transport from plasma to aqueous following administratin of timolol, to compare with CA inhibitors. b) Major effort will be given to the role of CA in normal lens, which our current works links to dissimilation of HCO3-. It appears likely that this mechanism fails in cataractous lens. BRAIN-CSF: Both as molecular probes and potential drugs, new agents (other than CA inhibitors) remain to be discovered that will reduce CSF flow. Such agents will be sought, with particular attention to their influence on ion transport. ENDOLYMPH: Basic information will be sought on CO2 equilibria and formation rate of endolymph. We shall measure effects of CA inhibitors on ion and fluid movement in inner ear. Because of the high concentration of CA in this locale, analogy to the other fluids and some clinical "impressions", it is possible that these studies may lead to effective treatment of Menieres disease. ENZYMOLOGY: Basic kinetics and inhibition studies of CA will be done on these tissues, with emphasis on the membrane-bound enzyme. These chemical data will be intimately linked to the physiological and pharmacological results, and together form the basis for rational treatment programs.