sorbinil and Corneal-Diseases

Diabetes mellitus has an effect on many organ systems including the eye, kidney and peripheral nerve. Many of these complications develop in animal models of diabetes, which has allowed some of the mechanisms of damage in target organs to be studied. Aldose reductase, an intracellular enzyme, converts glucose to sorbitol, and it is the intracellular accumulation of sorbitol which is thought to result in irreversible damage. In the diabetic eye the increased sorbitol accumulation in both the lens and the retina has been implicated in the pathogenesis of cataract and retinopathy, the major ocular complications of diabetes. In those experimental models which demonstrate characteristic diabetic complications, pharmacological inhibition of the enzyme aldose reductase has resulted in prevention of target organ damage. This paper summarises the experimental evidence upon which the clinical trials of aldose reductase inhibitors in diabetic patients have been initiated and the results of published drug trials in these patients.

Topics: Aldehyde Reductase; Animals; Cataract; Clinical Trials as Topic; Corneal Diseases; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Phthalazines; Rats; Retinal Vessels

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

Tissues of the eye affected by diabetes are the lens, cornea, and retina. The lens becomes cataractous through osmotic swelling of its cortical fibers. Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia. Dulcitol similarly accumulates in the presence of galactosemia. Cataractogenesis in both cases can be prevented by inhibitors of aldose reductase. The efficacy of synthetic inhibitors differs in various tissues and species, but they react with aldose reductase at a common structural site. The most promising inhibitor is sorbinil . Diabetic retinopathy is similarly related to sorbitol accumulation and may be prevented or reversed by inhibition of aldose reductase. Healing of corneal wounds in diabetes is facilitated by enzyme inhibition. Retinal vasculopathy of diabetes is due to selective loss of the intramural pericytes that normally form structural elements in the retinal capillary walls. The vulnerability of these cells is due to their aldose reductase content. Whether inhibition of aldose reductase will prevent retinopathy is being tested in a randomized trial conducted by the National Eye Institute.

Topics: Aldehyde Reductase; Animals; Axonal Transport; Cataract; Corneal Diseases; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Galactosemias; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Osmolar Concentration; Peripheral Nerves; Rats; Sorbitol; Structure-Activity Relationship; Sugar Alcohol Dehydrogenases