sorbinil and Aneurysm

Topics: Adult; Aldehyde Reductase; Aneurysm; Capillaries; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Edema; Humans; Imidazoles; Imidazolidines; Laser Therapy; Neovascularization, Pathologic; Retinal Diseases; Retinal Vessels; Sorbitol; Vitrectomy

A total of 497 patients aged 18 to 56 years with insulin-dependent diabetes mellitus for 1 to 15 years were randomly assigned to take oral sorbinil or placebo and followed up for a median of 41 months. The percentage of patients whose retinopathy severity grade at maximum follow-up had worsened by two or more levels was not significantly different between the two treatment groups (28% in the sorbinil group and 32% in the placebo group, P = .344). The number of microaneurysms increased at a slightly slower rate in the sorbinil group than in the placebo group, with statistically significant differences at 21 (P = .046) and 30 (P = .039) months but not at the maximum follow-up (P = .156). About 7% of the patients assigned sorbinil developed a hypersensitivity reaction in the first 3 months. On the basis of these results, it is unlikely that sorbinil administered at a dosage of 250 mg daily for 3 years has a clinically important effect on the course of retinopathy in adults with insulin-dependent diabetes of moderate duration. Our data are consistent, however, with a slightly slower progression rate in the microaneurysm count among patients assigned to take sorbinil, a finding of uncertain clinical importance.

Topics: Adolescent; Adult; Aldehyde Reductase; Aneurysm; Chi-Square Distribution; Diabetic Retinopathy; Drug Tolerance; Female; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Retinal Vessels; Sugar Alcohol Dehydrogenases

Vascular changes associated with early diabetic retinopathy that include the selective degeneration of pericytes, the formation of microaneurysms and acellular capillaries, and vessel dilation have been experimentally investigated in age- and sex-matched beagle dogs fed a 30% galactose diet and treated with or without the aldose reductase inhibitors sorbinil and/or M79175. Eyes from dogs in each group were periodically enucleated during a 36-month period and their retinal capillaries were examined as trypsin-digested flat preparations. These studies reveal that the destruction of retinal pericytes to form pericyte ghosts is the earliest observable retinal vessel change occurring after 19 to 21 months of galactose feeding. By 24 months, both an irregular distribution of endothelial cell nuclei near pericyte ghosts and the presence of acellular capillaries containing neither endothelial cells nor pericytes can be observed. This was followed by the histologic appearance of microaneurysms after 27 months and the funduscopic appearance of intraretinal hemorrhages after 33 months. Varicose enlargements of capillaries were also observed in the trypsin-digested preparations from dogs fed galactose for 33 to 36 months. All of these changes are linked to the initial aldose reductase-associated destruction of pericytes. The onset and progression of these retinal changes were retarded in a dose-dependent manner with aldose reductase inhibitors.

Topics: Aldehyde Reductase; Aneurysm; Animals; Capillaries; Diabetic Retinopathy; Dogs; Dose-Response Relationship, Drug; Female; Galactitol; Galactose; Imidazoles; Imidazolidines; Lens, Crystalline; Male; Retinal Vessels; Sugar Alcohol Dehydrogenases