Diabetic retina

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

They are universally present in tissues affected by the diabetic process in endothelial cells, retina, lens, peripheral nerve cells and kidney. 

Proliferative diabetic vitreoretinopathy (PDR) is characterised by the growth of blood vessels into the vitreous and neovascularisation of the retina. These neovascularisations lead to vitreous haemorrhage, creating additional fibrous epiretinal proliferations. 

Kowluru, A. Kowluru, R.A. Subcellular localization and characterization of nucleoside diphosphate kinase in rat retina effect of diabetes. Biosci. Rep., 18, 187-198 (1998)... 

Spaide RF, Fisher YL. Intravitreal hevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006, 26, 275-278. 

Pathologic neovascularization of the retina is central to several debilitating ocular diseases including proliferative diabetic retinopathy (PDR), age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). Diabetic retinopathy (primarily retinal NV) and the wet form of AMD (primarily choroidal NY) are the leading causes of blindness in developed countries. 

The retina is the most metabolically active tissue in the body and so is very vulnerable to the microvascular changes which occur in diabetes. Diabetes affects the eyes in a number of ways the most common is diabetic retinopathy, which involves increased thickness of the retinal basement membrane and increased permeability of its blood vessels. The severity of the retinopathy is related to the age of the patient, duration of the diabetic state and extent of glycaemic control. Later changes in the eye include macular oedema and retinal ischaemia, which threaten the sight of the patient. All these deleterious changes are minimized if blood glucose is tightly controlled. 

Several extended-release devices able to deliver a consistent level of corticosteroid to the retina have been devised. Two will be presented in this chapter, although other devices are under evaluation or in the development pipeline at the time of writing. The primary indications for these devices are persistent macular edema associated with several conditions, including diabetic retinopathy, retinal vascular occlusive disease, cataract surgery, and posterior uveitis. 

Fructose iodoacetates Microvascuiar iesions in retina Vascuiar changes in retina Diabetes-like condition... 

The participation of aldose reductase in the development of diabetic complications is assumed to be based on a triad of tissue effects sorbitol accumulation, myo-inositol depletion and decreased activity of Na/K-ATPase. These alterations, first described in the ocular lens, also occur in other tissues like the renal glomerulus, peripheral nerves and the retina. The enhanced activity of aldose reductase may therefore be involved in the development of diabetic neuropathy, diabetic retinopathy and diabetic nephropathy, although it may not be the sole factor underlying these complications. 

The overall accumulation of sorbitol in the retina of diabetic rats seems to be of little significance, but the distribution of the polyols in the different cellular locations could produce osmotic force. In alloxan-diabetic animals the above-mentioned triad of myo-inositol depletion, reduced Na/K-ATPase activity and activation of PKC following accumulation of sorbitol is seen and can be prevented by inhibition of aldose reductase (MacGregor and Matschinsky, 1985), although the impact of this system on the generation of diabetic retinopathy remains to be established. 

Patients with both type 1 and type 2 diabetes are at high risk for the development of chronic complications. Diabetes-specific microvascular pathology in tlie retina, renal glomerulus, and peripheral nerve produces retinopathy, nephropathy, and neuropathy. As a result of these microvascular complications, diabetes is the most frequent cause of new cases of bfindness in the industrialized world in persons between 25 and 74 years and the leading cause of end-stage renal disease.Diabetes is also associated with a marked increase in atherosclerotic macrovascular disease involving... 

Kumagai, A.K. (1999) Glucose transport in brain and retina implications in the management and complications of diabetes. Diabetes/Metabolism Research and Reviews, 15, 261-273. 

Diabetic Sequelae - While the development of insulin replacement therapy has greatly prolonged the diabetic s lifespan, it has not had a major impact in the prevention of the myriad of sequelae associated with longstanding diabetes. Kidney, retina, peripheral nerve, lens and the cardiovascular system all suffer dysfunctions secondary to diabetes. The multisystem nature of this disease has made difficult the development of a unifying hypothesis to explain these sequelae. 

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