Diabetic retinopathy treatment

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[. 

A number of inhibitors directed towards the active site of PKC have been developed [4]. Many of these have therapeutic potential and some are in clinical trials. The drug enzastaurin (LY317615) shows selectivity towards inhibiting PKC 3 and is currently in clinical trials for cancer. This drug has particular potential as a treatment for colon cancer because of the specific role ofPKC (311 in this disease (see above). A separate PKC (3 inhibitor, ruboxistaurin (LY333531) has been developed as a drug to treat the microvasculature complications of diabetes hyperactivation of both PKC (311 and PKC (31 contribute to diabetic retinopathy and microvasculature complications. 

Rosenlund EF, Haakens K, Brinchmann-Hansen O, Dahl-Jorgensen K, Hanssen KF. Transient proliferative diabetic retinopathy during intensified insulin treatment. Am J Ophthalmol 1988 105(6) 618-25. 

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

Effective, long lasting treatment of retinal neovascular disorders, including proliferative diabetic retinopathy and proliferative AMD, remains one of the greatest challenges in ophthalmology today. The number of individuals suffering from diabetes has... 

Galvez MI (2011) Protein kinase C inhibitors in the treatment of diabetic retinopathy. Review. Curr Pharm Biotechnol 12(3) 386-391... 

Two years ago she developed hypertension, which was treated with ben-droflumethiazide, 5mg daily. At that time, her blood urea level was 8.2 mmol/L, serum creatinine was 80 pmol/L, and dipstick urinalysis was negative for protein. She was also noted to have non-proliferative diabetic retinopathy, and given a course of laser treatment. 

Recently, thalidomide has gained approval for use in the United States as an immunomodulatory agent in the treatment of HIV-associated diseases, arthritis, myeloma, and diabetic retinopathy. The FDA has instituted the System of Thalidomide Education and Prescribing Safety (STEPS) to prevent accidental exposures during pregnancy. 

Ruboxistaurin (LY333531) 41 (Eli Lilly) is being evaluated in a Phase III trial for the treatment of diabetic macular oedema.224 Lilly had submitted an NDA in February 2006 to the FDA for the treatment of diabetic retinopathy and received an Approvable Letter in September 2006 that requested another Phase III trial for additional efficacy data. The EMEA also required further clinical data and, as a consequence, Lilly withdrew its European MAA. Ruboxistaurin 41225 228 competitively inhibits adenosine triphosphate (ATP) binding to PKC/i and is a synthetic analogue of staurosporine 42. 

Anthocyanins could play probably such diverse roles as the phenolic phytochemicals eaten as part of the human diet. Anthocyanins have been used for several therapeutic treatments for diabetes, retinopathy, fibrocystic disease and other age-related diseases [3], and vision disorders [4],... 

Thirty-one patients with various types of retinopathy were tested for the effect of anthocyanosides on the retinal vessels. Among these patients with the retinopathy types, especially the patients with diabetic retinopathy improved with a positive influence on the permeability and the tendency for hemorrhage. The internal treatment of the primary retinopathy seems to be very effective [56]. 

Substituted quinazolin-4(3H)-ones, (V), effective as CXCR3 chemokine receptor modulators and anthranilic acid amides, (VI), effective as VEGF-receptor tyrosine kinase inhibitors were prepared by Medina (5) and Bold (6), respectively, and used in the treatment of diabetic retinopathy and age-related macular degeneration. 

The indolocarbazole alkaloids and the biosynthetically related bisindolylmaleiraides constitute an important class of natural products, which have been isolated from actinomycetes, cyanobacteria, slime molds, and marine invertebrates [1-3], They display a wide range of biological activities, including antibacterial, antifungal, antiviral, hypotensive, antitumor, and/or neuroprotective properties. The antitumor and neuroprotective activities of indolocarbazoles are the result of one, or several, of the following mechanisms (a) inhibition of different protein kinases, (b) inhibition of DNA topoisomerases, or (c) direct DNA intercalation [3-6], Hundreds of indolocarbazole derivatives have been produced by chemical synthesis or semisynthesis [1,2,6], and several of them have entered clinical trials for the treatment of diverse types of cancer, Parkinson s disease or diabetic retinopathy [3,7]. 

The use of intravitreal corticosteroids is presently being explored in the treatment options of exudative macular degeneration and proliferative diabetic retinopathy. The rational fc>r their use stems from the feet that corticosteroids as a drug class represent one of the most... 

Calcium dobesilate is an antioxidant that has been used to treat diabetic retinopathy, in which it slows progression of the disease during long-term oral treatment by reducing microvascular permeability, leading to improved visual acuity (1). It not only acts as an antioxidant but also stimulates endothelial production of nitric oxide. 

A heavier-than-water fluorinated silicone oil was used in the treatment of 30 selected cases of complicated retinal detachment due to proliferative vitreoretinopathy (n = 19), proliferative diabetic retinopathy with traction detachment (n = 2), giant retinal tears (n = 5), ruptured globe with retinal detachment (n = 2), massive choroidal effusion with retinal detachment (n = 1), and acute retinal necrosis with retinal detachment (n = 1) (13). Initial retinal reattachment was achieved in all cases. Complications included redetachment (n = l), cataract (n = 6), raised intraocular pressure (n = 4), hypotony (n = 4), keratopathy (n = 3), uveitis sjme-chia formation (n = 3), phthisis (n = 2), choroidal hemorrhage (n — 1), and vitreous hemorrhage n = 1). 

Integrin ayPs, the vitronectin receptor, has been identi-hed as a promising potential target for the treatment of osteoporosis, diabetic retinopathy and cancer. Three classes of integrin antagonists are currently in preclinical and clinical development monoclonal antibodies targeting the extracellular domain of the heterodimer, vitaxin, synthetic peptides such as cilengitide and several peptidomimetics. ... 

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