The incidence of diabetic retinopathy is still increasing in developed countries. Tight glycemic control and laser therapy reduce vision loss and blindness, but do not reverse existing ocular damage and only slow the progression of the disease. New pharmacologic agents that are currently under development and are specifically directed against clearly defined biochemical targets (i.e. aldose reductase inhibitors and protein kinase C-beta inhibitors) have failed to demonstrate significant efficacy in the treatment of diabetic retinopathy in clinical trials. In contrast, calcium dobesilate (2,5-dihydroxybenzenesulfonate), which was discovered more than 40 years ago and is registered for the treatment of diabetic retinopathy in more than 20 countries remains, to our knowledge, the only angioprotective agent that reduces the progression of this disease. An overall review of published studies involving calcium dobesilate (CLS 2210) depicts a rather 'non-specific' compound acting moderately, but significantly, on the various and complex disorders that contribute to diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation.
[Show abstract][Hide abstract] ABSTRACT: The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR).
Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50x10(-6)/ min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months.
A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [-3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, > or =9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: -3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/ events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups.
Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.
Albrecht von Graæes Archiv für Ophthalmologie 01/2007; 244(12):1591-600. DOI:10.1007/s00417-006-0318-2 · 1.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer's disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.
Experimental Diabetes Research 02/2007; 2007(3):43603. DOI:10.1155/2007/43603 · 4.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) is widely recognized to be quite an important intercellular messenger in the cardiovascular and nervous systems or immunological reactions, including that in the eye. This molecule formed by constitutive NO synthase (NOS), endothelial (eNOS) and neuronal (nNOS), contributes to physiologically regulate ocular hemodynamics and cell viability and protects vascular endothelial cells and nerve cells or fibers against pathogenic factors associated with glaucoma, ischemia, and diabetes mellitus. Ocular blood flow is regulated by NO derived from the endothelium and efferent nitrergic neurons. Endothelial dysfunction impairs ocular hemodynamics by reducing the bioavailability of NO and increasing the production of reactive oxygen species (ROS). On the other hand, NO formed by inducible NOS (iNOS) expressed under influences of inflammatory mediators evokes neurodegeneration and cell apoptosis, leading to serious ocular diseases. NO over-produced by nNOS in the retina stimulated by excitotoxic amino acids or exposed to ischemia also mediates retinal injury. Because of these dichotomous roles of NO, which has both beneficial and pathogenic actions, one may face difficulties in constructing therapeutic strategies with NO supplementation or NOS inhibition. Up-to-date information concerning physiological roles of NO produced by the different NOS isoforms in the eye and interactions between NO and glaucoma, retinal ischemia, or diabetic retinopathy would help clinicians to select a valid pharmacological therapy that would be appropriate for a specific ocular disease.
Progress in Retinal and Eye Research 06/2007; 26(3):205-38. DOI:10.1016/j.preteyeres.2007.01.004 · 8.73 Impact Factor
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