الفهرس 
VASCULAR ENDOTHELIAL GROWTH FACTOROnly 14 pages are availabe for public view
 |  | from | 375 |  |  |
| | | from | 375 | | |
Abstract
D
iabetes mellitus is a chronic disorder characterized by the impaired metabolism of glucose due to insulin deficiency or its resistance, leading to hyperglycemia and late development of vascular and neuropathic complications. It is of two types: type 1, primarily caused by autoimmune pancreatic b-cell destruction and characterized by absolute insulin deficiency, and type 2 characterized by insulin resistance and relative insulin deficiency. The prevalence of diabetes in Egypt was estimated to be 7.3 million in 2011 and is estimated to be 12.4 million by the year 2030.
Diabetic retinopathy is a common and specific microvascular complication of diabetes, and remains the leading cause of preventable blindness in working-aged people worldwide. It is identified in a third of people with diabetes and associated with increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease, and heart failure. The increasing number of individuals with diabetes worldwide suggests that DR and DME will continue to be major contributors to vision loss and associated functional impairment for years to come. Several factors were found to influence diabetic retinopathy including duration of the disease (most important factor), age, level of hyperglycemia control, level of blood pressure control, puberty, pregnancy, hyperlipidemia, hyperviscosity, renal failure and anemia.
Diabetic Retinopathy (DR) is a progressive disease that includes the following stages: no apparent DR, non proliferative DR, and proliferative diabetic retinopathy (PDR). Non-proliferative diabetic retinopathy is further subdivided into mild (microaneurysms only), moderate and severe (presence of >20 intraretinal haemorrhages in each quadrant, two quadrants of venous beading, or one quadrant of prominent intraretinal microvascular abnormalities (IRMA). Proliferative diabetic retinopathy (PDR): one or more of: neovascularization (i.e. of the iris, angle, optic disc, or elsewhere), or vitreous/preretinal haemorrhage.
Macular edema can develop at any time in the progression of diabetic retinopathy.
Our understanding of the pathophysiological mechanisms underlying the development of diabetic retinopathy is constantly evolving with new research. Chronic exposure to hyperglycaemia and other causal risk factors (eg, hypertension) is believed to initiate a cascade of biochemical and physiological changes that ultimately lead to microvascular damage and retinal dysfunction. Several biochemical mechanisms have been proposed to modulate the pathogenesis of retinopathy through effects on cellular metabolism, signalling, and growth factors.2 Implicated pathways include the accumulation of sorbitol and advanced glycation end-products (AGE), oxidative stress, protein kinase C activation, infl ammation, and upregulation of the renin-angiotensin system and vascular endothelial growth factor.Vascular endothelial growth factor (VEGF) plays an essential role in the development of both proliferative diabetic retinopathy(PDR) and diabetic macular edema (DME).
The VEGF family includes placental growth factor (PLGF), VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E. These agents are the most important regulators of angiogenesis and vascular permeability; VEGF-A in particular, plays a pivotal role in pathologic ocular angiogenesis. VEGF is a pluripotent growth factor that functions as an endothelial cell-specific mitogen and vasopermeability factor and through these mechanisms the VEGF plays a critical role in promoting angiogenesis and vascular leakage Hypoxia represents the likely major inducer of vascular endothelial growth factor (VEGF) gene transcription By disrupting the intercellular tight junctions between the retinal endothelial cells, VEGF increases the extracellular accumulation of fluid from the intravascular compartment. Retinal ischemia leads to an increased production of intravitreal VEGF by pigment epithelial cells, pericytes, and endothelial cells, while inhibition of VEGF activity via successful panretinal photocoagulation decreases VEGF levels and inhibits retinal neovascularisation.In essence, VEGF is an attractive candidate as therapeutic target of pharmacological treatment in the management of DR.
Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) represent the most common causes of vision loss in patients affected by diabetes mellitus. Diabetic retinopathy (DR) needs special attention because of its high public health impact and impact on quality of life of patients. Early detection of retinopathy in individuals with diabetes is critical in preventing visual loss, but current methods of screening fail to identify a sizable number of high-risk patients. The control of diabetes associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is also important in preserving visual function and have been shown to significantly decrease the risk of development as well as progression of retinopathy and remain a cornerstone in the medical managementof DR.
Specific treatment options for diabetic retinopathy include retinal laser therapy (photocoagulation), vitreoretinal surgery, emerging pharmacological therapies including intravitreal corticosteroids, AGE inhibitors, and oral protein kinase C inhibitors, antioxidants, anti angiogenic drug and anti VEGF administration.
Laser photocoagulation remains the mainstay of ophthalmic therapy for vision-threatening diabetic retinopathy. However, despite its remarkable efficacy in prevention of visual loss when undertaken in a timely and appropriate manner, the destructive nature of laser is associated with significant ocular side-effects and no remarkable visual recovery. Thus, new approaches in the treatment of DR have been taken into account and, more specifically, the therapy employing antivascular endothelial growth factor (anti-VEGF) drugs have gained an increasing popularity and interest in the treatment of diabetic retinopathy.
There are 4 major anti-VEGF agents that have been evaluated in treating DR: pegaptanib sodium (Macugen), ranibizumab (Lucentis), bevacizumab intravitreal injection (Avastin), and VEGF Trap-Eye (VTE; aflibercept).
Pegaptanib sodium was approved by the FDA in December 2004 for the treatment of all subtypes of neovascular age-related macular degeneration (AMD) and is a selective VEGF antagonist that binds to the 165 isoform of VEGF.
Bevacizumab is a full-length monoclonal antibody that also binds all isoforms of VEGF-A. It is approved by the FDA for intravenous use in the treatment of metastatic colorectal cancer, non–small-cell lung cancer, metastatic renal cell carcinoma, and glioblastoma.Bevacizumab’s ocular use is off-label.
Ranibizumab was approved by the FDA in June 2006 for the treatment of all subtypes of neovascular AMD and was approved in 2010 for the treatment of macular edema associated with retinal vein occlusion and in 2012 for diabetic macular edema. Ranibizumab is a recombinant humanized immunoglobulin G1 к isotype therapeutic antibody fragment that binds to and inhibits the biologic activity of all isoforms of human VEGF-A.
VEGF Trap-Eye, also known as aflibercept, is the most recent anti-VEGF agent approved by the FDA, in 2011, for the treatment of neovascular AMD.VEGF Trap-Eye is a 115-kDa recombinant fusion protein consisting of the VEGF binding domains of the human VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin G1. VEGF Trap-Eye competitively inhibits VEGF and binds placental growth factors 1 and 2.
Early studies have suggested an important potential role for anti-VEGF agents in the treatment of diabetic retinopathy. For diabetic macular edema, intravitreal pegaptanib has some short-term benefit on visual acuity in treatment of diabetic macular edema as reported by phase II and Phase III Macugen Diabetic Retinopathy Study Group Trial.
To date, ranibizumab has been studied in patients with visual impairment due to DME in several clinical trials (Campochiaro et al., 2006; Nguyen et al., 2006 [READ-1]; Nguyen et al., 2009 and 2010 [READ-2]; Chun et al., 2006; Sisk & Gregori, 2008; Massin et al., 2010 [RESOLVE]; Mitchell et al., 2011 [RESTORE]; Elman et al., 2010 and 2011) with favourable outcomes in terms of visual acuity and central macular thickness.
Intravitreal bevacizumab has some beneficial shortterm effects on treatment-naïve eyes with DME and on eyes with laser-refractory DME as reported by multiple trials including Phase II Diabetic Retinopathy Clinical Research Network (DRCR.net) Trial, Ahmdaieh et al. (2009) and multiple other trials. Bevacizumab treatment is associated with improvements in both acuity andCMT. Repeat dosing has been shown to be necessary, and the optimal timing is somewhere between 3 and 12 weeks.
The VEGF TRAP EYE showed short term benefit on visual acuity and central macular thickness as reported by The DA VINCI Study (phase II study). Other anti VEGF agents are still in need of further research and reports of clinical trials are minimal.
Reported side-effects for each of the anti- VEGF medications for DME have been rare and procedure-related rather than medication effects.
For PDR, The Macugen diabetic retinopathy study and Gonzalez et al. (2009) reported the benefits of Pegatanib on regression of neovascularization. Early studies suggest that intravitreal bevacizumab decreases leakage from diabetic neovascular lesions in newly diagnosed and refractory disease. The effect is temporary, and it may be associated with TRD. Bevacizumab also holds promise for vitreous hemorrhage, post-PRP macular edema, and NVI. Several studies to date also indicate that bevacizumab is likely to prove a helpful adjunct to diabetic PPV for TRD, and potentially for non clearing vitreous hemorrhage. Small studies have associated intravitreal bevacizumab with earlier clearance of blood, fewer intraoperative complications, decreased operative time, less post-operative bleeding, and better visual outcomes. Finally, three small series suggest a potential beneficial effect of a single dose of bevacizumab to prevent worsening of DME after cataract surgery.
Intravitreal injection of anti VEGF drugs should be performed in a semi sterile area created for intravitreal injections or in an operation theater after the patient has signed an informed consent of the procedure and its possible complications. Proper sterilization and draping of the eye is mandatory to avoid any infectious hazard. Post operative antibiotic drops, evaluation of light perception, indirect opthalmoscopy and tonometry are necessary postoperative procedures and monitoring of the patient during the first week for any signs of infection.
Major concerns with anti-VEGF therapy for ocular diseases include: (1) repeat intravitreal injections; (2) risk of cerebrovascular accidents or cardiovascular complications; (3) possible retinal and neural toxicity due to cumulative dosing; (4) interference with physiologic functions of VEGF; and (5) economic and cost-effectiveness concerns.
There is also growing evidence that anti-VEGF drugs are beneficial among patients with active DME and PDR, including those who are candidates for surgery, although large randomized controlled trials need to be performed for PDR patients to determine when treatment should be initiated, what should be the recommended treatment intervals and when treatment should be held.