Current Pharmaceutical Biotechnology - Volume 12, Issue 3, 2011

Diabetic retinopathy (DR) remains one of the most serious and visually disabling complications of diabetes, particularly among working-age individuals in developed countries [1]. By 2030, approximately 366 million people are expected to have been affected by diabetes [2]. DR is not only a major cause of preventable blindness, but also accounts for a significant portion of the morbidity and mortality. At present, primary prevention occurs by improving metabolic control using intensive glycemic regulation, strict blood pressure control, and lipid modifying treatment. Standard therapy for DR includes panretinal photocoagulation (PRP) and vitrectomy—both invasive procedures that have considerable adverse effects. Considerable progress has been made in the delivery of ophthalmological care for DR over the past decade. Various adjunctive pharmacological therapies, including anti-vascular endothelial growth factor agents, have shown early promise in the treatment of DR. Intravitreal triamcinolone has been proven to have short-term beneficial effects in the treatment of DR and may be a useful adjunct in certain patients undergoing treatment with PRP. Intravitreal injection of the autologous plasmin enzyme is a safe and effective adjunct to vitreous surgery for the treatment of both DME and proliferative DR. The fluocinolone acetonide implantable device has shown medium-term efficacy against DME in several trials, despite the absence of U.S. FDA approval for its use to treat DR [3]. Intraocular drug delivery systems' sustained-release agents maximize drug efficacy while limiting the risk of systemic side effects. Currently clinical experiences for DR with non-biodegradable implants such as Retisert and Illuvien, which have longer periods of drug release compared to biodegradable implants and provide high local drug concentrations, continue to increase. Interest in the role of aldose reductase (AR), the first enzyme of the sorbitol pathway of glucose metabolism, has been renewed by recent clinical evidence linking the progression of retinopathy with the presence of AR activity [4]. Novel potent AR inhibitors that have recently become available, such as ranirestat and fidarestat, are of particular interest. Furthermore several protein kinase C (PKC) inhibitors such as Ruboxistaurin have been successful in reducing visual loss in patients with DR (in the PKC DRS2 trial). Therapies preventing superoxide accumulation are currently being developed, targeting multiple steps of oxidative stress and mitochondrial damage in diabetes. Pigment epithelium-derived factor (PEDF) has been discovered to be an endogenous anti-inflammatory and anti-oxidative agent that protects the progression of proliferative DR [5]. In summary, we live in exciting times, with various novel pharmacological agents in the process of being evaluated for the treatment of DR as well as DME in multicentre randomized clinical trials. As prospective randomized clinical trials accumulate data, the role of pharmacologic treatments will become clearer. More definitive studies on these therapies, elucidating their role alone or in combination, are warranted. Long-term safety and efficacy need to be clarified as well.

Diabetic retinopathy (DR) still represents one of the leading causes of vision loss worldwide. Since this condition affects the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, considering that they seldom reach therapeutic levels in the affected tissues. Systemic medications can be insufficient due to the eye's immunoprivileged condition and existence of both inner and outer blood-retinal barriers, which place limitations on the potential role of this route of administration for retinal diseases. In this setting, intraocular therapies have emerged as novel and vital tools in the ophthalmologist's armamentarium against DR, allowing for maximization of drug efficacy and limited risk of systemic side effects. Intravitreal injections of triamcinolone acetonide have been widely used for treating DR particularly in the 21st century. Other agents targeting molecules, such as anti-vascular endothelial growth factor, have also demonstrated a potential therapeutic role for treatment. Recent advances in ocular drug delivery methods have led to the development of intraocular implants, which help to provide prolonged treatment with controlled drug release. Moreover, they may add some potential advantages over traditional intraocular injections by delivering certain rates of drug directly to the site of action, amplifying the drug's half-life, contributing in the minimization of peak plasma levels of the drug, and avoiding the side effects associated with repeated intravitreal injections.

Diabetic retinopathy remains a major worldwide cause of preventable visual loss. Although photocoagulation and improved metabolic control are effective for patients with diabetic macular edema and proliferative diabetic retinopathy, some patients continue to lose vision despite treatment. Various classes of pharmacotherapy have shown promise in the treatment of diabetic retinopathy, including corticosteroids, anti-vascular endothelial growth factor agents, and others. Off-label intravitreal corticosteroids are associated with short-term anatomic and visual improvement in some patients, but these patients may require repeated intravitreal injections with cumulative risks of cataract formation, intraocular pressure elevation, and endophthalmitis. Various sustained-release corticosteroid delivery systems have been investigated for this purpose. The first to become widely available is the fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb, Rochester, NY), which received U.S. Food and Drug Administration approval to treat chronic, noninfectious posterior segment uveitis in 2005. This device also has been investigated as a treatment for diabetic macular edema. Multiple randomized clinical trials have demonstrated medium-term anatomic and visual improvement, but the device is associated with high risks of cataract formation and intraocular pressure elevation. At this time, the device is not widely used in the treatment of diabetic retinopathy. A smaller device, designed to be injected in a clinic setting (Iluvien, Alimera Sciences, Alpharetta, GA) is currently being investigated for the treatment of diabetic macular edema. Results from a phase 3 randomized controlled trial have recently reported medium-term efficacy and safety in the treatment of diabetic macular edema. Combination photocoagulation and pharmacotherapy with these devices has not yet been reported.

Retinopathy, the leading cause of acquired blindness in young adults, is one of the most feared complications of diabetes, and hyperglycemia is considered as the major trigger for its development. The microvasculature of the retina is constantly bombarded by high glucose, and this insult results in many metabolic, structural and functional changes. Retinal mitochondria become dysfunctional, its DNA is damaged and proteins encoded by its DNA are decreased. The electron transport chain system becomes compromised, further producing superoxide and providing no relief to the retina from a continuous cycle of damage. Although the retina attempts to initiate repair mechanisms by inducing gene expressions of the repair enzymes, their mitochondrial accumulation remains deficient. Understanding the molecular mechanism of mitochondrial damage should help identify therapies to treat/retard this sight threatening complication of diabetes. Our hope is that if the retinal mitochondria are maintained healthy with adjunct therapies, the development and progression of diabetic retinopathy can be inhibited.

Diabetic retinopathy is a common and devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. Recent large landmark clinical studies have shown that intensive control of blood glucose or blood pressure (BP) reduces the risk for diabetic retinopathy. However, the strict control of blood glucose or BP is often difficult to maintain. Further, current therapeutic options for the treatment of sightthreatening proliferative diabetic retinopathy (PDR) such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target PDR is actually desired for most patients with diabetes. Although various biochemical and hemodynamic pathways are implicated in the diabetic retinopathy, recent clinical study has substantiated the concept of “metabolic memory”, and suggested the active involvement of advanced glycation end products (AGEs) and oxidative stress in this sight-threatening disorder. We, along with others, have recently found that pigment epithelium-derived factor (PEDF), a glycoprotein with complex neuroprotective, anti-angiogenic, anti-oxidative, and anti-inflammatory properties, could potentially be exploited as a therapeutic option for the treatment of diabetic retinopathy. Therefore, this article summarizes the role of AGEs and oxidative stress in diabetic retinopathy and discusses a potential utility of the blockade of this system by PEDF in this devastating disorder.

The vascular endothelial growth factor (VEGF) plays a key role in the development of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), resulting in a significant visual loss among patients with diabetes mellitus. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and VEGF-R1 (soluble form) are key to angiogenesis and vasculogenesis. Furthermore, patients with diabetes have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Pegaptanib, ranibizumab, bevacizumab and roboxistaurin are the currently available anti-VEGF agents. Agents with activity occurring later down the angiogenic pathway and those drugs with potential to synergize with anti-VEGF-A technologies are being developed. In recent years, inhibition of ocular VEGF has emerged as a promising treatment modality for diabetes and is currently undergoing evaluation in clinical trials. A potential role for these anti-VEGF agents in the prevention of PDR and DME are also emerging.

Diabetic retinopathy is the most common microvascular complication of diabetes and the most severe of diabetic ocular complications. This review describes retinal changes at different stages of diabetic retinopathy and risk factors associated with this devastating disease. Special attention is focused on aldose reductase, the first enzyme of the sorbitol pathway of glucose metabolism. The current knowledge on the enzyme localization in the retina, and the role for increased aldose reductase activity in retinal capillary cell loss and formation of acellular capillaries, capillary basement membrane thickening, increased vascular permeability and disruption of blood-retinal barrier, and increased leukocyte adhesion to endothelial cells associated with early diabetic retinopathy, as well as neovascularization associated with advanced (proliferative) diabetic retinopathy, gained through the experimental studies in animal models of diabetes and galactose feeding, is described in detail. The review also analyzes the potential mechanisms underlying aldose reductase involvement in pathogenesis of diabetic retinopathy, and discusses interactions between aldose reductase and other pathogenetic factors such as formation of advanced glycation end-products, oxidative-nitrosative stress, protein kinase C, mitogen- activated protein kinase, and poly(ADP-ribose) polymerase activations, inflammation, and growth factor imbalances. A detailed analysis of clinical diabetic retinopathy trials of aldose reductase inhibitors is also provided.

Purpose, To review current data regarding protein Kinase C beta (PKCβ) inhibitors and its efficacy in reducing the burden of diabetic retinopathy (DR) and diabetic macular edema (DME). Data Sources, MEDLINE search (1980- 2009) and presentations to major meetings. Data Synthesis, DR and DME have emerged as the main cause of visual impairment in working age population. Treatments for DR and DME include good metabolic control, laser photocoagulation and vitrectomy. However, current therapeutic regimes have not yet provided satisfactory visual results. PKC is an intracellular signalling molecule and its activation plays an important role in the development of ocular complications and has become a field of great interest. Several PKC inhibitors have been investigated. Ruboxistaurin, an orally PKCβ inhibitor has demonstrated in vitro and in vivo benefits in dimisnish cell and blood flow alterations related to hyperglycemia and has a potential use as a therapy for DR and DME. The beneficial effect of Ruboxistaurin in them has been demonstrated in preclinical and clinical studies and controlled trials have been conducted during the last decade. The ability of Ruboxistaurin in reducing visual loss in patients with DR has been demonstrated in the PKC DRS2 trial and DME seems to respond to Ruboxistaurin with both anatomic and functional benefits. The manufacturer, Eli Lilly, has received an approvable letter from the FDA for the prevention of vision loss in patients with DR with Ruboxistaurin, but at this time the medication is not available for clinical use pending results of additional trials for this indication.

Research has proven that blood pressure is an important modifiable risk factor for diabetic retinopathy and that lowering high blood pressure significantly reduces the development and progression of retinopathy in both type 1 and type 2 diabetic patients. The renin-angiotensin-system (RAS) has been shown to become activated in diabetes. Hyperglycemia stimulates the angiotensin AT1-receptor and downstream chains of events resulting in diabetic end organ damage. Pharmacological RAS inhibition may thus be a beneficial therapeutic strategy in the management of diabetic retinopathy. The present review article details therapeutic RAS inhibition in diabetic retinopathy with an emphasis on recently published evidence. Future research on the potential effects of RAS blockade will be important while using these drugs as adjuncts in the treatment of diabetic retinopathy.

Diabetic retinopathy (DR) is one of the leading risk factors and causes of blindness worldwide. Tight glucose and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Photocoagulation is standard treatment for both DME and PDR. However, some patients suffer permanent visual loss despite therapy. Treatment with fibrates first showed reduction in hard exudates, an effect subsequently shown with statins in short term studies, in particular two randomized studies in patients with macular edema. In the FIELD study which pre-specified microvascular outcomes, fenofibrate reduced laser treatment for DME or PDR by 31%: 164 (3.4%) patients on fenofibrate vs. 238 (4.9%) on placebo (p<0.001). In the ophthalmology sub-study of FIELD, the composite exploratory endpoint of 2-step progression of ETDRS retinopathy grade, macular edema or laser treatment was significantly reduced by 34%: 53 (11.1%) patients on fenofibrate vs. 75 (16.1%) on placebo (p=0.022). Conversely, there was no reduction in laser treatment or reduced progression of retinopathy in two large scale studies of statins where cardiovascular events were significantly reduced. Neither class of lipid-lowering drugs consistently improved visual acuity. In the ACCORD-EYE study, the combination of fenofibrate and simvastatin reduced by 40% the rate of progression of diabetic retinopathy compared with simvastatin alone. Other studies are needed to establish the place of lipid lowering drugs in the treatment of macular edema and the prevention of vision loss.

Diabetic retinopathy remains a major cause of worldwide preventable blindness. The vitreo-retinal interface plays a critical role in the pathogenesis of diabetic retinopathy. The term pharmacologic vitreolysis refers to the use of enzymes to liquefy the vitreous gel, and to induce posterior vitreous detachment (PVD). Intravitreal ovine hyaluronidase injection was effective in clearing vitreous hemorrhage. Several human case series demonstrated that intravitreal injection of autologous plasmin enzyme was a safe and effective adjunct to vitreous surgery for the treatment of diabetic macular edema and proliferative diabetic retinopathy. Recently, it was shown that intravitreal injection of plasmin enzyme without the performance of vitrectomy induced complete PVD and reduced macular thickening due to refractory diabetic macular edema.

Vitreous constitutes about 80% of the volume of the human eye. It is an extended extracellular matrix that is composed of collagen, hyaluronan, and other extracellular matrix molecules, but mostly water. In both health as well as disease, especially diabetic retinopathy (DR), special attention should be drawn to the posterior vitreous cortex and its relation to the retinal surface. The important role of vitreous in the pathogenesis of proliferative DR has already been demonstrated by several experimental and clinical studies. Thus, vitreoretinal separation by pharmacologic vitreolysis and/or removal by surgical means are appropriate approaches to interrupt the pathogenic contribution of vitreous and prevent progression of diabetic retinopathy to more advanced stages. This review describes various aspects of the molecular morphology and structural anatomy of vitreous and the vitreoretinal interface, as well as the role of vitreous in the pathophysiology of DR. Lastly, this treatise provides a comprehensive analysis of novel vitreous modulators for pharmacologic vitreolysis in the treatment of DR. Microplasmin is currently the most promising approach to treat vitreoretinal traction by pharmacologic vitreolysis.

In patients with elevated progesterone levels at the beginning of an ART (assisted reproductive technology) treatment cycle, the outcome of controlled ovarian stimulation (COS) may be inappropriate. A prospective cohort study was conducted to investigate whether the administration of a GnRH antagonist prior to the start of COS in these patients could lead to a similar pregnancy rate than in case of normal progesterone. Four hundred eighty-four patients were included in this study between February 2009 and July 2009. COS was initiated on day 2 of the cycle when estradiol (E2) and progesterone (P) serum levels were normal (E2 ≤ 80 pg/ml, P ≤ 1.5 ng/ml; “normal P group”). When serum progesterone was > 1.5 ng/ml on day 2 of the cycle (“high P group”), stimulation was not initiated, instead a GnRH antagonist was administered at a dosage of 0.25 mg during three consecutive days. In both study groups, efficient ovarian stimulation ensued and pregnancy rates did not diverge significantly. The results of the study led us to conclude that administration of a GnRH antagonist normalizes progesterone levels in those cases with isolated elevated serum progesterone levels at the start of the ART treatment cycle, and that this pretreatment is compatible with adequate ovarian stimulation and results in acceptable pregnancy rates.

The phytoalexin resveratrol (3,4',5-trihydroxy-trans-stilbene) may attenuate cardiovascular disease in man. This study has determined whether treatment with resveratrol (1 mg/kg/day orally) prevented cardiac fibrosis and the decreased cardiovascular function in the DOCA-salt hypertensive rat as a model of human hypertension. Uninephrectomised rats (UNX) administered DOCA (25mg every 4th day sc) and 1% NaCl in drinking water for 28 days developed cardiac and vascular remodelling. In these DOCA-salt rats, resveratrol decreased inflammatory cell infiltration, decreased cardiac fibrosis (left ventricular interstitial and perivascular collagen content) and improved cardiac and vascular function. Resveratrol attenuated other features of cardiovascular remodelling such as increases in systolic blood pressure, left ventricular wet weight, left ventricular wall thickness, diastolic stiffness constant, as well as decreased cardiac contractility and prolonged action potential duration characteristic of DOCA-salt rats. In summary, resveratrol, at a nutritionally relevant dose, prevents or attenuates the adverse changes in the cardiovascular system. We propose that the anti-inflammatory and anti-fibrotic effects of resveratrol are responsible, at least in part, for its amelioration of cardiovascular remodelling in DOCA-salt rats. These actions of resveratrol could play an important role in the protective effects on the human cardiovascular system reported for this constituent of red wine.

A number of hypotheses have been put forth to explain the underlying abnormalities of schizophrenia. The widely held dopamine hypothesis suggests that positive symptoms are related to elevated subcortical dopamine transmission and that negative symptoms and cognitive impairments are associated with decreased cortical dopamine function. However, recent evidence suggests broader involvement of serotonergic, glutamatergic and other neurotransmitter systems and a growing body of evidence supports a role for nicotinic cholinergic systems. Based on post-mortem studies, there is a decreased density of neuronal nicotinic receptors (NNRs), especially the alpha7 NNR subtype, in the brains of schizophrenics. The alpha7 NNR subtype is the most abundant in the mammalian brain and has been shown to modulate multiple neuronal pathways that are compromised in schizophrenia, including dopaminergic, serotonergic, glutamatergic and GABAergic pathways. Familial linkage studies have associated regions of chromosome 15, which contains the alpha7 NNR gene, with schizophrenia and polymorphisms have been described in the promoter region of the alpha7 NNR gene. Observations from both animal and human studies that alpha7 NNR agonists can improve positive and negative symptoms as well as cognition to varying degrees further support the involvement of this receptor subtype in multiple deficits of schizophrenia and suggest that it may be feasible to develop novel therapies targeting alpha7 NNRs to treat all domains of the disease.

Huge volumes of data, produced by microarrays and next- generation sequencing, are now at the fingertips of scientists and allow to expand the scope beyond conventional drug design. New promiscuous drugs directed at multiple targets promise increased therapeutic efficacy for treatment of multi- factorial diseases. At the same time, more systematic tests for unwanted side effects are now possible. In this paper, we focus on the application of text mining and ontologies to support experimental drug discovery. Text mining is a high- throughput technique to extract information from millions of scientific documents and web pages. By exploiting the vast number of extracted facts as well as the indirect links between them, text mining and ontologies help to generate new hypotheses on drug target interactions. We review latest applications of text mining and ontologies suitable for target and drug-target interaction discovery in addition to conventional approaches. We conclude that mining the literature on drugs and proteins offers unique opportunities to support the laborious and expensive process of drug development.