Current Drug Therapy (v.7, #2)

Angiogenesis plays a critical role in human growth and development, as well as tissue repair and maintenance. Though angiogenesis can be stimulated by several metabolites and growth factors, vascular endothelial growth factor (VEGF) appears to be critical for all new vessel growth. VEGF includes several molecules that are classified according to structure and binding characteristics into the following groupings: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor. VEGF binds with 3 trans-membrane receptors (VEGFR1, VEGFR2, and VEGFR3) each of which initiates downstream signaling through intracellular tyrosine kinase activity. Binding to receptors is amplified by neuropilins, which interact with the heparin binding domain of VEGF and favorably present the receptor binding site to the receptor binding domain. Though VEGF may be synthesized by several cell types, the molecule’s primary target is vascular endothelial cells. VEGF exerts several effects on its target tissues: mitogenicity, vascular hyperpermeability, migration, survival factor, vasodilator, and chemoattraction. Two VEGF binding drugs (pegaptanib and ranibizumab) have been developed specifically for intraocular use. Aflibercept is being developed for both ophthalmologic and oncologic use, and bevacizumab has been used off-label to treat ocular diseases. Each of these drugs binds diffusible VEGF, thereby preventing its binding to the trans-membrane receptors. The drugs have undergone extensive pre-clinical trials in animal models.

Age-related macular Degeneration (AMD) is the most common cause of vision loss in patients over the age of 65 years in industrialized nations. Though most patients with AMD have the non-exudative (dry) form, most severe vision loss is due to exudative (wet) macular degeneration. Exudative AMD is characterized by the abnormal growth of neovascular membranes from the choriocapillaris into the subretinal or sub-retinal pigment epithelial space. Though the underlying pathophysiology of choroidal neovascularization is not completely understood, ischemia and inflammation are believed to play important roles. Neovascularization is largely driven by vascular endothelial growth factor A (VEGF-A) with VEGF165 appearing to be the most important isoform. The intravitreal administration of anti-VEGF drugs has become the preferred treatment for exudative macular degeneration. Three drugs are currently approved for the treatment of exudative AMD (pegaptanib, ranibizumab and aflibercept) and bevacizumab is frequently used off- label. Unlike laser photocoagulation and photodynamic therapy which only slowed the loss of vision, the anti-VEGF drugs frequently lead to long-term improvements in visual acuity. Several new anti-VEGF drugs are being developed for the treatment of exudative AMD.

The management of diabetic retinopathy has been guided for almost thirty years by results of the Diabetic Retinopathy Study (initially reported in 1976) and Early Treatment Diabetic Retinopathy Study (initially reported in 1985). The goal of therapy was to reduce the risk of severe visual loss in proliferative diabetic retinopathy and to reduce the risk of moderate visual loss in patients with clinically significant macular edema. Anti-VEGF therapy has been shown to cause regression of proliferative diabetic retinopathy and to provide a significant chance of improved vision which has been decreased due to diabetic macular edema. Although the efficacy of anti-VEGF therapy may be greater than the efficacy of focal/grid photocoagulation the greater treatment burden and costs associated with such therapy makes its adoption controversial.

Vascular endothelial growth factor (VEGF) is produced by the retina as a response to ischemia. In lower concentrations, VEGF induces retinal vascular hyperpermeability; in higher concentrations, intraocular neovascularization. Intraocular concentrations of VEGF after retinal vein occlusion (RVO) fall along a continuum. Therefore, most RVOs are, to some degree, ischemic, a revision of the dichotomous ischemic/ nonischemic classification commonly used from 1970- 2000. Anti-VEGF therapy is useful in treating RVOs with macular edema and intraocular neovascularization. The four drugs in use are pegaptanib, bevacizumab, ranibizumab, and aflibercept. For ranibizumab, there is level I evidence supporting effectiveness in treating macular edema following BRVO and CRVO. For aflibercept, there is level I evidence supporting effectiveness in treating macular edema following CRVO. For bevacizumab and pegaptanib, there is level II evidence for macular edema following BRVO and CRVO. For all four drugs, there is level I and II evidence of effectiveness against varieties of intraocular neovascularization. Durations of effectiveness depend on intraocular half lives and binding affinities of the different drugs for VEGF. In general, the durations of effectiveness of a single injection vary from one to three months with aflibercept seeming to have the longest duration of action. Concerns of potential adverse effects of these drugs on retinal capillary perfusion have not been validated.

The use and indications of anti-vascular endothelial growth factors (VEGF) are rapidly expanding, evolving and undergoing refinement in retinal diseases. This manuscript attempts to perform a critical appraisal of the diaspora of limited information available on the non- traditional applications (outside of AMD, DR and vascular occlusive diseases) and synthesize a review. As with any newer drug, only longitudinal studies will determine the true inherent value no matter how broad the current popular appeal appears to be due to very positive press. Although these drugs appear to be very effective in conventional applications, it is wise to deliberate prior to non-conventional use.

The cornea maintains avascularity by balancing angiogenic factors and anti-angiogenic agents. Stress on the cornea can disrupt this delicate equilibrium resulting in angiogenesis. Bevacizumab (Avastin®; Genentech, South San Francisco, CA) is a humanized monoclonal antibody which binds to all isoforms of vascular endothelial growth factor (VEGF)-A, thereby inhibiting angiogenesis. Recent studies have explored the role of bevacizumab in treating corneal neovascularization and ocular surface disease. Animal and human studies using both subconjunctival and topical bevacizumab reveal a reduction in corneal neovascularization. Evidence suggests that topical bevacizumab is safe and may be effective in the treatment of corneal neovascularization. Case studies suggest that bevacizumab may be useful in limiting the recurrence of corneal neovascularization when combined with corneal transplant surgery. A few reports have assessed the role of bevacizumab in pterygium surgery as well. These preliminary studies suggest that the use of subconjunctival bevacizumab may be beneficial in the treatment of pterygia but its benefit has not been defined. The role of bevacizumab in corneal and ocular surface disease continues to evolve.

Anti-VEGF Treatment of Glaucoma by Rick E. Bendel (126-130).
Challenges with surgical treatment of glaucoma are numerous and frequent, especially with the more complicated forms such as neovascular or uveitic glaucoma. Surgeries often fail which have driven the search for using a surgical adjunct to improve the outcomes and longevity of glaucoma procedures, while lowering their complication rates. VEGF levels have been found to be elevated in patients with both primary open angle glaucoma and secondary glaucomas. The use of anti-VEGF agents is now being investigated in the treatment of all types of glaucoma. The information is early and limited, but what is known will be reviewed in this article. In considering anti-VEGF agents in the treatment of glaucoma, some evidence suggests that anti-VEGF agents may induce glaucoma by elevating intraocular pressure, which will also be reviewed.

The development of anti-vascular endothelial growth factor (VEGF) therapy is both revolutionary and unprecedented in the history of ophthalmology. In the past ophthalmic drugs have been the reformulations of previously well characterized systemic drugs. Anti-VEGF therapies for retinal diseases represent the first time that systemic and ocular complications are being initially defined by the ophthalmic profession. The purpose of this chapter is to review both the described and potential complications of Anti-VEGF therapies. This chapter will describe obvious associated complications such as endophthalmitis and elevated intraocular pressure and non obvious complications such as exacerbation of hypertension, increased risk of thromboembolic events, renal thrombosis and issues with surgical wound healing.

CTX-M is the most frequent type of extended spectrum beta-lactamase. It is an important cause of anti-microbial resistance against cephalosporins and a recent concern in treating infections caused by Gram negative bacteria. Although Escherichia coli has become the major carrier of the genes, these enzymes were reported in many other bacterial species. The aim of this study was to determine risk factors associated with resistance in CTX-M producing E. coli isolated from patients admitted in Sanandaj city hospitals. The study was a case control investigation. A case patient was defined as a patient from whom a resistant strain of E. coli producing CTX-M was recovered. The control patient was the one who carried a cephalosporin sensitive E. coli strain. The presence of CTX-M was investigated both by a phenotypic method (double disk diffusion); as well as, genotypically by PCR. The potential risk factors for resistance trait were monitored with patient's history and current situations. The main risk factors for CTX-M associated infection were found to be associated with ICU hospitalization (OR 5.702 CI95% 2.286-14.223), mechanical ventilation (OR 5.043 CI 95% 2.082-12.213) and the presence of urinary catheter (OR 11.629 CI95% 3.694-36.613). In conclusion; ICU stay, mechanical ventilation and urinary tract catheter were found to be the most predisposing factors in spread of CTX-M family in hospital environments. It seems that more sophisticated programs are needed to control of this conditions.

Pyruvic acid is an organic acid found in most biological systems as an end product of the metabolism of sugar or starch and its carboxalate anion is known as pyruvate. Pyruvate enters in the Krebs cycle to generate the ATP. It is an effective scavenger of reactive oxygen species (ROS) and OH-. It also inhibits tumor necrosis factor-a production, iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) levels. Pyruvates have instability in solution, inorder to avoid this problem different analogs of pyruvate were developed. Treatment with ethyl pyruvate like pyruvate esters has been shown to be effective in a wide variety of preclinical models. In this review, reported pharmacological actions of pyruvate analogues like anti inflammatory, antioxidants, anticancer, neuroprotective etc are discussed.