Current Pharmaceutical Design - Volume 23, Issue 4, 2017

Background: The preferred approach for the treatment of neovascular age-related macular degeneration (AMD) is frequent intravitreal injections of the anti-vascular endothelial growth factor (VEGF) agents. However, considering the limitations of current anti-VEGF approaches, including the need for frequent injections, inadequate response in some patients, and a relatively short duration of effect, several new therapeutic modalities are under evaluation. Methods: A comprehensive review of the literature was performed on the new treatment modalities for neovascular AMD, and the relevant studies were discussed. Results: The treatment modalities for neovascular AMD include new anti-VEGF drugs, new drug delivery systems and new targets in the pathogenic cascade of choroidal neovascularization. These new modalities are in different phases of clinical development. Conclusion: The results of the completed studies reporting the new therapeutic modalities for neovascular AMD thus far are promising.

Background: The global prevalence of AMD is projected to be 196 million by the year 2020. Despite substantial progress in the development of new therapies for wet AMD using inhibition of vascular endothelial growth factor (VEGF), the severe visual impairment associated with geographic atrophy in dry AMD remains untreatable. A number of therapeutic options for dry AMD are being developed and are in various stages of clinical trials. Methods: Review of literature. Results: Enhancers of choroidal blood flow, neuroprotectants and anti-complement factors are the key targets in the research for the treatment of dry AMD. These molecules aim to promote the function of the retinal pigment epithelium and preserve the photoreceptors. Conclusion: New molecules are being developed for the treatment of dry AMD, and anti-complement therapy appears to be the most promising among them.

Age-related macular degeneration (AMD) is a leading cause of irreversible visual loss and is primarily treated with nutritional supplementation as well as with anti-vascular endothelial growth factor (VEGF) agents for certain patients with neovascular disease. AMD is a complex disease with both genetic and environmental risk factors. In addition, treatment outcomes from nutritional supplementation and anti-VEGF agents vary considerably. Therefore, it is reasonable to suspect that there may be pharmacogenetic influences on these treatments. Many series have reported individual associations with variants in complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and other loci. However, at this time there are no validated associations. With respect to AMD, pharmacogenetics remains an intriguing area of research but is not helpful for routine clinical management.

Background: Acute-onset postoperative endophthalmitis is an uncommon but potentially serious complication of cataract surgery. Since there are relatively few randomized clinical trials comparing the timing and administration of prophylactic antibiotics, there are wide variations in prevention practices around the world. Methods: Literature review. Results: Antibiotics may be used before surgery, during surgery, or after surgery in an attempt to decrease the rates of endophthalmitis. Antibiotics may be delivered by various routes, including topical, subconjunctival, in the irrigating solution, or by bolus intracameral injection. Polymerase chain reaction and other DNA identification techniques for bacterial isolates and their antibiotic sensitivity profiles will play an important role in future management strategies. Conclusion: There is no consensus regarding the precise use of antibiotics in the perioperative period. Because of increased multidrug-resistant bacteria, evolving strategies are needed to address these issues.

Risk reduction and the attainment of good outcomes in contemporary cataract surgery depend in part on patient compliance with a postoperative regimen of topical eye drops. Topical drops are expensive and challenging to instill properly for patients. The consequences of noncompliance or poor compliance can be significant for the patient (in the case of a complication) and for society (in the case of development of antibiotic resistance). For all of these reasons, new approaches that reduce the need for topical therapy are beginning to emerge, including intracameral injection, sustained or slow-release drug delivery mechanisms, and the recently introduced “Dropless cataract surgery,” which involves intravitreal injection of single-use, compounded combination of antibiotics and corticosteroids. This paper is a review of the rationale for reducing topical therapy in cataract surgery prophylaxis, and what is known to date about the efficacy and safety of the dropless approach.

Background: Acute-onset postoperative endophthalmitis after cataract surgery remains a rare but important cause of visual loss. There is no global consensus regarding the optimal strategies for prophylaxis of endophthalmitis and practices vary substantially around the world, especially with respect to the use of intracameral antibiotics. The European Society of Cataract & Refractive Surgeons in a randomized clinical trial (2007) reported an approximately 5-fold reduction in endophthalmitis rates associated with the use of intracameral cefuroxime. Despite this report, the use of intracameral antibiotics has not been universally adopted. Methods: Various endophthalmitis prophylaxis patterns around the world (including the United States, Canada, Australia/New Zealand, Japan, China, India, Indonesia, South Africa, Argentina, Russia, Sweden and Mexico) are compared. Each contributing author was asked to provide similar information, including endophthalmitis rates based on published studies, current practice patterns, and in some cases original survey data. Various methods were used to obtain this information, including literature reviews, expert commentary, and some new survey data not previously published. Results: Many different practice patterns were reported from around the world, specifically with respect to the use of intracameral antibiotics. Conclusion: There is no worldwide consensus regarding endophthalmitis prophylaxis with cataract surgery.

Postoperative endophthalmitis is typically caused by patient’s conjunctival bacterial flora or contaminated solutions and instruments. Visual outcome is often poor in severe cases, and treatment is especially difficult when endophthalmitis is caused by multidrug resistant bacteria. Povidone-iodine is used worldwide due to its wide-spectrum antimicrobial activity, absence of resistant bacteria to povidone-iodine, and low cost. Furthermore, the effective concentration against microorganisms and safe concentration for ocular tissues have been well established. For ocular surface washing, the safe and highly bactericidal concentrations range from 0.050 to 0.500%. Repeated washing of the ocular surface with 0.250% povidone-iodine every 20-30 seconds during ophthalmic surgeries eliminates the conjunctival normal flora, minimizing the passage of bacteria into intraocular compartment, and is thus useful for the prevention of endophthalmitis. The concentration range of 0.013%-0.027% is effective for the treatment of endophthalmitis and nontoxic to intraocular tissues. In a small case series, 4 eyes with endophthalmitis were treated by vitrectomy using 0.025% povidone-iodine in Balanced Salt Solution (BSS) PLUS for vitreous irrigation. In all eyes, endophthalmitis was resolved with no ocular complications and visual acuity was improved. When performing ophthalmic surgeries, washing the ocular surface with saline containing 0.250% povidone-iodine every 20-30 seconds is safe for ocular tissues and effective for the prevention of endophthalmitis. A small case series suggested the effectiveness and safety of using irrigation solution containing 0.025% povidone-iodine in vitrectomy for the treatment of endophthalmitis, but this treatment method remains to be established.

Background: Toxic optic neuropathies (TONs) often present with a gradual and bilateral decrease in visual acuity, scotomas and optic disc pallor. Obtaining an accurate history is the critical first step in determining the etiology of TONs. Methods: This updated review contains a thorough analysis of the current PubMed-indexed literature on the most common agents responsible for TONs, including methanol, ethambutol, amiodarone, linezolid, tumor necrosis factor alpha inhibitors and phosphodiesterase 5 inhibitors. Results: The reviewed articles are mainly case reports presenting new and controversial aspects of the above agents. New treatment strategies, such as erythropoietin for methanol optic neuropathy, are being proposed for TONs, a condition that was previously regarded as untreatable. Conclusion: TONs could cause significant disability due to visual impairment. In case of early diagnosis and drug withdrawal, most TONs are treatable. Patients need to be appropriately counseled, and prescribing physicians should be especially made aware of TON-inducing medications.

Background: Glaucoma comprises a group of neurodegenerative diseases resulting in retinal ganglion cell death within the optic nerve head. It is projected to affect almost 80 million people worldwide by 2020. The condition’s asymptomatic nature translates to over half of glaucoma sufferers being unaware of their condition. By the time of diagnosis, irreversible blindness is likely to have occurred. Prime areas of glaucoma research therefore include identification and optimization of risk factors for the disease, accurate and early diagnostic tools and novel therapeutic methods. Methods: The goal of this review was to summarize main areas of latest glaucoma research into risk factors of glaucoma, diagnostic tools and treatments. PubMed was used to search for terms including glaucoma risk factors, glaucoma diagnostics, glaucoma treatment, glaucoma drug delivery and glaucoma IOP. Results: The evidence for risk factors of low CSF pressure, IOP, smoking, vascular risk factors and light toxicity is described. Latest diagnostic and monitoring techniques for glaucoma include SD-OCT, DARC and IOP telemetry. Current and emerging medical and surgical treatments in glaucoma are discussed. Rho kinase inhibitors have the potential to both lower IOP and also provide neuroprotection, several of which are in clinical trials. Several other new medical treatments such as calcium channel blockers and neurotrophic agents also have the capacity to provide neuroprotection. Minimally Invasive Glaucoma Surgery (MIGS) devices provide an improved safety profile compared to traditional trabeculectomy; the latest ab interno and ab externo devices are described. Novel drug delivery methods, including punctual plugs and contact lenses, help overcome the challenges with patient adherence. Conclusion: The ultimate goals are to reduce the individual patient risk factors associated with glaucoma, diagnose the condition early and to find treatments that not only reduce IOP but also reverse neurodegeneration of RGCs. The usage of combinations of novel medical and surgical treatments may help maximize IOP reduction and neuroprotection.

Background: Dry eye disease (DED) is a multifactorial disease of the tears and ocular surface that results in symptoms such as discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface. The principal pathological mechanisms of DED are hyperosmolarity and inflammation. These mechanisms are deeply interrelated and lead to a self-perpetuating “vicious circle”. Methods: The objective of this review is to describe novel pharmacological and non-pharmacological treatments for DED. Results: Based on the better understanding of the physiopathology of the disease, new treatment strategies have been developed. Conclusion: The focus of the management of DED has been taken away from just reducing symptoms and redirected towards specific targets of its physiopathology, being inflammation the most addressed topic.

Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial disease of complex I of the respiratory chain. Patients typically present with subacute vision loss in one eye followed by the loss of vision in the second eye approximately 4-8 weeks later, ultimately leading to blindness. Therapeutic interventions have so far failed to prevent this vision loss; however, there has been recent interest in new managements for this prototypic mitochondrial disease. A review of the literature was performed and articles were identified using PubMed (the search terms LHON and treatment were used). These publications were paired to the clinical trials listed on the clinicaltrials.gov website. There are eighteen studies including 5 phase II/III clinical trials in LHON listed on the clinicaltrials.gov website and they vary from oral medication to eye drops and intravitreal injections. In this review, we discuss failed and active therapies and the future of clinical trials in LHON.

Background: Tobacco smoking has detrimental influence on human health and is one of the leading causes of preventable mortality worldwide, associated with lung cancer, chronic obstructive lung disease and cardiovascular disease. Aim: The analysis of the influence of tobacco smoking on pathology of the anterior segment of the eye in adults and children. Methods: A comprehensive review of the literature performed through MEDLINE and PubMed searches, was published during the period 2000-2016. Results: In adults, tobacco smoking is associated with hyperopia, delayed corneal epithelial healing and progression of Fuchs’ endothelial corneal dystrophy. Smoking is a strong risk factor for age-related nuclear cataract. However, smoking is not associated with pterygium, and its influence on dry eye symptoms, central corneal thickness and progression of primary open glaucoma remains controversial. Smoking during pregnancy increases risk of convergent or divergent strabismus or poor stereo acuity, however, its influence on anophtalmia, microphtalmia, amblyopia and hyperopic refractive error is controversial. Conclusion: Tobacco smoking plays an important role in the pathogenesis of many diseases of anterior eye segment leading to visual impairment in adults and children.

Background: Tobacco smoking has detrimental influence on human health. Aim: The analysis of influence of tobacco smoking on retina diseases, uveitis, optic neuropathies, and thyroidassociated orbitopathy in adults and children. Methods: A comprehensive review of the literature performed through MEDLINE and PubMed searches, covering the years 2000-2016. Results: In adults, tobacco smoking is a strong risk factor for age-related macular degeneration, polypoidal choroidal vasculopathy, uveitis and inflamed cystoid macular edema as well as Grave`s ophthalmopathy. Tobacco smoking reduces thickness of the retina and choroid, plays a role in episcleritis, sclerits, tobacco optic neuropathy, and Leber's hereditary optic neuropathy. In children, maternal smoking is a significant risk factor for stages 3 and 4 retinopathy of prematurity, optic nerve hypoplasia among babies with a birth weight over 2500 g and thinner retinal nerve fiber layer. Conclusion: Tobacco smoking plays an important role in the pathogenesis of many posterior eye segment diseases leading to blindness in adults and children.

Basal cell caricnoma (BCC), the most common periocular magliancy, is treated with complete surgical excision. However, in patients not amenable to surgery or when surgical resection means loss of vital organs or disfiguring procedures due to locally advanced or metastatic disease, targeting the hedgehog pathway offers a novel treatment approach for such patients. Mutation in PTCH1 and SMO has been identified in patients with basal cell nevoid syndrome as well as in patients with sporadic BCC. Inhibition of SMO by vismodegib or sonidegib, the two sonic hedgehog inhibitor drugs approved by the Food and Drug Administration in the United States, has shown overall response rate for locally advanced and metastatic BCC around 50%. The most common side effects were muscle cramps, weight loss, fatigue, and lost appetite. Resistance to vismodegib has been attributed to mutation in SMO or activation of RAS/MAPK pathway. New research into dual inhibition aims to overcome this resistance and provide more lasting response.

Background: The cornea is transparent tissue that serves as the window of the eye, allowing light to enter from the outer environment. The corneal endothelium maintains corneal transparency; thus, its dysfunction results in corneal haziness and causes severe vision loss. The only available therapeutic choice for treating corneal endothelial dysfunction has been transplantation using donor corneas; consequently, researchers have been pressed to develop new therapeutic options. Methods: The goal of the review is to provide an overview of the research into Rho kinase (ROCK) inhibitors in the field of corneal endothelium therapy and the potential for clinical use of ROCK inhibitors. Results: We reported that ROCK inhibitor enhances wound healing in the corneal endothelium. We further proposed the development of ROCK inhibitors as drugs that suppress the incidence of bullous keratopathy following severe corneal endothelial damage, especially that occurring during cataract surgery, one of the leading causes of corneal transplantation. We also proposed the use of ROCK inhibitors as adjunct drugs for cell-based therapeutic treatment of corneal endothelial dysfunction. ROCK inhibitors promote the engraftment of injected cultured corneal endothelial cells to the recipient cornea, thereby enabling the regeneration of corneal endothelium. Of note, we have initiated clinical research into cell injection therapy using a ROCK inhibitor as an adjunct drug. Conclusion: This review documents the potency of ROCK inhibitors in clinical use, both as eye drops and as adjunct drugs for cell-based therapy for the treatment of corneal endothelial dysfunction.