Current Pharmaceutical Design - Volume 21, Issue 32, 2015

The number of elderly patients using anticoagulant and antiplatelet treatment in prevention of thromboembolism has significantly increased in recent years. It was believed for many years that those patients may be at higher risk for hemorhages during ocular surgery. Different strategies were proposed to prevent these complications, including discontinuation of anticoagulants, dose reduction, or substitution with low molecular weight heparin. The objective of this work was to evaluate the results of studies presenting the results of vitreoretinal surgeries in patients continuing antiplatelet and/or anticoagulant treatment. We performed a PubMed search of possible intraoperative and postoperative hemorrhages in patients receiving anticoagulant and/or antiplatelet therapy during vitreoretinal surgery in 2007-2014. In most of the studies reviewed there was no substantial increase in intraoperative and postoperative hemorrhages risks during vitreoretinal surgery. However, in some studies, a substantially increased risk has been identified. We conclude that the available data is insufficient to decide whether to continue or discontinue anticoagulant and/or antiplatelet therapy during vitreoretinal surgery and we recommend an individualized approach in consultation with the patient’s medical doctors and anesthesiologists.

Nutritional supplements are widely taken by the general population and several of these products are marketed specifically to improve eye health. The aim of this review is to summarise the evidence for the benefit of supplementation with antioxidant vitamins and other micronutrients for three of the most common eye diseases of the elderly: age-related macular degeneration (AMD), cataract and dry eye syndrome (DES). Although the potential importance of diet and nutrition in these conditions is strongly supported by data from observational studies, evidence from randomised controlled trials (RCTs) on the benefit of nutritional supplementation is generally lacking. However, there is high quality evidence to support the use of an Age-Related Eye-Disease Study (AREDS) supplement containing antioxidants (β-carotene, vitamin C and vitamin E) and zinc to slow progression in those at moderate to high risk of developing advanced AMD. Recent data from the AREDS2 trial provided data to suggest that β-carotene could be replaced with lutein and zeaxanthin on the basis of improved safety without compromising efficacy. Although there is currently insufficient evidence to recommend the routine use of any of the commercially available supplements in cataract and DES, given the public health importance of these conditions further research into the benefit of dietary modification or nutritional supplementation should be a priority.

Elevated eye pressure is the main risk factor for glaucoma; intraocular pressure rises when the ratio between aqueous humor formation (inflow) and its outflow is unbalanced. Currently, the main goal of medical treatment is the reduction of intraocular pressure. Five main classes of topical drugs are available; they include betablockers, carbonic anhydrase inhibitors, prostaglandin derivatives, sympathomimetics and miotics. Beta-blockers and carbonic anhydrase inhibitors slow the formation of aqueous humor and may be considered as “inflow” drugs; the other three classes reduce the resistance to the drainage of aqueous humor and may be considered as “outflow” drugs. Despite the variety of drugs accessible in the market, there is a real need for ophthalmologists to have more potent medications for this disease. This review focuses on medical treatment of glaucoma with particular attention to novel molecules in pre-clinical or clinical development.

Uveitis is a term applied to a broad range of conditions characterized by intraocular inflammation. The pharmacological treatment of uveitis is controversial, with limited high-level evidence to inform most of the key treatment decisions that face the patient and clinician on a daily basis. In this review we identified twelve systematic reviews (including two Cochrane reviews) focused on key therapeutic questions in infectious and noninfectious uveitis. Our analysis of these reviews demonstrates the paucity of trial evidence available to inform these important clinical decisions. We consider the reasons for this, and look at the way forward for clinical trials in uveitis, so that we can move from controversy to clarity in the pharmacotherapy of uveitis.

Macular edema (ME) is a common, final pathway for many different ocular and systemic diseases. The most common diseases include: diabetic retinopathy (DR), retinal vascular disorders (such as central and branch retinal vein occlusion), and uveitis. The complex and multifactorial pathophysiological mechanisms leading to ME, are still poorly understood. Inflammation plays a crucial role in the genesis of ME, as demontrsated by significant increase of different cytokines and chemokines, (besides vascular endothelial growth factors-VEGF) in ocular fluids. Currently, intravitreal steroids and anti-VEGF drugs are the most used treatments in ME of retinal vascular origin. This review will address the most important (with highest level of scientific evidence and longest followup) results on the use of intravitreal steroids and anti-VEGF drugs, starting from molecular basis to the most updated randomized clinical trials.

Several medications are associated with retinal vascular toxicity. These include intraocular aminoglycosides, oral contraceptives, interferon alpha, several other agents, and talc, which occurs as a vehicle in some oral medications that may be abused intravenously. As a group, these entities represent a small but clinically relevant category of retinal toxicity from medications. Some of the manifestations (e.g., retinal vascular occlusion) are nonspecific, but others are more specific, including clinically visible talc emboli in retinal vessels. Toxicity may be asymptomatic or may cause irreversible visual loss. By maintaining a high index of suspicion, the correct diagnosis can usually be made.

Proliferative vitreoretinopathy (PVR) can occur in eyes with rhegmatogenous retinal detachment (RRD) or after RRD surgery, and it is the most common cause of failure of this surgery, accounting for about 75% of all primary failures. Complex biological pathways induce PVR development, with growth factors and cytokines from the vitreous and from the serum (as a result of the breakdown of the blood-retinal barrier) stimulating RPE and Muller cells transformation and proliferation, and membrane formation and contraction. Identification of pre-operative risk factors, recognition of the early signs of PVR, use of adequate surgical techniques and of pharmacological therapy can reduce the PRV incidence. Steroids can influence the inflammatory and proliferative components of PVR, by reducing the breakdown of the blood-retinal barrier, and the proliferation of Müller cell and of RPE cells. Some new formulation of intravitreal steroids are promising tool for the prevention of the PVR formation in eyes treated by vitreoretinal surgery.

Endophthalmitis following intravitreal injection is uncommon. There are currently no randomized clinical trials evaluating the role of prophylactic topical antibiotics in this setting. Many large series have reported that topical antibiotics do not decrease, and may in fact increase the rate of endophthalmitis. The reason for this apparent paradoxical finding is unknown but may be due to changes in conjunctival flora due to repeated exposure to antibiotics. At this time, antiseptics (specifically povidone-iodine), rather than antibiotics, are preferred for the majority of patients undergoing intravitreal injections.

Pseudophakic cystoid macular edema (PCME) remains the most common cause of poor visual outcome following cataract surgery. Whereas acute PCME may resolve itself spontaneously, some patients will suffer from vision impairment and will be difficult to treat. Although PCME has already been described approximately 50 years ago, its pathophysiology remains uncertain and a multitude of mechanisms have been suggested. As broad as the mechanisms, as many are the treatment options. Topical nonsteroidal anti-inflammatory agents (NSAIDs) and corticosteroids either as mono- or combined therapy are a commonly used first line approach. When ineffective, systemic treatment with these agents may be an option. Alternatively, intravitreal application of corticosteroids and anti-vascular endothelial growth factor (anti-VEGF) may offer an effective option, if first-line treatment fails. A critical evaluation of the current literature revealed that the optimal treatment of PCME remains unclear and requires further investigation. In addition, prevention should be of foremost importance and remains an open issue. Identification of risk factors, application of NSAIDs and consequent follow-up are potential essential steps in the avoidance of this complication.

High myopia is a major cause of uncorrectable visual impairment. It imposes major challenges and costs for refractive correction, and for the treatment of associated pathological complications. In the last 60 years, there has been a marked increase in the prevalence of high myopia in younger generations in developed countries in East and Southeast Asia, and there are signs of similar, but less pronounced increases in North America and Europe. In some parts of the world, 70-90% of children completing high schools are now myopic, and as many as 20% may be highly myopic. It is now clear that myopia results from excessive axial elongation of the eye, and this greater rate of axial elongation appears to be environmentally driven. Experimental studies have examined the biochemical mechanisms involved in regulation of axial elongation; and, from these studies, some options have emerged for preventing the development of myopia or slowing myopia progression. Atropine eye drops have been quite extensively used in clinical practice in Asian countries. This long-lasting treatment could be beneficial, but has clear limitations and complications. Recent reports suggest that a low concentration of atropine, which has less severe side-effects, is also effective. But, a decision to use an invasive treatment such as atropine drops, even at low doses, requires careful consideration of the risk of myopia progression. A decision to use atropine in pre-myopic patients would require even more careful consideration of the risks. Here, we review the current literature relevant to the prevention of myopia progression with atropine drops.

Diabetic macular edema (DME) represents the most common cause of vision loss in patients affected by diabetes mellitus. Although the pathophysiology of DME is not wholly understood, vascular endothelial growth factor (VEGF) has been identified as a key contributor to the development of DME. In addition, latest information suggests that acute and chronic inflammatory changes occur, contributing to the DME pathogenesis. The current therapeutic approach for DME is mainly based on the administration of anti-VEGF molecules. In particular, VEGF-inhibitors that have been studied for diabetic retinopathy include pegaptanib, ranibizumab, bevacizumab, and aflibercept. The present review analyzes the main characteristics of each molecule, describing the most important results of clinical trails.

PET/CT with choline is a diagnostic tool useful for imaging prostate cancer patients. The overall published papers in this field are referred to three variants of the same radiopharmaceutical: 11C-Choline, 18FMethylcholine and 18F-Ethylcholine. As no data has been reported on the theoretical differences between these three variants of radiolabeled choline, this study aims to explore the knowledge on the physiological distribution of these three tracers, to compare data of imaging acquisition protocols and to verify the theoretical equivalence in terms of diagnostic accuracy and potential false positive cases that can occur in clinical practice. A literature research about published papers was conducted regarding the physiological distribution, imaging acquisition protocols and diagnostic performance of 11C-choline, 18F-methylcholine and 18F-ethylcholine PET/CT. Minimal differences of the “in vivo” bio-distribution of the variants of radiolabeled choline were registered. Several imaging acquisition protocols were utilized, considering the different half-decay of 11C and 18F and the early urinary excretion of 18F-FECH. The diagnostic accuracy resulted similar for all the tracers, despite an insignificant amount of data for 18F-FECH; however, some pitfalls were documented for all the variants, related to the intrinsic properties of choline as a non-tumour specific tracer. Finally, our clinical experience with the two fluorinated kinds of choline has also been reported describing the “in vivo” bio-distribution with semi-quantitative measurement of Standardised Uptake Value in target organs. The literature suggests these three variants of choline equally useful to be considered for prostate cancer imaging. A standardisation of acquisition protocols for fluorinated choline PET/CT has also been proposed.

Current clinical practice guidelines recommend dosing anti-tuberculosis drugs according to ideal body weight and provide dosing caps for most first-line agents. However, this recommendation may be placing corpulent patients with tuberculosis at risk as increased total body weight is associated with an increased risk of clinical failure. Patients with diabetes are at an increased risk of developing tuberculosis and typically weigh more than patients with tuberculosis alone. All these factors in-combination stress the importance of evaluating the effect of weight on the pharmacokinetics of first-line anti-tuberculosis drugs. Multiple studies suggest the use of total body weight based dosing for rifampin. Less data are available for pyrazinamide and ethambutol, but both appear to be candidates for total body weight based dosing. The study evaluating levofloxacin concluded that no adjustment is required. However, the larger variability in obese patients is concerning as to whether “one size fits all” dosing is optimal for levofloxacin. The vast majority of the isoniazid’s pharmacokinetic variability is due to NAT2*4 status. However, more extensive analysis of slow and fast metabolizers is needed to determine the effect of weight within each subgroup. Moxifloxacin does not appear to be affected by weight, but doses of at least 800 mg are likely needed to optimize its pharmacokinetic/pharmacodynamic target attainment. Future pharmacokinetic evaluations should focus on recruiting a wide range of patient weights. These analyses should take advantage of the full weight distribution instead of arbitrarily dichotomizing patients into obese vs. non-obese persons. A subsequent evaluation of the safety and effectiveness of optimized dosing regimens is needed.

Background: Inhaled corticosteroids (ICS) treatment for asthma control is generally focused on lung function and symptoms, but inadequately correlated with airway inflammation. Objective: To compare asthma control in a group of patients whose treatment was based on fraction of exhaled nitric oxide (FENO) and sputum eosinophils (intervention group) with a group in whom treatment was based on clinical score (control group). Study design and primary outcome: Randomized parallel-group longitudinal 24-month study including 5 visits every 6 months. A combination of asthma exacerbation rate and symptom score at 24 months was the primary outcome. Participants: Fourteen patients with eosinophilic asthma per group were included. Results: In the intervention group, exacerbation rate/patient/year was reduced at 12 months (0.82) (-73%) and, to a greater extent at 24 months (0.5) (-84%) compared with baseline (3.21, p<0.01). In the control group, a significant reduction in exacerbation rate/patient/year was only observed between month 12 (3.0) and 24 (2.0, -33%, p<0.01). At 24 months, exacerbation rate was lower (-75%) in the intervention (0.5) than in the control group (2.0, p<0.05). Compared with baseline, mean symptom scores at 24 months were reduced in both groups (intervention group: -72%; control group: - 60%), but were lower in the intervention (8.1±1.0, p<0.05; -27%) than in the control group (11±2.6). ICS dose gradually increased in both groups throughout the study, with no between-group differences. Conclusion: Compared with conventional strategy, longitudinal monitoring of FENO and sputum eosinophils improves eosinophilic asthma control in terms of reduced symptoms and exacerbations without additional increase e in ICS treatment.

Lung cancer is the leading cause of death from cancer worldwide with limited available treatment options in absence of specific molecular alteration. New therapeutic approaches for addressing non small cell lung cancer (NSCLC) are urgently needed. Angiogenesis plays a central role in the tumor growth and metastatic dissemination which stimulates multiple cells to build new abnormal microvessels and leads to tumor microenvironment alterations. This process involves many factors, such as, the vascular endothelial growth factor (VEGF) that has a dominant role, the fibroblast growth factors (FGFs) and the plateled-derived growth factor (PDGF) that together contribute to resistance to VEGF/VEGFR- directed therapy. To date, bevacizumab is currently the only angiogenesis inhibitor that has been approved for the treatment of patients with advanced NSCLC in first-line setting. Moreover, in the last year, two new antiangiogenic agents have been approved for the treatment of patients with advanced NSCLC in second line setting. This review describes the new antiangiogenic agents in the treatment of advanced NSCLC.