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Tumor growth is intricately linked to the process of angiogenesis, with a key role played by vascular endothelial growth factor (VEGF) and its associated signaling pathways. Notably, these pathways also play a pivotal "housekeeping" role in renal physiology. Over the past decade, the utilization of VEGF signaling inhibitors has seen a substantial rise in the treatment of diverse solid organ tumors, diabetic retinopathy, age-related macular degeneration, and various ocular diseases. However, this increased use of such agents has led to a higher frequency of encountering renal adverse effects in clinical practice. This review comprehensively addresses the incidence, pathophysiological mechanisms, and current evidence concerning renal adverse events associated with systemic and intravitreal antiangiogenic therapies targeting VEGF-A and its receptors (VEGFR) and their associated signaling pathways. Additionally, we briefly explore strategies for mitigating potential risks linked to the use of these agents and effectively managing various renal adverse events, including but not limited to hypertension, proteinuria, renal dysfunction, and electrolyte imbalances., (© 2024. The Author(s).)

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by dry and itchy skin. Recently, it has been reported that oxidative stress is involved in skin diseases, possibly including AD. Vitamin C, also referred to as ascorbic acid, is a vital water-soluble compound that functions as an essential nutrient. It plays a significant role as both an antioxidant and an additive in various pharmaceutical and food products. Despite the fact that vitamin C is easily oxidized, we have developed NXP081, a single-stranded DNA aptamer that selectively binds to vitamin C, thereby inhibiting its oxidation. The objective of the current research was to examine the impact of NXP081, an animal model of AD induced by 2,4-dinitrofluorobenzene (DNFB). The experimental drug NXP081, when taken orally, showed promising results in reducing inflammation and improving the skin conditions caused by DNFB. The administration of NXP081 resulted in a significant reduction in ear swelling and a noticeable improvement in the appearance of skin lesions. In addition, the administration of NXP081 resulted in a significant decrease in the migration of mast cells in the skin lesions induced by DNFB. Moreover, NXP081 inhibited the production of interferon-gamma (IFN-γ) in CD4 + T cells that were activated and derived from the lymph nodes. Our findings provide useful information about the anti-inflammatory effect of NXP081 on AD.

Background: Vitamin C (also known as L-ascorbic acid) plays a critical role in reactive oxygen species (ROS) reduction and cell regeneration by protecting cell from oxidative stress. Although vitamin C is widely used in cosmetic and therapeutic markets, there is considerable evidence that vitamin C easily undergoes oxidation by air, pH, temperature, and UV light upon storage. This deficiency of vitamin C decreases its potency as an antioxidant and reduces the shelf-life of products containing vitamin C as its ingredient. To overcome the deficiency of vitamin C, we have developed Aptamin C, an innovative DNA aptamer maximizing the antioxidant efficacy of vitamin C by binding to the reduced form of vitamin C and delaying its oxidation., Methods: Binding of Aptamin C with vitamin C was determined using ITC analysis. ITC experiment was performed 0.2 mmol/L vitamin C that was injected 25 times in 2 µL aliquots into the 1.8 mL sample cell containing the Aptamin C at a concentration of 0.02 mmol/L. The data were fitted to a one-site binding isotherm using with origin program for ITC v.5.0., Results: To investigate the effect of Aptamin C and vitamin C complex in human skins, both in vitro and clinical tests were performed. We observed that the complex of Aptamin C and vitamin C was significantly effective in wrinkle improvement, whitening effect, and hydration increase. In the clinical test, subjects treated with the complex showed dramatic improvement in skin irritation and itching. No adverse reaction was presented by Aptamin C complex in the test., Conclusion: Taken together, these results showed that Aptamin C, an innovative novel compound, should potentially be served as a key cosmeceutical ingredient for a range of skin conditions., (© 2019 The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc.)

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab ( ClinicalTrials.gov identifier: NCT01486797 ). Further clinical development of this novel CXCL12 inhibitor is thus warranted., (Copyright© 2019 Ferrata Storti Foundation.)

Background and Objective: The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations., Patients and Methods: We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified., Results: A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all)., Conclusion: The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140-e157.]., (Copyright 2019, SLACK Incorporated.)

Importance: Current studies assessing the risk of stroke, myocardial infarction (MI), and death in patients undergoing intravitreal anti-vascular endothelial growth factor (VEGF) therapy are inconclusive. To our knowledge, no population-based studies have been performed to examine these potential risks., Objective: To examine whether patients with exudative age-related macular degeneration (AMD) receiving intravitreal anti-VEGF injections have a higher incidence of MI, stroke, or death compared with control populations., Design, Setting, and Participants: This population-based, retrospective cohort study included 504 patients from Olmsted County, Minnesota, identified through the Rochester Epidemiology Project (REP) database as receiving at least 1 intravitreal anti-VEGF injection for exudative AMD from January 1, 2004, to December 31, 2013. Three age- and sex-matched control groups of individuals who did not receive anti-VEGF treatment and were derived from the REP database were also studied: control individuals with exudative AMD in the era before anti-VEGF (January 1, 1990, to December 31, 2003), controls with dry AMD, and controls without AMD. Data analysis was performed from September 1, 2016, to September 1, 2017., Main Outcomes and Measures: Five-year risk of stroke, MI, and death were assessed in patients compared with controls using Kaplan-Meier and multivariate analysis with Cox proportional hazards regression models., Results: The study included 504 patients (321 female [63.7%]; mean [SD] age, 76.5 [10.0] years) who received at least 1 intravitreal anti-VEGF injection for exudative AMD during the study period. Kaplan-Meier analysis revealed a 5-year risk of 7.2% for stroke, 6.1% for MI, and 30.0% for death. Patients who received anti-VEGF had no increased risk of stroke or MI compared with controls with dry AMD (n = 504), controls with exudative AMD (n = 473), or controls without AMD (n = 504). There was an increased risk of mortality compared with controls with exudative AMD in the era prior to anti-VEGF therapy but not the other control groups on multivariate analysis (hazard ratio, 1.63; 95% CI, 1.30-2.04; P < .001)., Conclusions and Relevance: This population-based study revealed that intravitreal anti-VEGF therapy for exudative AMD was not associated with consistent increases in the risk of stroke, MI, or death compared with no therapy in patients with or without AMD. It appears to be likely the cardiac events these patients experience are not attributable to their anti-VEGF therapy.

Objectives: To evaluate the efficacy and safety of anti-vascular endothelial growth factor (VEGF) agents and corticosteroids for the treatment of macular oedema (ME) secondary to central retinal vein occlusion (CRVO)., Design: Systematic review and network meta-analysis., Participants: Patients from previously reported randomised controlled trials (RCTs) comparing anti-VEGF and corticosteroids for the treatment of ME secondary to CRVO., Methods: Literature searches were conducted using PubMed, Medline, Embase, Cochrane Library and clinicaltrials.gov until March 2017. Therapeutic effects were estimated using the proportions of patients gaining/losing ≥15 letters, best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Treatment safety was estimated using the proportions of adverse events, namely increased intraocular pressure (IOP), cataracts, vitreous haemorrhage (VH) and retinal tear. The software ADDIS (V.1.16.8) was used for analysis. Treatment effect and safety of different drugs could be ranked based on simulation., Results: Eleven RCTs comprising 2060 patients were identified. Regarding patients gaining ≥15 letters, aflibercept and ranibizumab were significantly more effective than sham/placebo at 6 months. Regarding patients losing ≥15 letters at 6 months, ranibizumab showed significant improvement compared with dexamethasone. Aflibercept, bevacizumab or ranibizumab showed greater improvements in BCVA than sham/placebo at 6 months. Intravitreal ranibizumab injection demonstrated greater CRT reduction than both sham and dexamethasone did. Dexamethasone had a higher risk of increased IOP than aflibercept and ranibizumab. Ranibizumab demonstrated a greater risk of cataracts than dexamethasone. Aflibercept and ranibizumab demonstrated low incidence of VH and retinal tear, respectively. Aflibercept had a slight advantage over ranibizumab as assessed by benefit-risk analysis., Conclusions: Anti-VEGF agents have advantages in the treatment of ME secondary to CRVO. Aflibercept and ranibizumab showed marked BCVA improvement and CRT reduction. Aflibercept may have a slight advantage over ranibizumab. The results of this study can serve as a reference for clinicians to provide patient-tailored treatment., Prospero Registration Number: CRD42017064076., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO., Objectives: The 2014 update of this review found high-quality evidence of benefit with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO. The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs using network meta-analysis methods., Search Methods: We searched various electronic databases on 26 April 2017., Selection Criteria: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO., Data Collection and Analysis: We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study., Main Results: Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference., Authors' Conclusions: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. Aflibercept may confer some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms but it is unclear whether this applies to the long-term. There is a need for more evidence on the long-term (greater than two years) comparative effects of these anti-VEGF agents. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death.

Purpose of Review: Since the selection of the first thrombin-binding aptamer in 1992, the use of nucleic acid aptamers to target specific coagulation factors has emerged as a valuable approach for generating novel anticoagulant and procoagulant therapeutics. Herein, we highlight the most recent discoveries involving application of aptamers for those purposes., Recent Findings: Learning from the successes and pitfalls of the FIXa-targeting aptamer pegnivacogin in preclinical and clinical studies, the latest efforts to develop antidote-controllable anticoagulation strategies for cardiopulmonary bypass that avoid unfractionated heparin involve potentiation of the exosite-binding factor X (FX)a aptamer 11F7t by combination with either a small molecule FXa catalytic site inhibitor or a thrombin aptamer. Recent work has also focused on identifying aptamer inhibitors of contact pathway factors such as FXIa and kallikrein, which may prove to be well tolerated and effective antithrombotic agents in certain clinical settings. Finally, new approaches to develop procoagulant aptamers to control bleeding associated with hemophilia and other coagulopathies involve targeting activated protein C and tissue plasminogen activator., Summary: Overall, these recent findings exemplify the versatility of aptamers to modulate a variety of procoagulant and anticoagulant factors, along with their capacity to be used complementarily with other aptamers or drugs for wide-ranging applications.

Aptamers are synthetic molecules structured as single-stranded DNA or RNA oligonucleotides that can be designed to mimic the functional properties of monoclonal antibodies. They bind to the target molecules (typically soluble or cell-bound proteins) with high affinity (with picomolar to low nanomolar range) and specificity, and therefore can be an alternative to therapeutic antibodies or peptide ligands. This paper reviews published data regarding pharmacokinetics, pharmacodynamics and safety of aptamers from preclinical and clinical studies. Aptamers have been developed for the treatment of a variety of diseases, including cancer, macular degeneration,g cardiovascular disease, diabetes and anaemia of chronic diseases. There are several preclinical studies with unmodified aptamers, but the vast majority of aptamer trials in humans have been conducted with modified aptamers, because unmodified aptamers demonstrate metabolic instability, as well as rapid renal filtration and elimination. Various strategies have been developed to improve the pharmacokinetic profile of aptamers. Aside from chemical modification of nucleotides in order to stabilize them against nuclease degradation, the main modification to extend the half-life is pegylation. Therefore, the process of pegylation as well as its benefits and possible shortcomings will briefly be discussed., (Copyright © 2018 Medical University of Vienna. Published by Elsevier B.V. All rights reserved.)

Transmembrane receptor tyrosine kinases (RTKs) play crucial roles in cancer cell proliferation, survival, migration and differentiation. Area of intense research is searching for effective anticancer therapies targeting these receptors and, to date, several monoclonal antibodies and small-molecule tyrosine kinase inhibitors have entered the clinic. However, some of these drugs show limited efficacy and give rise to acquired resistance. Emerging highly selective compounds for anticancer therapy are oligonucleotide aptamers that interact with their targets by recognizing a specific three-dimensional structure. Because of their nucleic acid nature, the rational design of advanced strategies to manipulate aptamers for both diagnostic and therapeutic applications is greatly simplified over antibodies. In this manuscript, we will provide a comprehensive overview of oligonucleotide aptamers as next generation strategies to efficiently target RTKs in human cancers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We describe two cases of cutaneous eruptions of pigmented purpuric dermatoses (PPDs) arising after exposure to medications not previously reported in the literature as causing these reactions. Specifically, two women had biopsy-proven PPDs, one after exposure to an over-the-counter iodine supplement marketed as an extract from "Norwegian kelp," and the other after intraocular injections of pegaptanib, a vascular endothelial growth factor inhibitor. The eruption occurred shortly after beginning the medication and resolved upon discontinuation. This highlights the importance of considering over-the-counter and intraocular medications when assessing cutaneous eruptions that may be medication related, such as PPDs.

Background: Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis in foetal life. Researchers have recently attempted to use anti-VEGF agents for the treatment of retinopathy of prematurity (ROP), a vasoproliferative disorder. The safety and efficacy of these agents in preterm infants with ROP is currently uncertain., Objectives: To evaluate the efficacy and safety of anti-VEGF drugs when used either as monotherapy, that is without concomitant cryotherapy or laser therapy, or in combination with planned cryo/laser therapy in preterm infants with type 1 ROP (defined as zone I any stage with plus disease, zone I stage 3 with or without plus disease, or zone II stage 2 or 3 with plus disease)., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 11), MEDLINE (1966 to 11 December 2016), Embase (1980 to 11 December 2016), CINAHL (1982 to 11 December 2016), and conference proceedings., Selection Criteria: Randomised or quasi-randomised controlled trials that evaluated the efficacy or safety of administration, or both, of anti-VEGF agents compared with conventional therapy in preterm infants with ROP., Data Collection and Analysis: We used standard Cochrane and Cochrane Neonatal methods for data collection and analysis. We used the GRADE approach to assess the quality of the evidence., Main Results: Six trials involving a total of 383 infants fulfilled the inclusion criteria. Five trials compared intravitreal bevacizumab (n = 4) or ranibizumab (n = 1) with conventional laser therapy (monotherapy), while the sixth study compared intravitreal pegaptanib plus conventional laser therapy with laser/cryotherapy (combination therapy).When used as monotherapy, bevacizumab/ranibizumab did not reduce the risk of complete or partial retinal detachment (3 studies; 272 infants; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.21 to 5.13; risk difference (RD) 0.00, 95% CI -0.04 to 0.04; very low-quality evidence), mortality before discharge (2 studies; 229 infants; RR 1.50, 95% CI 0.26 to 8.75), corneal opacity requiring corneal transplant (1 study; 286 eyes; RR 0.34, 95% CI 0.01 to 8.26), or lens opacity requiring cataract removal (3 studies; 544 eyes; RR 0.15, 95% CI 0.01 to 2.79). The risk of recurrence of ROP requiring retreatment also did not differ between groups (2 studies; 193 infants; RR 0.88, 95% CI 0.47 to 1.63; RD -0.02, 95% CI -0.12 to 0.07; very low-quality evidence). Subgroup analysis showed a significant reduction in the risk of recurrence in infants with zone I ROP (RR 0.15, 95% CI 0.04 to 0.62), but an increased risk of recurrence in infants with zone II ROP (RR 2.53, 95% CI 1.01 to 6.32). Pooled analysis of studies that reported eye-level outcomes also revealed significant increase in the risk of recurrence of ROP in the eyes that received bevacizumab (RR 5.36, 95% CI 1.22 to 23.50; RD 0.10, 95% CI 0.03 to 0.17). Infants who received intravitreal bevacizumab had a significantly lower risk of refractive errors (very high myopia) at 30 months of age (1 study; 211 eyes; RR 0.06, 95% CI 0.02 to 0.20; RD -0.40, 95% CI -0.50 to -0.30; low-quality evidence).When used in combination with laser therapy, intravitreal pegaptanib was found to reduce the risk of retinal detachment when compared to laser/cryotherapy alone (152 eyes; RR 0.26, 95% CI 0.12 to 0.55; RD -0.29, 95% CI -0.42 to -0.16; low-quality evidence). The incidence of recurrence of ROP by 55 weeks' postmenstrual age was also lower in the pegaptanib + laser therapy group (76 infants; RR 0.29, 95% CI 0.12 to 0.7; RD -0.35, 95% CI -0.55 to -0.16; low-quality evidence). There was no difference in the risk of perioperative retinal haemorrhages between the two groups (152 eyes; RR 0.62, 95% CI 0.24 to 1.56; RD -0.05, 95% CI -0.16 to 0.05; very low-quality evidence). However, the risk of delayed systemic adverse effects with any of the three anti-VEGF drugs is not known., Authors' Conclusions: Implications for practice: Intravitreal bevacizumab/ranibizumab, when used as monotherapy, reduces the risk of refractive errors during childhood but does not reduce the risk of retinal detachment or recurrence of ROP in infants with type 1 ROP. While the intervention might reduce the risk of recurrence of ROP in infants with zone I ROP, it can potentially result in higher risk of recurrence requiring retreatment in those with zone II ROP. Intravitreal pegaptanib, when used in conjunction with laser therapy, reduces the risk of retinal detachment as well as the recurrence of ROP in infants with type 1 ROP. However, the quality of the evidence was very low to low for most outcomes due to risk of detection bias and other biases. The effects on other critical outcomes and, more importantly, the long-term systemic adverse effects of the drugs are not known. Insufficient data precludes strong conclusions favouring routine use of intravitreal anti-VEGF agents - either as monotherapy or in conjunction with laser therapy - in preterm infants with type 1 ROP., Implications for Research: Further studies are needed to evaluate the effect of anti-VEGF agents on structural and functional outcomes in childhood and delayed systemic effects including adverse neurodevelopmental outcomes.

Background: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO., Objectives: The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods., Search Methods: We searched various electronic databases on 26 April 2017., Selection Criteria: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO., Data Collection and Analysis: We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study., Main Results: Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference., Authors' Conclusions: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death.

Purpose: To investigate a certain set of methodological limitations in published anti-vascular endothelial growth factor (VEGF) randomized controlled trials (RCTs)., Design: Descriptive methodological study., Methods: We did a PubMed search with the terms "bevacizumab OR ranibizumab OR pegaptanib OR aflibercept" and the limitations "humans" and "randomized controlled trials" in 15 of the highest-impact-factor general medicine and ophthalmology journals. We included only RCTs published as original articles, where an anti-VEGF agent was used to treat eye disease. Two independent observers (O.A., P.K.) read through each article and classified the articles according to a predefined set of criteria., Results: The PubMed search yielded 209 articles, and 93 were classified as eligible. In most of the studies, the study drug was bevacizumab (52.6%, n = 49), followed by ranibizumab (44.1%, n = 41), pegaptanib (7.5%, n = 7), and aflibercept (5.4%, n = 5). Basic epidemiologic data, including sex distribution (2.2%, n = 2) and mean age (3.2%, n = 3), were missing in 3.2% of the published RCTs. The power calculation for efficacy was mentioned in 48% (n = 45) of the published work, and a power calculation for safety was considered in only 1 study (1.1%). Only 6 RCTs (6.5%) reported negative results., Conclusions: Power calculations for efficacy, an important component of an RCT, were missing in 51% of the RCTs we surveyed, while a power calculation for safety was only present in 1.1%. Around 60% of the published RCTs were labeled as an "efficacy and safety trial," and none of those studies had a power calculation for safety., (Copyright © 2016 Elsevier Inc. All rights reserved.)

AS1411 is a g-quadruplex-forming aptamer capable of selectively entering cancer cells by nucleolin receptor-mediated uptake. In this study, we investigated the cell internalization properties and plasticity of AS1411 carrying different locked nucleic acid-containing cargo oligonucleotides (ONs) for delivery into A549 and U2OS cells. We found that internalization efficiency is highly governed by ON cargo chemistry and composition since the inherent antitumor properties of AS1411 were lost when attached to a nontoxic ON, noTox. However, a toxic ON, Tox, demonstrated potent cytotoxicity after aptamer-mediated uptake in A549 cells. We also examined the effect of unlocked nucleic acid (UNA) modifications in the loop region of the aptamer, and how the cargo ONs and UNA incorporation affect the secondary structure of AS1411, in the presence or absence of two novel ellipticine derivatives. These findings add new insights to the design and future applications of aptamer-guided delivery of ON cargo to cancer cells.

Purpose: To review the literature regarding ocular hypertension following intravitreal antivascular endothelial growth factor therapy, and to propose a novel mechanism for the development of ocular hypertension as a result of such therapy., Methods: The PubMed database was used to identify publications by using combinations of the search terms, "glaucoma," "ocular hypertension," "pegaptanib," "bevacizumab," "ranibizumab," "aflibercept," "anti-vascular endothelial growth factor," intraocular pressure," and "intravitreal." The reference lists of these publications were also reviewed for relevant articles., Results: Numerous articles have been published describing ocular hypertension, either immediate-term/short-term or delayed/sustained, following intravitreal antivascular endothelial growth factor therapy. Ocular hypertension has been reported following intravitreal pegaptanib, bevacizumab, and ranibizumab, and aflibercept. On the basis of the fact that vascular endothelial growth factor, normally present as a vascular modulating and reparative growth factor, is known to upregulate endothelial nitric oxide (NO) synthase, and that NO has been shown to decrease intraocular pressure in both normal and glaucomatous human and animal eyes, we propose a novel mechanism for sustained ocular hypertension following intravitreal antivascular endothelial growth factor therapy. We propose that such intravitreal therapy may lead to decreased NO in the anterior segment, which then leads to trabecular meshwork constriction, decreased outflow facility, and increased intraocular pressure., Conclusions: Sustained ocular hypertension following the intravitreal administration of antivascular endothelial growth factor agents is a potentially serious side effect that has not been adequately explained. Further investigation is necessary to determine the role of NO in the mediation of this adverse effect.

Purpose: To investigate the influence of complement component C5a inhibition on laser-induced choroidal neovascularization (CNV) in mice using a C5a specific L-aptamer., Methods: In C57BL/6 J mice CNV was induced by argon-laser, C5a-inhibitor (NOX-D20) was intravitreally injected in three concentrations: 0.3, 3.0, and 30 mg/ml. The unPEGylated derivate (NOX-D20001) was applied at 3.0 mg/ml; the vehicle (5 % glucose) was injected in controls. Vascular leakage was evaluated using fluorescence angiography, CNV area was examined immunohistochemically. Activated immune cells surrounding the CNV lesion and potential cytotoxicity were analyzed., Results: Compared to controls, CNV areas were significantly reduced after NOX-D20 injection at a concentration of 0.3 and 3.0 mg/ml (p = 0.042; p = 0.016). NOX-D20001 significantly decreased CNV leakage but not the area (p = 0.007; p = 0.276). At a concentration of 30 mg/ml, NOX-D20 did not reveal significant effects on vascular leakage or CNV area (p = 0.624; p = 0.121). The amount of CD11b positive cells was significantly reduced after treatment with 0.3 and 3.0 mg/ml NOX-D20 (p = 0.027; p = 0.002). No adverse glial cell proliferation or increased apoptosis were observed at effective dosages., Conclusions: Our findings demonstrate that the targeted inhibition of complement component C5a reduces vascular leakage and neovascular area in laser-induced CNV in mice. NOX-D20 was proven to be an effective and safe agent that might be considered as a therapeutic candidate for CNV treatment. The deficiency of activated immune cells highlights promising new aspects in the pathology of choroidal neovascularization, and warrants further investigations.

Purpose: To review the available evidence regarding the safety and efficacy of therapies for the treatment of macular edema (ME) associated with central retinal vein occlusion (CRVO)., Methods: A literature search of the PubMed database was last conducted in March 2014 with no date restrictions but limited to articles published in English. A literature search of the Cochrane Library was also conducted in March 2014 with no date restrictions and without a language limitation. The combined searches yielded 108 citations, of which 20 were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous panel to review in full text. Three additional studies were also identified for panel review. The level of evidence of these selected studies was reviewed by the panel methodologist., Results: There were 7 citations representing 4 clinical trials that provided level I evidence supporting the use of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME associated with CRVO, including intravitreal ranibizumab (2), aflibercept (3), and bevacizumab (2). There were 3 citations representing 2 studies with level I evidence for intravitreal corticosteroid injection with dexamethasone intravitreal implant (2 citations) or triamcinolone (1 citation), although cataract and glaucoma were observed in these studies. Level I evidence is available on the limited benefit of macular grid-pattern laser photocoagulation (1 citation). Eight other citations reviewed were rated as level II, and 4 citations were rated as level III. Long-term efficacy results (≥2 years of follow-up) are limited to intravitreal ranibizumab at this time, and few studies have evaluated combination therapy with anti-VEGF and corticosteroid versus monotherapy of either class of drug., Conclusions: Level I evidence indicates that intravitreal anti-VEGF pharmacotherapy is safe and effective over 2 years for ME associated with CRVO and that delay in treatment is associated with worse visual outcomes. In addition, level I evidence demonstrates short-term efficacy of intravitreal corticosteroid but also an association with a higher frequency of adverse events., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

This paper reports an in vivo evaluation of toxicology and biodistribution of a highly anisotropic Au nanoconstruct composed of a gold nanostar (AuNS) core and a ligand shell of a G-quadruplex DNA aptamer AS1411 (Apt) supporting both targeting and therapy capabilities. We examined the toxicity of the nanoconstructs (Apt-AuNS) at four different injected concentrations. At the highest dose tested (48 mg/kg), maximal tolerated dose was not reached. Clinical pathology showed no apparent signs of acute toxicity. Interestingly, the nanoconstructs circulated longer in female rats compared to male rats. In two different tumor models, the biodistribution of Apt-AuNS, especially tumor accumulation, was different. Accumulation of Apt-AuNS was 5 times higher in invasive breast cancer tumors compared to fibrosarcoma tumors. These results provide insight on identifying a tumor model and nanoconstruct for in vivo studies, especially when an in vitro therapeutic response is observed in multiple cancer cell lines. From the clinical editor: This study investigated the toxicity and distribution of aptamer loaded gold nanostars in a rodent model of invasive breast cancer and fibrosarcoma. Acute toxicity was not identified even in the highest studied doses. Fivefold accumulation was demonstrated in the breast cancer model compared to the fibrosarcoma model. Studies like this are critically important in further clarifying the potential therapeutic use of these nanoconstructs, especially when ex vivo effects are clearly demonstrated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To observe the frequency of complications in patients undergoing intravitreal anti-VEGF injections for different ocular diseases in a five-year period., Materials and Methods: Charts of patients receiving intravitreal anti-VEGF were retrospectively reviewed. Out of 1173 eyes, 762 were treated with bevacizumab, 382 with ranibizumab, and 29 with pegaptanib. Data recorded included demographic information, clinical findings, total injections received, and info about the onset of adverse effects., Results: 12.86% of the eyes treated with bevacizumab presented side-effects, while ratings in the ranibizumab and pegaptanib groups were 15.97% and 20.69%, respectively. Odds ratios calculated comparing incidences after each anti-VEGF are 0.78 (bevacizumab versus ranibizumab, p = 0.152), 0.57 (bevacizumab versus pegaptanib, p = 0.227), and 0.73 (ranibizumab versus pegaptanib, p = 0.508). A total of 185 complications were detected (62.16% after bevacizumab). Ocular side-effects registered were 40 cases of sustained intraocular pression (IOP) elevation, one infectious uveitis, one retinal detachment, and one sub-retinal hemorrhage. Other cases were related to transient IOP elevation immediately after injection. Systemic complications registered were one case of nausea, one episode of chest pain with acute vision loss, and one case of acute blood hypertension., Conclusions: The majority of significant complications occurred in patients receiving multiple bevacizumab administrations. However, results may be affected by the difference in the utilization amount for each drug. AMD patients were the most represented, probably due to greater indication to treatment.

Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates the atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. The objective of the current study was to analyze the effect of anti-VEGF therapy on cardiovascular risk factors in patients with exudative age related macular degeneration. A total of 73 patients with exudative age related macular degeneration (without previous anti-VEGF therapy) were treated with two anti-VEGF: Ranibizumab and Pegaptanib sodium. The follow up was 6 months. The following parameters were determined before and after treatment: homocysteine, lipids (total cholesterol, triglycerides, HDL-c, LDL-c), C-Reactive Protein and fibrinogen. There were not statistically significant differences in parameters studied before and after treatment with both Pegaptanib sodium and Ranibizumab, except C-Reactive Protein. Of all patients analyzed, only 3 of them have initially C-Reactive Protein levels above normal levels and after antiangiogenic therapy, there was a significant increase in C-Reactive Protein. We have not found results in our study who to suspect that treatment with anti-VEGF in the patients with exudative age related macular degeneration increases cardiovascular risk predictors. However, after therapy was increased the CRP and fibrinogen may mean that anti-VEGF contribute an alteration of endothelial homeostasis in exudative AMD.

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.

Purpose: The purpose of this study is to conduct a comparative analysis of the suspected adverse drug reactions (ADRs) associated with intravitreal bevacizumab, ranibizumab and pegaptanib in the WHO database in order to have a real-life information on these drugs, which now is only based on data coming from clinical trials., Methods: ADR reports for intravitreal use of bevacizumab, ranibizumab and pegaptanib from January 2002 to December 2012 were selected from the WHO-VigiBase. Reporting odds ratio (ROR) with confidence interval of 95 % and p value was calculated. The analysis was performed for drug-reaction pairs. The Medical Dictionary for Regulatory Activities (MedDRA) terminology for ADRs was used., Results: The analysis was performed on 3180 reports corresponding to 7753 drug-reaction pairs. Significant RORs for endophthalmitis and uveitis (1.90, 95 % confidence interval (CI) 1.48-2.43, and 10.62, 6.62-17.05, respectively) were retrieved for bevacizumab, and cerebrovascular accident and myocardial infarction produced significant ROR (1.54, 1.14-2.10 and 1.73, 1.18-2.53, respectively) for ranibizumab. Pegaptanib was significantly associated with visual impairment (1.98, 1.12-3.5, p = 0.02), nausea (3.29, 1.57-6.86, p < 0.001), vomiting (2.91, 1.2-7.07, p = 0.01) and drug hypersensitivity (8.75, 3.1-24.66, p < 0.001)., Conclusions: Our data showed an elevated disproportionality for cardiovascular ADRs in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost.

Purpose: The present study evaluates the safety of the biologics approved for the treatment of ocular diseases., Methods: The European medicines agency Website was searched to identify biologics with approved ophthalmologic therapeutic indications. A systematic search was performed using MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and the International Clinical Trials Registry Platform up to December 2013. Pre-marketing, phase III randomized controlled trials (RCT), postmarketing clinical trials, observational longitudinal studies, and case reports involving adverse events (AE) were included. Methodological quality was assessed by Downs & Black checklist. All European spontaneous reports of AE included in the Eudravigilance up to December 2013 were also considered. AE were classified as ocular (related and non-related with the injection procedure) and non-ocular (related or non-related with vascular endothelial growth factor inhibition). Incidences of all reported AEs were estimated., Results: Pegaptanib, ranibizumab, and aflibercept were identified as ophthalmic biologics. Fourteen premarketing RCT, 7 postmarketing clinical trials, 31 observational studies, along with 31 case reports and 7,720 spontaneous reports were identified and included in this study. Both in pre- and postmarketing settings, ocular AEs were more frequent than non-ocular AEs. Premarketing safety data inform the most common AEs. Postmarketing studies suggest an increased number of events such as retinal pigmented epithelium tears (0.6%-24%), thromboembolic events (0.8%-5%), and mortality (2.8%-4%)., Conclusions: This study highlights the need to properly evaluate the risk for rare, serious, and long-term AEs, such as thromboembolic events, since they can lead to imbalances in the benefit-risk ratio of biologics in ophthalmology.

Purpose: To evaluate the efficacy and safety of intravitreal injections of pegaptanib sodium in subjects with diabetic macular edema (DME)., Methods: There were 243 subjects with DME who were randomized to receive, every 6 weeks, either an intravitreal injection of pegaptanib sodium or a sham injection. The study was double-masked for the first 24 weeks, and then an open label phase continued to week 54. The primary efficacy endpoint was evaluated at week 24, and safety was assessed throughout the 54 weeks., Results and Conclusion: The proportion of subjects who experienced more than 10 letters improvement of visual acuity in ETDRS chart from baseline to week 24 was statistically significantly greater (p-value = 0.0003) in the pegaptanib sodium group, 20.3%, than in the sham group, 5.0%. The incidence of treatment-related adverse events was similar between the treatment groups (pegaptanib sodium group: 10.6%, sham group: 10.0%). The reported adverse events were mainly mild or moderate ophthalmic events and related to the injection procedure. During open-label phase up to 54 weeks, no new safety concerns were identified compared with the double-masked phase. However, in light of the issue concerning proper maintenance of masking of the study treatments, the study was not considered as a well-controlled, double-masked study.

The use of medications directed against vascular endothelial growth factor (VEGF) signaling has revolutionized the treatment of age-related macular degeneration (AMD) and many other retinal diseases in the last decade. However, the rapidly increasing use of these agents has led to a rise in treatment-associated complications. One of the most feared by patients and ophthalmologists is post-injection endophthalmitis, which can result in severe vision loss and, in rare cases, loss of the eye. The aim of this article is to review the incidence, clinical findings, risk factors, management, and visual outcomes in cases of endophthalmitis following intravitreal injections of anti-VEGF medications.

Intravitreal injections for the treatment of retinal disorders and intraocular infection have become a common ophthalmic procedure, and injections of anti-vascular endothelial growth factor agents or steroids are frequently performed for the treatment of diabetic macular edema or other diabetic vascular pathology. Diabetic patients may be at higher risk of adverse events than non-diabetic individuals given frequent systemic co-morbidities, such as cardiovascular and renal disease, susceptibility to infection, and unique ocular pathology that includes fibrovascular proliferation. Fortunately, many associated complications, including endophthalmitis, are related to the injection procedure and can therefore be circumvented by careful attention to injection techniques. This review highlights the safety profile of intravitreal injections in patients with diabetes. Although diabetic patients may theoretically be at higher risk than non-diabetic patients for complications, a comprehensive review of the literature does not demonstrate substantial increased risk of intravitreal injections in patients with diabetes.

Introduction: Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy. Pegaptanib octasodium (Macugen) was the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration. It is a selective anti-VEGF agent, which only blocks VEGF. It has been shown to be safe and effective in treatment of DME in randomized controlled trials and it may be a safer first-line treatment in patients with diabetes with a predisposition to cardiovascular risk factors., Areas Covered: This review covers the pharmacokinetics of pegaptanib octasodium. The authors also evaluate pegaptanib octasodium's clinical efficacy, safety and tolerability in DME., Expert Opinion: DME is the most common cause of visual loss in patients with diabetes. Pegaptanib has been found to be more effective than laser therapy alone for center-involving DME, its efficacy might be slightly worse than other pan-VEGF blockers, but the number of patients that have significant improvement of vision after treatment are similar to those treated with pan-VEGF blockers. As a selective VEGF blocker, it may have a better ocular and systemic safety profile than pan-VEGF blocking agents. It is reasonable to consider pegaptanib as the first-line treatment for center-involving DME with pan-VEGF blockers reserved for non-responders.

Objective: To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter dose interval., Materials and Methods: An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, nonclinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients., Results: Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced ~ 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the inter dose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses., Conclusions: These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their inter dose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the inter dose interval during long-term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient.

Purpose: To evaluate the incidence of presumed endophthalmitis (EO) after intravitreal injection (IVI) of anti-vascular endothelial growth factor agents performed in the operating room., Methods: Retrospective study at 2 Swiss eye hospitals between 2004 and 2012. Hospital records were used to identify patients treated with an IVI of an anti-vascular endothelial growth factor agent between 2004 and 2012 and those treated for EO, defined as any intraocular inflammation treated with intravitreal antibiotics. All IVIs were performed using standard sterile technique in a Swiss Class 1 operating room. No patient received preinjection topical antibiotics. Postinjection topical antibiotics were used only in one hospital., Results: A total of 40,011 IVIs were performed at the 2 centers during the study period. Of the IVIs, ranibizumab was injected in 36,398 (91%), bevacizumab in 3,518 (9%), aflibercept in 89 (0.2%), and pegaptanib in 6 (<0.1%). Three cases of post-IVI presumed EO occurred, yielding a combined incidence of 0.0075% per injection (95% confidence interval: 0.0026-0.0220%) or 1 case per 13,337 IVIs. Two of the three cases of EO occurred in patients using post-IVI antibiotics. All three cases followed ranibizumab injection and were culture negative by anterior chamber tap or vitreous biopsy., Conclusion: The risk of EO after IVI performed under the sterile conditions of the operating room was very low.

Background: The usefulness and the impact of Direct Healthcare Professional Communications (DHPCs, or 'Dear Doctor letters') in changing the clinical behaviour of physicians have been debated. Changes in the current risk communication methods should preferably be based on the preferences of the healthcare professionals, to optimize the uptake of the message., Objective: The aim of this study was to assess whether safety issues are communicated more effectively with an additional e-mail sent by the Dutch Medicines Evaluation Board (MEB) than with the DHPC only., Methods: A randomized controlled trial was conducted amongst ophthalmologists and hospital pharmacists in the Netherlands, who were the target group of a DHPC that was issued for pegaptanib, a drug that is administered intra-ocularly in patients with macular degeneration. The intervention group (N = 110) received the pegaptanib DHPC, as well as the MEB e-mail. The control group (N = 105) received the traditional paper-based DHPC only. Two weeks later, the study population received an invitation to fill out an online questionnaire. Questions were asked about the respondents' knowledge and attitude regarding the pegaptanib issue, and any action they had consequently taken. Additional questions were asked about their satisfaction with the DHPC and the e-mail, and their preferred source of such information., Results: Forty respondents (18.6%) completed the questionnaire. Eighty-one percent of the respondents in the intervention group (N = 21) and 47% of the control group (N = 19) correctly indicated that a serious increase in intra-ocular pressure could be caused by pegaptanib injections (Fishers' exact test, p = 0.046). Nine respondents in the intervention group versus none of the control group respondents indicated that they had taken action in response to the pegaptanib safety issue (Fishers' exact test, p = 0.01). The majority of both the intervention group and the control group confirmed that they would like to receive an MEB e-mail with safety information about drugs in the future (90 and 95 %, respectively)., Conclusion: The results of this study indicate that an additional e-mail might strengthen the uptake of the safety information provided to healthcare professionals, who prefer to receive an e-mail from the MEB as a source of such information, as well as the DHPC. This study may serve as a starting point for new strategies to improve risk communication regarding safety issues associated with drugs and its impact on prescribing.

Purpose: To explore the efficacy and safety of pegaptanib sodium as maintenance therapy in Japanese patients with neovascular, age-related macular degeneration (AMD) after induction therapy (LEVEL-J study)., Methods: A multi-center, prospective study was conducted at 21 medical institutions between 2009 and 2011. Of Japanese neovascular AMD patients with choroidal neovascularization who showed improvement in visual acuity (VA) with induction therapy, those who were scheduled for intravitreal injections of pegaptanib as maintenance therapy were recruited. LogMAR VA was assessed. Booster treatment (unscheduled treatment with other agents) was allowed during the study period if symptoms were judged to have worsened. Safety was assessed by monitoring adverse events and intraocular pressure (IOP)., Results: Of 75 patients included in the analysis, 80 % completed the 54-week study period. Their mean age was 74.7 ± 6.9 years, and 54 patients (72.0 %) were men. The mean number of pegaptanib injections was 5.7 ± 2.6. Booster treatment was not required in 40 eyes (53.3 %). Mean logMAR VA was 0.61 ± 0.31 before induction therapy, 0.26 ± 0.24 before maintenance therapy, and 0.29 ± 0.28 at 54 weeks. No notable change in VA was observed during maintenance therapy. Adverse events were reported in 4 patients (5.3 %), including increased intraocular pressure, cancer, gallstones and recurrence of breast cancer, but mean IOP remained stable during maintenance therapy., Conclusions: The results of this exploratory study suggest that maintenance therapy with pegaptanib is potentially an effective and well-tolerated option in Japanese patients with neovascular AMD in whom induction therapy has been successful.

Background: To report the morphologic and functional outcomes resulting from the use of intravitreal pegaptanib (IVP) sodium (Macugen) in patients with myopic choroidal neovascularization., Methods: An open-label, nonrandomized, prospective clinical trial was performed. Morphologic outcome, such as foveal thickness, was assessed by optical coherence tomography, whereas functional outcomes were assessed by best-corrected visual acuity and microperimetry. Treatment protocol consisted of 3 consecutive IVP (0.3 mg/0.05 mL; baseline, 6th week, and 12th week). Follow-up checks were scheduled at the following intervals: baseline, 18, 24, 36, and 48 weeks., Results: Twenty eyes from 20 patients were studied. All patients completed follow-up at 48 weeks. After IVP, a significant decrease in foveal thickness occurred (-20%), and at the end of follow-up, choroidal neovascularization closure was obtained in all eyes. An improvement of functional parameters was recorded in all patients (best-corrected visual acuity from 25.5 ± 8.09 letters to 45.5 ± 8.16 letters, P < 0.0001; microperimetry from 8.40 ± 2.14 dB to 10.8 ± 2.05 dB, P < 0.01). The mean number of IVP was 3, and none of patients met the re-treatment criterion during the entire follow-up period. Neither ocular nor systemic side effects were observed., Conclusion: The findings demonstrate that the selective inhibition of VEGF-165 isoform by IVP is an effective treatment for myopic choroidal neovascularization.

This document summarizes the current consensus opinion of the Exaggerated Pharmacology (EP) Subcommittee of the Oligonucleotide Safety Working Group on the appropriate strategies to assess potential adverse effects caused by an "exaggerated" degree of the intended pharmacologic activity of an oligonucleotide (ON). The Subcommittee focused its discussions primarily on the ON subclasses that impact expression of "host" (i.e., human gene products--antisense, small interfering RNAs, and related ONs that target messenger RNA), with later and more limited discussions on aptamer, immunostimulatory, and microRNA subclasses. It is expected that many of these principles will be relevant to other subclasses but will need to be carefully considered as those development programs advance towards clinical trials. The recommendations may also serve as a frame of reference when designing Good Laboratory Practice safety studies with ONs, with regard to the study design elements that address assessment of EP. It is also hoped that these recommendations will establish a foundation for discussion with regulatory agencies on this subject.

Aim: This observational study was performed to evaluate the efficacy and safety of intra-vitreal injections of pegaptanib during a 12-month follow-up period., Patients and Methods: Forty eyes (20 patients) affected by diabetic macular edema were monitored. Twenty were subjected to treatment, and 20 were controls. The treatment involved a cycle of three intravitreal injections of pegaptanib (0.3 mg every 6 weeks), at the end of which treated patients were submitted to a monthly follow-up for a period of 12 months. The aim was to evaluate the clinical condition of the eye after therapy and gauge the efficacy of the long-term use of this drug. Specific criteria were used to measure the efficacy and safety of pegaptanib. Regarding efficacy, we considered the following: an average improvement in the power of vision, or visual acuity, of →10 letters (2 lines), equivalent to an average logMAR score of →0.2, and a reduction in the central macular thickness of →250 μm. Regarding safety, we considered the occurrence of undesired eye and systemic side effects correlated to either the drug itself or the injection procedure., Results: The logMAR score for the measurement of visual acuity at T3 (third intra-vitreal injection at week 13) with respect to T0 decreased from 0.7 ± 0.277 to 0.445 ± 0.216, suggesting an improvement, while the mean Early Treatment Diabetic Retinopathy Study (ETDRS) score increased from 25.75 ± 13.046 to 34.300 ± 11.770 letters. The central macular thickness was reduced from the initial value of 746.95 ± 293.601 to 334.050 ± 93.997 μm. In seven controls, we registered a worsening both in terms of visual acuity and macular thickness in some eyes, justifying a continuation of therapy in eight eyes of the control group., Conclusions: Pegaptanib proved to be efficacious and safe for the treatment of diabetic macular edema throughout the 12-month followup. To evaluate its long-term efficacy, further studies are required with larger numbers of patients and longer observational follow-up periods.

Vascular endothelial growth factor (VEGF) is a potent promoter of angiogenesis involved in a wide variety of physiologic processes. Intravitreal injections targeting VEGF have transformed the treatment of neovascular retinal diseases. Currently, there are four anti-VEGF agents in use: bevacizumab, ranibizumab, pegaptanib, and aflibercept. The success and frequency of anti-VEGF therapy have made the ocular safety profile of these agents of vital importance. This paper focuses on sterile endophthalmitis. In this paper, we compare the incidences of posttreatment sterile endophthalmitis among the four agents, review the mechanism of actions, and discuss the most prevalent hypotheses leading to sterile endophthalmitis.

ROP remains a major cause of childhood blindness worldwide. The smallest, sickest infants develop the most severe forms of zone 1 ROP. Such eyes may not be successfully treated by near confluent laser to the avascular retina (current standard of care). With an understanding of ROP pathogenesis, vascular endothelial growth factor inhibitors (anti-VEGF) are being given only when VEGF is elevated in retina and vitreous. Careful screening allows proper timing of administration. Ideal dose (perhaps different for mild and severe cases) and drug (interrupting only pathologic neovascularization and not normal angiogenesis) remain unproven. The author discusses controversial use of anti-VEGF with documented efficacy, observed local complications, and potential systemic toxicities (none observed in six years) to allow retention of vision for severe zone 1 ROP. The benefits have been demonstrated, however, local and systemic risks in these developing premature infants must be carefully studied (both short and long term)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Vascular endothelial growth factor (VEGF) inhibitor medications such as ranibizumab, pegaptanib and bevacizumab are in use for the treatment of neovascular age-related macular degeneration (AMD) and other retinal conditions, although only ranibizumab and pegaptanib are approved for these conditions. In contrast, bevacizumab was developed for the intravenous systemic treatment of colorectal cancer and is not formulated for intravitreal use, but is commonly used off-label in ophthalmology. European Union legislation permits the use of drugs outside the terms of their licence ('off-label') only under certain circumstances, such as during clinical trials, compassionate/named patient use in the absence of a licensed alternative, emergency scenarios (e.g., pandemics) or at the discretion of a treating physician. In such cases, patients should be fully informed regarding their treatment and any potential risks involved. Off-label drug use can be an important tool to provide patients with treatment in cases of unmet medical need. However, the use of an unlicensed medicinal product, when a suitable licensed alternative is available, puts prescribing physicians at risk of liability if safety issues arise. Emerging clinical evidence suggests safety differences exist between ranibizumab and bevacizumab.

Objective: To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME)., Methods: Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists., Results: At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies., Conclusions: Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aptamers, or nucleic acid ligands, have gained clinical interest over the past 20 years due to their unique characteristics, which are a combination of the best facets of small molecules and antibodies. The high binding affinity and specificity of aptamers allows for isolation of an artificial ligand for theoretically any therapeutic target of interest. Chemical manipulations of aptamers also allow for fine-tuning of their bioavailability, and antidote control greatly expands their clinical use. Here we review the various methods of antidote control of aptamer therapeutics--matched oligonucleotide antidotes and universal antidotes. We also describe the development, recent progress, and potential future therapeutic applications of these types of aptamer-antidote pairs.

Background and Research Question: The authors address the question of whether vascular endothelial growth factor inhibitors (anti-VEGF) lead to better clinical outcomes than current treatments in patients with clinically manifest diabetic macular oedema (DMO), which is the leading cause of vision loss in the working age population in developed countries., Methods: The authors performed a systematic literature search in common databases and compiled the evidence according to the GRADE methodology. The authors analysed clinically relevant improvement of visual acuity, vision-related quality of life and local or systemic adverse events., Results: In a proportion of patients (on average 25%), VEGF inhibitors result in better visual acuity (≥15 ETDRS letters or equivalent) than in patients treated with laser photocoagulation or sham injection. The number of injections required for long-term improvement as well as the general long-term efficacy is unknown. The evidence is not sufficient to confirm safety of the products in patients with DMO and does not suggest superiority of a single product., Conclusion: For some patients with DMO, VEGF inhibitors seem to be more effective as a short-term treatment option than alternative therapies. The evidence is not of sufficient quality to confirm safety. Decisions on financing should take into account the high price difference between the products and ongoing research.

Purpose: Neovascular age-related macular degeneration (AMD) is a leading cause of blindness, with an increasing incidence as the elderly population expands. Large, multi-center, randomized, clinical trials have been conducted exploring the safety and efficacy of anti-VEGF treatments. This paper aims to discuss the safety and efficacy of pegaptanib, ranibizumab, aflibercept and bevacizumab. New therapeutic agents and treatment strategies are also discussed., Procedures: Evidence available from prospective, multicenter, clinical studies and from a selective literature search is utilized to present the results of VEGF inhibition in neovascular AMD and to generate evidence-based recommendations., Results: Anti-VEGF treatment is indicated in choroidal neovascularization with active disease and produces a significant benefit in visual acuity., Conclusions: With the advent of anti-VEGF therapy, the prognosis of choroidal neovascularization has changed dramatically. Data from well-conducted clinical trials suggest that approved anti-VEGF drugs are effective and well tolerated., (Copyright © 2012 S. Karger AG, Basel.)

To report on a patient who developed a lamellar macular hole 1 month after an intravitreal pegaptanib sodium injection. Interventional case report. A 66 year old patient developed a lamellar macular hole 1 month after an intravitreal pegaptanib sodium injection for diabetic macular edema (DME). The pathogenesis of the lamellar macular hole in our case can be attributed to the intravitreal injection that may have induced vitreous incarceration, causing vitreoretinal traction at the macula and development of a lamellar macular hole. Alternatively or in association, pegaptanib itself may have caused the lamellar macular hole by inducing sudden reduction of the DME and exacerbation of tangential traction of the posterior vitreous on the overlying macular retina. Lamellar macular hole seems to be a potential complication of pegaptanib injection even in patients without pretreatment clinically detectable vitreomacular traction.

Background: Intravitreal ranibizumab and pegaptanib are registered for neovascular age-related macular degeneration. No formal safety study has been conducted for intravitreal bevacizumab. These anti-vascular endothelial growth factor (anti-VEGF) drugs are being used on a large scale in daily practice for different ocular diseases. The objective of the present study was to systematically assess and compare the incidences of adverse events of anti-VEGFs., Methods: A systematic search was conducted in April 2009 with no date restrictions in PubMed, Embase, Toxline, and the Cochrane library. We used the terms pegaptanib, bevacizumab, ranibizumab, intravitreal, and specific and general terms for adverse events. Studies describing adverse events after anti-VEGF injections and the official safety data were included., Results: Two hundred and seventy-eight articles were included, and the incidences of adverse events were calculated separately for effect, safety, and specific side effect studies. The incidences of serious ocular and nonocular adverse events were approximately below 1 per 100 injections for intravitreal bevacizumab, intravitreal ranibizumab, and intravitreal pegaptanib. Most mild ocular adverse events were below 5 per 100 injections., Conclusion: The reported rates of serious adverse events were low after anti-VEGF injections. There is no sufficient evidence to conclude that there is a difference in incidences between the anti-VEGFs.

Congenital thrombotic thrombocytopenic purpura (TTP) is a very rare but potentially life-threatening disorder. This phase I/II trial compared the pharmacokinetics and pharmacodynamics and safety of three different administration modes of the anti-von Willebrand factor (VWF) aptamer ARC1779. This was a prospective clinical trial with a partial cross-over design: three periods comprised subcutaneous injections of 50 mg of ARC1779 on seven subsequent days, a low-dose infusion of ARC1779 (0.002 mg/kg/min) for 24-72 hours and a high-dose infusion (0.004-0.006 mg/kg/min) up to 72 hours. ARC1779 concentrations were determined with high performance liquid chromatography, VWF inhibition was measured with enzyme immunoassay and platelet function was determined with the platelet function analyser (PFA-100) and impedance aggregometry. ARC1779 was well tolerated without any bleeding at concentrations spanning over three orders of magnitude. The daily s.c. injection yielded plasma levels (0.5 μg/ml) of the drug that were too low to sufficiently suppress VWF. The low-dose i.v. infusion increased platelet counts in one patient, whereas the high i.v. dose increased plasma concentrations up to 69 μg/ml, completely blocked free A1 domains, VWF-dependent platelet plug formation and enhanced platelet counts in 2/3 patients. In conclusion, infusion of ARC1779 dose-dependently inhibits VWF-dependent platelet function and during infusion ARC1779 increases or stabilises platelet counts in congenital TTP. However, the tested doses, particularly the daily s.c. injections, did not correct all clinical or laboratory features of TTP.

The wet form of age related macular degeneration (AMD), known also as exudative or neovascular, is characterized by the formation of a pathological choroidal neovascular membrane (CNV) responsible for most cases of severe blindness. Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein acting as a growth factor selective for endothelial cells; it regulates angiogenesis and enhances vascular permeability and plays a leading role in this disorder. The consistent association between CNV and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular AMD. The importance of VEGF for the development of AMD-related CNV has led to the development of a strategy able to block its pathologic effects. The rationale is that a blockade of VEGF actions could be effective in arresting choroidal angiogenesis and also reducing the vascular permeability, which is frequently the main cause of visual acuity deterioration. However, VEGF has also important functions in vascular physiology. The effects of anti-VEGF therapy may inhibit these functions. Herein we report the systemic adverse events secondary to intravitreal administration of these compounds i.e. the main cardiovascular effects (thrombosis, hemorrhage, hypertension, proteinuria), as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thrombophlebitis.

Purpose: Retinal pigment epithelium (RPE) tears may develop as a complication after anti-VEGF (vascular endothelial growth factor) treatment for pigment epithelial detachments (PEDs) in exudative age-related macular degeneration (AMD). This retrospective study analyses best-corrected visual acuity (BCVA) and foveal involvement after RPE tears that are associated with anti-VEGF therapy due to PED in exudative AMD., Methods: A total of 37 patients with RPE tears during anti-VEGF therapy (bevacizumab 12, ranibizumab 21 and pegaptanib 4 eyes) for progressive PED in AMD (PED with occult choroidal neovascularization 25 eyes and PED with retinal angiomatous proliferation 12 eyes) were included in this study. We analyzed BCVA and different morphologic aspects by means of appearance on fluorescein angiography and optical coherence tomography. Mean follow-up was 88 weeks., Results: RPE tears were diagnosed a mean of 56 days after the first injection. BCVA deteriorated after RPE tear and during follow-up significantly (P<0.001), with 53.2% of eyes being legally blind (WHO, world health organization) at 12 months. RPE-free foveal area, foveal wrinkling of the RPE, and fibrotic scar development were significantly associated with worse visual acuity., Discussion: RPE tears can be observed in 12-15% of treated eyes during anti-VEGF therapy for PED in exudative AMD. Owing to the close time relationship with the therapy, this complication must be taken into consideration. Visual prognosis is associated with a decrease in vision in the long term, often resulting in a severe visual disability. Relevant factors for a negative visual prognosis were the potential foveal involvement of the central RPE and morphologic fibrovascular transformation of the RPE tear.