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Open accessJournal ArticleDOI: 10.3390/JCM10050981

Inflammatory Complications of Intravitreal Anti-VEGF Injections.

02 Mar 2021-Journal of Clinical Medicine (Multidisciplinary Digital Publishing Institute)-Vol. 10, Iss: 5, pp 981
Abstract: Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is a commonly used therapy for numerous retinal diseases. The most commonly used of these medications are bevacizumab, ranibizumab, aflibercept, and brolucizumab. However, intravitreal administration of these agents is also associated with several inflammatory and non-inflammatory adverse events. The three inflammatory adverse events are sterile intraocular inflammation, brolucizumab-associated retinal vasculitis, and post-injection endophthalmitis. This narrative review summarizes the current literature regarding these conditions, including their epidemiology, presentation, management, outcomes, and pathogenesis. The inflammatory adverse events also share a number of overlapping features, which can make them difficult to discern from one another in a clinical context. This review discusses certain distinguishing features of these conditions that may aid providers in discerning between them and establishing the correct diagnosis.

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Topics: Intravitreal administration (55%), Endophthalmitis (53%), Aflibercept (51%) ... show more
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Open accessJournal ArticleDOI: 10.3390/JCM10112436
Prem Nimesh Patel1, Veeral ShethInstitutions (1)
Abstract: Age-related macular degeneration (AMD) is one of the most common causes of vision loss. Advanced forms of AMD are seen in primarily two types—neovascular AMD (nAMD) with the presence of choroid neovascularization and non-neovascular AMD (nnAMD) with geographic atrophy. Neovascular AMD is characterized by choroidal neovascularization (CNV), which leads to a cascade of complications, including exudation, leakage, and ultimately fibrosis with photoreceptor loss. Inhibition of VEGF represents the current standard of care. However, there is a tremendous gap between the outcomes in randomized clinical trials and real-world settings. New agents for nAMD might offer the potential to improve treatment outcomes and reduce treatment of frequent intravitreal injections. We summarize all the newer molecules, their pivotal clinical trial results, and their unique mechanisms of action; these include longer-acting agents, combination strategies, sustained release, and genetic therapies.

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2 Citations


Open accessJournal ArticleDOI: 10.18240/IJO.2021.09.18
Abstract: AIM To study the effect of topical dorzolamide 2% on macular thickness reduction in diabetic cystoid macular edema (CME). METHODS This was a prospective, non-randomized, open study including eyes with diabetic macular edema (DME). All eyes received topical dorzolamide 2% three times daily for one month. Changes in best-corrected visual acuity (BCVA), and central macular thickness (CMT) by optical coherence tomography) were evaluated at 1wk, 1, and 3mo post-treatment. RESULTS Ninety-three eyes (84 patients) were included. Mean±SD (logMAR) BCVA improved significantly from 1.08±0.26 pretreatment to 0.66±0.24 at 1mo and 0.87±0.26 at 3mo post-treatment (P<0.001 both). The mean±SD CMT was significantly reduced from 535.27±97.4 µm at baseline to 357.43±125.8 µm at 1mo and 376.23±114.5 µm at 3mo post-treatment (P<0.001 both). No significant ocular or systemic side effects were recorded. CONCLUSION Topical dorzolamide 2% results in significant improvement of mean BCVA and reduction of mean CMT at 3mo post-treatment. It can be used as an effective, affordable, and safe therapy for treatment of non-refractory diabetic CME.

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Topics: Dorzolamide (60%), Macular edema (55%)

1 Citations


Open accessJournal ArticleDOI: 10.18502/JOVR.V16I4.9757
Abstract: Age-related macular degeneration and its complication, subretinal neovascularization, are common causes of progressive, irreversible impairment of central vision. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the visual outcome and provided an evolution in the treatment of retinal disease. The current four anti-VEGF drugs - pegaptanib, ranibizumab, aflibercept, and bevacizumab - have been administered for many years. A new anti-VEGF agent, brolucizumab, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for the treatment of wet age-related macular degeneration. Brolucizumab is a novel single-chain fragment variable antibody that inhibits all isoforms of VEGF-A and has been suggested to have more tissue penetration. Despite all the benefits, there are some reports of serious side effects that need to be understood in managing patients. Brolucizumab has been reported to cause occlusive retinal vasculitis in the setting of intraocular inflammation, which has not been seen in other anti-VEGF medications. A PubMed and Scopus search was performed and all article types were included. In the present article, we have reviewed the reported side effects of brolucizumab.

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Topics: Ranibizumab (65%), Pegaptanib (61%), Macular degeneration (59%) ... show more

Open accessJournal ArticleDOI: 10.3390/BIOMEDICINES9091203
Kenny T. Lin1, Athena Wang1, Alexandra B. Nguyen1, Janaki Iyer1  +1 moreInstitutions (1)
12 Sep 2021-Biomedicines
Abstract: With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions induced by cataract surgery, such as suturing and stromal hydration, are less than ideal due to the potential for surgically induced astigmatism or wound leakage. Vitrectomy performed on patients with diabetic retinopathy requires an artificial vitreous substitute, with current offerings having many shortcomings such as retinal toxicity. The use of stem cells has also been investigated in retinal degenerative diseases; however, an optimal delivery system is required for successful transplantation. The incorporation of hydrogels into ocular therapy has been a critical focus in overcoming the limitations of current treatments. Previous reviews have extensively documented the use of hydrogels in drug delivery; thus, the goal of this review is to discuss recent advances in hydrogel technology in surgical applications, including dendrimer and gelatin-based hydrogels for ocular adhesives and a variety of different polymers for vitreous substitutes, as well as recent advances in hydrogel-based retinal pigment epithelium (RPE) and retinal progenitor cell (RPC) delivery to the retina.

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Topics: Transplantation (53%), Vitrectomy (51%), Retinal pigment epithelium (50%)

Open accessJournal ArticleDOI: 10.1089/HUM.2021.132
Shun-Yun Cheng1, Yongwen Luo2, Anneliese Malachi1, Jihye Ko1  +9 moreInstitutions (2)
19 Jul 2021-Human Gene Therapy
Abstract: The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.

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89 results found


Journal ArticleDOI: 10.1016/J.AJO.2005.03.057
Abstract: Purpose To begin a process of standardizing the methods for reporting clinical data in the field of uveitis. Design Consensus workshop. Methods Members of an international working group were surveyed about diagnostic terminology, inflammation grading schema, and outcome measures, and the results used to develop a series of proposals to better standardize the use of these entities. Small groups employed nominal group techniques to achieve consensus on several of these issues. Results The group affirmed that an anatomic classification of uveitis should be used as a framework for subsequent work on diagnostic criteria for specific uveitic syndromes, and that the classification of uveitis entities should be on the basis of the location of the inflammation and not on the presence of structural complications. Issues regarding the use of the terms "intermediate uveitis," "pars planitis," "panuveitis," and descriptors of the onset and course of the uveitis were addressed. The following were adopted: standardized grading schema for anterior chamber cells, anterior chamber flare, and for vitreous haze; standardized methods of recording structural complications of uveitis; standardized definitions of outcomes, including "inactive" inflammation, "improvement'; and "worsening" of the inflammation, and "corticosteroid sparing," and standardized guidelines for reporting visual acuity outcomes. Conclusions A process of standardizing the approach to reporting clinical data in uveitis research has begun, and several terms have been standardized.

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2,686 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1102673
Abstract: Background Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. Methods In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Results Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. Conclusions At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).

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Topics: Ranibizumab (73%), Pegaptanib (53%), Bevacizumab (53%) ... show more

2,208 Citations


Journal ArticleDOI: 10.1038/NRD3003
Abstract: Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.

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694 Citations


Journal ArticleDOI: 10.1016/J.OPHTHA.2007.01.017
Sophie J. Bakri1, Melissa R. Snyder1, Joel M. Reid1, Jose S. Pulido1  +1 moreInstitutions (1)
01 May 2007-Ophthalmology
Abstract: Purpose To describe the pharmacokinetics of 1.25 mg of intravitreal bevacizumab (Avastin). Design Experimental animal study. Participants Twenty Dutch-belted rabbits. Methods One eye of each of 20 rabbits was injected with 1.25 mg of intravitreal bevacizumab. Both eyes of each of 4 rabbits were enucleated at days 1, 3, 8, 15, and 29. Bevacizumab concentrations were measured in aqueous fluid, whole vitreous, and serum. Main Outcome Measures Bevacizumab concentrations in the aqueous, vitreous, and serum. Results Whereas vitreous concentrations of bevacizumab declined in a monoexponential fashion with a half-life of 4.32 days, concentrations of >10μg/ml bevacizumab were maintained in the vitreous humor for 30 days. Bevacizumab concentrations in the aqueous humor of the injected eye reached a peak concentration of 37.7 μg/ml 3 days after drug administration. A maximum serum concentration of 3.3 μg/ml was achieved 8 days after intravitreal injection and the concentration fell below 1 μg/ml 29 days after injection. Elimination of bevacizumab from the aqueous humor and serum paralleled that found in the vitreous humor, with half-life values of 4.88 days and 6.86 days, respectively. Very low concentrations of bevacizumab were detected in the fellow uninjected eye. Concentrations of bevacizumab in the vitreous of the fellow eye varied incrementally, from 0.35 ng/ml at 1 day to 11.17 ng/ml at 4 weeks. Concentrations of bevacizumab in the aqueous humor of the fellow eye reached their peak at 1 week, at 29.4 ng/ml, and declined to 4.56 ng/ml at 4 weeks. Conclusion The vitreous half-life of 1.25 mg intravitreal bevacizumab is 4.32 days in a rabbit eye. Very small amounts of bevacizumab were detected in the serum and in the fellow uninjected eye.

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648 Citations


Journal ArticleDOI: 10.1167/IOVS.04-0601
Abstract: PURPOSE Ranibizumab (rhuFab V2; Lucentis, Genentech, South San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF, thereby blocking vessel permeability and angiogenesis in neovascular age-related macular degeneration. This study evaluated the pharmacokinetic (PK) and serum bioavailability of ranibizumab after a single intravitreal (ITV) or intravenous (IV) dose in cynomolgus monkeys. METHODS Monkeys received ranibizumab as either a bilateral ITV dose (500 or 2000 microg/eye; n = 6/group) or a single IV dose (1000 or 4000 microg/animal; n = 4/group). After ITV administration, ranibizumab concentrations were measured in several ocular compartments and in serum for 10 days and, after IV administration, for 48 hours. Pharmacokinetic parameters were estimated by compartmental and noncompartmental methods. RESULTS Ranibizumab cleared in parallel from all ocular compartments, with a terminal half-life of approximately 3 days. It distributed rapidly to the retina (6-24 hours), and concentrations were approximately one third that in the vitreous. After ITV injection, bioavailability (F) was 50% to 60%. Serum concentrations were very low, reflecting wider distribution and faster clearance when ranibizumab reached the serum. After IV administration, the terminal half-life was approximately 0.5 day. CONCLUSIONS This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.

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523 Citations


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