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Kengkla P, Panyasing Y, Thayananuphat A, Tuntivanich N. Effect of Subconjunctival Injection of Canine Adipose-Derived Mesenchymal Stem Cells on Canine Spontaneous Corneal Epithelial Defects. Animals (Basel) 2024; 14:3270. [PMID: 39595323 PMCID: PMC11591453 DOI: 10.3390/ani14223270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Spontaneous chronic corneal epithelial defects (SCCEDs) are characterized by nonadherent corneal epithelium leading to poor attachment to the corneal stroma. The objective of this study was to characterize corneal outcomes concurrently with the quantification of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor-A (VEGF-A) in tear fluid after the subconjunctival injection of canine adipose-derived mesenchymal stem cells (cAD-MSCs) in canine SCCEDs. Ten eyes with SCCEDs, which were nonresponsive to two rounds of diamond burr debridement, were included in this study. All eyes received a single subconjunctival injection of 1 × 106 cAD-MSCs. Ophthalmic examinations were performed before treatment and on day 7, 14, and 21 after treatment. Tear samples were collected for the quantification of TNF-α and VEGF-A concentrations by a canine multiplex immunoassay. Nine out of ten eyes revealed complete healing by day 21. The mean healing time was 10.89 ± 1.7 days. All eyes showed a decreased degree of ocular discomfort, in accordance with the degree of corneal characteristics. The concentrations of VEGF-A significantly reduced from pre-treatment (4334.91 ± 1275.92 pg/mL) to day 21 post-treatment (3064.61 ± 1028.66 pg/mL). No significant difference in TNF-α concentration was observed before/after treatment. In conclusion, the single use of a subconjunctival injection of cAD-MSCs could be used as an alternative treatment for canine SCCEDs.
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Affiliation(s)
- Pechchalee Kengkla
- Department of Veterinary Surgery, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Yaowalak Panyasing
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Aree Thayananuphat
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand;
| | - Nalinee Tuntivanich
- Department of Veterinary Surgery, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand;
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Wu D, Chan KE, Lim BXH, Lim DKA, Wong WM, Chai C, Manotosh R, Lim CHL. Management of corneal neovascularization: Current and emerging therapeutic approaches. Indian J Ophthalmol 2024; 72:S354-S371. [PMID: 38648452 PMCID: PMC467007 DOI: 10.4103/ijo.ijo_3043_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/16/2023] [Accepted: 12/25/2023] [Indexed: 04/25/2024] Open
Abstract
Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV.
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Affiliation(s)
- Duoduo Wu
- Department of Ophthalmology, National University Hospital, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Blanche Xiao Hong Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Dawn Ka-Ann Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wendy Meihua Wong
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Charmaine Chai
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ray Manotosh
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chris Hong Long Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
- Singapore Eye Research Institute, Singapore
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Rocher M, Benayoun Y, Quilbe S, Laribi S, Fournie P, Leveziel N, Trone MC, Bourcier T, Robert PY. [A randomized study of subconjonctival bevacizumab (Avastin®) injection for corneal neovascularization]. J Fr Ophtalmol 2024; 47:104152. [PMID: 38696862 DOI: 10.1016/j.jfo.2024.104152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 05/04/2024]
Abstract
PURPOSE The goal of this phase III, comparative, multicentric, randomized, double-blinded clinical trial was to investigate the superiority of subconjunctival bevacizumab injections versus placebo in the treatment of corneal neovascularization. PATIENTS AND METHODS We included 38 eyes (38 patients) with corneal neovascularization. Twenty patients received bevacizumab and 18 placebos. Patients received 3 monthly injections of either 5mg (0.2mL) bevacizumab or placebo. The main criteria of success was reduction of the surface area of corneal neovascularization after 3months (M3) versus baseline, as measured using semi-automatic analysis of color photographs. RESULTS The percentage of neovascularized corneal surface decreased by -8.6%±32.8 with bevacizumab, versus -2.6%±20.8 with placebo (p=0.5284). Four patients were determined to be responders (reduction of more than 30%), 3 in the bevacizumab group and 1 in the placebo group, all with neovascularization of less than 1year duration. When restricting the analysis to neovascularization of less than 1 year duration, the difference approached the threshold for significance (-31.8%±42.4 in the bevacizumab group and -0.9%±23.1 in the placebo group) (p=0.0637), as well as the number of responders (3/6 in the bevacizumab group versus 1/10 in the placebo group) (p=0.1181). No serious adverse event was reported. CONCLUSION This study shows the efficacy of subconjunctival bevacizumab injection in the reduction of neovascularized corneal surface area versus placebo, but only when the neovascularization has been present less than 1year. Nevertheless, the study did not attain the statistical power to pass the threshold of significance.
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Affiliation(s)
- M Rocher
- CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France
| | - Y Benayoun
- CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France
| | - S Quilbe
- CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France
| | - S Laribi
- CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France
| | - P Fournie
- CHU de Toulouse, 2, rue Charles-Viguerie, 31300 Toulouse, France
| | - N Leveziel
- CHU de Poitiers, 2, rue de la Milétrie, 86000 Poitiers, France
| | - M-C Trone
- CHU de Saint Etienne, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France
| | - T Bourcier
- CHU de Strasbourg, 1, place de l'hôpital, BP 426, 67091 Strasbourg cedex, France
| | - P-Y Robert
- CHU Dupuytren, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France.
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Lai SC, Loh EW, Chiou DI, Hong CT. Efficacy and safety of anti-vascular endothelial growth factor agents on corneal neovascularization: A meta-analysis. World J Clin Cases 2023; 11:7337-7349. [PMID: 37969435 PMCID: PMC10643059 DOI: 10.12998/wjcc.v11.i30.7337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/26/2023] [Accepted: 10/08/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Corneal neovascularization (CoNV) is the second major cause of blindness. Vascular endothelial growth factor (VEGF) inhibitors, e.g., bevacizumab, have been used to prevent CoNV. AIM We conducted an updated systematic review and meta-analysis of clinical trials to examine the efficacy and safety of anti-VEGF in CoNV. METHODS A literature search was conducted using three electronic databases. Mean difference (MD), standard mean difference (SMD), and relative risk (RR) are used to estimate the effect size. RESULTS Nine randomized controlled and three non-randomized trials were obtained. The pooled results demonstrated a significant reduction of CoNV area/Length (SMD = -1.17, 95%CI: -1.58 to -0.75), best corrected visual acuity (MD = -0.54, 95%CI: -0.91 to -0.17), and graft rejection (RR = 0.44, 95%CI: 0.24 to 0.8) and failure (RR = 0.39, 95%CI: 0.19 to 0.78) rates in the anti-VEGF group than the placebo group. A non-significant reduction of the epithelial defect was also observed in the bevacizumab group compared with the placebo (RR = 0.56, 95%CI: 0.30 to 1.06). Compared with a placebo, the unsynthesizable trials also support that bevacizumab improves visual acuity, CoNV, graft rejection, and failure rates. Trials reporting other comparisons revealed the superiority of combined remedy with bevacizumab compared to other treatments in reducing CoNV. CONCLUSION Anti-VEGF agents, mainly bevacizumab, are an effective and safe treatment for CoNV of all causes and prevent corneal graft rejection and failure in corneal transplantation.
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Affiliation(s)
- Shih-Chung Lai
- Department of Ophthalmology, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - El-Wui Loh
- Center for Evidence-Based Health Care, Department of Medical Research, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Medical Imaging, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Du-I Chiou
- Department of Ophthalmology, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Chien-Tai Hong
- Department of Neurology, Taipei Medical University-Shuang Ho Hospital, New Taipei 23561, Taiwan
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Lim YJ, Cho CH. A Case of Iris Neovascularization in Severe Fungal Keratitis Treated with Intracameral Bevacizumab. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2022. [DOI: 10.3341/jkos.2022.63.5.472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Purpose: We report a case in which iris neovascularization (NVI) improved after intracameral bevacizumab injection in a patient who exhibited fungal keratitis with NVI.Case summary: A 47-year-old man experienced a tree branch-induced injury to his right eye and was treated for keratitis for 1 month. However, his condition deteriorated and he was referred to our hospital. Initial slit lamp biomicroscopy findings showed a large, thick central deep stromal infiltration with a concentric circle shaped feathery-like margin, epithelial defect, satellite lesion, fungal ball, hypopyon, and NVI. Aspergíllus fumigatus was isolated in the corneal scraping culture. Amphotericin B, voriconazole, and natamycin were administered as topical treatment along with systemic amphotericin B. After treatment, the corneal lesions gradually improved, but NVI worsened. After the 5th week, total hyphema occurred; anterior chamber irrigation and intracameral bevacizumab injection were performed. Two weeks postoperatively, the NVI exhibited complete regression; corneal stromal melting with descemetocele appeared after 8 weeks. Penetrating keratoplasty was performed and NVI was no longer observed at 6 months after surgery.Conclusions: For the treatment of iris neovascularization in patients with infectious keratitis, intracameral bevacizumab injection at an appropriate time may be effective.
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Singh SK, Kumar D, Nagpal S, Dubey SK, Rathore AS. A Charge Variant of Bevacizumab Offers Enhanced FcRn-Dependent Pharmacokinetic Half-Life and Efficacy. Pharm Res 2022; 39:851-865. [PMID: 35355206 DOI: 10.1007/s11095-022-03236-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/14/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Lysine variants of monoclonal antibodies (mAbs) result from incomplete clipping of the C-terminal lysine residues of the heavy chain. Although the structure of the lysine variants has been determined for several mAb products, a detailed study that investigates the impact of lysine charge variants on PK/PD and preclinical safety is yet to be published. OBJECTIVE An in-depth investigation of the impact of C- terminal lysine clipping of mAbs on safety and efficacy for bevacizumab charge variants. METHOD Charge variant isolation using semi-preparative chromatography is followed by a comparative analysis of FcRn binding, pharmacokinetics, and pharmacodynamics in relevant animal models. RESULTS K1 variant exhibited improved FcRn binding affinity (4-fold), half-life (1.3-fold), and anti-tumor activity (1.3-fold) as compared to the K0 (main) product. However, the K2 variant, even though exhibited higher FcRn affinity (2-fold), displayed lower half-life (1.6-fold) and anti-tumor activity at medium and low doses. Differential proteomic analysis revealed that seven pathways (such as glycolysis, gluconeogenesis, carbon metabolism, synthesis of amino acids) were significantly enriched. Higher efficacy of the K1 variant is likely due to higher bioavailability of the drug, leading to complete downregulation of the pathways that facilitate catering of the energy requirements of the proliferating tumor cells. On the contrary, the K2 variant exhibits a shorter half-life, resulting only in partial reduction in the metabolic/energy requirements of the growing tumor cells. CONCLUSION Overall, we conclude that the mAb half-life, dosage, and efficacy of a biotherapeutic product are significantly impacted by the charge variant profile of a biotherapeutic product.
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Affiliation(s)
- Sumit K Singh
- School of Biochemical Engineering, IIT(BHU), Varanasi, India
| | - Deepak Kumar
- Department of Chemical Engineering, IIT, DBT Center of Excellence for Biopharmaceutical Technology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India
| | | | - Sunil K Dubey
- R&D Healthcare Division, Emami Limited, Kolkata, India
| | - Anurag S Rathore
- Department of Chemical Engineering, IIT, DBT Center of Excellence for Biopharmaceutical Technology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India.
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7
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Corneal Allografts: Factors for and against Acceptance. J Immunol Res 2021; 2021:5372090. [PMID: 34642632 PMCID: PMC8502534 DOI: 10.1155/2021/5372090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/26/2021] [Accepted: 09/21/2021] [Indexed: 12/21/2022] Open
Abstract
Cornea is one of the most commonly transplanted tissues worldwide. However, it is usually omitted in the field of transplantology. Transplantation of the cornea is performed to treat many ocular diseases. It restores eyesight significantly improving the quality of life. Advancements in banking of explanted corneas and progressive surgical techniques increased availability and outcomes of transplantation. Despite the vast growth in the field of transplantation laboratory testing, standards for corneal transplantation still do not include HLA typing or alloantibody detection. This standard practice is based on immune privilege dogma that accounts for high success rates of corneal transplantation. However, the increasing need for retransplantation in high-risk patients with markedly higher risk of rejection causes ophthalmology transplantation centers to reevaluate their standard algorithms. In this review we discuss immune privilege mechanisms influencing the allograft acceptance and factors disrupting the natural immunosuppressive environment of the eye. Current developments in testing and immunosuppressive treatments (including cell therapies), when applied in corneal transplantation, may give very good results, decrease the possibility of rejection, and reduce the need for retransplantation, which is fairly frequent nowadays.
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Foo VHX, Ke M, Tan CQL, Schmetterer L, Mehta JS, Ang M. Anterior Segment Optical Coherence Tomography Angiography Assessment of Corneal Vascularisation After Combined Fine-Needle Diathermy with Subconjunctival Ranibizumab: A Pilot Study. Adv Ther 2021; 38:4333-4343. [PMID: 34241779 DOI: 10.1007/s12325-021-01849-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/25/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION To describe anterior segment optical coherence tomography angiography (AS-OCTA) imaging to monitor corneal vascularisation (CoNV) and scar reduction after combined fine-needle diathermy (FND) with subconjunctival ranibizumab. METHODS Prospective clinical study of six eyes from six subjects with corneal scar and CoNV which underwent combined FND with subconjunctival ranibizumab. All eyes were imaged using slit-lamp photography (SLP) and AS-OCTA (Optovue, Inc., Fremont, CA, wavelength: 840 nm) before and after the operation, with two independent masked assessors analysing all images. Main outcome measures were changes in median corneal scar area and vessel density (AS-OCTA) comparing pre- and postoperative imaging up to month 3 and 6. RESULTS The mean age of the subjects was 60 ± 23 years, with three males and three females. CoNV and corneal scarring involving the visual axis were present in all eyes, secondary to previous infective keratitis (n = 3), severe blepharokeratoconjunctivitis (n = 2), or chemical injury (n = 1). Follow-up time frame ranged from 2 to 6 months postoperation. There was a reduction in median corneal scar area from 30.2 mm2 (IQR 18.7-38.5) before surgery to 14.8 mm2 (IQR 7.1-19.6) after surgery, with a median reduction of 37.1% (IQR = - 3.1-86.9, p = 0.046). There was also a reduction in median cornea vessel density (AS-OCTA) from 20.8% (IQR 16.1-20.8) before surgery to 17.6% (IQR 14.0-17.6) after surgery, with a median reduction of 15.1% (IQR 13.2-15.1, p < 0.001). CONCLUSIONS Combined imaging of SLP and AS-OCTA is useful for monitoring treatment response of corneal scarring and CoNV after combined FND with subconjunctival Ranibizumab.
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Affiliation(s)
- Valencia Hui Xian Foo
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore
| | - Mengyuan Ke
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore
| | - Chelsea Qiu Lin Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Leopold Schmetterer
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore
- Department of Ophthalmology and Visual Science, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore
- SERI-NTU Advanced Ocular Engineering (STANCE), 50 Nanyang Drive, Singapore, 637553, Singapore
- Institute for Health Technologies, Nanyang Technological University, 50 Nanyang Drive, Singapore, 637553, Singapore
- Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Institute of Clinical and Experimental Ophthalmology, Klybeckstrasse 141, WKL 420, 4057, Basel, Switzerland
| | - Jodhbir S Mehta
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore
- Department of Ophthalmology and Visual Science, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Marcus Ang
- Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore.
- Department of Ophthalmology and Visual Science, Duke-NUS Graduate Medical School, 8 College Road, Singapore, 169857, Singapore.
- Department of Ophthalmology and Visual Sciences, Duke-NUS Medical School, Cornea and Refractive Service, Singapore National Eye Center, 11 Third Hospital Avenue, Singapore, 168751, Singapore.
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Arshad S, Petsoglou C, Lee T, Al-Tamimi A, Carnt NA. 20 years since the Herpetic Eye Disease Study: Lessons, developments and applications to clinical practice. Clin Exp Optom 2021; 104:396-405. [PMID: 33689622 DOI: 10.1080/08164622.2021.1877531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Herpes Simplex Virus (HSV) is the most common virus that causes eye disease. Although around 60% of the world's population are seropositive for HSV antigens, fortunately, it is estimated that only 1% of seropositive individuals develop eye disease. The most common ocular manifestation of HSV is keratitis, while uveitis and retinal necrosis occur in a small number of cases. HSV keratitis is a debilitating disease, for several reasons: pain , photophobia, and vision loss in acute disease, latency of the virus which leads to infection reactivation from various triggers, scarring, and neovascularisation, leading to permanent vision loss with poor visual rehabilitation prospects. The Herpetic Eye Disease Study (HEDS) was a landmark series of randomised controlled trials in the 1990s that set the benchmark for evidence-based treatment guidelines for anterior eye herpetic disease. Since this time, there has been a change in the distribution of seroprevalence of herpes in the community, a simplified diagnostic classification, advances in treatment options, an emergence of new and a better understanding of risk factors, and discoveries in science that show promise for vaccine and novel future treatments. However, many of the principles of the HEDS study remain rightly entrenched in clinical practice. In this article, the HEDS study is revisited 20 years on through the lens of published literature, to determine current best practise and look towards the future.
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Affiliation(s)
- Sana Arshad
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia.,Centre for Vision Research, Westmead Institute for Medical Research, Sydney, Australia
| | | | - Taehwan Lee
- Faculty of Medicine and Health, UNSW, Sydney, Australia
| | | | - Nicole A Carnt
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia.,Centre for Vision Research, Westmead Institute for Medical Research, Sydney, Australia.,Faculty of Medicine and Health, UNSW, Sydney, Australia.,Institute of Ophthalmology, University College London, London, UK
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Therapeutic Strategies for Corneal Wound Angiogenesis. CURRENT PATHOBIOLOGY REPORTS 2020. [DOI: 10.1007/s40139-020-00206-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Gupta AA, Mammo DA, Page MA. Intrastromal bevacizumab in the management of corneal neovascularization: a retrospective review. Graefes Arch Clin Exp Ophthalmol 2019; 258:167-173. [PMID: 31713747 DOI: 10.1007/s00417-019-04519-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/03/2019] [Accepted: 10/21/2019] [Indexed: 12/23/2022] Open
Abstract
PURPOSE To evaluate the long-term safety and efficacy of intrastromal bevacizumab for treatment of deep corneal neovascularization in candidates for high-risk cornea grafting. METHODS A single-center retrospective study involving 14 eyes of 14 patients with chronic deep corneal neovascularization, treated with intrastromal bevacizumab by a single provider from 2011 to present. Intrastromal bevacizumab (0.05-0.1 mL of 2.5 mg/0.1 mL) was administered every 4-8 weeks. On average 1-3 intrastromal injections were performed prior to corneal grafting (penetrating keratoplasty or deep anterior lamellar keratoplasty). RESULTS 64.2% patients had neurotrophic keratitis secondary to herpes zoster or simplex. Neovascularization was encroaching the visual axis in 50% and was paracentral in 42.8%. After intrastromal bevacizumab injection, 14.2% had complete regression of neovascularization, avoiding the need of future corneal transplant. Persistent neovascularization was noticed in 21.4%. Successful penetrating keratoplasty was performed in 57% of patients. Minimal adverse effects were noted; temporary epithelial defect was seen in two eyes and self-limited intrastromal hemorrhage in one. There was no evidence of recurrence of neovascularization or graft rejection in the transplant group (mean follow-up 3 years). CONCLUSION Intrastromal bevacizumab appears to be a safe and effective modality in the treatment of chronic corneal neovascularization, producing durable regression of corneal neovascularization and allowing for durable success of subsequent corneal transplants in high-risk patients.
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Affiliation(s)
- Archana A Gupta
- Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Phillips Wagensteen Building, Ninth Floor, 516 Delaware Street SE, Minneapolis, MN, 55455, USA
| | - Danny A Mammo
- Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Phillips Wagensteen Building, Ninth Floor, 516 Delaware Street SE, Minneapolis, MN, 55455, USA.
| | - Michael A Page
- Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Phillips Wagensteen Building, Ninth Floor, 516 Delaware Street SE, Minneapolis, MN, 55455, USA
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12
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de Aguiar RB, de Moraes JZ. Exploring the Immunological Mechanisms Underlying the Anti-vascular Endothelial Growth Factor Activity in Tumors. Front Immunol 2019; 10:1023. [PMID: 31156623 PMCID: PMC6530399 DOI: 10.3389/fimmu.2019.01023] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/23/2019] [Indexed: 12/14/2022] Open
Abstract
Several studies report the key role of the vascular endothelial growth factor (VEGF) signaling on angiogenesis and on tumor growth. This has led to the development of a number of VEGF-targeted agents to treat cancer patients by disrupting the tumor blood vessel supply. Of them, bevacizumab, an FDA-approved humanized monoclonal antibody against VEGF, is the most promising. Although the use of antibodies targeting the VEGF pathway has shown clinical benefits associated with a reduction in the tumor blood vessel density, the inhibition of VEGF-driven vascular effects is only part of the functional mechanism of these therapeutic agents in the tumor ecosystem. Compelling reports have demonstrated that VEGF confers, in addition to the activation of angiogenesis-related processes, immunosuppressive properties in tumors. It is also known that structural remodeling of the tumor blood vessel bed by anti-VEGF approaches affect the influx and activation of immune cells into tumors, which might influence the therapeutic results. Besides that, part of the therapeutic effects of antiangiogenic antibodies, including their role in the tumor vascular network, might be triggered by Fc receptors in an antigen-independent manner. In this mini-review, we explore the role of VEGF inhibitors in the tumor microenvironment with focus on the immune system, discussing around the functional contribution of both bevacizumab's Fab and Fc domains to the therapeutic results and the combination of bevacizumab therapy with other immune-stimulatory settings, including adjuvant-based vaccine approaches.
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Roshandel D, Eslani M, Baradaran-Rafii A, Cheung AY, Kurji K, Jabbehdari S, Maiz A, Jalali S, Djalilian AR, Holland EJ. Current and emerging therapies for corneal neovascularization. Ocul Surf 2018; 16:398-414. [PMID: 29908870 DOI: 10.1016/j.jtos.2018.06.004] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/10/2018] [Accepted: 06/12/2018] [Indexed: 02/08/2023]
Abstract
The cornea is unique because of its complete avascularity. Corneal neovascularization (CNV) can result from a variety of etiologies including contact lens wear; corneal infections; and ocular surface diseases due to inflammation, chemical injury, and limbal stem cell deficiency. Management is focused primarily on the etiology and pathophysiology causing the CNV and involves medical and surgical options. Because inflammation is a key factor in the pathophysiology of CNV, corticosteroids and other anti-inflammatory medications remain the mainstay of treatment. Anti-VEGF therapies are gaining popularity to prevent CNV in a number of etiologies. Surgical options including vessel occlusion and ocular surface reconstruction are other options depending on etiology and response to medical therapy. Future therapies should provide more effective treatment options for the management of CNV.
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Affiliation(s)
- Danial Roshandel
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA; Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Alireza Baradaran-Rafii
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Albert Y Cheung
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Khaliq Kurji
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA
| | - Sayena Jabbehdari
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Alejandra Maiz
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Setareh Jalali
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.
| | - Edward J Holland
- Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA.
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Liu X, Wang S, Wang X, Liang J, Zhang Y. Recent drug therapies for corneal neovascularization. Chem Biol Drug Des 2017; 90:653-664. [PMID: 28489275 DOI: 10.1111/cbdd.13018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/17/2017] [Accepted: 04/25/2017] [Indexed: 12/18/2022]
Affiliation(s)
- Xinyao Liu
- Department of Ophthalmology; The 2nd Teaching Hospital of Jilin University; Changchun Jilin China
| | - Shurong Wang
- Department of Ophthalmology; The 2nd Teaching Hospital of Jilin University; Changchun Jilin China
| | - Xuanzhong Wang
- Department of Ophthalmology; The 2nd Teaching Hospital of Jilin University; Changchun Jilin China
| | - Jiaming Liang
- Department of Ophthalmology; The 2nd Teaching Hospital of Jilin University; Changchun Jilin China
| | - Yan Zhang
- Department of Ophthalmology; The 2nd Teaching Hospital of Jilin University; Changchun Jilin China
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15
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Shahsuvaryan ML. Therapeutic Potential of Ranibizumab in Corneal Neovascularization. Trends Pharmacol Sci 2017; 38:667-668. [PMID: 28606479 DOI: 10.1016/j.tips.2017.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 05/17/2017] [Indexed: 10/19/2022]
Abstract
Ranibizumab is a humanized, affinity-matured vascular endothelial growth factor (VEGF) antibody fragment that neutralizes all isoforms of VEGF and is FDA approved for use in ophthalmology. Recently it was suggested that ranibizumab may be useful in the treatment of corneal neovascularization, but in reality this therapy is not yet evidence based.
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16
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Management of high-risk corneal transplantation. Surv Ophthalmol 2016; 62:816-827. [PMID: 28012874 DOI: 10.1016/j.survophthal.2016.12.010] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 12/14/2022]
Abstract
The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal grafting has high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates because of a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered; however, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been used for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use, as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments, as well as tolerance-inducing methods, show promising horizons in the management of high-risk corneal transplantation in near future.
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17
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Bogdanovich S, Kim Y, Mizutani T, Yasuma R, Tudisco L, Cicatiello V, Bastos-Carvalho A, Kerur N, Hirano Y, Baffi JZ, Tarallo V, Li S, Yasuma T, Arpitha P, Fowler BJ, Wright CB, Apicella I, Greco A, Brunetti A, Ruvo M, Sandomenico A, Nozaki M, Ijima R, Kaneko H, Ogura Y, Terasaki H, Ambati BK, Leusen JH, Langdon WY, Clark MR, Armour KL, Bruhns P, Verbeek JS, Gelfand BD, De Falco S, Ambati J. Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther 2016; 1. [PMID: 26918197 PMCID: PMC4763941 DOI: 10.1038/sigtrans.2015.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.
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Affiliation(s)
- Sasha Bogdanovich
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Younghee Kim
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Takeshi Mizutani
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Reo Yasuma
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Laura Tudisco
- Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy
| | - Valeria Cicatiello
- Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy
| | - Ana Bastos-Carvalho
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Nagaraj Kerur
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Yoshio Hirano
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Judit Z Baffi
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Valeria Tarallo
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy
| | - Shengjian Li
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Tetsuhiro Yasuma
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Parthasarathy Arpitha
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Benjamin J Fowler
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Charles B Wright
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA
| | - Ivana Apicella
- Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy
| | - Adelaide Greco
- Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy
| | - Arturo Brunetti
- Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy
| | - Menotti Ruvo
- Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy
| | | | - Miho Nozaki
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ryo Ijima
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kaneko
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichiro Ogura
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroko Terasaki
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Balamurali K Ambati
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA
| | - Jeanette Hw Leusen
- Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wallace Y Langdon
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia
| | - Michael R Clark
- Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Kathryn L Armour
- Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Pierre Bruhns
- Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris, France
| | - J Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Bradley D Gelfand
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA
| | - Sandro De Falco
- Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano, Italy
| | - Jayakrishna Ambati
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA
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18
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Benayoun Y, Petellat F, Leclerc O, Dost L, Dallaudière B, Reddy C, Robert PY, Salomon JL. [Current treatments for corneal neovascularization]. J Fr Ophtalmol 2015; 38:996-1008. [PMID: 26522890 DOI: 10.1016/j.jfo.2015.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Revised: 09/12/2015] [Accepted: 09/17/2015] [Indexed: 11/27/2022]
Abstract
The extension of blood vessels into the normally avascular stroma defines corneal neovascularization. Though this phenomenon, pathophysiological and clinical features are well characterized, therapeutic modalities have been hindered by a lack of safe, efficacious and non-controversial treatments. In this literature review, we focus on available therapeutic options in light of recent evidence provided by animal and clinical studies. First, this review will focus on pharmacological treatments that target angiogenesis. The low cost and market availability of bevacizumab make it the first anti-angiogenic therapy choice, and it has demonstrable efficacy in reducing corneal neovascularization when administered topically or subconjunctivally. However, novel anti-angiogenic molecules targeting the intracellular pathways of angiogenesis (siRNA, antisense oligonucleotides) provide a promising alternative. Laser therapy (direct photocoagulation or photo-dynamic therapy) and fine needle diathermy also find a place in the treatment of stabilized corneal neovascularization alone or in association with anti-angiogenic therapy. Additionally, ocular surface reconstruction using amniotic membrane graft or limbal stem cell transplantation is essential when corneal neovascularization is secondary to primary or acquired limbal deficiency.
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Affiliation(s)
- Y Benayoun
- Clinique ophtalmologique François-Chénieux, 18, rue du Général-Catroux, 87039 Limoges cedex, France; Institut de recherche et d'innovation en sciences de la vision (IRIS-Vision), 18, rue du Général-Catroux, 87039 Limoges cedex, France.
| | - F Petellat
- Clinique ophtalmologique François-Chénieux, 18, rue du Général-Catroux, 87039 Limoges cedex, France; Institut de recherche et d'innovation en sciences de la vision (IRIS-Vision), 18, rue du Général-Catroux, 87039 Limoges cedex, France
| | - O Leclerc
- Service d'ophtalmologie, hôpital Dupuytren, CHU de Limoges, 87042 Limoges cedex, France
| | - L Dost
- Service d'ophtalmologie, hôpital Dupuytren, CHU de Limoges, 87042 Limoges cedex, France
| | - B Dallaudière
- Service de radiologie, hôpital Pellegrin, CHU de Bordeaux, 33000 Bordeaux, France
| | - C Reddy
- Baylor Scott & White Memorial Hospital, Texas A&M University, Texas, États-Unis
| | - P-Y Robert
- Service d'ophtalmologie, hôpital Dupuytren, CHU de Limoges, 87042 Limoges cedex, France
| | - J-L Salomon
- Clinique ophtalmologique François-Chénieux, 18, rue du Général-Catroux, 87039 Limoges cedex, France; Institut de recherche et d'innovation en sciences de la vision (IRIS-Vision), 18, rue du Général-Catroux, 87039 Limoges cedex, France
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19
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Voiculescu OB, Voinea LM, Alexandrescu C. Corneal neovascularization and biological therapy. J Med Life 2015; 8:444-8. [PMID: 26664467 PMCID: PMC4656949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Corneal avascularity is necessary for the preservation of optimal vision. The cornea maintains a dynamic balance between pro- and antiangiogenic factors that allows it to remain avascular under normal homeostatic conditions. Corneal neovascularization (NV) is a condition that can develop in response to inflammation, hypoxia, trauma, or limbal stem cell deficiency and it is a significant cause of blindness. New therapeutic options for diseases of the cornea and ocular surface are now being explored in experimental animals and clinical trials. Antibody based biologics are being tested for their ability to reduce blood and lymphatic vessel ingrowth into the cornea, and to reduce inflammation. Numerous studies have shown that biologics with specificity for VEGF A such as bevacizumab and ranibizumab (a recombinant antibody and an antibody fragment, respectively) or anti-tumor necrosis factor-α microantibody, are effective in the treatment of corneal neovascularization.
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Affiliation(s)
- OB Voiculescu
- Department of Cellular and Molecular Medicine,
”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - LM Voinea
- Department of Ophthalmology, University Emergency Hospital Bucharest, Romania
| | - C Alexandrescu
- Department of Ophthalmology, University Emergency Hospital Bucharest, Romania
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20
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Wu B, Wu H, Liu X, Lin H, Li J. Ranibizumab versus bevacizumab for ophthalmic diseases related to neovascularisation: a meta-analysis of randomised controlled trials. PLoS One 2014; 9:e101253. [PMID: 24983855 PMCID: PMC4077727 DOI: 10.1371/journal.pone.0101253] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 06/03/2014] [Indexed: 11/18/2022] Open
Abstract
Background Bevacizumab is believed to be as effective and safe as ranibizumab for ophthalmic diseases; however, its magnitude of effectiveness and safety profile remain controversial. Thus, a meta-analysis and systematic review appears necessary. Methods PubMed and EMBASE were systematically searched with no restrictions. All relevant citations comparing ranibizumab and bevacizumab were considered for inclusion. Pooled effect estimates were obtained using a fixed- and random-effects meta-analysis. Results Nine independent randomised-controlled clinical trials (RCTs) involving 2,289 participants were identified. Compared with bevacizumab, the overall combined weighted mean difference (WMD) of the mean change in visual acuity for ranibizumab was 0.52 letters (95% CI −0.11–1.14). The odds ratios (ORs) of gaining ≥15, gaining 5–14, losing 5–14 and losing ≤15 letters were 1.10 (95% CI 0.90–1.33), 0.93 (95% CI 0.77–1.11), 0.89 (95% CI 0.65–1.22) and 0.95 (95% CI 0.73–1.25), respectively. The risk of serious systemic events increased by 17% (95% CI 6%–27%, p = 0.0042) for bevacizumab treatment in comparison with ranibizumab. No statistically significant differences between the two treatments were found for the nonfatal arterial thrombotic events, ocular serious adverse, death from vascular and all causes events. Conclusions Bevacizumab is not inferior to ranibizumab as a treatment for achieving visual acuity. The use of bevacizumab was associated with an increased risk of developing serious systemic events. Weighing the costs and health outcomes is necessary when selecting between bevacizumab and ranibizumab for ophthalmic diseases. Due to the limitations of the available data, further research is needed.
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Affiliation(s)
- Bin Wu
- Department of Pharmacy, Ren Ji Hospital, affiliated with the School of Medicine, Shanghai Jiao tong University, Shanghai, China
| | - Haixiang Wu
- Department of Ophthalmology, and Visual Science, Eye, and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyan Liu
- Department of Pharmacy, Ren Ji Hospital, affiliated with the School of Medicine, Shanghai Jiao tong University, Shanghai, China
| | - Houwen Lin
- Department of Pharmacy, Ren Ji Hospital, affiliated with the School of Medicine, Shanghai Jiao tong University, Shanghai, China
| | - Jin Li
- Department of Ophthalmology, Ren Ji Hospital, affiliated with the School of Medicine, Shanghai Jiao tong University, Shanghai, China
- * E-mail:
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