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Bege M, Ghanem Kattoub R, Borbás A. The 20th Anniversary of Pegaptanib (MacugenTM), the First Approved Aptamer Medicine: History, Recent Advances and Future Prospects of Aptamers in Therapy. Pharmaceutics 2025; 17:394. [PMID: 40143057 PMCID: PMC11944999 DOI: 10.3390/pharmaceutics17030394] [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: 03/03/2025] [Revised: 03/15/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known as chemical antibodies form a smaller, yet equally interesting group of oligonucleotides that can recognize a wide range of molecular targets. Despite their high potential, only two aptamers have been approved to date, pegaptanib (MacugenTM) and avacincaptad pegol (IzervayTM), both for the treatment of age-related macular degeneration (AMD). Targeting vascular endothelial growth factor (VEGF), which plays an important role in the pathogenesis of many eye diseases, pegaptanib emerged as the first anti-VEGF agent and was used in various indications, further inspiring the development of other anti-VEGF therapies. In this review, we summarize the history of the first approved aptamer medicine, pegaptanib. We describe its chemistry and track its development from the earliest stages to the preclinical phase, clinical trials, and eventual regulatory approval. Additionally, we evaluate its position among other therapeutic agents and provide a comprehensive overview of pegaptanib's efficacy, safety, and cost-effectiveness, comparing these aspects with those of monoclonal antibodies with similar indications, bevacizumab and ranibizumab.
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Affiliation(s)
- Miklós Bege
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (M.B.); (R.G.K.)
| | - Rasha Ghanem Kattoub
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (M.B.); (R.G.K.)
- Doctoral School of Pharmaceutical Sciences, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt. 98., 4032 Debrecen, Hungary
| | - Anikó Borbás
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary; (M.B.); (R.G.K.)
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Blazes M, Ngadisastra C, Li PR, Lee CS, Lee JS, See LC, Lin KK. INCIDENCE AND PROGRESSION OF AGE-RELATED MACULAR DEGENERATION AMONG PATIENTS WITH AND WITHOUT OBSTRUCTIVE SLEEP APNEA: A National Cohort Study. Retina 2025; 45:198-206. [PMID: 39454055 DOI: 10.1097/iae.0000000000004293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2024]
Abstract
PURPOSE Obstructive sleep apnea (OSA) may increase the risk of age-related macular degeneration (AMD) due to repetitive oxygen deprivation or other mechanisms, though whether OSA increases the risk of AMD progression is unknown. The authors analyzed associations between OSA and AMD risk in the Taiwanese population. METHODS The authors identified patients diagnosed with OSA between 2000 and 2018 in the Taiwan National Health Insurance Research Database and used 1:1 propensity score matching on demographics and comorbidities to create a non-OSA cohort. The authors used Cox proportional hazard modeling to investigate the risk of AMD and the risk of progression from nonexudative to exudative AMD in OSA versus non-OSA patients. RESULTS A total of 66,869 OSA patients were matched with 66,869 non-OSA patients. The hazard ratio of AMD in the OSA cohort was 1.36 (95% confidence interval, 1.29-1.43, P < 0.0001). The hazard ratio for progression from nonexudative to exudative AMD for the OSA cohort was 0.94 (95% confidence interval, 0.77-1.14, P = 0.5073). CONCLUSION Obstructive sleep apnea is associated with a higher risk of developing AMD. However, no increased risk of AMD progression is observed among people with OSA and existing nonexudative AMD.
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Affiliation(s)
- Marian Blazes
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Caitlyn Ngadisastra
- Department of Ophthalmology, University of Washington, Seattle, Washington
- Roger and Angie Karalis Johnson Retina Center, Seattle, Washington
| | - Pei-Ru Li
- Department of Public Health, School of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Cecilia S Lee
- Department of Ophthalmology, University of Washington, Seattle, Washington
- Roger and Angie Karalis Johnson Retina Center, Seattle, Washington
| | - Jiahn-Shing Lee
- Department of Ophthalmology, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- Department of Medicine, School of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Lai-Chu See
- Department of Public Health, School of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan City, Taiwan ; and
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
| | - Ken-Kuo Lin
- Department of Ophthalmology, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- Department of Medicine, School of Medicine, Chang Gung University, Taoyuan City, Taiwan
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Malvasi M, Calandri A, Pacella E, Vingolo EM. Effects on corneal endothelium of intravitreal injection of anti-VEGF drugs. Cutan Ocul Toxicol 2024:1-14. [PMID: 39560148 DOI: 10.1080/15569527.2024.2422914] [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: 01/22/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/20/2024]
Abstract
PURPOSE Intravitreal drug administration has become the gold standard for the treatment of many retinal diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusion (RVO). The frequency of this procedure has increased significantly after the introduction of anti-VEGF drugs, since the rise in the average age of the population, which is closely correlated with these diseases. In order to ensure therapeutic success in these patients with chronic retinal diseases, intravitreal treatment with anti-VEGF requires a long-term maintenance regimen with repeated administrations. For this reason today, we must consider the risks linked to complications associated with the long-term application of this therapy. Our study aims to investigate whether the intravitreal injection of anti-VEGF may lead to damage to the corneal endothelium, either directly through the administration procedure or indirectly due to the drug's toxicity. We aimed to establish a clear correlation between intravitreal drug administration and a statistically significant reduction in corneal endothelial cell count in the treated eye when compared to the untreated eye. The study also sought to assess whether different toxicities might be present between different types of drugs belonging to the same anti-VEGF family. MATERIALS AND METHODS The study was conducted by examining a cohort of 133 patients suffering from different diseases: AMD, EMD and RVO. All patients underwent measurement of the endothelial count with CellChek® 20, considering the value measured at the first injection as time zero and reassessed at each subsequent treatment session. The measurement of the endothelial count was performed both on the eye under treatment (TE) and in the eye not undergoing intravitreal injection (NTE) with anti-VEGF drugs for each injection cycle. Different anti-VEGF drugs such as Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab were used for intravitreal therapy. The test patients were included in a 12-month follow-up programme, in which the measurement intervals are dictated by the treatment plan. RESULTS The statistical analysis performed on the corneal endothelial cell counts showed that the ECD (endothelial cell density) parameter decreases with each administration of the drug. The analysis of the difference in the mean endothelial cell counts of the TE reveals that the difference in the number of endothelial cells between the first and second counts in TE is 54.00; greater than the difference in the number of cells found in NTE, which was 13.42. Both the difference between the TE and NTE cell counts are statistically significant. In the case of the TE, the p-value is <0.001, while in the case of the NTE the p-value is still significant as <0.05. The hypothesis that the different types of anti-VEGF drugs could determine the decrease in endothelial cell count differently was also evaluated. No statistically significant data emerged from the analyses (p-value is >0.05). CONCLUSIONS The study demonstrated a statistically significant reduction of corneal endothelial cells in patients undergoing intravitreal injection treatment per number of injections with anti-VEGF, this reduction being independent of the type of anti-VEGF used (Bevacizumab, Ranibizumab, Aflibercept and Brolucizumab).
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Affiliation(s)
| | | | - Elena Pacella
- Department of Sense Organs, Sapienza University of Rome, Rome, Italy
| | - Enzo Maria Vingolo
- Department of Sense Organs, Sapienza University of Rome, Rome, Italy
- Department of Ophthalmology, Fiorini Hospital Terracina AUSL, Terracina, Latina, Italy
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Huang Y, Tang T, Wang D, Gao Y, Zhang M. Global, regional, and national burden of age-related macular degeneration, 1990-2019: an age-period-cohort analysis based on the Global Burden of Disease 2019 Study. Front Public Health 2024; 12:1486168. [PMID: 39502824 PMCID: PMC11534605 DOI: 10.3389/fpubh.2024.1486168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Objectives This study aimed to explore the burden of disease and disparities in age-related macular degeneration (AMD) at the global, regional, and national levels from 1990 to 2019 using data from the Global Burden of Disease (GBD) 2019 study, with a particular focus on associations with age, period, and cohort. Methods We derived disability-adjusted life years (DALYs) and age-standardized rates of AMD from the GBD 2019. We used an age-period-cohort (APC) model to estimate the overall annual percentage changes in DALYs (net drifts), the annual percentage changes in different age groups (local drifts), the longitudinal age profiles (longitudinal age-specific rates), and the relative risks of period and cohort (period and cohort effects) between 1990 and 2019. Further analysis was conducted by country, region, gender and sociodemographic index (SDI). Results Globally, the number of DALYs increased from 296771.9321 (95% uncertainty interval [UI], 205462.8041-418699.8184) in 1990 to 564055.0967 (95% UI, 392930.6967-789194.6407) in 2019 (59.7% were female), while the age-standardized DALYs rates decreased from 8.29 per 100,000 (95% UI, 5.8-11.58/100,000) to 7.05 per 100,000 (95% UI, 4.92-9.84/100,000). With increasing age, the burden of AMD increased, and the DALYs rates in female was greater than that in male in all age groups. The burden of disease varied across SDI regions and countries. The top three countries in terms of the number of DALYs were China, India and Italy, accounting for 45% of the global total. Conclusion The burden of AMD varied according to SDI, country, and sex from 1990 to 2019. Due to global population growth and aging, AMD will continue to be a major public health problem in the future, and relevant health policies need to be continuously improved and optimized.
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Affiliation(s)
- Yufan Huang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Tong Tang
- Institutes for Systems Genetics, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Dongyue Wang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Yunxia Gao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
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Avram O, Durmus B, Rakocz N, Corradetti G, An U, Nittala MG, Terway P, Rudas A, Chen ZJ, Wakatsuki Y, Hirabayashi K, Velaga S, Tiosano L, Corvi F, Verma A, Karamat A, Lindenberg S, Oncel D, Almidani L, Hull V, Fasih-Ahmad S, Esmaeilkhanian H, Cannesson M, Wykoff CC, Rahmani E, Arnold CW, Zhou B, Zaitlen N, Gronau I, Sankararaman S, Chiang JN, Sadda SR, Halperin E. Accurate prediction of disease-risk factors from volumetric medical scans by a deep vision model pre-trained with 2D scans. Nat Biomed Eng 2024:10.1038/s41551-024-01257-9. [PMID: 39354052 DOI: 10.1038/s41551-024-01257-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/23/2024] [Indexed: 10/03/2024]
Abstract
The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for 'slice integration by vision transformer'), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.
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Affiliation(s)
- Oren Avram
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Berkin Durmus
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Nadav Rakocz
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Giulia Corradetti
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
- Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ulzee An
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Muneeswar G Nittala
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
- Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Prerit Terway
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Akos Rudas
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Zeyuan Johnson Chen
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yu Wakatsuki
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | | | - Swetha Velaga
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Liran Tiosano
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Federico Corvi
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Aditya Verma
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY, USA
| | - Ayesha Karamat
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Sophiana Lindenberg
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Deniz Oncel
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Louay Almidani
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Victoria Hull
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | - Sohaib Fasih-Ahmad
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA
| | | | - Maxime Cannesson
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Charles C Wykoff
- Retina Consultants of Texas, Retina Consultants of America, Houston, TX, USA
- Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA
| | - Elior Rahmani
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Corey W Arnold
- Department of Radiology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Pathology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Bolei Zhou
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Noah Zaitlen
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ilan Gronau
- School of Computer Science, Reichman University, Herzliya, Israel
| | - Sriram Sankararaman
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jeffrey N Chiang
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Srinivas R Sadda
- Doheny Eye Institute, University of California, Los Angeles, Pasadena, CA, USA.
- Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Eran Halperin
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA.
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Moraru AD, Danielescu C, Iorga RE, Moraru RL, Zemba M, Branisteanu DC. Review of Guideline Recommendations for Optimal Anti-VEGF Therapy in Age-Related Macular Degeneration. Life (Basel) 2024; 14:1220. [PMID: 39459520 PMCID: PMC11508937 DOI: 10.3390/life14101220] [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: 06/28/2024] [Revised: 09/09/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Neovascular age-related macular degeneration is a progressive, blinding macular disease that has become a burden both in healthcare systems and the global economy. The vascular endothelial growth factor (VEGF) is the main agent involved in the pathogenic process of the disease. The main goal of the age-related macular degeneration treatment is to maintain and improve visual acuity by injecting intravitreal anti-VEGF agents in either a reactive or proactive manner. Subretinal and intraretinal fluids are the main biomarkers that should be considered when managing the frequency of the therapy. This review discusses both functional and morphological treatment criteria according to current recommendations as opposed to real-life situations encountered during day-to-day clinical practice and highlights situations in which the benefits of continuing therapy are arguable in terms of improving patients' quality of life. Optimizing the treatment regimen represents an important aim of current clinical ophthalmological practice, as age-related macular degeneration patients usually have a long follow-up period.
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Affiliation(s)
- Andreea Dana Moraru
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania; (A.D.M.); (D.C.B.)
- Department of Ophthalmology, ‘N. Oblu’ Clinical Hospital, 700309 Iași, Romania
| | - Ciprian Danielescu
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania; (A.D.M.); (D.C.B.)
- Department of Ophthalmology, ‘N. Oblu’ Clinical Hospital, 700309 Iași, Romania
| | - Raluca Eugenia Iorga
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania; (A.D.M.); (D.C.B.)
- Department of Ophthalmology, ‘N. Oblu’ Clinical Hospital, 700309 Iași, Romania
| | | | - Mihail Zemba
- Department of Ophthalmology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Daniel Constantin Branisteanu
- Department of Ophthalmology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania; (A.D.M.); (D.C.B.)
- Department of Ophthalmology, Railway Clinical Hospital, 700506 Iași, Romania
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Song JS, Kim MS, Joo K, Park SJ, Woo SJ, Park KH. INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION AND POOR VISUAL ACUITY. Retina 2024; 44:1486-1494. [PMID: 39167570 DOI: 10.1097/iae.0000000000004154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
PURPOSE To investigate the significance of intravitreal anti-vascular endothelial growth factor treatment in patients with neovascular age-related macular degeneration and poor visual acuity. METHODS Retrospective study of patients with neovascular age-related macular degeneration with baseline best-corrected visual acuity of ≤20/200. Patients were divided into regular treatment and scarce treatment groups according to whether they underwent consecutive intravitreal anti-vascular endothelial growth factor treatments at intervals of ≤4 months or not. RESULTS A total of 131 eyes were included: 87 and 44 eyes in the regular treatment and scarce treatment groups, respectively. The regular treatment group showed significantly improved preservation of lesion size at both Years 1 and 2, with significantly fewer incidences of new subretinal hemorrhage. Improvements in visual acuity, reduction in central subfield macular thickness, and maximal height of choroidal neovascularization were significantly favorable in the regular treatment group at Year 1, and central subfield macular thickness was significantly decreased at Year 2. Survival analysis revealed that the regular treatment group had significantly greater preservation of visual acuity and lesion size than that in the scarce treatment group. CONCLUSION Maintaining intravitreal anti-vascular endothelial growth factor treatment for patients with neovascular age-related macular degeneration and poor vision showed significant advantages in visual acuity and lesion size stability and reduced the incidence of new subretinal hemorrhage, which suggests preservation of paracentral vision.
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Affiliation(s)
- Jae Shin Song
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Ophthalmology, Armed Forces Capital Hospital, Seongnam, Korea ; and
| | - Min Seok Kim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kwangsic Joo
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang Jun Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Se Joon Woo
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyu Hyung Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
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8
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Popovic MM, Balas M, Sadda SR, Sarraf D, Huang R, Bakri SJ, Berrocal A, Chang A, Gemmy Cheung CM, Garg S, Hillier RJ, Holz FG, Johnson MW, Kaiser PK, Kertes PJ, Lai TYY, Noble J, Park SS, Paulus YM, Querques G, Rachitskaya A, Ruamviboonsuk P, Saidkasimova S, Sandinha MT, Steel DH, Terasaki H, Weng CY, Williams BK, Wu L, Muni RH. International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials. Ophthalmology 2024:S0161-6420(24)00366-X. [PMID: 38878904 DOI: 10.1016/j.ophtha.2024.06.011] [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: 09/16/2023] [Revised: 04/10/2024] [Accepted: 06/06/2024] [Indexed: 07/25/2024] Open
Abstract
PURPOSE Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN Systematic review and Delphi consensus process. PARTICIPANTS Twenty-five international retinal specialists participated in the Delphi consensus survey. METHODS A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. MAIN OUTCOME MEASURES The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Marko M Popovic
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | - Michael Balas
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | - SriniVas R Sadda
- Doheny Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - David Sarraf
- Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Ryan Huang
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | - Sophie J Bakri
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
| | - Audina Berrocal
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
| | - Andrew Chang
- Sydney Retina Clinic, Sydney Eye Hospital, University of New South Wales, Sydney, Australia
| | - Chui Ming Gemmy Cheung
- Department of Ophthalmology, National University of Singapore, Singapore, Republic of Singapore
| | - Sunir Garg
- Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Wills Eye Hospital, Philadelphia, Pennsylvania
| | - Roxane J Hillier
- Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Frank G Holz
- Department of Ophthalmology, University of Bonn, Bonn, Germany
| | - Mark W Johnson
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan
| | | | - Peter J Kertes
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | - Timothy Y Y Lai
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong, China
| | - Jason Noble
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
| | - Susanna S Park
- Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, California
| | - Yannis M Paulus
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan
| | - Giuseppe Querques
- Department of Ophthalmology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | | | - Paisan Ruamviboonsuk
- Department of Ophthalmology, College of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand
| | | | - Maria Teresa Sandinha
- Department of Eye and Visual Science, University of Liverpool, Merseyside, United Kingdom
| | - David H Steel
- Sunderland Eye Infirmary, Sunderland, United Kingdom
| | | | - Christina Y Weng
- Cullen Eye Institute, Baylor College of Medicine, Houston, Texas
| | - Basil K Williams
- Cincinnati Eye Institute, Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Lihteh Wu
- Department of Ophthalmology, Asociados de Mácula Vitreo y Retina de Costa Rica, San José, Costa Rica
| | - Rajeev H Muni
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada.
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9
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Damasceno NA, Oliveira JAE, Yannuzzi NA, Flynn Jr H, Maia M, Damasceno EF, Farah ME. Potential Risk Factors for Ocular Pain in Patients Undergoing Multiple Intravitreal Injections of Anti-Vascular Endothelial Growth Factor. Clin Ophthalmol 2024; 18:1691-1699. [PMID: 38863678 PMCID: PMC11166166 DOI: 10.2147/opth.s463016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/29/2024] [Indexed: 06/13/2024] Open
Abstract
Purpose To assess ocular pain in patients undergoing multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) who have previous factors that may influence pain sensitivity. Methodology This is a prospective, observational, case series study involving patients who underwent multiple (≥3) pro re nata intravitreal injections of ranibizumab or aflibercept to treat any cause of chorioretinal vascular disease. Ocular pain was assessed by the numerical analog scale during intravitreal injection. For this study, the main variable was ocular pain and the secondary variables included age, sex, previous history of glaucoma, primary retinal vascular disease, severe dry eye history, trigeminal pain, scleral buckle surgery, collagen diseases, fibromyalgia, severe migraine history, pars plana vitrectomy, scleral thickness measurements, and type of anti-VEGF. Results In a total of 894 patients, 948 eyes (4822 intravitreal injections), 793 patients (88.6%) had ocular pain sensitivity between no pain to mild pain, 80 patients (8.9%) had moderate ocular pain, 15 patients (1.6%) had severe ocular pain, and 6 patients (0.7%) had extremely severe ocular pain. Patients with severe dry eye (p = 0.01) and previous history of scleral buckle surgery (p = 0.01) showed a significant correlation with ocular pain during intravitreal injection. Pars plana scleral thickness (>550 um) and diabetic neuropathy were associated with ocular pain but did not meet the criteria for statistical significance (p = 0.09 and p = 0.06, respectively). Conclusion Dry eye and prior scleral buckle surgery may contribute to pain associated with intravitreal injection. These issues should be taken into consideration in patients undergoing multiple intravitreal injections.
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Affiliation(s)
- Nadyr A Damasceno
- HNMD, Hospital Naval Marcilio Dias, Department of Ophthalmology, Rio de Janeiro, RJ, Brazil
- UNIFESP, Universidade Federal de São Paulo, Department of Ophthalmology, São Paulo, SP, Brazil
| | | | - Nicolas A Yannuzzi
- BPEI, Bascom Palmer Eye Institute, Department of Ophthalmology, Miami, FL, USA
| | - Harry Flynn Jr
- BPEI, Bascom Palmer Eye Institute, Department of Ophthalmology, Miami, FL, USA
| | - Mauricio Maia
- UNIFESP, Universidade Federal de São Paulo, Department of Ophthalmology, São Paulo, SP, Brazil
| | - Eduardo F Damasceno
- UFF, School of Medicine, Universidade Federal Fluminense, Department of Ophthalmology, Niteroi, RJ, Brazil
| | - Michel Eid Farah
- UNIFESP, Universidade Federal de São Paulo, Department of Ophthalmology, São Paulo, SP, Brazil
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10
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Kuchroo M, DiStasio M, Song E, Calapkulu E, Zhang L, Ige M, Sheth AH, Majdoubi A, Menon M, Tong A, Godavarthi A, Xing Y, Gigante S, Steach H, Huang J, Huguet G, Narain J, You K, Mourgkos G, Dhodapkar RM, Hirn MJ, Rieck B, Wolf G, Krishnaswamy S, Hafler BP. Single-cell analysis reveals inflammatory interactions driving macular degeneration. Nat Commun 2023; 14:2589. [PMID: 37147305 PMCID: PMC10162998 DOI: 10.1038/s41467-023-37025-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 02/27/2023] [Indexed: 05/07/2023] Open
Abstract
Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer's disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.
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Affiliation(s)
- Manik Kuchroo
- Department of Neuroscience, Yale University, New Haven, CT, USA
| | | | - Eric Song
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA
| | - Eda Calapkulu
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA
| | - Le Zhang
- Department of Neuroscience, Yale University, New Haven, CT, USA
- Department of Neurology, Yale University, New Haven, CT, USA
| | - Maryam Ige
- Yale School of Medicine, New Haven, CT, USA
| | | | - Abdelilah Majdoubi
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA
| | - Madhvi Menon
- Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK
| | - Alexander Tong
- Department of Computer Science, Yale University, New Haven, CT, USA
| | | | - Yu Xing
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA
| | - Scott Gigante
- Computational Biology, Bioinformatics Program, Yale University, New Haven, CT, USA
| | - Holly Steach
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Jessie Huang
- Department of Computer Science, Yale University, New Haven, CT, USA
| | - Guillaume Huguet
- Mila-Quebec AI institute, Montréal, QC, Canada
- Department of Mathematics and Statistics, Université de Montréal, Montréal, QC, Canada
| | - Janhavi Narain
- Department of Computer Science, Rutgers University, New Brunswick, NJ, USA
| | - Kisung You
- Department of Genetics, Yale University, New Haven, CT, USA
| | - George Mourgkos
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA
| | | | - Matthew J Hirn
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, USA
- Department of Mathematics, Michigan State University, East Lansing, MI, USA
| | - Bastian Rieck
- Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
| | - Guy Wolf
- Mila-Quebec AI institute, Montréal, QC, Canada
- Department of Mathematics and Statistics, Université de Montréal, Montréal, QC, Canada
| | - Smita Krishnaswamy
- Department of Computer Science, Yale University, New Haven, CT, USA.
- Department of Genetics, Yale University, New Haven, CT, USA.
| | - Brian P Hafler
- Department of Pathology, Yale University, New Haven, CT, USA.
- Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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11
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Soga H, Inoue T, Urade Y, Ueta T, Kawashima H, Kaburaki T, Aihara M. Attenuation of Laser-Induced Choroidal Neovascularization by Blockade of Prostaglandin D2 Receptor 2. Transl Vis Sci Technol 2023; 12:5. [PMID: 37133840 PMCID: PMC10166117 DOI: 10.1167/tvst.12.5.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023] Open
Abstract
Purpose The purpose of this study was to investigate the impact of prostaglandin D2 (PGD2) receptor 2 (DP2) on choroidal neovascularization (CNV) formation in mice. Methods Using a laser-induced CNV model, the CNV size of wild-type (WT) mice treated with DP2 antagonist (CAY10471 or OC000459) was compared with that of untreated mice. Vascular endothelial growth factor (VEGF) and MCP-1 levels were also compared between the two groups. Similar experiments were performed comparing DP2 knockout (DP2KO) mice with WT mice (8 and 56 weeks old). The number of infiltrating macrophages to laser spots was also compared between the WT and DP2KO mice. We administered a DP2 antagonist to 15-methyl PGD2 (a DP2 agonist)-stimulated ARPE-19 cells and measured VEGF secretion by enzyme-linked immunosorbent assay. Tube formation assay was performed on human umbilical vein endothelial cells with or without a DP2 antagonist. Results CNV sizes were significantly smaller in mice treated with CAY10471 or OC000459 than in those treated with vehicle. Similarly, the CNV size of DP2KO mice was significantly smaller than that of WT mice. The number of macrophages at laser spots in DP2KO mice was significantly lower than that in WT mice. The VEGF concentration of lasered DP2KO mice's eyes was significantly lower than that of lasered WT mice' eyes. DP2 antagonist treatment suppressed VEGF secretion in ARPE-19 cells under 15-methyl PGD2 stimulation. The tube formation assay suggested that lumen formation was inhibited by a DP2 antagonist. Conclusions DP2 blockade attenuated choroidal neovascularization. Translational Relevance Drugs targeting DP2 are potentially a novel treatment for age-related macular degeneration.
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Affiliation(s)
- Hirotsugu Soga
- Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Tatsuya Inoue
- Department of Ophthalmology and Micro-Technology, Yokohama City University School of Medicine, Minami-ku, Yokohama, Kanagawa, Japan
| | - Yoshihiro Urade
- Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Hirono Satellite Laboratories, Isotope Science Center, the University of Tokyo, Hirono-mati, Futaba-gun, Fukushima, Japan
| | - Takashi Ueta
- Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Hidetoshi Kawashima
- Department of Ophthalmology, Jichi Medical University, Shimotsuke-City, Tochigi, Japan
| | - Toshikatsu Kaburaki
- Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Department of Ophthalmology, Jichi Medical University Saitama Medical Center, Omiya-ku, Saitama, Japan
| | - Makoto Aihara
- Department of Ophthalmology, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
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12
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Nhàn NTT, Maidana DE, Yamada KH. Ocular Delivery of Therapeutic Agents by Cell-Penetrating Peptides. Cells 2023; 12:1071. [PMID: 37048144 PMCID: PMC10093283 DOI: 10.3390/cells12071071] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Cell-penetrating peptides (CPPs) are short peptides with the ability to translocate through the cell membrane to facilitate their cellular uptake. CPPs can be used as drug-delivery systems for molecules that are difficult to uptake. Ocular drug delivery is challenging due to the structural and physiological complexity of the eye. CPPs may be tailored to overcome this challenge, facilitating cellular uptake and delivery to the targeted area. Retinal diseases occur at the posterior pole of the eye; thus, intravitreal injections are needed to deliver drugs at an effective concentration in situ. However, frequent injections have risks of causing vision-threatening complications. Recent investigations have focused on developing long-acting drugs and drug delivery systems to reduce the frequency of injections. In fact, conjugation with CPP could deliver FDA-approved drugs to the back of the eye, as seen by topical application in animal models. This review summarizes recent advances in CPPs, protein/peptide-based drugs for eye diseases, and the use of CPPs for drug delivery based on systematic searches in PubMed and clinical trials. We highlight targeted therapies and explore the potential of CPPs and peptide-based drugs for eye diseases.
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Affiliation(s)
- Nguyễn Thị Thanh Nhàn
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA;
| | - Daniel E. Maidana
- Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, IL 60612, USA;
- Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA
| | - Kaori H. Yamada
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA;
- Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, IL 60612, USA;
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13
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Brown K, Bunce C, Onabanjo O, Strong SA, Patel PJ. Is preventable sight loss truly preventable? An exploration of a public health indicator for sight loss due to age-related macular degeneration in England. Eye (Lond) 2023; 37:516-523. [PMID: 35197562 PMCID: PMC9905582 DOI: 10.1038/s41433-022-01933-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 11/19/2021] [Accepted: 01/11/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Age-related macular degeneration accounts for the majority of severe sight impairment and sight impairment registration and certifications in adults in the UK [1, 2]. Whilst these treatments are effective in arresting nAMD progression, there is currently no treatment for GA [1, 3, 4]. METHODS This paper provides an update to the data collected by Bunce et al. [3] and details the number of people certified together with incidence rates for the various types of AMD by: sex, sight impairment status, and for all ages using the 2016/2017 and 2017/2018 CVI due to AMD data for England from the Moorfields Eye Hospital, supplemented with 2017-2018 PHOF indicator 4.12i/E12a data. The study population includes individuals of all ages in England who were newly certified with visual impairment due to AMD. RESULTS Between 2016 and 2017, CVIs due to AMD totalled to 11,215; between 2017 and 2018, CVIs due to AMD totalled to 10,914. The PHOF indicator 4.12i/E12a assessed showed that overall rates of AMD certifications have steadily declined in England from 131.5 per 100,000 in 2010/2011 to 106.7 per 100,000 in 2017/2018. CONCLUSION As treatment is available for nAMD, a reduction in nAMD certifications could be expected; however, growth of the elderly population in England combined with there currently being no treatment available for GA means AMD certification rates should be increasing. Therefore, it is postulated that not all cases of AMD are being certified and registered with some likely going undiagnosed.
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Affiliation(s)
- Kelsey Brown
- Kings College London School of Population Health and Environmental sciences, Faculty of Life Science and Medicine, London, SW10 0LB, UK.
| | - Catey Bunce
- grid.5072.00000 0001 0304 893XResearch Data & Statistics Unit, Royal Marsden Clinical Trials Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - Oluwaseun Onabanjo
- grid.13097.3c0000 0001 2322 6764Kings College London School of Population Health and Environmental sciences, Faculty of Life Science and Medicine, London, UK
| | - Stacey A. Strong
- grid.451056.30000 0001 2116 3923NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Praveen J. Patel
- grid.451056.30000 0001 2116 3923NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
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14
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Seyyar S, Mete A, Tıskaoğlu N. Evaluation of YouTube videos as a patient information source on intravitreal injection procedures. J Fr Ophtalmol 2022; 45:748-755. [DOI: 10.1016/j.jfo.2022.02.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/14/2022] [Accepted: 02/14/2022] [Indexed: 12/01/2022]
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15
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Ma D, Kumar M, Khetan V, Sen P, Bhende M, Chen S, Yu TTL, Lee S, Navajas EV, Matsubara JA, Ju MJ, Sarunic MV, Raman R, Beg MF. Clinical explainable differential diagnosis of polypoidal choroidal vasculopathy and age-related macular degeneration using deep learning. Comput Biol Med 2022; 143:105319. [PMID: 35220077 DOI: 10.1016/j.compbiomed.2022.105319] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study aims to achieve an automatic differential diagnosis between two types of retinal pathologies with similar pathological features - Polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) from volumetric optical coherence tomography (OCT) images, and identify clinically-relevant pathological features, using an explainable deep-learning-based framework. METHODS This is a retrospective study with data from a cross-sectional cohort. The OCT volume of 73 eyes from 59 patients was included in this study. Disease differentiation was achieved through single-B-scan-based classification followed by a volumetric probability prediction aggregation step. We compared different labeling strategies with and without identifying pathological B-scans within each OCT volume. Clinical interpretability was achieved through normalized aggregation of B-scan-based saliency maps followed by maximum-intensity-projection onto the en face plane. We derived the PCV score from the proposed differential diagnosis framework with different labeling strategies. The en face projection of saliency map was validated with the pathologies identified in Indocyanine green angiography (ICGA). RESULTS Model trained with both labeling strategies achieved similar level differentiation power (>90%), with good correspondence between pathological features detected from the projected en face saliency map and ICGA. CONCLUSIONS This study demonstrated the potential clinical application of non-invasive differential diagnosis using AI-driven OCT-based analysis, with minimal requirement of labeling efforts, along with clinical explainability achieved through automatically detected disease-related pathologies.
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Affiliation(s)
- Da Ma
- Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA; School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada.
| | - Meenakshi Kumar
- Shri Bhagwan Mahavir Vitreoretinal Service, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Vikas Khetan
- Shri Bhagwan Mahavir Vitreoretinal Service, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Parveen Sen
- Shri Bhagwan Mahavir Vitreoretinal Service, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Muna Bhende
- Shri Bhagwan Mahavir Vitreoretinal Service, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Shuo Chen
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada
| | - Timothy T L Yu
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada
| | - Sieun Lee
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada; Mental Health & Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Eduardo V Navajas
- Department of Ophthalmology & Visual Sciences, The University of British Columbia, Vancouver, BC, Canada; University of British Columbia Vancouver General Hospital, Eye Care Centre, Vancouver, BC, Canada
| | - Joanne A Matsubara
- Department of Ophthalmology & Visual Sciences, The University of British Columbia, Vancouver, BC, Canada; University of British Columbia Vancouver General Hospital, Eye Care Centre, Vancouver, BC, Canada
| | - Myeong Jin Ju
- Department of Ophthalmology & Visual Sciences, The University of British Columbia, Vancouver, BC, Canada; University of British Columbia Vancouver General Hospital, Eye Care Centre, Vancouver, BC, Canada; School of Biomedical Engineering, University of British Columbia, BC, Canada
| | - Marinko V Sarunic
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada; Institute of Ophthalmology, University College London, London, UK; Department of Medical Physics and Biomedical Engineering, University College London, United Kingdom
| | - Rajiv Raman
- Shri Bhagwan Mahavir Vitreoretinal Service, Medical Research Foundation, Sankara Nethralaya, Chennai, India.
| | - Mirza Faisal Beg
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada.
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16
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Platelet Lysate as a Promising Medium for Nanocarriers in the Management and Treatment of Ocular Diseases. CURRENT OPHTHALMOLOGY REPORTS 2022. [DOI: 10.1007/s40135-022-00285-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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17
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Miller A, Wilneff MA, Yazji A, Petrinec E, Carbone M, Miller C, McCrossin C, Donkor R, Miller DG. Analysis of urgent follow up visits and complications after intravitreal injections: a retrospective cohort study. Int J Retina Vitreous 2022; 8:8. [PMID: 35042547 PMCID: PMC8764861 DOI: 10.1186/s40942-021-00358-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Intravitreal injections (IVIs), a common treatment in ophthalmology, result in acute complications and urgent follow-up visits causing significant burden to both patient and physician. We evaluated the incidence of acute complications following IVIs which occurred within seven days of injection. METHODS A retrospective cohort study conducted at a private retinal practice, in Cleveland, Ohio. Using the practice management software database, we examined 73,286 injections of patients with unscheduled or urgent visits within 7 days of an injection from August 1st,2018 to August 1st,2020. Data collected included: age, gender, eye, medication injected, diagnosis, reason for urgent follow-up, time between injection and urgent follow-up, and type of anesthesia administered. Data was analyzed using SPSS v.28 (SPSS Inc., Chicago IL). RESULTS Study included 73,286 injections, with 441 injections (n = 441) resulting in urgent follow-up visits (0.60%). Mean patient age was 72.1 (± 30.4) years, with 187 male (42.4%) and 254 female (57.6%) patients. IVI medications included: aflibercept (60.3%), ranibizumab (22.4%), bevacizumab (13.4%), dexamethasone intravitreal implant (2%), triamcinolone acetonide (1.6%) brolucizumab (1.59%), fluocinolone acetonide intravitreal implant 0.19 mg (0.2%), and fluocinolone acetonide intravitreal implant 0.18 mg (0.03%) (Table 1). Medications associated with urgent visits included: aflibercept (42.9%), bevacizumab (37.4%), ranibizumab (7.9%), dexamethasone intravitreal implant (6.8%), brolucizumab (2.7%), and triamcinolone acetonide (2.3%) (Table 2). Days between injection and urgent follow-up was on average 3.96 ± 2.14 days. Urgent follow-ups included blurred vision in 164 patients (37.2% of urgent visits), flashes, floaters or posterior vitreous detachment (PVD) in 55 (12.5%), pain in 42 (9.5%), 43 (9.8%) corneal abrasions, 33 (7.5%) subconjunctival hemorrhages, corneal dryness or foreign body sensation in 30 (6.6%), endophthalmitis in 20 (4.5%), 18 (4.1%)vitreous hemorrhages, iritis or uveitis in 11 (2.5%), miscellaneous complications in 9 (2.0%), 7 (1.6%) elevated intraocular pressures, choroidal neovascular membrane in 4 (0.9%), 4 (0.9%) retinal detachments or tears, and 2 (0.45%) traumatic cataracts (Table 3). CONCLUSION IVIs resulted in 0.60% urgent/unscheduled follow-up visits within 7 days of injection. Most common causes were blurred vision and symptoms of PVD.
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Affiliation(s)
- Alexander Miller
- Northeastern Ohio Medical University, Rootstown, OH, USA
- University Hospital - Mason Eye Clinic, Columbia, MO, USA
| | - Matthew A Wilneff
- Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA
| | - Andrew Yazji
- Northeastern Ohio Medical University, Rootstown, OH, USA
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA
| | - Emily Petrinec
- Northeastern Ohio Medical University, Rootstown, OH, USA
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA
| | - Michael Carbone
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | - Chase Miller
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA
| | | | - Richard Donkor
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA
| | - David G Miller
- Retina Associates of Cleveland Inc, 24075 Commerce Park, Cleveland, OH, USA.
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18
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Daien V, Finger RP, Talks JS, Mitchell P, Wong TY, Sakamoto T, Eldem BM, Korobelnik JF. Evolution of treatment paradigms in neovascular age-related macular degeneration: a review of real-world evidence. Br J Ophthalmol 2021; 105:1475-1479. [PMID: 33130553 PMCID: PMC8543219 DOI: 10.1136/bjophthalmol-2020-317434] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/27/2020] [Accepted: 10/03/2020] [Indexed: 11/20/2022]
Abstract
The aim of this work was to evaluate the contribution of real-world evidence (RWE) in changing anti-vascular endothelial growth factor (VEGF) therapy treatment practices and improving real-world treatment strategies for neovascular age-related macular degeneration (nAMD).A PubMed literature search was performed to review the large number of English-language studies conducted to investigate the real-world effectiveness of anti-VEGF (aflibercept and ranibizumab) treatment paradigms available for nAMD.The evidence for pro re nata (PRN), treat-and-extend (T&E) and fixed bimonthly dosing regimens for anti-VEGF treatment of nAMD were reviewed and findings are summarised. RWE demonstrated that T&E regimens optimise visual outcomes while reducing burden on patients, clinics and physicians, compared with both fixed-dose and PRN regimens.RWE has helped to develop and improve real-world treatment strategies in nAMD, with the aim of optimising visual outcomes and reducing treatment burden in clinical practice. Of the various regimens, a T&E regimen is most likely to adequately balance clinical outcomes and treatment burden for patients with nAMD.
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Affiliation(s)
- Vincent Daien
- Department of Ophthalmology, Gui de Chauliac Hospital, Montpellier, France
- The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, Australia
| | - Robert P Finger
- Department of Ophthalmology, University of Bonn, Bonn, Germany
| | - James S Talks
- Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Paul Mitchell
- Centre for Vision Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia
| | - Tien Y Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Duke-NUS Medical School, Singapore
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Bora M Eldem
- Faculty of Medicine, Ophthalmology Department, Hacettepe University, Ankara, Turkey
| | - Jean-François Korobelnik
- Service D'ophtalmologie, CHU de Bordeaux, Bordeaux, France
- Bordeaux Population Health Research Center, University of Bordeaux, Talence, France
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19
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Sanabria MR, Alonso-Tarancón AM, Calles-Monar PS, Ibañez P, García de Arriba S, Alvarez N, Piñuel JA, Coco RM, Fernández I. Silicone microbubbles after anti-vascular endothelial growth factor injections in patients with wet age-related macular degeneration: incidence, quantification and secondary optical coherence tomography artfacts. Acta Ophthalmol 2021; 99:e1051-e1055. [PMID: 33421336 DOI: 10.1111/aos.14743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 12/05/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE To report the incidence and quantity of silicone oil microbubbles and the relationship with the number of intravitreal anti-vascular endothelial growth factor (VEGF) injections and evaluate if microbubbles induce artefacts on optical coherence tomography (OCT) images. METHODS Observational, descriptive, cross-sectional study. Patients with wet age-related macular degeneration were included who had been treated for 1 year minimally with anti-VEGF injections repackaged in the hospital pharmacy. Detection and quantification of silicone microbubbles by mydriatic biomicroscopic examination were conducted 1 month after the last injection. The numbers of microbubbles were quantified on a scale of 0-3: 0, none; 1 scarce (1-10 microbubbles); 2 moderate (10-30); or 3 numerous (>30). Shadowing on OCT images was classified as 0-3: 0, none; 1 obscuring some retinal layers; 2 obscuring all retinal layers; or 3 obscuring the retinal thickness. RESULTS The study included 142 eyes of 98 patients (mean age, 82.4 years + 7.3; range, 65-97) treated with 2377 injections. Microbubbles were detected in 127 (89.4%) eyes, 62 (43.6%) with numerous microbubbles and 36 (25.4%) and 29 (20.4%), respectively, with scarce and moderate numbers. A positive correlation was found between the numbers of injections and intravitreal silicone (rho, 0.7). Optical coherence tomography (OCT) artefacts were detected in 11 eyes; the artefacts obscured all retinal layers in three eyes. No significant relationship could be established between the appearance of floaters and the microbubbles. CONCLUSION The presence and number of silicone microbubbles were correlated with the number of intravitreal injections. Microbubbles can produce OCT artefacts, which can hinder the treatment decision.
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Affiliation(s)
- Maria R Sanabria
- Palencia University Hospital Complex, Palencia, Spain
- Institute of Applied Ophthalmobiology, University of Valladolid, Valladolid, Spain
| | | | | | | | | | - Nuria Alvarez
- Palencia University Hospital Complex, Palencia, Spain
| | | | - Rosa M Coco
- Institute of Applied Ophthalmobiology, University of Valladolid, Valladolid, Spain
- OFTARED Health Research Thematic Network, Carlos III Health Institute, Madrid, Spain
| | - Itziar Fernández
- Institute of Applied Ophthalmobiology, University of Valladolid, Valladolid, Spain
- Department of Statistics, University of Valladolid, Valladolid, Spain
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20
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Lee RH, Tirpack AR, Davis JL, Sayed MS, Chopra V, Gedde SJ. Posterior cyclodialysis cleft following intravitreal injection. Am J Ophthalmol Case Rep 2021; 23:101134. [PMID: 34169182 PMCID: PMC8208962 DOI: 10.1016/j.ajoc.2021.101134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/02/2021] [Accepted: 05/27/2021] [Indexed: 11/15/2022] Open
Abstract
Purpose To describe an unusual complication of an intravitreal injection. Observation Here, we report a case of hypotony following an intravitreal injection due to a posterior cyclodialysis cleft and describe its management and resolution. Conclusions Posterior cyclodialysis clefts are a rare cause of hypotony following intravitreal injection. Posterior clefts may not be visualized by conventional gonioscopy. Ultrasound biomicroscopy may be useful in aiding diagnosis. Importance This report highlights a rare cause of hypotony following intravitreal injection and illustrates the importance of adjunctive imaging for accurate diagnosis.
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Affiliation(s)
- Rachel H Lee
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Aubrey R Tirpack
- Department of Ophthalmology, Cincinnati Eye Institute, Cincinnati, OH, USA
| | - Janet L Davis
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Mohamed S Sayed
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Vikas Chopra
- Department of Ophthalmology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Steven J Gedde
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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21
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Shokr H, Gherghel D. European Society of Cardiology/European Society of Hypertension versus the American College of Cardiology/American Heart Association guidelines on the cut-off values for early hypertension: a microvascular perspective. Sci Rep 2021; 11:3473. [PMID: 33568754 PMCID: PMC7876123 DOI: 10.1038/s41598-021-83096-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/11/2021] [Indexed: 11/09/2022] Open
Abstract
The aim of this study was to investigate retinal and peripheral microvascular function in asymptomatic individuals that fall into different BP groups when using either the ESC/ESH or the ACC/AHA guidelines. Retinal and peripheral microvascular function was assessed in 358 participants by means of dynamic retinal vessel analysis and digital thermal monitoring, respectively. Blood pressure and lipid panel were also evaluated. Retinal vascular function measured in all groups belonging to the ACC/ASH classifications were within the normal values for age-matched normal population. Individuals classed as grade 1 hypertension according to the ESC/ESH guidelines, however, exhibited a significantly decreased artery baseline (p = 0.0004) and MC (p = 0.040), higher slopeAD (p = 0.0018) and decreased vein MC (p = 0.0446) compared to age matched normal individuals. In addition, they also had significant lower artery baseline, artery BDF, MD and MC than individuals classed as stage 1 hypertension based on the ACC/ASH guidelines (p = 0.00022, p = 0.0179, p = 0.0409 and p = 0.0329 respectively). Peripheral vascular reactivity (aTR) was lower in ESC /ESH grade I compared to those graded ACC/ASH stage I hypertension (p = 0.0122). The conclusion of this study is that microvascular dysfunctions is present at multiple levels only in individuals with ESC/ESH grade 1 hypertension. This observation could be important when deciding personalised care in individuals with early hypertensive changes.
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Affiliation(s)
- H Shokr
- Vascular Research Laboratory, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - D Gherghel
- Vascular Research Laboratory, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
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22
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Lin X, Lou L, Miao Q, Wang Y, Jin K, Shan P, Xu Y. The pattern and gender disparity in global burden of age-related macular degeneration. Eur J Ophthalmol 2020; 31:1161-1170. [PMID: 32498618 DOI: 10.1177/1120672120927256] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE To explore the trend patterns and gender disparity in global burden of age-related macular degeneration (AMD) by year, age, and socioeconomic status using disability-adjusted life-years (DALYs) from Global Burden of Disease (GBD) study 2017. METHODS DALYs and impairment data caused by AMD were extracted from GBD Study 2017. World Bank income level (WBIL) and human development index (HDI) in 2017 were cited as indicators of socioeconomic status. The Gini coefficients and the concentration indexes were calculated to unveil trends in between-country inequality. The association between gender inequality and socioeconomic levels was analyzed by Pearson correlation. RESULTS Total age-standardized DALYs of AMD showed a slightly descending pattern in recent years. However, gender disparity has existed since 1990 for almost three decades, with female being more heavily impacted. This pattern became more obvious with aging and varied among different WHO and WBIL regions. Meanwhile, female subjects tended to have higher vision impairments. Gini coefficients of AMD burden increased from 0.423 to 0.448, while the ones of female-to-male ratio fluctuated around 0.11 between 1990 and 2017, with concentration indexes changing from 0.024 to -0.057 and 0.046 to 0.029 respectively. Female-minus-male difference (r = 0.1721, p = 0.0195) and female-to-male ratio (r = 0.2072, p = 0.0048) of age-standardized DALYs rates were positively related to HDI. CONCLUSIONS Though global AMD health care is progressing, gender imbalance in disease burden of AMD distribution barely improved. Gender sensitive health policy should be emphasized for the increasing elder population and relieving the higher AMD burden of females.
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Affiliation(s)
- Xiling Lin
- Department of Endocrinology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Lixia Lou
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Qi Miao
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Yijie Wang
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Kai Jin
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Pengfei Shan
- Department of Endocrinology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
| | - Yufeng Xu
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou, Zhejiang, China
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23
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Zhong P, He M, Yu H, Wu Q, Peng Q, Huang M, Xue Y, Yang X. A Meta-Analysis of Cardiovascular Events Associated with Intravitreal Anti-VEGF Treatment in Patients with Retinal Vein Occlusion. Curr Eye Res 2020; 45:615-622. [PMID: 31670978 DOI: 10.1080/02713683.2019.1687727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/17/2019] [Accepted: 10/25/2019] [Indexed: 02/05/2023]
Abstract
Purpose: Retinal vein occlusion is associated with an increased risk of cardiovascular diseases. Anti-vascular endothelial growth factor has been widely used as a treatment option. However, the systemic safety of intravitreal anti-vascular endothelial growth factor for retinal vein occlusion patients is still unclear.Materials and Methods: A meta-analysis was conducted to investigate all randomized controlled trials published up to February 2019 of retinal vein occlusion patients who received intravitreal anti-vascular endothelial growth factor vs. control treatments. Fixed effect models were used and results were reported as odds ratios and 95% confidence intervals.Results: Eight trials that evaluated 2320 patients were retrieved. Anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events (odds ratio,1.54; 95% confidence interval, 0.66-3.57), hypertension (odds ratio, 0.92; 95% confidence interval, 0.63-1.33), or heart rate disorders (odds ratio,1.53; 95% confidence interval, 0.37-6.28) when compared with control treatment. Subgroup analyses did not show a significant increase of cardiovascular events in aflibercept (odds ratio,1.96; 95% confidence interval, 0.44-8.81) vs. ranibizumab trials (odds ratio, 1.47; 95% confidence interval, 0.54-4.02); 0.5 mg ranibizumab trials (odds ratio, 1.73; 95% confidence interval, 0.61-4.96) vs. 0.3 mg ranibizumab trials (odds ratio, 0.70; 95% confidence interval, 0.14-3.59); nor branch retinal vein occlusion (odds ratio, 1.32; 95% confidence interval, 0.40-4.33) vs. central retinal vein occlusion trials (odds ratio, 1.93; 95% confidence interval, 0.59-6.29).Conclusions: Intravitreal administration of anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events, hypertension or heart rate disorders in retinal vein occlusion patients.
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Affiliation(s)
- Pingting Zhong
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Miao He
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Honghua Yu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qiaowei Wu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Southern Medical University, Guangzhou, China
| | - Qingsheng Peng
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Manqing Huang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yunlian Xue
- Statistics Office, Information and Statistics Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaohong Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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24
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Bhuiyan A, Wong TY, Ting DSW, Govindaiah A, Souied EH, Smith RT. Artificial Intelligence to Stratify Severity of Age-Related Macular Degeneration (AMD) and Predict Risk of Progression to Late AMD. Transl Vis Sci Technol 2020; 9:25. [PMID: 32818086 PMCID: PMC7396183 DOI: 10.1167/tvst.9.2.25] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 02/21/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose To build and validate artificial intelligence (AI)-based models for AMD screening and for predicting late dry and wet AMD progression within 1 and 2 years. Methods The dataset of the Age-related Eye Disease Study (AREDS) was used to train and validate our prediction model. External validation was performed on the Nutritional AMD Treatment-2 (NAT-2) study. First Step An ensemble of deep learning screening methods was trained and validated on 116,875 color fundus photos from 4139 participants in the AREDS study to classify them as no, early, intermediate, or advanced AMD and further stratified them along the AREDS 12 level severity scale. Second step: the resulting AMD scores were combined with sociodemographic clinical data and other automatically extracted imaging data by a logistic model tree machine learning technique to predict risk for progression to late AMD within 1 or 2 years, with training and validation performed on 923 AREDS participants who progressed within 2 years, 901 who progressed within 1 year, and 2840 who did not progress within 2 years. For those found at risk of progression to late AMD, we further predicted the type (dry or wet) of the progression of late AMD. Results For identification of early/none vs. intermediate/late (i.e., referral level) AMD, we achieved 99.2% accuracy. The prediction model for a 2-year incident late AMD (any) achieved 86.36% accuracy, with 66.88% for late dry and 67.15% for late wet AMD. For the NAT-2 dataset, the 2-year late AMD prediction accuracy was 84%. Conclusions Validated color fundus photo-based models for AMD screening and risk prediction for late AMD are now ready for clinical testing and potential telemedical deployment. Translational Relevance Noninvasive, highly accurate, and fast AI methods to screen for referral level AMD and to predict late AMD progression offer significant potential improvements in our care of this prevalent blinding disease.
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Affiliation(s)
- Alauddin Bhuiyan
- iHealthScreen Inc., New York, NY, USA
- New York University, New York, NY, USA
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
- DUKE-NUS School of Medicine, Singapore
| | - Daniel Shu Wei Ting
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
- DUKE-NUS School of Medicine, Singapore
| | | | - Eric H. Souied
- Department of Ophthalmology, Hôpital Intercommunal de Créteil, Université, Creteil, France
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25
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Horita S, Watanabe M, Katagiri M, Nakamura H, Haniuda H, Nakazato T, Kagawa Y. Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye-drops among rats, rabbits and monkeys. Pharmacol Res Perspect 2019; 7:e00545. [PMID: 31763044 PMCID: PMC6864407 DOI: 10.1002/prp2.545] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/23/2019] [Accepted: 10/23/2019] [Indexed: 11/13/2022] Open
Abstract
Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in patients over the age of 60 years. Choroidal neovascularization (CNV) is the hallmark of neovascular AMD and vascular endothelial growth factor (VEGF) plays a causal role in the formation of CNV. Although regorafenib and pazopanib, small molecule VEGF receptor (VEGFR) inhibitors, were developed as eye-drops, their efficacies were insufficient in clinical. In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser-induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the posterior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was nano-crystalized to improve its drug delivery to the posterior eye tissues. The nano-crystalized formulation of regorafenib showed higher concentrations in the posterior segments in rabbits compared to its microcrystal suspension. From these studies, large interspecies differences were found in ocular delivery to the posterior segments after ocular instillation. Such large interspecies difference could be the reason for the insufficient efficacies of regorafenib and pazopanib in clinical studies. Nano-crystallization was suggested to be one of the effective ways to overcome this issue.
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Affiliation(s)
- Shinya Horita
- R&D DivisionKyowa Kirin Co., Ltd.Sunto‐gunShizuokaJapan
- Department of Clinical PharmaceuticsSchool of Pharmaceutical SciencesUniversity of ShizuokaSunto‐gunShizuokaJapan
| | - Miwa Watanabe
- R&D DivisionKyowa Kirin Co., Ltd.Sunto‐gunShizuokaJapan
| | - Mai Katagiri
- R&D DivisionKyowa Kirin Co., Ltd.Sunto‐gunShizuokaJapan
| | | | - Hiroki Haniuda
- Production DivisionKyowa Kirin Co., Ltd.Sunto‐gunShizuokaJapan
| | | | - Yoshiyuki Kagawa
- Department of Clinical PharmaceuticsSchool of Pharmaceutical SciencesUniversity of ShizuokaSunto‐gunShizuokaJapan
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26
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Keel S, Li Z, Scheetz J, Robman L, Phung J, Makeyeva G, Aung K, Liu C, Yan X, Meng W, Guymer R, Chang R, He M. Development and validation of a deep-learning algorithm for the detection of neovascular age-related macular degeneration from colour fundus photographs. Clin Exp Ophthalmol 2019; 47:1009-1018. [PMID: 31215760 DOI: 10.1111/ceo.13575] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 05/24/2019] [Accepted: 06/13/2019] [Indexed: 12/17/2022]
Abstract
IMPORTANCE Detection of early onset neovascular age-related macular degeneration (AMD) is critical to protecting vision. BACKGROUND To describe the development and validation of a deep-learning algorithm (DLA) for the detection of neovascular age-related macular degeneration. DESIGN Development and validation of a DLA using retrospective datasets. PARTICIPANTS We developed and trained the DLA using 56 113 retinal images and an additional 86 162 images from an independent dataset to externally validate the DLA. All images were non-stereoscopic and retrospectively collected. METHODS The internal validation dataset was derived from real-world clinical settings in China. Gold standard grading was assigned when consensus was reached by three individual ophthalmologists. The DLA classified 31 247 images as gradable and 24 866 as ungradable (poor quality or poor field definition). These ungradable images were used to create a classification model for image quality. Efficiency and diagnostic accuracy were tested using 86 162 images derived from the Melbourne Collaborative Cohort Study. Neovascular AMD and/or ungradable outcome in one or both eyes was considered referable. MAIN OUTCOME MEASURES Area under the receiver operating characteristic curve (AUC), sensitivity and specificity. RESULTS In the internal validation dataset, the AUC, sensitivity and specificity of the DLA for neovascular AMD was 0.995, 96.7%, 96.4%, respectively. Testing against the independent external dataset achieved an AUC, sensitivity and specificity of 0.967, 100% and 93.4%, respectively. More than 60% of false positive cases displayed other macular pathologies. Amongst the false negative cases (internal validation dataset only), over half (57.2%) proved to be undetected detachment of the neurosensory retina or RPE layer. CONCLUSIONS AND RELEVANCE This DLA shows robust performance for the detection of neovascular AMD amongst retinal images from a multi-ethnic sample and under different imaging protocols. Further research is warranted to investigate where this technology could be best utilized within screening and research settings.
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Affiliation(s)
- Stuart Keel
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Zhixi Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
| | - Jane Scheetz
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Liubov Robman
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia.,Monash University Melbourne, Melbourne, Victoria, Australia
| | - James Phung
- Monash University Melbourne, Melbourne, Victoria, Australia
| | - Galina Makeyeva
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - KhinZaw Aung
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Chi Liu
- Healgoo Interactive Medical Technology Co. Ltd., Guangzhou, China
| | - Xixi Yan
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Wei Meng
- Healgoo Interactive Medical Technology Co. Ltd., Guangzhou, China
| | - Robyn Guymer
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | - Robert Chang
- Department of Ophthalmology, Byers Eye Institute at Stanford University, Palo Alto, California
| | - Mingguang He
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia.,State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China
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27
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Borkenstein AF, Borkenstein E. Cataract surgery with implantation of a high-add intraocular lens LENTIS® MAX LS-313 MF80 in end-stage, age-related macular degeneration: A case report of magnifying surgery. Clin Case Rep 2019; 7:74-78. [PMID: 30656012 PMCID: PMC6332778 DOI: 10.1002/ccr3.1912] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 11/05/2022] Open
Abstract
A new treatment option for cataracts and advanced ARMD: the simultaneous intravitreal injection of anti-vascular endothelial growth factor and implantation of a high-add IOL. We believe major opportunities arise from a new subcategory in cataract surgery-called magnifying surgery (MAGS). Our case proves the potential of this brand-new technology.
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Affiliation(s)
- Andreas F. Borkenstein
- Borkenstein & Borkenstein, Private PracticePrivatklinik der Kreuzschwestern GrazGrazAustria
| | - Eva‐Maria Borkenstein
- Borkenstein & Borkenstein, Private PracticePrivatklinik der Kreuzschwestern GrazGrazAustria
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28
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Song H, Bush RA, Zeng Y, Qian H, Wu Z, Sieving PA. Trans-ocular Electric Current In Vivo Enhances AAV-Mediated Retinal Gene Transduction after Intravitreal Vector Administration. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2018; 13:77-85. [PMID: 30719486 PMCID: PMC6350231 DOI: 10.1016/j.omtm.2018.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 12/14/2018] [Indexed: 01/31/2023]
Abstract
Adeno-associated virus (AAV) vector-mediated gene delivery is a promising approach for therapy, but implementation in the eye currently is hampered by the need for delivering the vector underneath the retina, using surgical application into the subretinal space. This limits the extent of the retina that is treated and may cause surgical injury. Vector delivery into the vitreous cavity would be preferable because it is surgically less invasive and would reach more of the retina. Unfortunately, most conventional, non-modified AAV vector serotypes penetrate the retina poorly from the vitreous; this limits efficient transduction and expression by target cells (retinal pigment epithelium and photoreceptors). We developed a method of applying a small and safe electric current across the intact eye in vivo for a brief period following intravitreal vector administration. This significantly improved AAV-mediated transduction of retinal cells in wild-type mice following intravitreal delivery, with gene expression in retinal pigment epithelium and photoreceptor cells. The low-level current had no adverse effects on retinal structure and function. This method should be generally applicable for other AAV serotypes and may have broad application in both basic research and clinical studies.
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Affiliation(s)
- Hongman Song
- Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA
| | - Ronald A Bush
- Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA
| | - Yong Zeng
- Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA
| | - Haohua Qian
- National Eye Institute, NIH, Bethesda, MD 20892, USA
| | - Zhijian Wu
- National Eye Institute, NIH, Bethesda, MD 20892, USA
| | - Paul A Sieving
- Section for Translational Research on Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA.,National Eye Institute, NIH, Bethesda, MD 20892, USA
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29
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Du XL, Li WB, Hu BJ. Application of artificial intelligence in ophthalmology. Int J Ophthalmol 2018; 11:1555-1561. [PMID: 30225234 PMCID: PMC6133903 DOI: 10.18240/ijo.2018.09.21] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022] Open
Abstract
Artificial intelligence is a general term that means to accomplish a task mainly by a computer, with the least human beings participation, and it is widely accepted as the invention of robots. With the development of this new technology, artificial intelligence has been one of the most influential information technology revolutions. We searched these English-language studies relative to ophthalmology published on PubMed and Springer databases. The application of artificial intelligence in ophthalmology mainly concentrates on the diseases with a high incidence, such as diabetic retinopathy, age-related macular degeneration, glaucoma, retinopathy of prematurity, age-related or congenital cataract and few with retinal vein occlusion. According to the above studies, we conclude that the sensitivity of detection and accuracy for proliferative diabetic retinopathy ranged from 75% to 91.7%, for non-proliferative diabetic retinopathy ranged from 75% to 94.7%, for age-related macular degeneration it ranged from 75% to 100%, for retinopathy of prematurity ranged over 95%, for retinal vein occlusion just one study reported ranged over 97%, for glaucoma ranged 63.7% to 93.1%, and for cataract it achieved a more than 70% similarity against clinical grading.
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Affiliation(s)
- Xue-Li Du
- Tianjin Medical University Eye Hospital, Tianjin 300384, China
| | - Wen-Bo Li
- Tianjin Medical University Eye Hospital, Tianjin 300384, China
| | - Bo-Jie Hu
- Tianjin Medical University Eye Hospital, Tianjin 300384, China
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Lu Q, Lu L, Chen B, Chen W, Lu P. Efficacy comparison of intravitreal injections of conbercept and ranibizumab for severe proliferative diabetic retinopathy. Can J Ophthalmol 2018; 54:291-296. [PMID: 31109466 DOI: 10.1016/j.jcjo.2018.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 06/05/2018] [Accepted: 06/13/2018] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To determine the efficacy of preoperative intravitreal injections of conbercept (IVC) and ranibizumab (IVR) on postoperative best-corrected visual acuity (BCVA), vitreous hemorrhage (VH), and neovascular glaucoma (NVG) in a population with proliferative diabetic retinopathy (PDR) undergoing vitrectomy. DESIGN Retrospective, cross-sectional study. PARTICIPANTS 386 patients with severe PDR (428 eyes). METHODS The patients who did not receive IVC or IVR were assigned to group A (125 eyes), the patients who received IVR (0.5 mg) were assigned to group B (146 eyes), and the patients who received IVC (0.5 mg) were assigned to group C (157 eyes). RESULTS Both group B (p = 0.009) and group C (p = 0.002) had better postoperative BCVA than group A. Early postoperative VH occurred significantly less frequently in group B (22.60%; p = 0.007) and group C (12.10%; p < 0.001) than in group A (37.60%). Importantly, the incidences of postoperative NVG in group B (2.74%; p = 0.001) and group C (0.64%; p < 0.001) were both significantly less than that in group A (15.20%). However, there was no significant difference in the incidences of postoperative NVG between groups B and C (p = 0.325). CONCLUSIONS The contribution of preoperative IVC to an improved BCVA for patients with severe PDR was better than that of IVR, and IVC decreased the risk of postoperative early VH. Pretreatment with IVC or IVR reduced the incidence of postoperative NVG based on the 24-month follow-up data.
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Affiliation(s)
- Qianyi Lu
- Department of Ophthalmology, First Affiliated Hospital of Soochow University, Suzhou
| | - Li Lu
- Department of Ophthalmology, Anhui Provincial Hospital, First Affiliated Hospital of University of Science and Technology of China, Hefei
| | - Bin Chen
- Department of Ophthalmology, Changshu No. 1 People's Hospital, Changshu
| | - Wei Chen
- Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, China
| | - PeiRong Lu
- Department of Ophthalmology, First Affiliated Hospital of Soochow University, Suzhou.
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Budzinskaya MV, Plyukhova AA, Sorokin PA. [Anti-VEGF therapy resistance in neovascular age-related macular degeneration]. Vestn Oftalmol 2018; 133:103-108. [PMID: 28980574 DOI: 10.17116/oftalma20171334103-108] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
With account to the increase in the elderly population in most of the developed countries, the WHO defines age-related macular degeneration (AMD) as one of the main causes of blindness in the world. A large percentage of disability is accounted for by exudative, or neovascular, form of AMD. Today, a total of 5 anti-VEGF drugs exist that are recommended for treatment of exudative AMD: pegaptanib, ranibizumab, bevacizumab, aflibercept, and conbercept. Despite significant progress in the treatment of neovascular AMD yielded by the introduction into clinical practice of anti-VEGF drugs, some patients report a lack (down to complete lack) of response with standard treatment patterns and even a decrease in treatment efficacy after repeated intravitreal injections.
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Affiliation(s)
- M V Budzinskaya
- Research Institute of Eye Disease, 11 A, B, Rossolimo St., Moscow, Russia, 119021
| | - A A Plyukhova
- Research Institute of Eye Disease, 11 A, B, Rossolimo St., Moscow, Russia, 119021
| | - P A Sorokin
- Eyesight Recovery Center, 11 A, B, Rossolimo St., Moscow, Russia, 119021
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Mohamad NA, Ramachandran V, Ismail P, Mohd Isa H, Chan YM, Ngah NF, Md Bakri N, Ching SM, Hoo FK, Wan Sulaiman WA. Prevalence and treatment patterns of ranibizumab and photodynamic therapy in a tertiary care setting in Malaysia. Int J Ophthalmol 2017; 10:1889-1897. [PMID: 29259909 PMCID: PMC5733518 DOI: 10.18240/ijo.2017.12.16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 08/22/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To describe the prevalence and changes in treatment patterns of ranibizumab and photodynamic therapy (PDT) among retinal disease patients who attended the Ophthalmology Clinic in the tertiary care Hospital Selayang from 2010 to 2014. METHODS Study subjects were recruited retrospectively using the Electronic Medical Record (EMR) database software in Hospital Selayang. Demographic data, medical history, diagnostic procedure, treatments and diagnosis of patients were recorded. RESULTS The five-year analysis included 821 patients with a mean age of 65.9±11.73y. Overall, there were a higher number of males (63.1%) and a higher number of Chinese (47.4%) patients. Among the 821 patients, 62.9% received ranibizumab injection followed by 19.2% PDT therapy and 17.9% had ranibizumab combined with PDT therapy. Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) were the most common retinal eye diseases reported, recording prevalence of 25.0% and 45.6%, respectively. The trend in ranibizumab treatment was reported to increase while PDT showed a decrease in trend from year 2010 to 2014. In terms of treatment, following multiple logistic regression, AMD was associated with the subjects being more likely to have received ranibizumab monotherapy (P<0.001) while PCV was associated with more likely to have received PDT (P<0.001) and PDT combined with ranibizumab therapy (P<0.001). CONCLUSION The tertiary care setting in Malaysia is consistent with management of patients from other countries whereby ranibizumab is the most common treatment given to patients with AMD, while PCV patients most commonly receive PDT and ranibizumab combined with PDT therapy.
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Affiliation(s)
- Nur Afiqah Mohamad
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Vasudevan Ramachandran
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Patimah Ismail
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Hazlita Mohd Isa
- Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur 56000, Malaysia
| | - Yoke Mun Chan
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Nor Fariza Ngah
- Department of Ophthalmology, Hospital Selayang, Lebuhraya Selayang-Kepong, Batu Caves 68100, Malaysia
| | - Norshakimah Md Bakri
- Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Siew Mooi Ching
- Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Fan Kee Hoo
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
| | - Wan Aliaa Wan Sulaiman
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400, Malaysia
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Intravitreal Bevacizumab and Cardiovascular Risk in Patients with Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies. Drug Saf 2017; 39:517-41. [PMID: 26951234 DOI: 10.1007/s40264-016-0408-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Intravitreal bevacizumab (IVTB) is used to treat age-related macular degeneration (ARMD), although its use is off-label and its cardiovascular safety has not been unequivocally established. OBJECTIVES Our objective was to assess the cardiovascular safety of IVTB in patients with ARMD. METHODS We conducted a systematic review and meta-analysis of published randomized controlled trials (RCTs) and observational studies. RESULTS Of the 2028 non-duplicate records, five RCTs versus ranibizumab (N = 3038, 12/24 months), four RCTs comparing different regimens (N = 809, 12/23 months), one RCT versus pegaptanib, photodynamic therapy (PDT), or sham (N = 131, 12 months), and three observational studies versus PDT, ranibizumab, or pegaptanib (~150,000 or 1666 patients/12 months and 317 patients/1-2 years, respectively) had a low risk of bias/high quality and ≥20 patients per arm with ≥6 months and ≥3 injections of treatment. RCT-based comparisons with PDT or pegaptanib are negligible. Observational data have not demonstrated differences [all-cause mortality, myocardial infarction (MI), stroke], but the level of evidence is "very low" (imprecise, indirect). RCT-based comparisons with ranibizumab did not demonstrate differences regarding some outcomes, although certain point estimates were at the level of a relevant harm/benefit [all-cause mortality odds ratio (OR) 1.103, 95 % confidence interval (CI) 0.641-1.898; vascular mortality OR 1.380, 95 % CI 0.476-3.997; MI OR 0.551, 95 % CI 0.265-1.146; stroke OR 0.657, 95 % CI 0.260-1.660; transitory ischemic attack OR 1.536, 95 % CI 0.444-5.313; atherothrombotic events (ATEs) OR 1.007, 95 % CI 0.641-1.593; venous thromboembolism OR 2.325, 95 % CI 0.963-5.612] or suggested a higher risk with bevacizumab (hypertension OR 7.512, 95 % CI 1.056-52.3), but estimates were based on sparse data, were extremely imprecise, and commonly exhibited considerable heterogeneity/inconsistency. The level of evidence per outcome was "low" or "very low". Observational data did not demonstrate difference (all-cause mortality, MI, stroke), or suggested a higher risk with bevacizumab (ATE), but were imprecise and indirect (level of evidence "very low"). RCT-based comparisons of different IVTB regimens suffered from the same limitations. CONCLUSION Published data on IVTB in AMRD provide only a low level of evidence on its cardiovascular safety and do not support any finite conclusions.
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Singh N, Srinivasan S, Muralidharan V, Roy R, V J, Raman R. Prevention of Age-Related Macular Degeneration. Asia Pac J Ophthalmol (Phila) 2017; 6:520-526. [PMID: 29204995 DOI: 10.22608/apo.2017416] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 11/06/2017] [Indexed: 11/08/2022] Open
Abstract
Age-related macular degeneration (AMD) compromises quality of life. However, the available therapeutic options are limited. This has led to the identification of modifiable risk factors to prevent the development or alter the natural course and prognosis of AMD. The identification and modification of risk factors has the potential for greater public health impact on reducing morbidity from AMD. Likewise, identifying the imaging clues and genetic clues could serve as a guide to recognizing the propensity for progression to severe and end stages of the disease. Several attempts, both successful and unsuccessful, have been made for interventions that could delay the progression of AMD. Of these, pharmacological interventions have shown promising results. The Age-Related Eye Disease Study 1 and 2 have shown the beneficial role of antioxidants in a selected group of patients.
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Affiliation(s)
- Niharika Singh
- Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | - Sangeetha Srinivasan
- Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | - Vinata Muralidharan
- Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | | | - Jayprakash V
- Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | - Rajiv Raman
- Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
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Watanabe K, Masafumi U, Mohamed YH, Watanabe T, Doi Y, Azusa F, Kitaoka T. Safety of Intravitreal Injection Guide. ACTA ACUST UNITED AC 2017. [DOI: 10.1177/2474126417728622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Purpose: To evaluate the safety of our developed intravitreal injection guide. Methods: Retrospective review of all case notes for consecutive patients treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections at the Department of Ophthalmology, Nagasaki University Hospital in Japan between January 2013 and December 2014. We included all patients who had at least 1 intravitreal anti-VEGF injection done within the study period. Data collected included demographics, indications of intravitreal anti-VEGF injections, type of injected drug, usage of intravitreal guide, experience of physicians, and any complication that occurred during or after the procedure. Results: The study included 256 patients (154 males and 102 females) who underwent 992 intravitreal anti-VEGF injections from January 2013 until December 2014. The mean age of the patients was 70.8 ± 11.3 years. Of total injections, 907 (91.44%) were done using the intravitreal guide, 60 (6.04%) were done without using the guide, and only 25 (2.52%) injections were not determined. Local complications include 1 (0.1%) case uveitis, 1 (0.1%) case retinal tear, and 1 (0.1%) case amaurosis fugax. There were no major complications as cataract, retinal detachment, and endophthamitis. No systemic complication was encountered. All complications occurred in the guide group without statistically significant difference in comparison to without guide group ( P = 1.0). All complications were related to experienced group without significant difference in comparison to limited experienced group ( P = .28). Conclusion: We conclude that the process of intravitreal injection with our developed intravitreal injection guide is safe and easy even for limited experienced physicians.
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Affiliation(s)
- Kei Watanabe
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Uematsu Masafumi
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yasser H. Mohamed
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Department of Ophthalmology, EL-Minia University Hospital, EL-Minia, Egypt
| | - Takehito Watanabe
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yusuke Doi
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Fujikawa Azusa
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takashi Kitaoka
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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Enseleit F, Michels S, Sudano I, Stahel M, Zweifel S, Schlager O, Becker M, Winnik S, Nägele M, Flammer AJ, Neidhart M, Graf N, Matter CM, Seifert B, Lüscher TF, Ruschitzka F. SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration. Ophthalmologica 2017; 238:205-216. [PMID: 28866675 DOI: 10.1159/000478665] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 06/12/2017] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD). METHODS In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.5 mg or bevacizumab 1.25 mg at 4-week intervals and were subsequently followed every 4 weeks and treated according to a pro re nata regime for up to 1 year. Patients with dry AMD served as controls. The primary endpoint was the change in EF assessed by flow-mediated dilatation (FMD) after 2 months of treatment with VEGF inhibitors in patients with AMD compared to patients with dry AMD. FMD was assessed with B-mode high-resolution ultrasonography of the left brachial artery. RESULTS 24 patients with neovascular AMD and 26 patients with dry ADM were included in the trial. Treatment with VEGF inhibitors did not significantly change FMD (from 4.7 ± 2.4 to 3.9 ± 1.9% after 8 weeks, p = 0.07, and to 5.1 ± 2.0% after 1 year; p = 0.93 vs. baseline, respectively). CONCLUSIONS EF did not significantly differ between patients with neovascular AMD treated with intravitreal VEGF inhibition and patients with dry AMD.
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Affiliation(s)
- Frank Enseleit
- Department of Ophthalmology, City Hospital Triemli Zurich, Zurich, Switzerland
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Zheng J, Zhao S, Yu X, Huang S, Liu HY. Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth. Theranostics 2017; 7:1373-1388. [PMID: 28435472 PMCID: PMC5399600 DOI: 10.7150/thno.17826] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 01/23/2017] [Indexed: 12/16/2022] Open
Abstract
CD44 and EpCAM play crucial roles in intraperitoneal ovarian cancer development. In this study, we developed an RNA-based bispecific CD44-EpCAM aptamer that is capable of blocking CD44 and EpCAM simultaneously by fusing single CD44 and EpCAM aptamers with a double stranded RNA adaptor. With the aid of a panel of ovarian cancer cell lines, we found that bispecific CD44-EpCAM aptamer was much more effective than either single CD44 or EpCAM aptamer in the ability to inhibit cell growth and to induce apoptosis. When these aptamers were tested in intraperitoneal ovarian cancer xenograft model, bispecific CD44-EpCAM aptamer suppressed intraperitoneal tumor outgrowth much more significantly than single CD44 and EpCAM aptamer either alone or in combination. The enhanced efficacy of bispecific CD44-EpCAM aptamer is most likely to be attributed to its increased circulation time over the single aptamers. Moreover, we showed that bispecific CD44-EpCAM aptamer exhibited no toxicity to the host and was unable to trigger innate immunogenicity. Our study suggests that bispecific CD44-EpCAM aptamer may represent a promising therapeutic agent against advanced ovarian cancer.
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Imai A, Toriyama Y, Iesato Y, Hirabayashi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Liu T, Xian X, Zhai L, Dai K, Tanimura K, Liu T, Cui N, Yamauchi A, Murata T, Shindo T. Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:999-1015. [PMID: 28322199 DOI: 10.1016/j.ajpath.2017.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/19/2017] [Indexed: 11/29/2022]
Abstract
Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.
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Affiliation(s)
- Akira Imai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yuichi Toriyama
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Yasuhiro Iesato
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Kazutaka Hirabayashi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Sakurai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Akiko Kamiyoshi
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Yuka Ichikawa-Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Hisaka Kawate
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Megumu Tanaka
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Tian Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Xian Xian
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Liuyu Zhai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Kun Dai
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Keiya Tanimura
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Teng Liu
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | - Nanqi Cui
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan
| | | | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Takayuki Shindo
- Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
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Danyliv A, Glanville J, McCool R, Ferreira A, Skelly A, Jacob RP. The Clinical Effectiveness of Ranibizumab Treat and Extend Regimen in nAMD: Systematic Review and Network Meta-Analysis. Adv Ther 2017; 34:611-619. [PMID: 28188433 PMCID: PMC5350194 DOI: 10.1007/s12325-017-0484-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Indexed: 11/25/2022]
Abstract
Introduction Neovascular age-related macular degeneration (nAMD) is a chronic eye condition that causes severe deterioration of vision and ultimately blindness. Two vascular endothelial growth factor inhibitors are approved for nAMD treatment in Europe: ranibizumab and aflibercept. The European license for ranibizumab was updated with an individualized “treat and extend” (T&E) regimen, which involves more proactive treatment based on changes in best corrected visual acuity (BCVA) and/or anatomical outcomes. The aim of this publication is to compare the efficacy of the ranibizumab T&E regimen with other approved dosing regimens for nAMD on the basis of outcomes identified from a systematic review and subsequent NMA. Methods Following a systematic search of publications, to identify relevant studies, a repeated-measures network meta-analysis (NMA) was performed to estimate the relative effectiveness of ranibizumab T&E versus approved dosing regimens of ranibizumab and aflibercept. The analysis focused on licensed treatment regimens for nAMD. We examined mean change from baseline in BCVA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Results The systematic literature review identified 22,949 records, of which 23 studies were included in the NMA. At 12 months, the ranibizumab T&E dosing regimen vs ranibizumab pro re nata (PRN) was associated with small differences in change in BCVA, between 1.86 letter gain at 12 months and 2.35 letter gain at 24 months. A similar difference was observed in the aflibercept dosing regimen versus ranibizumab T&E ; 1.94 letter gain at 12 months and 3.31 letter gain at 24 months. All doses of ranibizumab and aflibercept showed similar effectiveness, and the differences between treatment options were not significant. Conclusion This study used novel repeated-measures NMA to synthesize efficacy results when treatment effects were reported at multiple follow-up times. This repeated-measures NMA suggests that treating patients with the ranibizumab T&E regimen yields similar effectiveness compared to other approved ranibizumab and aflibercept dosing regimens for nAMD treatment. Funding: Novartis Pharmaceuticals UK Ltd, Surrey, UK. Electronic supplementary material The online version of this article (doi:10.1007/s12325-017-0484-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Julie Glanville
- York Health Economics Consortium, University of York, York, UK
| | - Rachael McCool
- York Health Economics Consortium, University of York, York, UK
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He J, Long C, Huang Z, Zhou X, Kuang X, Liu L, Liu H, Tang Y, Fan Y, Ning J, Ma X, Zhang Q, Shen H. PTEN Reduced UVB-Mediated Apoptosis in Retinal Pigment Epithelium Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3681707. [PMID: 28321407 PMCID: PMC5340936 DOI: 10.1155/2017/3681707] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/22/2017] [Accepted: 01/26/2017] [Indexed: 02/06/2023]
Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness and progressive loss of central vision in the elderly population. The important factor of AMD pathogenesis is the degeneration of retinal pigment epithelial (RPE) cells by oxidative stress. Inactivation of PTEN can disrupt intercellular adhesion in the RPE cells, but the mechanism of oxidative stress is less known. Here we presented evidence that UVB-mediated oxidative stress induced apoptosis in ARPE-19 cells. Downregulation of the expression of PTEN in UVB-irradiative RPE cells triggered DNA damage and increased the level of UVB-induced apoptosis by activating p53-dependent pathway. However, overexpression of PTEN increased cell survival by suppressing p-H2A in response to DNA damage and apoptosis. When using Pifithrin-α (one of p53 inhibitors), the level of p53-dependent apoptosis was significantly lower than untreated, which suggested that p53 was possibly involved in PTEN-dependent apoptosis. Thus, it elucidated the molecular mechanisms of UVB-induced damage in RPE cells and may offer an alternative therapeutic target in dry AMD.
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Affiliation(s)
- Jia He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Chongde Long
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Zixin Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Xin Zhou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Xielan Kuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
- Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Lanying Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Huijun Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Yan Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Yuting Fan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Jie Ning
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Xinqi Ma
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Qingjiong Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
| | - Huangxuan Shen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
- Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China
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Wu J, Cho E, Giovannucci EL, Rosner BA, Sastry SM, Willett WC, Schaumberg DA. Dietary Intakes of Eicosapentaenoic Acid and Docosahexaenoic Acid and Risk of Age-Related Macular Degeneration. Ophthalmology 2017; 124:634-643. [PMID: 28153441 DOI: 10.1016/j.ophtha.2016.12.033] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 11/15/2016] [Accepted: 12/21/2016] [Indexed: 02/03/2023] Open
Abstract
PURPOSE To evaluate the associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the intermediate and advanced stages of age-related macular degeneration (AMD). DESIGN Prospective cohort study. PARTICIPANTS We followed 75 889 women from the Nurses' Health Study and 38 961 men from the Health Professionals Follow-Up Study who were at least 50 years old, from 1984 to 2012 and 1986 to 2010, respectively. Cohort participants are mostly white (≥95%). METHODS We assessed dietary intake by a validated food frequency questionnaire (FFQ) at baseline and every 4 years. We calculated cumulative average intakes of EPA and DHA from FFQs and also computed predicted erythrocyte and plasma scores directly from food intake using regression models. Cox proportional hazards models were used to compute the associations with AMD outcomes. MAIN OUTCOME MEASURES We confirmed 1589 incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse, owing primarily to AMD, by medical record review. RESULTS For intermediate AMD, the pooled hazard ratio (HR) between the 2 cohorts for DHA comparing the extreme quintiles of intake was 0.78 (95% confidence interval [CI], 0.66-0.92; P trend, 0.008) and for EPA + DHA was 0.83 (95% CI, 0.71-0.98; P trend, 0.03). The pooled HR for fatty fish, comparing ≥5 servings per week to almost never, was 0.61 (95% CI, 0.46-0.81; P trend, <0.001). For advanced AMD, the pooled HR for DHA was 1.01 (95% CI, 0.84-1.21; P trend, 0.75) and for fatty fish was 0.80 (95% CI, 0.59-1.08; P trend, 0.11). Secondary analyses using predicted erythrocyte and plasma scores of EPA and DHA yielded slightly stronger inverse associations for intermediate AMD and similar results for advanced AMD. CONCLUSIONS Higher intakes of EPA and DHA may prevent or delay the occurrence of visually significant intermediate AMD. However, the totality of current evidence for EPA and DHA and advanced AMD is discordant, though there was no association with advanced AMD in the present study.
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Affiliation(s)
- Juan Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
| | - Eunyoung Cho
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Department of Epidemiology, Brown School of Public Health, Providence, Rhode Island
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Bernard A Rosner
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Walter C Willett
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Debra A Schaumberg
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Global Medical Affairs, Ophthalmics, Shire, Lexington, Massachusetts; Center for Translational Medicine, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah
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Hajek A, Brettschneider C, Lühmann D, Eisele M, Mamone S, Wiese B, Weyerer S, Werle J, Pentzek M, Fuchs A, Stein J, Luck T, Bickel H, Weeg D, Heser K, Jessen F, Maier W, Scherer M, Riedel-Heller SG, König HH. Does Visual Impairment Affect Social Ties in Late Life? Findings of a Multicenter Prospective Cohort Study in Germany. J Nutr Health Aging 2017; 21:692-698. [PMID: 28537334 DOI: 10.1007/s12603-016-0768-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To investigate how visual impairment affects social ties in late life longitudinally. DESIGN Population-based prospective cohort study. SETTING Individuals in old age were recruited via general practitioners' offices (at six study centers) in Germany. They were interviewed every 18 months. PARTICIPANTS Individuals aged 75 years and above at baseline. Follow-up wave 2 (36 months after baseline, n=2,443) and wave 4 (72 months after baseline, n=1,618) were used for the analyses presented here. MEASUREMENTS Social ties were assessed using the 14-item form of the questionnaire for social support (F-SozU K-14). Visual impairment was self-rated on a three level Likert scale (no impairment, mild visual impairment, or severe/profound visual impairment). RESULTS Adjusting for sociodemographic factors, hearing impairment and comorbidity, fixed effects regressions revealed that the onset of mild visual impairment decreased the social support score, in particular the emotional support score. Additionally, the onset of mild hearing impairment decreased the social support score in men. Moreover, increasing age decreased the social support score in the total sample and in both sexes. Loss of spouse and increasing comorbidity did not affect the social support score. CONCLUSION Our results highlight the importance of visual impairment for social ties in late life. Consequently, appropriate strategies in order to delay visual impairment might help to maintain social ties in old age.
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Affiliation(s)
- A Hajek
- Dr. André Hajek, University Medical Center, Hamburg-Eppendorf, Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, Telephone +49 40 7410 52877; Fax +49 40 7410 40261, E-mail:
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Labrador-Velandia S, Alonso-Alonso ML, Alvarez-Sanchez S, González-Zamora J, Carretero-Barrio I, Pastor JC, Fernandez-Bueno I, Srivastava GK. Mesenchymal stem cell therapy in retinal and optic nerve diseases: An update of clinical trials. World J Stem Cells 2016; 8:376-383. [PMID: 27928464 PMCID: PMC5120242 DOI: 10.4252/wjsc.v8.i11.376] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/20/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells (MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in I/II phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase III-IV. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases.
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Kim SH, Kim H, Ku HJ, Park JH, Cha H, Lee S, Lee JH, Park JW. Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration. Redox Biol 2016; 10:211-220. [PMID: 27810736 PMCID: PMC5094379 DOI: 10.1016/j.redox.2016.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 10/20/2016] [Accepted: 10/21/2016] [Indexed: 11/21/2022] Open
Abstract
Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF), secreted by the retinal pigment epithelium (RPE), in pathological angiogenesis and the development of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA) is a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH), which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS). Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.
Oxalomalate reduces VEGF expression in RPE cells by promoting HIF-1α degradation. Oxalomalate activates pVHL-mediated HIF-1α degradation by regulation of ATM-Chk2-E2F1 axis. Inhibition of IDH enzymes by oxalomalate activates ROS-mediated ATM signaling axis. Oxalomalate inhibits CNV-related angiogenesis in in vivo mouse model of AMD.
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Affiliation(s)
- Sung Hwan Kim
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Hyunjin Kim
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Hyeong Jun Ku
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Jung Hyun Park
- Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea
| | - Hanvit Cha
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Seoyoon Lee
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Jin Hyup Lee
- Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea; Institutes of Natural Sciences, Korea University, Sejong, Republic of Korea.
| | - Jeen-Woo Park
- School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
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Effect of intravitreal anti-vascular endothelial growth factor agents on blood pressure – a cross-sectional analysis. J Hypertens 2016; 34:2099-100. [DOI: 10.1097/hjh.0000000000001050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Tabatabaei A, Mafi M, Shoar S, Naderan M. Clinical risk factors for age-related macular degeneration: A case-control study. Oman J Ophthalmol 2016; 9:120. [PMID: 27433044 PMCID: PMC4932797 DOI: 10.4103/0974-620x.184535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Affiliation(s)
- Ali Tabatabaei
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Mafi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Shoar
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Naderan
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Yang S, Zhao J, Sun X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:1857-67. [PMID: 27330279 PMCID: PMC4898027 DOI: 10.2147/dddt.s97653] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
As a progressive chronic disease, age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment worldwide. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor (VEGF) plays a vital role in the formation of choroidal neovascularization. Intravitreal injections of anti-VEGF agents have been recommended as a first-line treatment for neovascular AMD. However, persistent fluid or recurrent exudation still occurs despite standardized anti-VEGF therapy. Patients suffering from refractory or recurrent neovascular AMD may develop mechanisms of resistance to anti-VEGF therapy, which results in a diminished therapeutic effect. Until now, there has been no consensus on the definitions of refractory neovascular AMD and recurrent neovascular AMD. This article aims at clarifying these concepts to evaluate the efficacy of switching drugs, which contributes to making clinical decision more scientifically. Furthermore, insight into the causes of resistance to anti-VEGF therapy would be helpful for developing possible therapeutic approaches, such as combination therapy and multi-target treatment that can overcome this resistance.
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Affiliation(s)
- Shiqi Yang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jingke Zhao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; Eye Research Institute of Shanghai Jiao Tong University, Shanghai, People's Republic of China; Shanghai Key Laboratory of Fundus Disease, Shanghai, People's Republic of China
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48
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Zhu Y, Zhao KK, Tong Y, Zhou YL, Wang YX, Zhao PQ, Wang ZY. Exogenous NAD(+) decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy. Sci Rep 2016; 6:26322. [PMID: 27240523 PMCID: PMC4886526 DOI: 10.1038/srep26322] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 05/03/2016] [Indexed: 01/08/2023] Open
Abstract
Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD+) administration significantly blocked RPE cell death induced by 300 μM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells. Exogenous NAD+ administration significantly decreased intracellular and intranuclear ROS levels in H2O2-treated RPE cells. In addition, NAD+ administration to H2O2-treated RPE cells inhibited the activation of PARP-1 and protected the RPE cells against necrotic death. Moreover, exogenous NAD+ administration up-regulated autophagy in the H2O2-treated RPE cells. Inhibition of autophagy by LY294002 blocked the decrease of intracellular and intranuclear ROS level. Besides, inhibition of autophagy by LY294002 abolished the protection of exogenous NAD+ against H2O2-induced cell necrotic death. Taken together, our findings indicate that that exogenous NAD+ administration suppresses H2O2-induced oxidative stress and protects RPE cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD+ administration might be potential value for the treatment of AMD.
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Affiliation(s)
- Ying Zhu
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
| | - Ke-Ke Zhao
- Department of Ophthalmology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yao Tong
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
| | - Ya-Li Zhou
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
| | - Yi-Xiao Wang
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
| | - Pei-Quan Zhao
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
| | - Zhao-Yang Wang
- Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University Scool of Medicine, Shanghai, China
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Safety and complications of intravitreal injections performed in an Asian population in Singapore. Int Ophthalmol 2016; 37:325-332. [PMID: 27236451 DOI: 10.1007/s10792-016-0241-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 04/22/2016] [Indexed: 12/12/2022]
Abstract
There has been a rapid rise in the use of intravitreal injections, such as anti-vascular endothelial growth factor (anti-VEGF) agents, performed over the past few years for the treatment of ocular neovascular diseases. This study aims to review the systemic and ocular adverse events among patients treated at a tertiary eye center over a period of 8 years. A retrospective review of all intravitreal injections of anti-VEGF performed over an 8-year period at a tertiary eye care center in Singapore was done. We report the frequency of systemic and ocular adverse events and compared it among the various anti-VEGF agents. A total of 14 001 intravitreal injections were performed on 2225 patients from January 1, 2007 to December 31, 2014, and this included 9992 bevacizumab (71.4 %), 3306 ranibizumab (23.6 %) and 703 aflibercept (5.0 %) injections. Systemic complications related to treatment were 26 (1.17 %) deaths (from any cause), of which 11 (0.49 %) were from fatal thromboembolic events, 7 (0.31 %) non-fatal thromboembolic events and two (0.09 %) serious non-ocular hemorrhage. Ocular complications included one (0.007 %) endophthalmitis, three (0.021 %) traumatic cataracts, and one (0.007 %) retinal detachment. Rates of death and thromboembolic events were similar among ranibizumab (lucentis), bevacizumab (avastin) and aflibercept (Eylea). The systemic and ocular complications associated with intravitreal injections among Asian patients at a tertiary eye center are relatively low and reflect the safety of the treatments.
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50
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Du JD, Fong WK, Caliph S, Boyd BJ. Lipid-based drug delivery systems in the treatment of wet age-related macular degeneration. Drug Deliv Transl Res 2016; 6:781-792. [DOI: 10.1007/s13346-016-0299-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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