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Jansook P, Sigurdsson HH, Loftsson T. A look to the future: cyclodextrins and cyclodextrin-based drug delivery to the retina. Expert Opin Drug Deliv 2025:1-18. [PMID: 40105773 DOI: 10.1080/17425247.2025.2482049] [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: 12/15/2024] [Revised: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 03/20/2025]
Abstract
INTRODUCTION Retinal diseases are a leading cause of vision loss, affecting millions of people worldwide. Current treatment options are based on invasive methods such as intravitreal injections. Therefore, there is a need for alternative therapeutic strategies that are both effective and more patient-friendly. AREAS COVERED Topical drug delivery has gained attention as a preferred noninvasive approach, although it is hindered by several ocular barriers. Cyclodextrin (CD)-based nanoparticles have emerged as a promising strategy to overcome these limitations by enhancing drug permeability in the posterior segment of the eye. This review discusses the potential of CDs as enabling pharmaceutical excipients, their role in improving ocular drug bioavailability, and provides examples of CD-based eye drop formulations currently under development or undergoing clinical trials. Also, the role of CDs as active pharmaceutical agents in ophthalmology is discussed. EXPERT OPINION CD-based nanoparticle eye drops present a promising solution and have shown clinical success. CDs are approved pharmaceutical excipients for eye drop formulations and can act as active pharmaceutical ingredients for the treatment of inherent retinal diseases. Future innovations in hybrid CD-based delivery systems and integration of novel therapeutic compounds could provide more efficient and targeted treatment options for retinal diseases.
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Affiliation(s)
- Phatsawee Jansook
- Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok, Thailand
- Cyclodextrin Application and Nanotechnology-Based Delivery Systems Research Unit, Chulalongkorn University, Pathumwan, Bangkok, Thailand
| | - Hákon H Sigurdsson
- Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
| | - Thorsteinn Loftsson
- Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
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2
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Boscia G, Feo A, Savastano A, Viggiano P, Landini L, Clemente A, Scotti G, Grassi MO, Parisi G, Giancipoli E, Alessio G, Boscia F, Mastropasqua R, Reibaldi M, Romano MR, Borrelli E. Intravitreal Dexamethasone Implant in Vitreoretinal Surgery: An Overview of the Literature. Graefes Arch Clin Exp Ophthalmol 2025:10.1007/s00417-025-06797-7. [PMID: 40108023 DOI: 10.1007/s00417-025-06797-7] [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: 09/16/2024] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND The sustained-release intravitreal 0.7 mg dexamethasone implant (DEX implant) (Ozurdex®, Allergan®, an AbbVie Company, North Chicago, Illinois, USA) is widely used to treat various inflammatory retinal disorders. Notably, its application is expanding in the field of vitreoretinal surgery. METHODS We conducted a comprehensive literature search across the Web of Science, PubMed, EMBASE, and ScienceDirect databases for articles related to Ozurdex and its applications in vitreoretinal disorders. Additionally, relevant studies were identified from the reference lists of retrieved articles. Our search was limited to studies written in English or those in other languages that provided an English abstract with sufficient information. RESULTS Multiple studies have demonstrated the efficacy and safety of the DEX implant across a broad spectrum of vitreoretinal and post-surgical conditions. Notably, the implant's unique pharmacokinetics remain largely unaffected by the vitrectomized status of the eye, ensuring consistent effectiveness in vitreoretinal surgery. Our research highlights the primary off-label applications of the DEX implant, which include epiretinal membrane (ERM), rhegmatogenous retinal detachment (RRD), post-surgical cystoid macular edema (PSCME), and refractory diabetic macular edema (DME). CONCLUSION This review highlights the increasing role of the DEX implant in vitreoretinal surgery, emphasizing its effectiveness and safety in various surgical and post-surgical settings, while also addressing associated complications.
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Affiliation(s)
- Giacomo Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy.
| | - Alessandro Feo
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
| | - Alfonso Savastano
- Libera Università Mediterranea Degennaro, Casamassima, Italy, BA
- Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, Italy, BA
| | - Pasquale Viggiano
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Luca Landini
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Arcangelo Clemente
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Giacomo Scotti
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Maria Oliva Grassi
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Guglielmo Parisi
- Department of Surgical Sciences, University of Turin, Turin, Italy
- Department of Ophthalmology, City of Health and Science" Hospital, Turin, Italy
| | | | - Giovanni Alessio
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Francesco Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", Bari, Italy
| | - Rodolfo Mastropasqua
- Department of Medicine and Science of Ageing, Ophthalmology Clinic, University G. D'Annunzio Chieti- Pescara, Chieti, Italy
| | - Michele Reibaldi
- Department of Surgical Sciences, University of Turin, Turin, Italy
- Department of Ophthalmology, City of Health and Science" Hospital, Turin, Italy
| | - Mario R Romano
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Department of Ophthalmology, Eye Unit Humanitas Gavazzeni-Castelli, Via Mazzini 11, Bergamo, Italy
| | - Enrico Borrelli
- Department of Surgical Sciences, University of Turin, Turin, Italy
- Department of Ophthalmology, City of Health and Science" Hospital, Turin, Italy
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Soundara Pandi SP, Winter H, Smith MR, Harkin K, Bojdo J. Preclinical Retinal Disease Models: Applications in Drug Development and Translational Research. Pharmaceuticals (Basel) 2025; 18:293. [PMID: 40143072 PMCID: PMC11944893 DOI: 10.3390/ph18030293] [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: 01/26/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025] Open
Abstract
Retinal models play a pivotal role in translational drug development, bridging preclinical research and therapeutic applications for both ocular and systemic diseases. This review highlights the retina as an ideal organ for studying advanced therapies, thanks to its immune privilege, vascular and neuronal networks, accessibility, and advanced imaging capabilities. Preclinical retinal disease models offer unparalleled insights into inflammation, angiogenesis, fibrosis, and hypoxia, utilizing clinically translatable bioimaging tools like fundoscopy, optical coherence tomography, confocal scanning laser ophthalmoscopy, fluorescein angiography, optokinetic tracking, and electroretinography. These models have driven innovations in anti-inflammatory, anti-angiogenic, and neuroprotective strategies, with broader implications for systemic diseases such as rheumatoid arthritis, Alzheimer's, and fibrosis-related conditions. By emphasizing the integration of the 3Rs principles and novel imaging modalities, this review highlights how retinal research not only enhances therapeutic precision but also minimizes ethical concerns, paving the way for more predictive and human-relevant approaches in drug development.
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Affiliation(s)
| | - Hanagh Winter
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
| | - Madeleine R. Smith
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
| | - Kevin Harkin
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - James Bojdo
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
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Forte P, Feo A, Sarraf D, Romano MR, Nicolò M. Current insights and challenges in the management of perifoveal vascular anomalous complex (PVAC): a systematic review of multimodal imaging features and treatment strategies. Eye (Lond) 2025; 39:449-459. [PMID: 39702788 PMCID: PMC11794436 DOI: 10.1038/s41433-024-03544-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 11/25/2024] [Accepted: 12/11/2024] [Indexed: 12/21/2024] Open
Abstract
The aim of this article is to comprehensively review the multimodal imaging (MMI) features that define perifoveal vascular anomalous complex (PVAC) and to update the optimal treatment strategies for this disorder with a focus also on the underlying pathogenetic mechanisms. This systematic review was performed based on a search of the PubMed and Embase databases of relevant papers on the subject of PVAC. PVAC is characterized by well-defined MMI findings, including remarkable morphological features with optical coherence tomography (OCT) and OCT angiography (OCTA). The recognition of this lesion is important because of treatment implications as this entity is typically unresponsive to anti-vascular endothelium growth factor (VEGF) therapy. Thermal focal laser (TFL) can have better success in reducing exudation associated with PVAC. Other therapeutic modalities include subthreshold micropulse laser (SML), steroid and anti-inflammatory treatments. In total, this review captured 25 scientific articles covering the treatment of exudative PVAC cases. Accurate multimodal imaging characterization of PVAC is essential for differential diagnosis and management. There are a multitude of similar lesions described in the literature with overlapping MMI features and clinical contexts. These various lesions will be described and defined in an effort to provide clarity of differentiation. We recommend the "PVAC" nomenclature to denote a distinct, primary condition, consistent with its original definition. On the other hand, we support the consolidation of "TelCap" lexicon to characterize the secondary lesion occurring in the context of diabetic retinopathy (DR), retinal vein occlusion (RVO), and other causal retinal vascular disorders.
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Affiliation(s)
- Paolo Forte
- IRCCS Ospedale Policlinico San Martino, Eye Unit, Genova, Italy
- DINOGMI, University of Genoa, Genoa, Italy
| | - Alessandro Feo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy.
- Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - David Sarraf
- Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, University of California Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Greater Los Angeles VA Healthcare Center, Los Angeles, CA, USA
| | - Mario R Romano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
- Department of Ophthalmology, Eye Unit Humanitas Gavazzeni-Castelli, Bergamo, Italy
| | - Massimo Nicolò
- IRCCS Ospedale Policlinico San Martino, Eye Unit, Genova, Italy
- DINOGMI, University of Genoa, Genoa, Italy
- Macula Onlus Foundation, Genoa, Italy
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5
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Bourauel L, Petrak M, Holz FG, Mercieca K, Weber C. Short-Term Safety and Efficacy of PreserFlo™ Microshunt in Patients with Refractory Intraocular Pressure Elevation After Dexamethasone Implant Intravitreal Injection. J Clin Med 2025; 14:507. [PMID: 39860513 PMCID: PMC11765877 DOI: 10.3390/jcm14020507] [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: 12/13/2024] [Revised: 01/08/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Background: The PreserFlo™ MicroShunt (PFMS) is a bleb-forming device considered to be less invasive than traditional glaucoma surgery such as trabeculectomy. This study evaluates the 1-year success rates as well as safety profile of PFMS in patients having high intraocular pressure (IOP) and/or glaucoma refractory to drop therapy with a history of prior intravitreal dexamethasone therapy. Methods: A total of 16 eyes after PFMS implantation due to elevated IOP after intravitreal dexamethasone implant (DEX-I) administration were included in this retrospective cohort study. Success rates and secondary outcomes were evaluated. Results: Qualified and complete success rates at 12 months, respectively, were 14/16 and 12/16 eyes for criterion A, 13/16 and 11/16 eyes for B, 13/16 and 11/16 eyes for C, and 6/16 and 6/16 eyes for D. The overall mean (range) preoperative IOP decreased from 27 (16-38) mmHg to 13 (10-17) mmHg at 12 months. BCVA was not significantly different up to 12 months (p = 0.63). The preoperative mean (range) number of medications decreased from 3.56 (2-4) to 0.31 (0-3) at 12 months. One eye underwent needling twice, and two eyes were revised surgically. One patient needed replacement of the PFMS. There were no hypotony-related complications. Conclusions: The PFMS is an effective surgical option for patients with steroid-induced IOP elevation. It demonstrates satisfactory short-term success rates, a reduced need for pressure-lowering eye drops, an excellent safety profile with minimal postoperative care, and a low complication rate. Additional interventions such as needling or revisions were infrequently necessary. However, PFMS may not be the ideal choice for cases requiring a low target pressure (≤12 mmHg).
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Affiliation(s)
- Leonie Bourauel
- Department of Ophthalmology, University of Bonn, 53127 Bonn, Germany
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Won J, Kang J, Kang W. Comparative Ocular Pharmacokinetics of Dexamethasone Implants in Rabbits. J Ocul Pharmacol Ther 2024; 40:608-614. [PMID: 39046957 DOI: 10.1089/jop.2024.0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024] Open
Abstract
Purpose: Dexamethasone eye implant has been used to treat macular edema and non-infectious uveitis. To date, its ocular pharmacokinetics are not fully characterized, and the development of generic preparations is in progress, as the patent of the original brand expires soon. Therefore, this work was designed to 1) determine the time course of vitreous dexamethasone concentrations following intravitreal implantation in rabbits and 2) explore the alternative use of NDF-SI01 from a pharmacokinetic point of view compared to Ozurdex®, which is currentlyused in the market. Methods: Ozurdex® and NDF-SI01 were implanted into the right and left eyes of the rabbit, respectively. A serial vitreous collection was performed to minimize the sacrifice of animals, and dexamethasone concentrations were measured by HP LC-MS/MS. Results: After implantation, dexamethasone concentration reaches the maximum concentration (3.1 μg/mL) in 19.5 days and decreases with a half-life of 40.3 h. AUC and clearance are 683.9 μg·h/mL and 1.29 mL/h, respectively. There is no significant difference in pharmacokinetic parameters between NDF-SI01 and Ozurdex®. The overall patterns of the cumulative release of both implants are similar. Conclusions: NDF-SI01 could alternate Ozurdex® in clinics based on the in vivo comparative pharmacokinetic study and in vitro dissolution test.
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Affiliation(s)
- Jihyun Won
- College of Pharmacy, Chung-Ang University, Seoul, South Korea
| | - Juhyung Kang
- College of Pharmacy, Chung-Ang University, Seoul, South Korea
| | - Wonku Kang
- College of Pharmacy, Chung-Ang University, Seoul, South Korea
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7
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Zhang Y, Xing Z, Deng A. Prediction of treatment outcome for branch retinal vein occlusion using convolutional neural network-based retinal fluorescein angiography. Sci Rep 2024; 14:20018. [PMID: 39198599 PMCID: PMC11358400 DOI: 10.1038/s41598-024-71061-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 08/23/2024] [Indexed: 09/01/2024] Open
Abstract
Deep learning techniques were used in ophthalmology to develop artificial intelligence (AI) models for predicting the short-term effectiveness of anti-VEGF therapy in patients with macular edema secondary to branch retinal vein occlusion (BRVO-ME). 180 BRVO-ME patients underwent pre-treatment FFA scans. After 3 months of ranibizumab injections, CMT measurements were taken at baseline and 1-month intervals. Patients were categorized into good and poor prognosis groups based on macular edema at the 4th month follow-up. FFA-Net, a VGG-based classification network, was trained using FFA images from both groups. Class activation heat maps highlighted important locations. Benchmark models (DesNet-201, MobileNet-V3, ResNet-152, MansNet-75) were compared for training results. Performance metrics included accuracy, sensitivity, specificity, F1 score, and ROC curves. FFA-Net predicted BRVO-ME treatment effect with an accuracy of 88.63% and an F1 score of 0.89, with a sensitivity and specificity of 79.40% and 71.34%, respectively.The AUC of the ROC curve for the FFA-Net model was 0.71. The use of FFA based on deep learning technology has feasibility in predicting the treatment effect of BRVO-ME. The FFA-Net model constructed with the VGG model as the main body has good results in predicting the treatment effect of BRVO-ME. The typing of BRVO in FFA may be an important factor affecting the prognosis.
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Affiliation(s)
- Yupeng Zhang
- Department of Ophthalmology, Afffliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, Shandong, China
| | - Zhen Xing
- Department of Ophthalmology, Afffliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, Shandong, China
| | - Aijun Deng
- Department of Ophthalmology, Afffliated Hospital of Shandong Second Medical University, Weifang, 261000, Shandong, China.
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Thareja A, Leigh T, Hakkarainen JJ, Hughes H, Alvarez-Lorenzo C, Fernandez-Trillo F, Blanch RJ, Ahmed Z. Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina. Int J Pharm 2024; 660:124305. [PMID: 38852749 DOI: 10.1016/j.ijpharm.2024.124305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/11/2024]
Abstract
With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p < 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded.
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Affiliation(s)
- Abhinav Thareja
- Neuroscience and Ophthalmology Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom.
| | - Thomas Leigh
- School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom; Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin 2, Ireland.
| | | | - Helen Hughes
- Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), School of Science & Computing, Department of Science, South East Technological University, Cork Road, Waterford City X91 K0EK, Ireland.
| | - Carmen Alvarez-Lorenzo
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+DFarma, Facultad de Farmacia, iMATUS and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
| | - Francisco Fernandez-Trillo
- School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom; BioMedNano Group, Centro de Investigacións Científicas Avanzadas (CICA), Facultade de Ciencias Rúa As Carballeiras, Universidade da Coruna, 15008 A Coruña, Galicia, Spain.
| | - Richard J Blanch
- Neuroscience and Ophthalmology Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom; Academic Department of Military Surgery & Trauma, Royal Centre for Defence Medicine, United Kingdom; Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, West Midlands, United Kingdom; Centre for Trauma Sciences Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom.
| | - Zubair Ahmed
- Neuroscience and Ophthalmology Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom; Centre for Trauma Sciences Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom.
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Pietzuch M, Mantel I, Ambresin A, Tappeiner C, Nagyova D, Donati G, Pfister IB, Schild C, Garweg JG. Intravitreal Dexamethasone as a Rescue for Anti-Vascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration with Persistent Disease Activity and High Treatment Demand. J Ocul Pharmacol Ther 2024; 40:361-369. [PMID: 38117666 DOI: 10.1089/jop.2023.0105] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023] Open
Abstract
Purpose: To assess the impact of switching to, or adding, an intravitreal dexamethasone implant (Dex; Ozurdex®) in anti-vascular endothelial growth factor (VEGF) therapy on disease stability and treatment intervals in eyes with neovascular age-related macular degeneration (nAMD) and persistent disease activity and high treatment demand. Methods: This retrospective noncomparative multicenter longitudinal case series included pseudophakic eyes with nAMD and persistent retinal fluid despite regular anti-VEGF therapy (ranibizumab or aflibercept) that received at least 1 intravitreal Dex implant. Visual acuity, central retinal thickness (CRT), and intraocular pressure were recorded before, and after, the addition of Dex to anti-VEGF therapy. Results: Sixteen eyes of 16 patients met the inclusion criteria of persistent fluid despite anti-VEGF therapy, under treatment intervals of ≤7 weeks in 14 instances. Patients were 80.9 ± 7.4 years old and had received 25.5 ± 17.4 anti-VEGF injections before Dex over a period of 36.4 ± 21.9 months before switching. The treatment interval increased from 5.5 ± 3.2 weeks between the last anti-VEGF and first Dex injection to 11.7 ± 7.3 weeks thereafter (P = 0.022). CRT remained stable (385.3 ± 152.1, 383.9 ± 129.7, and 458.3 ± 155.2 μm before switching as well as 12 and 24 months after switching; P = 0.78 and P = 0.36, respectively). An insignificant mean short-term early increase in visual acuity was not sustained over time. Conclusions: The addition of Dex resulted in a relevant and sustained increase in treatment intervals, whereas CRT and visual acuity remained stable in these difficult-to-treat eyes. It may be discussed whether inflammation or other steroid-responsive factors play a significant role in cases of nAMD with nonsatisfactory responses to anti-VEGF.
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Affiliation(s)
- Marlena Pietzuch
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik, Bern, Switzerland
- Department of Ophthalmology, Bern University Hospital, Bern, Switzerland
| | - Irmela Mantel
- Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Lausanne, Switzerland
| | - Aude Ambresin
- Swiss Visio Clinic Montchoisi, Lausanne, Switzerland
| | - Christoph Tappeiner
- Department of Ophthalmology, Pallas Kliniken, Olten, Switzerland
- Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Medical Faculty, University of Bern, Bern, Switzerland
| | - Dana Nagyova
- Department of Ophthalmology, Pallas Kliniken, Olten, Switzerland
| | - Guy Donati
- Centre Ophtalmologique de la Colline, Hirshlanden Clinics and Clinique d'Ophtalmologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Isabel B Pfister
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik, Bern, Switzerland
| | - Christin Schild
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik, Bern, Switzerland
| | - Justus G Garweg
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik, Bern, Switzerland
- Department of Ophthalmology, Bern University Hospital, Bern, Switzerland
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10
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Zhang T, Liu Z, Li N. The application of dexamethasone implants in uveitis treatment. Front Med (Lausanne) 2024; 11:1402396. [PMID: 39005654 PMCID: PMC11239344 DOI: 10.3389/fmed.2024.1402396] [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: 03/17/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
Uveitis refers to a group of ocular inflammatory diseases that can significantly impair vision. Although systemic corticosteroid therapy has shown substantial efficacy in treating uveitis, extensive use of corticosteroids is associated with significant adverse effects. Recently, a biodegradable, sustained-release implant, namely dexamethasone intravitreal implant (Ozurdex), has been reported for treating non-infectious and infectious uveitis. This review aims to summarize the experiences with Ozurdex treatment across various forms of uveitis and to assist readers in understanding the appropriate timing and potential side effects of Ozurdex in uveitis treatment, thereby maximizing patient benefits in uveitis management.
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Affiliation(s)
- Tian Zhang
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Zhutao Liu
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Na Li
- Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China
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Morya AK, Nishant P, Ramesh PV, Sinha S, Heda A, Salodia S, Prasad R. Intraocular lens selection in diabetic patients: How to increase the odds for success. World J Diabetes 2024; 15:1199-1211. [PMID: 38983821 PMCID: PMC11229963 DOI: 10.4239/wjd.v15.i6.1199] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/23/2024] [Accepted: 04/23/2024] [Indexed: 06/11/2024] Open
Abstract
The incidence of cataracts is significantly higher in diabetic individuals, particularly in younger age groups, with rates quadrupled in those under 65 and doubled in those over 65 compared to non-diabetics. Cataract surgery in diabetic patients poses many challenges: Poor epithelial healing, decreased corneal sensitivity, increased central corneal thickness, decreased endothelial cell count, variable topography, poor pupillary dilatation, anterior capsular phimosis, posterior capsular opacification (PCO), chances of progression of diabetic retinopathy (DR), zonular weakness, and vitreous prolapse and diabetic macular edema. Selection of an appropriate intraocular lens (IOL) is crucial for visual rehabilitation and monitoring DR. The choice of IOL in diabetic cataract patients is a challenging scenario. Square-edge IOLs are favored for their capacity to mitigate PCO, whereas hydrophilic counterparts may incur calcification in the setting of proliferative DR. The advisability of premium IOLs for achieving spectacle independence warrants judicious evaluation, particularly in the presence of advanced retinopathy. Optimal IOL placement within the capsular bag is advocated to minimize postoperative complications. Rigorous preoperative assessment and informed patient counseling regarding IOL options are indispensable for optimizing surgical outcomes. This review article covers various aspects regarding the choice of IOLs in different case scenarios and complications in the diabetic population.
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Affiliation(s)
- Arvind Kumar Morya
- Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801113, Bihar, India
| | - Prasanna Venkatesh Ramesh
- Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy 620017, Tamil Nadu, India
| | - Sony Sinha
- Department of Ophthalmology-Vitreo-Retina, Neuro-Ophthalmology and Oculoplasty, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Sarika Salodia
- Department of Safety, Global Medical Safety, Lundbeck, Singapore 307591, Singapore
| | - Ripunjay Prasad
- Department of Ophthalmology, RP Eye Institute, Delhi 110001, India
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12
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Vitiello L, Salerno G, Coppola A, De Pascale I, Abbinante G, Gagliardi V, Lixi F, Pellegrino A, Giannaccare G. Switching to an Intravitreal Dexamethasone Implant after Intravitreal Anti-VEGF Therapy for Diabetic Macular Edema: A Review. Life (Basel) 2024; 14:725. [PMID: 38929708 PMCID: PMC11204630 DOI: 10.3390/life14060725] [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: 04/27/2024] [Revised: 05/27/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
Among working-age people, diabetic retinopathy and diabetic macular edema are currently considered the main causes of blindness. Nowadays, intravitreal injections are widely acknowledged as a significant milestone in ophthalmology, especially for the treatment of several retinal diseases, including diabetic macular edema. In particular, anti-vascular endothelial growth factor (VEGF) agents are typically the first line of treatment; however, monthly injections are required, at least, during the loading dosage. Notably, an intravitreal 0.7 mg dexamethasone (DEX) implant (Ozurdex®, AbbVie Inc., North Chicago, IL, USA) is considered a legitimate substitute treatment for diabetic eyes that have not responded to anti-VEGF treatment. In fact, clinical trials and real-life studies have demonstrated the effectiveness and safety of an intravitreal DEX implant in treating such conditions over a period of three to six months. For this reason, wisely selecting diabetic patients might be crucial to decreasing the load of injections in clinics and hospitals. The purpose of this review is to analyze the available scientific literature to highlight the benefits, efficacy, and clinical criteria for choosing whether to switch from intravitreal anti-VEGF therapy to an intravitreal DEX implant in diabetic macular edema.
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Affiliation(s)
- Livio Vitiello
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Giulio Salerno
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Alessia Coppola
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Ilaria De Pascale
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Giulia Abbinante
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Vincenzo Gagliardi
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Filippo Lixi
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, CA, Italy; (F.L.); (G.G.)
| | - Alfonso Pellegrino
- Eye Unit, “Luigi Curto” Hospital, Azienda Sanitaria Locale Salerno, 84035 Polla, SA, Italy; (G.S.); (A.C.); (I.D.P.); (G.A.); (V.G.); (A.P.)
| | - Giuseppe Giannaccare
- Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, CA, Italy; (F.L.); (G.G.)
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13
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Taheri SL, Poorirani S, Mostafavi SA. Intraocular drug delivery systems for Diabetic retinopathy: Current and future prospective. BIOIMPACTS : BI 2024; 15:30127. [PMID: 39963560 PMCID: PMC11830143 DOI: 10.34172/bi.30127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 02/20/2025]
Abstract
In pharmaceutical research and development, novel drug delivery systems represent a significant advancement aimed at enhancing the efficacy of therapeutic agents through innovative delivery mechanisms. The primary objective of these systems is to transport therapeutic compounds to specific target sites, such as tumors and afflicted tissues, with the dual purpose of mitigating side effects and toxicity associated with the drugs while concurrently augmenting therapeutic effectiveness. Numerous innovative drug delivery strategies have been scrutinized for their applicability in the context of targeted ocular drug delivery. Diverse novel carriers, including but not limited to implants, hydrogels, metal nanoparticles, Nano-liposomes, micelles, solid lipid nanoparticles (SLN), emulsions, and biodegradable nanoparticles, have been harnessed to facilitate the controlled release of pharmaceutical agents to the retina and vitreous. These carriers offer distinct advantages, such as enhanced intraocular drug delivery, precise control over drug release kinetics, heightened stability, and superior entrapment efficiency. This comprehensive review seeks to elucidate the current strides made in the realm of carriers and their contemporary applications in treating diabetic retinopathy (DR). Furthermore, it underscores these carriers' pivotal role in achieving efficacious intraocular drug delivery. Additionally, this article explores the various administration routes, potential future advancements, and the multifaceted challenges confronting the domain of novel carriers in treating DR. In conclusion, novel formulations are introduced to surmount the challenges associated with intraocular drug delivery.
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Affiliation(s)
- Sayed Latif Taheri
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Safoora Poorirani
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sayed Abolfazl Mostafavi
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Abraham MK, Madanan AS, Varghese S, R S L, Shkhair AI, N S V, George S. Fluorescent Enzymatic Sensor Based Glucose Oxidase Modified Bovine Serum Albumin-Gold Nanoclusters for Detection of Glucose. Chempluschem 2024; 89:e202300601. [PMID: 38241333 DOI: 10.1002/cplu.202300601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/13/2024] [Accepted: 01/18/2024] [Indexed: 01/21/2024]
Abstract
An enzymatic fluorescent probe is developed for the selective detection of glucose. In this work, a Bovine Serum Albumin stabilized gold nanocluster (BSA-AuNCs) was synthesized by microwave assisted method, and it is modified with glucose oxidase, thereby a fluorescent enzymatic sensor (BSA-AuNCs@GoX) was designed for the sensitive detection of glucose with a limit of detection of 0.03 mM. The red fluorescence exhibited by the probe is quenched by the production of H2O2 on addition of glucose via. a static quenching mechanism from UV visible absorption and Fluorescence lifetime results. The developed probe exhibits good selectivity and sensitivity with other coexisting molecular species such as glycine, creatinine, methionine, histidine, uric acid, albumin, and ions such as sodium, potassium, calcium, magnesium, zinc etc. that appear in the body fluid. The practical applicability was studied in paper strip and extended its reproducibility in biological matrixes such as human serum and urine and found a good recovery percentage of 94-101 %. By this way, we have fabricated an effective fluorescent enzymatic "turn-off" sensing probe for the detection of glucose.
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Affiliation(s)
- Merin K Abraham
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Anju S Madanan
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Susan Varghese
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Lekshmi R S
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Ali Ibrahim Shkhair
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Vijila N S
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
| | - Sony George
- Department of Chemistry, School of Physical and Mathematical Sciences, Research Centre, University of Kerala, Kariavattom Campus, Thiruvananthapura, 695581, Kerala, India Phone
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15
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Costello MA, Liu J, Wang Y, Qin B, Xu X, Li Q, Smith WC, Lynd NA, Zhang F. Manufacturing dexamethasone intravitreal implants: Process control and critical quality attributes. Int J Pharm 2023; 647:123515. [PMID: 37844672 DOI: 10.1016/j.ijpharm.2023.123515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/20/2023] [Accepted: 10/13/2023] [Indexed: 10/18/2023]
Abstract
Over 20 long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been approved by the FDA to date. PLGA is a biodegradable polymer that can extend drug release from these dosage forms for up to six months after administration. Despite the commercial success of several of these formulations, there are still a limited number of products that utilize PLGA, and there are currently no generic counterparts of these products on the market. Significant technical challenges are associated with preparation of chemically and structurally equivalent formulations that yield an equivalent drug release profile to the reference listed drug (RLD) both in vitro and in vivo. In this work, Ozurdex (dexamethasone intravitreal implant) was used as a model system to explore how the manufacturing process of PLGA-based solid implants impacts the quality and performance of the dosage form. Control of implant structural characteristics, including diameter, internal porosity, and surface roughness, was required to maintain accurate unit dose potency. Implants were prepared by a continuous hot-melt extrusion process that was thoroughly characterized to show the importance of precise feeding control to meet dimensional specifications. Five extruder die designs were evaluated using the same hot-melt extrusion process to produce five structurally-distinct implants. The structural differences did not alter the in vitro drug release profile when tested in both normal saline and phosphate-buffered saline (pH 7.4); however, implant porosity was shown to impact the mechanical strength of the implants. This work seeks to provide insight into the manufacturing process of PLGA-based solid implants to support development of future novel and generic drug products.
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Affiliation(s)
- Mark A Costello
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Joseph Liu
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Yan Wang
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Bin Qin
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Xiaoming Xu
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA
| | - Qi Li
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - William C Smith
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA
| | - Nathaniel A Lynd
- University of Texas at Austin, McKetta Department of Chemical Engineering and Texas Materials Institute, Austin, TX, USA
| | - Feng Zhang
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
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16
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Spinetta R, Petrillo F, Reibaldi M, Tortori A, Mazzoni M, Metrangolo C, Gelormini F, Ricardi F, Giordano A. Intravitreal DEX Implant for the Treatment of Diabetic Macular Edema: A Review of National Consensus. Pharmaceutics 2023; 15:2461. [PMID: 37896220 PMCID: PMC10610055 DOI: 10.3390/pharmaceutics15102461] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/16/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023] Open
Abstract
Diabetic macular edema (DME)'s therapeutic approach can frequently be challenging. The purpose of the review is to propose evidence-based recommendations on the employment of intravitreal dexamethasone implants (DEX) when approaching patients suffering from DME. Seven national consensuses redacted by different groups of retina specialists from Europe and Asia were examined and confronted. Each consensus was redacted utilizing a Delphi approach, in person meetings, or by reviewing the literature. DEX can be studied as a first-line strategy in individuals suffering from DME with inflammatory OCT biomarkers, in vitrectomized eyes, in patients with recent cardiovascular events, in pregnant women, in patients scheduled to undergo cataract surgery or with poor compliance. The other parameters considered were the indications to the DME treatment, when to switch to DEX, the definition of non-responder to anti-VEGFs agents and to the DEX implant, whether to combine DEX with laser photocoagulation, the association between glaucoma and DEX, and the management of DEX and the cataract. Although several years have passed since the introduction of DEX implants in the DME treatment, there is still not a unified agreement among retina specialists. This paper compares the approach in the DME treatment between countries from different continents and provides a broader and worldwide perspective of the topic.
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Affiliation(s)
| | - Francesco Petrillo
- Department of Medical Sciences, Eye Clinic, Turin University, 10024 Turin, Italy; (M.R.); (F.G.); (F.R.)
| | - Michele Reibaldi
- Department of Medical Sciences, Eye Clinic, Turin University, 10024 Turin, Italy; (M.R.); (F.G.); (F.R.)
| | - Antonia Tortori
- Ophthalmology Unit, Surgery Department, Piacenza Hospital, 29121 Piacenza, Italy;
| | - Maria Mazzoni
- University Center for Studies on Gender Medicine, University of Ferrara, 44124 Ferrara, Italy;
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy
| | - Cristian Metrangolo
- Ophthalmology Unit, Ospedale di Circolo e Fondazione Macchi, ASST Sette Laghi, 21100 Varese, Italy;
| | - Francesco Gelormini
- Department of Medical Sciences, Eye Clinic, Turin University, 10024 Turin, Italy; (M.R.); (F.G.); (F.R.)
| | - Federico Ricardi
- Department of Medical Sciences, Eye Clinic, Turin University, 10024 Turin, Italy; (M.R.); (F.G.); (F.R.)
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
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17
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Puranen J, Ranta VP, Ruponen M, Urtti A, Sadeghi A. Quantitative intravitreal pharmacokinetics in mouse as a step towards inter-species translation. Exp Eye Res 2023; 235:109638. [PMID: 37657528 DOI: 10.1016/j.exer.2023.109638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/17/2023] [Accepted: 08/28/2023] [Indexed: 09/03/2023]
Abstract
Although mouse models are widely used in retinal drug development, pharmacokinetics in mouse eye is poorly understood. In this study, we applied non-invasive in vivo fluorophotometry to study pharmacokinetics of intravitreal fluorescein sodium (molecular weight 0.38 kDa) and fluorescein isothiocyanate-dextran (FD-150; molecular weight 150 kDa) in mice. Intravitreal half-lives of fluorescein and FD-150 in mouse eyes were 0.53 ± 0.06 h and 2.61 ± 0.86 h, respectively. These values are 8-230 times shorter than the elimination half-lives of similar compounds in the human vitreous. The apparent volumes of distribution in the mouse vitreous were close to the anatomical volume of the mouse vitreous (FD-150, 5.1 μl; fluorescein, 9.6 μl). Dose scaling factors were calculated from mouse to rat, rabbit, monkey and human translation. Based on pharmacokinetic modelling and compound concentrations in the vitreous and anterior chamber, fluorescein is mainly eliminated posteriorly across blood-retina barrier, but FD-150 is cleared via aqueous humour outflow. The results of this study improve the knowledge of intravitreal pharmacokinetics in mouse and facilitate inter-species scaling in ocular drug development.
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Affiliation(s)
- Jooseppi Puranen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland.
| | - Veli-Pekka Ranta
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland
| | - Marika Ruponen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland
| | - Arto Urtti
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland; Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, FI-00790, Finland
| | - Amir Sadeghi
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210, Kuopio, Finland.
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18
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Visioli G, Alisi L, Mastrogiuseppe E, Albanese GM, Romano E, Iannetti L, Armentano M, Giovannetti F, Gharbiya M. OCT biomarkers as predictors of visual improvement in diabetic macular edema eyes receiving dexamethasone implants. Int J Retina Vitreous 2023; 9:35. [PMID: 37316930 PMCID: PMC10265769 DOI: 10.1186/s40942-023-00473-w] [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: 03/29/2023] [Accepted: 05/13/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Several optical coherence tomography (OCT) biomarkers have been proposed as predictors for functional and anatomical outcomes in Diabetic Macular Edema (DME). This study aims to examine the impact of these OCT features on the visual acuity improvement of patients with DME after long-acting Dexamethasone intravitreal implants (DEX-I) injection. Furthermore, the safety and impact of DEX-I on clinical parameters, including intraocular pressure (IOP) were assessed. METHODS In this retrospective observational study, we reviewed the medical records of naïve and non-naïve eyes with DME who received at least one DEX-I. The primary endpoint was visual acuity improvement of ≥ 5 ETDRS letters at 1 month and 4 months after treatment. Secondary outcomes were the changes in OCT biomarkers and the impact of DEX-I on IOP at 1 and 4 months of follow-up. Linear panel regression analysis was used to test for differences in central subfield thickness (CST) over time and it was stratified according to biomarkers at baseline. Finally, a logistic regression analysis was used to identify factors predicting visual improvement at 1 and 4 months. RESULTS We included 33 eyes of which 63.6% were at an advanced stage of DME. Overall, CST, cube average thickness (CAT), cube volume (CV), and intraretinal cystoid spaces > 200 μm (ICS) decreased following DEX-I injection (p < 0.001). Additionally, a thicker CST at baseline was observed in eyes with better visual improvement at one month (p = 0.048). After logistic regression analysis, CST was retained as the only predictor for visual improvement at one month (p = 0.044). Furthermore, panel regression analysis identified a relation between subfoveal neuroretinal detachment (SND) at baseline and CST increase at four months. Lastly, only 15.2% of the eyes necessitated topical medication for IOP reduction, with no differences observed when stratifying between naïve and non-naïve eyes. CONCLUSION Our analyses suggest that a ticker baseline CST may serve as a positive predictor of early visual improvement and SND presence at baseline may be a negative prognostic factor for CST increase 4 months after DEX-I injection. Other well-known biomarkers, such as disorganization of the inner retinal layers (DRIL) and hyperreflective foci (HF), did not demonstrate prognostic value on visual outcomes, at least within the first four months following the injection.
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Affiliation(s)
- Giacomo Visioli
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Ludovico Alisi
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Elvia Mastrogiuseppe
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Giuseppe Maria Albanese
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy.
| | - Enrico Romano
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Ludovico Iannetti
- Ophthalmology Unit, Head and Neck Department, Policlinico Umberto I University Hospital, Sapienza University of Rome, Rome, Italy
| | - Marta Armentano
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Francesca Giovannetti
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
| | - Magda Gharbiya
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I, Sapienza University of Rome, viale del Policlinico 155, Rome, 00161, Italy
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19
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Ramos H, Hernández C, Simó R, Simó-Servat O. Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications. Int J Mol Sci 2023; 24:ijms24108796. [PMID: 37240138 DOI: 10.3390/ijms24108796] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.
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Affiliation(s)
- Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
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20
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Chi SC, Kang YN, Huang YM. Efficacy and safety profile of intravitreal dexamethasone implant versus antivascular endothelial growth factor treatment in diabetic macular edema: a systematic review and meta-analysis. Sci Rep 2023; 13:7428. [PMID: 37156823 PMCID: PMC10167345 DOI: 10.1038/s41598-023-34673-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 05/05/2023] [Indexed: 05/10/2023] Open
Abstract
To better understand the efficacy of intravitreal dexamethasone implant (Ozurdex) versus antivascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). A systematic review and meta-analysis. The study included randomized control trials (RCTs) and non-randomized control trials (Non-RCTs) before December 2021 that compare the efficacy of Ozurdex-related therapyand anti-VEGF therapy. We searched PubMed, Cochrane Library, and EMBASE. The quality of the included studies was assessed carefully. 30 studies were included. Regarding BCVA change, the overall result revealed no significant differences between Ozurdex and anti-VEGF therapies in patients with nonresistant DME, but Ozurdex group had significantly more VA improvement than anti-VEGF therapies in patients with resistant DME (MD 0.12, 95% CI 0.02-0.21). In terms of central retinal thickness (CRT) decrease, there was a significant difference between Ozurdex therapy and anti-VEGF therapy in patients with nonresistant DME (MD 48.10, 95% CI 19.06-77.13) and resistant DME (MD 65.37, 95% CI 3.62-127.13). Overall, Ozurdex therapy resulted in significantly greater VA improvement and CRT decrease than anti-VEGF therapy in resistant DME patients. Ozurdex therapy was not inferior to anti-VEGF therapy in patients with nonresistant DME.
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Affiliation(s)
- Sheng-Chu Chi
- Department of Ophthalmology, Faculty of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-No Kang
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
- Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yi-Ming Huang
- Department of Ophthalmology, Faculty of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
- National Yang Ming Chiao Tung University, Taipei, Taiwan.
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21
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Iyer SS, Radhakrishnan NS, Roohipourmoallai R, Guerin CM, Maylath JS, Garson N. Chronic ocular small vessel disease: An overview of diabetic retinopathy and its relationship with cardiovascular health. AMERICAN HEART JOURNAL PLUS : CARDIOLOGY RESEARCH AND PRACTICE 2023; 29:100270. [PMID: 38510674 PMCID: PMC10945896 DOI: 10.1016/j.ahjo.2023.100270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 03/22/2024]
Abstract
Diabetic retinopathy (DR) is a potentially blinding disease originating from small vessel damage in the retina in chronic hyperglycemic states. DR has a complex multi-pathway driven pathogenesis resulting in diabetic macular edema and retinal ischemia, the former being the most common cause of vision impairment in DR. Hypoxia induced cytokines stimulate vascular endothelial growth factor (VEGF) production and subsequent angiogenesis with resultant mechanical retinal damage over time. Anti-VEGF therapy is effective for the treatment of center-involving diabetic macular edema. There is evolving evidence showing the effectiveness of anti-VEGF as both adjuvant and monotherapy in the treatment of proliferative DR, however laser photocoagulation continues to remain the standard of care. DR in large cohort studies has been shown to be an independent risk factor for the development of cardiovascular disease and mortality. In addition, changes in retinal vascular caliber ratios may have implications for risk of macrovascular events with a gender discrepancy towards women.
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Affiliation(s)
- Siva S.R. Iyer
- Vitreoretinal Associates, Gainesville, FL, United States of America
| | - Nila S. Radhakrishnan
- University of Florida College of Medicine, Department of Medicine, United States of America
| | - Ramak Roohipourmoallai
- University of South Florida College of Medicine, Department of Ophthalmology, United States of America
| | - Cynthia M. Guerin
- Texas Tech Department of Ophthalmology and Visual Sciences, United States of America
| | - Jeremy S. Maylath
- Texas Tech Department of Ophthalmology and Visual Sciences, United States of America
| | - Nickolas Garson
- University of Florida College of Medicine, Department of Ophthalmology, United States of America
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22
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Costello MA, Liu J, Chen B, Wang Y, Qin B, Xu X, Li Q, Lynd NA, Zhang F. Drug release mechanisms of high-drug-load, melt-extruded dexamethasone intravitreal implants. Eur J Pharm Biopharm 2023; 187:46-56. [PMID: 37037387 DOI: 10.1016/j.ejpb.2023.04.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/27/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023]
Abstract
Ozurdex is an FDA-approved sustained-release, biodegradable implant formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for up to 6 months. Hot-melt extrusion is used to prepare the 0.46 mm × 6 mm, rod-shaped implant by embedding the drug in a matrix of poly(lactic-co-glycolic acid) (PLGA) in a 60:40 drug:polymer ratio by weight. In our previous work, the Ozurdex implant was carefully studied and reverse engineered to produce a compositionally and structurally equivalent implant for further analysis. In this work, the reverse-engineered implant is thoroughly characterized throughout the in vitro dissolution process to elucidate the mechanisms of controlled drug release. The implant exhibits a triphasic release profile in 37 °C normal saline with a small burst release (1-2 %), a one-week lag phase with limited release (less than10 %), and a final phase where the remainder of the dose is released over 3-4 weeks. The limited intermolecular interaction between dexamethasone and PLGA renders the breakdown of the polymer the dominating mechanism of controlled release. A close relationship between drug release and total implant mass loss was observed. Unique chemical and structural differences were seen between the core of the implant and the implant surface driven by diffusional limitations, autocatalytic hydrolysis, and osmotic effects.
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Affiliation(s)
- Mark A Costello
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Joseph Liu
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Beibei Chen
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Yan Wang
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Bin Qin
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Xiaoming Xu
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA
| | - Qi Li
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Nathaniel A Lynd
- University of Texas at Austin, McKetta Department of Chemical Engineering and Texas Materials Institute, Austin, TX, USA
| | - Feng Zhang
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
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23
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Castleberry S. Preclinical modeling of intravitreal suspensions. Int J Pharm 2023; 636:122807. [PMID: 36898620 DOI: 10.1016/j.ijpharm.2023.122807] [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: 01/12/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023]
Abstract
There are a number of obstacles that complicate the development of intravitreal delivered small molecules therapies. One serious complication is the potential need for complex polymer depot formulations early in the drug discovery process. The development of such formulations often requires substantial investment of time and material which may not be readily available in preclinical development. Herein I present a diffusion limited pseudo-steady state model to provide prediction of drug release from an intravitreally administered suspension formulation. By using such a model, a preclinical formulator may be able to more confidently determine if development of a complex formulation is required or if a simple suspension may work to support a study design. In this report, the model is used to predict the intravitreal preformance of two different molecules (triamcinolone acetonide and GNE-947) at multiple dose levels in rabbit eyes as well as provide a prediction for the performance of a marketed formulation of Trimacinolone Acetonide in humans.
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Affiliation(s)
- Steven Castleberry
- Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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24
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Costello MA, Liu J, Wang Y, Qin B, Xu X, Li Q, Lynd NA, Zhang F. Reverse engineering the Ozurdex dexamethasone intravitreal implant. Int J Pharm 2023; 634:122625. [PMID: 36690129 DOI: 10.1016/j.ijpharm.2023.122625] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/09/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
Ozurdex is a biodegradable implant formulated for sustained-release delivery of the corticosteroid dexamethasone to the posterior segment of the eye. The small, rod-shaped implant is administered directly to the vitreous using a dedicated applicator, and releases drug for up to 6 months after administration. Sustained release is achieved by embedding dexamethasone in a matrix of 50:50 poly(lactic-co-glycolic acid) (PLGA). In this work, the Ozurdex implant was thoroughly characterized to enable the reverse engineering of a compositionally and structurally equivalent implant. Advanced imaging techniques such as scanning electron microscopy (SEM) and microcomputed tomography (microCT) revealed that the Ozurdex implant exhibits an irregular surface and an internal porosity of 6% due to a large number of discrete voids approximately 3 μm in diameter. Thermal and spectroscopic analyses showed limited interaction between the drug and the polymer, resulting in a two-phase system of dexamethasone crystals embedded within a PLGA matrix. Reverse-engineered implants with properties similar to Ozurdex were prepared using a two-step hot-melt extrusion process. The reverse-engineered implants exhibited a triphasic drug release profile similar to Ozurdex. This work seeks to provide insight into the manufacturing process and characterization of PLGA-based solid implants to support future generic product development.
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Affiliation(s)
- Mark A Costello
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Joseph Liu
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA
| | - Yan Wang
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Bin Qin
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Xiaoming Xu
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Testing and Research, Silver Spring, MD, USA
| | - Qi Li
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Research and Standards, Silver Spring, MD, USA
| | - Nathaniel A Lynd
- University of Texas at Austin, McKetta Department of Chemical Engineering and Texas Materials Institute, Austin, TX, USA
| | - Feng Zhang
- University of Texas at Austin, College of Pharmacy, Department of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
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25
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Shastri DH, Silva AC, Almeida H. Ocular Delivery of Therapeutic Proteins: A Review. Pharmaceutics 2023; 15:pharmaceutics15010205. [PMID: 36678834 PMCID: PMC9864358 DOI: 10.3390/pharmaceutics15010205] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/25/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Therapeutic proteins, including monoclonal antibodies, single chain variable fragment (ScFv), crystallizable fragment (Fc), and fragment antigen binding (Fab), have accounted for one-third of all drugs on the world market. In particular, these medicines have been widely used in ocular therapies in the treatment of various diseases, such as age-related macular degeneration, corneal neovascularization, diabetic retinopathy, and retinal vein occlusion. However, the formulation of these biomacromolecules is challenging due to their high molecular weight, complex structure, instability, short half-life, enzymatic degradation, and immunogenicity, which leads to the failure of therapies. Various efforts have been made to overcome the ocular barriers, providing effective delivery of therapeutic proteins, such as altering the protein structure or including it in new delivery systems. These strategies are not only cost-effective and beneficial to patients but have also been shown to allow for fewer drug side effects. In this review, we discuss several factors that affect the design of formulations and the delivery of therapeutic proteins to ocular tissues, such as the use of injectable micro/nanocarriers, hydrogels, implants, iontophoresis, cell-based therapy, and combination techniques. In addition, other approaches are briefly discussed, related to the structural modification of these proteins, improving their bioavailability in the posterior segments of the eye without affecting their stability. Future research should be conducted toward the development of more effective, stable, noninvasive, and cost-effective formulations for the ocular delivery of therapeutic proteins. In addition, more insights into preclinical to clinical translation are needed.
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Affiliation(s)
- Divyesh H. Shastri
- Department of Pharmaceutics & Pharmaceutical Technology, K.B. Institute of Pharmaceutical Education and Research, Kadi Sarva Vishwavidyalaya, Sarva Vidyalaya Kelavani Mandal, Gandhinagar 382016, India
- Correspondence:
| | - Ana Catarina Silva
- FP-I3ID (Instituto de Investigação, Inovação e Desenvolvimento), FP-BHS (Biomedical and Health Sciences Research Unit), Faculty of Health Sciences, University Fernando Pessoa, 4249-004 Porto, Portugal
- UCIBIO (Research Unit on Applied Molecular Biosciences), REQUIMTE (Rede de Química e Tecnologia), MEDTECH (Medicines and Healthcare Products), Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Hugo Almeida
- UCIBIO (Research Unit on Applied Molecular Biosciences), REQUIMTE (Rede de Química e Tecnologia), MEDTECH (Medicines and Healthcare Products), Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Mesosystem Investigação & Investimentos by Spinpark, Barco, 4805-017 Guimarães, Portugal
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26
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Xu H, Chen M. Immune response in retinal degenerative diseases - Time to rethink? Prog Neurobiol 2022; 219:102350. [PMID: 36075351 DOI: 10.1016/j.pneurobio.2022.102350] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/24/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022]
Abstract
Retinal degeneration comprises a group of diseases whereby either the retinal neurons or the neurovascular unit degenerates leading to the loss of visual function. Although the initial cause varies in different conditions, inflammation is known to play an important role in disease pathogenesis. Recent advances in molecular and cell biology and systems biology have yielded unexpected findings, including the heterogeneity of immune cells in the degenerative retina, bidirectional neuron-microglia cross talk, and links to the gut microbiome. Here we discuss the immune response in retinal degenerative conditions, taking into account both regional (retinal) and systemic factors. We propose to classify retinal degeneration into dry and wet forms based on whether the blood-retinal barrier (BRB) is breached and fluid is accumulated in retinal parenchyma. The dry form has a relatively intact BRB and is characterised by progressive retinal thinning. Immune response to degenerative insults is dominated by the retinal defence system, which remains to be regulated by neurons. In contrast, the wet form has retinal oedema due to BRB damaged. Inflammation is executed by infiltrating immune cells as well as the retinal defence system. The gut microbiome will have easy access to the retina in wet retinal degeneration and may affect significantly retinal immune response.
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Affiliation(s)
- Heping Xu
- Aier Institute of Optometry and Vision Science, Changsha 410000, China; The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, BT9 7BL, UK.
| | - Mei Chen
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, BT9 7BL, UK.
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27
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Xia Y. The management of cataract surgery in diabetic patients. J Perioper Pract 2022; 32:361-367. [PMID: 35445624 DOI: 10.1177/17504589221091063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
A cataract in the eye is a major cause of vision loss in diabetic patients, which occurs earlier and develops faster than non-diabetic patients, and often requires surgery for treatment. However, diabetic patients undergoing cataract surgery have a higher risk of intraoperative and postoperative complications than non-diabetic patients. For diabetic patients undergoing any surgery, careful perioperative assessment and management are required to reduce postoperative complications and improve surgical outcomes. Better understanding of their needs may guide perioperative practitioners to manage their care appropriately. This article presents recent evidence and guidance associated with the preoperative, intraoperative and postoperative management of diabetic patients undergoing cataract surgery and to inform perioperative practitioners of the challenges and potential complications to provide the best care and improve sight.
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Affiliation(s)
- Yu Xia
- Beijing Aerospace General Hospital, Beijing, China
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28
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Balaratnasingam C, An D, Hein M, Yu P, Yu DY. Studies of the retinal microcirculation using human donor eyes and high-resolution clinical imaging: Insights gained to guide future research in diabetic retinopathy. Prog Retin Eye Res 2022; 94:101134. [PMID: 37154065 DOI: 10.1016/j.preteyeres.2022.101134] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/18/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022]
Abstract
The microcirculation plays a key role in delivering oxygen to and removing metabolic wastes from energy-intensive retinal neurons. Microvascular changes are a hallmark feature of diabetic retinopathy (DR), a major cause of irreversible vision loss globally. Early investigators have performed landmark studies characterising the pathologic manifestations of DR. Previous works have collectively informed us of the clinical stages of DR and the retinal manifestations associated with devastating vision loss. Since these reports, major advancements in histologic techniques coupled with three-dimensional image processing has facilitated a deeper understanding of the structural characteristics in the healthy and diseased retinal circulation. Furthermore, breakthroughs in high-resolution retinal imaging have facilitated clinical translation of histologic knowledge to detect and monitor progression of microcirculatory disturbances with greater precision. Isolated perfusion techniques have been applied to human donor eyes to further our understanding of the cytoarchitectural characteristics of the normal human retinal circulation as well as provide novel insights into the pathophysiology of DR. Histology has been used to validate emerging in vivo retinal imaging techniques such as optical coherence tomography angiography. This report provides an overview of our research on the human retinal microcirculation in the context of the current ophthalmic literature. We commence by proposing a standardised histologic lexicon for characterising the human retinal microcirculation and subsequently discuss the pathophysiologic mechanisms underlying key manifestations of DR, with a focus on microaneurysms and retinal ischaemia. The advantages and limitations of current retinal imaging modalities as determined using histologic validation are also presented. We conclude with an overview of the implications of our research and provide a perspective on future directions in DR research.
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Affiliation(s)
- Chandrakumar Balaratnasingam
- Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia; Department of Ophthalmology, Sir Charles Gairdner Hospital, Western Australia, Australia.
| | - Dong An
- Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Martin Hein
- Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Paula Yu
- Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Dao-Yi Yu
- Lions Eye Institute, Nedlands, Western Australia, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
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29
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Kim K, Kim ES, Kim DG, Yu SY. The effect of intravitreal dexamethasone implantation on diabetic macular edema refractory to anti-vascular endothelial growth factor treatment. EXPERT REVIEW OF OPHTHALMOLOGY 2022. [DOI: 10.1080/17469899.2022.2118715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Kiyoung Kim
- Department of Ophthalmology, Kyung Hee University Hospital, Kyung Hee University, Seoul, South Korea
| | - Eung Suk Kim
- Department of Ophthalmology, Kyung Hee University Hospital, Kyung Hee University, Seoul, South Korea
| | - Do Gyun Kim
- Department of Ophthalmology, Myongji Hospital, Hanyang University Medical Center, Goyang-si, South Korea
| | - Seung-Young Yu
- Department of Ophthalmology, Kyung Hee University Hospital, Kyung Hee University, Seoul, South Korea
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30
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Majd E, Minai-Tehrani D, Mollasalehi H. Does dexamethasone inhibit glucose oxidase: an analysis in kinetics and molecular study. Horm Mol Biol Clin Investig 2022; 44:5-10. [PMID: 36044370 DOI: 10.1515/hmbci-2022-0030] [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: 03/19/2022] [Accepted: 07/20/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Glucose oxidase is an enzyme that is widely used in biosensors, especially kits for measuring blood sugar. Many diabetics use this type of kit to determine their blood sugar level. Aspergillus niger is the most important source of glucose oxidase for use in biosensors. Diabetes causes secondary diseases in patients for which medications are prescribed to improve them. Dexamethasone, a corticosteroid, is one of the drugs prescribed to diabetics to cure some secondary diseases. In this study, the effect of this drug on glucose oxidase was investigated from a kinetic and molecular point of view. METHODS In this study, the kinetics of drug binding to the enzyme was measured and the type of inhibition was determined by Lineweaver-Burk plot. The Ki value of the drug was determined by drawing the secondary curve. Using fluorescence spectrophotometry and molecular docking, the binding of the drug to the enzyme was confirmed. RESULTS The results showed that the drug inhibits the enzyme non-competitively. Determining the kinetics parameters of the drug-enzyme interaction showed that the drug acts as a potent inhibitor. Study at the molecular level by fluorescence spectrophotometer showed that the drug attachment alters the enzyme conformation to more compaction. In silico results showed that the drug is placed between two helices that are outside the active site and binds to the enzyme by three hydrogen bonds. CONCLUSIONS The result of this study is useful because it suggests that in diabetic patients taking dexamethasone, the amount of glucose declared by the kit may not be real due to the inhibition of glucose oxidase.
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Affiliation(s)
- Edris Majd
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University (GC), Tehran, Iran
| | - Dariush Minai-Tehrani
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University (GC), Tehran, Iran
| | - Hamidreza Mollasalehi
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University (GC), Tehran, Iran
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31
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Al Qassimi N, Kozak I, Al Karam M, Neri P, Aduriz-Lorenzo PM, Attawan A, Awadalla M, El Khashab A, Abdul-Nabi M, Safar A, Al Shamsi H, Rao P, Rao M, Farid A, Gurbaxani A. Management of Diabetic Macular Edema: Guidelines from the Emirates Society of Ophthalmology. Ophthalmol Ther 2022; 11:1937-1950. [PMID: 35896888 PMCID: PMC9437198 DOI: 10.1007/s40123-022-00547-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/27/2022] [Indexed: 11/27/2022] Open
Abstract
In the United Arab Emirates, retinopathy has been shown to be present in 19% of the diabetic population, with diabetes identified in up to 40% of individuals aged over 55 years. Despite the prevalence of diabetic retinal diseases, there are no unified national guidelines on the management of diabetic macular edema (DME). These published guidelines are based on evidence taken from the literature and published trials of therapies, and consensus opinion of a representative expert panel with an interest in this condition, convened by the Emirates Society of Ophthalmology. The aim is to provide evidence-based, clinical guidance for the best management of different aspects of DME, with a special focus on vision-threatening diabetic retinopathy. Treatment should be initiated in patients with best-corrected visual acuity 20/30 or worse, and/or features of DME as seen on optical coherence tomography (OCT) with central retinal thickness (CRT) of at least 300 μm or in symptomatic patients with vision better than 20/25, and/or CRT less than 300 μm where there are OCT features consistent with center-involving macular edema. The treatment of DME is effective irrespective of glycated hemoglobin (HbA1c) level, and treatment must not be denied or delayed in order to optimize systemic parameters. All ophthalmic treatment options should be discussed with the patient for better compliance and expectations. Non-center-involving DME can be initially observed until progression toward the center is documented. Macular laser no longer has a primary role in center-involving DME, and anti-vascular endothelial growth factor (anti-VEGF) therapy should be considered as first-line treatment for all patients, unless contraindicated. If anti-VEGF is contraindicated, a steroid dexamethasone implant can be considered for first-line treatment. Recommendations for the treatment of DME in special circumstances and in relapsing and refractory DME are also discussed.
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Affiliation(s)
| | - Igor Kozak
- Moorfields Eye Hospital, Abu Dhabi, United Arab Emirates
| | | | - Piergiorgio Neri
- Cleveland Clinic, Abu Dhabi, United Arab Emirates
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
- Khalifa University, Abu Dhabi, United Arab Emirates
| | | | | | | | | | - Mohamed Abdul-Nabi
- Sheikh Shakhbout Medical City in Association With Mayo Clinic, Abu Dhabi, United Arab Emirates
| | - Ammar Safar
- Moorfields Eye Hospital, Dubai, United Arab Emirates
| | | | - Prasan Rao
- Medcare Eye Centre, Dubai, United Arab Emirates
| | - Madhav Rao
- Burjeel Hospital, Abu Dhabi, United Arab Emirates
| | - Amr Farid
- Magrabi Eye Hospital, Dubai, United Arab Emirates
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32
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Parravano M, Allegrini D, Carnevali A, Costanzo E, Giannaccare G, Giorno P, Scorcia V, Spedicato GA, Varano M, Romano MR. Effectiveness of a Hydrophilic Curcumin-Based Formulation in Coadjuvating the Therapeutic Effect of Intravitreal Dexamethasone in Subjects With Diabetic Macular Edema. Front Pharmacol 2022; 12:726104. [PMID: 35058773 PMCID: PMC8763693 DOI: 10.3389/fphar.2021.726104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Purpose: This study evaluates if the addition of a curcumin formulation with a polyvinylpyrrolidone-hydrophilic carrier (CHC; Diabec®, Alfa Intes, Italy) to intravitreal injections of dexamethasone (DEX-IVT) can affect the morphological retinal characteristics, extending the steroid re-treatment period in patients with diabetic macular edema (DME). Methods: A randomized controlled clinical trial was carried out in DME patients, randomly assigned to receive DEX-IVT or DEX-IVT and a CHC. The evaluation of the mean difference of central retinal thickness (CRT) was the primary aim. Secondary aims were the evaluations of best-corrected visual acuity, differences in the predetermined retinal layer thickness, the number/time of re-treatment, and the assessment of safety. Results: A total of 73 DME patients were included (35 in the control group and 38 in the combined therapy group). In both the control and combined therapy groups, the mean CRT change from T0 to the 6 months’ evaluation was significant (p = 0.00). The mean CRT result was significantly different at month 4 (p = 0.01) between the control and combined therapy groups, with a greater reduction in the combined therapy group, in particular, in patients with ≤10 years of diabetes. A trend of CRT reduction in the combined therapy group has been observed also considering patients with subfoveal neuroretinal detachment. In addition, we observed that the reduction of inner retinal layer thickness was greater in the combination group, in comparison with controls. Conclusion: The combination of a CHC to DEX-IVT is a promising therapeutic option in case of DME, in particular, for patients with early-stage diabetes and with an inflammatory phenotype. Further studies will be necessary to confirm these findings.
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Affiliation(s)
| | | | - Adriano Carnevali
- Ophthalmology Unit, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | | | - Giuseppe Giannaccare
- Ophthalmology Unit, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | | | - Vincenzo Scorcia
- Ophthalmology Unit, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | | | | | - Mario R Romano
- Department of Ophthalmology, Bergamo, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Kicková E, Sadeghi A, Puranen J, Tavakoli S, Sen M, Ranta VP, Arango-Gonzalez B, Bolz S, Ueffing M, Salmaso S, Caliceti P, Toropainen E, Ruponen M, Urtti A. Pharmacokinetics of Pullulan-Dexamethasone Conjugates in Retinal Drug Delivery. Pharmaceutics 2021; 14:pharmaceutics14010012. [PMID: 35056906 PMCID: PMC8779473 DOI: 10.3390/pharmaceutics14010012] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/11/2021] [Accepted: 12/17/2021] [Indexed: 12/11/2022] Open
Abstract
The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan-dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan-dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan-dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan-dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.
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Affiliation(s)
- Eva Kicková
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (E.K.); (S.S.); (P.C.)
| | - Amir Sadeghi
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
| | - Jooseppi Puranen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
| | - Shirin Tavakoli
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00710 Helsinki, Finland;
| | - Merve Sen
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Str. 7, D-72076 Tübingen, Germany; (M.S.); (B.A.-G.); (S.B.); (M.U.)
| | - Veli-Pekka Ranta
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
| | - Blanca Arango-Gonzalez
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Str. 7, D-72076 Tübingen, Germany; (M.S.); (B.A.-G.); (S.B.); (M.U.)
| | - Sylvia Bolz
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Str. 7, D-72076 Tübingen, Germany; (M.S.); (B.A.-G.); (S.B.); (M.U.)
| | - Marius Ueffing
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn-Str. 7, D-72076 Tübingen, Germany; (M.S.); (B.A.-G.); (S.B.); (M.U.)
| | - Stefano Salmaso
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (E.K.); (S.S.); (P.C.)
| | - Paolo Caliceti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (E.K.); (S.S.); (P.C.)
| | - Elisa Toropainen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
| | - Marika Ruponen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
| | - Arto Urtti
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland; (A.S.); (J.P.); (V.-P.R.); (E.T.); (M.R.)
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00710 Helsinki, Finland;
- Institute of Chemistry, St. Petersburg State University, Petergof, Universitetskii pr. 26, 198504 St. Petersburg, Russia
- Correspondence:
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Karti O, Saatci AO. Place of intravitreal dexamethasone implant in the treatment armamentarium of diabetic macular edema. World J Diabetes 2021; 12:1220-1232. [PMID: 34512888 PMCID: PMC8394236 DOI: 10.4239/wjd.v12.i8.1220] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 04/25/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic macular edema (DME) is a very important and well-known cause of visual loss in diabetics. Blood–retina barrier disruption and consequent intraretinal fluid accumulation may lead to retinal thickening at the posterior pole namely DME. Even though it is not clearly understood, current evidence suggests that chronic low-grade inflammation characterized with various cytokines has a major role in the occurrence of DME. Clinical trials are continuously shaping our treatment approaches for the eyes with DME. Today, vascular endothelial growth factor (VEGF) inhibitor and steroid administrations are the main alternatives in DME treatment. Dexamethasone (DEX) implant (Ozurdex®; Allergan, Inc., Irvine, CA, United States) was approved by the United States Food & Drug Administration in 2014 for DME treatment. The implant is made up of a biodegradable solid copolymer that is broken down by releasing its active ingredient into the vitreous cavity over time. Biphasic release feature of this sustained-release drug delivery system ensures its efficacy for up to 6 mo with an acceptable and manageable safety profile. DEX implant provides a favorable anatomical and functional outcome in DME as shown in several randomized-controlled studies but has a relatively higher ocular side-effect profile such as increased risk of cataract formation and raised intraocular pressure when compared to the gold standard anti-VEGF agents. Thus, DEX implant becomes the second-line treatment option demonstrating inadequate clinical response to anti-VEGF therapy. However, it can be preferred as the first-line treatment in vitrectomized and pseudophakic eyes. Even in some selected conditions DEX implant is favored over anti-VEGF agents where the use of VEGF-inhibitors is either inappropriate or contraindicated such as the patients with a recent history of a major cardiovascular or cerebrovascular event, pregnancy and noncompliant to frequent visits. This mini-review briefly overviews the efficacy, safety profile and complications of DEX implant and summarizes the outcome of DEX implant administration in major clinical studies on DME treatment.
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Affiliation(s)
- Omer Karti
- Department of Ophthalmology, İzmir Democracy University, İzmir 35330, Turkey
| | - Ali Osman Saatci
- Department of Ophthalmology, Dokuz Eylul University, İzmir 35330, Turkey
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Kucukkomurcu E, Sahin T. Anterior chamber changes assessment by Scheimpflug analysis after intravitreal dexamethasone implantation. Eur J Ophthalmol 2021; 32:336-340. [PMID: 34218720 DOI: 10.1177/11206721211029467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To evaluate structural changes in the anterior chamber and intraocular pressure (IOP) changes following intravitreal dexamethasone implantation. METHODS Forty-two eyes of 42 patients that received intravitreal dexamethasone implant for the management of macular edema secondary to diabetic retinopathy or branch retinal vein occlusion (BRVO) were included in the study. IOP was measured by Goldmann applanation tonometry. Anterior chamber depth (ACD) and iridocorneal angle (ICA) was measured by a Scheimflug camera (Sirius, CSO, Italy) the day before the injection of the dexamethasone implant and on postoperative day 1, first week, and first month. RESULTS Mean IOP was 15.14 ± 2.77 mmHg before the procedure and, 15.67 ± 3.70 mmHg, 15.86 ± 3.11 mmHg, 16.21 ± 2.75 mmHg on day 1, first week, and first month following intravitreal dexamethasone implantation, respectively. Mean ICA and ACD were significantly higher in pseudophakic eyes compared to phakic eyes. However, there was no statistically significant change in ICA before and after the procedure (on postoperative day 1, first week, and first month) among both phakic and pseudophakic patients (p = 0.783). Similarly, ACD remained unchanged after the procedure (on postoperative day 1, first week, and first month) compared to the initial measurement (p = 0.802). CONCLUSION This study confirmed that there was an increase in IOP. However, these changes were not accompanied with a change in ACD or ICA.
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Affiliation(s)
| | - Tayfun Sahin
- Department of Ophthalmology, Hitit University School of Medicine, Corum, Turkey
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Pullulan Based Bioconjugates for Ocular Dexamethasone Delivery. Pharmaceutics 2021; 13:pharmaceutics13060791. [PMID: 34073275 PMCID: PMC8227697 DOI: 10.3390/pharmaceutics13060791] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 11/16/2022] Open
Abstract
Posterior segment eye diseases are mostly related to retinal pathologies that require pharmacological treatments by invasive intravitreal injections. Reduction of frequent intravitreal administrations may be accomplished with delivery systems that provide sustained drug release. Pullulan-dexamethasone conjugates were developed to achieve prolonged intravitreal drug release. Accordingly, dexamethasone was conjugated to ~67 kDa pullulan through hydrazone bond, which was previously found to be slowly cleavable in the vitreous. Dynamic light scattering and transmission electron microscopy showed that the pullulan-dexamethasone containing 1:20 drug/glucose unit molar ratio (10% w/w dexamethasone) self-assembled into nanoparticles of 461 ± 30 nm and 402 ± 66 nm, respectively. The particles were fairly stable over 6 weeks in physiological buffer at 4, 25 and 37 °C, while in homogenized vitreous at 37 °C, the colloidal assemblies underwent size increase over time. The drug was released slowly in the vitreous and rapidly at pH 5.0 mimicking lysosomal conditions: 50% of the drug was released in about 2 weeks in the vitreous, and in 2 days at pH 5.0. In vitro studies with retinal pigment epithelial cell line (ARPE-19) showed no toxicity of the conjugates in the cells. Flow cytometry and confocal microscopy showed cellular association of the nanoparticles and intracellular endosomal localization. Overall, pullulan conjugates showed interesting features that may enable their successful use in intravitreal drug delivery.
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Vural E, Hazar L. Assessment of Inflammation Biomarkers in Diabetic Macular Edema Treated with Intravitreal Dexamethasone Implant. J Ocul Pharmacol Ther 2021; 37:430-437. [PMID: 33961524 DOI: 10.1089/jop.2020.0130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Purpose: To evaluate inflammation biomarkers in diabetic macular edema (DME) treated with intravitreal dexamethasone implant (Ozurdex®). Methods: This retrospective single-center study investigated 64 eyes of 64 patients with DME who were nonresponsive to prior antivascular endothelial growth factor and treated with intravitreal Ozurdex. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio were calculated. Visual acuity and optical coherence tomography markers, including hyper-reflective dots and subretinal fluid (SRF), were determined, and central retinal thickness was also evaluated monthly for 3 months. Results: The average age was 64.06 ± 7.81 (48-84) years. The baseline NLR and MLR were significantly higher in patients with better visual outcomes (P = 0.029 and P = 0.048, respectively). Better anatomical outcomes were observed in the presence of SRF (P = 0.027). No significant differences were observed in the rates of the presence of SRF and hyper-reflective points about the better functional outcome (P > 0.05). Conclusions: SRF as an imaging biomarker, and NLR and MLR as blood biomarkers, stand out as markers of inflammation and were found to be associated with better response to Ozurdex implantation in DME.
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Affiliation(s)
- Esra Vural
- Department of Ophthalmology, Kayseri City Hospital, Kayseri, Turkey
| | - Leyla Hazar
- Department of Ophthalmology, Dicle University School of Medicine, Diyarbakır, Turkey
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COMPARISON OF INTRAVITREAL DEXAMETHASONE IMPLANT AND AFLIBERCEPT IN PATIENTS WITH TREATMENT-NAIVE DIABETIC MACULAR EDEMA WITH SEROUS RETINAL DETACHMENT. Retina 2021; 40:1044-1052. [PMID: 30950970 DOI: 10.1097/iae.0000000000002537] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE To compare the efficacy and safety of intravitreal dexamethasone (DEX) implant versus aflibercept in patients with treatment-naive diabetic macular edema with inflammatory biomarkers. METHODS Ninety-eight eyes of 62 treatment-naive patients with diabetic macular edema with serous retinal detachment and hyperreflective foci were enrolled. Each patient was randomized to receive either aflibercept or DEX implant treatment. The treatment protocol included 3 monthly injections of 2 mg of aflibercept as a loading phase in the anti-vascular endothelial growth factor group and 0.7 mg of DEX implant in the DEX group and then pro re nata treatment. Primary outcome measures were mean changes in visual acuity and central retinal thickness at the end of the 12-month follow-up. RESULTS Forty-eight eyes of 29 patients were received DEX implant, and 50 eyes of 33 patients received the aflibercept injection. Mean central retinal thickness decreased from 615.2 µm at baseline to 297.7 µm at 12 months in the DEX group (P < 0.001) and from 576.5 µm to 367.4 µm in the aflibercept group (P < 0.001). Except for the first month, mean central retinal thickness reduction was significantly higher in the DEX group (P < 0.05, Mann-Whitney U Test). Visual acuity improved significantly at the end of the follow-ups (46.3-52.7 Early Treatment Diabetic Retinopathy Study letters in the DEX group and 47.5-56.8 Early Treatment Diabetic Retinopathy Study letters in the aflibercept group at 12 months, P < 0.001, paired-sample t-test). Adjusting by baseline values, the increase in mean visual acuity during the 12-month follow-ups favored the aflibercept group (P < 0.01), 25% of the DEX-treated eyes and 42% of the aflibercept treated eyes experienced 10 or more Early Treatment Diabetic Retinopathy Study letters visual gain (P: 0.058). The DEX group received significantly fewer (2.6 vs. 7.2) injections (P: 0.001). CONCLUSION It was observed that the both of DEX implant and aflibercept were effective and safe in treatment-naive diabetic macular edema patients with inflammatory phenotype. Anatomical results were found to be better in the DEX group, and functional results were found to be better in the aflibercept group. In pseudophakic eyes, the functional superiority of aflibercept ceased to exist, and the low number of injections in the DEX implant group was seen as an advantage.
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Wang JK, Huang TL, Hsu YR, Chang PY. Effect of dexamethasone intravitreal implant for refractory and treatment-naive diabetic macular edema in Taiwanese patients. J Chin Med Assoc 2021; 84:326-330. [PMID: 33433135 DOI: 10.1097/jcma.0000000000000483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Dexamethasone (DEX) implant has been shown to improve visual and anatomic function in patients with diabetic macular edema (DME). The purpose of this study was to investigate the efficacy and safety of DEX implant between refractory and naive eyes with DME. METHODS We retrospectively reviewed data from pseudophakic patients with center-involved DME who received DEX implant (1 + as needed retreatment) from May 2015 to May 2017. Baseline clinical characteristics, changes in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were analyzed and compared between the two groups. Adverse events were recorded. RESULTS Thirty-four eyes of 31 patients refractory to anti-vascular endothelial growth factor agents and 41 eyes of 38 treatment-naive patients were reviewed. Baseline characteristics were comparable between the two groups (p > 0.05). In the refractory eyes, significant improvements in both BCVA and CFT were observed at 1 month post DEX implant and sustained throughout 6 months. Mean change from baseline in BCVA at 6 months was -0.17 ± 0.35 logMAR (7.29 ± 16.22 letters) and 155.44 ± 112.67 μm in CFT. Similar trends of improvement were seen in treatment-naive eyes; however, the visual improvement (-0.30 ± 0.29 logMAR [16.42 ± 14.38 letters]) was significantly better than the refractory group, with significantly less injections (1.54 ± 0.49 versus 1.82 ± 0.38, p = 0.007). Between-group changes in CFT were comparable. No serious ocular complications occurred, and about a quarter of the patients had elevated intraocular pressures that were manageable with topical medications. CONCLUSION To our knowledge, this was the first study comparing DEX implant between treatment-naive and refractory Asian patients with DME. Intravitreal DEX implant can effectively treat refractory and treatment-naive patients with DME. In addition, superior visual outcomes were observed in the naive group comparing to the refractory group following DEX implant treatment in Taiwanese pseudophakic eyes with DME.
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Affiliation(s)
- Jia-Kang Wang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
- Department of Electrical Engineering, Yuan Ze University, Taoyuan, Taiwan, ROC
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Healthcare Administration and Department of Nursing, Oriental Institute of Technology, New Taipei City, Taiwan, ROC
- Department of Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Tzu-Lun Huang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
- Department of Electrical Engineering, Yuan Ze University, Taoyuan, Taiwan, ROC
| | - Yung-Ray Hsu
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
- Department of Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Pei-Yao Chang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan, ROC
- Department of Medicine, National Taiwan University, Taipei, Taiwan, ROC
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Kaya M, Kocak N, Ozturk T, Bolluk V, Ayhan Z, Kaynak S. Intravitreal ranibizumab and dexamethasone implant injections as primary treatment of diabetic macular edema: simultaneously double protocol. Eye (Lond) 2021; 35:777-785. [PMID: 32398852 PMCID: PMC8027799 DOI: 10.1038/s41433-020-0949-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 04/09/2020] [Accepted: 04/29/2020] [Indexed: 12/19/2022] Open
Abstract
PURPOSE To assess the 12-month efficacy and safety of simultaneously administered intravitreal dexamethasone implant (DEX implant) and ranibizumab (simultaneous double protocol) injections in comparison with ranibizumab monotherapy as the first-line treatment of diabetic macular oedema (DMO). METHODS Prospective, consecutive, clinical interventional study. Patients were randomized into two groups: 24 naive DMO patients (34 eyes) who received simultaneous double-protocol therapy and 22 DMO patients (34 eyes) who received ranibizumab monotherapy were included. Monthly ranibizumab (0.5 mg) was administered for the first 6 months and later on, an as-needed treatment basis. DEX implant injection was performed at any time during the loading dose of the three consecutive monthly injections of ranibizumab, and with as-needed reinjections of ranibizumab from 6th month onwards. Change in visual acuity was the primary efficacy endpoint. Secondary efficacy endpoints were a gain of ≥15 letters and a change in the central foveal thickness. RESULTS Mean BCVA increased from baseline to month 12 in the simultaneously double-protocol therapy group compared with the ranibizumab monotherapy group (21.6 versus 9.6 letters [P < 0.001]). The corresponding proportions of eyes gaining ≥15 letters were 60% versus 29.4% (P < 0.0001). Moreover, the mean reductions in the central foveal thickness were 413 versus 282 µm (P = 0.001). At 12 month, the simultaneous double-protocol therapy decreased a significant number of foveal cysts and subfoveal neuroretinal detachment compared with those by ranibizumab monotherapy. CONCLUSIONS The simultaneous addition of DEX implant at any time during the three monthly loading doses of ranibizumab in patients with DMO significantly improved the visual outcomes and revealed superior anatomic outcomes than those with the ranibizumab monotherapy.
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Affiliation(s)
- Mahmut Kaya
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey.
| | - Nilufer Kocak
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Taylan Ozturk
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Volkan Bolluk
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Ziya Ayhan
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Suleyman Kaynak
- Department of Ophthalmology, Dokuz Eylul University School of Medicine, Izmir, Turkey
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Peptidomimetics Therapeutics for Retinal Disease. Biomolecules 2021; 11:biom11030339. [PMID: 33668179 PMCID: PMC7995992 DOI: 10.3390/biom11030339] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/11/2021] [Accepted: 02/20/2021] [Indexed: 12/28/2022] Open
Abstract
Ocular disorders originating in the retina can result in a partial or total loss of vision, making drug delivery to the retina of vital importance. However, effectively delivering drugs to the retina remains a challenge for ophthalmologists due to various anatomical and physicochemical barriers in the eye. This review introduces diverse administration routes and the accordant pharmacokinetic profiles of ocular drugs to aid in the development of safe and efficient drug delivery systems to the retina with a focus on peptidomimetics as a growing class of retinal drugs, which have great therapeutic potential and a high degree of specificity. We also discuss the pharmacokinetic profiles of small molecule drugs due to their structural similarity to small peptidomimetics. Lastly, various formulation strategies are suggested to overcome pharmacokinetic hurdles such as solubility, retention time, enzymatic degradation, tissue targeting, and membrane permeability. This knowledge can be used to help design ocular delivery platforms for peptidomimetics, not only for the treatment of various retinal diseases, but also for the selection of potential peptidomimetic drug targets.
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Lytvynchuk LM, Petrovski G, Dam A, Hiemstra J, Wimmer T, Savytska I, Binder S, Stieger K. Novel Needle for Intravitreal Drug Delivery: Comparative Study of Needle Tip Aspirates, Injection Stream and Penetration Forces. Clin Ophthalmol 2021; 15:723-734. [PMID: 33642853 PMCID: PMC7903950 DOI: 10.2147/opth.s297139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/21/2021] [Indexed: 12/03/2022] Open
Abstract
Purpose To study the efficacy of a novel needle for intravitreal injection (IVI) in comparison to the conventional needle under experimental conditions. Methods The newly designed 30-gauge (G) needle (NDN) (EP 18158 542.3, patent pending) with occluded outer orifice and a side port for drug delivery was compared to the conventional standard hypodermic 30 G needle for IVI (SHN). An animal study to obtain needle tip aspirates was performed on 10 albino rat eyes. During IVIs, cellular content, which was cut by the needle tip, was aspirated. Cellular material was studied in regard to cell types and their quantity. The injection stream was studied using trypan blue dye in vitro and pig cadaver eyes. The penetration force was tested on polyurethane Testing Foil Strips PU 04 (Melab, Leonberg, Germany) by applying a velocity of 100 mm/min. The results were analyzed using descriptive statistics, correlation matrices and t-test methods with p<0.05 as statistically significant. Results Cytological analysis of the needle aspirates showed the presence of cellular content in each case. The amount of conjunctival, ciliary body epithelial cells and granulated basophilic protein sediments (sign of cellular damage) in the case of the NDN tips was significantly lower compared to the SHN. The average penetration force of the NDN was 0.791 N, and in the case of the SHN was 0.566 N. The injection stream study revealed a difference in the initial injection phase between the two needle types, although the diffuse filling of the vitreous area which surrounded the needle tip appeared to be similar. Discussion The NDN demonstrated superior performance with regard to a significantly reduced number of cells being captured by the needle tip. Delivery of the injected fluid into the vitreous cavity was comparable. In order to investigate superior properties of the NDN needle design, further studies with improved prototypes would be necessary.
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Affiliation(s)
- Lyubomyr M Lytvynchuk
- Department of Ophthalmology, Justus-Liebig-University Giessen, Eye Clinic, University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany.,Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria
| | - Goran Petrovski
- Center of Eye Research, Department of Ophthalmology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Adien Dam
- Vitreq B.V., MG Vierpolders, the Netherlands
| | | | - Tobias Wimmer
- Department of Ophthalmology, Justus-Liebig-University Giessen, Eye Clinic, University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany
| | - Iryna Savytska
- Department of Experimental Surgery, A.A.Shalimov National Institute of Surgery and Transplantology, National Academy of Medical Science of Ukraine, Kyiv, Ukraine
| | - Susanne Binder
- Karl Landsteiner Institute for Retinal Research and Imaging, Vienna, Austria.,Department of Ophthalmology, Sigmund Freud University, Eye Center Donaustadt, Vienna, Austria
| | - Knut Stieger
- Department of Ophthalmology, Justus-Liebig-University Giessen, Eye Clinic, University Hospital Giessen and Marburg GmbH, Campus Giessen, Giessen, Germany
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Choovuthayakorn J, Phinyo P, Tantraworasin A, Kunavisarut P, Patikulsila D, Chaikitmongkol V, Watanachai N, Pathanapitoon K. Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in Clinical Practice of Single Center: Three-Year Outcomes. Ophthalmic Res 2020; 64:483-493. [PMID: 33053556 DOI: 10.1159/000512300] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/10/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION The objective of this study was to explore visual and anatomical outcomes in patients who underwent intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection for visual impairment from center-involved diabetic macular edema (CI-DME) in clinical practice. METHODS Medical records of consecutive CI-DME patients who initiated treatment with intravitreal bevacizumab injection between January 2012 and December 2016 and were followed for at least 12 months were retrospectively reviewed. Visual and anatomical changes after treatment over a 36-month period were evaluated. RESULTS There were 286 patients (423 eyes) with a mean (standard deviation, SD) age of 56.8 (8.5) years included in this study. One hundred and forty-six (51%) patients were female, and 137 (47.9%) patients received bilateral eye treatment. Mean (SD) presenting visual acuity (VA) of overall eyes was 50.2 (19.6) letter scores. Stratified by baseline vision, eyes with initial VA worse than 20/40 achieved a statistically significant VA improvement, compared to baseline, by +8.4, +6.9, and +5.4 letters at 12, 24, and 36 months, respectively, with all p values <0.001. However, when initial VA was 20/40 and better, a non-statistically significant change in mean VA by +2.0, -3.5, and -3.6 letters were noted at the same time point (p value between 0.078 and 0.273). Unlike visual changes, a statistically significant decline in central subfield thickness compared to baseline was noted at the end of months 12, 24, and 36 in both initial VA subgroups (all p values <0.001). Nevertheless, even though the median number of given injections considerably decreased from 6 in the first 12 months to 2 in the second 12-month period and 1 in the final 12-month interval, required ophthalmic clinic visits decreased in frequency with median numbers of 10, 7, and 6 appointments in each consecutive 12-month duration. CONCLUSION This study supports the benefits of practical intravitreal anti-VEGF utilization to manage CI-DME in real-world settings. The improvement of vision in eyes presenting with poor baseline VA and maintenance of vision in eyes with better baseline VA were demonstrated through the 3-year review of each case. However, the burden of frequent monitoring warrants further evaluation of long-term compliance and efficacy.
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Affiliation(s)
- Janejit Choovuthayakorn
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Phichayut Phinyo
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Clinical Epidemiology and Clinical Statistics Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Apichat Tantraworasin
- Clinical Epidemiology and Clinical Statistics Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Paradee Kunavisarut
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Direk Patikulsila
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Voraporn Chaikitmongkol
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nawat Watanachai
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kessara Pathanapitoon
- Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Sarkar B, Siddiqui Z, Kim KK, Nguyen PK, Reyes X, McGill TJ, Kumar VA. Implantable anti-angiogenic scaffolds for treatment of neovascular ocular pathologies. Drug Deliv Transl Res 2020; 10:1191-1202. [PMID: 32232681 PMCID: PMC7483832 DOI: 10.1007/s13346-020-00753-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The retinal physiology can accrue oxidative damage and inflammatory insults due to age and metabolic irregularities. Two notable diseases that involve retinal and choroidal neovascularization are proliferative diabetic retinopathy and wet age-related macular degeneration. Currently, these diseases are mainly treated with anti-VEGF drugs (VEGF = vascular endothelial growth factor), generally on a monthly dosage scheme. We discuss recent developments for the treatment of these diseases, including bioactive tissue-engineered materials, which may reduce frequency of dosage and propose a path forward for improving patient outcomes. Graphical abstract Development of materials for long-term intravitreal delivery for management of posterior segment diseases.
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Affiliation(s)
- Biplab Sarkar
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA
| | - Zain Siddiqui
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA
| | - Ka Kyung Kim
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA
| | - Peter K Nguyen
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA
| | - Xavier Reyes
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA
| | - Trevor J McGill
- Casey Eye Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Vivek A Kumar
- Department of Biomedical Engineering, New Jersey Institute of Technology, 138 Warren St. LSEB 316, Newark, NJ, 07102, USA.
- Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
- Department of Restorative Dentistry, Rutgers School of Dental Medicine, Newark, NJ, USA.
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Bayat AH, Karataş G, Kurt MM, Elçioğlu MN. The corneal effects of intravitreal dexamethasone implantation. Ther Adv Ophthalmol 2020; 12:2515841420947544. [PMID: 32844147 PMCID: PMC7418223 DOI: 10.1177/2515841420947544] [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: 05/12/2020] [Accepted: 07/13/2020] [Indexed: 11/21/2022] Open
Abstract
Objectives: To evaluate the corneal effects of the intravitreal dexamethasone implantation using corneal topography and specular microscopy. Material and methods: 27 eyes of the 27 patients who received a single intravitreal dexamethasone implantation dose for diabetic macular edema were enrolled in this study. Sirius topography and EM-3000 specular microscopic examinations were performed at the initial examination (baseline), and then on the first day, during the first week, and 1 month after IDI. Changes in corneal parameters were investigated. Results: The mean age was 58.66 ± 6.59 years. 15 patients were men, and 12 were women. The mean disease duration was 12.2 ± 2.4 months, and mean glycosylated hemoglobin (HbA1c) was 7.2 ± 1.1. After dexamethasone injection, the mean central corneal thickness, endothelial cell density, and coefficient variation of cell area presented a statistically significant decrease (p < 0.05). Anterior segment parameters, such as anterior chamber depth, iridocorneal angle, sim K1 and K2 keratometry, pupillary diameter, horizontal visible iris diameter, and corneal astigmatism did not change (p > 0.05). Conclusion: Intravitreal dexamethasone implantation affects corneal endothelial cell structure but does not appear to affect corneal topography parameters.
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Affiliation(s)
- Alper Halil Bayat
- Department of Ophthalmology, Esenler Hospital, Medipol University, APT: 5 Bahceler, AVE Esenler, Istanbul 34250, Turkey
| | - Gamze Karataş
- Department of Ophthalmology, Okmeydanı Research &Traning Hospital, University of Health Sciences, İstanbul, Turkey
| | | | - Mustafa Nuri Elçioğlu
- Department of Ophthalmology, Okmeydanı Research &Traning Hospital, University of Health Sciences, İstanbul, Turkey
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Ratra D, Sharma U, Dalan D. Efficacy and safety of intravitreal dexamethasone implant in treatment naïve eyes with diabetic macular edema: Real world experience. Eur J Ophthalmol 2020; 31:1899-1906. [PMID: 32772850 DOI: 10.1177/1120672120949761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE To evaluate the efficacy and safety of intravitreal dexamethasone implant in treatment naïve eyes with diabetic macular edema (DME). METHODS A retrospective analysis of treatment naïve eyes with DME which received intravitreal dexamethasone implant between January 2016 and March 2018 was done. Demographic details of the patients, ocular examination findings at baseline and on follow up visits were noted. Morphological features of DME and central macular thickness were noted on optical coherence tomography at each visit. The details regarding additional treatment for macular edema on follow up were noted. RESULTS Sixty five eyes were included in the study. The mean age was 59.14 ± 9.59 years. The follow up ranged from 6 to 48 months. Psuedophakic eyes showed visual improvement whereas the phakic eyes showed stable vision. The central foveal thickness showed significant reduction (p = 0.05) in all the eyes. The best corrected visual acuity at final follow up (+0.65 logMAR) was slightly less as compared to baseline (+0.62 logMAR). Retreatment was needed in 37% eyes and antiglaucoma medications in 8% eyes. Cataract progression was noted in 24 eyes (37%); 17 eyes (26.1%) underwent surgery. Notably, 27 eyes (41.5%) had some degree of macular ischemia at baseline. And five eyes (7.7%) showed progression of retinopathy leading to vitreous hemorrhage. CONCLUSION Dexamethasone implant is helpful in reducing the macular thickness and stabilizing the vision in treatment naïve DME; requiring less number of treatment sessions. However, it does not prevent progression of diabetic retinopathy. The visual improvement may be affected by cataract and macular ischemia.
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Affiliation(s)
- Dhanashree Ratra
- Department of Vitreoretinal Diseases, Sankara Nethralaya, Chennai, India
| | | | - Daleena Dalan
- Department of Vitreoretinal Diseases, Sankara Nethralaya, Chennai, India
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Iovino C, Mastropasqua R, Lupidi M, Bacherini D, Pellegrini M, Bernabei F, Borrelli E, Sacconi R, Carnevali A, D’Aloisio R, Cerquaglia A, Finocchio L, Govetto A, Erba S, Triolo G, Di Zazzo A, Forlini M, Vagge A, Giannaccare G. Intravitreal Dexamethasone Implant as a Sustained Release Drug Delivery Device for the Treatment of Ocular Diseases: A Comprehensive Review of the Literature. Pharmaceutics 2020; 12:pharmaceutics12080703. [PMID: 32722556 PMCID: PMC7466091 DOI: 10.3390/pharmaceutics12080703] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 12/13/2022] Open
Abstract
Drug delivery into the vitreous chamber remains a great challenge in the pharmaceutical industry due to the complex anatomy and physiology of the eye. Intravitreal injection is the mainstream route of drug administration to the posterior segment of the eye. The purpose of this review is to assess the current literature about the widening use of the intravitreal 0.7 mg dexamethasone (Dex) implant, and to provide a comprehensive collection of all the ocular disorders that benefit from Dex administration. Although anti-vascular endothelial growth-factors (VEGFs) have been largely indicated as a first-choice level, the Dex implant represents an important treatment option, especially in selected cases, such as vitrectomized eyes or patients in whom anti-VEGF failed or are contraindicated. In this article, the safety profile as well as the list of the possible complications related to intravitreal Dex injection are also discussed.
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Affiliation(s)
- Claudio Iovino
- Department of Surgical Sciences, Eye Clinic, University of Cagliari, 09124 Cagliari, Italy
- Correspondence: ; Tel.: +39-070-609-2319
| | - Rodolfo Mastropasqua
- Institute of Ophthalmology, University of Modena and Reggio Emilia, 41121 Modena, Italy;
| | - Marco Lupidi
- Department of Surgical and Biomedical Sciences, Section of Ophthalmology, University of Perugia, S. Maria della Misericordia Hospital, 06129 Perugia, Italy; (M.L.); (A.C.)
- Fondazione per la Macula Onlus, DINOMGI., University Eye Clinic, 16132 Genova, Italy
- Centre de l’Odéon, 113 Boulevard St Germain, 75006 Paris, France
| | - Daniela Bacherini
- Department of Neurosciences, Psychology, Drug Research and Child Health, Eye Clinic, University of Florence, AOU Careggi, 50139 Florence, Italy; (D.B.); (L.F.)
| | - Marco Pellegrini
- Ophthalmology Unit, S. Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy; (M.P.); (F.B.)
| | - Federico Bernabei
- Ophthalmology Unit, S. Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy; (M.P.); (F.B.)
| | - Enrico Borrelli
- Department of Ophthalmology, Hospital San Raffaele, University Vita Salute San Raffaele, 20132 Milan, Italy; (E.B.); (R.S.)
| | - Riccardo Sacconi
- Department of Ophthalmology, Hospital San Raffaele, University Vita Salute San Raffaele, 20132 Milan, Italy; (E.B.); (R.S.)
| | - Adriano Carnevali
- Department of Ophthalmology, University “Magna Graecia,” 88100 Catanzaro, Italy; (A.C.); (G.G.)
| | - Rossella D’Aloisio
- Department of Medicine and Science of Ageing, Ophthalmology Clinic, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy;
| | - Alessio Cerquaglia
- Department of Surgical and Biomedical Sciences, Section of Ophthalmology, University of Perugia, S. Maria della Misericordia Hospital, 06129 Perugia, Italy; (M.L.); (A.C.)
| | - Lucia Finocchio
- Department of Neurosciences, Psychology, Drug Research and Child Health, Eye Clinic, University of Florence, AOU Careggi, 50139 Florence, Italy; (D.B.); (L.F.)
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V2PD, UK
| | - Andrea Govetto
- Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, 63631 Milan, Italy; (A.G.); (S.E.); (G.T.)
- Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol BS12LX, UK
| | - Stefano Erba
- Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, 63631 Milan, Italy; (A.G.); (S.E.); (G.T.)
| | - Giacinto Triolo
- Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, 63631 Milan, Italy; (A.G.); (S.E.); (G.T.)
| | - Antonio Di Zazzo
- Ophthalmology Complex Operative Unit, Campus Bio Medico University Hospital, 00128, Rome, Italy;
| | | | - Aldo Vagge
- University Eye Clinic, DINOGMI, Polyclinic Hospital San Martino IRCCS, 16132 Genoa, Italy;
| | - Giuseppe Giannaccare
- Department of Ophthalmology, University “Magna Graecia,” 88100 Catanzaro, Italy; (A.C.); (G.G.)
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Alessio G, Boscia F, Caporossi A, Panozzo G, Reibaldi M, Staurenghi G, Varano M, Bandello F. Dexamethasone implants in patients with diabetic macular edema undergoing cataract surgery: Italian expert panel consensus statements. Eur J Ophthalmol 2020; 31:1122-1127. [PMID: 32635762 DOI: 10.1177/1120672120939500] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Intravitreal corticosteroid implants based on sustained-release dexamethasone provide effective retinal delivery of drug for around 6 months for the treatment of diabetic macular edema (DME). As current recommendations on the management of patients with DME undergoing cataract surgery are limited, this article aims to highlight issues and provide guidance on the use of dexamethasone intravitreal implants (DEX-DDS) in patients with DME undergoing cataract surgery, based on the consensus findings of a panel of Italian experts. METHODS The panel developed a survey regarding the use of DEX-DDS in patients with DME undergoing cataract surgery, following a comprehensive literature search. The results of the survey were discussed at an experts' meeting in September 2018, with a structured approach to determining consensus. The routine management of patients with DME undergoing cataract surgery was also developed for use as a basis of discussion to highlight current issues. RESULTS Eight consensus statements are presented, along with key issues that highlight controversial/outstanding issues in the use of DEX-DDS in DME patients with cataracts. CONCLUSION The consensus statements can help provide practical guidance for clinicians in daily practice on the rationale, patient diagnosis and selection, and optimal management of patients with DME undergoing cataract surgery.
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Affiliation(s)
- Giovanni Alessio
- Department of Medical Science, Neuroscience and Sense Organs, Eye Clinic, University of Bari "A. Moro", Bari, Italy
| | - Francesco Boscia
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Aldo Caporossi
- Fondazione Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, Rome, Lazio, Italy
| | | | - Michele Reibaldi
- Department of Ophthalmology, University of Catania, Catania, Italy
| | - Giovanni Staurenghi
- Department of Biomedical and Clinical Science Sacco Hospital, University of Milan, Milan, Italy
| | | | - Francesco Bandello
- Department of Ophthalmology, IRCCS Ospedale San Raffaele, University Vita-Salute, Milan, Italy
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Eandi CM, De Geronimo D, Giannini D, Polito MS, Tosi GM, Neri G, Le Mer Y, Varano M, Parravano M. Baseline SD-OCT characteristics of diabetic macular oedema patterns can predict morphological features and timing of recurrence in patients treated with dexamethasone intravitreal implants. Acta Diabetol 2020; 57:867-874. [PMID: 32114643 PMCID: PMC7311372 DOI: 10.1007/s00592-020-01504-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/11/2020] [Indexed: 12/31/2022]
Abstract
AIMS To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I). METHODS This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence. RESULTS Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes. CONCLUSIONS Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.
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Affiliation(s)
- Chiara M Eandi
- Department of Surgical Sciences, University of Torino, C. Dogliotti 14, 10126, Turin, Italy.
- Department of Ophthalmology, Jules-Gonin Eye Hospital, University of Lausanne, Fondation Asile des aveugles, Lausanne, Switzerland.
- Department of Ophthalmology, Fondation Ophtalmologique A. De Rothschild, Paris, France.
| | | | | | - Maria Sole Polito
- Department of Surgical Sciences, University of Torino, C. Dogliotti 14, 10126, Turin, Italy
| | - Gian Marco Tosi
- Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Giovanni Neri
- Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Yannick Le Mer
- Department of Ophthalmology, Fondation Ophtalmologique A. De Rothschild, Paris, France
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Wang JK, Huang TL, Chang PY. Effect of dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes of Taiwanese patients with treatment-naïve diabetic macular edema. J Formos Med Assoc 2020; 119:1619-1625. [PMID: 32482606 DOI: 10.1016/j.jfma.2020.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 02/28/2020] [Accepted: 04/15/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND/PURPOSE Vitrectomy may affect intravitreal drug clearance and efficacy for treating diabetic macular edema (DME). This study aimed to evaluate functional and anatomical outcomes of intravitreal dexamethasone (DEX) implant for vitrectomized and nonvitrectomized eyes with treatment-naïve DME in Taiwanese patients. METHODS In this retrospective single-center study, we reviewed treatment-naïve patients who received DEX implant monotherapy for center-involved DME from January 2015 to May 2017. Retreatments were provided at least 4 months apart as needed. The primary outcomes included changes from baseline in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) at Month 6. Adverse events were recorded. RESULTS Twenty-seven eyes in 27 patients had prior vitrectomy and 43 eyes in 41 patients without vitrectomy. Baseline data were comparable. Overall, the improvements in BCVA and CFT were significant by 1 month post-treatment and sustained throughout the study (all p < 0.05). At Month 6, BCVA improved by 16.5 and 12.1 letters, and CFT reduced by 138.0 and 121.9 μm in vitrectomized and nonvitrectomized eyes, respectively, with a mean of 1.5 DEX implant injection. No significant differences in clinical outcomes were seen between the two groups (all p > 0.05). DEX implant injection was well tolerated. About 30% of patients had post-injection intraocular pressure value > 20 mmHg, and all were manageable with topical hypotensive agents, and no serious ocular complication was observed. CONCLUSION In this 6-month retrospective study, intravitreal DEX implant was effective in Taiwanese patients with treatment-naïve DME regardless of vitrectomy status.
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Affiliation(s)
- Jia-Kang Wang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Electrical Engineering, Yuan Ze University, Taoyuan City, Taiwan; Department of Medicine, National Yang Ming University, Taipei City, Taiwan; Department of Healthcare Administration and Department of Nursing, Oriental Institute of Technology, New Taipei City, Taiwan; Department of Medicine, National Taiwan University, Taipei City, Taiwan.
| | - Tzu-Lun Huang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Electrical Engineering, Yuan Ze University, Taoyuan City, Taiwan
| | - Pei-Yao Chang
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medicine, National Taiwan University, Taipei City, Taiwan
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