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1
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Silnitsky S, Rubin SJS, Zerihun M, Qvit N. An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. Int J Mol Sci 2023; 24:17600. [PMID: 38139428 PMCID: PMC10743896 DOI: 10.3390/ijms242417600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).
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Affiliation(s)
- Shmuel Silnitsky
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Samuel J. S. Rubin
- Department of Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA;
| | - Mulate Zerihun
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel; (S.S.); (M.Z.)
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2
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Muns SM, Villegas VM, Flynn HW, Schwartz SG. Update on current pharmacologic therapies for diabetic retinopathy. Expert Opin Pharmacother 2023; 24:1577-1593. [PMID: 37431888 DOI: 10.1080/14656566.2023.2230139] [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: 04/04/2023] [Revised: 06/16/2023] [Accepted: 06/23/2023] [Indexed: 07/12/2023]
Abstract
INTRODUCTION Diabetic retinopathy is a major cause of visual loss worldwide. The most important clinical findings include diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). AREAS COVERED PubMed was used for our literature review. Articles from 1995 to 2023 were included. Pharmacologic treatment of diabetic retinopathy generally involves the use of intravitreal anti-vascular endothelial growth factor (VEGF) therapy for DME and PDR. Corticosteroids remain important second-line therapies for patients with DME. Most emerging therapies focus on newly identified inflammatory mediators and biochemical signaling pathways involved in disease pathogenesis. EXPERT OPINION Emerging anti-VEGF modalities, integrin antagonists, and anti-inflammatory agents have the potential to improve outcomes with reduced treatment burdens.
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Affiliation(s)
- Sofía M Muns
- Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico
| | - Victor M Villegas
- Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Harry W Flynn
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Stephen G Schwartz
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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3
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Pan D, Xu L, Guo M. The role of protein kinase C in diabetic microvascular complications. Front Endocrinol (Lausanne) 2022; 13:973058. [PMID: 36060954 PMCID: PMC9433088 DOI: 10.3389/fendo.2022.973058] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Protein kinase C (PKC) is a family of serine/threonine protein kinases, the activation of which plays an important role in the development of diabetic microvascular complications. The activation of PKC under high-glucose conditions stimulates redox reactions and leads to an accumulation of redox stress. As a result, various types of cells in the microvasculature are influenced, leading to changes in blood flow, microvascular permeability, extracellular matrix accumulation, basement thickening and angiogenesis. Structural and functional disorders further exacerbate diabetic microvascular complications. Here, we review the roles of PKC in the development of diabetic microvascular complications, presenting evidence from experiments and clinical trials.
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Affiliation(s)
- Deng Pan
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lin Xu
- Gynecological Department of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ming Guo
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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4
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Bhandari S, Nguyen V, Fraser-Bell S, Di Tanna GL, Gillies MC. Real-world prognosis of eyes with diabetic macular oedema receiving treatment with vascular endothelial growth factor (VEGF) inhibitors. Hippokratia 2021. [DOI: 10.1002/14651858.cd015030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Sanjeeb Bhandari
- Macular Research Group, Save Sight Institute; The University of Sydney; Sydney Australia
| | - Vuong Nguyen
- Macular Research Group, Save Sight Institute; The University of Sydney; Sydney Australia
| | - Samantha Fraser-Bell
- Macular Research Group, Save Sight Institute; The University of Sydney; Sydney Australia
| | | | - Mark C Gillies
- Macular Research Group, Save Sight Institute; The University of Sydney; Sydney Australia
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5
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Silva M, Peng T, Zhao X, Li S, Farhan M, Zheng W. Recent trends in drug-delivery systems for the treatment of diabetic retinopathy and associated fibrosis. Adv Drug Deliv Rev 2021; 173:439-460. [PMID: 33857553 DOI: 10.1016/j.addr.2021.04.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/05/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
Diabetic retinopathy is a frequent microvascular complication of diabetes and a major cause of visual impairment. In advanced stages, the abnormal neovascularization can lead to fibrosis and subsequent tractional retinal detachment and blindness. The low bioavailability of the drugs at the target site imposed by the anatomic and physiologic barriers within the eye, requires long term treatments with frequent injections that often compromise patient's compliance and increase the risk of developing more complications. In recent years, much effort has been put towards the development of new drug delivery platforms aiming to enhance their permeation, to prolong their retention time at the target site and to provide a sustained release with reduced toxicity and improved efficacy. This review provides an overview of the etiology and pathophysiology of diabetic retinopathy and current treatments. It addresses the specific challenges associated to the different ocular delivery routes and provides a critical review of the most recent developments made in the drug delivery field.
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Affiliation(s)
- Marta Silva
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau
| | - Tangming Peng
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau
| | - Xia Zhao
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau
| | - Shuai Li
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau
| | - Mohd Farhan
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau
| | - Wenhua Zheng
- Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau.
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Kutlutürk Karagöz I, Allahverdiyev A, Bağırova M, Abamor EŞ, Dinparvar S. Current Approaches in Treatment of Diabetic Retinopathy and Future Perspectives. J Ocul Pharmacol Ther 2020; 36:487-496. [DOI: 10.1089/jop.2019.0137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Işıl Kutlutürk Karagöz
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
- Department of Ophthalmology, Ümraniye Trn. And Rch. Hospital, Istanbul, Turkey
| | - Adil Allahverdiyev
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Melehat Bağırova
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Sahar Dinparvar
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
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7
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Assessment of PKA and PKC inhibitors on force and kinetics of non-failing and failing human myocardium. Life Sci 2018; 215:119-127. [PMID: 30399377 DOI: 10.1016/j.lfs.2018.10.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/22/2018] [Accepted: 10/29/2018] [Indexed: 01/08/2023]
Abstract
AIMS Heart failure (HF) is a prevalent disease that is considered the foremost reason for hospitalization in the United States. Most protein kinases (PK) are activated in heart disease and their inhibition has been shown to improve cardiac function in both animal and human studies. However, little is known about the direct impact of PKA and PKC inhibitors on human cardiac contractile function. MATERIAL AND METHODS We investigated the ex vivo effect of such inhibitors on force as well as on kinetics of left ventricular (LV) trabeculae dissected from non-failing and failing human hearts. In these experiments, we applied 0.5 μM of H-89 and GF109203X, which are PKA and PKC inhibitors, respectively, in comparison to their vehicle DMSO (0.05%). KEY FINDINGS AND CONCLUSION Statistical analyses revealed no significant effect for H-89 and GF109203X on either contractile force or kinetics parameters of both non-failing and failing muscles even though they were used at a concentration higher than the reported IC50s and Kis. Therefore, several factors such as selectivity, concentration, and treatment time, which are related to these PK inhibitors according to previous studies require further exploration.
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Sivaprasad S, Vasconcelos JC, Prevost AT, Holmes H, Hykin P, George S, Murphy C, Kelly J, Arden GB. Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2018; 6. [PMID: 29519744 PMCID: PMC5908782 DOI: 10.1016/s2213-8587(18)30036-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND We aimed to assess 24-month outcomes of wearing an organic light-emitting sleep mask as an intervention to treat and prevent progression of non-central diabetic macular oedema. METHODS CLEOPATRA was a phase 3, single-blind, parallel-group, randomised controlled trial undertaken at 15 ophthalmic centres in the UK. Adults with non-centre-involving diabetic macular oedema were randomly assigned (1:1) to wearing either a light mask during sleep (Noctura 400 Sleep Mask, PolyPhotonix Medical, Sedgefield, UK) or a sham (non-light) mask, for 24 months. Randomisation was by minimisation generated by a central web-based computer system. Outcome assessors were masked technicians and optometrists. The primary outcome was the change in maximum retinal thickness on optical coherence tomography (OCT) at 24 months, analysed using a linear mixed-effects model incorporating 4-monthly measurements and baseline adjustment. Analysis was done using the intention-to-treat principle in all randomised patients with OCT data. Safety was assessed in all patients. This trial is registered with Controlled-Trials.com, number ISRCTN85596558. FINDINGS Between April 10, 2014, and June 15, 2015, 308 patients were randomly assigned to wearing the light mask (n=155) or a sham mask (n=153). 277 patients (144 assigned the light mask and 133 the sham mask) contributed to the mixed-effects model over time, including 246 patients with OCT data at 24 months. The change in maximum retinal thickness at 24 months did not differ between treatment groups (mean change -9·2 μm [SE 2·5] for the light mask vs -12·9 μm [SE 2·9] for the sham mask; adjusted mean difference -0·65 μm, 95% CI -6·90 to 5·59; p=0·84). Median compliance with wearing the light mask at 24 months was 19·5% (IQR 1·9-51·6). No serious adverse events were related to either mask. The most frequent adverse events related to the assigned treatment were discomfort on the eyes (14 with the light mask vs seven with the sham mask), painful, sticky, or watery eyes (14 vs six), and sleep disturbance (seven vs one). INTERPRETATION The light mask as used in this study did not confer long-term therapeutic benefit on non-centre-involving diabetic macular oedema and the study does not support its use for this indication. FUNDING The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
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Affiliation(s)
- Sobha Sivaprasad
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK.
| | - Joana C Vasconcelos
- Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK
| | - A Toby Prevost
- Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK
| | - Helen Holmes
- King's Clinical Trials Unit at King's Health Partners, King's College London, London, UK
| | - Philip Hykin
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK
| | - Sheena George
- Hillingdon Hospital, Hillingdon Hospitals National Health Service Foundation Trust, Uxbridge, UK
| | - Caroline Murphy
- King's Clinical Trials Unit at King's Health Partners, King's College London, London, UK
| | - Joanna Kelly
- King's Clinical Trials Unit at King's Health Partners, King's College London, London, UK
| | - Geoffrey B Arden
- Institute of Ophthalmology and Moorfields Eye Hospital, London, UK
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Srinivasan S, Hande P, Shetty J, Murali S. Efficiency of fenofibrate in facilitating the reduction of central macular thickness in diabetic macular edema. Indian J Ophthalmol 2018; 66:98-105. [PMID: 29283132 PMCID: PMC5778593 DOI: 10.4103/ijo.ijo_566_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
PURPOSE The purpose of this study is to study the benefit of addition of oral fenofibrate to the current regimen of diabetic macular edema (DME) management and quantify its effect on macular thickness and visual function in DME. METHODS Fifty-three eyes of 50 patients were randomized into treatment (Group A) (oral fenofibrate 160 mg/day) and control groups (Group B). Both groups underwent treatment of DME as per the standard treatment protocol of our hospital including intravitreal injections (anti-vascular endothelial growth factor/steroid) and grid laser. Patients were followed up every 2 months to note the visual acuity and central macular thickness (CMT) for 6 months. RESULTS Our groups were matched with respect to age (P = 0.802), mean diabetic age (P = 0.878), serum HbA1C levels (P = 0.523), and serum triglyceride levels (P = 0.793). The mean reduction in CMT was 136 μ in Group A and 83 μ in Group B at the end of 6 months. This difference was statistically significant (P = 0.031). Visual acuity improvement was 0.15 in Group A and 0.11 in Group B at the end of 6 months (P = 0.186). On subgroup analysis in Group A, we found that there was no difference in reduction of CMT between hypertensives and normotensives (P = 0.916), in patients with normal triglyceride levels and increased triglyceride levels (P = 0.975). CONCLUSION Addition of fenofibrate to the standard protocol of DME management seems to facilitate reduction of CMT and probably have an added benefit on the visual functions.
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Affiliation(s)
- Srilakshmi Srinivasan
- Department of Vitreo Retina, Bangalore West Lions Super Speciality Eye Hospital, Bengaluru, Karnataka, India
| | - Prathibha Hande
- Department of Vitreo Retina, Bangalore West Lions Super Speciality Eye Hospital, Bengaluru, Karnataka, India
| | - Jyoti Shetty
- Department of Vitreo Retina, Bangalore West Lions Super Speciality Eye Hospital, Bengaluru, Karnataka, India
| | - Sindhu Murali
- Department of Vitreo Retina, Bangalore West Lions Super Speciality Eye Hospital, Bengaluru, Karnataka, India
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10
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Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review. J Ophthalmol 2018; 2018:1694187. [PMID: 29576875 PMCID: PMC5822768 DOI: 10.1155/2018/1694187] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 10/12/2017] [Accepted: 11/07/2017] [Indexed: 01/01/2023] Open
Abstract
Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular and clinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatory changes in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of available pharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Direct injections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DR and diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated with adverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic, hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progression of DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities after transplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in the current and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases, PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceutical company websites.
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Hooper P, Boucher MC, Cruess A, Dawson KG, Delpero W, Greve M, Kozousek V, Lam WC, Maberley DAL. Excerpt from the Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2017; 52 Suppl 1:S45-S74. [PMID: 29074014 DOI: 10.1016/j.jcjo.2017.09.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Philip Hooper
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)..
| | - Marie Carole Boucher
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Alan Cruess
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Keith G Dawson
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Walter Delpero
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Mark Greve
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Vladimir Kozousek
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Wai-Ching Lam
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - David A L Maberley
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
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12
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Zhong C, Wu Y, Chang H, Liu C, Zhou L, Zou J, Qi Z. Effect of PKC inhibitor on experimental autoimmune myocarditis in Lewis rats. Oncotarget 2017; 8:54187-54198. [PMID: 28903333 PMCID: PMC5589572 DOI: 10.18632/oncotarget.17018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 03/31/2017] [Indexed: 12/19/2022] Open
Abstract
Myocarditis is a major cause of sudden, unexpected death in young people. However, it is still one of the most challenging diseases to treat in cardiology. In the present study, we showed that both expression level and activity of PKC-α were up-regulated in the rat heart of experimental autoimmune myocarditis (EAM). Intraperitoneal administration of PKC inhibitor (Ro-32-0432) at the end of the most severe inflammation period of EAM still significantly reduced the EAM induced expression of failure biomarkers. Furthermore, Ro-32-0432 reduced the ratio of Bax/Bcl-2 and suppressed the expression of cleaved caspase-3, both of which were increased in the heart of the EAM rats, suggesting an anti-apoptotic role of Ro-32-0432. Besides, Ro-32-0432 suppressed EAM-induced cardiac fibrosis and release of pro-inflammatory cytokines IL-1β and IL-17. These results suggest that inhibition of PKC may serve as a potential therapeutic strategy for the treatment of myocarditis.
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Affiliation(s)
- Chunlian Zhong
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China
| | - Yang Wu
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China.,Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China
| | - He Chang
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China.,Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China
| | - Chunxiao Liu
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China.,Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China
| | - Li Zhou
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China
| | - Jun Zou
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China
| | - Zhi Qi
- Department of Basic Medical Sciences, Medical College of Xiamen University, Xiang'an Nan Lu, Xiamen, China
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13
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Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling. Int J Mol Sci 2017; 18:ijms18040688. [PMID: 28358314 PMCID: PMC5412274 DOI: 10.3390/ijms18040688] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/06/2017] [Accepted: 03/14/2017] [Indexed: 12/28/2022] Open
Abstract
Background: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 μM), was applied to test the involvement of PKC. Results: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. Conclusions: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.
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Liew G, Wong VW, Ho IV. Mini Review: Changes in the Incidence of and Progression to Proliferative and Sight-Threatening Diabetic Retinopathy Over the Last 30 Years. Ophthalmic Epidemiol 2017; 24:73-80. [DOI: 10.1080/09286586.2016.1259638] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Gerald Liew
- Centre for Vision Research, Westmead Millennium Institute of Medical Research, University of Sydney, Sydney, Australia
| | - Vincent W. Wong
- Liverpool Diabetes Collaborative Research Unit, Ingham Institute of Applied Science, Sydney, Australia
| | - I-Van Ho
- Save Sight Institute, University of Sydney, Sydney, Australia
- Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
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15
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Kim EL, Moshfeghi AA. Effect of Intravitreal Anti-VEGF Therapy on the Severity of Diabetic Retinopathy. CURRENT OPHTHALMOLOGY REPORTS 2016. [DOI: 10.1007/s40135-016-0094-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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16
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Das J. Novel N-pyrimidin-4-yl-3-amino-pyrrolo [3, 4-C] pyrazole derivatives as PKC kinase inhibitors: a patent evaluation of US2015099743 (A1). Expert Opin Ther Pat 2015; 26:523-8. [PMID: 26593678 DOI: 10.1517/13543776.2015.1124088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Protein kinase Cβ (PKCβ) is a member of the PKC family of serine/threonine kinases that has been implicated in the pathophysiology of diabetic complications. Developing small molecule drugs targeting this PKC isozyme is a rational approach for treating these disease states. PKCβ belongs to the conventional class of PKC and contains both regulatory and kinase domain. Numerous compounds of different chemical classes were designed targeting the kinase domain, but achieved very limited success in clinical trials. AREAS COVERED This patent application reports the synthesis of about 100 new N-pyrimidin-4-yl-3-amino-pyrolo [3, 4-C] pyrazole derivatives and their competitive inhibition constant (Ki) for protein kinase C βII (PKCβII), one of the two splice variants of PKCβ. The compounds compete with ATP at the kinase domain of PKCβII, and inhibit with high potency having Ki values in the 0.1-181 nM range. The compounds are claimed to be selective towards PKCβI, PKCβII and PKCα over other protein kinases. Several routes of administration of these compounds are discussed for possible treatment of diabetes and related diseases. EXPERT OPINION This is an important effort toward developing PKC-based drugs for diabetic complications. Further biological evaluations of these compounds are required before proceeding toward clinical trails.
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Affiliation(s)
- Joydip Das
- a Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy , University of Houston , Houston , TX , USA
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Abstract
In diabetes, retinal blood flow is compromised, and retinal hypoxia is likely to be further intensified during periods of darkness. During dark adaptation, rod photoreceptors in the outer retina are maximally depolarized and continuously release large amounts of the neurotransmitter glutamate-an energetically demanding process that requires the highest oxygen consumption per unit volume of any tissue of the body. In complete darkness, even more oxygen is consumed by the outer retina, producing a steep fall in the retinal oxygen tension curve which reaches a nadir at the depth of the mitochondrial-rich rod inner segments. In contrast to the normal retina, the diabetic retina cannot meet the added metabolic load imposed by the dark-adapted rod photoreceptors; this exacerbates retinal hypoxia and stimulates the overproduction of vascular endothelial growth factor (VEGF). The use of nocturnal illumination to prevent dark adaptation, specifically reducing the rod photoreceptor dark current, should ameliorate diabetic retinopathy.
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Affiliation(s)
- David J Ramsey
- Department of Ophthalmology, Lahey Hospital & Medical Center, Tufts University School of Medicine, 41 Mall Road, Burlington, MA, 01805, USA.
| | - G B Arden
- University College London, London, UK.
- Moorfields Eye Hospital NHS Foundation Trust, London, UK.
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Das A, McGuire PG, Rangasamy S. Diabetic Macular Edema: Pathophysiology and Novel Therapeutic Targets. Ophthalmology 2015; 122:1375-94. [PMID: 25935789 DOI: 10.1016/j.ophtha.2015.03.024] [Citation(s) in RCA: 395] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 02/23/2015] [Accepted: 03/17/2015] [Indexed: 12/15/2022] Open
Abstract
Diabetic macular edema (DME) is the major cause of vision loss in diabetic persons. Alteration of the blood-retinal barrier is the hallmark of this disease, characterized by pericyte loss and endothelial cell-cell junction breakdown. Recent animal and clinical studies strongly indicate that DME is an inflammatory disease. Multiple cytokines and chemokines are involved in the pathogenesis of DME, with multiple cellular involvement affecting the neurovascular unit. With the introduction of anti-vascular endothelial growth factor (VEGF) agents, the treatment of DME has been revolutionized, and the indication for laser therapy has been limited. However, the response to anti-VEGF drugs in DME is not as robust as in proliferative diabetic retinopathy, and many patients with DME do not show complete resolution of fluid despite multiple intravitreal injections. Potential novel therapies targeting molecules other than VEGF and using new drug-delivery systems currently are being developed and evaluated in clinical trials.
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Affiliation(s)
- Arup Das
- Department of Surgery/Ophthalmology, University of New Mexico School of Medicine, Albuquerque, New Mexico; New Mexico VA Health Care System, Albuquerque, New Mexico.
| | - Paul G McGuire
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico
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Zaidi FH, Ansari E. New treatments for diabetic macular edema. World J Ophthalmol 2015; 5:45-54. [DOI: 10.5318/wjo.v5.i2.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/10/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
This work comprehensively reviews the latest treatment options for diabetic macular edema (DME) used in its management and presents further work on the topic. Diabetic retinopathy is an important and increasingly prevalent cause of preventable blindness worldwide. To meet this increasing burden there has recently been a proliferation of pharmacological therapies being used in clinical practice. A variety of medical treatment options now exist for DME. These include non-steroidal anti-inflammatory drugs such as nepafenac, as well as intravitreal steroids like triamcinolone (kenalog). Long-term results up to 7 years after commencing treatment are presented for triamcinolone. Studies are reviewed on the use of dexamethasone (ozurdex) and fluocinolone (Retisert and Iluvien implants) including the FAME studies. A variety of anti-vascular endothelial growth factor (anti-VEGF) agents used in DME are considered in detail including ranibizumab (lucentis) and the RESTORE, RIDE, RISE and Diabetic Retinopathy Clinical Research Network (DRCR.net) studies. Bevacizumab (avastin) and pegaptinib (macugen) are also considered. The use of aflibercept (eylea) is reviewed including the significance of the DA VINCI, VISTA-DME, VIVID-DME and the DRCR.net studies which have recently suggested potentially greater efficacy when treating DME for aflibercept in patients with more severely reduced visual acuity at baseline. Evidence for the anti-VEGF agent bevasiranib is also considered. Studies of anti-tumour necrosis factor agents like infliximab are reviewed. So are studies of other agents targeting inflammation including minocycline, rapamycin (sirolimus) and protein kinase C inhibitors such as midostaurin and ruboxistaurin. The protein kinase C β inhibitor Diabetic Macular Edema Study is considered. Other agents which have been suggested for DME are discussed including cyclo-oxygenase-2 inhibitors like celecoxib, phospholipase A2 inhibitors, recombinant erythropoietin, and monoclonal anti-interleukin antibodies such as canakinumab. The management of DME in a variety of clinical scenarios is also discussed - in newly diagnosed DME, refractory DME including after macular laser, and postoperatively after intraocular surgery. Results of long-term intravitreal triamcinolone for DME administered up to seven years after commencing treatment are considered in the context of the niche roles available for such agents in modern management of DME. This is alongside more widely used treatments available to the practitioner such as anti-VEGF agents like aflibercept (Eylea) and ranibizumab (Lucentis) which at present are the mainstay of pharmacological treatment of DME.
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Diabetic Retinopathy Clinical Research Network, Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, Maker MP, Jampol LM, Melia M. Topical nepafenec in eyes with noncentral diabetic macular edema. Retina 2015; 35:944-56. [PMID: 25602634 PMCID: PMC4408212 DOI: 10.1097/iae.0000000000000403] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE To evaluate the effect of a topical, nonsteroidal antiinflammatory drug, nepafenac 0.1%, in eyes with noncentral diabetic macular edema. METHODS Multicenter, double-masked randomized trial. Individuals with good visual acuity and noncentral-involved diabetic macular edema were randomly assigned to nepafenac 0.1% (N = 61) or placebo (nepafenac vehicle, N = 64) 3 times a day for 12 months. The primary outcome was mean change in optical coherence tomography retinal volume at 12 months. RESULTS Mean baseline retinal volume was 7.8 mm. At 12 months, in the nepafenac and placebo groups respectively, mean change in retinal volume was -0.03 mm and -0.02 mm (treatment group difference: -0.02, 95% confidence interval: -0.27 to 0.23, P = 0.89). Central-involved diabetic macular edema was present in 7 eyes (11%) and 9 eyes (14%) at the 12-month visit (P = 0.79), respectively. No differences in visual acuity outcomes were identified. One study participant developed a corneal melt after using nepafenac in the nonstudy eye, which had a history of severe dry eye. No additional safety concerns were evident. CONCLUSION In eyes with noncentral diabetic macular edema and good visual acuity, topical nepafenac 0.1% 3 times daily for 1 year likely does not have a meaningful effect on optical coherence tomography-measured retinal thickness.
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Affiliation(s)
| | | | | | | | | | | | - Neil M. Bressler
- Wilmer Eye Institute, Johns Hopkins University School of Medicine
| | - Manvi P. Maker
- North Shore University Health System, Pritzker School of Medicine-University of Chicago
| | - Lee M. Jampol
- Feinberg School of Medicine, Northwestern University
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Lin YT, Chen YC, Peng YT, Chen L, Liu JH, Chen FL, Tung TH. Evidence-Based Medicine of Screening of Diabetic Retinopathy among Type 2 Diabetes: A Clinical Overview. Health (London) 2015. [DOI: 10.4236/health.2015.77103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Simó R, Ballarini S, Cunha-Vaz J, Ji L, Haller H, Zimmet P, Wong TY. Non-traditional systemic treatments for diabetic retinopathy: an evidence-based review. Curr Med Chem 2015; 22:2580-9. [PMID: 25989912 PMCID: PMC4997935 DOI: 10.2174/0929867322666150520095923] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/05/2015] [Accepted: 05/18/2015] [Indexed: 01/07/2023]
Abstract
The rapid escalation in the global prevalence diabetes, with more than 30% being afflicted with diabetic retinopathy (DR), means it is likely that associated vision-threatening conditions will also rise substantially. This means that new therapeutic approaches need to be found that go beyond the current standards of diabetic care, and which are effective in the early stages of the disease. In recent decades several new pharmacological agents have been investigated for their effectiveness in preventing the appearance and progression of DR or in reversing DR; some with limited success while others appear promising. This up-to-date critical review of non-traditional systemic treatments for DR is based on the published evidence in MEDLINE spanning 1980-December 2014. It discusses a number of therapeutic options, paying particular attention to the mechanisms of action and the clinical evidence for the use of renin-angiotensin system blockade, fenofibrate and calcium dobesilate monohydrate in DR.
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Affiliation(s)
- Rafael Simó
- Diabetes and Metabolism Reseach Unit. Vall d'Hebron Research Institute. Universitat Autonoma de Barcelona and Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII). Barcelona, Spain Pg. Vall d'Hebron 119-129. 08035 Barcelona, Spain.
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Current nanotechnology approaches for the treatment and management of diabetic retinopathy. Eur J Pharm Biopharm 2014; 95:307-22. [PMID: 25536109 DOI: 10.1016/j.ejpb.2014.12.023] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 12/08/2014] [Accepted: 12/15/2014] [Indexed: 01/08/2023]
Abstract
Diabetic retinopathy (DR) is a consequence of diabetes mellitus at the ocular level, leading to vision loss, and contributing to the decrease of patient's life quality. The biochemical and anatomic abnormalities that occur in DR are discussed in this review to better understand and manage the development of new therapeutic strategies. The use of new drug delivery systems based on nanoparticles (e.g. liposomes, dendrimers, cationic nanoemulsions, lipid and polymeric nanoparticles) is discussed along with the current traditional treatments, pointing out the advantages of the proposed nanomedicines to target this ocular disease. Despite the multifactorial nature of DR, which is not entirely understood, some strategies based on nanoparticles are being exploited for a more efficient drug delivery to the posterior segment of the eye. On the other hand, the use of some nanoparticles also seems to contribute to the development of DR symptoms (e.g. retinal neovascularization), which are also discussed in light of an efficient management of this ocular chronic disease.
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Sivaprasad S, Arden G, Prevost AT, Crosby-Nwaobi R, Holmes H, Kelly J, Murphy C, Rubin G, Vasconcelos J, Hykin P. A multicentre phase III randomised controlled single-masked clinical trial evaluating the clinical efficacy and safety of light-masks at preventing dark-adaptation in the treatment of early diabetic macular oedema (CLEOPATRA): study protocol for a randomised controlled trial. Trials 2014; 15:458. [PMID: 25417120 PMCID: PMC4255925 DOI: 10.1186/1745-6215-15-458] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 11/05/2014] [Indexed: 11/30/2022] Open
Abstract
Background This study will evaluate hypoxia, as a novel concept in the pathogenesis of diabetic macular oedema (DMO). As the oxygen demand of the eye is maximum during dark-adaptation, we hypothesize that wearing light-masks during sleep will cause regression and prevent the development and progression of DMO. The study protocol comprises both an efficacy and mechanistic evaluation to test this hypothesis. Method/Design This is a phase III randomised controlled single-masked multicentre clinical trial to test the clinical efficacy of light-masks at preventing dark-adaptation in the treatment of non-central DMO. Three hundred patients with non-centre-involving DMO in at least one eye will be randomised 1:1 to light-masks and control masks (with no light) to be used during sleep at night for a period of 24 months. The primary outcome is regression of non-central oedema by assessing change in the zone of maximal retinal thickness at baseline on optical coherence tomography (SD-OCT). Secondary outcomes will evaluate the prevention of development and progression of DMO by assessing changes in retinal thickness in different regions of the macula, macular volume, refracted visual acuity and level of retinopathy. Safety parameters will include sleep disturbance. Adverse events and measures of compliance will be assessed over 24 months. Participants recruited to the mechanistic sub-study will have additional retinal oximetry, multifocal electroretinography (ERG) and microperimetry to evaluate the role of hypoxia by assessing and comparing changes induced by supplemental oxygen and the light-masks at 12 months. Discussion The outcomes of this study will provide insight into the pathogenesis of DMO and provide evidence on whether a simple, non-invasive device in the form of a light-mask can help prevent the progression to centre-involving DMO and visual impairment in people with diabetes.
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Affiliation(s)
- Sobha Sivaprasad
- NIHR Moorfields Biomedical Research Centre, 162, City Road, London EC1V 2PD, England.
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Massin P, Peto T, Ansquer JC, Aubonnet P, MacuFEN Study Investigators FT. Effects of fenofibric acid on diabetic macular edema: the MacuFen study. Ophthalmic Epidemiol 2014; 21:307-17. [PMID: 25133794 DOI: 10.3109/09286586.2014.949783] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE Fenofibrate reduced progression of diabetic retinopathy in two large randomized studies. The effect of 135 mg fenofibric acid on diabetic macular edema (DME) was evaluated in subjects with existing DME. METHODS In this double-blind, randomized, placebo-controlled study, 110 subjects with DME not requiring immediate photocoagulation or intraocular treatment with adequate diabetes and blood pressure control received either fenofibric acid or placebo once daily for 1 year. Total macula volume (TMV) and thickness were measured in the worse eye and all eligible eyes with time-domain optical coherence tomography at baseline and quarterly thereafter. RESULTS TMV decreased by -0.35 mm(3) (within-group difference) after fenofibric acid treatment and by -0.11 mm(3) after placebo. The between-group comparison of the change was -0.25 mm(3) (95% confidence interval, CI, -0.645-0.155; p = 0.227, worse eye analysis). Weighted inner zone thickness and volume decreased by -18.7 µm and -0.13 mm(3), respectively, for within group difference after fenofibric acid and by -3.1 µm and -0.02 mm(3), respectively, after placebo. Considering all eligible eyes, thicknesses at central zone, mean inner zone, and entire retina decreased by -21.3 µm, -19.8 µm, and -20.4 µm, respectively, after fenofibric acid. No between-group difference in changes of these measurements was observed. Triglycerides decreased by 23% after fenofibric acid (vs 4% after placebo, p = 0.001) and high-density lipoprotein cholesterol increased by 8% (vs 0.3%, p = 0.014). No safety concern was identified. CONCLUSION Subjects treated with fenofibric acid had a modest improvement in TMV, although the study was probably underpowered to detect a benefit over placebo after 1 year.
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Lu D, Zhang L, Bao D, Lu Y, Zhang X, Liu N, Ge W, Gao X, Li H, Zhang L. Calponin1 inhibits dilated cardiomyopathy development in mice through the εPKC pathway. Int J Cardiol 2014; 173:146-53. [PMID: 24631115 DOI: 10.1016/j.ijcard.2014.02.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/24/2014] [Accepted: 02/08/2014] [Indexed: 01/12/2023]
Abstract
BACKGROUND Calponin1 (CNN1) is involved in the regulation of smooth muscle contraction in physiological situation and it also expresses abnormally in a variety of pathological situations. We found that the expression of CNN1 decreased significantly in the heart tissue of a cTnT(R141W) transgenic dilated cardiomyopathy (DCM) mouse model and an adriamycin (ADR)-induced DCM mouse model, suggesting that CNN1 is involved in the pathogenesis of DCM. However, the role of CNN1 on cardiac function, especially on pathogenesis of DCM, has not been clarified. In this study, we tested whether rescued expression of CNN1 could prevent the development of DCM and investigated its possible mechanisms. METHODS AND RESULTS The DCM phenotypes were significantly improved with the transgenic expression of CNN1 in the cTnT(R141W)×CNN1 double transgenic (DTG) mice, which was demonstrated by the survival, cardiac geometry and function analyses, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The expression of CNN1 could also resist the cardiac geometry breakage and dysfunction in the ADR-induced DCM mice model. Meanwhile, the epsilon isoform of protein kinase C (εPKC) activator and inhibitor could reverse the activation of εPKC/ERK/mTOR pathway and DCM phenotypes in the cTnT(R141W) and cTnT(R141W)×CNN1 double transgenic (DTG) mice. CONCLUSIONS εPKC/ERK/mTOR pathway activation induced by the rescued expression of CNN1 contributed to the improvement of cardiac dysfunction and pathological changes observed in the DTG mice. CNN1 could be a therapeutic target to prevent the development of DCM and heart failure (HF).
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Affiliation(s)
- Dan Lu
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Li Zhang
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Dan Bao
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Yingdong Lu
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Xu Zhang
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Ning Liu
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Wenping Ge
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Xiang Gao
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, China
| | - Lianfeng Zhang
- Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, China.
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Tang J, Herda AA, Kern TS. Photobiomodulation in the treatment of patients with non-center-involving diabetic macular oedema. Br J Ophthalmol 2014; 98:1013-5. [PMID: 24682183 DOI: 10.1136/bjophthalmol-2013-304477] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
PURPOSE Far-red/near-infrared phototherapy or photobiomodulation (PBM) has recently been reported to be an effective and non-invasive treatment method to inhibit lesions of diabetic retinopathy (DR) in animals. This study investigated the safety and efficacy of PBM in diabetic patients to treat non-center-involving diabetic macular oedema (NCDME). METHODS This was a non-randomised, consecutive, case series, where 4 patients with type 2 diabetes with NCDME were treated for 160 s per day with PBM for 2-9 months. Demographic data including age, sex, HbA1c%, electronic ETDRS visual acuity, and retinal and macular thickness were measured using spectral domain ocular coherence tomography (SD-OCT) before and after treatment. RESULTS Four eyes of 4 patients were treated, with fellow eyes serving as untreated controls. Daily PBM treatment for only 80 s per treatment twice daily caused a significant reduction in focal retinal thickening in all 4 treated eyes. No adverse effects attributable to therapy were noted by the patients or study investigators during the study period. CONCLUSIONS PBM potentially offers a non-invasive and cost-effective therapeutic option for patients with NCDME. Further studies of this therapeutic option in DR are warranted.
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Affiliation(s)
- Johnny Tang
- Department of Ophthalmology, University of Kansas Medical Center, Prairie Village, Kansas, USA Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA
| | - Ashley A Herda
- Department of Ophthalmology, University of Kansas Medical Center, Prairie Village, Kansas, USA
| | - Timothy S Kern
- Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Fan HC, Fernández-Hernando C, Lai JH. Protein kinase C isoforms in atherosclerosis: Pro- or anti-inflammatory? Biochem Pharmacol 2014; 88:139-49. [DOI: 10.1016/j.bcp.2014.01.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 01/06/2014] [Accepted: 01/07/2014] [Indexed: 12/12/2022]
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Abu El-Asrar AM. Evolving strategies in the management of diabetic retinopathy. Middle East Afr J Ophthalmol 2014; 20:273-82. [PMID: 24339676 PMCID: PMC3841944 DOI: 10.4103/0974-9233.119993] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR), the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Tight glycemic and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Focal/grid photocoagulation and panretinal photocoagulation are standard treatments for both DME and PDR, respectively. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with DME. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal antivascular endothelial growth factor agents in patients with center-involving DME. Combination therapy reduces the frequency of injections needed to control edema. Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Emerging therapies include fenofibrate, ruboxistaurin, renin-angiotensin system blockers, peroxisome proliferator-activated receptor gamma agonists, pharmacologic vitreolysis, and islet cell transplantation.
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Affiliation(s)
- Ahmed M Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Abstract
Diabetes mellitus (DM) has assumed epidemic proportions and as a consequence, diabetic retinopathy is expected to be a major societal problem across the world. Diabetic retinopathy (DR) affects the vision by way of proliferative disease that results in vitreous hemorrhage and traction retinal detachment or by way of diabetic maculopathy (DME). The present-day management of diabetic retinopathy revolves around screening the diabetics for evidence of retinopathy and treating the retinopathy with laser photocoagulation. DME is treated with laser photocoagulation and/or intra- vitreal injection of anti-vascular endothelial growth factor (VEGF) agents or steroids. Laser remains the mainstay of treatment and is potentially destructive. Systemic management aims at preventing or delaying the onset of retinopathy; reversing the early retinopathy; or delaying the progression of established retinopathy. Evidence from multiple studies has confirmed the protective role of rigid control of blood glucose and blood pressure. The evidence for lipid control versus maculopathy was less definitive. However, the use of fenofibrates (originally used for lowering serum lipids) has shown a benefit on both proliferative disease and maculopathy outside their lipid-lowering effect. Other drugs being tried are the Protein Kinase C (PKC) inhibitors, other peroxisome proliferator-activated receptors (PPAR) agonists, Forsoklin (which binds GLUT 1 receptor), minocycline (for its anti inflammatory effect), and Celecoxib (Cox-2 inhibitor).
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Affiliation(s)
- Gopal Lingam
- Department of ophthalmology, National University Health System, Singapore ; National University of Singapore, Singapore ; Singapore Eye Research Institute, Singapore
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Kuppermann BD. Sustained-release dexamethasone intravitreal implant for treatment of diabetic macular edema. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.10.82] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abu El-Asrar AM, Al-Mezaine HS, Ola MS. Pathophysiology and management of diabetic retinopathy. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.09.52] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Al-Latayfeh M, Silva PS, Sun JK, Aiello LP. Antiangiogenic therapy for ischemic retinopathies. Cold Spring Harb Perspect Med 2013; 2:a006411. [PMID: 22675660 DOI: 10.1101/cshperspect.a006411] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Neovascularization is a common pathological process in various retinal vascular disorders including diabetic retinopathy (DR), age-related macular degeneration (AMD) and retinal vein occlusion (RVO). The development of neovascular vessels may lead to complications such as vitreous hemorrhage, fibrovascular tissue formation, and traction retinal detachments. Ultimately, irreversible vision loss may result. Various proangiogenic factors are involved in these complex processes. Different antiangiogenic drugs have been formulated in an attempt treat these vascular disorders. One factor that plays a major role in the development of retinal neovascularization is vascular endothelial growth factor (VEGF). Anti-VEGF agents are currently FDA approved for the treatment of AMD and RVO. They are also extensively used as an off-label treatment for diabetic macular edema (DME), proliferative DR, and neovascular glaucoma. However, at this time, the long-term safety of chronic VEGF inhibition has not been extensively evaluated. A large and rapidly expanding body of research on angiogenesis is being conducted at multiple centers across the globe to determine the exact contributions and interactions among a variety of angiogenic factors in an effort to determine the therapeutic potential of antiangiogenic agent in the treatment of a variety of retinal diseases.
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Affiliation(s)
- Motasem Al-Latayfeh
- Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
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Abstract
Protein kinase C (PKC) has been a tantalizing target for drug discovery ever since it was first identified as the receptor for the tumour promoter phorbol ester in 1982. Although initial therapeutic efforts focused on cancer, additional indications--including diabetic complications, heart failure, myocardial infarction, pain and bipolar disorder--were targeted as researchers developed a better understanding of the roles of eight conventional and novel PKC isozymes in health and disease. Unfortunately, both academic and pharmaceutical efforts have yet to result in the approval of a single new drug that specifically targets PKC. Why does PKC remain an elusive drug target? This Review provides a short account of some of the efforts, challenges and opportunities in developing PKC modulators to address unmet clinical needs.
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Ford JA, Lois N, Royle P, Clar C, Shyangdan D, Waugh N. Current treatments in diabetic macular oedema: systematic review and meta-analysis. BMJ Open 2013; 3:e002269. [PMID: 23457327 PMCID: PMC3612765 DOI: 10.1136/bmjopen-2012-002269] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 02/01/2013] [Accepted: 02/01/2013] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events DATA SOURCE MEDLINE, EMBASE, Web of Science with Conference Proceedings and the Cochrane Library (inception to July 2012). Certain conference abstracts and drug regulatory web sites were also searched. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS Randomised controlled trials were used to assess clinical effectiveness and observational trials were used for safety. Trials which assessed triamcinolone, dexamethasone, fluocinolone, bevacizumab, ranibizumab, pegaptanib or aflibercept in patients with DMO were included. STUDY APPRAISAL AND SYNTHESIS METHODS Risk of bias was assessed using the Cochrane risk of bias tool. Study results are narratively described and, where appropriate, data were pooled using random effects meta-analysis. RESULTS Anti-VEGF drugs are effective compared to both laser and placebo and seem to be more effective than steroids in improving BCVA. They have been shown to be safe in the short term but require frequent injections. Studies assessing steroids (triamcinolone, dexamethasone and fluocinolone) have reported mixed results when compared with laser or placebo. Steroids have been associated with increased incidence of cataracts and intraocular pressure rise but require fewer injections, especially when steroid implants are used. LIMITATIONS The quality of included studies varied considerably. Five of 14 meta-analyses had moderate or high statistical heterogeneity. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS The anti-VEGFs ranibizumab and bevacizumab have consistently shown good clinical effectiveness without major unwanted side effects. Steroid results have been mixed and are usually associated with cataract formation and intraocular pressure increase. Despite the current wider spectrum of treatments for DMO, only a small proportion of patients recover good vision (≥20/40), and thus the search for new therapies needs to continue.
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Affiliation(s)
- John Alexander Ford
- Department of Population Health and Primary Care, Faculty of Medicine and Health Sciences,Norwich Medical School, University of East Anglia, Norwich,UK
| | - Noemi Lois
- Centre for Vascular and Visual Sciences, Queens University, Belfast, UK
| | - Pamela Royle
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, Coventry, UK
| | | | - Deepson Shyangdan
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, Coventry, UK
| | - Norman Waugh
- Warwick Evidence, Division of Health Sciences, Warwick Medical School, Coventry, UK
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Klaassen I, Van Noorden CJF, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res 2013; 34:19-48. [PMID: 23416119 DOI: 10.1016/j.preteyeres.2013.02.001] [Citation(s) in RCA: 502] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 12/19/2012] [Accepted: 02/01/2013] [Indexed: 12/16/2022]
Abstract
Breakdown of the inner endothelial blood-retinal barrier (BRB), as occurs in diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, uveitis and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing loss of vision. The central mechanism of altered BRB function is a change in the permeability characteristics of retinal endothelial cells caused by elevated levels of growth factors, cytokines, advanced glycation end products, inflammation, hyperglycemia and loss of pericytes. Subsequently, paracellular but also transcellular transport across the retinal vascular wall increases via opening of endothelial intercellular junctions and qualitative and quantitative changes in endothelial caveolar transcellular transport, respectively. Functional changes in pericytes and astrocytes, as well as structural changes in the composition of the endothelial glycocalyx and the basal lamina around BRB endothelium further facilitate BRB leakage. As Starling's rules apply, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular edema. The understanding of the complex cellular and molecular processes involved in BRB leakage has grown rapidly in recent years. Although appropriate animal models for human conditions like diabetic macular edema are lacking, these insights have provided tools for rational design of drugs aimed at restoring the BRB as well as for design of effective transport of drugs across the BRB, to treat the chronic retinal diseases such as diabetic macular edema that affect the quality-of-life of millions of patients.
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Affiliation(s)
- Ingeborg Klaassen
- Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Gupta N, Mansoor S, Sharma A, Sapkal A, Sheth J, Falatoonzadeh P, Kuppermann B, Kenney M. Diabetic retinopathy and VEGF. Open Ophthalmol J 2013; 7:4-10. [PMID: 23459241 PMCID: PMC3580758 DOI: 10.2174/1874364101307010004] [Citation(s) in RCA: 186] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 10/17/2012] [Accepted: 12/14/2012] [Indexed: 12/20/2022] Open
Abstract
Diabetic retinopathy remains the leading vascular-associated cause of blindness throughout the world. Its treatment requires a multidisciplinary interventional approach at both systemic and local levels. Current management includes laser photocoagulation, intravitreal steroids, and anti-vascular endothelial growth factor (VEGF) treatment along with systemic blood sugar control. Anti-VEGF therapies, which are less destructive and safer than laser treatments, are being explored as primary therapy for the management of vision-threatening complications of diabetic retinopathy such as diabetic macular edema (DME). This review provides comprehensive information related to VEGF and describes its role in the pathogenesis of diabetic retinopathy, and in addition, examines the mechanisms of action for different antiangiogenic agents in relation to the management of this disease. Medline (Pubmed) searches were carried out with keywords “VEGF”, “diabetic retinopathy”, and “diabetes” without any year limitation to review relevant manuscripts used for this article.
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Affiliation(s)
- N Gupta
- Gavin Herbert Eye Institute, University of California, Irvine, USA
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Tarr JM, Kaul K, Wolanska K, Kohner EM, Chibber R. Retinopathy in diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 771:88-106. [PMID: 23393674 DOI: 10.1007/978-1-4614-5441-0_10] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With the incidence, and prevalence of diabetes mellitus increasing worldwide, diabetic retinopathy is expected to reach epidemic proportions. The aim of this chapter is to introduce diabetic retinopathy, a leading cause of blindness in people of the working age. The clinical course of retinopathy, anatomical changes, its pathogenesis and current treatment are described, followed by an overview of the emerging drug therapies for the potential treatment of this sight-threatening complication of diabetes.
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Affiliation(s)
- Joanna M Tarr
- Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK
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Smiddy WE. Clinical Applications of Cost Analysis of Diabetic Macular Edema Treatments. Ophthalmology 2012; 119:2558-62. [DOI: 10.1016/j.ophtha.2012.09.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 08/16/2012] [Accepted: 09/10/2012] [Indexed: 01/22/2023] Open
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Wenick AS, Bressler NM. Diabetic macular edema: current and emerging therapies. Middle East Afr J Ophthalmol 2012; 19:4-12. [PMID: 22346109 PMCID: PMC3277023 DOI: 10.4103/0974-9233.92110] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Diabetic macular edema is a leading cause of vision impairment among people within the working- age population. This review discusses the pathogenesis of diabetic macular edema and the treatment options currently available for the treatment of diabetic macular edema, including for focal/grid photocoagulation, intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor agents. The biologic rationale for novel therapeutic agents, many of which are currently being evaluated in clinical trials, also is reviewed.
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Affiliation(s)
- Adam S Wenick
- Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine and Hospital, Baltimore, MD, USA
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41
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Al Shamsi H, Ghazi NG. Diabetic macular edema: new trends in management. Expert Rev Clin Pharmacol 2012; 5:55-68. [PMID: 22142159 DOI: 10.1586/ecp.11.67] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The treatment of diabetic macular edema may be evolving from a laser ablative approach into a pharmacotherapeutic approach. The exponential growth that has occurred over the past decade in the retinal pharmacotherapy field has led to the development of several pharmacotherapies for retinal vascular diseases such as diabetic macular edema. Many of these agents, in the form of intravitreal injections or sustained delivery devices, have already undergone clinical trial testing for safety and efficacy and many others are currently being similarly evaluated. Some of these agents have proven to be more efficacious than traditional laser therapy, and it is possible that traditional laser therapy for diabetic macular edema may be abandoned altogether in the near future, especially with the introduction of the micropulse laser. However, more research and experience is still needed in order to determine the best treatment agent or combination of therapeutic modalities, as well as the best treatment regimen for a given patient. In this article, we briefly review the major new developments in the field of diabetic macular edema treatment. In addition, we touch on some of the promising forthcoming therapies.
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Affiliation(s)
- Hanan Al Shamsi
- Vitroretinal Division, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia
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Hooper P, Boucher MC, Cruess A, Dawson KG, Delpero W, Greve M, Kozousek V, Lam WC, Maberley DAL. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2012; 47:S1-30, S31-54. [PMID: 22632804 DOI: 10.1016/j.jcjo.2011.12.025] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Qi HP, Bi S, Wei SQ, Cui H, Zhao JB. Intravitreal versus subtenon triamcinolone acetonide injection for diabetic macular edema: a systematic review and meta-analysis. Curr Eye Res 2012; 37:1136-47. [PMID: 22793880 DOI: 10.3109/02713683.2012.705412] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To compare the efficacy of intravitreal (IV) triamcinolone acetonide (IVTA) versus subtenon (ST) triamcinolone acetonide (STTA) injection for the treatment of diabetic macular edema (DME). METHODS Searches for randomized clinical trials published between 1 January 1950 and 15 March 2011 were conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Library included in the present meta-analysis are five randomized controlled trials, each with a minimum follow-up of 3 mo. All included studies evaluated the efficacy of TA for the treatment of refractory DME, and compared IVTA with STTA by measuring visual acuity (VA), central macular thickness (CMT), and intraocular pressure (IOP). RESULTS One mo post-injection, treatment with IVTA had significantly improved VA (MD, -0.14 logMAR; 95% CI = -0.16 to -0.13) and reduced CMT (MD = -174.02 μm; 95% CI = -249.97 to -98.08) compared with STTA. At 3 mo post-injection, treatment with IVTA had significantly improved VA (MD = -0.07 logMAR; 95% CI = -0.09 to -0.05) and reduced CMT (MD = -119.46 μm; 95% CI = -176.55 to -62.36) compared with STTA. The benefits of either treatment were no longer significant at 6 mo, and patients had to be retreated. Compared with STTA, IVTA injections produced no difference in IOPs at 1 mo, higher IOPs at 3 mo, and lower IOP values at 6 months CONCLUSIONS Within 3 mo, IVTA is more effective than is STTA in improving VA and reducing CMT in patients with refractory DME. However, the benefits of either regimen were no longer evident at 6 mo.
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Affiliation(s)
- Hui-Ping Qi
- Department of Ophthalmology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Aronis KN, Mantzoros CS. A brief history of insulin resistance: from the first insulin radioimmunoassay to selectively targeting protein kinase C pathways. Metabolism 2012; 61:445-9. [PMID: 22304840 DOI: 10.1016/j.metabol.2012.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 01/03/2012] [Indexed: 12/29/2022]
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Affiliation(s)
- David A Antonetti
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, USA
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Emerging pharmacotherapies for diabetic macular edema. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:548732. [PMID: 22474425 PMCID: PMC3299388 DOI: 10.1155/2012/548732] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2011] [Revised: 10/27/2011] [Accepted: 10/27/2011] [Indexed: 12/20/2022]
Abstract
Diabetic macular edema (DME) remains an important cause of visual loss in patients with diabetes mellitus. Although photocoagulation and intensive control of systemic metabolic factors have been reported to achieve improved outcomes in large randomized clinical trials (RCTs), some patients with DME continue to lose vision despite treatment. Pharmacotherapies for DME include locally and systemically administered agents. We review several agents that have been studied for the treatment of DME.
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Oral protein kinase c β inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2. Retina 2012; 31:2084-94. [PMID: 21862954 DOI: 10.1097/iae.0b013e3182111669] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C β inhibitor trials. METHODS Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity ≥45 letters (∼20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in ≥1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (≥15-letter loss sustained for the last 6 months of study). RESULTS In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A ≥15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a ≥15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified. CONCLUSION Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema.
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Affiliation(s)
- Stephen L. Belmonte
- From the Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, NY
| | - Burns C. Blaxall
- From the Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, NY
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Abstract
Heart failure (HF) involves changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity. Collectively, these changes have been referred to as 'cardiac remodeling'. Understanding the components of this process with the goal of stopping or reversing its progression has become a major objective. This concept is often termed 'reverse remodeling', and is successfully achieved by inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and device therapies such as cardiac resynchronization or ventricular assist devices. Not every method of reverse remodeling has long-lasting clinical efficacy. However, thus far, every successful clinical treatment with long-term benefits on the morbidity and mortality of patients with HF reverses remodeling. Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features. Here, we review the current evidence for reverse remodeling by existing therapies, and discuss novel approaches that are rapidly moving from preclinical to clinical trials.
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Chan WC, Tsai SH, Wu AC, Chen LJ, Lai CC. Current Treatments of Diabetic Macular Edema. INT J GERONTOL 2011. [DOI: 10.1016/j.ijge.2011.09.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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