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Intravitreal vascular endothelial growth factors hypertension, proteinuria, and renal injury: a concise review.
Hanna, RM, Ahdoot, RS, Kim, MS, Jhaveri, KD, Kalantar-Zadeh, K, Kurtz, IB
Current opinion in nephrology and hypertension. 2022;(1):47-56
Abstract
PURPOSE OF REVIEW Nearly 20 years ago, vascular endothelial growth factor (VEGF)inhibitors (VEGFi) were adapted from systemic use from antiangiogenesis roles to intravitreal uses. Initially bevacizumab a murine immunoglobulin was injected 'off label' as a treatment for diabetic macular edema and age-related macular degeneration. Throughout the following decade aflibercept and finally ranibizumab were adapted and obtained Food and Drug Administration approval for intravitreal use. Initially systemic absorption was thought to be quite low after intravitreal injections and was quoted as being 200-fold lower than levels postulated to induce significant VEGF inhibition. Pharmacodynamic studies obtained in 2014 and again in 2017 revealed significant systemic absorption and detectable VEGF inhibition, this has since been confirmed in multiple subsequent studies. RECENT FINDINGS A few case reports of renal dysfunction and glomerular disease related to VEGFi were initially identified. Mixed findings on effects on blood pressure were noted in studies. More recently, 32 cases of de-novo glomerular disease and/or proteinuria exacerbation were identified. New studies have corroborated increased blood pressure, proteinuria exacerbation in patients with pre-existing nephrotic syndrome, and systemic VEGF depletion. Further, the most common lesion of systemic VEGFi nephrotoxicity, thrombotic microangiopathy, has recently been reported by our group. SUMMARY We will review the pharmacokinetic, translational, and epidemiological data that year upon year establish the finite-yet real risk of intravitreal VEGFi.
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2.
Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.
Ehlers, JP, Yeh, S, Maguire, MG, Smith, JR, Mruthyunjaya, P, Jain, N, Kim, LA, Weng, CY, Flaxel, CJ, Schoenberger, SD, et al
Ophthalmology. 2022;(1):88-99
Abstract
PURPOSE To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.
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3.
A New Era in Reducing Treatment Burden in Retinal Disease.
Retina (Philadelphia, Pa.). 2021;(Suppl 1):S1-S12
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4.
Anti-VEGF Mediated Immunomodulatory Role of Phytochemicals: Scientific Exposition for Plausible HCC Treatment.
Kumar, AR, Devan, AR, Nair, B, Nath, LR
Current drug targets. 2021;(11):1288-1316
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid tumours and the second leading cause of cancer-related mortality worldwide. Advanced-recurrent HCC often requires a systemic drug therapy where multi tyrosine kinase inhibitor, Sorafenib represents the first-line therapy option. But it exhibited very limited survival benefit and tumour response due to the early emergence of drug resistance and drug-related adverse effect. Immunotherapy approaches now being widely studied as an effective alternative treatment for HCC. Several immune checkpoint inhibitors (ICI), such as Nivolumab and Pembrolizumab, are approved as monotherapy in sorafenib-resistant HCC patients. But, the existence of a plethora of immunosuppressive signals in the tumour microenvironment often leads to unsuccessful immunotherapies. In this context, combinatorial immunotherapies are getting much acceptance as a way to improve therapeutic outcomes by blocking immunosuppressive signals in the tumour microenvironment (TME). The combination of Vascular Endothelial Growth Factor (VEGF) inhibitors with ICI resulted in significant synergistic effects in various preclinical and clinical studies. However, the adverse effects associated with current synthetic VEGF inhibitors limit its clinical utility. In this review, we have summarized the potential of phytochemicals, especially the category of flavonoids, alkaloids, glycosides, terpenoids, and coumarin, as the available-affordable-safe-effective repositories of VEGF inhibitors. Their possibilities as an alternative for synthetic VEGF inhibitors by synergistic combination with ICI are reviewed, thereby enhancing patient compliance and survival rates. This review highlights the demand for a detailed investigation of the plausible role of plant-based anti-angiogenic-immunotherapy combination against HCC.
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5.
Diabetic Retinopathy and Vascular Endothelial Growth Factor Gene Insertion/Deletion Polymorphism.
Khan, SZ, Ajmal, N, Shaikh, R
Canadian journal of diabetes. 2020;(3):287-291
Abstract
Diabetic retinopathy (DR) is a microvascular complication of the retina of the eye and represents a major cause of blindness worldwide. It is a complex disorder characterized by both genetic and environmental factors. The vascular endothelial growth factor (VEGF) gene is among the main candidate genes for DR, as it is also involved in several other diseases, such as microvascular complications of diabetes mellitus and cancer. The VEGF gene is extremely polymorphic. The 18-bp fragment (insertion/deletion) polymorphism at the -2549 position of the promoter region of the VEGF gene is of great importance. In this review, we highlight the DR and VEGF gene (insertion/deletion) polymorphism. In addition, we assess this association in various DR populations and in other microvascular complications, such as diabetic nephropathy, diabetic peripheral neuropathy and cancer.
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6.
Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab.
Khan, M, Aziz, AA, Shafi, NA, Abbas, T, Khanani, AM
Cells. 2020;(8)
Abstract
This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.
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7.
Lutein and zeaxanthin attenuates VEGF-induced neovascularisation in human retinal microvascular endothelial cells through a Nox4-dependent pathway.
Keegan, G, Pardhan, S, Chichger, H
Experimental eye research. 2020;:108104
Abstract
Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR) are two of the most common and severe causes of vision loss in the population. Both conditions are associated with excessive levels of vascular endothelial growth factor (VEGF) in the eye which results in an increase in the formation of new blood vessels through a process called neovascularisation. As such, anti-VEGF therapies are currently utilised as a treatment for patients with AMD however they are associated with painful administration of injections and potential degeneration of healthy endothelium. There is therefore growing interest in alternate treatment options to reduce neovascularisation in the eye. The use of carotenoids, lutein (L) and zeaxanthin (Z), has been shown to improve vision loss parameters in patients with AMD, however the underlying mechanisms are not well-understood. We studied the impact of these compounds on neovascularisation processes using an in vitro cell model of the retinal microvascular endothelium. Our findings show that L and Z reduced VEGF-induced tube formation whilst, in combination (5:1 ratio), the compounds significantly blocked VEGF-induced neovascularisation. The carotenoids, individually and in combination, reduced VEGF-induced oxidative stress concomitant with increased activity of the NADPH oxidase, Nox4. We further demonstrated that the Nox4 inhibitor, GLX7013114, attenuated the protective effect of L and Z. Taken together, these findings indicate the protective effect of the carotenoids, L and Z, in reducing VEGF-mediated neovascularisation via a Nox4-dependent pathway. These studies implicate the potential for these compounds to be used as a therapeutic approach for patients suffering from AMD and proliferative DR.
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8.
Current concepts of pharmacotherapy of diabetic macular edema.
Haritoglou, C, Maier, M, Neubauer, AS, Augustin, AJ
Expert opinion on pharmacotherapy. 2020;(4):467-475
Abstract
Introduction: Diabetic macular edema (DME) is a sight threatening disease and a major cause for blindness for people in working age. The pathogenesis is multifactorial and complex. The pharmacotherapy of DME addresses both the inhibition of vascular endothelial growth factor (VEGF) by the intravitreal injection of VEGF inhibitors and inflammatory processes by the intravitreal application of steroids. Several trials have been published reporting on the efficacy and safety of these treatments.Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on the role of inflammation and VEGF expression in DME. It discusses newly published clinical trials on intravitreal pharmacotherapy for DME. The literature was searched using Medline/PubMed and was selected given its relevance for the topic to be discussed.Expert opinion: Our knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Some of these insights have been successfully transferred into current treatment strategies already including VEGF suppression or anti-inflammatory treatments using steroids. The identification of additional pathophysiological aspects and their relevance as potential treatment targets will be a future challenge in the treatment of DME. A better knowledge on the complex pathophysiology will also help to establish combination strategies.
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9.
Dexamethasone and Anti-VEGF Combination Therapy for the Treatment of Diabetic Macular Edema.
Al-Khersan, H, Hariprasad, SM, Salehi-Had, H
Ophthalmic surgery, lasers & imaging retina. 2019;(1):4-7
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10.
A literature analysis on anti-vascular endothelial growth factor therapy (anti-VEGF) using a bibliometric approach.
Yeung, AWK, Abdel-Daim, MM, Abushouk, AI, Kadonosono, K
Naunyn-Schmiedeberg's archives of pharmacology. 2019;(4):393-403
Abstract
We performed the current study to assess the citation performance of research works on anti-vascular endothelial growth factor (anti-VEGF) therapy. We searched Web of Science (WoS) to identify relevant publications and analyze them with reference to their publication year, journal title, citation count, WoS category, and article type. The bibliometric software (VOSviewer) was used for citation analyses of countries and journals and to generate a term map that visualizes the recurring terms appearing in the titles and abstracts of published articles. The literature search resulted in 7364 articles, with a mean citation count of 26.2. Over half of them (50.2%) were published during the past 5 years. Original articles constituted the majority (67.8%). The publications were mainly classified into WoS categories of ophthalmology (43.2%) and oncology (20.6%). The most prolific ophthalmology and cancer journals were Investigative Ophthalmology & Visual Science (7.3%) and Cancer Research (1.4%), respectively. The correlation between journal impact factor and citation count was weak to moderate (for journals with impact factor up to 5 and 10, respectively), and open-access articles had significantly more citations than non-open-access articles (p < 0.001). The frequently targeted tumors by anti-VEGF therapy included metastatic colorectal cancer (196; 49.2 citations per article (CPA)), breast cancers (167; 37.2 CPA), and renal cell carcinoma (122; 38.2 CPA). The frequently targeted eye pathologies were age-related macular degeneration (828; 18.2 CPA), diabetic macular edema (466; 10.8 CPA), and diabetic retinopathy (358; 31.9 CPA). These results indicate that anti-VEGF therapy has a wide range of applications and its publications are highly cited.