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https://www.readbyqxmd.com/read/27778249/targeting-tie2-for-treatment-of-diabetic-retinopathy-and-diabetic-macular-edema
#1
Peter A Campochiaro, Kevin G Peters
Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization...
December 2016: Current Diabetes Reports
https://www.readbyqxmd.com/read/27236272/enhanced-benefit-in-diabetic-macular-edema-from-akb-9778-tie2-activation-combined-with-vascular-endothelial-growth-factor-suppression
#2
Peter A Campochiaro, Arshad Khanani, Michael Singer, Sunil Patel, David Boyer, Pravin Dugel, Saleema Kherani, Barbara Withers, Laura Gambino, Kevin Peters, Mitchell Brigell
PURPOSE: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME). DESIGN: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial. PARTICIPANTS: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites. METHODS: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0...
August 2016: Ophthalmology
https://www.readbyqxmd.com/read/26642851/interfering-with-ve-ptp-stabilizes-endothelial-junctions-in-vivo-via-tie-2-in-the-absence-of-ve-cadherin
#3
Maike Frye, Martina Dierkes, Verena Küppers, Matthias Vockel, Janina Tomm, Dagmar Zeuschner, Jan Rossaint, Alexander Zarbock, Gou Young Koh, Kevin Peters, Astrid Fee Nottebaum, Dietmar Vestweber
Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators...
December 14, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/25439435/treatment-of-diabetic-macular-edema-with-an-inhibitor-of-vascular-endothelial-protein-tyrosine-phosphatase-that-activates-tie2
#4
MULTICENTER STUDY
Peter A Campochiaro, Raafay Sophie, Michael Tolentino, Daniel M Miller, David Browning, David S Boyer, Jeffrey S Heier, Laura Gambino, Barbara Withers, Mitchell Brigell, Kevin Peters
PURPOSE: AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). DESIGN: Open-label, dose-escalation clinical trial. PARTICIPANTS: Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22...
March 2015: Ophthalmology
https://www.readbyqxmd.com/read/25180601/targeting-ve-ptp-activates-tie2-and-stabilizes-the-ocular-vasculature
#5
Jikui Shen, Maike Frye, Bonnie L Lee, Jessica L Reinardy, Joseph M McClung, Kun Ding, Masashi Kojima, Huiming Xia, Christopher Seidel, Raquel Lima e Silva, Aling Dong, Sean F Hackett, Jiangxia Wang, Brian W Howard, Dietmar Vestweber, Christopher D Kontos, Kevin G Peters, Peter A Campochiaro
Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV...
October 2014: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/23899555/effects-of-vascular-endothelial-protein-tyrosine-phosphatase-inhibition-on-breast-cancer-vasculature-and-metastatic-progression
#6
Shom Goel, Nisha Gupta, Brian P Walcott, Matija Snuderl, Cristina T Kesler, Nathaniel D Kirkpatrick, Takahiro Heishi, Yuhui Huang, John D Martin, Eleanor Ager, Rekha Samuel, Shuhan Wang, John Yazbek, Benjamin J Vakoc, Randall T Peterson, Timothy P Padera, Dan G Duda, Dai Fukumura, Rakesh K Jain
BACKGROUND: The solid tumor microvasculature is characterized by structural and functional abnormality and mediates several deleterious aspects of tumor behavior. Here we determine the role of vascular endothelial protein tyrosine phosphatase (VE-PTP), which deactivates endothelial cell (EC) Tie-2 receptor tyrosine kinase, thereby impairing maturation of tumor vessels. METHODS: AKB-9778 is a first-in-class VE-PTP inhibitor. We examined its effects on ECs in vitro and on embryonic angiogenesis in vivo using zebrafish assays...
August 21, 2013: Journal of the National Cancer Institute
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