Phase II feasibility study to evaluate the safety and efficacy of EP-2104R for Magnetic Resonance Imaging of thrombi in the arterial vasculature and cardiac chambers

开始日期2005-11-25

申办/合作机构

EPIX Pharmaceuticals, Inc.

EUCTR2004-004700-20-CZ / Not yet recruitingN/A

Phase II Feasibility study of safety and efficacy of Magnetic Resonance Imaging of Thrombi with EP-2104R in the detection in Venous Thromboembolism (VTE)

开始日期2005-03-11

申办/合作机构

EPIX Pharmaceuticals, Inc.

100 项与 Gadolinium Labeled Fibrin-Binding Peptide(Epix) 相关的临床结果

登录后查看更多信息

100 项与 Gadolinium Labeled Fibrin-Binding Peptide(Epix) 相关的转化医学

登录后查看更多信息

100 项与 Gadolinium Labeled Fibrin-Binding Peptide(Epix) 相关的专利（医药）

登录后查看更多信息

项与 Gadolinium Labeled Fibrin-Binding Peptide(Epix) 相关的文献（医药）

2022-09-01·European Journal of Nuclear Medicine and Molecular Imaging

Fibrin-targeting molecular MRI in inflammatory CNS disorders

Article

作者: Hamm, Bernd ; Silva, Rafaela V ; Kaneko, Takaaki ; Tietze, Anna ; Paul, Friedemann ; Lohmeier, Johannes ; Makowski, Marcus R ; Prüss, Harald ; Taupitz, Matthias ; Caravan, Peter ; Infante-Duarte, Carmen

AbstractBackgroundFibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer’s disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury.PurposeTo investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment.Materials and methodsSpecificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables.ResultsFor the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p = .008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p = .006). CNS fibrin deposition corresponded to immunoinflammatory activity (R2 = 0.85, p < .001) and disability (R2 = 0.81, p < .001) in a model for MS, which suggests a clinical role for staging and monitoring. Additionally, EP2104-R showed substantially higher SNR (M ± SD, 6.6 ± 1 (EP2104-R) vs. 2.7 ± 0.4 (gadobutrol), p = .004) than clinically used contrast media, which increases sensitivity for lesion detection.ConclusionsMolecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment.

2020-04-01·Investigative Radiology1区 · 医学

Molecular Magnetic Resonance Imaging of Fibrin Deposition in the Liver as an Indicator of Tissue Injury and Inflammation

1区 · 医学

Article

作者: Mozhdeh Sojoodi ; Kenneth K Tanabe ; Ricard Masia ; Alexander S Guimaraes ; Bryan C Fuchs ; Carlos F G C Geraldes ; Helena S Leitão ; Peter Caravan ; Sergei Shuvaev ; Iliyana Atanasova

Rationale and ObjectivesLiver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation.MethodsWeekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non–fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation.ResultsAfter 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0–4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis.ConclusionsEP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.

2017-05-04·JCI Insight1区 · 医学

Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis

1区 · 医学

ArticleOA

作者: Probst, Clemens K ; Black, Katharine E ; Brazee, Patricia L ; Violette, Shelia M ; Rotile, Nicholas J ; Van Cott, Elizabeth M ; Blasi, Francesco ; Shea, Barry S ; Caravan, Peter ; Tager, Andrew M ; Sosnovik, David E ; Weinreb, Paul H

Fibrotic lung disease, most notably idiopathic pulmonary fibrosis (IPF), is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to lung fibrosis is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on thrombin activity and its downstream signaling pathways. Direct thrombin inhibition with dabigatran significantly inhibited protease-activated receptor-1 (PAR1) activation, integrin αvβ6 induction, TGF-β activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time (UTE) lung magnetic resonance imaging (MRI) with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of thrombin can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/αvβ6/TGF-β axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct thrombin inhibitors that our data suggest could benefit these patients.

100 项与 Gadolinium Labeled Fibrin-Binding Peptide(Epix) 相关的药物交易

登录后查看更多信息