Abstract 2780: A First-in-Class Oligonucleotide Drug-Antidote Pair Efficiently Modulates Factor IXa Activity in Human Subjects - A Nascent Platform for Antidote-Controlled Periprocedural Anticoagulation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mark Y Chan ◽  
Mauricio G Cohen ◽  
Christopher P Rusconi ◽  
John H Alexander ◽  
Shelley K Myles ◽  
...  
Keyword(s):  
Human Subjects ◽  
Stable Coronary Artery Disease ◽  
Serious Adverse Events ◽  
Factor Ixa ◽  
Complementary Oligonucleotide ◽  
Artery Disease ◽  
Novel Target ◽  
Intervention Trials ◽  
Rebound Increase ◽  
Factor Ixa Inhibition

Background: Safe and active reversibility of anticoagulation is highly desirable. Factor IXa, critical for rapid thrombin generation on platelet surfaces, is a novel target for regulating coagulation. The REG1 System comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, selectively binds and inhibits IXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-factor IXa activity. Methods: To explore the feasiblity of testing the REG1 system in catheter-based intervention trials, we analyzed data from 2 randomized dose-escalation studies of REG1: phase 1a with 84 healthy subjects and phase 1b with 50 patients with stable coronary artery disease taking aspirin and/or clopidogrel. Results: An intravenous (IV) bolus of RB006 produced a similar dose-dependent activated partial thromboplastin time (aPTT) increase in both populations; a weight-adjusted dose of 1mg/kg RB006 consistently achieved 100% factor IXa inhibition (figure 1 ), a level effectively eliminating artifical surface thrombosis in animal models. IV bolus RB007 in a 2:1 antidote:drug ratio reversed the aPTT to <10% above the upper limit of normal within a median of 1 min (IQR 1–2), with no rebound increase up to 7 days. Despite dual antiplatelet use in 19 subjects, no major bleeding or other serious adverse events occurred. Conclusions: These exploratory data support the safe regulation of coagulation with a factor IXa-specific drug-antidote system. The pharmacodynamic response elicted by a 1mg/kg RB006 dose and 2:1 antidote:drug ratio appears suitable for catheter-based intervention studies. Figure 1. Relative APTT and % Factor IXa inhibition versus RB008 Dose (mg/kg)

scholarly journals Phase 1b Randomized Study of Antidote-Controlled Modulation of Factor IXa Activity in Patients With Stable Coronary Artery Disease

Circulation ◽  
2008 ◽  
Vol 117 (22) ◽  
pp. 2865-2874 ◽  
Author(s):  
Mark Y. Chan ◽  
Mauricio G. Cohen ◽  
Christopher K. Dyke ◽  
Shelley K. Myles ◽  
Laura G. Aberle ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Stable Coronary Artery Disease ◽  
Randomized Study ◽  
Factor Ixa ◽  
Phase 1B ◽  
Artery Disease

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

1991 ◽  
Vol 65 (05) ◽  
pp. 504-510 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
Walter Bernini ◽  
Guido Lazzerini ◽  
Giuliana Buti Strata ◽  
...  
Keyword(s):  
Platelet Function ◽  
Low Dose ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Stable Coronary Artery Disease ◽  
High Dose ◽  
Single Drug ◽  
Before And After ◽  
Serum Thromboxane ◽  
Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease

Diabetes ◽  
1997 ◽  
Vol 46 (9) ◽  
pp. 1491-1496 ◽  
Author(s):  
M. Maki ◽  
P. Nuutila ◽  
H. Laine ◽  
L. M. Voipio-Pulkki ◽  
M. Haaparanta ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Glucose Uptake ◽  
Stable Coronary Artery Disease ◽  
Myocardial Glucose Uptake ◽  
Artery Disease

Coronary Artery Disease and Endothelial Dysfunction: Novel Diagnostic and Therapeutic Approaches

2020 ◽  
Vol 27 (7) ◽  
pp. 1052-1080 ◽  
Author(s):  
Evangelos Oikonomou ◽  
Gerasimos Siasos ◽  
Vasiliki Tsigkou ◽  
Evanthia Bletsa ◽  
Maria-Evi Panoilia ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Stable Coronary Artery Disease ◽  
Therapeutic Interventions ◽  
Therapeutic Approaches ◽  
Cardiovascular Prognosis ◽  
Ultrasound Evaluation ◽  
Artery Disease

Coronary artery disease is the leading cause of morbidity and mortality worldwide. The most common pathophysiologic substrate is atherosclerosis which is an inflammatory procedure that starts at childhood and develops throughout life. Endothelial dysfunction is associated with the initiation and progression of atherosclerosis and is characterized by the impaired production of nitric oxide. In general, endothelial dysfunction is linked to poor cardiovascular prognosis and different methods, both invasive and non-invasive, have been developed for its evaluation. Ultrasound evaluation of flow mediated dilatation of the branchial artery is the most commonly used method to assessed endothelial function while intracoronary administration of vasoactive agents may be also be used to test directly endothelial properties of the coronary vasculature. Endothelial dysfunction has also been the subject of therapeutic interventions. This review article summarizes the knowledge about evaluation of endothelial function in acute coronary syndromes and stable coronary artery disease and demonstrates the current therapeutic approaches against endothelial dysfunction.

Microvascular (dys)Function in Stable Coronary Artery Disease: Cross Talk with Epicardial Segments

2018 ◽  
Vol 24 (25) ◽  
pp. 2900-2905
Author(s):  
Lucian Calmac ◽  
Vlad Bataila ◽  
Bogdan Dragoescu ◽  
Cosmin Mihai ◽  
Alexandru Scafa-Udriste ◽  
...  
Keyword(s):  
Coronary Flow ◽  
Stable Coronary Artery Disease ◽  
Microvascular Dysfunction ◽  
Complex Interaction ◽  
Diagnostic Tools ◽  
Pathological State ◽  
Hemodynamic Parameters ◽  
Artery Disease ◽  
Epicardial Stenosis ◽  
Current Guidelines

Myocardial ischemia is the consequence of an unbalance between coronary flow that can be achieved and myocardial metabolic needs. Pathological state of both epicardial and intramyocardial vessels may be responsible for inducing ischemia. However, revascularization decision should be based on the severity of each epicardial lesion that is evaluated. There are different diagnostic tools that may help for the evaluation of each compartment which is based on the measurement of coronary hemodynamics. Pressure-derived indices are recommended by current guidelines for evaluation of epicardial stenosis significance. We assess the complex interaction between hemodynamic parameters in order to understand how different parameters are influenced in the settings of microvascular dysfunction.

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