The Experts below are selected from a list of 42 Experts worldwide ranked by ideXlab platform
David Bergqvist - One of the best experts on this subject based on the ideXlab platform.
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inhibition of heparin resistant microarterial thrombosis by recombinant hirudin a specific thrombin inhibitor
Plastic and Reconstructive Surgery, 1995Co-Authors: Bjorn Arnljots, David BergqvistAbstract:The effects of heparin boluses comparable with those commonly used during angioplasty procedures were compared with equal gravimetric doses of recombinant Desulfatohirudin (CGP 39393) in a rabbit model of microarterial thrombosis. Seven-millimeter segments of the central arteries of the ears were isolated between microvascular clamps and subjected to arteriotomy and deep vessel wall trauma. Arteriotomies were closed with continuous 10-0 sutures. Five minutes before vascular reperfusion (opening of vascular clamps), boluses of heparin (1.00 mg/kg), hirudin (1.00 mg/kg), hirudin (0.25 mg/kg), or vehicle (saline) were administered to groups of 10 rabbits in a blind, random fashion. Neither agent prolonged arteriotomy bleeding times relative to vehicle. All active agents significantly increased patency rates versus vehicle at 30 minutes after reperfusion, though reduced vessel patency was noted in a substantial portion of vessels in the groups receiving 0.25 mg hirudin or 1.00 mg/kg heparin. Patency rates at 120 minutes were only improved by the 1.00 mg/kg hirudin dose, and in accord, thrombus weights were significantly reduced only by the 1.00 mg/kg dose of hirudin. In contrast, the anticoagulant response (measured as the activated partial thromboplastin time and anti-IIa and anti-Xa activities) was considerably more pronounced and of longer duration after administration of heparin and hirudin. This is consistent with the hypothesis that the inactivation of clot-bound thrombin that is produced by specific thrombin inhibition (hirudin) but not by cofactor-mediated thrombin inhibition (heparin) is of pivotal importance in achieving a profound and sustained antithrombotic effect following vascular trauma. While heparin boluses seem to be of doubtful value, hirudin seems a promising strategy in context with angioplasty procedures.
Ian J Sarembock - One of the best experts on this subject based on the ideXlab platform.
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effect of thrombin inhibition with Desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits
Circulation, 1996Co-Authors: Michael Ragosta, William L Barry, Lawrence W Gimple, David S Gertz, Kyle W Mccoy, George A Stouffer, Coleen A Mcnamara, Eric R Powers, Gary K Owens, Ian J SarembockAbstract:Background Thrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation. Methods and Results Femoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 h...
Jeffrey L Anderson - One of the best experts on this subject based on the ideXlab platform.
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a pilot trial of recombinant Desulfatohirudin compared with heparin in conjunction with tissue type plasminogen activator and aspirin for acute myocardial infarction results of the thrombolysis in myocardial infarction timi 5 trial
Journal of the American College of Cardiology, 1994Co-Authors: Christopher P Cannon, Carolyn H Mccabe, Timothy D Henry, Marc J Schweiger, Robert S Gibson, Hiltrud S Mueller, Richard C Becker, Neal S Kleiman, Mark J Haugland, Jeffrey L AndersonAbstract:Abstract Objectives. The purpose of this study was to assess the value of recombinant Desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction. Background. Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion. Methods. The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed. Results. The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 How was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS). Conclusions. Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.
Isaiah J Fidler - One of the best experts on this subject based on the ideXlab platform.
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inhibition of murine melanoma experimental metastasis by recombinant Desulfatohirudin a highly specific thrombin inhibitor
Cancer Research, 1991Co-Authors: Noriko Esumi, Dominic Fan, Isaiah J FidlerAbstract:Recombinant Desulfatohirudin (r-hirudin), a highly specific inhibitor of thrombin, was examined to determine whether it would inhibit production of experimental lung metastasis by B16-F10 melanoma cells. In in vitro assays using mouse plasma, the high level of procoagulant activity in B16-F10 cells was significantly inhibited by r-hirudin in a dose-dependent manner. From 15 to 120 min after s.c. administration into C57BL/6 mice, r-hirudin (10 mg/kg) markedly prolonged clotting time in a time course pattern that directly correlated with that of blood distribution of 125I-labeled r-hirudin. The production of experimental lung metastasis by B16-F10 cells was significantly inhibited by r-hirudin administered s.c. at time points ranging from 120 min before to 60 min after tumor cell inoculation with the most significant effects found in mice given r-hirudin 15 or 2 min before the i.v. injection of tumor cells. The organ distribution of [125I]IdUrd-labeled tumor cells demonstrated a clear difference in the lungs of mice treated with r-hirudin and the lungs of control mice, and these differences directly correlated with the number of lung tumor colonies found 3 weeks later. The inhibition of lung metastasis was not due to direct antitumor effects of r-hirudin. These results suggest that inhibition of coagulation events by r-hirudin significantly inhibit experimental lung metastasis during a critical time of 60 min after the entry of tumor cells into the circulation.
Stephan Fischer - One of the best experts on this subject based on the ideXlab platform.
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comparison of Desulfatohirudin revasc and heparin as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary thrombosis
British Journal of Pharmacology, 1996Co-Authors: Ulrich Martin, Liesel Dorge, Stephan FischerAbstract:1. We compared the direct thrombin inhibitor, Desulfatohirudin (REVASC) and the indirect thrombin inhibitor, heparin, as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary artery thrombosis. 2. Reteplase (BM 06.022) is a recombinant unglycosylated variant of human tissue-type plasminogen activator. Thrombus formation in anaesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 210 min with an electromagnetic flow probe. Twenty eight dogs were randomized to receive i.v. heparin (120 iu kg-1 bolus plus 80 iu kg-1 per h) or i.v. hirudin (2.0 mg kg-1 bolus plus 2.0 mg kg-1 per h) 10 min before thrombolysis preceded by i.v. acetylsalicyclic acid (20 mg kg-1) 5 min prior to anticoagulation. Every dog received an i.v. double bolus injection of 0.14 + 0.14 u kg-1 ( = 0.24 + 0.24 mg kg-1) reteplase, 30 min apart, 1 h after thrombus formation. 3. At comparable reperfusion rates (12 out of 12 vs. 15 out of 16 dogs), hirudin enhanced time to reperfusion (14.3 +/- 1.4 vs. 23.2 +/- 3.4 min; P < 0.05) and completely prevented reocclusion after reperfusion in contrast to heparin (0 out of 11 vs. 7 out of 11 dogs; P < 0.05). Coronary blood flow quality was improved by hirudin as shown by a higher maximum blood flow after reperfusion (130 +/- 14.3 vs. 83 +/- 9.3% of baseline; P < 0.05), a higher blood flow level at 20, 30, 40, and 50 min after onset of thrombolysis (P < 0.05) and a longer cumulative patency time (195 +/- 1.7 vs. 166 +/- 12 min; P < 0.05). Activated partial thromboplastin time and buccal mucosa bleeding time were prolonged (P < 0.05) by either anticoagulant, but did not differ significantly between groups. 4. The direct thrombin inhibitor, Desulfatohirudin, enhanced thrombolysis, prevented reocclusion and increased blood flow as compared with the indirect thrombin inhibitor, heparin, when investigated at one dose level each and used in conjunction with reteplase.