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Benedict R Lucchesi - One of the best experts on this subject based on the ideXlab platform.

  • Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis.
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • effect of sodium hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein iib iiia receptor antagonist crl42796
    British Journal of Pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

  • Prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein IIb/IIIa receptor antagonist CRL42796
    British journal of pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

  • Orally Effective CVS-1123 Prevents Coronary Artery Thrombosis in the Conscious Dog
    Circulation, 1996
    Co-Authors: Geoffrey R. Cousins, George P. Vlasuk, Gregory S. Friedrichs, Yuji Sudo, Sam S. Rebello, William E. Rote, Thomas G. Nolan, Christine Mendoza, Benedict R Lucchesi
    Abstract:

    Background We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 [(CH3CH2CH2)2-CH-CO-Asp(OCH3)-Pro-Arg-CHO; MW, 575]. The object was to determine whether thrombin inhibition could reduce the incidence of occlusive Coronary Artery Thrombosis in response to arterial wall injury. Methods and Results Arterial wall injury was induced in conscious dogs by a 150-μA anodal current applied to the intimal surface of the circumflex Coronary Artery 30 minutes after oral CVS-1123 (20 mg/kg every 8 hours for three doses; n=11) or placebo containing diluent (n=10). Dogs were monitored for 8 hours and at 24 hours. The Coronary Artery remained patent for 24 hours in 8 of 11 CVS-1123–treated dogs. All dogs (n=10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, the plasma CVS-1123 concentration was 13±1 μg/mL, reaching a maximum of 15±1 μg/mL after the second dose and 4.4±0.5 μg/mL at 24 hours. Ex vivo platelet aggregation to γ-thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 ( P

Christer Mattsson - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of Coronary Artery Thrombosis.
    Thrombosis research, 2005
    Co-Authors: Jan-arne Björkman, Tommy Abrahamsson, Viveca Nerme, Christer Mattsson
    Abstract:

    The objective of this study was to test the hypothesis if thrombolysis induced by recombinant tissue-type plasminogen activator, (rt-PA) could be facilitated by inhibiting carboxypeptidase U (CPU, active Thrombin Activatable Fibrinolysis Inhibitor, TAFIa) activity. The efficacy of rt-PA alone, or in combination with the carboxypeptidase inhibitor MERGETPA, was compared in a dog model of Coronary Artery Thrombosis. Twenty dogs were randomised in two groups, one received rt-PA, 1 mg kg(-1), as intravenous infusion over 20 min starting 30 min after thrombus formation, and the other group received rt-PA, 1 mg kg(-1), as group one with the addition of MERGEPTA 5 mg kg(-1) starting 25 min prior to Coronary Artery occlusion and followed by infusion of 5 mg kg(-1) h(-1) until the end of experiment. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Both groups had similar baseline characteristics with respect to haemodynamic parameters, i.e., heart rate, blood pressure and Coronary Artery blood flow. Coadministration of rt-PA and MERGETPA resulted in significant decrease in time to lysis (15+/-1.5 min vs. 20+/-1.7 min, p=0.03), increased patency time (87+/-16 min vs. 46+/-12 min, p=0.047) and increased Coronary blood flow during patency (1131 mL h(-1) vs. 405 mL h(-1), p=0.015), compared to rt-PA alone. These results indicate that an inhibitor of CPU activity may have a beneficial effect in patients undergoing thrombolytic therapy by attaining shorter time to reperfusion and improved Coronary patency.

  • Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of Coronary Artery Thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran).
    Thrombosis and haemostasis, 2002
    Co-Authors: Christer Mattsson, Viveca Nerme, J. A. Björkman, T. Abrahamsson, Katinka Schatteman, Judith Leurs, S. Scharpe, Dirk Hendriks
    Abstract:

    To test the hypothesis that the direct thrombin inhibitor, melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with melagatran, was given to dogs with a Coronary Artery Thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA±melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in Coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1,+ melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no Coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following melagatran treatment. These results demonstrate that melagatran attenuates generation of CPU in the Coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.

  • Antithrombotic activity of inogatran, a new low-molecular-weight inhibitor of thrombin, in a closed-chest porcine model of Coronary Artery Thrombosis
    Cardiovascular research, 1996
    Co-Authors: Yozo Uriuda, Qing-dong Wang, Lars Grip, Lars Rydén, Per-ove Sjöquist, Christer Mattsson
    Abstract:

    Objective: To characterize the antithrombotic activitiy of inogatran per se in a porcine model of copper-coil-induced Coronary Artery Thrombosis and to compare its effect with that of heparin and ASA. Methods: Forty-eight pigs were assigned to one of the following groups: (1) saline; (2) heparin, (a) 75 and (b) 150 IU/kg/h; (3) acetylsalicylic acid (ASA), 12.5 mg/kg; (4) ASA 12.5 mg/kg + inogatran, 0.06 mg/kg/h; (5) ASA 12.5 mg/kg + inogatran, 0.30 mg/kg/h; (6) inogatran, 0.30 mg/kg/h; (7) inogatran, 0.60 mg/kg/h; (8) inogatran, 1.5 mg/kg/h. Computerized vectorcardiography was applied to monitor Coronary occlusion and reperfusion. Results: Cumulative time in which Coronary arteries were patent, expressed as a percentage of the treatment time (i.e., 90 min) in heparin- and ASA-treated pigs, was 8 ± 6 and 14 ± 7%, respectively. This is not significantly different from placebo-treated pigs. Inogatran-treated pigs showed a dose-dependent antithrombotic effect, and the average patency rates were 34 ± 39, 54 ± 37 and 80 ± 32%, in groups 6, 7 and 8, respectively. Combined treatment with inogatran and ASA did not significantly improve the antithrombotic effect. A partial antithrombotic effect of inogatran was maintained for, on average, at least 150 min after the end of treatment, as evidenced by patency rates of 31 ± 43, 52 ± 48 and 62% ± 44, in groups 6, 7, and 8, respectively. Conclusion: Inogatran inhibits the formation of arterial Thrombosis more effectively than heparin or ASA. Inhibition of clot-bound thrombin and thrombin-induced platelet activation may be the mechanisms behind this effect. Our findings also suggest that a thrombus formed in the presence of inogatran is more susceptible to spontaneous endogenous fibrinolysis.

James K. Hennan - One of the best experts on this subject based on the ideXlab platform.

  • Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis.
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents Coronary Artery Thrombosis
    Thrombosis and haemostasis, 2006
    Co-Authors: James K. Hennan, Robert E. Swillo, Gwen A. Morgan, Courtney E. Leik, Jonathan M. Brooks, Gray D. Shaw, Robert G. Schaub, David L. Crandall, George P. Vlasuk
    Abstract:

    Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Iba ,leading to platelet adhesion, activation and Thrombosis. Blockade of vWF-GPIba interactions by GPG-290 was investigated in a canine model of Coronary Artery Thrombosis alone and in combination with clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105±34 and 156±23 (p

  • effect of sodium hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein iib iiia receptor antagonist crl42796
    British Journal of Pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

  • Prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein IIb/IIIa receptor antagonist CRL42796
    British journal of pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

Edward M Driscoll - One of the best experts on this subject based on the ideXlab platform.

  • Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis.
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • effect of sodium hydrogen exchange inhibition on myocardial infarct size after Coronary Artery Thrombosis and thrombolysis
    Pharmacology, 2006
    Co-Authors: James K. Hennan, Edward M Driscoll, Terrance D. Barrett, Peter S. Fischbach, Benedict R Lucchesi
    Abstract:

    This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary Artery Thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 × 5 min). Thrombolysis with intraCoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 ± 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 ± 3.6%) or after (22.0 ± 2.3%) 60-min ischemia or preconditioning (18.4 ± 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 ± 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 ± 1.1%) and ischemic preconditioning (35.0 ± 4.8%) provided significant cardioprotection compared to control (45.9 ± 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 ± 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as Thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.

  • prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein iib iiia receptor antagonist crl42796
    British Journal of Pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

  • Prevention of experimental carotid and Coronary Artery Thrombosis by the glycoprotein IIb/IIIa receptor antagonist CRL42796
    British journal of pharmacology, 2002
    Co-Authors: James K. Hennan, Tingting Hong, David E Willens, Edward M Driscoll, Thierry A Giboulot, Benedict R Lucchesi
    Abstract:

    The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and Coronary Artery Thrombosis. In the carotid Artery Thrombosis model, occlusion occurred in all control vessels (time to Thrombosis 47.6±8.9 min). After treatment with low dose CRL42796 (15 μg kg−1 loading dose +0.31 μg kg−1 min−1 i.v.), two of five vessels occluded. Time to Thrombosis increased significantly to 155.2±23.1 min. When the drug infusion was increased (0.69 μg kg−1 min−1), each of five vessels remained patent. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. A combination of oral aspirin (4.6 mg kg−1 −41, −17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. Coronary Artery Thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to Thrombosis increased with both doses (Control, 90.8±10.4 min; low dose, 165.8±14.2 min; high dose, >180.0±0 min). The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and Coronary Artery Thrombosis. British Journal of Pharmacology (2002) 136, 927–937. doi:10.1038/sj.bjp.0704744

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  • Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of Coronary Artery Thrombosis
    Journal of the American College of Cardiology, 1992
    Co-Authors: Ulrich Martin, Gisbert Sponer, Klaus Strein
    Abstract:

    The thrombolytic and systemic effects of BM 06.022 were evaluated and compared with those of alteplase, anistreplase, streptokinase and urokinase in a canine model of Coronary Artery Thrombosis. BM 06.022 consists of the kringle-2 and protease domains of human tissue plasminogen activator (t-PA) and is unglycosylated because of its expression in Escherichia coli cells. Thrombus formation in anesthetized open chest dogs was induced by electrical injury to the intimal surface of the left circumflex Coronary Artery at a high level site of obstruction. In heparinized dogs, none of six vehicle-treated animals exhibited reperfusion. Reperfusion was achieved in four of six dogs at 18.3 +/- 6 min after intravenous bolus injection of 140 kU/kg (0.24 mg/kg) of BM 06.022, whereas four of six dogs exhibited reperfusion later (p less than 0.05) at 76.5 +/- 16.1 min during infusion of 1.33 mg/kg of alteplase (0.13 mg/kg as initial bolus injection, followed by 0.66 mg/kg over 1 h and 0.53 mg/kg over 2 h). Significantly later (p less than 0.05) reperfusion than that achieved with BM 06.022 was achieved in five of six dogs at 57.8 +/- 12.1 min after intravenous injection of 0.4 U/kg of anistreplase. Streptokinase (21,000 IU/kg over 60 min) and urokinase (20,000 IU/kg as an intravenous bolus injection, followed by 20,000 IU/kg over 89 min) each induced reperfusion in three of six dogs but at 67 +/- 12 and 84.3 +/- 17.1 min (p less than 0.05 vs. BM 06.022), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)