piperidines and Coronary-Thrombosis

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Topics: Acute Disease; Aspirin; Causality; Coronary Disease; Coronary Thrombosis; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Postoperative Complications; Stents; Syndrome

We tested the hypothesis that simultaneous inhibition of the endothelial integrin alpha(v)beta(3) and the platelet glycoprotein IIb/IIIa receptor will substantially reduce infarct size in a model of acute coronary thrombosis and primary angioplasty.. Dogs were subjected to thrombus formation in the left anterior descending coronary artery followed by primary angioplasty. Prior to angioplasty, they were randomized into 3 treatment groups. Group 1 (n=7) received saline; Group 2 (n=9) received MK-383 that inhibits only IIb/IIIa; and Group 3 (n=9) received CP-4715, that inhibits both IIb/IIIa and alpha(v)beta(3).. There was a 59% reduction in infarct size in dogs receiving CP-4715 compared to controls (p=0.002) and a 37% reduction compared to the dogs receiving MK-383 (p=0.04). Myocardium microthrombi were seen to be reduced similarly with both drugs on post-mortem (99m)Tc-DMP444 autoradiography that reflects in vivo IIb/IIIa receptor activity. In vivo imaging using echistatin-conjugated and leukocyte-targeted microbubbles revealed significant alpha(v)beta(3) inhibition and reduction in active leukocyte recruitment only in Group 3 dogs. Myocardial blood flow and regional function after reperfusion were also significantly better in this group.. Simultaneous inhibition of IIb/IIIa and alpha(v)beta(3) causes a marked reduction in infarct size in a model of acute coronary thrombosis and primary PTCA that is associated with reduced myocardial microthrombi and inflammation, as well as improved myocardial blood flow and regional function. These results may have important implications in the treatment of acute coronary syndromes.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Animals; Coronary Thrombosis; Dogs; Integrin alphaVbeta3; Male; Models, Animal; Myocardial Infarction; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrimidines; Random Allocation; Tirofiban; Tyrosine

In patients with acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal myocardial infarction and repeat percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical thrombosis models. This report documents the preclinical data of Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.

Topics: Acute Disease; Animals; Benzodiazepines; Coronary Thrombosis; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Male; Piperidines; Platelet Aggregation

Topics: Antithrombins; Coronary Thrombosis; Drug Therapy, Combination; Glycine; Humans; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombin; Treatment Outcome

The aim of the present study was to develop a coronary thrombolysis model using the copper coil technique in closed-chest pigs. The first goal (protocol I) was to obtain a reproducible size of myocardial infarction by controlling the coronary occlusion period, a prerequisite for evaluation of myocardioprotective interventions. The second goal (protocol II) was to study if thrombin and platelet aggregation inhibitors influence the rate of thrombolysis, the degree of reocclusion, and the time of coronary patency when added to a thrombolytic regimen (recombinant tissue-type plasminogen activator, rt-PA). Coronary thrombosis was produced by insertion of a thrombogenic copper coil into the LAD of 40 anesthetized pigs. The animals were divided into six groups as follows: Protocol I, group 1: Open-chest, lysis initiated with intracoronary rt-PA (50 mg) concomitant with intravenous heparin and acetylsalicylic acid (ASA) (n=6). Group 2: Closed-chest, lysis initiated with intracoronary rt-PA concomitant with intravenous heparin and ASA (n=10). Protocol II, group 3: Closed-chest, lysis initiated with intravenous rt-PA (n=6). Group 4: Closed-chest, lysis initiated with intravenous rt-PA concomitant with heparin (n=6). Group 5: Closed-chest, lysis initiated with intravenous rt-PA concomitant with inogatran, a low molecular weight thrombin inhibitor (n=6). Group 6: Closed-chest, lysis initiated with intravenous rt-PA immediately after intravenous administration of ASA (n=6). Protocol 1; Reperfusion was achieved in all closed- and open-chest pigs. The time to thrombolysis was 5+/-1.6 and 6+/-3.0 min (mean+/-SD) for closed- and open-chest pigs, respectively. Reocclusions were rare (one in group 1). The size of the ischemic myocardial area was 21+/-11% of the left ventricular area in group 1 and 22+/-6% in group 2. The corresponding values for infarct size as a proportion of the ischemic area were 58+/-10% and 68+/-14%, respectively. The closed-chest model was subsequently used to study the effect of the thrombin and platelet aggregation inhibitors (inogatran, heparin, and ASA) as conjunctive agents to rt-PA-induced thrombolysis (groups 3-6). To mimic its clinical use, rt-PA was administered intravenously. Time to lysis after rt-PA only (group 3) was 33+/-24 min. Concomitant treatment with heparin (group 4), inogatran (group 5), and ASA (group 6) did not significantly influence time to lysis. All adjunctive compounds did, however, prolong the time to reocclusion, which oc. The described closed-chest pig model was feasible as regards the induction and lysis of a thrombus in the left coronary artery, giving reproducible areas of myocardial ischemia and infarction. This model was useful for the evaluation of pharmacological interventions in the thrombolysis process.

Topics: Animals; Antithrombins; Aspirin; Blood Flow Velocity; Coronary Thrombosis; Glycine; Hemodynamics; Heparin; Myocardial Ischemia; Piperidines; Reperfusion Injury; Swine; Thrombolytic Therapy

Napsagatran, a new synthetic direct thrombin inhibitor, was compared with heparin in a canine model of coronary thrombosis and concomitantly in an ex vivo perfusion chamber model. Occlusive thrombosis of the left circumflex coronary artery was induced by electrical injury. In parallel, arterial subendothelium was exposed to native blood using an annular perfusion chamber for 5, 10 and 20 min at a wall shear rate of 650/s. Dogs received saline, heparin (40 and 70 U/kg/h) or napsagatran (3 and 10 microgram/kg/min). Heparin (40 U/kg/h) and napsagatran (3 microgram/kg/min) delayed or prevented in vivo thrombotic occlusion, but only napsagatran (10 microgram/kg/min) significantly decreased the intracoronary thrombus when compared with saline. High-dose heparin (70 U/kg/h) or napsagatran (10 microgram/kg/min) decreased the platelet-rich thrombus after a 20-min chamber perfusion. Neither heparin nor napsagatran decreased the thrombus volume after a 5-min perfusion. Heparin (70 U/kg/h) and napsagatran (10 microgram/kg/min) prolonged the activated partial thromboplastin time differently (>x6 and x1.4, respectively, P<0.01), whereas the activated clotting time was prolonged equally (x2.5). Thus napsagatran in this model shows arterial antithrombotic effects similar to those of heparin. The chamber experiments suggest that neither compound affects the initiation of platelet thrombus formation. In arterial thrombosis, the activated clotting time has a higher predictive value than the activated partial thromboplastin time when a direct thrombin inhibitor is compared with heparin.

Topics: Animals; Antithrombins; Coronary Thrombosis; Disease Models, Animal; Dogs; Female; Fibrinolytic Agents; Heparin; Male; Naphthalenes; Partial Thromboplastin Time; Perfusion; Piperidines

To characterize the antithrombotic activity 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.. 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.. 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.. 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.

Topics: Animals; Aspirin; Coronary Thrombosis; Disease Models, Animal; Female; Glycine; Heparin; Male; Piperidines; Swine; Thrombin

We wished to characterize MDL 28,133A (1-(4-fluorophenyl)-2-[4-[(4-methanesulfonamidophenyl)carbonyl]-1- piperidinyl-ethanone HCl), a potent 5-HT2 receptor antagonist, on platelet aggregation and platelet thrombosis and determined its effect on thrombolysis with streptokinase (SK) in dogs with coronary thrombosis. MDL 28,133A and ritanserin, 0.3-1 microM, competitively inhibited 5-HT-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro. The pA2 values and slopes were 6.29 +/- 0.09, -0.96 +/- 0.14, and 6.58 +/- 0.09, =1.64 +/- 0.34 for MDL 28,133A and ritanserin, respectively, suggesting that both agents are similar in potency to 5-HT2 receptor antagonists. MDL 28,133A (0.01 mg/kg, p.o.) produced inhibition of arachidonic acid-induced platelet aggregation in whole blood from conscious dogs ex vivo for > or = 2 h, indicating oral bioavailability. The magnitude and duration of the effect of MDL 28,133A on platelet aggregation in whole blood was similar to that of ketanserin (2.5 mg/kg, p.o.). MDL 28,133A (0.001-0.03 mg/kg, i.v.) completely abolished cyclic flow reductions (CFRs) in stenosed and partially deendothelialized left anterior descending coronary arteries of anesthetized dogs for at least 120 min without affecting systemic blood pressure (BP) and heart rate, thus indicating that MDL 28,133A is a potent antithrombotic agent. Ketanserin (0.5 mg/kg, i.v.) also abolished CFRs, but produced a significant decrease in systemic BP as well. MDL 28,133A (0.001 mg/kg, i.v.) shortened time to reperfusion (15 +/- 1 vs. 36 +/- 8 min), prolonged time to reocclusion (112 +/- 6 vs. 85 +/- 6 min), and increased total volume reflow (20 +/- 2 vs. 10 +/- 2%) in dogs with coronary artery thrombosis undergoing thrombolysis with SK (1,000 U/min, i.a.). Reocclusion rate was not affected by MDL 28,133A (4 of 5 vs. 4 of 6). Treatment with heparin (150 U/kg, i.v. every hour for 2 h) alone or in combination with MDL 28,133A did not improve time to reperfusion but enhanced total volume reflow and prevented reocclusion. MDL 28,133A is a potent 5-HT2 receptor antagonist that inhibits platelet thrombosis and facilitates thrombolysis in vivo. The impeding effect of MDL 28,133A in coronary thrombosis and the lack of hemodynamic effects suggests that MDL 28,133A may be of benefit in treatment of hyperthrombotic conditions without having hemodynamic side effects.

Topics: Administration, Oral; Animals; Biological Availability; Blood Platelets; Blood Pressure; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Therapy, Combination; Electric Stimulation; Female; Heart Rate; Heparin; In Vitro Techniques; Male; Piperidines; Platelet Aggregation; Ritanserin; Serotonin; Serotonin Antagonists; Streptokinase

Blockade of platelet 5HT2 receptors prevents coronary artery thrombi. This study explores the dispersal of established thrombus by such 5HT2 antagonism.. Seven open chest anaesthetised beagles were used in a repeated measures study of the action of MDL 11,939 to remove the participation of platelet 5HT2 receptors in the natural history of intracoronary thrombosis with cyclic blood flow reduction. Endothelial damage and critical diameter constrictors were applied to the circumflex coronary artery, and systemic blood pressure and circumflex blood flow were measured continuously.. Cyclic flow reductions, which were established by build up and embolisation of platelet thrombi, were completely abolished by the 5HT2 antagonist MDL 11,939. The dose given in the first two experiments was 0.5 mg.kg-1, reduced to 0.2 mg.kg-1 for the third. Subsequent animals received 0.1 mg.kg-1. Mean blood pressure rose slightly. Adrenaline infusion at 0.4 micrograms.kg-1.min-1 failed to restore cyclic flow reductions in any animal and caused a small flow increase without affecting mean blood pressure. The pattern of blood flow restitution after administration of MDL 11,939 was of great interest. In all the animals flow spontaneously increased in a stepwise fashion (a double step in five dogs). The step up was markedly different from the increase in flow seen during adrenaline infusion.. (1) These results are further evidence of the importance of serotonin as a mediator of platelet thrombus in stenosed coronary arteries. (2) The apparent dissipation of thrombi by MDL 11,939 may be of importance.

Topics: Animals; Blood Platelets; Blood Pressure; Coronary Thrombosis; Dogs; Epinephrine; Female; Male; Piperidines; Receptors, Serotonin; Regional Blood Flow; Serotonin Antagonists

The aim was to determine the role of 5-HT derived from activated platelets in the formation of intracoronary thrombi in dogs.. Canine coronary thrombi were produced by inserting a small catheter filled with collagen powder into the endothelial-injured partially occluded left anterior descending coronary artery. The effects of intravenous DV-7028, a selective 5-HT2 receptor antagonist (bolus of 0.1 mg.kg-1, followed by 0.3 mg.kg-1.h-1 by infusion), and intravenous aspirin (1 mg.kg-1, followed by 3 mg.kg-1.h-1) in this experimental thrombus model were examined.. 43 dogs of either sex were used. In experiment A, DV-7028 (n = 12) or saline (n = 11) was given. In experiment B, aspirin (n = 10) or saline (n = 10) was given.. DV-7028 significantly reduced the formation of coronary thrombi by 51% and attenuated the decrease in coronary blood flow without affecting systemic blood pressure and heart rate. There was a significant relationship between the thrombus weight and the decrease in coronary blood flow (p less than 0.005). Aspirin failed to prevent the formation of coronary thrombi.. The results suggest that 5-HT is involved in the platelet thrombosis and that inhibitory effect of DV-7028, a 5-HT2 receptor antagonist, on coronary thrombus formation was superior to that of aspirin.

Topics: Animals; Aspirin; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Administration Schedule; Piperidines; Serotonin Antagonists; Triazines

The aim of the study was to test the hypothesis that platelet serotonin 5HT2 receptors are important in the genesis of thrombosis in stenosed coronary arteries.. The specific serotonin 5HT2 receptor antagonist, ritanserin was used as a pharmacological tool to examine the effect of removal of the participation of the 5HT2 receptors on thrombus growth, in a paired statistical design.. The study involved 10 open chest anaesthetised dogs, with constrictors of critical diameter applied to the left circumflex coronary artery.. Blood flow was monitored in the left circumflex coronary arteries, distal to the critical stenosis. Flow reductions occurred that have previously been shown to be caused by the accumulation of platelet thrombi. By embolising the thrombi, the process could be monitored cyclically (cyclic flow reductions). The specific serotonin 5HT2 receptor antagonist, ritanserin, abolished cyclic flow reductions at a dose of 0.5 mg.kg-1. There was no effect on blood pressure or heart rate on administration of ritanserin at any dose. The serotonin blockade by ritanserin also prevented the reestablishment of cyclic flow reductions by adrenaline infusion (0.4 micrograms.kg-1.min-1), but required ritanserin doses up to 1.5 mg.kg-1. Ex vivo aggregation of platelets was reduced in blood taken from the dogs after ritanserin administration.. These results constitute further evidence of the possible importance of serotonin as a mediator of platelet thrombosis in stenosed coronary arteries.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Dogs; Dose-Response Relationship, Drug; Epinephrine; Female; Male; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Serotonin; Ritanserin; Serotonin Antagonists