Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anistreplase is a thrombolytic agent comprising a complex of streptokinase, lys-plasminogen, and a p-anisoyl group, which temporarily protects the catalytic center of the enzyme complex. Streptokinase was previously shown to reduce infarct size (IS) in dogs with a fibrin-rich clot in the left anterior descending coronary artery (LAD) without necessarily producing reperfusion. Therefore, we hypothesized that IS in this model would be reduced by anistreplase. In addition, we studied the effect of tissue-type plasminogen activator (t-PA) on IS, testing our hypothesis in anesthetized dogs in which thrombin (100 U) and calcium (50 microliters, 0.05 M) were sequentially injected into the LAD to form a thrombus, anistreplase [0.01, 0.05, or 0.10 U/kg intravenous (i.v.) bolus], t-PA (0.1, 0.5, 2, or 8 micrograms/kg/min infusion for 60 min) or vehicle (VEH) was administered 55 min later. Anistreplase (0.05 or 0.10 U/kg) significantly (p < 0.05) reduced clot weight (VEH 22 +/- 3 mg; anistreplase 0.05 U/kg, 13 +/- 4 mg; anistreplase 0.10 U/kg, 0.7 +/- 0.6 mg), increased incidence of reperfusion (VEH 0%; anistreplase 0.05 U/kg, 42%; anistreplase 0.10 U/kg, 100%) and reduced IS (VEH 23 +/- 3%; anistreplase, 0.05 U/kg, 14 +/- 2%; anistreplase 0.10 U/kg, 15 +/- 2%). t-PA reduced thrombin weight (VEH 26 +/- 3 mg; 2 micrograms/kg/min t-PA 12 +/- 4; 8 micrograms/kg/min t-PA 2 +/- 2 mg) and increased incidence of reperfusion (VEH 0%; 2 micrograms/kg/min 75%; 8 micrograms/kg/min 100%), but IS was not altered (VEH 19 +/- 3%; 0.1 microgram/kg/min 18 +/- 3%; 0.5 microgram/kg/min 23 +/- 2%; 2 micrograms/kg/min 16 +/- 5%; 8 micrograms/kg/min: 19 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1995 Apr
PMID:Cardioprotection and thrombolysis by anistreplase in anesthetized dogs. 759 32

The antiproliferative properties of carvedilol, a newly developed multiple-action antihypertensive agent, were evaluated in early passage cultured rat aortic vascular smooth muscle cells. Carvedilol (10(-7)-10(-5) M) produced concentration-dependent decreases in basal and endothelin-1-stimulated mitogenesis of rat aortic vascular smooth muscle cells. The IC50 for inhibition of [3H]thymidine incorporation by carvedilol in both basal and endothelin-1-stimulated rat aortic vascular smooth muscle cells was approximately 1 microM. Carvedilol (10 microM) inhibited basal mitogenesis by approximately 65%, and endothelin-1-stimulated mitogenesis by approximately 95%. Carvedilol (1-10 microM) also produced significant concentration-dependent inhibition of the mitogenic response mediated by thrombin (0.5 U/ml), epidermal growth factor (1 nM), platelet-derived growth factor (1 nM), and angiotensin II (5 nM). Endothelin-1- or PDGF A/B-induced increases in cell number were also significantly inhibited by carvedilol (10 microM). The antimitogenic effect of carvedilol on cell growth was reversible. The inhibitory effect of carvedilol was not shared by other beta-adrenoceptor antagonists such as labetalol (10 microM), celiprolol (10 microM), or sotalol (10 microM), which did not significantly affect [3H]thymidine incorporation in rat vascular smooth muscle cells. Propranolol (10 microM) was the only beta-adrenoceptor antagonist tested that inhibited [3H]thymidine incorporation, with effects of approximately 50 and 75% on basal and endothelin-1-mediated stimulation, respectively. In contrast, celiprolol (10 microM) produced significant stimulation of DNA synthesis (125% over basal). The calcium channel antagonist nifedipine (10 microM) inhibited basal and endothelin-1-mediated mitogenesis by 58 and 72%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1993 Feb
PMID:Carvedilol inhibits vascular smooth muscle cell proliferation. 767 55

We briefly review and compare the current knowledge of growth mechanisms for the mitogenic response of endothelial cells and smooth-muscle cells to injury. For the endothelium, this focuses on the evidence that growth control involves two components: an endogenous inhibition mechanism, which can be overcome either by fibroblast growth factor (FGF) or by other agents that disrupt cell-cell junctions, and a separate mechanism, which requires FGF to allow cells to respond to a mitogenic effect. The smooth-muscle cell story is more complex; however, there is evidence here as well of an endogenous inhibitory mechanism, which may be overcome by a wide variety of agents. Platelet-derived growth factor, long seen as a major mitogen, does not itself now appear to be a major mitogen in vivo. In contrast, FGF also seems to play a major role in initiating smooth-muscle replication. Other molecules, including angiotensin II, bradykinin, thrombin, and catecholamines, are beginning to appear to play major roles in control of smooth-muscle replication in vivo as well.
J Cardiovasc Pharmacol 1993
PMID:Growth control and morphogenesis in the development and pathology of arteries. 768 Nov 30

Direct inhibition of thrombin with agents such as hirudin and argatroban reduces reocclusion rates during experimental coronary thrombolysis. We compared the adjunctive potential of the tripeptide thrombin inhibitor D-methyl-phenylalanyl-prolyl-arginal (LY294468) during thrombolysis with tissue-type plasminogen activator (t-PA) with the less specific tripeptide thrombin inhibitor Boc-D-phenylalanyl-prolyl-arginal (LY178207) and the standard anticoagulant heparin. The left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and coronary blood flow (CBF) was measured in 26 anesthetized dogs. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the artery, producing an occlusive thrombus. Thrombolytic/adjunctive therapy was started 1 h later in the following groups: (a) t-PA alone (0.9 mg/kg, 1-h infusion), (b) t-PA + LY294468 (0.5 or 1 mg/kg/h, 2-h infusion), (c) t-PA + LY178207 (0.5 or 1 mg/kg/h, 2-h infusion), and (d) t-PA + heparin (80 U/kg bolus + 30 U/kg/h, 2-h infusion). LY294468 provided antireocclusive efficacy (time to reocclusion = > 200 min as compared with 65 min for t-PA alone; six of nine patent vessels vs. zero of six, respectively, at the end of the experiment), with no bleeding liability during t-PA-induced thrombolysis. Heparin and LY178207 were ineffective adjunctive agents. Heparin, however, significantly increased template bleeding times. LY294468 was effective as an adjunctive agent during thrombolysis and may represent a safer (less bleeding) and more effective adjunctive agent than heparin.
J Cardiovasc Pharmacol 1993 Apr
PMID:Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis: a comparison with heparin in a canine model of coronary artery thrombosis. 768 4

The effect of high-dose aprotinin treatment on hemostatic activation during cardiopulmonary bypass in pediatric patients having cardiac operations was investigated. Sixty patients weighing less than 10 kg undergoing cardiac operations for different types of congenital heart diseases were studied: 20 patients were treated with aprotinin 2 x 15,000 KIU/kg, 20 patients with 2 x 30,000 KIU/kg, and 20 patients without aprotinin treatment served as the control group. Different split products of fibrinogen and/or fibrin and the fibrinolytic activity on fibrin plates were measured to assess fibrinolytic activation. F1/F2 prothrombin fragments, thrombin-antithrombin III-complex, and fibrin monomers were measured to estimate thrombin activation. There was a significant dose-dependent reduction in fibrin-fibrinogen split product formation during cardiopulmonary bypass: In the high-dose aprotinin group the concentration of the split products at the end of bypass was 1.5 +/- 0.6 micrograms/ml, compared with 3.4 +/- 3.0 micrograms/ml in the low-dose aprotinin group and 6.7 +/- 3.5 micrograms/ml in the control group (p < 00.5). Fibrinolytic activation on fibrin plates was also significantly reduced by aprotinin. Fibrin monomer formation was significantly diminished at the end of cardiopulmonary bypass in the high-dose group: 9.2 +/- 5.2 micrograms/ml compared with 21.6 +/- 14 micrograms/ml in the control group (p < 00.5). Elastase in complex with alpha 1-protease inhibitor at the end of bypass was increased to the same amount in the three groups: 784 +/- 278 ng/mL (control group), 693 +/- 189 ng/ml (low-dose aprotinin), and 719 +/- 270 ng/mL (high dose aprotinin) (no significant difference). Blood loss 6 hours postoperatively was significantly (p < 00.5) less in the high-dose group (99 +/- 32 ml/m2) than in the control group (164 +/- 87 ml/m2; low-dose group: 160 +/- 106 ml/m2). These observations suggest an attenuation of hemostatic activation during cardiopulmonary bypass with less plasmin formation and, because of inhibition of contact activation, less thrombin generation with aprotinin treatment. Thus the thrombotic-thrombolytic equilibrium is kept more balanced after cardiopulmonary bypass. High-dose aprotinin treatment is recommended for pediatric patients undergoing cardiac operations.
J Thorac Cardiovasc Surg 1993 Apr
PMID:Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. 768 69

Cardiopulmonary bypass for heart operations is associated with a whole body inflammatory reaction. The main factors involved in this reaction are the contact system and the complement system. The activation of the contact system is considered mainly responsible for impaired hemostasis because it affects platelet function. The activation of the complement system is considered the main cause for organ dysfunction, particularly of the lung, due to activation of leukocytes. This study in 10 neonates was undertaken to evaluate if there are effects of activation of the contact and the complement systems in neonatal extracorporeal life support comparable to those during cardiopulmonary bypass for cardiac operations. Two periods of blood activation during extracorporeal life support could be distinguished. The initial blood-material interaction at the onset of extracorporeal life support resulted in activation of both the contact and the complement systems. The contact activation was apparent by elevated factor XIIa-C1 esterase inhibitor complexes, decreased kallikrein inhibitory capacity, thrombin-antithrombin III formation, and moderate generation of fibrin(ogen) degradation products. The complement activation was characterized by elevated C3a, decreased leukocyte count, elastase release, and tumor necrosis factor-alpha production. This initial activation pattern subsided by 24 hours. A second activation period was observed 72 hours after the onset of extracorporeal life support, which was characterized only by increased clotting and fibrinolytic activity while no activation of the complement system was observed. We conclude that the initial activation pattern in extracorporeal life support is similar to that observed during cardiopulmonary bypass for cardiac operations. The contact activation that affects platelets might explain the continuous platelet consumption observed during extracorporeal life support. In this period, as in cardiopulmonary bypass, aprotinin given in the pump prime might be effective to prevent platelet consumption and impairment of hemostasis also in extracorporeal life support. The complement activation and leukocyte inflammatory reaction during the initial period are able to cause a capillary leak syndrome and might therefore explain the frequently observed temporary compromised lung function in extracorporeal life support. This reaction, as in cardiopulmonary bypass, might be reduced by the use of specific drugs or heparin coating also in extracorporeal life support. The cause of the second period of activation during extracorporeal life support requires further studies before adequate measures can be recommended.
J Thorac Cardiovasc Surg 1993 May
PMID:Blood activation during neonatal extracorporeal life support. 768 35

In a prospective randomized double-blind study, the activated clotting time (ACT), heparin use, parameters of anticoagulation, and thrombin activation during extracorporeal circulation were studied in 20 patients who underwent aortocoronary bypass operations. The patients were divided into two groups: Group A was given a placebo, while Group B was given aprotinin according to the high-dosage Trasylol scheme. During ACT-controlled heparinization (ACT > 460 s) there was a significant heparin reduction in Group B (22,100 USP-E) in comparison to Group A (35,200 USP-E). Despite this lower quantity of total heparin, the ACT in Group B was significantly extended (Group B = 837 s, Group A = 492 s). The ACT did not correlate thereby with the heparin concentration or the total quantity of heparin in either group. In contrast to the control group, there was no increased thrombin generation in the aprotinin group. The thrombin-antithrombin III complexes (Group A = 143 micrograms/L, Group B = 102 micrograms/L) as well as the specific dimers (Group A = 2755 ng/ml, Group B = 448 ng/ml) were significantly lower under the use of aprotinin. The connection between the ACT, the heparin concentration, and the aprotinin concentration was further investigated in an ex-vivo model. The ACT samples were diluted with the aim of eliminating the influence of aprotinin. Under these conditions it was shown that for heparin concentrations between 2-4 U/ml there was a parallel shift of the ACT/heparinconcentration curve with the addition of aprotinin in a defined concentration range of 200-300 KIU.(ABSTRACT TRUNCATED AT 250 WORDS)
Thorac Cardiovasc Surg 1993 Feb
PMID:Activated clotting time, anticoagulation, use of heparin, and thrombin activation during extracorporeal circulation: changes under aprotinin therapy. 769 Jan 65

The ability of recombinant platelet factor 4 and protamine to neutralize heparin after cardiopulmonary bypass was compared in anesthestized baboons. Clotting titration curves of heparinized baboon blood demonstrate an anticoagulant effect of protamine that is not seen with recombinant platelet factor 4. Neither drug caused meaningful changes in central pressures or cardiac output within 30 minutes after injection. After 30 minutes of cardiopulmonary bypass, recombinant platelet factor 4 normalized thrombin times and activated partial thromboplastin times within minutes of injection, but protamine did not. Neither drug altered bleeding times. Recombinant platelet factor 4 caused a species-specific leukopenia in baboons and significantly increased activated complement protein 3 (C3a) more than protamine. However, the increase in plasma C3a was small and neither drug caused a significant increase in plasma neutrophil elastase-alpha 1 proteinase inhibitor complex. We conclude that recombinant platelet factor 4 is effective and safe in baboons, does not have an anticoagulant effect with excess concentration, and reverses in vivo heparin more rapidly than protamine. The data support progression to a clinical trial.
J Thorac Cardiovasc Surg 1995 Apr
PMID:Reversal of heparin anticoagulation by recombinant platelet factor 4 and protamine sulfate in baboons during cardiopulmonary bypass. 771 25

A discrete fall in the ACT (activated coagulation time) has been observed in patients with known activation of the coagulation cascade. Injury to the coronary artery resulting in thrombin activation, whether spontaneous as in the case of acute myocardial infarction or planned as with percutaneous transluminal coronary angioplasty (PTCA), may therefore be reflected in a change in ACT values. We reviewed the records of patients undergoing PTCA at St. Luke's Episcopal Hospital/Texas Heart Institute from January 1990 through December 1992 for information regarding ACT values and clinical events. A total of 469 patients, whose record contained adequate information for study inclusion, were divided into four separate groups: acute myocardial infarction (group I, n = 62), unstable angina with heparin therapy that was withdrawn at least 4 hr prior to PTCA (group II, n = 102), unstable angina with heparin therapy continued until the time of PTCA (group III, n = 154), and stable angina undergoing elective PTCA (group IV, n = 151). Heparin was discontinued 12-15 hr after the procedure in all but group I where anticoagulation was often maintained up to 72 hr. ACT values were measured prior to the PTCA procedure (baseline), after the initial heparin bolus of 10,000 U (postheparin) and approximately 12-18 hr after the procedure (heparin withdrawal).(ABSTRACT TRUNCATED AT 250 WORDS)
Cathet Cardiovasc Diagn 1995 Jan
PMID:Activated clotting times in acute coronary syndromes and percutaneous transluminal coronary angioplasty. 772 56

Z-stents partially covered with an expandable Dacron mesh into which epinephrine and thrombin were infiltrated, were used to reopen both mainstem bronchi, stenosed by bronchogenic carcinoma and to deliver hemostatic agents to the lesion. On follow-up 4 and 6 weeks later, airway patency was retained, the tumor surface was compressed, and the glossy surface of the stent suggested that it was covered with mucosa. For treatment of airway stenosis due to cancer invasion, a stent covered with a Dacron mesh sheet is thought to be effective in compressing the tumor and preventing tumor ingrowth into the stent.
Cardiovasc Intervent Radiol
PMID:Treatment of malignant tracheobronchial stenosis by Dacron mesh-covered Z-stents. 818 30


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