Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 micrograms/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 micrograms/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 micrograms/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 micrograms/kg G4120 or 1 mg/kg Argatroban alone had very little effect (less than 20% inhibition). ID50 was obtained with the combination of 3 micrograms/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 micrograms/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation. The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.
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PMID:Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model. 144 May 1

The antithrombotic properties of bolus i.v. injections of heparin, of recombinant hirudin (r-hirudin) or of the synthetic competitive thrombin inhibitor Argatroban were investigated in a quantitative hamster femoral vein platelet-rich mural thrombosis model. Heparin at a dose of 100 U/kg prolonged the activated partial thromboplastin time from 26 +/- 15 to 177 +/- 45 sec (P = .001), but did not significantly inhibit platelet-rich thrombus formation (7 +/- 44% inhibition, P = NS vs. placebo). However, 400 U/kg of heparin produced total inhibition of thrombus formation (101 +/- 14+, P less than .06 vs. control). R-hirudin and argatroban inhibited thrombus formation in a dose-dependent manner: 50% inhibition was obtained with 1.4 mg/kg for r-hirudin and with 2.0 mg/kg for Argatroban. A linear correlation was observed between the percentage of inhibition of thrombus formation vs. Activated partial thromboplastin time (r = 0.57, P = .003 for r-hirudin and r = 0.66, P = .002 for Argatroban). These results suggest that thrombin plays a pivotal role in platelet-rich mural thrombus formation, that this small animal model may be useful for investigation of the pharmacodynamics of synthetic thrombin inhibitors and that platelet-rich thrombus formation is inhibited effectively by heparin, r-hirudin and Argatroban. However, r-hirudin and Argatroban cause less profound changes in the coagulant function at doses that inhibit platelet-rich thrombus formation than heparin.
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PMID:Comparative antithrombotic effects of heparin, recombinant hirudin and argatroban in a hamster femoral vein platelet-rich mural thrombosis model. 160 94

We here present a Japanese family with type I hereditary heparin cofactor II (HC II) deficiency. The propositus (a 61-year-old man) suffered from angina pectoris and coronary artery disease was confirmed by coronary angiography. He underwent percutaneous transluminal coronary angioplasty (PTCA) four times in one year. Combined use of heparin, aspirin, and nitrates could not prevent the return of his symptoms and restenosis of segment 6 of the left anterior descending artery. His HC II activity and antigen levels were 49% and 50%, respectively, and his daughter also showed similar low levels. Cerebral infarction had occurred in two family members. Argatroban, a selective potent thrombin inhibitor, was administered after the fourth PTCA for the purpose of preventing reocclusion and achieved a successful outcome. A relationship between HC II deficiency and thrombosis has not yet been established. Our case suggests that standard heparin therapy is not effective in preventing restenosis in such individuals, in whom the process is accelerated by thrombin generation at the site where PTCA produces rupture of the atherosclerotic plaque. Argatroban may be more effective under low HC II conditions because of its potent inhibition of thrombin activity at sites of vascular wall damage.
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PMID:Hereditary heparin cofactor II deficiency and coronary artery disease. 161 93

We investigated the effects of the thrombin inhibitor, argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid) on the endothelium-derived relaxing factor-nitric oxide (EDRF-NO)-dependent relaxant, and the endothelial cell-independent constrictor actions of thrombin. Experiments were performed in isolated rings of canine coronary arteries. Argatroban inhibited thrombin-induced relaxation (range of thrombin activity 0.003-0.3 U/ml), with an ED50 of 0.3 microM. The ED50 value was not different from inhibition of thrombin amidolytic cleavage of the chromogenic substrate N-p-tosylgly-pro-arg-p-nitroanilide acetate (TOGSPAN 0.28 microM), but inhibition was highly selective. Argatroban did not block EDRF-NO-dependent relaxations to trypsin (0.003-0.3 U/ml; Emax -88.7 + 2.0% without vs. -88.1 +/- 2.7% with argatroban), acetylcholine (ACh 1 nM to 1 microM; Emax -90.5 +/- 4.7% and -88.6 +/- 3.1%, with and without argatroban, respectively), or the calcium ionophore A23187 (1 nM to 1 microM; Emax -98.5 +/- 1.2 vs. -99.4 +/- 0.6%). The inhibitory effects of argatroban on thrombin-induced constriction were then compared with those of the irreversible thrombin inhibitor D-phenylalanyl-L-prolyl L-arginine chloromethyl ketone (PPACK). The highest concentration of argatroban (10 microM) inhibited the vasoconstrictor effects of thrombin but did not completely block the effects (Emax 21.4 +/- 8.1% of KCl constriction without argatroban and Emax 14.0 +/- 5.2% of KCl-induced constriction with argatroban). In contrast, both a 10- and a 100-fold lower concentration of PPACK (0.1-1 microM) prevented the thrombin-induced increase in tension. Thrombin-induced constriction therefore appeared to disclose mechanistic differences between the two thrombin inhibitors. Thrombin vasomotor actions were inhibited by argatroban, however, and this may contribute significantly to the therapeutic effect of argatroban.
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PMID:Argatroban and inhibition of the vasomotor actions of thrombin. 750 29

The effect of argatroban, an anti-thrombin agent, on a 1.5 x 6.0 cm caudally-based flap raised on the backs of Wistar female rats was studied. Argatroban was administered to one group via an implanted osmotic pump, and nothing was administered to a control group. In experiment 1, the effect was evaluated by survival length (ratio of length to width) and a statistically significant difference (p < 0.01) was found between the argatroban group and the control group. In experiment 2, at 3 spots along the midline (M1, M2, M3) in each group, ISO2 (a parameter of oxygen saturation) and IHb (a parameter of hemogrobin concentration) were measured with a reflectance spectrophotometer, and FLOW (a parameter of blood flow) and MASS (a parameter of blood mass) were measured with a laser Doppler flowmeter. M1 was a distal spot of flap, M2 was a proximal spot on the flap and M3 was a spot beside the flap used as a control. At M1, flaps in both groups became necrotic. At M2, flaps in the argatroban group survived, whereas those in the control group became necrotic, and each parameter indicated improvement in blood circulation only in the argatroban group. Thus, argatroban, which antagonizes thrombin, can improve microvascular circulation in congestive tissue and consequently help the flap survive. Argatroban has advantages over other agents that have been given to increase the length of the surviving experimented flap. In comparison with heparin, the coagulation time is easier to control. Also argatroban does not dilate peripheral vessels, which may be a demerit of alprostadil. Argatroban also promotes the reaction of plasminogen activator. The serum concentration of argatroban in this study was almost equal to that used clinically. Therefore, argatroban may be useful when elevating a flap clinically.
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PMID:[Effect of argatroban on flap survival length]. 755 23

The inhibitory effects of argatroban on clot- or fibrin-bound human thrombin were studied using the thrombin-specific chromogenic substrate S2238 (200 microM). These effects were compared to those of recombinant hirudin (rHV2 Lys 47) and the heparin/antithrombin III complex. Argatroban concentration-dependently inhibited the cleavage of S2238 by a thrombin solution, which had been titrated to give the same change in OD405 nm as fibrin-bound thrombin, with an IC50 of 1.1 microM with 90% inhibition at 8 microM. rHV2 Lys 47 and heparin had IC50 values of 1.2 nM and 0.003 U/ml respectively under these conditions. However, when the compounds were tested against fibrin-bound thrombin, argatroban had an IC50 of 2.8 microM with 65% inhibition at 8 microM, whereas rHV2 Lys 47 had an IC50 of 23 nM (with only 56% inhibition at 200 nM), and heparin had an IC50 of 0.5 +/- 0.38 U/ml (with only 58% inhibition at 5 U/ml); i. e. the two compounds were 19 and 168 times less active against fibrin-bound thrombin than against thrombin in solution. The differences between the inhibitory effects of the compounds against thrombin bound to a plasma clot were even more striking in that the IC50 of argatroban was increased from 1.1 (vs. thrombin in solution) to 2.7 microM, while, although rHV2 Lys 47 and heparin had IC50 values of 2.8 nM and 0.004 U/ml against thrombin in solution, they had little (32% inhibition by 4 microM rHV2 Lys 47) or no effect (even at 5.0 U/ml heparin) against the amidolytic activity of a plasma clot.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. 785 88

1. The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in three models of thrombosis in the rat, and in the tail transection bleeding time test. Heparin was studied as a reference anticoagulant. 2. In the model of venous thrombosis induced by thromboplastin followed by stasis of the abdominal vena cava, argatroban had an ED50 of 125 micrograms kg-1, when administered as an i.v. bolus 5 min prior to the thromboplastin injection: the ED50 of heparin was 42 micrograms kg-1, where ED50 is the dose which reduces the weight of the thrombus by 50% compared with that of the control animals. When the two compounds were administered by continuous i.v. infusion, argatroban (ED50 = 1.5 micrograms kg-1 min-1) had the same potency as heparin (ED50 = 1.2 micrograms kg-1 min-1). 3. Argatroban was active in the arterio-venous shunt model with an ED50 of 0.6 mg kg-1 when the compound was given as a bolus. The ED50 of heparin was 0.04 mg kg-1 under the same conditions. The two compounds had ED50 values of 6 micrograms kg-1 min-1 (argatroban) and 3 micrograms kg-1 min-1 (heparin), when administered by continuous i.v. infusion. 4. When tested against occlusive arterial thrombus formation by electrical stimulation of the left carotid artery, both compounds given as either an i.v. bolus or a continuous infusion led to dose-dependent increases in the duration of post-lesion vessel patency. Heparin bolus was more active than argatroban on a weight basis, in that 2 mg kg-1 gave a similar increase in the time to occlusion as 8 mg kg-1 argatroban. As in the other models, when given as continuous infusions, argatroban (111% increase in time to occlusion at 20 tg kg-1, min-1) had similar activity to that of heparin (180% increase at 25 jg kg-1 min-1) on a weight basis. Hoever, the antithrombotic effects of argatroban were accompanied by only moderate changes in the coagulation parameters (thrombin time and activated partial thromboplastin time, APTT), whereas, even at a subthreshold dose of heparin (12.5 pg kg-1 min-1), both the thrombin time and the APTT were greater than 150 s.5. Infusions of both compounds caused dose-dependent increases in the tail transection bleeding time,with the dose of argatroban that doubles the bleeding time (11 I g kg-1 min-1) being five times greater than that of heparin (EDI, = 2.2 fig kg-1 min-1).6. These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in rat models of venous 'mixed' and arterial thrombosis, this effect can be obtained with a lower degree of systemic anticoagulation than with heparin in the arterial model, and argatroban has a lower haemorrhagic potential than that of heparin.
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PMID:Antithrombotic actions of argatroban in rat models of venous, 'mixed' and arterial thrombosis, and its effects on the tail transection bleeding time. 788 74

Ischemic cerebral infarcts induce hypercoagulation and microthrombosis in the surrounding region, thus leading to vascular occlusion. We determined whether microthrombi contribute to the spreading of ischemic lesions following thrombotic middle cerebral artery (MCA) occlusion and also determined whether argatroban, a selective thrombin inhibitor, reduces the formation of the microthrombi and the area of the ischemic lesions. The rat left MCA was occluded by a platelet-rich thrombus formed following the photochemical reaction between rose bengal and green light. Microthrombi were histologically identified in the left hemisphere. The extent of ischemic lesions and microthrombi containing fibrin increased in a time-dependent manner after MCA occlusion. Argatroban inhibited the formation of microthrombi up to 3 hr after MCA occlusion; beyond 3 hr, it was ineffective. Argatroban also significantly (P < 0.01) reduced the size of ischemic cerebral lesions at 6 hr after MCA occlusion. It is concluded that the formation of microthrombi contributes to the progression of ischemic lesions in the early stage. It is likely that thrombin generated following thrombotic MCA occlusion contributes to the progression of ischemic lesions by promoting the formation of microthrombi. Argatroban can reduce the formation of microthrombi and ischemic lesions in the early stage.
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PMID:Effect of argatroban on microthrombi formation and brain damage in the rat middle cerebral artery thrombosis model. 856 51

Clot-associated thrombin retains amidolytic activity, and is resistant to inhibition by heparin, but not to low molecular weight thrombin inhibitors. We show that clot-associated thrombin induces platelet aggregation, is resistant to heparin:antithrombin III, less so to recombinant hirudin (rHV2Lys47) but not to argatroban, an active-site directed thrombin inhibitor. Fibrin clots prepared with human fibrinogen and thrombin were used to aggregate rabbit washed platelets assessed by single platelet counting, thromboxane B2 (TXB2) immunoassay and scanning electron microscopy. Fibrin clots decreased platelet counts, and released TXB2. Electron microscopy showed platelet aggregates on the clot surface. Argatroban concentration-dependently inhibited such aggregation with IC50s of 21 nM and 13 nM versus aggregation and TXB2 release respectively. The IC50s of Argatroban against fluid-phase thrombin producing similar aggregation were 12 nM (aggregation) and 33 nM (TXB2). rHV2Lys47 was less active against clot-induced aggregation (IC50 = 1.8 nM) than against fluid-phase thrombin (IC50 = 0.06 nM). Heparin had an IC50 of 0.02 mU/ml against aggregation induced by fluid-phase thrombin, but much greater concentrations are required to inhibit clot-induced aggregation (IC50 = 48 mU/ml). These data provide a basis for the superiority of direct-acting thrombin inhibitors over heparin in platelet rich thrombi.
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PMID:Inhibition by Argatroban, a specific thrombin inhibitor, of platelet activation by fibrin clot-associated thrombin. 871 95

1. The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in a canine model of coronary cyclic flow having some of the characteristics of acute unstable angina. Heparin was studied as a reference anticoagulant. 2. Localized endothelial damage was induced in the circumflex coronary artery of anaesthetized open-chest foxhounds and a critical stenosis was applied by use of a Lexan constrictor placed around the artery at the site of endothelial damage. An electro-magnetic flow probe was placed distal to the lesion, and cyclic flow variations (CFVs) were observed, as thrombi formed at the site of the arterial lesion and were dislodged. Test compounds were administered by i.v. infusion commencing 1 h after the appearance of CFVs, and maintained for 1 h. On termination of the treatments, coronary flow was observed for a further 60 min. A series of blood samples were taken at predetermined times throughout each experiment in order to determine the coagulation parameters, thrombin time (TT) activated partial thromboplastin time (aPTT) and for the determination of fibrinopeptide A (FpA) levels before, during and post-treatment. 3. Argatroban and heparin showed antithrombotic effects in this model. Argatroban dose-dependently increased the minimum coronary flow at the nadir of the CFVs from 5.4 +/- 1.7 to 9.1 +/- 2.1 ml min-1 (30 micrograms kg-1 min-1, P = 0.041) and from 2.9 +/- 0.9 to 16.3 +/- 4.5 ml min-1 (100 micrograms kg-1 min-1, P = 0.023, n = 8 dogs at each dose level). Heparin (5 and 15 iu kg-1 min-1) also increased minimum flow, but the increase was not statistically significant at the 5% level, although the P value in animals treated with 15 iu kg-1 min-1 (P = 0.0521, n = 6 dogs) fell just outside this limit. Although neither compound significantly decreased the overall CFV frequency, argatroban (100 micrograms kg-1 min-1) significantly (P < 0.01) decreased the number of large amplitude CFVs (minimum coronary flow < 10 ml min-1) by 63%, and heparin (15 iu kg-1 min-1) caused a 50% decrease in this parameter (P < 0.05). 4. The thrombin times were increased by a factor greater than 10 during antithrombotic treatment, irrespective of the compound or doses used. Heparin treatment induced 17 and > 30 fold increases in aPTT at 5 and 15 iu kg-1 min-1 respectively. However, argatroban produced only 2 and 3 fold increases in aPTT at 30 and 100 micrograms kg-1 min-1, despite significant antithrombotic effects. FpA levels were reduced in the presence of both argatroban and heparin. 5. These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in a canine model of coronary cyclic flow.
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PMID:Antithrombotic actions of the thrombin inhibitor, argatroban, in a canine model of coronary cyclic flow: comparison with heparin. 876


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