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At least 991 records · Page 55Linked to original sources
PubMed2000

Argatroban, a thrombin inhibitor, decreased mortality after 10 min of forebrain ischemia in the gerbil.

We investigated whether anticoagulant therapy with heparin or a selective thrombin inhibitor, argatroban, may ameliorate the postischemic cerebral circulation and attenuate mortality after 10 min of forebrain ischemia. Postischemic subcutaneous injection of argatroban (5 mg/kg) significantly attenuated mortality (9.1%) compared with non-treatment (45.5%) during 14 days' observation period. This effect coincided with: (1) increased cortical CBF after reperfusion; (2) attenuation of brain edema; and (3) less severe cell damages in the cerebral cortex. In contrast, nine of the 22 gerbils treated with heparin (830 IU/kg) were found dead on the next day due to massive bleeding in the surgical wound and 13 bleeding-avoided gerbils did not show significant amelioration in mortality (30.8%). These findings suggest that argatroban is an effective anticoagulant for prevention of cell damage after a relatively long forebrain ischemia.

Animals↗
PubMed2000

Spatiotemporal dynamics of fibrin formation and spreading of active thrombin entering non-recalcified plasma by diffusion.

The spatiotemporal dynamics of clot growth was studied in non-stirred non-recalcified plasma where thrombin entered by diffusion. Under these conditions, the clot rapidly grew for 30-45 min and then stopped growing on reaching 0.4-0.5 mm in size. The dynamics of clot growth and its size almost did not depend on the thrombin concentration in the range from 50 to 400 nM. FITC-thrombin was shown to permeate the growing clot. The clot size in antithrombin-deficient plasma increases with decreasing antithrombin concentration, being 1.5 mm in the plasma depleted of antithrombin to 5% of its initial level. The data on the spatial distribution of amidolytic activity in the growth zone of the clot suggested that thrombin was not the sole source of this activity. Analysis showed that this additional activity arising during thrombin diffusion into plasma was largely accounted for by thrombin-alpha(2)-macroglobulin complex.

Antithrombins↗
PubMed1999

Anticoagulant therapy in unstable angina.

The goal of anticoagulant therapy in unstable angina is to prevent progression of a subocclusive coronary thrombus to complete occlusion of the coronary artery, thereby preventing myocardial infarction and death. Although these have been many advances in therapy with anticoagulants, considerable morbidity and mortality remains. Also, although combination therapy with potent novel anticoagulants and antiplatelet agents may be an alternative strategy, this needs to be balanced against the risks of hemorrhagic complications. More precise and biologically relevant methods of monitoring anticoagulant effect, along with appropriately modified doses given in combination offers promise.

Angina, Unstable↗
PubMed1999

A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study.

OBJECTIVES: This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI). BACKGROUND: Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA. METHODS: One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min. RESULTS: TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23). CONCLUSIONS: Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.

Adult↗
PubMed2000

Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation.

The authors attempted experimental and clinical use of argatroban as an alternative anticoagulant in left heart bypass with the centrifugal pump, percutaneous cardiopulmonary support (PCPS), and extracorporeal membrane oxygenation (ECMO) to determine if it has complementary effects in preventing thrombus formation without aggravating bleeding tendency. Its reversible binding to thrombin and its short half-life contributed to reduce the risk of excessive blood loss without clot formation within the extracorporeal circulation circuit during thoracic aortic surgery using left heart bypass. PCPS and ECMO were safely performed at doses ranging from 0.5 to 10 micrograms/kg/min to maintain activated clotting time at approximately 200 seconds. Although experimental studies showed argatroban to be advantageous in preserving platelet and fibrinogen, further clinical investigations are necessary.

Animals↗
PubMed1999

Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model.

Argatroban is a selective thrombin inhibitor synthesized in Japan. Argatroban, which has a high affinity for thrombin, and markedly inhibits thrombin-induced reactions, has been used in patients with artherosclerosis obliterans. The efficiency of argatroban, instead of heparin, as an anticoagulant in dog models of cardiopulmonary bypass was explored. In the first study, argatroban was administered as a bolus plus infusion for 1 h during cardiopulmonary bypass at doses of 1.0 mg + 10 microg/kg per min, 2.0 mg + 10 microg/kg per min and 3.0 mg + 10 microg/kg per min (n = 2 per group). Activated clotting time and arterial gas analyses were performed beforehand and 10 min thereafter. In the second study, there were four groups. In the first group (n = 5), no coated extracorporeal circuit was used and heparin (2 mg/kg) was used as an anticoagulant. In the second group (n = 5), a coated extracorporeal circuit was used and heparin was used (2 mg/kg) as an anticoagulant. In the third group (n = 3), no coated extracorporeal circuit was used and argatroban (2.0 mg + 10 microg/kg per min) was used as an anticoagulant. In the fourth group (n = 5), a coated extracorporeal circuit was used and argatroban was used (2.0 mg + 10 microg/kg per min) as an anticoagulant. All animals were perfused for 120 min at 40 ml/kg per minute. Platelet count, activated clotting time, thrombin-antithrombin III complex, antithrombin III, fibrinogen, fibrinogen degradation products and C3a were measured to evaluate platelet, coagulofibrinolytic and the complement system. Activated clotting time values and the effect of argatroban during cardiopulmonary bypass indicated a dose-dependent response. The next highest dosing group (2.0 mg + 10 microg/kg per minute) had activated clotting time values of 250-300 seconds during cardiopulmonary bypass, and fell after reaching near-normal levels within 60 minutes. No clots were noted in the extracorporeal circuit. The argatroban group showed lower levels in their coagulofibrinolytic system compared with the heparin group. The platelet count remained at a high level in the argatroban group. It is concluded that the combination of heparinized cardiopulmonary bypass circuits, and the use of argatroban as an anticoagulant, is safe and reduces the activation of coagulation and fibrinolytic systems and preserves platelet count.

Animals↗
PubMedDate not supplied

Use of a direct thrombin inhibitor (argatroban) during pulse-spray thrombolysis in experimental thrombosis.

PURPOSE: To evaluate the effectiveness of intravenous and intrathrombic injection of the thrombin inhibitor argatroban during pulse-spray pharmacomechanical thrombolysis (PSPMT) in experimental venous thrombosis. MATERIALS AND METHODS: Clots were produced in the inferior vena cava in 52 rabbits by placement of steel coils and balloon injury to the vessel wall. Two days later, clots were treated with PSPMT. Several treatment methods were used: intrathrombic saline, intrathrombic tissue plasminogen activator (t-PA), intrathrombic t-PA with intrathrombic and intravenous heparin, intrathrombic t-PA with intravenous argatroban, and intrathrombic t-PA with intrathrombic and intravenous argatroban at two different doses. After treatment, the rabbits were killed and residual clot was weighed. Pretreatment clot weight was estimated and clot lysis was assessed. RESULTS: PSPMT with t-PA and adjunctive intrathrombic heparin resulted in greater lysis than PSPMT with only t-PA (percentage of residual clot, 59% +/- 14 vs 81% +/- 28; P = .02). Addition of intravenous argatroban did not increase lysis, but adjunctive intrathrombic argatroban significantly increased lysis at low doses (37% +/- 16; P = .02) and high doses (34% +/- 6; P = .006) compared with t-PA and intrathrombic heparin. CONCLUSION: In a rabbit model of venous thrombosis, the use of intrathrombic argatroban during PSPMT with t-PA significantly improved clot lysis.

Animals↗
PubMed2006

On-chip titration of an anticoagulant argatroban and determination of the clotting time within whole blood or plasma using a plug-based microfluidic system.

This paper describes extending plug-based microfluidics to handling complex biological fluids such as blood, solving the problem of injecting additional reagents into plugs, and applying this system to measuring of clotting time in small volumes of whole blood and plasma. Plugs are droplets transported through microchannels by fluorocarbon fluids. A plug-based microfluidic system was developed to titrate an anticoagulant (argatroban) into blood samples and to measure the clotting time using the activated partial thromboplastin time (APTT) test. To carry out these experiments, the following techniques were developed for a plug-based system: (i) using Teflon AF coating on the microchannel wall to enable formation of plugs containing blood and transport of the solid fibrin clots within plugs, (ii) using a hydrophilic glass capillary to enable reliable merging of a reagent from an aqueous stream into plugs, (iii) using bright-field microscopy to detect the formation of a fibrin clot within plugs and using fluorescent microscopy to detect the production of thrombin using a fluorogenic substrate, and (iv) titration of argatroban (0-1.5 microg/mL) into plugs and measurement of the resulting APTTs at room temperature (23 degrees C) and physiological temperature (37 degrees C). APTT measurements were conducted with normal pooled plasma (platelet-poor plasma) and with donor's blood samples (both whole blood and platelet-rich plasma). APTT values and APTT ratios measured by the plug-based microfluidic device were compared to the results from a clinical laboratory at 37 degrees C. APTT obtained from the on-chip assay were about double those from the clinical laboratory but the APTT ratios from these two methods agreed well with each other.

Anticoagulants↗
PubMed2002

Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands.

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Binding affinities for sulfonamide inhibitors with human thrombin using Monte Carlo simulations with a linear response method.

The binding of sulfonamide inhibitors to human thrombin is examined to evaluate the viability of calculating free energies of binding, deltaGb, utilizing Monte Carlo (MC) statistical mechanics with a linear response approach. Coulombic and van der Waals energy components determined from MC simulations of the bound and unbound inhibitors solvated in water plus a solvent-accessible surface area term, as an index for cavity formation, were correlated with the free energies of binding for the inhibitor MD-805 and six derivatives. The best correlations yield an average error of 0.8 kcal/mol for the seven binding affinities, which cover an observed range of 6.0 kcal/mol. The MC simulations also provided insights into the interactions occurring in the active site and the origins of variations in deltaGb. Equatorial placement of the carboxylate group at C2 in the piperidine ring of the inhibitors causes electrostatic destabilization with the side chain of Glu-H192, while axial disposition of the C4-methyl group reduces favorable hydrophobic interactions in the P-pocket of the enzyme.

Antithrombins↗
PubMed1999

Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced stereogenicity and improved potency.

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

Animals↗