Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P35237 (thrombin inhibitor)
 2,012 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin has been implicated as a contributing factor to restenosis after vessel reopening procedures. We compared the ability of the direct thrombin inhibitor recombinant (r-) hirudin to reduce neointimal growth in different animal models of arterial injury. Carotid arteries of rats, rabbits, and hypercholesterolemic minipigs were injured by withdrawal of an inflated balloon catheter. In addition, we used a double-lesion model in rabbits, which involved balloon angioplasty of a preexisting lesion induced by carotid denudation 4 weeks earlier. r-Hirudin was given in all four animal models as a short-term application (bolus of 1 mg/kg i.v. immediately before injury, followed by infusion of 1 mg.kg-1.h-1 for 2 hours, and an injection of 6 mg/kg SC). Additionally, we investigated the effects of prolonged treatment (intravenous infusion for 3 and 14 days) in rats. Inhibition of thrombin was monitored by determination of activated partial thromboplastin time, and histomorphometric analysis of the arteries was performed after 2 (rats) or 4 (rabbits and minipigs) weeks. In rabbits, short-term r-hirudin treatment reduced neointimal area by 59% (single-injury model, P = .05) and 44% (double-injury model, P = .02). In rats and minipigs no inhibition of neointimal growth was observed after short-term r-hirudin application. A 3- or 14-day infusion of r-hirudin in rats, however, resulted in 25% (P = .007) and 27% (P = .003) reductions in neointimal area, respectively. In conclusion, there is considerable interspecies variation in the time frame of susceptibility for reduction of neointimal growth by inhibition of thrombin after arterial injury. These results demonstrate the importance of testing potential antirestenotic treatments in an array of different animal models.
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PMID:Comparison of the effects of the thrombin inhibitor r-hirudin in four animal models of neointima formation after arterial injury. 885 29

The aim of the present work was to study how human umbilical vein smooth muscle cells (HUVSMC) can initiate the coagulation process and to investigate the responses of these cells to thrombin. Exposure of HUVSMC to recalcified human plasma led to a time-dependent production of thrombin, measured both as amidolytic activity and as release of fibrinopeptide A. Thrombin activity was dose-dependently reduced by an anti-human tissue factor antibody (76 +/- 3% at 10 micrograms/ml) and by inhibitors like heparin, rec-hirudin, hirulog 1, Napap and hirunorm, a novel hirudin-like thrombin inhibitor (IC50 = 2 +/- 0.4, 8 +/- 1, 130 +/- 22, 199 +/- 29 and 68 +/- 8 nM, respectively). The release of fibrinopeptide A was similarly prevented (IC50 = 14 +/- 1, 132 +/- 25 and 50 +/- 8 nM for rec-hirudin, Napap and hirunorm, respectively). Exogenously added thrombin increased thymidine incorporation into HUVSMC to 240 +/- 30% of basal (EC50 = 0.49 +/- 0.09 nM) and thrombin inhibitors blocked this effect (IC50 = 10 +/- 3, 37 +/- 17, 343 +/- 165 and 1402 +/- 758 nM for rec-hirudin, hirunorm, Napap and hirulog-1, respectively). Also recalcified human plasma was mitogenic for HUVSMC and its effect was mainly due to endogenously generated thrombin, as shown by the use of thrombin inhibitors. In conclusion, HUVSMC are capable of initiating the extrinsic coagulation cascade, leading to the formation of thrombin which promotes clotting and stimulates DNA synthesis. Thrombin inhibitors prevent both coagulative and cellular effects of thrombin.
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PMID:Human umbilical vein smooth muscle cells as a model to study thrombin generation and function: effect of thrombin inhibitors. 890 3

Thrombin is a multifunctional serine protease with central functions in hemostasis, but demonstration of its role in the initiation and maintenance of cell proliferation which occurs following vascular injury is still lacking. To determine the role played by thrombin and its receptor in neointimal accumulation of smooth muscle cells in a rabbit carotid artery model, we have used an 18 mer antisense phosphorothioate oligonucleotide (ODN) directed against the translation initiation region of the human thrombin receptor gene. The antisense ODN inhibited in a dose-dependent manner thrombin- or thrombin receptor activating peptide-induced human aortic smooth muscle cell proliferation. The growth-inhibitory effect of thrombin receptor antisense ODN was preventable by an excess of sense oligomer and specific for thrombin. The suppression of growth was accompanied by a marked decrease of the level of thrombin receptor expression as evidenced by [125I]-thrombin binding to smooth muscle cells. Under the same experimental conditions, the corresponding sense ODN was inactive. The effect of the antisense ODN on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to endothelial injury was then investigated. The topical application of the antisense (500 microg/artery) but not the sense ODN dissolved in F127 pluronic gel around the injured artery resulted, 2 weeks after the application, in a dramatic reduction of the expression of the thrombin receptor mRNA and protein levels as determined by in situ hybridization and immunohistochemistry. However, intimal smooth muscle cell accumulation as estimated by an intimal to medial cross-sectional area ratio was reduced only by 2.7% (vs. 10.3% for the sense ODN), whereas r-hirudin (200 microg/kg/day, s.c.), a potent direct thrombin inhibitor significantly reduced the formation of neointima in denuded carotid arteries (35.4% inhibition, P = 0.03).
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PMID:Intimal hyperplasia following vascular injury is not inhibited by an antisense thrombin receptor oligodeoxynucleotide. 900 39

Thrombotic complications are frequent with indwelling central venous catheters and result in catheter dysfunction, vascular obstruction and may also contribute to catheter-associated infections. The pathogenesis of catheter thrombosis is not well characterized but may involve vessel damage, local stasis and catheter-associated thrombin formation. We have, therefore, measured the thrombin activity associated with central venous catheters removed from patients and have also determined the ability of hirudin to inactivate catheter-associated thrombin. We obtained 48 catheters from 46 patients and removed 1 cm portions for study. These were taken from the distal end, 5 cm proximal, and 15 cm proximal from the end. Following washing, thrombin activity was measured with a chromogenic assay. Thrombin was associated with 40 of 48 catheters and with 100 of 144 segments with a mean activity of 132 +/- 27 microU/cm with a range of 0 to 2,160 microU/cm. Incubation in hirudin reduced the activity from a mean of 122 +/- 33 microU/cm to 18 +/- 6 microU/cm (p < .001). Scanning electron microscopy of selected catheters showed that some had areas of fibrin deposition which was not apparent visually. The findings indicate that indwelling central venous catheters frequently have associated thrombin activity which can be inhibited by a direct-acting thrombin inhibitor such as birudin.
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PMID:Thrombin activity associated with indwelling central venous catheters. 903 48

Exposure of rat aortic vascular smooth muscle cells to alpha-thrombin resulted in the appearance of sis-inducing factor-A (SIF-A)-like DNA binding activity. This response to alpha-thrombin was delayed (detectable at 1 hour) compared with the rapid activation (15 to 30 minutes) by platelet-derived growth factor and the cytokine interleukin-6. alpha-Thrombin-induced SIF-A was sensitive to treatment with the tyrosine kinase inhibitor genistein. The thrombin inhibitor hirudin prevented the alpha-thrombin-mediated SIF-A induction. Cycloheximide had no effect on the ability of alpha-thrombin to induce SIF-A, suggesting that induction does not require new protein synthesis. alpha-Thrombin-induced SIF-A could be resolved into two additional subcomplexes termed SIF-A, and SIF-As. Antibodies against Stat3 reacted with alpha-thrombin-induced SIF-Af, suggesting that Stat3 or a related protein is present in this subcomplex. Induction of SIF-A DNA binding activity may contribute to alpha-thrombin-mediated cellular responses, including wound healing, cell proliferation, and inflammation in the vasculature.
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PMID:Alpha-thrombin stimulates sis-inducing factor-A DNA binding activity in rat aortic smooth muscle cells. 903 27

In addition to its role in coagulation, thrombin is involved in the inflammatory process by inducing vessel neutrophilic infiltration. Thrombin induces endothelial P-selectin expression and platelet activating factor release, which participate to induce early neutrophil adhesion and activation. We employed HUVEC and now show that thrombin induces the production of the chemokine IL-8 in a time- and dose-dependent fashion. Similarly, thrombin induced E-selectin expression on HUVEC. Both IL-8 secretion and E-selectin expression were preceded by an increase in steady state levels of the respective mRNAs. Thrombin action on HUVEC was inhibited by the specific thrombin inhibitor, hirudin. In addition, these effects of thrombin on HUVEC were mimicked by the 14-amino acid thrombin receptor agonist peptide, which triggers the native thrombin receptor in a similar fashion to thrombin itself. Although IL-1 and TNF-alpha also induce IL-8 and E-selectin, the thrombin effects in these experiments were not mediated by those cytokines, since neither IL-1 receptor antagonist nor anti-TNF-alpha Ab inhibited the effects of thrombin. Furthermore, IL-1alpha, IL-1beta, and TNF-alpha were not detected in the supernatants of thrombin-activated HUVEC. Although intracellular IL-1alpha was found in thrombin-activated HUVEC, antisense IL-1alpha had no inhibitory effect on IL-8 secretion. These results demonstrate that in addition to short term endothelial activation, thrombin also functions as a long acting proinflammatory agent by inducing endothelial synthesis of the mediators required for neutrophils activation and extravazation during inflammation.
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PMID:Thrombin induces endothelial type II activation in vitro: IL-1 and TNF-alpha-independent IL-8 secretion and E-selectin expression. 916 65

The effects of thrombin on adenylyl cyclase activity were examined in rat adrenal medullary microvascular endothelial cells (RAMEC). Confluent RAMEC monolayers were stimulated for 5 min with cAMP-generating agents in the absence and presence of thrombin, and intracellular cAMP was measured with a radioligand binding assay. Thrombin (0.001-0.25 U/ml) dose-dependently inhibited IBMX-, isoproterenol- and forskolin-stimulated cAMP accumulation. A peptide agonist of the thrombin receptor, gamma-thrombin, and the serine proteases trypsin and plasmin, also inhibited agonist-stimulated cAMP levels, while proteolytically inactive PPACK- or DIP-alpha-thrombins were without effect. Moreover, the thrombin inhibitor hirudin abolished the inhibitory effect of thrombin but not of the peptide agonist. These results suggest that the inhibitory action of thrombin on cAMP accumulation is mediated by a proteolytically-activated thrombin receptor. The inhibitor of G(i)-proteins pertussis toxin abolished the inhibitory effect of thrombin on isoproterenol- or IBMX-stimulated cAMP production, while the phorbol ester PMA partly impaired it. The protein kinase C inhibitors staurosporine or H7 and the intracellular Ca2+ chelator BAPTA-AM were without effect. Collectively, our data suggest that the thrombin receptor in RAMEC is negatively coupled to adenylyl cyclase through a pertussis toxin-sensitive G(i)-protein.
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PMID:The thrombin receptor in adrenal medullary microvascular endothelial cells is negatively coupled to adenylyl cyclase through a Gi protein. 919 75

Hirudin is a specific and direct-acting thrombin inhibitor superior to heparin as an anticoagulant. Thrombin is a multifunctional molecule that acts as a serine protease locally generated from prothrombin during blood coagulation related to injury and/or inflammation. We previously reported that thrombin might be involved in the inflammatory response, glial reaction, and scar formation that occurred in central nervous system (CNS). Here we studied the suppressive effects of hirudin on the inflammation, vimentin-positive astrocytes, and glial fibrillary acidic protein (GFAP)-positive astrocytes using rat cerebral ablation models. Hirudin and vehicle solution soaked in Gelform were administered to the cavity of the traumatic brain defect. Brains were examined by conventional histologic and immunohistologic technique. Antibodies for monocytes/macrophages, GFAP, and vimentin were used to assess the infiltration of inflammatory cells and reaction of astrocytes. The number of the inflammatory cells, vimentin-positive astrocytes, and GFAP-positive astrocytes were quantitatively analyzed. Hirudin suppressed the infiltration of inflammatory cells and the increase in vimentin-positive astrocytes, but had no effects on the increase in GFAP-positive astrocytes. These data suggest that thrombin may play an important role in inflammatory and glial responses to CNS injury, and that hirudin can be a candidate for the therapeutic agent that minimizes the secondary brain damage following the inflammation, and the glial reaction mediated by vimentin-positive astrocytes near the lesion site.
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PMID:Hirudin suppresses the invasion of inflammatory cells and the appearance of vimentin-positive astrocytes in the rat cerebral ablation model. 938 93

Current clinical use of heparin as an antithrombotic agent is limited by suboptimal efficacy and safety considerations. Thrombin's central role in thrombosis makes it an attractive target to develop more effective and safer antithrombotic agents. BCH-2763 is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog, with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors were effective on both arterial and venous thrombosis at markedly lower fold aPTT increases than heparin. The antithrombotic doses of all inhibitors against venous thrombosis were less than against arterial thrombosis. The rank order of potency based on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763 (1.2) > inogatran (1.5) > r-hirudin (1.8) > hirulog (3.3) > argatroban (> 3.0); heparin required a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog: 0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative IC50s did not correlate with their antithrombotic efficacy. In summary, direct thrombin inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763 may offer an improved therapeutic index in the treatment of thromboembolic complications over heparin and other direct thrombin inhibitors.
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PMID:BCH-2763, a novel potent parenteral thrombin inhibitor, is an effective antithrombotic agent in rodent models of arterial and venous thrombosis--comparisons with heparin, r-hirudin, hirulog, inogatran and argatroban. 949 3

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.
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PMID:Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. 957 50


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