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)

The study evaluated the role of thrombin in activation of vascular smooth muscle cells early after vascular injury. The direct thrombin inhibitor Hirulog (10 mg/kg SQ tid) or vehicle was administered to rabbits over 3 days following balloon injury to the abdominal aorta and the right iliac artery. Hirulog treatment yielded marked systemic anticoagulation as evidenced by an about 3.5-fold prolongation of quantitative thrombin time one hour after an injection, but with a reduction to almost baseline levels at the end of the dosing interval. After 3 days, proliferating cells in the right iliac artery were enumerated. The expression of intercellular adhesion molecule 1, macrophage-colony stimulating factor, tumor necrosis factor alpha, and interleukin-1beta as markers for inflammatory activation of the vessel wall was examined by immunohistochemistry and graded semiquantitatively. Mitotic indices did not differ between control and Hirulog-treated animals. There was also no difference in the expression of markers of inflammatory activation between both groups. In conclusion, thrombin inhibition by Hirulog administration does not reduce acutely (within 3 days) vascular smooth muscle cell proliferation or inflammatory activation after angioplasty. Thrombin inhibitors may therefore limit restenosis in the rabbit by acting later or via other, unknown pathways. The lack of effect of the thrombin inhibitor on the cellular events during the early phase of the response to balloon injury may explain the failure of such strategies to reduce restenosis in recent clinical trials despite effects towards acute thrombotic complications. Together, these results suggest that acute thrombin generation is not a crucial stimulus for early smooth muscle cell proliferation and inflammatory activation after vascular injury.
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PMID:Systemic thrombin inhibition by Hirulog does not alter medial smooth muscle cell proliferation and inflammatory activation after vascular injury in the rabbit. 1054 23

Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood-material contact.
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PMID:Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces. 1055 48

Previous studies have indicated that apart from playing an important role in hemostasis and thrombosis, thrombin may also contribute to the development of postangioplasty restenosis caused by the stimulation of vascular smooth muscle cell (VSMC) proliferation. Because thrombin generation in vivo is accompanied by platelet activation and release of smooth muscle cell (SMC) growth factors such as serotonin, we examined the possible interaction between these two compounds on VSMC proliferation. Thrombin (0.01 to 100 nmol/L), thrombin receptor-activating peptide (0.1 to 1000 micromol/L), and serotonin (5HT; 0.1 to 1000 micromol/L) increased tritiated thymidine incorporation into the DNA of canine aortic VSMCs in a dose-dependent manner. When thrombin and 5HT were added together at sub-threshold concentrations, they acted synergistically in inducing tritiated thymidine incorporation. These findings were paralleled by a 90%+/-5% increase in the cell number at 48 hours, as compared with a 37%+/-2% increase with 50 micromol/L serotonin and a 13%+/-3% increase with 0.1 nmol/L thrombin. We also demonstrated that a brief exposure to thrombin (1 hour) is sufficient to show its potentiating effect on serotonin. The mitogenic effect of serotonin and its synergistic interaction with thrombin on VSMC proliferation was abolished by serotonin type 2 receptor antagonist LY281067. Similarly, gamma-hirudin--a direct thrombin inhibitor--blocked the mitogenic effect of thrombin and its synergistic interaction with serotonin. When LY281067 and gamma-hirudin were used together, they abolished the mitogenic effects of both the agonists. Because clot-bound active thrombin can escape inactivation by anti-thrombin, this thrombin may potentiate the mitogenic effect of serotonin and keep the SMCs in a proliferative state for a long period of time. These findings support the use of 5HT2 receptor antagonists in combination with thrombin inhibitors in the prevention of SMC proliferation after coronary angioplasty.
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PMID:Synergy between thrombin and serotonin in inducing vascular smooth muscle cell proliferation. 1059 95

Early cellular events in the lung which may lead to the development of pulmonary metastases (PM) are still poorly understood. Thrombin, a key component of the coagulation cascade, may be involved in the development of PM as it has been shown to be an enhancer of platelet-tumor interaction in vitro and metastasis in vivo, and because it has been found in high levels in lungs from patients with PM. In this study, we assessed the potential role of thrombin in promoting PM by inducing an enhancement of tumor cell adhesion to platelets and tumor cell chemoinvasion and proliferation. We used bronchoalveolar lavage fluid (BALF) from 20 patients with PM. Results were compared with those from healthy controls. We found an enhancement of adhesion of PM-BALF-treated tumor cells to untreated platelets. BALF from patients with PM significantly increased chemoinvasion and proliferation in three human tumor cell lines. These activities were attenuated significantly by a thrombin inhibitor: hirudin. These results indicate that the thrombin present in the lungs of patients with PM is, at least in part, responsible for their adhesive, invasive and mitogenic activity on three different tumor cell lines. They also suggest that thrombin may be involved in the development of PM.
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PMID:Evidence that thrombin present in lungs of patients with pulmonary metastasis may contribute to the development of the disease. 1059 26

Thrombin plays a key role in the control of thrombus formation, for which reason its inhibition has become a target for new antithrombotics. Important issues in the profile of the ideal thrombin inhibitor are: potency, selectivity, oral bioavailability, half-life in the circulatory system and safety. Although many potent direct inhibitors of thrombin have been discovered, most of these inhibitors lack sufficient oral bioavailability. This is often associated with the presence of highly basic functionalities such as guanidine or amidine. These basic functionalities in the P1 moiety are preferred by thrombin and are present in the first generation of thrombin inhibitors. Recently, several orally active direct thrombin inhibitors have been disclosed. Most of these inhibitors originate from leads of the first generation. Two major optimization strategies could be identified to further improve these leads: A: maintain the highly basic P1 moiety and compensate its negative effects, and B: reduce the basicity of the P1 moiety and compensate for the decrease in inhibitory activity. The progress made using these strategies is evaluated. In addition, screening large sets of compounds yielded new structures that provide useful starting points for optimization. The optimization strategy used to convert leads from screening into potent orally active thrombin inhibitors is also be evaluated.
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PMID:Strategies and progress towards the ideal orally active thrombin inhibitor. 1060 61

The effects of the thrombin inhibitor argatroban on the number of inflammatory cells and reactive astrocytes were investigated in a rat brain injury model. Gelatin sponge soaked with thrombin inhibitor (treatment group) or saline (control group) was placed in the brain defect to assess the infiltration of inflammatory cells by hematoxylin-eosin and immunohistochemical staining. Expression of polymorphonuclear leukocytes (PMNs) and monocyte/macrophage (Mo/Mo) cells, and vimentin (VIM)-positive astrocytes and glial fibrillary acidic protein (GFAP)-positive astrocytes were compared between groups. In the treatment group, infiltration of both PMNs and Mo/Mo cells, and the number of VIM-positive astrocytes were significantly reduced, but the number of GFAP-positive astrocytes was not different from the control group. Thrombin inhibitor suppresses the infiltration of inflammatory cells and excessive gliosis caused by VIM-positive astrocytes, but not expression of GFAP-positive astrocytes, suggesting minimization of secondary brain damage and promotion of the conditions required for neural regeneration.
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PMID:Thrombin inhibitor ameliorates secondary damage in rat brain injury: suppression of inflammatory cells and vimentin-positive astrocytes. 1070 74

Vascular restenosis is one of the major concerns for the treatment of atherosclerotic cardiovascular diseases using therapeutic vascular procedures. Hirulog-1, a synthetic thrombin inhibitor, effectively reduced ischemic events in coronary heart disease patients and caused less hemorrhagic complications compared to heparin. Thrombin stimulated the expression of platelet-derived growth factor (PDGF) in vascular cells. PDGF receptor blockers reduced angioplasty-induced restenosis in the swine model. The present study examined the effects of hirulog-1 on vascular stenosis, platelet deposition and the expression of PDGF in rat carotid arteries injured by balloon catheter. Multiple intravenous infusions of hirulog-1 (1 mg/kg/h for 4 h for 6 times), but not bolus injection or 1-2 times of infusion, reduced neointima/media ratio by 50% in balloon-injured carotid arteries compared to injured animals receiving saline alone. Activated partial thromboplastin time in hirulog-1-treated rats was significantly prolonged compared to saline controls but shorter than that in animals receiving heparin (50 U/kg/h). One of heparin-treated rat, but none of hirulog-1-treated, died from bleeding complication. Hirulog-1 injection transiently reduced platelet deposition on denuded intima visualized by scanning electron microscopy. Abundance of PDGF in neointima of injured carotid arteries detected by immunohistochemistry was significantly decreased following infusions of hirulog-1. The results suggest that balloon catheter injury induced neointima formation and the overexpression of PDGF in the neointima of rat carotid artery may be effectively suppressed by infusions with hirulog-1, a thrombin-specific inhibitor.
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PMID:Hirulog-1 reduces expression of platelet-derived growth factor in neointima of rat carotid artery induced by balloon catheter injury. 1075 93

Thrombin contributes to the pathogenesis of acute myocardial infarction and reocclusion after thrombolysis. Thrombolytic therapy is known to induce a paradoxic increase in thrombin generation. Specific thrombin inhibition enhances thrombolytic therapy in experimental models. The aim of this study was to determine thrombin generation in patients with acute myocardial infarction treated with rt-PA and conjunctive therapy with the specific thrombin inhibitor, recombinant hirudin. Thrombin generation was determined in 17 patients with acute myocardial infarction treated with front-loaded rt-PA (100 mg/90 min) and conjunctive therapy with recombinant hirudin (HBW 023 bolus 0.4 mg/kg, infusion of 0.15 mg/kg/h) over 48 hours. Mean free hirudin plasma levels of 1320-1545 ng/mL produced a stable anticoagulation with mean aPTT values between 63 and 81 seconds throughout the treatment period. Thrombin generation increased during thrombolysis, indicated by a transient elevation of prothrombin fragment 1.2 levels, which were 3.0 nmol/L at baseline, 11.1 nmol/L after 30 minutes, 8.3 nmol/L after 60 minutes, 3.1 nmol/L after 12 hours, and 1.5 nmol/L after 24 hours, respectively. In contrast, thrombin-antithrombin III complex levels during and after thrombolysis did not exceed the baseline level of 21.8 ug/L. Thrombin-hirudin complex levels increased constantly during the 48-hour treatment period from 3.1 ug/L at baseline to 64.2 ug/L. All patients had an open infarct vessel (TIMI 2/3 potency) after 36-48 hours. Thrombolysis with rt-PA is associated with a significant increase in thrombin generation, which is not blocked by r-hirudin, whereas circulating thrombin seems to be effectively inhibited by r-hirudin.
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PMID:Thrombin Generation in Patients with Acute Myocardial Infarction Treated with Front-Loaded rt-PA and Recombinant Hirudin (HBW 023). 1076 16

Thrombin is the key serine proteinase of the coagulation cascade and therefore a suitable target for inhibition of blood coagulation. A number of pharmacologically active secondary metabolites from mushrooms have already been isolated, thus providing the rationale for screening for new thrombin inhibitors in mushrooms. In this study, inhibitory activities of mushroom extracts on thrombin and trypsin were measured using the chromogenic substrates H-D-phenylalanine-L-pipecolyl-L-arginine-paranitroaniline dihydrochloride (S-2238) for thrombin and N-benzoyl-D,L-Arg-p-nitroanilide (BAPNA) for trypsin. The inhibitory activities of extracts from 95 Basidiomycete species have been determined. The majority of samples inhibited trypsin and thrombin with various potencies; however, some extracts showed no activity against one or both of the enzymes. An aqueous extract of Gleophyllum odoratum exhibited high inhibitory activity on both thrombin and trypsin (72 and 60%, respectively), while extracts of Clitocybe gibba, Amanita virosa, Cantharellus lutescens, Suillus tridentinus, Hypoloma fasciculare and Lactarius badiosanguineus considerably inhibited thrombin (49, 48, 36, 34, 32 and 31%, respectively) and showed no inhibitory activity on trypsin. The results at this point are promising for further research with the objective of finding an effective and safe thrombin inhibitor.
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PMID:Screening for selective thrombin inhibitors in mushrooms. 1130 74

We have previously demonstrated that thrombin upregulation of insulin-like growth factor-1 receptor (IGF-1R) is essential for thrombin-induced mitogenic signaling. To characterize the mechanisms involved, we studied transcription of the IGF-1R gene in rat aortic smooth muscle cells. Thrombin markedly increased IGF-1R mRNA levels, peaking at 3 hours (112+/-7% above control). This effect was mimicked by the hexapeptide SFFLRN (that functions as a tethered ligand) and was blocked by the thrombin inhibitor hirudin. Nuclear run-on assays indicated that thrombin stimulated IGF-1R gene transcription by 2.1-fold, and this was confirmed with the use of actinomycin D. Thrombin-mediated upregulation of IGF-1R mRNA and protein levels was protein kinase C independent but was completely inhibited by the protein tyrosine kinase inhibitor genistein and by the antioxidants N-acetyl-L-cysteine and pyrrolidinedithiocarbamate, suggesting the involvement of reactive oxygen species. The thrombin-induced increase in IGF-1R mRNA was inhibitable by diphenyleneiodonium chloride but not by other inhibitors of cellular oxidase systems, suggesting that NAD(P)H oxidase was necessary for the increase. Furthermore, inhibitors of the epidermal growth factor receptor kinase, Janus kinase-2 kinase, and Src kinase did not block the effect. Thus, thrombin transcriptionally regulates the IGF-1R gene via a redox-sensitive protein tyrosine kinase-dependent pathway that does not require protein kinase C activation. In view of our prior data indicating that IGF-1R density is a critical determinant of vascular smooth muscle cell growth, our findings have particular relevance to understanding mechanisms whereby growth factors such as thrombin regulate vascular proliferation in vivo.
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PMID:Thrombin regulates insulin-like growth factor-1 receptor transcription in vascular smooth muscle: characterization of the signaling pathway. 1137 74


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