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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 microM for trypsin, 0.029 microM for pancreatic kallikrein, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, and Ki values for these proteases were 0.021 and 0.18 microM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 microM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 microM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 microM, while camostat revealed no inhibition by concentrations up to 1 microM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 microM, respectively, the corresponding values for camostat being 350 and 150 microM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and C1s in complement pathway.
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PMID:[Inhibitory effects of sepimostat mesilate (FUT-187) on the activities of trypsin-like serine proteases in vitro]. 773 78

Z-D-Phe-Pro-boroMpg-OPin (9a)1,2 has been shown previously to be a highly specific inhibitor of thrombin in spite of lacking an arginine-like guanidino group at the P1 site. A range of compounds have been synthesized based upon this lead compound, varying the neutral side chain at the P1 site. Of the 20 examples based upon the structures at P2 and P3 of Z-D-X-Pro (X being Phe or beta,beta-diphenylalanine), all were found to be effective inhibitors of thrombin (Ki's between 10 and 100 nM). Furthermore all exhibited a high specificity toward thrombin having values for a Ki(trypsin)/Ki(thrombin) ratio of between 10- and 100-fold. High ratio values were found for a number of the compounds tested against a range of serine proteinases (plasmin, factor Xa, kallikrein, urokinase, protein Ca, chymotrypsin, elastase, and cathepsin G). As far as potency toward thrombin, compounds containing the methoxypropyl group at P1 were favored over those with a methoxy grouping on a shorter alkyl chain (8) or without the methoxy group (1-5). The compounds display potent anticoagulant activity with values for 18 in thrombin time of 0.63 microM and in activated partial thromboplastin time of 2.0 microM. 11B NMR has been used to confirm interaction of the boron atom with the active site. From the high specificity shown with all the compounds we propose that the compounds, constitute a new class of thrombin inhibitors.
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PMID:Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin. 773 10

To clarify the effect of atrial fibrillation (AF) on the fibrino-coagulation system, fibrino-coagulation parameters in the paroxysmal period of AF were determined in 13 patients with paroxysmal atrial fibrillation (PAF) and compared with those in the non-paroxysmal period of AF, and with those in normal subjects. Estimated titers of hemoglobin and hematocrit in the paroxysmal period of AF were significantly higher than those in the non-paroxysmal period and also higher than those in normal subjects. The activated partial thromboplastin time in the paroxysmal period was also longer than that in the non-paroxysmal period of AF or in normal subjects. However, other estimated parameters, such as prothrombin time, fibrinogen, thrombin-antithrombin III, beta-thromboglobulin, platelet factor 4, D-dimer and plasmin inhibitor complex, did not show any significant deviation. These results conflict with those of previous reports which indicated that the fibrino-coagulation system was enhanced in cases of chronic AF. Our results suggest that there is no significant activation of the fibrino-coagulation system, except for obvious hemoconcentration, within the first few hours after the onset of PAF. Thus, in terms of the properties of blood coagulation, thromboembolism is preventable if antiarrhythmic therapy is administered within several hours after the onset of PAF.
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PMID:Effect of atrial fibrillation on the fibrino-coagulation system--study in patients with paroxysmal atrial fibrillation. 780 80

Amyloid precursor protein forms that contain Kunitz protease inhibitor domains are released from activated platelets, T-lymphocytes, and leukocytes and inhibit trypsin, plasmin, and activated factor XI. We investigated the effects of amyloid precursor protein isoforms on activated Hageman factor (factor XII), activated factor X (Stuart factor), and thrombin. Recombinant amyloid precursor proteins with or without the Kunitz domain, 770 and 695 amino acids, respectively, were produced in insect cells by Baculovirus expression (BAC770 and BAC695). Neither BAC695 nor BAC770 inhibited human alpha-thrombin or activated factor X. The partial thromboplastin time was prolonged by both amyloid precursor proteins, only one of which, BAC770, contains the Kunitz protease inhibitor domain. Both forms of amyloid precursor proteins inhibited ellagic acid-induced activation of Hageman factor but did not inhibit activated Hageman factor. Bismuth subgallate, which is an insoluble analog of ellagic acid, lost its ability to activate Hageman factor on being exposed to BAC770. Inhibition of ellagic acid-induced activation of Hageman factor by both forms of amyloid precursor protein was enhanced by heparin. These findings suggested that the heparin-binding domain of amyloid precursor proteins is not in the Kunitz domain. This heparin-binding domain may block the activation of Hageman factor by negatively charged agents. Thus, amyloid precursor proteins may be involved in the control of hemostasis, properties not all dependent on the Kunitz domain.
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PMID:Inhibitory action of amyloid precursor protein against human Hageman factor (factor XII). 784 73

Recently, an increased frequency of thromboembolic events has been reported after the administration of anticancer drugs. The precise mechanism by which these vascular phenomena occur is unknown. The current work aims at evaluating the alterations of the coagulation and the fibrinolysis systems during the administration of antineoplastic agents by means of newly developed markers of haemostasis. This investigation comprised 25 lung cancer patients treated with multidrug combination chemotherapy. D-dimer, plasmin-alpha 2-antiplasmin complex, fibrin degradation products, fibrinogen, antithrombin III, thrombin-antithrombin III complex, prothrombin time and activated partial thromboplastin time were measured from samples taken before and on days 2, 5, 7, 14 and 21 after the administration of antineoplastic drugs. A significant reduction in plasma concentration of fibrinolytic activity markers, DD and PAP, was observed on days 5 and 7, and on days 2, 5, 7 and 14, respectively, following the administration of chemotherapeutic drugs. Statistically significant shortening of PT and APTT on days 2, 5, 7 and 14, as well as significant elevation of the thrombin generation marker TAT were observed on days 5 and 7 after chemotherapy. These results show that relatively higher levels of coagulation activation and a lower fibrinolytic activity occur during cytotoxic drug therapy compared with basal values. Small variations of haemostatic values and a short follow-up period may explain why no thrombotic events were observed during this study. Although further studies must be done to clarify these findings, the results of this investigation suggest that an imbalance of the coagulation-fibrinolysis system might be a contributing factor in the pathogenesis of thrombotic complications during chemotherapy.
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PMID:Alteration of coagulation and fibrinolysis systems after multidrug anticancer therapy for lung cancer. 799 12

Twenty-two patients on regular hemodialysis treatment suffering from renal anemia were treated with intravenous recombinant human erythropoietin (rhEPO) for more than 8 weeks. Before and 4 and 8 weeks after the start of rhEPO administration, we measured prothrombin time, activated partial thromboplastin time, fibrinogen (FBG), antithrombin III activity (ATIII), plasminogen activity (PLG), alpha 2-plasmin inhibitor activity (alpha 2 PI), alpha 2-plasmin inhibitor-plasmin complex (alpha 2 PIC), and cross-linked fibrin degradation products (XL-FDP) in citrated plasma to determine whether rhEPO treatment enhances coagulation and fibrinolytic activity. The pretreatment values of FBG, alpha 2 PIC, and XL-FDP were significantly higher than the normal control values. The pretreatment values of ATIII, PLG, and alpha 2 PI were significantly lower than the normal control values. Platelet count and FBG were significantly increased 4 and 8 weeks after treatment with rhE-PO. The prothrombin time was significantly shortened 8 weeks after rhEPO treatment, but the activated partial thromboplastin time did not change. PLG was significantly decreased 4 and 8 weeks after rhEPO treatment, and ATIII and alpha 2 PI were significantly decreased 8 weeks after rhEPO treatment. alpha 2 PIC was significantly increased 8 weeks after rhEPO treatment, and XL-FDP was significantly increased 4 and 8 weeks after rhEPO treatment. These data suggest that in patients on regular hemodialysis treatment coagulation and fibrinolysis are already enhanced before the start of rhEPO treatment and that rhEPO administration further enhances these disorders.
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PMID:Enhanced coagulation and fibrinolysis during treatment with recombinant human erythropoietin in patients undergoing chronic hemodialysis. 804 58

Consumptive coagulation disorders are frequently observed in critically ill patients secondary to other underlying diseases. Initial hypercoagulability leads to subsequent hypocoagulability due to consumption of procoagulant proteins, inhibitors, and platelets. This process evolves in three distinct phases: an initial increase in coagulation activity is characterised by the activation of coagulation factors and platelets without any clinical symptoms of a haemorrhagic diathesis. The ongoing process of activation and accelerated consumption of coagulation factors and inhibitors causes a critical reduction in the haemostatic potential. The time of onset of the clinical symptoms of bleeding depends on the patient's underlying disease and its pharmacological management. Coagulation processes that are restricted locally under normal conditions become disseminated when the inhibitory potential--mainly represented by antithrombin III (AT III)--is exhausted. Therefore, thrombin formation occurs, especially in the microcirculation, where fibrin clot deposition begins to cause inhomogeneities of blood flow and thus to reduce oxygen delivery to the tissues. Hypocoagulability, reactive hyperfibrinolysis, and diffuse bleeding lead to an irreversible systemic breakdown of haemostatic mechanisms (disseminated intravascular coagulation, DIC). The laboratory diagnosis of accelerated consumption is based on the course of global coagulation tests (e.g., prothrombin time, activated partial thromboplastin time, platelet count) and more sensitive ("dynamic") activation parameters such as prothrombin fragment F1 + 2, thrombin-AT III complex, fibrin monomers, or d-dimer. Measurements of plasminogen, tissue plasminogen activator, plasminogen activator inhibitor 1, and alpha 2-antiplasmin-plasmin complex provide information on fibrinolytic turnover.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Diagnosis and therapy of disseminated intravascular coagulation]. 804 68

Activated protein C (APC)-protein C inhibitor (PCI) complex and APC-alpha 1antitrypsin (alpha 1AT) complex levels were measured in 29 patients positive for lupus anticoagulant (LA). LA was considered positive if two of the following three criteria were fulfilled: (1) prolongation of the activated partial thromboplastin time, (2) prolongation of the kaolin clotting time (KCT) and KCT mixing test, and (3) prolongation of the dilute Russell's viper venom time (DRVVT) and DRVVT/DRVVT with high lipid concentration. Plasma thrombin-antithrombin III (AT-III) complex and plasmin-alpha 2-antiplasmin inhibitor complex levels in patients positive for LA were increased slightly, but not significantly, and FDP-D-dimer and t-PA levels were not markedly increased. Plasma PAI-1 level in the LA-positive patients was significantly increased compared with normal volunteers. AT-III activity, protein C antigen, PCI antigen, and protein S antigen levels in the LA-positive patients were virtually normal, while protein C activity was slightly, but not significantly, decreased. APC-PCI complex level was increased in all LA-positive patients, and was not detectable in patients with systemic lupus erythematosus and normal volunteers. APC-alpha 1AT complex was increased slightly, in only two LA-positive patients; it was not detectable in the other patients or in the normal volunteers. These findings suggest that patients positive for LA are in a hypercoagulable state and that protein C activity in such patients is decreased, due to the activation of this protein.
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PMID:Increased activated protein C-protein C inhibitor complex level in patients positive for lupus anticoagulant. 805 49

Potent active-site inhibitors of human tissue factor-Factor VIIa (TF.FVIIa) have been selected from Alzheimer's amyloid beta-protein precursor inhibitor (APPI) Kunitz domain libraries displayed on phage. Eight randomized positions on the extended primary binding loop (P5 through P4') and positions 34 and 39 were examined in three separate libraries. Libraries contained from 3.2 x 10(5) to 3.2 x 10(6) potential variants resulting from replacing up to 5 positions with all 20 amino acids. Following 4 rounds of selection against FVIIa associated with immobilized tissue factor (TF), 12 clones from each library were sequenced. Variants were purified by trypsin affinity chromatography and reverse-phase high performance liquid chromatography, and characterized for their ability to inhibit TF.FVIIa chromogenic activity. Measured apparent equilibrium dissociation constants (Ki*) ranged from about 10 to 500 nM. From sequence and activity data, an overall consensus sequence, TF7I-C, was constructed by site-directed mutagenesis. TF7I-C differed from APPI at 4 key residues, T11P, M17L, S19L, and G39Y, and inhibited TF.FVIIa with a Ki* = 1.9 +/- 0.4 nM, which represented an increase in binding affinity of more than 150-fold compared to APPI. At 40 microM, TF7I-C prolonged the clotting times 3.5-fold in a prothrombin time assay and > 10-fold at 7 microM in an activated partial thromboplastin time assay. Prolongation of the activated partial thromboplastin time correlates with potent inhibition of FXIa (Ki* = 0.8 nM) and plasma kallikrein (Ki* = 1.2 nM). TF7I-C also inhibited plasmin (Ki* = 40 nM) and FXa (Ki* = 55 nM), but not activated protein C, thrombin, or FXIIa (Ki* > 10 microM each).
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PMID:Kunitz domain inhibitors of tissue factor-factor VIIa. I. Potent inhibitors selected from libraries by phage display. 807 37

Active-site inhibitors of the human tissue factor-Factor VIIa complex (TF.FVIIa) that are both potent and specific have been selected from Alzheimer's amyloid beta-protein precursor inhibitor (APPI) Kunitz domain libraries using a strategy termed competitive phage selection. Phage display Libraries I-III, previously sorted by direct selection, were sorted by competitive selection against immobilized TF.FVIIa in which increasing amounts of Factor XIa (FXIa) were added to the selection buffer to remove phage with high affinity for FXIa. The most striking difference in the selected Kunitz domain sequences was at the P4' position where Lys was highly preferred instead of Leu which was found here by direct selection (Dennis, M. S., and Lazarus, R. A. (1994) J. Biol. Chem. 269, 22129-22136). In addition, both Lys and Arg were selected in the P1 position as opposed to Arg alone. A new library (Library IV) was constructed which contained all previously observed amino acids at 9 positions in the primary and secondary binding loops of APPI. Comparable results were obtained by sorting Library IV against immobilized TF.FVIIa in the presence of either FXIa alone or FXIa, plasma kallikrein, and plasmin. The Kunitz domains obtained by either competitive selection strategy potently inhibited TF.FVIIa, with Ki* values ranging from about 2 to 20 nM; the Ki* values were generally > 1 microM for FXIa and plasma kallikrein and ranged from 4 to 200 nM for plasmin. Variants selective for TF.FVIIa were assayed for free FVIIa and FXa inhibitory activity and characterized in coagulation assays. A rationale for the selection of Lys at both the P4' and P1 positions based upon comparison of sequences and structures of relevant serine proteases and inhibitors is presented.
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PMID:Kunitz domain inhibitors of tissue factor-factor VIIa. II. Potent and specific inhibitors by competitive phage selection. 807 38


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