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)

We report a patient who was treated with recombinant (r)-hirudin for heparin-induced thrombocytopenia and developed a flush reaction twice upon re-exposure to 25 mg of subcutaneous r-hirudin. Antihirudin IgG antibodies developed. The patient received 50 mg of PEG-hirudin subcutaneously over 2 days. No side-effects occurred. The level of IgG antihirudin antibodies increased. Ecarin clotting time and thrombin inhibition S2238 assay were not influenced by the patient's IgG antihirudin antibody. PEG-hirudin may be used in patients with intolerance to r-hirudin because of a dissociation of the allergenic and immunogenic properties of the pegylated drug.
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PMID:Treatment of an acute flush reaction caused by subcutaneous r-hirudin with pegylated hirudin. 1075 10

The deleterious role of fibrin deposition in arthritic joints prompted us to explore the effect of the thrombin inhibition on the course of collagen-induced arthritis (CIA) in the mouse. CIA was induced in male DBA/1J mice using native chicken type II collagen. The thrombin inhibitor polyethyleneglycol-hirudin (PEG-hirudin) was given for 16 days, starting 20 days after the first immunization (preventive treatment) or at the onset of clinical signs of arthritis (curative treatment). All the mice treated with PEG-hirudin had a significantly prolonged clotting time compared with control mice. PEG-hirudin, administered in a preventive way, led to significantly reduced incidence and severity of CIA during most of the treatment period, as assessed by clinical scoring. Accordingly, histological features showed a significant diminution of synovial hyperplasia in PEG-hirudin-treated mice compared with untreated mice. There was also a significant downmodulation of the synovial proinflammatory IL-1beta and IL-12p35 cytokine mRNAs in treated mice. Intra-articular fibrin, evaluated by immunohistochemistry, was significantly reduced in treated mice compared with control mice and correlated with both clinical and histological scorings. Most importantly, once arthritis was established, PEG-hirudin also showed a curative effect. In conclusion, PEG-hirudin can both prevent the onset of CIA in a dose-dependent manner and ameliorate established arthritis, suggesting that thrombin inhibition may offer a new therapeutic approach in arthritis.
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PMID:Amelioration of collagen-induced arthritis by thrombin inhibition. 1123 64

We studied the effects of hemoglobin-vesicles modified with PEG (PEG-HbV), a type of liposome-encapsulated hemoglobin (LEH), on human platelet functions in vitro. The effect of a low concentration of PEG-HbV (Hb; 5.8 mg/dl) was assessed by examining an agonist-induced aggregation response, and that of relatively high concentrations of PEG-HbV (Hb; 0.29, 1 and 2 g/dl) by measuring the release of RANTES (Regulated upon activation, normal T-cell expressed and presumably secreted) from platelets, which is regarded as a marker of platelet activation. The preincubation of platelets with PEG-HbV at 5.8 mg/dl of Hb did not affect platelet aggregation induced by collagen, thrombin and ristocetin. The pretreatment of platelet-rich plasma (PRP) with PEG-HbV at concen trations up to 2 g/dl of Hb had no aberrant effects on the collagen-induced RANTES release. Furthermore, the collagen-induced release of RANTES from PRP was not affected by longer incubation with PEG-HbV at 2 g/dl of Hb. The basal levels of RANTES from PRP were unchanged in the presence of PEG-HbV. These results suggest that PEG-HbV, at the concentrations studied, have no aberrant effects on platelet functions in the presence of plasma.
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PMID:Effects of poly(ethyleneglycol)-modified hemoglobin vesicles on agonist-induced platelet aggregation and RANTES release in vitro. 1135 35

The suitability of existing topical fibrin glue preparations for tissue sealing or local drug delivery applications is greatly limited by their poor mechanical properties and the limited capacity of fibrinogen (Fgn) to actively bind growth factors or other therapeutic agents. Poly(ethylene glycol) (PEG) offers potential solutions to these problems by providing a mechanism for increasing the number of crosslinks between adjacent fibrin monomer molecules or for covalently crosslinking Fgn to therapeutic agents. The feasibility of this approach requires the full biological activity, or clottability, of PE glycolated Fgn. This study characterizes the clot characteristics of Fgn modified to varying degrees with monofunctional succinimidyl propionate PEG (5000 Da). The data indicate that, although thrombin clotting times are significantly altered, Fgn maintains 90% of its capacity to clot upon the addition of up to 5 PEG/Fgn. Further derivatization significantly decreases the Fgn clottability. The addition of up to 5 PEG/Fgn has little, if any, effect on the kinetics of degradation by plasmin. The results suggest that limited modification of Fgn with lysine-reactive PEG allows therapeutic enhancement of fibrin glues.
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PMID:Modification of fibrinogen with poly(ethylene glycol) and its effects on fibrin clot characteristics. 1140 Jan 30

Three methods for measuring pegylated hirudin (PEG-hirudin), a new antithrombotic agent, in blood were compared using clinical samples. The ecarin clotting time (ECT) was performed in whole blood using a point-of-care device (TAS analyzer). The ECT was also performed in plasma, using a clotting assay in a conventional automated coagulation analyzer. Finally, a chromogenic method was used, based on thrombin inhibition and the substrate S-2238. Both clotting assays showed a linear relationship between the ECT and the PEG-hirudin concentration up to 3.0 microg/ml. The chromogenic substrate method was linear only between 0.1 and 1.0 microg/ml PEG-hirudin. The intra-assay coefficient of variation was 3.0% for the automated ECT method, 6.4% for the point-of-care ECT method and 3.4% for the chromogenic method. The inter-assay coefficient of variation was approximately 10% for both clotting methods and 3.2% for the chromogenic method. There was a high correlation (r = 0.954) in PEG-hirudin concentration between both ECT methods over the entire measuring range. The correlation of the chromogenic method with any ECT was significantly less (r < 0.89), even if only PEG-hirudin concentrations < 1.0 microg/ml were taken into account (r < 0.92). Although we clearly prefer the conventional ECT, any of the other methods may be used for monitoring PEG-hirudin in patients treated with this drug, depending on the specific application and local circumstances.
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PMID:Comparison of three methods for measuring PEG-hirudin in blood. 1168 47

There is a medical need for robust, biocompatible hydrogels that can be rapidly crosslinked in situ through the use of gentle and non-toxic triggers, which could be used as a surgical adhesive, a bone-inductive material, or for drug and gene delivery. The complete gelation system described here includes calcium-loaded liposomes, hrFactor XIII. thrombin, and an enzymatic substrate based on a four-armed PEG in which each arm terminates with a 20mer peptide sequence derived from the gamma-chain of fibrin. Controlled release of calcium ions for efficient hrFXIII activation was accomplished by thermal triggering of a tailored liposome phase transition at 37 degrees C, which allowed the entire gelation system to be stored in aqueous solution at room temperature without premature gelation. When the system temperature was raised to 37 degrees C (body temperature), the released calcium activates the hrFactor XIII, and gelation was observed to occur within 9 min. Rheological studies performed to quantitatively determine the storage modulus (G') of the gel during oscillatory shear show that it behaves as a robust, elastic solid. Scanning electron microscopy studies revealed the hydrogel to have a very dense morphology overall, however spherical voids are observed in regions where calcium-loaded liposomes were entrapped during gelation.
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PMID:In situ crosslinking of a biomimetic peptide-PEG hydrogel via thermally triggered activation of factor XIII. 1205 19

The purpose of this study was to investigate the pharmacodynamics of PEG-Hirudin and its potential interactions with acetylsalicylic acid (ASA 325 mg once daily from days 1-3). In a randomized, 2-way cross-over trial, 6 healthy volunteers received PEG-Hirudin (i.v. bolus of 0.2 mg/kg + 0.02 mg/kg/h for 24 hours) and placebo (i.v. bolus + 24-hour infusion). In a further randomized, 3-way cross-over trial another 9 healthy volunteers received ASA (325 mg) or oral placebo from days 1 to 3 and PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 h) or i.v. placebo on day 3. Assessments included bleeding time (BT), collagen (1 microgram ml(-1))-induced platelet aggregation (CIPA), platelet adhesion, ecarin clotting time (ECT), activated clotting time (ACT), plasma anti-factor IIa activity (aIIa), and activated partial thromboplastin time (aPTT). Ten minutes after the PEG-Hirudin injection/starting the infusion, mean plasma concentration was 3.1 microgram/mL and aPTT, ECT, and ACT were prolonged up to 80, 309, and 233 seconds, respectively. During the last 8 hours of the 24-hour infusion mean PEG-Hirudin plasma concentration was 1.3 microgram/mL. In the interaction study, ASA significantly inhibited CIPA. At 6 hours after administration, on day 3 mean BT was 6.5 minutes after PEG-Hirudin alone, 18.2 minutes after ASA alone, and 32.9 minutes after combined administration of ASA and PEG-Hirudin. PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 hours) administered alone or together with 325 mg ASA proved to be safe in healthy volunteers. Combined use of PEG-Hirudin and ASA significantly increased the mean bleeding time compared to ASA or PEG-Hirudin monodrug administration. None of the clotting parameters or platelet function tests correlated with the prolongation of the bleeding time.
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PMID:Effects of PEG-hirudin in clotting parameters and platelet function and its interaction with aspirin in healthy volunteers. 1264 28

The work deals with estimation of thrombin preparation having such features as: sedimentation activity 3000-3200 NIH un. per 1 mg of protein and 97% of active centres. The enzyme isolated has been estimated according to the amidolytic activity on synthetic substrates S-2160 and BAPNA being equal 5200 and 185 milli un/mg of protein, respectively. According to the electrophoresis in PAAG in the presence of Ds-Na the preparation is homogenous, its molecular mass is 36000. The fibrinogen sedimentation time dependence on the isolated thrombin concentration has been estimated as well as the comparative analysis with the thrombin of the firm "Sigma" with the previously calibrated activity using the international standartion (coded P4) has been conducted. The absence of proportionality between the substrate sedimentation time and the preparation concentration has been determined. It has been revealed, that if the experimental findings are presented in the units 1/t against the thrombin units NIH the right lines are received within the limits used. The defreezing and secondary freezing of the preparation preserved under -20 degrees C have been showed as rendering an essential effect on thrombin activity. In order of the enzyme stabilizing at preserving the thrombin isolated has been concentrated applying the amycon membranes (MWCo: 30,000). While applying the thrombin water-saline solution in the conditions selected the preparation has showed itself practically stable during a year without utilizing any admixtures. The essential effect on thrombin has been found from the side of 1% glycin, 0.5% PEG, 1% saccharose and so on. The thrombin isolated high functional homogeneity, its stability permit to recommend the preparation as an operative standard.
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PMID:[Human thrombin: enzymatic properties, stability and standardization of preparation]. 1291 52

Sulfonated polyrotaxanes (PRx-SO(3)'s), in which sulfonated alpha-cyclodextrins (alpha-CDs) were threaded onto the poly(ethylene glycol) (PEG) segments in a PEG-b-poly(propylene glycol) (PPG)-b-PEG triblock copolymer (Pluronic) capped with benzyloxycarbonyl (Z)-L-phenylalanine (Z-L-Phe), were prepared as a novel surface-modifying biomaterial. Surface modification of the polyurethane (PU) was carried out by blending the PRx-SO(3)'s with a PU solution, followed by solution casting. The incorporated PRx-SO(3)'s led to the enhanced hydrophilicity by changing the surface properties of the PU matrix. Modified PUs showed the stable entrapment of the PRx-SO(3)'s with little extraction into water and enhanced mechanical properties after exposure to water compared to the PU control. The incorporated PRx-SO(3)'s repelled the proteins and kept them from closely approaching the surface areas, prevented platelet activation by thrombin, and effectively repelled bacteria. These results suggest that both the supramolecular structure of the polyrotaxanes and exposure of the sulfonated groups onto the surfaces contribute to these phenomena. Thus, surface modification with PRx-SO(3)'s is suggested to be useful for the fabrication of biocompatible medical devices.
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PMID:In vitro biocompatibility assessment of sulfonated polyrotaxane-immobilized polyurethane surfaces. 1291 43

The purpose of this study was to determine the in vitro effects of different anticoagulant drugs on fibrinopeptide A (FPA) generation inhibition and to identify whether there is any correlation between FPA generation, Hemochron ACT, global clotting assays, and chromogenic assays. Unfractionated heparin is a conventionally used anticoagulant. New anticoagulant drugs such as low molecular weight heparins (LMWHs), pentasaccharide, and antithrombin drugs are now approved for various indications. Anti-Xa drugs are in various phases of clinical development. The influence of different anticoagulant agents has been studied on fibrinopeptide A generation, Hemochron celite ACT, global clotting assays, and chromogenic anti-Xa and anti-IIa assays. Different LMWHs (Clivarin, Dalteparin, Enoxaparin, and Tinzaparin), anti-Xa agents (Pentasaccharide, DX-9065a and unfractionated heparin), and anti-IIa agents (PEG-Hirudin, Hirudin, Efegatran and Argatroban) were studied. The blood from healthy volunteers (n=4) was drawn for each drug. Imuclone FPA enzyme-linked immunosorbent kit assay, Hemochron celite ACT assay, global clotting assays (PT, APTT, Heptest-HI, thrombin time), and Loyola chromogenic anti-Xa and anti-IIIa assays were studied. Pentasaccharide demonstrated minimal effects on the whole blood clotting time such as ACT and on inhibition of FPA generation (IC50 > 25 microg/mL). DX-9065a exhibited a significant prolongation of ACT and marked inhibition of FPA generation (IC50 = 4.12 microg/mL). Unfractionated heparin showed a marked inhibition of FPA generation (IC50 = 5.16 microg/mL). Pentasaccharide, DX-9065a and UFH showed a marked correlation between ACT and inhibition of FPA generation. LMWHs demonstrated concentration-dependent inhibition of FPA generation. LMWHs studied showed good correlation between FPA generation inhibition and ACT test. Similar correlation was seen between FPA generation inhibition and the APTT, anti Xa (heptest-HI assay) and anti-IIa activity. Anti-IIa drugs demonstrated concentration-dependent inhibition of FPA generation. Their FPA generation inhibition potency is correlated with the ACT assay. A strong correlation between Hemochron ACT and FPA generation inhibition was observed. Based on this significant correlation, the FPA generation inhibition can be predicted by point-of-care ACT assay.
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PMID:Influence of different anticoagulant agents on fibrinopeptide a generation. 1465 37


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