Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a novel recombinant soluble human thrombomodulin, ART-123, on protein C activation was investigated by measuring plasma prothrombinase activity in four healthy male volunteers. ART-123 at a dose of 0.3 mg was administered as a bolus intravenous injection for 1 minute. Plasma ART-123 concentration and prothrombinase activity were determined before and immediately, 24, and 48 hours after injection, and thromboelastography was recorded before and immediately and 24 hours after injection. The mean elimination half-life was 19.82 +/- 2.10 hours. Compared with pretreatment levels, ART-123 reduced prothrombinase activity by 44.2 +/- 11.7%, 52.1 +/- 10.8%, and 61.0 +/- 14.7%, respectively, immediately, 24, and 48 hours after injection, suggesting that ART-123 activated the protein C pathway. ART-123 did not affect thromboelastography values. There were no abnormal findings for objective signs or laboratory tests, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, coagulation and hemostatic parameters, blood chemistry, and urinalysis. Based on these observations, ART-123 at a dose of 0.3 mg can activate the protein C pathway in healthy volunteers.
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PMID:A novel recombinant soluble human thrombomodulin, ART-123, activates the protein C pathway in healthy male volunteers. 965 May 44

Asahi Kasei is developing a recombinant thrombomodulin (ART-123), a human protein with both thrombin inhibiting and protein C stimulating activities, for the potential treatment of thromboembolism and blood clotting disorders, such as disseminated intravascular thromboembolism [169907]. By September 2000, it had entered phase III trials [383525]. A patent, US-05916874, claiming a method for treating liver injury and whose composition comprises a thrombomodulin, was published in 1999 by the company.
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PMID:ART-123 Asahi Kasei. 1221 14

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. In the US, approximately 260000 cases are diagnosed annually. Current drugs for the prevention and treatment of venous thromboembolism (VTE) include heparin, low-molecular-weight heparins and warfarin. Since they possess several disadvantages, researchers are investigating improved anticoagulants. To understand how any promising anticoagulant would work, a review of the pathophysiology and regulation of the coagulation cascade is provided. The more prominent drugs reviewed include tissue factor pathway inhibitor protein, nematode anticoagulant protein, Factor IX inhibitors, anti-Factor Xa inhibitors (DX-9065a (Daiichi Seiyaku Co Ltd), YM-60828 (Yamanouchi Pharmaceutical Co Ltd), fondaparinux, idraparinux (Sanofi-Synthelabo/NV Organon)), selective thrombin inhibitors (oral heparin, ximelagatran (AstraZeneca plc)) and enhancers of natural anticoagulants (activated protein C, ART-123 (Asahi Kasei Pharma Corp)).
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PMID:New anticoagulants for venous thromboembolic disease. 1473 Apr 67

Human thrombomodulin (hTM) is an endothelial cell-associated protein with potent natural anticoagulant activity by converting thrombin from a procoagulant protease to an anticoagulant. ART-123 is a recombinant soluble hTM (amino acid residues 1-498), and we focused on the physical adsorption of ART-123 onto a polymeric biomaterial surface to develop an antithrombogenic blood-contacting material with preventing the denaturation of hTM and the remaining chemical reagents. The adsorption of hTM onto polysulfone (PSF) films was analyzed quantitatively by quartz crystal microbalance analysis. The adsorption constant and the maximum adsorption amount, calculated by the assumption of a Langmuir-type adsorption, showed that hTM adsorbed with a relatively weak interaction onto the PSF film. The hydrophilic protein lysozyme also showed a Langmuir-type monolayer adsorption, although hydrophobic catalase and fibrinogen showed multilayer adsorption accompanying the denaturation. The physically adsorbed hTM showed high coenzymatic activity for the activation of protein C, as well as anticoagulant activity. Furthermore, the surface wettability of the PSF film was easily controllable by the physical adsorption of hydrophobic and hydrophilic bioactive proteins. The physical adsorption of hTM or bioactive proteins onto polymeric biomaterials will be instrumental for developing an antithrombogenic blood-contacting biomaterial, and for controlling the surface properties of biomaterials.
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PMID:Physical adsorption of human thrombomodulin (ART-123) onto polymeric biomaterials for developing an antithrombogenic blood-contacting material. 1758 6

More than 95% of mugwort pollen-allergic individuals are sensitized to Art v 1, the major allergen in mugwort pollen. Interestingly, the CD4 T cell response to Art v 1 involves only one single immunodominant peptide, Art v 1(25-36) (KCIEWEKAQHGA), and is highly associated with the expression of HLA-DR1. Therefore, we investigated the molecular basis of this unusual immunodominance among allergens. Using artificial APC expressing exclusively HLA-DRB1*0101 and HLA-DRA*0101, we formally showed that DR1 acts as restriction element for Art v 1(25-36)-specific T cell responses. Further assessment of binding of Art v 1(25-36) to artificial HLA-DR molecules revealed that its affinity was high for HLA-DR1. Amino acid I27 was identified as anchor residue interacting with DR molecules in pocket P1. Additionally, Art v 1(25-36) bound with high affinity to HLA-DRB1*0301 and *0401, moderately to HLA-DRB1*1301 and HLA-DRB5*0101, and weakly to HLA-DRB1*1101 and *1501. T cell activation was also inducible by Art v 1(25-36)-loaded, APC-expressing HLA molecules other than DR1, indicating degeneracy of peptide binding and promiscuity of TCR recognition. Specific binding of HLA-DRB1*0101 tetramers containing Art v 1(19-36) allowed the identification of Art v 1(25-36)-specific T cells by flow cytometry. In summary, the immunodominance of Art v 1(25-36) relies on its affinity to DR1, but is not dictated by it. Future investigations at the molecular HLA/peptide/TCR and cellular level using mugwort pollen allergy as a disease model may allow new insights into tolerance and pathomechanisms operative in type I allergy, which may instigate new, T cell-directed strategies in specific immunotherapy.
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PMID:Characterization of HLA class II/peptide-TCR interactions of the immunodominant T cell epitope in Art v 1, the major mugwort pollen allergen. 1871 38

ART-123 is a recombinant soluble human thrombomodulin (hTM) with potent anticoagulant activity, and is available for developing antithrombogenic surfaces by immobilization. We focused on improving blood compatibility on the dialyzer surface by the physical adsorption of ART-123 as a safe yet simple method without using chemical reagents. The physical adsorption mechanism and anticoagulant activities of adsorbed hTM on the surface of a polysulfone (PSF) membrane containing polyvinylpyrrolidone (PVP) as a model dialyzer were investigated in detail. The PVP content of the PSF-PVP films was saturated at 20 wt% after immersion in Tris-HCl buffer, even with the addition of over 20 wt% PVP. The surface morphology of the PSF-PVP films was strongly influenced by the PVP content, because PVP covered the outermost surface of the PSF-PVP films. The adsorption speed of hTM slowed dramatically with increasing PVP content up to 10 wt%, but the maximum adsorption amount of hTM onto the PSF-PVP film surface was almost the same, regardless of the PVP content. The PSF-PVP film with the physically adsorbed hTM showed higher protein C activity as compared to the PSF film, it showed excellent blood compatibility due to the protein C activity and the inhibition properties of platelet adhesion. The physical adsorption of hTM can be useful as a safe yet simple method to improve the blood compatibility of a dialyzer surface.
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PMID:Improvement of blood compatibility on polysulfone-polyvinylpyrrolidone blend films as a model membrane of dialyzer by physical adsorption of recombinant soluble human thrombomodulin (ART-123). 2131 Jan 10

Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated activation of protein C. Recently, we conducted a multicentre, double-blind, randomized trial to evaluate the efficacy and safety of recombinant human soluble thrombomodulin (rhsTM, also known as ART-123) for the treatment of disseminated intravascular coagulation (DIC), and found that rhsTM therapy is more effective and safer than low-dose heparin therapy. Thus, in 2008, rhsTM (Recomodulin) was approved for the treatment of DIC in Japan. Here we re-evaluate the therapeutic basis of this drug from the view of its anticoagulant, anti-inflammatory, and cytoprotective properties. Structurally, the extracellular portion of TM is composed of three domains: an N-terminal lectin-like domain (TM-D1), followed by an epidermal growth factor (EGF)-like domain (TM-D2), and an O-glycosylation-rich domain (TM-D3). TM-D2 and TM-D3 are important for the protein's anticoagulant cofactor activities, i.e. inhibition of thrombin and activation of protein C. TM-D1 plays an important role in attenuation of inflammatory responses, through inhibition of leukocyte adhesion to endothelial cells, inhibition of complement pathways, neutralization of lipopolysaccharide (LPS), and sequestration and degradation of pro-inflammatory high-mobility group box 1 protein (HMGB1). Thus, TM on the surface of endothelial cells prevents dissemination of pro-coagulant and pro-inflammatory molecules, and by doing so, allows these molecules to act locally at the site of injury. In patients with sepsis and DIC, TM expression is down-regulated, which may result in dissemination of pro-coagulant and pro-inflammatory molecules throughout the systemic circulation. Replacement with rhsTM may offer therapeutic value in such conditions.
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PMID:Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. 2178 Dec 52

Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC.
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PMID:Dysregulation of inflammatory and hemostatic markers in sepsis and suspected disseminated intravascular coagulation. 2425 94

We have generated engineered APC to present immunodominant peptides derived from the major aero-allergens of birch and mugwort pollen, Bet v 1142-153 and Art v 125-36, respectively. Jurkat-based T cell reporter lines expressing the cognate allergen-specific T cell receptors were used to read out the presentation of allergenic peptides on the engineered APC. Different modalities of peptide loading and presentation on MHC class II molecules were compared. Upon exogenous loading with allergenic peptides, the engineered APC elicited a dose-dependent response in the reporter T cells and the presence of chemical loading enhancers strongly increased reporter activation. Invariant chain-based MHC class II targeting strategies of endogenously expressed peptides resulted in stronger activation of the reporters than exogenous loading. Moreover, we used Bet v 1 as model allergen to study the ability of K562 cells to present antigenic peptides derived from whole proteins either taken up or endogenously expressed as LAMP-1 fusion protein. In both cases the ability of these cells to process and present peptides derived from whole proteins critically depended on the expression of HLA-DM. We have identified strategies to achieve efficient presentation of allergenic peptides on engineered APC and demonstrate their use to stimulate T cells from allergic individuals.
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PMID:Creation of an engineered APC system to explore and optimize the presentation of immunodominant peptides of major allergens. 2753 32

Recombinant human soluble thrombomodulin (ART-123) is an anticoagulant and anti-inflammatory agent clinically used for treatment of disseminated intravascular coagulation. Preclinical studies have shown that ART-123 reduces hepatic ischemia/reperfusion. Although ART-123 may therefore have clinical benefit in orthotopic liver transplantation, the substantial alterations in the hemostatic system may complicate its use in this setting. Here, we studied the in vitro effect of ART-123 on coagulation of patients with end-stage liver disease undergoing liver transplantation. Ten patients with end-stage liver disease undergoing liver transplantation were included in this study. Plasma samples of 10 healthy individuals were included to establish reference values. Different concentrations of ART-123 were added to plasma samples, and peak thrombin generation and clot lysis times (CLTs) were determined. In patient samples, plasma was profoundly resistant to the anticoagulant action of ART-123, as reflected by significantly higher median inhibitory concentration (IC50 ) values of peak thrombin generation compared with controls. This might be partially explained by low levels of protein C, protein S, and elevated levels of factor VIII during transplantation. Intraoperative levels of thrombin activatable fibrinolysis inhibitor were significantly lower when compared with controls. However, ART-123-dependent prolongation of CLTs was not significantly different from healthy controls. In conclusion, this study suggests that ART-123 is unlikely to provoke bleeding in patients undergoing liver transplantation because proposed clinical dosages have a virtually absent anticoagulant effect in these patients. Clinical studies are required to confirm the safety of ART-123 and efficacy on alleviating ischemia/reperfusion injury during liver transplantation.
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PMID:Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin. 3006 6


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