Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Argatroban, a direct thrombin inhibitor, has been used in Japan since the early 1980's and was recently approved for use in the United States for patients with heparin-induced thrombocytopenia. However, its use has been studied in other clinical settings including, myocardial infarction, percutaneous coronary intervention and cerebral thrombosis. The doses used in the different clinical situations vary, but argatroban offers the advantage of not requiring renal adjustment. Because of its small molecular weight, argatroban has the ability to inhibit both clot bound and soluble thrombin. This paper provides a comprehensive review of both indicated and off label uses of argatroban. Pharmacology, pharmacokinetics, adverse events and drug interactions with argatroban are also discussed.
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PMID:A synopsis of the clinical uses of argatroban. 1172 65

Argatroban is a synthetic direct thrombin inhibitor which has been used in Japan for three indications, namely, chronic arterial occlusion, acute cerebral thrombosis and hemodialysis in AT-deficient patients or in patients with decreased AT. In patients with chronic arterial occlusion, argatroban increased the skin temperature, reduced the size of skin ulcers, and decreased the thrombin-antithrombin complex. In patients with acute cerebral thrombosis, neuronal symptoms improved significantly compared with the placebo group, wherein activated partial thromboplastin time (aPTT) was prolonged by about 1.5-fold and fibrinopeptide A was reduced. In some patients in whom hemodialysis is difficult due to the generation of blood clots in the dialyzer, hemodialysis is now possible with the replacement of heparin by argatroban.
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PMID:Development of argatroban as an anticoagulant and antithrombin agent in Japan. 1281 Oct 8

The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and nafamostat mesilate (1989) were developed in Japan and used for DIC and acute pancreatitis to inhibit protease enzymes. Argatroban is a unique antithrombin product developed by Japanese researchers in 1990, and is used for vascular or cerebral thrombosis. After noticing in 1968 that aspirin inhibits platelet aggregation and prevents myocardial infraction, projects for developing antiplatelet drugs were initiated worldwide. Ticlopidine, originally developed in France, was introduced in 1981 and prevailed widely in Japan for reducing the risk of thrombotic stroke. Aspirin itself was recognized by the FDA (USA) as an antithrombotic drug in 1988, and was also approved by Japanese authorities in 2000. PGE1 clathrate compounds have also been developed as antiplatelet drugs; alprostadil alfadex for injection (1979), and limaprost alfadex for oral use (1988). The PGI2 product, beraprost sodium, for oral use followed them in 1992. Other antiplatelet drugs with unique mechanisms explored in Japan: Ozagrel (1988), which inhibits TXA2 synthetase, cilostazol (1988), which inhibits cAMP phosphodiesterase, and sarpogrelate (1993), which blocks 5HT in platelets, are the notable drugs in this field. Ethyl icosapentate, from fish oil, is available for antiplatelet therapy. Concerning the fibrinolytic system, plasminogen activators are useful for thromboembolism. The streptokinase from bacterial origin developed in the USA and Europe was not introduced, and urokinase (1965) was the first plasminogen activator developed in Japan. Then tissue plasminogen activators (t-PA) tisokinase (cell culture, 1991), alteplase (genetical recombination, 1991), nateplase (genetical recombination, 1996), monteplase (1998) and pamiteplase (1998) were developed and approved for acute myocardial infarction. Nasaruplase (prourokinase, cell culture,1991) was also approved for the same indication. While the development of the hemostatic drugs ceased in the 1960s, avid project studies for antithrombotic drugs including fibrinolytics began in the 1980s and are progressing now towards new molecular targets. This may be due to the increasing tendency of cardiovascular thromboembolic diathesis in Japan. (The figures in parentheses are the years approved by the Japanese Ministry of Health, Labor and Welfare.)
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PMID:[A 50-year history of new drugs in Japan-the development and trends of hemostatics and antithrombotic drugs]. 1457 69

Coagulation factor (F)XI was first described as a member of the contact pathway of coagulation. However, the 'classic' theory of the extrinsic and intrinsic pathway has been revised and FXI was found to be activated by thrombin and to play a role in sustained thrombin generation and fibrinolysis inhibition. Recent studies have pointed to a disproportionate role of FXI in thrombosis and hemostasis. The observations that human congenital FXI deficiency is generally accompanied by mild and injury-related bleeding, and that experimental, provoked bleeding in animals is unaffected by FXI deficiency or FXI inhibition, suggest that the FXI amplification pathway is less important for normal hemostasis in vivo. In contrast, elevated plasma levels of FXI may contribute to human thromboembolic disease and the antithrombotic efficacy of FXI inhibition has been demonstrated in numerous animal models of arterial, venous and cerebral thrombosis. Whether severe FXI deficiency in humans protects against thromboembolic events remains unclear, although some evidence exists that the occurrence of ischemic stroke or venous thrombosis is low in severely FXI-deficient patients. Because of its distinctive function in thrombosis and hemostasis, FXI is an attractive target for the treatment and prevention of thromboembolism. A novel strategy for FXI inhibition is the use of antisense technology which has been studied in various thrombosis and bleeding animal models. The results are promising and support the concept that targeting FXI might serve as a new, effective and potentially safer alternative for the treatment of thromboembolic disease in humans.
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PMID:Coagulation factor XI as a novel target for antithrombotic treatment. 2072 68

To detect in vivo activated platelets in humans as well as in animal models of thrombosis, we developed a new murine monoclonal antibody, 2T60, specific for activated human and rabbit platelets by immunizing with human thronibin-activated platelets. 2T60 (IgG(1) subclass) showed a great difference between binding to the thrombin-activated and resting human and rabbit platelets on ELISA and flow cytometer analysis. Immunoblotting analysis revealed that 2T60 reacted with a 130 or 106 kDa protein of human or rabbit platelets, respectively, only under non-reducing conditions. (125)I-labeled 2T60 inserted into the intermediate gel of CIE of solubilized human platelets was incorporated into a immunoprecipitation line. 2T60 immunoprecipitated a protein of 130 or 115 kDa from human or rabbit platelets, respectively, which had been activated and (125)I-surface-labeled. The N-terminal sequence of the affinity purified 2T60 antigen of human platelets was identical to that of GMP 140. There were differences in the carbohydrate chain content of GMP 140 between human and rabbit platelets. In experimental cerebral thrombosis of rabbits that had been injected with 2T60, the platelets adhering to the exposed subendothelium and contained in thrombi were found to bind 2T60 prominently. These results suggest that 2T60 may be a useful tool for clinical and experimental studies of thrombotic disease.
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PMID:Detection of In Vivo Activated Platelets in Experimental Cerebral Thrombosis: Studies Using a New Monoclonal Antibody 2T60, Specific for Activated Human and Rabbit Platelets. 2104 51

Accumulating evidence within the last two decades indicates the association between cardiovascular disease (CVD) and chronic inflammatory state. Under normal conditions fibrin clots are gradually degraded by the fibrinolytic enzyme system, so no permanent insoluble deposits remain in the circulation. However, fibrinolytic therapy in coronary and cerebral thrombosis is ineffective unless it is installed within 3-5 hours of the onset. We have shown that trivalent iron (FeIII) initiates a hydroxyl radical-catalyzed conversion of fibrinogen into a fibrin-like polymer (parafibrin) that is remarkably resistant to the proteolytic dissolution and thus promotes its intravascular deposition. Here we suggest that the persistent presence of proteolysis-resistant fibrin clots causes chronic inflammation. We study the effects of certain amphiphilic substances on the iron- and thrombin-induced fibrinogen polymerization visualized using scanning electron microscopy. We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD. The only way to prevent iron overload is by supplementation with iron chelating agents. However, administration of free radical scavengers as effective protection against persistent presence of fibrin-like deposits should also be investigated to contribute to the prevention of cardiovascular and other degenerative diseases.
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PMID:Iron-induced fibrin in cardiovascular disease. 2372 Dec 62


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