Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P13726 (thromboplastin)
 8,888 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antithrombotic and antiplatelet therapies are the cornerstones of management of cardiovascular disorders today. Due to the safety and efficacy limitations of the classic antithrombotic, unfractionated heparin, considerable effort has been directed at developing novel anticoagulants. Direct thrombin inhibitors as a class of drugs offer inhibition of clot-bound as well as fluid-phase thrombin and a more predictable anticoagulant response. Specifically, argatroban, a synthetic small molecule direct thrombin inhibitor, selectively inhibits the catalytic site of thrombin in a reversible manner. Overall, argatroban's short half-life, ease of monitoring with an activated partial thromboplastin time, and safety in renal failure patients make this drug the preferable mode therapy for prevention of thrombosis in heparin-induced thrombocytopenia. The role of adjunctive argatroban therapy in acute coronary syndromes and during percutaneous coronary intervention is currently being studied.
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PMID:Argatroban. 1199 59

Because patients with heparin-induced thrombocytopenia (HIT) have an extremely high frequency of developing thrombosis, treatment options other than heparin are essential. Prophylaxis against thrombosis should also be considered. The current American College of Chest Physicians guidelines for the treatment of acute heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) include the use of danaparoid, lepirudin or argatroban, alone or in combination with warfarin. For documented clinical thrombosis associated with HIT, patients should be treated with a direct thrombin inhibitor at therapeutic activated partial thromboplastin time for 7 to 10 days. Warfarin should not be used during the acute phase of HIT, unless a thrombin inhibitor is being used simultaneously. Conversion to warfarin can be done when the acute phase of HIT has passed. Due to the high likelihood of cross-reactivity, the use of low molecular weight heparins in patients with HIT is not recommended. For prophylactic treatment of HIT patients, despite a lack of other indications for anticoagulation, a direct thrombin inhibitor can be initiated with a low level of anticoagulation until the thrombocytopenia resolves. This regimen is continued until laboratory evidence is provided that the HIT antibody is no longer detectable. HIT patients, in addition to needing anticoagulation to treat thrombosis, can require anticoagulation for non HIT-related events, such as for the treatment of myocardial infarction, unstable angina and long-term anticoagulation for heart valves or atrial fibrillation. For these situations, and if immediate anticoagulation is needed, the use of a direct thrombin inhibitor with switch-over to warfarin is a useful option. However, optimal dosing regimens have not been established in all cases.
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PMID:Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia. 1221 10

Argatroban is a peptidomimimetic synthetic direct thrombin inhibitor with reversible and specific properties resulting in predictable anticoagulant effects. Usually, argatroban therapy is monitored by the activated dotting time (ACT) or activated partial thromboplastin time (aPTT). While other global dotting tests for the monitoring of anticoagulants are useful, their applicability to antithrombin agents (particularly of argatroban at higher dosages) is rather questionable. In this study, we sought to compare the argatroban anticoagulant levels in patients undergoing percutaneous transluminal angioplasty (PTCA) and stenting procedures, utilizing both functional and absolute quantitation methods. Argatroban produced a comparable increase of ACT and HMT, 5 to 10 minutes after administration. The level of anticoagulation achieved (400-450 seconds with ACT and HMT) following a slow bolus of argatroban (350 microg/kg) was maintained throughout the procedure using 25 microg/kg/min infusion. Following discontinuation of argatroban at the end of the procedure, the ACTs and HMTs showed a comparable progressive reduction in the anticoagulant response, which reflected the elimination of argatroban 2 to 3 hours after the procedure. No significant differences between the three methods (Hemotec, Hemochron, and HMT) were noted at any given sampling time. Argatroban dosage at 350 microg/kg intravenous slow bolus followed by 25 microg/kg/min infusion was adequate to perform PTCA and stenting procedures. There was no incidence of bleeding complications. Absolute quantitation of argatroban levels in patient plasmas by a newly developed HPLC method was found to be quite comparable with the ecarin dotting time (ECT) results. The ECT system was found to be less sensitive when compared to other tests, and therefore, could be used as a point-of-care test during the PTCA/stenting procedures to monitor argatroban.
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PMID:Monitoring of argatroban in ARG310 study: potential recommendations for its use in interventional cardiology. 1236 Nov 98

Recombinant hirudins (r-hirudins) are potent direct thrombin inhibitors increasingly used for alternative anticoagulation, especially in heparin-induced thrombocytopenia. R-hirudins are almost exclusively eliminated by the kidneys, and a close correlation between r-hirudin clearance and endogenous creatinine clearance has been observed. Accordingly, the pharmacokinetics of r-hirudin are altered in patients with renal insufficiency. A decline of renal r-hirudin clearance is associated with an increase of r-hirudin half-life and the area under the curve (AUC). Therefore, renal impairment necessitates reduction of r-hirudin dose to avoid overdose or inadequate accumulation of the thrombin inhibitor. To this end, close monitoring of r-hirudin anticoagulation is required, which at best is performed by measuring r-hirudin blood levels by ecarin clotting times (ECT) or chromogenic assays, in addition to activated partial thromboplastin time (aPTT). Recent studies showed that r-hirudin anticoagulation is feasible in acute or chronic renal failure treated with continuous or intermittent renal replacement therapy, if appropriate r-hirudin dosing and adequate monitoring are warranted. High-volume hemofiltration with r-hirudin-permeable hemodialyzers constitutes a valuable means to markedly reduce r-hirudin blood concentration and total r-hirudin body content in case of r-hirudin overdose or r-hirudin-associated bleeding. In the future, the hepatically eliminated direct thrombin inhibitor argatroban may facilitate alternative anticoagulation in patients with renal insufficiency.
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PMID:Hirudin in renal insufficiency. 1242 Feb 43

DPC423 [1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of coagulation factor Xa (fXa) (K(i): 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of DPC423, enoxaparin (low-molecular-weight heparin), and argatroban (thrombin inhibitor) on arterial thrombosis and hemostasis in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED(50) values were 0.4 mg/kg/h for enoxaparin (n = 6), 0.13 mg/kg/h for argatroban (n = 6), and 0.6 mg/kg/h for DPC423 (n = 12). DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 +/- 12 for argatroban, 69 +/- 13 for heparin, 4 +/- 3 for enoxaparin, 5 +/- 4 for DPC423, and -3 +/- 2 for the vehicle (n = 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for DPC423 and enoxaparin. The combination of aspirin and DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis.
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PMID:Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits. 1243 19

SSR182289A competitively inhibits human thrombin (K(i) = 0.031 +/- 0.002 microM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K(i) = 54 +/- 2 microM), factor Xa (K(i) = 167 +/- 9 microM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K(i) values >250 microM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC100 thrombin time 96 +/- 7 nM) and inhibited tissue factor-induced thrombin generation (IC50 of 0.15 +/- 0.02 microM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC50 value of 32 +/- 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 +/- 356%; ecarin clotting time (ECT), 1134 +/- 204%; and activated partial thromboplastin time (aPTT), 91 +/- 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 +/- 425%; ECT, 2017 +/- 341%; and aPTT, 113 +/- 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.
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PMID:SSR182289A, a novel, orally active thrombin inhibitor: in vitro profile and ex vivo anticoagulant activity. 1243 43

N-[3-[[[(1S)-4-(5-Amino-2-pyridinyl)-1-[[4-difluoromethylene)-1-piperidinyl]carbonyl]butyl]amino]sulfonyl][1,1'-biphenyl]-2-yl]acetamide hydrochloride (SSR182289A) is a novel, potent, and selective thrombin inhibitor. We have examined the antithrombotic properties of SSR182289A administered by i.v. and p.o. routes in several different animal thrombosis models in comparison with reference antithrombotic agents. Oral administration of SSR182289A produced dose-related antithrombotic effects in the following models; rat venous thrombosis (ED(50) 0.9 mg/kg p.o.), rat silk thread arterio-venous (AV) shunt (ED(50) 3.8 mg/kg p.o.), rat thromboplastin-induced AV shunt (ED(50) 3.1 mg/kg p.o.), rat carotid artery thrombosis (ED(200) 5.9 mg/kg p.o.), and rabbit venous thrombosis (ED(50) 7.5 mg/kg p.o.). Administered as an i.v. bolus, SSR182289A showed antithrombotic activity in the above models with ED(50)/ED(200) values in the range of 0.2 to 1.9 mg/kg i.v. SSR182289A increased rat tail transection bleeding time at doses > or =10 mg/kg p.o. In the rat thromboplastin-induced AV shunt model, SSR182289A 10 mg/kg p.o. produced marked antithrombotic effects at 30, 60, 120, and 240 min after administration. Hence, SSR182289A demonstrates potent oral antithrombotic properties in animal venous, AV-shunt, and arterial thrombosis models.
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PMID:Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor. 1253 8

Ecarin clotting time and activated partial thromboplastin time are coagulation tests that meet the definition of a biomarker. Prolongation of these coagulation times closely correlated with blood concentrations of the oral thrombin inhibitor LB-30057 (CI-1028) during a phase 1 study. But this simply reflects their functioning as enzyme inhibition assays of drug concentration. Directly adding the drug to blood results in the same concentration-response relationship. Changes in coagulation tests only demonstrate that ex vivo clot formation has been altered, not that an in vivo process has been affected. To be most informative in drug development, biomarker assays should measure in vivo drug effects, not drug concentrations.
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PMID:Are coagulation times biomarkers? Data from a phase I study of the oral thrombin inhibitor LB-30057 (CI-1028). 1261 62

Argatroban is a small molecule direct thrombin inhibitor. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, absence of antibody formation and no need for initial dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT); and it is approved in Japan and Korea for treatment of various thrombotic disorders. Argatroban has been shown in limited trials to provide reliable anticoagulation during percutaneous coronary interventions on HIT and non-HIT patients. Preliminary reports document the feasibility of using argatroban for anticoagulation during peripheral vascular interventions, hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the activated partial thromboplastin time for low doses and the activated clotting time for high doses. The ease of monitoring argatroban, its 'turn-on/turn-off' characteristic and its consistent safety profile provide the rationale to continue studies of argatroban as an anticoagulant in clinical settings.
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PMID:An overview of the direct thrombin inhibitor argatroban. 1281 Oct 6

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


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