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)

Pharmacological profiling of recombinant hirudin (r-hirudin) has shown that this selective tight-binding thrombin inhibitor is a potent, well-tolerated anticoagulant. Clinical pharmacological studies were performed in human volunteers after single and repeated doses of 0.1-0.5 mg/kg. Generally, administration of r-hirudin was tolerated without side effects. Thrombin time and partial thromboplastin time were prolonged dependent on the r-hirudin level in plasma. Platelet counts, fibrinogen level and fibrinolytic system remained unchanged. Bleeding time was not prolonged. On intravenous injection, r-hirudin was rapidly distributed into the extracellular space and eliminated, with a dose-dependent half-life of 1-2 h (first-order kinetics). After subcutaneous administration, the rH level in blood reached plateau values within 60-120 min. The high recovery of unchanged r-hirudin in the urine identified renal excretion as the predominant route of r-hirudin clearance.
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PMID:Clinical pharmacology of recombinant hirudin. 189 88

Several laboratory methods are available to measure the anticoagulant activity of recombinant hirudin (r-hirudin), a potent thrombin inhibitor. These assays include clot-based, amidolytic, immunologic and physicochemical techniques. Although r-hirudin, like heparin, is an effective anticoagulant, the mechanism of action of the two agents is different. Thus it is not surprising that the global tests, such as the prothrombin time (PT), partial thromboplastin time (APTT) and the Heptest (Haemachem, Inc., St. Louis, Mo., USA), do not show adequate responses to r-hirudin. In the range of 0.5-10.0 microgram/ml, where full anticoagulation is achieved, as determined by animal models of thrombosis, these assays show little to no prolongation of the time to clot. In order to find a more suitable assay system, modifications of the above assays were evaluated. The diluted APTT and diluted Heptest showed linear concentration-dependent responses to lower levels of r-hirudin with an enhanced sensitivity than that of the classical assays. On the other hand, the diluted thrombin time was too sensitive. Whole-blood clotting assays, ACT and thrombelastograph, effectively measured r-hirudin levels up to 25 micrograms/ml. The amidolytic anti-factor IIa assay, specific for evaluating direct thrombin inhibition, was very effective particularly when modified to decrease the sample:thrombin ratio. This assay may be useful in quality control since it is biochemically defined, and reagents are easily standardized. The relevance of the results of the anti-IIa assay to clinical conditions, however, remains to be determined. Thrombin generation assays have limited value in monitoring the anticoagulant effect of r-hirudin since the effect of thrombin inhibition by r-hirudin on coagulation feedback mechanisms, and thus the effect on thrombin generation, appears to be minimal. Immunologic methods such as ELISA and RIA are under development, but they may only be useful for the direct quantitation of absolute levels of r-hirudin and not for monitoring the clinical anticoagulant action. Furthermore, these assays are only sensitive to sub-microgram/ml levels. Therefore, thrombin-based clotting and amidolytic assays may at present be the best choice for evaluating the functional, clinical antithrombotic effects of r-hirudin.
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PMID:Laboratory assays for the evaluation of recombinant hirudin. 130 Oct 38

We investigated the properties of an artificial chimeric peptide that contains an Arg-Gly-Asp (RGD)-tripeptide, the versatile cell recognition signal of extracellular matrix protein components, coupled to a carboxyl-terminal fragment of the highly specific alpha-thrombin inhibitor, hirudin (residues 53-64): WGRGDSANGDFEEIPEEYL (RGD-hirudin53-64). Hirudin53-64 and RGD-hirudin53-64 inhibited the fibrinogen clotting activity of alpha-thrombin and prolonged the activated partial thromboplastin time of human plasma. In addition, both peptides afforded total protection to thrombin from trypsionolysis. Neither hirudin53-64 nor RGD-hirudin53-64 dramatically interfered with the thrombin-antithrombin inhibition reaction either in the absence or presence of added heparin. alpha-Thrombin-induced platelet aggregation was effectively inhibited by hirudin53-64 and RGD-hirudin53-64. Unlike hirudin53-64, RGD-hirudin53-64 in solution inhibited integrin-mediated endothelial cell and fibroblast cell attachment to polystyrene wells in the presence of fetal bovine serum. Collectively, our results demonstrate that RGD-hirudin53-64 has anticoagulant/antiplatelet aggregation activity attributable to its hirudin sequence and integrin-directed cell attachment activity due to its RGD site. Our results suggest that this chimeric motif may serve as a prototype for a new class of anticoagulants where an integrin-specific sequence "targets" the peptide to a cell (ultimately through the platelet integrin alpha IIb beta 3) trapped amid a thrombus with ensuing proteinase inhibition.
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PMID:Chimeric antithrombin peptide. Characterization of an Arg-Gly-Asp (RGD)- and hirudin carboxyl terminus-containing synthetic peptides. 205 Jun 91

The effect of heparin and of the synthetic competitive thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (argatroban) on platelet-rich arterial thrombosis was studied in a rabbit model, consisting of a 4-6-mm everted ("inside-out") femoral arterial segment. Intravenous injection of heparin (200 units/kg) failed to prevent occlusion within 60 minutes in all 10 rabbits, whereas intravenous argatroban infusion at a rate of 100 or 200 micrograms/kg/min for 60 minutes, which prolonged the thrombin time more than fourfold, prevented thrombosis in nine of 13 rabbits (p = 0.002 vs. i.v. heparin). Intra-arterial infusion of 200 units/kg heparin over 60 minutes prevented occlusion in six of nine rabbits (p = 0.003 vs. i.v. heparin), whereas intra-arterial argatroban at a rate of 100 micrograms/kg/min for 60 minutes prevented thrombosis in all 10 rabbits (p = 0.00001 vs. i.v. heparin). Patency of femoral arterial segments was maintained after the end of the intra-arterial heparin and intravenous or intra-arterial argatroban infusion for up to 3 hours despite normalization of the thrombin time and partial thromboplastin time. Pathologic examination of the graft revealed that the inverted adventitial surface was covered by layers of platelets without platelet aggregation or fibrin deposition. These findings indicate that thrombin plays an important role in platelet-rich arterial thrombosis, and that the thrombogenic stimulus is rapidly attenuated by short-term infusion of the synthetic thrombin inhibitor. Selective thrombin inhibition can constitute an alternative approach to the prevention of arterial occlusion after angioplasty or thrombolytic therapy in patients with unstable coronary syndromes.
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PMID:Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition. 229 28

Three p-amidinophenyl esters have been synthesized and characterized as irreversible inhibitors of the vitamin-K dependent proteinases; factors IXa, Xa and thrombin (Turner et al. [4]).+ In the present report we describe the in vitro and in vivo effects of these agents on standard coagulation tests in vitro and in blood from animals treated with the compounds. At a concentration of 500 microM, the three esters increased the activated partial thromboplastin time (PTT) of pooled human plasma 3 to 5-fold. The prothrombin time increased 1.4 to 3.7-fold under similar conditions. The p-amidinophenyl ester of cinnamic acid (CINN) showed the most pronounced effect on both assays. This ester also is the best inhibitor of human factors IXa and Xa, while the p-amidinophenyl ester of benzoic acid (BENZ) is a slightly better alpha-thrombin inhibitor (4). The effect of these esters on the thrombin clotting time correlated with in vitro kinetic measurements of alpha-thrombin inhibition rates. Both BENZ and CINN increased the assay endpoint more than 6-fold. The three esters also were studied using mouse plasma. A comparable effect on the PTT was noted. Intravenous administration of 300 microliter of 1 mM CINN as a single bolus in mice caused a 2.3-fold increase in the PTT which remained 1.2-fold normal 2 h later. The BENZ and alpha-methyl-cinnamic acid (MECINN) esters were somewhat less effective as predicted from their in vitro effect on the PTT. This investigation and previous studies indicate that these compounds demonstrate low toxicity at therapeutic levels. It is concluded that the p-amidinophenyl esters may be useful in antithrombotic therapy.
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PMID:Evaluation of p-amidinophenyl esters as potential antithrombotic agents. 243 36

Amounts of human brain thromboplastin that do not stimulate thrombin generation in platelet poor plasma, were shown to advance by about 4 min an explosive formation of thrombin that occurs after recalcification in the presence of blood platelets. This synergistic effect is inhibited by the specific thrombin inhibitor hirudin and mimicked by adding low concentrations (less than 5 nM) of thrombin to platelet rich plasma. It is our conclusion that small amounts of thrombin, generated under the influence of thromboplastin induced procoagulant activity in the blood platelets. This activity is most likely mainly due to procoagulant phospholipids. Heparin inhibits this effect and retards the explosive thrombin formation. It does not, however, diminish the peak amount of thrombin eventually formed, because heparin neutralizing material released from the activated platelets quenches the heparin effect.
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PMID:The effect of trace amounts of tissue factor on thrombin generation in platelet rich plasma, its inhibition by heparin. 274 91

The effects of the newly available biotechnology product, recombinant desulphatohirudin (CGP 39393) have been investigated in rats. This highly potent and selective thrombin inhibitor exhibited marked anticoagulant properties with controllable titration of anticoagulant effect, as measured by activated partial thromboplastin time (APTT), up to nearly four times control values. Furthermore, CGP 39393 exhibited impressive antithrombotic activity in vivo. In an arteriovenous shunt model of thrombus formation on a cotton-thread, the compound was capable of complete inhibition of thrombus development (ED50 = 0.3 mg/kg i.v. and 1.0 mg/kg s.c.). Venous stasis thrombosis was also highly susceptible to inhibition by CGP 39393 (ED50 = 0.01 mg/kg i.v. and 0.45 mg/kg s.c.). Comparison of the anticoagulant and antithrombotic activities of the compound shows that potent antithrombotic effects (83-97% inhibition in the rat shunt model) are achieved within the generally acceptable range of anticoagulation. These results suggest a clear potential for this new agent in the clinical treatment of thrombotic disease.
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PMID:Recombinant desulphatohirudin (CGP 39393) anticoagulant and antithrombotic properties in vivo. 274 92

Blood from adult male Wistar rats clotted rapidly in glass or siliconized tubes; the clots retracted and did not lyse. The serum prothrombin, plasma prothrombin and activated partial thromboplastin times were shorter than those of normal humans. In contrast, the thrombin and reptilase times were longer than those of normal human plasma, due apparently to the presence of a low-grade thrombin inhibitor in rat plasma. Coagulation factors, X, VIIIR:vW and IX assayed lower in rat than human plasma, while factors VIII:C and anti-thrombin III were higher. Values for other coagulation factors (II, V, VII, XI, XII and Fletcher) fell within the human range. Platelets were small and numerous. They aggregated well with ADP but poorly or not at all with collagen, ristocetin, thrombin, epinephrine, arachidonic acid and pig or bovine plasmas. Leukocytes numbered 4-8 X 10(3) cells/mm3, a near human range and were predominantly lymphocytic. Erythrocytes were small (MCV = 56-60 fl) and numerous (5.5-6.4 X 10(6) cells/mm3).
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PMID:Comparative hematology and coagulation: studies on rodentia (rats). 286 3

We examined the effect of a synthetic thrombin inhibitor, MCI-9038, on two experimental animal models of disseminated intravascular coagulation (DIC). In a model that DIC induced by the intravenous infusion of thrombin, MCI-9038 suppressed the decrease of platelet count by about 50% at a dose of 0.2 micrograms/kg/min and almost completely at 2 micrograms/kg/min. When MCI-9038 was administered orally, the suppressive effect was also observed. Heparin suppressed the platelet count decrease by about 50% at 1 unit/kg/min. In another model of DIC induced by lactic acid and tissue thromboplastin infusion, MCI-9038 prevented the decrease of platelet count and the consumption of coagulation factors. The suppression effect by about 50% on these changes was observed at a dose of 3.16 micrograms/kg/min. Thromboelastogram pattern indicating the consumption coagulopathy in control experiments was normalized by the MCI-9038 administration. Heparin suppressed the decrease of fibrinogen content as effectively as MCI-9038, but it was less effective on the platelet count decrease. From these results, it was concluded that MCI-9038 might be useful for the treatment of DIC.
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PMID:Effect of a synthetic thrombin inhibitor MCI-9038 on experimental models of disseminated intravascular coagulation in rabbits. 360 10

This study reports on the anticoagulant, antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor (SDTI) in comparison with standard heparin (SH). The anticoagulant effect was determined with the thrombin clotting time (TCT) and the activated partial thromboplastin time (APTT). SDTI was more potent than SH in prolonging the TCT, but as potent as SH in prolonging the APTT. The antithrombotic effect was determined using a modified Wessler model in the rabbit, either 30 min after a continuous IV infusion of increasing doses or at various times after a single SC injection (20 mg/kg). After continuous IV infusion of 187 micrograms/kg/h of SDTI and of 60 micrograms/kg/h of SH, significant thrombus prevention effects were obtained (59 and 57% respectively). Increasing the dose of SDTI up to 3000 micrograms/kg/h did not significantly improve the antithrombotic effect. After SC injection, a significant antithrombotic effect was observed for 12 h with SDTI but for more than 24 h with SH. The bleeding effect was studied using the rabbit ear model 15 min after a continuous infusion of 7.5 and 15 mg/kg/h: the amounts of blood loss were dose-dependent and comparable for SDTI and SH. These studies also indicated that SDTI possesses a considerable shorter half-life in comparison with SH. Accordingly, the ex vivo concentrations generated after continuous IV infusion or SC injection of the same dose were higher for SH than for the SDTI.
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PMID:Antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor and of standard heparin in the rabbit. 367 29


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