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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of new peptidyl (alpha-aminoalkyl)phosphonate diphenyl esters containing the 4-amidinophenyl group were synthesized and tested as irreversible inhibitors for thrombin and other trypsin-like enzymes. These phosphonates irreversibly inhibited several coagulation enzymes and trypsin. Boc-D-Phe-Pro-(4-AmPhGly)P(OPh)2 is the best human thrombin inhibitor in the series with a k(obs)/[I] value of 11,000 M-1 s-1, and it inhibits thrombin more than 5-fold more effectively than the other enzymes tested. Z-(4-AmPhGly)P(OPh)2 is the best inhibitor for plasma kallikrein with a k(obs)/[I] value of 18,000 M-1 s-1. Generally, the (4-AmPhGly)P(OPh)2 derivatives are better inhibitors of thrombin and trypsin than the corresponding (4-AmPhe)P(OPh)2 derivatives which contain an extra CH2 separating the amidinophenyl group from the peptide backbone. The amidino phosphonates did not inhibit acetylcholinesterase and were chemically stable in neutral buffers. In addition, the inhibited trypsin derivative did not regain any enzyme activity after removal of excess inhibitor and incubation in a pH 7.5 buffer for 1 day. Boc-D-Phe-Pro-(4-AmPhGly)P(OPh)2 and D-Phe-Pro-(4-AmPhe)P(OPh)2 prolonged the prothrombin time ca. 2-fold and prolonged the activated partial thromboplastin time ca. 3-4-fold in human plasma at concentrations of 63 and 125 microM, respectively. The novel amidine-containing peptidyl phosphonates reported here are thus effective anticoagulants in vitro, and they may have utility for use in vivo.
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PMID:Novel amidine-containing peptidyl phosphonates as irreversible inhibitors for blood coagulation and related serine proteases. 829 9

Peptide boronic acid derivatives have proven to be very potent inhibitors of serine proteases with boroarginine derivatives being particularly potent thrombin inhibitors. The importance of the charged side chain of arginine has been investigated by synthesizing a derivative in which this side chain has been replaced by a neutral one. This boronic acid derivative, D-benzyloxycarbonyl (Z)-Phe-Pro-methoxypropylglycine-pinanediol (MpgC10H16), inhibited thrombin by a competitive mechanism with an inhibition constant (Ki) of 8.9 nM. In comparison to boroarginine derivatives, Z-D-Phe-Pro-boroMpgC10H16 displayed higher selectivity for thrombin over trypsin (Ki = 1.1 microM) and plasmin (Ki = 15.7 microM). Prolongation of thrombin time and activated partial thromboplastin time were observed with micromolar concentrations of Z-D-Phe-Pro-boroMpgC10H16. In a thrombin-dependent in vitro aggregation assay with human platelets, Z-D-Phe-Pro-boroMpgC10H16 inhibited aggregation with an IC50 of 85 nM. When tested in a thrombin-dependent platelet accumulation model in the rat, a bolus injection of (Z)-D-Phe-Pro-boroMpgC10H16 (0.3-3 mg/kg) inhibited platelet accumulation. Thus, the substitution of the charged guanidino group in the P1 side chain by the neutral methoxy group resulted in a potent and highly selective thrombin inhibitor with an interesting pharmacological profile with in vitro as well as in vivo models.
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PMID:In vitro and in vivo characterization of a neutral boron-containing thrombin inhibitor. 844 49

The mediators of photochemically induced thrombosis in the femoral artery of guinea pig were investigated. The femoral artery was occluded by a thrombus about 7 min after the initiation of photochemical reaction between rose bengal and green light. Pretreatment with a specific thromboxane (TX) A2 receptor antagonist, vapiprost, a platelet-activating factor (PAF) antagonist, WEB-2086, and ADP-induced platelet aggregation inhibitor, ticlopidine, prolonged the time to occlusion. Within the range of doses used, platelet aggregation in whole blood, which was induced by U-46619, PAF and ADP ex vivo, was inhibited by vapiprost, WEB-2086 and ticlopidine, respectively. In contrast, argatroban, a thrombin inhibitor, had no effect on the time to occlusion, although the dose of argatroban was sufficient to delay the prothrombin time and the activated partial thromboplastin time and to inhibit thrombin-induced platelet aggregation ex vivo. These results suggest that TXA2, PAF and ADP are involved in photochemically induced thrombosis of the guinea pig femoral artery, although the coagulation cascade does not play an important role.
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PMID:Roles of platelet-activating factor, thromboxane A2, ADP and thrombin in thrombogenesis in the guinea pig. 844 34

Hirulog (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095-101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers. In a randomized, placebo-controlled study (n = .54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 l kg-1 h-1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p < 0.001) and subcutaneous administration (r = 0.7, p = 0.002). To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide's activity. At the administered dose of 0.6 mg kg-1 h-1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. 845 28

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.
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PMID:Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease. 845 53

Recombinant desulfatohirudin (HI), a potent and specific thrombin inhibitor, was compared with heparin (HE) as an adjunct to streptokinase thrombolysis. In pentobarbital-anesthetized dogs, an occlusive thrombus (whole blood+thrombin) was introduced into the left anterior descending coronary artery (LAD) with superimposed endothelial damage and distal high-grade stenosis. Intravenous infusion of saline (vehicle), HI (0.3 mg/kg followed by 0.3 mg/kg per hour, 1 mg/kg followed by 1 mg/kg per hour, or 2 mg/kg followed by 2 mg/kg per hour), or HE (60 units/kg followed by 40 units/kg per hour or 100 units/kg followed by 60 units/kg per hour) was initiated 15 minutes before streptokinase (750,000 units for 60 minutes) administration. Vessel patency was monitored for 180 minutes after streptokinase administration with a volume flow probe on the proximal LAD. In dogs treated with no adjunctive agent (saline control), none of the vessels were recanalized with streptokinase. Both HI and HE promoted reperfusion, inhibited reocclusion, and reduced the residual thrombus mass in a dose-dependent fashion. However, at comparable levels of therapeutic anticoagulation (activated partial thromboplastin time [APTT] = 1.5-2.0 times baseline) HI exhibited a higher incidence of reperfusion (eight of eight dogs [100%] versus one of eight dogs [12%]), a shorter time to reperfusion (33 +/- 6 versus 59 minutes), a longer duration of initial reperfusion (106 +/- 21 versus 10 minutes), and a smaller residual thrombus mass than did HE. Likewise, the slope of the relation between the APTT prolongation and the total reperfusion time ("anticoagulation/antithrombosis profile") was almost five times higher for the combined HI data than for the HE data. Our results indicate that HI is more effective than HE in enhancing and sustaining coronary recanalization with streptokinase at a HI dose that modestly prolongs coagulation time and does not alter bleeding times.
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PMID:Comparison of hirudin and heparin as adjuncts to streptokinase thrombolysis in a canine model of coronary thrombosis. 847 21

Activation of the blood coagulation cascade results in the formation of factor Xa (FXa) in either its intrinsic or extrinsic pathways, which in turn converts prothrombin to thrombin. We recently described the synthesis and characterization of DX-9065a, a highly selective FXa inhibitor, as an orally active anticoagulant agent (1). Although DX-9065a potently inhibited human FXa (2), a much larger dosage was required to inhibit thrombus formation in a rat thrombosis model (3): The plasma concentration of DX-9065a after administration of a dose which reduced thrombus formation by 50% in rats was in the microM range, or 40 times higher than the Ki value for FXa. From this, several assumptions arise, namely that an unknown mechanism other than FXa inhibition contributes to the antithrombotic effect of DX-9065a, or that the efficacy of DX-9065a differs among species. However, as the anticoagulant effect of DX-9065a was closely consistent with anti-Xa activity in plasma and as DX-9065a inhibited only FXa activity (2), the former assumption could be disregarded. To clarify the latter, we examined the inhibitory effect of DX-9065a on FXa from several animal species and its anticoagulant effect ex vivo in these species. Further, we also compared the anticoagulant effect of DX-9065a in plasma from each species with that of NAPAP, a benzamidine-derived direct thrombin inhibitor (4).
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PMID:Species differences in anticoagulant and anti-Xa activity of DX-9065a, a highly selective factor Xa inhibitor. 857 44

Catalytically active thrombin, acting locally, is thought to mediate neointima formation after arterial injury. We constructed an adenovirus vector, AdHV-1.2, containing a complementary DNA for the thrombin inhibitor hirudin. AdHV-1.2 directed the synthesis and secretion of biologically active hirudin from vascular cells in vitro. In vivo gene transfer of hirudin into smooth muscle cells of injured rat carotid arteries resulted in peak secretion of at least 34+/-23 pg hirudin per vessel per 24 hours, and resulted in a significant (P<0.05) 35% reduction in neointima formation. Systemic partial thromboplastin times were not affected by local hirudin expression. These results support the hypothesis that local thrombin activity contributes to neointima formation after arterial injury and suggest that local delivery of a highly specific antithrombin may constitute an effective intervention for arterial proliferative disease.
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PMID:Local adenoviral-mediated expression of recombinant hirudin reduces neointima formation after arterial injury. 861 27

The mechanism by which intracerebral hemorrhage leads to the formation of brain edema is unknown. This study assesses the components of blood to determine if any are toxic to surrounding brain. Various solutions were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; brain edema and ion contents were measured. Whole blood caused an increase in brain water content and ion changes consistent with brain edema. Concentrated blood cells, serum from clotted blood, and plasma from unclotted blood all failed to provoke edema formation when infused directly into the brain. On the other hand, activation of the coagulation cascade by adding prothrombinase to plasma did produce brain edema. The edema response to whole blood could be prevented by adding a specific thrombin inhibitor, hirudin, to the injected blood. This study indicates that thrombin plays an important role in edema formation from an intracerebral blood clot.
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PMID:Edema from intracerebral hemorrhage: the role of thrombin. 861 42

Napsagatran, a new synthetic direct thrombin inhibitor, was compared with heparin in a canine model of coronary thrombosis and concomitantly in an ex vivo perfusion chamber model. Occlusive thrombosis of the left circumflex coronary artery was induced by electrical injury. In parallel, arterial subendothelium was exposed to native blood using an annular perfusion chamber for 5, 10 and 20 min at a wall shear rate of 650/s. Dogs received saline, heparin (40 and 70 U/kg/h) or napsagatran (3 and 10 microgram/kg/min). Heparin (40 U/kg/h) and napsagatran (3 microgram/kg/min) delayed or prevented in vivo thrombotic occlusion, but only napsagatran (10 microgram/kg/min) significantly decreased the intracoronary thrombus when compared with saline. High-dose heparin (70 U/kg/h) or napsagatran (10 microgram/kg/min) decreased the platelet-rich thrombus after a 20-min chamber perfusion. Neither heparin nor napsagatran decreased the thrombus volume after a 5-min perfusion. Heparin (70 U/kg/h) and napsagatran (10 microgram/kg/min) prolonged the activated partial thromboplastin time differently (>x6 and x1.4, respectively, P<0.01), whereas the activated clotting time was prolonged equally (x2.5). Thus napsagatran in this model shows arterial antithrombotic effects similar to those of heparin. The chamber experiments suggest that neither compound affects the initiation of platelet thrombus formation. In arterial thrombosis, the activated clotting time has a higher predictive value than the activated partial thromboplastin time when a direct thrombin inhibitor is compared with heparin.
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PMID:Effects of napsagatran (Ro 46-6240), a new synthetic thrombin inhibitor and of heparin in a canine model of coronary artery thrombosis: comparison with an ex vivo annular perfusion chamber model. 861 69


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