Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo antithrombotic activity of RPR 20844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p<0.05 vs. saline-treated animals) by RPR120844 at 30 and 100 microg/kg/min. At doses of 10, 30 and 100 microg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8+/-0.3, 1.5+/-0.9 and 2.4+/-0.6 microM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR 120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.
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PMID:RPR120844, a novel, specific inhibitor of coagulation factor Xa inhibits venous thrombosis in the rabbit. 1034 9

These studies were designed to examine the pharmacodynamic profile and antithrombotic efficacy of RPR120844, a competitive inhibitor of coagulation factor Xa, with a K(i) of 7 nM against human factor Xa. In vitro, RPR120844 doubled activated partial thromboplastin time (APTT) at concentrations of 1.54, 1.48, and 0.74 microM in plasma obtained from humans, dogs, and rats, respectively. Intravenous bolus administration of RPR 120844 at 0.3, 1, and 3 mg/kg to rats resulted in maximal increases in APTT of 1.8-, 2.6-, and 8.4-fold over baseline, respectively. The effect on prothrombin time (PT) was less pronounced, resulting in a 4.4-fold increase at 3 mg/kg. These effects were rapidly reversible; APTT and PT returned to control values by 30 min after dosing. Intragastric administration to rats at 50, 100, and 200 mg/kg resulted in modest increases in APTT and PT of 1.5- and 1.3-fold over baseline at the highest dose. Plasma levels were estimated by anti-Xa activity by using an amidolytic, chromogenic assay. Plasma levels were 0.65, 1.29, and 2.45 microM at 30 min after dosing at 50, 100, and 200 mg/kg, respectively. Intravenous administration to dogs at 0.1 and 0.3 mg/kg produced maximal increases in APTT of 1.7- and 2.4-fold over baseline, respectively. Intragastric administration to dogs at 50 mg/kg resulted in maximal increases in APTT and PT of 1.7- and 1.1-fold over baseline, with peak plasma levels of 3.9 microM observed at 15 min after dosing. In a rat model of FeCl2-induced carotid artery thrombosis, RPR120844 (3 mg/kg, i.v. bolus + 300 microg/kg/min constant infusion; n = 4) significantly increased time-to-occlusion from 18+/-1 min (vehicle, n = 4) to 60 min (maximal observation time) and reduced thrombus mass from 5.5 +/- 0.2 mg (vehicle) to 1.4 +/- 0.2 mg. These results indicate that RPR120844 is a potent, selective inhibitor of Xa that exhibits oral activity and is efficacious in a standard model of arterial thrombosis.
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PMID:Pharmacodynamic activity and antithrombotic efficacy of RPR120844, a novel inhibitor of coagulation factor Xa. 1059 21

RPR 130737 inhibited factor Xa (FXa) with a Ki of 2.4 nM and also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C, plasmin, tissue-plasminogen activator and trypsin. RPR 130737 prolonged plasma activated partial thromboplastin time and prothrombin time in a dose-dependent fashion. In the activated partial thromboplastin time assay, the concentrations required for doubling coagulation time were 0.32 microM (human), 0.61 microM (monkey), 0.44 microM (dog), 0.15 microM (rabbit), and 0.82 microM (rat). The concentrations required to double prothrombin time were 0.86 microM (human), and 1.26 microM (monkey), 1.15 microM (dog), 0.39 microM (rabbit) and 7.31 microM (rat). Kinetic studies revealed that RPR 130737 was a fast binding, reversible and competitive inhibitor for FXa when Spectrozyme FXa, a chromogenic substrate, was used. A coupled-enzyme assay measuring thrombin activity following prothrombinase conversion of prothrombin to thrombin indicated that RPR 130737 was a potent inhibitor for prothrombinase-bound FXa. In this assay, RPR 130737 showed IC50s of 17 nM and 35.9 nM, respectively when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or gel-filtered platelets were used as the phospholipid source. An FX-deficient plasma clotting-time correction assay further demonstrated that RPR 130737 was a specific inhibitor of FXa. RPR 130737 showed no effect on platelet aggregation in vitro. These results indicate that RPR 130737 has the potential to be developed as an antithrombotic agent based on its potent and selective inhibitory effect against FXa.
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PMID:In vitro characterization of a novel factor Xa inhibitor, RPR 130737. 1101 77

A 39-year-old white woman presented with a history of aortoiliac occlusive disease diagnosed in 1992 attributed to oral contraceptive use. Shortly thereafter, aortoiliac replacement was performed. Mild hyperlipidemia was diagnosed in 2001. At the current clinic visit, she presented to her primary care physician with a 3-month history of postprandial midepigastric abdominal pain relieved by vomiting and a 30-pound weight loss. Her evaluation included an esophagogastroduodenoscopy, a colonoscopy, and an abdominal ultrasound, all of which were within normal limits. Because of her medical history, the patient underwent an arteriogram, which revealed brachiocephalic stenosis (Figure 1), occlusion of the left subclavian artery (Figures 2a and 2b), and narrowing of the superior and inferior mesenteric arteries (not shown). Since she had discontinued her oral contraceptives in 1992 and her hyperlipidemia was mild, the rheumatology service was consulted to evaluate this patient. On physical examination, she had decreased left brachial and radial pulses and a right carotid bruit. Laboratory evaluation revealed a normal complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, and C - reactive protein. Subsequent testing included a prothrombin time, activated partial thromboplastin time, protein S, protein C, reptilase time, antithrombin III, anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, homocysteine, RPR, and a lipid profile. All test results were within normal limits. Due to the severity of her abdominal pain, the patient underwent superior mesenteric artery (SMA) bypass surgery. Sections from the aorta resected in 1992 are shown in Figures 3 and 4.
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PMID:Pathology case of the month. 39-year-old woman with abdominal pain and weight loss. Takayasu's arteritis (TA). 1555 91