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Thrombus Weight (thrombus + weight)
Selected AbstractsInhalable liposomes of low molecular weight heparin for the treatment of venous thromboembolismJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2010Shuhua Bai Abstract This study tests the feasibility of inhalable pegylated liposomal formulations of low molecular weight heparin (LMWH) for treatment of two clinical manifestations of vascular thromboembolism: deep vein thrombosis (DVT) and pulmonary embolism (PE). Conventional distearoyl- sn -glycero-3-phosphoethanolamine (DSPE) and long-circulating pegylated (DSPE,PEG-2000 and DSPE,PEG-5000) liposomes were prepared by hydration method. Formulations were evaluated for particle size, entrapment efficiency, stability, pulmonary absorption, anticoagulant, and thrombolytic effects in rats. Pulmonary absorption was monitored by measuring plasma antifactor Xa activity; anticoagulant and thrombolytic effects were studied by measuring reduction in thrombus weight and amount of dissolved radioactive clot in the blood, respectively. Pegylated liposomal were smaller and showed greater drug entrapment efficiency than conventional liposomes. All formulations produced an increase in pulmonary absorption and circulation time of LMWH upon first dosing. Three repeated dosings of conventional liposomes resulted in decreased half-life and bioavailability; no changes in these parameters were observed with pegylated liposomes. PEG-2000 liposomes were effective in reducing thrombus weight when administered every 48,h over 8 days. In terms of thrombolytic effects and dosing frequency, PEG-2000 liposomes administered via the pulmonary route at a dose of 100,U/kg were as effective as 50,U/kg LMWH administered subcutaneously. This paper suggests that inhalable pegylated liposomes of LMWH could be a potential noninvasive approach for DVT and PE treatment. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4554,4564, 2010 [source] Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studiesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2008P. C. WONG Summary.,Background:,Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Objective:,We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. Methods:,Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. Results:,In vitro, apixaban is potent and selective, with a Ki of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa Ki (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC2× (,m, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 ,m did not alter human and rabbit platelet aggregation to ADP, ,-thrombin, and collagen. In vivo, the values for antithrombotic ED50 (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED3× (dose that increased BT by 3-fold) were 0.27 ± 0.03, 0.11 ± 0.03, 0.07 ± 0.02 and > 3 mg kg,1 h,1 i.v. for apixaban, 0.05 ± 0.01, 0.05 ± 0.01, 0.27 ± 0.08 and > 3 mg kg,1 h,1 i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 ± 0.04, 0.27 ± 0.01, 0.08 ± 0.01 and 0.70 ± 0.07 mg kg,1 day,1 p.o. for the oral anticoagulant warfarin, respectively. Conclusions:,In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits. [source] Antithrombotic Effect of Enoxaparin in Clinically Healthy Cats: A Venous Stasis ModelJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2010C.M. Van De Wiele Background: Systemic arterial thromboembolic events are a serious complication of cardiac disease in cats. Objectives: To determine if enoxaparin induces an antithrombotic effect in cats at a dosage of 1 mg/kg SC q12h and if this antithrombotic effect is predicted by anti-Xa activity. Animals: Fourteen clinically healthy cats were divided into 3 groups: control (4 cats), treated and assessed at 4 hours (5 cats), and treated and assessed at 12 hours (5 cats). Methods: A venous stasis model was used and the extent of thrombus formation estimated by measuring thrombus weight and accretion of 125I-fibrinogen. Plasma anti-Xa activity was measured in treated cats. Results: There was a significant reduction in thrombus formation in the 4 h group compared with control (median weight, 0.000 versus 0.565 mg/mm, P < .01; median %125I-fibrinogen accretion, 0.0 versus 42.0%, P < .01). There was a reduction in thrombus formation in the 12 h group (median weight, 0.006 mg/mm, P= .09; median %125I-fibrinogen accretion, 3.83%, P= .09) but this reduction was not significant. The median percent thrombus inhibition for treated cats was 100.0% at 4 hours and 91.4% at 12 hours. Plasma anti-Xa activity was not significantly correlated with thrombus formation. Conclusions and Clinical Importance: This pilot study demonstrates that enoxaparin, when administered at a dosage of 1 mg/kg SC q12h, produces an antithrombotic effect in a venous statsis model in clinically healthy cats. Furthermore, this study demonstrates that anti-Xa activity is a poor predictor of enoxaparin's antithrombotic effect. [source] Pharmacological Profile and Therapeutic Potential of BM-573, a Combined Thromboxane Receptor Antagonist and Synthase InhibitorCARDIOVASCULAR THERAPEUTICS, Issue 1 2005Alexandre Ghuysen ABSTRACT BM-573 (N-terbutyl-N,-[2-(4,-methylphenylamino)-5-nitro-benzenesulfonyl]urea), a torsemide derivative, is a novel non-carboxylic dual TXA2 synthase inhibitor and receptor antagonist. The pharmacological profile of the drug is characterized by a higher affinity for the thromboxane receptor than that of SQ-29548, one of the most powerful antagonists described to date, by a complete prevention of human platelet aggregation induced by arachidonic acid at a lower dose than either torsemide or sulotroban, and by a significantly prolonged closure time measured by the platelet function analyser (PFA-100®). Moreover, at the concentrations of 1 and 10 ,M, BM-573 completely prevented production of TXB2 by human platelets activated by 0.6 mM of arachidonic acid. BM-573 prevents rat fundus contraction induced by U-46619 but not by prostacyclin or other prostaglandins. Despite possessing a chemical structure very similar to that of a diuretic torsemide, BM-573 has no diuretic activity. BM-573 does not prolong bleeding time and, unlike some of the other sulfonylureas, has no effect on blood glucose levels. In vivo, BM-573 appears to have antiplatelet and antithrombotic activities since it reduced thrombus weight and prolonged the time to abdominal aorta occlusion induced by ferric chloride. BM-573 also relaxed rat aorta and guinea pig trachea precontracted with U-46619. In pigs, BM-573 completely antagonized pulmonary hypertensive effects of U-46619 and reduced the early phase of pulmonary hypertension in models of endotoxic shock and pulmonary embolism. Finally, BM-573 protected pigs from myocardial infarction induced by coronary thrombosis. These results suggest that BM-573 should be viewed as a promising therapeutic agent in the treatment of pulmonary hypertension and syndromes associated with platelet activation. [source] | ||||||||||