Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034065 (pulmonary embolism)
 14,979 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Betrixaban is an oral direct inhibitor of factor Xa (FXa) being developed for the prevention of venous thromboembolism (VTE). Its antithrombotic effects had not been previously tested in patients. This exploratory clinical trial in the US and Canada randomized 215 patients undergoing elective total knee replacement (TKR) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o. bid or enoxaparin 30 mg s.c. q12h, respectively, for 10-14 days. The betrixaban dosage was blinded, but enoxaparin was not. Primary efficacy outcome was the incidence of VTE, consisting of deep-vein thrombosis (DVT) on mandatory unilateral (operated leg) venography, symptomatic proximal DVT, or pulmonary embolism (PE) through Day 10-14. Safety outcomes included major and clinically significant non-major bleeds through 48 h after treatment. All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee. Of 214 treated patients, 175 (82%) were evaluable for primary efficacy. VTE incidence was 14/70 (20%; 95% CI: 11, 31) for betrixaban 15 mg, 10/65 (15%; 95% CI: 8, 27) for betrixaban 40 mg, and 4/40 (10%; 95% CI: 3, 24) for enoxaparin. No bleeds were reported for betrixaban 15 mg, 2 (2.4%) clinically significant non-major bleeds with betrixaban 40 mg, and one (2.3%) major and two (4.6%) clinically significant non-major bleeds with enoxaparin. A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed. Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied.
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PMID:A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). 1913 91

Thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke often result in long-term disability and/or mortality. The anticoagulants currently available have been effective in the treatment and prevention of these disorders; however, parenteral administration, variable pharmacokinetics and pharmacodynamics, drug and dietary interactions, and a requirement for frequent monitoring of efficacy and safety limit use of these drugs. Rivaroxaban is a novel, oral factor Xa inhibitor in clinical development for the treatment and prevention of thromboembolic diseases. Rivaroxaban is a small molecule directed at active sites, and the agent mechanistically differs from traditional anticoagulants, such as heparins and fondaparinux, in that its activity is independent of antithrombin and its ability to inhibit prothrombinase bound factor Xa. In addition, preclinical and clinical trial data indicate that rivaroxaban has predictable pharmacokinetics and pharmacodynamics, which are features that differentiate it from oral vitamin K antagonists. Phase II studies showed that rivaroxaban is safe and well tolerated across a wide range of doses. Furthermore, completed phase III studies demonstrated its efficacy in the prevention of venous thromboembolism after orthopedic surgery. Additional studies are now under way to evaluate the use of rivaroxaban in the treatment and prevention of other venous and arterial thromboembolic conditions.
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PMID:Rivaroxaban: a novel, oral, direct factor Xa inhibitor. 1917 May 87

Plactin, a family of cyclopentapeptides, enhances fibrinolytic activity by elevating the activity of cellular urokinase-type plasminogen activator (u-PA), a protease involved in a variety of extracellular proteolytic events. Factor(s) in the blood plasma is an absolute requirement for this plactin activity. In this study, we found that plactin promoted plasma cofactor-dependent conversion of inactive single-chain u-PA to active two-chain u-PA on U937 cells. Using plactin-affinity chromatography, we identified prothrombin as one of the plasma cofactors. In incubations of U937 cells with prothrombin and Xa, plactin increased the formation of thrombin, which cleaved single-chain u-PA to afford the inactive two-chain form. Thrombin-cleaved two-chain u-PA was alternatively activated by cellular cystatin-sensitive peptidase activity, yielding fully active two-chain u-PA. In a purified system, plactin bound to prothrombin, altered its conformation and dually modulated factor Xa-mediated proteolytic activation of prothrombin to alpha-thrombin. Plactin inhibited the activation catalyzed by Xa in complex with Va, Ca(2+) and phospholipids (prothrombinase), whereas the activations catalyzed by nonmembrane-associated Xa were enhanced markedly by plactin. Plactin inhibited in vitro plasma coagulation, which involved prothrombinase formation. Plactin did not cause prothrombin activation or thrombosis in normal mice at doses that produced a protective effect in a thrombin-induced pulmonary embolism mouse model. Therefore, the dual modulation of prothrombin activation by plactin may be interpreted as leading to anticoagulation under physiological coagulating conditions.
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PMID:Dual modulation of prothrombin activation by the cyclopentapeptide plactin. 1947 92

Rivaroxaban is a novel oral direct factor Xa inhibitor. It is currently awaiting approval from the US Food and Drug Administration as a prophylaxis for venous thromboembolism in total knee and hip replacements. Based on phase II and III trials, rivaroxaban has been shown to be as efficacious, if not more, as traditional antithrombotic therapy with similar safety profiles. The Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of Deep Vein Thrombosis and Pulmonary Embolism (RECORD) phase III trials have shown rivaroxaban 10 mg once daily to be superior to the low molecular weight heparin, enoxaparin, when used for prophylaxis of venous thromboembolism in orthopedic surgeries. Rivaroxaban has been shown to have tolerable adverse effects and a low potential for drug-drug or drug-food interactions. It has the major advantages of once daily oral dosing and no required laboratory monitoring, giving it the potential to replace current antithrombotics in the market today.
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PMID:Rivaroxaban: an oral direct factor Xa inhibitor for the prevention of thromboembolism. 1952 81

The expertise and the advice of vascular specialists are important in diagnosis and treatment of venous thromboembolism (VTE) and equally important for thromboprophylaxis. Thus, vascular specialists are expected to have significant knowledge of the exposing and disposing risk factors for VTE. They are also expected to be familiar with the risk groups for VTE and the appropriate measures for thromboprophylaxis. Because different pharmacological prophylactic strategies are available, angiologists must be familiar with the properties, the specific labeling and the product information regarding their drugs of choice. Being familiar with the pharmacological profile and the potential risk of impaired renal function due to drug accumulation is essential for angiologists, both for the treatment and prophylaxis of VTE. Appropriate time intervals between application of thromboprophylaxis and spinal or epidural anaesthesia should be observed. This is also important for the recently available oral thrombin- and factor Xa-inhibitors. Presently available data do not support routine pharmacological prophylaxis for patients in the low VTE-risk group. Rather, individual risk benefit assessment is required in these patients. Patients with moderate or high VTE risk should receive pharmacological thromboprophylaxis. There is clear evidence and recommendation for prolonged administration of thromboprophylaxis over a 4-week period in patients following major orthopaedic surgery, such as hip replacement, hip fracture and in cancer surgery patients. Pulmonary embolism (PE) remains the most common preventable cause of death among hospitalized patients. Therefore, angiologists have a central role in ensuring adequate and consistent implementation of thromboprophylaxis, which is the number one strategy to improve patient safety in hospitals.
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PMID:Thromboprophylaxis--key points for the angiologist. 1958 1

This study tests the hypothesis that pegylated cationic liposomes are a viable carrier for inhalable formulations of low molecular weight heparin, an anionic drug. Cationic liposomal formulations of low molecular weight heparin were prepared by the hydration method using 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt), cholesterol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]. The formulations were characterized for particle size, entrapment efficiency, pulmonary absorption and pharmacological efficacy. For absorption studies, the formulations were administered to anesthetized male Sprague-Dawley rats via the pulmonary route and drug absorption was monitored by measuring plasma anti-factor Xa activity. The pharmacological efficacy of the formulations was studied in rodent models of pulmonary embolism and deep vein thrombosis. The mean particle size of the liposomes was 104.8+/-20.7 nm and the drug entrapment efficiency was 90.3+/-0.1%. The half-life of the cationic liposomal formulation was 10.6+/-0.2h, a 2.2-fold increase compared to low molecular weight heparin formulated in saline, and the relative bioavailability was approximately 73.4+/-19.1% when compared to subcutaneously administered drug. A once-every-other-day inhaled dose of the formulation showed similar efficacy in reducing thrombus weight as a once-daily dose of subcutaneously administered drug. Likewise, cationic liposomal formulations administered via the pulmonary route 6h prior to embolization in the lungs showed a thrombolytic effect comparable to that of low molecular weight heparin administered subcutaneously 2h before embolization. Histological examination of lung tissue and measurement of injury markers in bronchoalveolar lavage fluid suggest that the formulations did not produce extensive damage. The results demonstrate that pegylated cationic liposomes could be a viable carrier for an inhalable formulation of low molecular weight heparin.
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PMID:Cationic liposomes as carriers for aerosolized formulations of an anionic drug: safety and efficacy study. 1961 95

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a major cause of morbidity and mortality in patients undergoing major orthopedic surgery. Routine thromboprophylaxis has been the standard of care over the last 20 years. Currently available options for the prevention of VTE in major orthopedic surgery include low molecular weight heparins, vitamin K antagonists, and, more recently, the synthetic pentasaccharide fondaparinux. Although effective, all these drugs have several limitations and new oral antithrombotics offering predictable, effective and safe anticoagulation are strongly needed. This overview focuses on the most advanced oral direct inhibitors to factor Xa rivaroxaban, apixaban, LY517717 and YM150; specifically, the results of phase II and III studies and the designs of ongoing clinical trials in patients undergoing elective hip and knee replacement are reviewed.
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PMID:Oral factor Xa inhibitors for thromboprophylaxis in major orthopedic surgery: a review. 1969 78

The formation of blood clots is a significant threat to individuals with limited mobility, whether in the hospital or recovering in an outpatient setting. Prevention of deep vein thrombosis and pulmonary embolism has been found to be cost-effective when compared with treating an existing thrombosis. Despite these positive findings, compliance with the clinical practice guidelines is less than ideal. The National Consensus Standards for the Prevention and Care of Deep Vein Thrombosis Project identified 4 domains to address the problem of noncompliance related to venous thromboembolism: risk assessment, diagnosis, prevention, and treatment.The objective of treating an existing deep vein thrombosis is to prevent further extension of the clot. Pharmacological interventions for both prevention and treatment include unfractionated heparin, low-molecular-weight heparin, selective factor Xa inhibitors, and vitamin K antagonists; nonpharmacological interventions include mechanical measures, such as inferior vena cava filters, graduated compression stockings, and intermittent pneumatic compression devices. Pharmacological interventions interfere with various factors of the coagulation cascade. An adverse effect commonly associated with these drugs is excessive bleeding. The mechanism of action surrounding mechanical interventions is to increase venous return and decrease the risk of pooling of blood in the leg veins. These interventions are effective only if implemented. Clinical application of clinical practice guidelines is imperative to protect patients at risk.
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PMID:Venous thromboembolism: pharmacological and nonpharmacological interventions. 1985 63

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a major cause of morbidity and mortality in patients undergoing major orthopedic surgery, and routine thromboprophylaxis has been the standard of care over the last 20 years. Currently available options for the prevention of VTE in major orthopedic surgery include low-molecular-weight heparins, vitamin K antagonists and, more recently, the synthetic pentasaccharide fondaparinux. Although effective, these drugs have several limitations, and new oral antithrombotics offering predictable, effective and safe anticoagulation are strongly needed. This overview focuses on the most advanced oral direct inhibitors of factor Xa, rivaroxaban, apixaban, LY517717, YM150 and betrixaban. Specifically, the results of phase II and III studies and the designs of ongoing clinical trials in patients undergoing elective hip and knee replacement are reviewed.
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PMID:Oral factor Xa inhibitors for venous thromboembolism prevention in major orthopedic surgery: a review. 1999 30

The main objectives in the treatment of venous thromboembolism are to prevent clot extension and pulmonary embolism, to reduce mortality and to prevent recurrent thromboembolic events as well as postthrombotic disorders. Initial and effective anticoagulation with heparin, preferably with low molecular weight heparin (LMWH), or with fondaparinux is the most important measure. Unfractioned heparin (UFH) is as effective as LMWH, but requires coagulation-monitoring and is associated with a higher risk of heparin-induced thrombocytopenia. In patients with renal insufficiency direct determination of anti-factor Xa activity and dose adjustment is recommended, since drug accumulation can occur over time. In those patients UFH instead of LMWH might be favored. Long-term treatment should be administered with vitamin K-antagonists (INR-target range 2-3) for a duration of 3 to 6 months. In case of recurrent venous thromboembolism, indefinite therapy is recommended. Additional treatment with compression stockings is reasonable. Patients who do not require hospital treatment for other conditions, who have a low bleeding risk, no excessive venous congestion and no symptomatic pulmonary embolism can safely be treated at home. In most cases bed rest is not necessary. Thrombolysis or surgical thrombectomy is seldomly indicated in severe thromboembolism.
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PMID:[Treatment of venous thromboembolism]. 2010 57


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