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)

Pulmonary emboli are detectable by filling defects in the pulmonary vasculature upon pulmonary angiography. Emboli derived from venous thrombi are rich in fibrin to which thrombin remains bound. Hirudin, a specific thrombin inhibitor, binds to thrombin to yield a 1:1 stoichiometric complex. We examined whether 131I-recombinant hirudin (r-hirudin) could be used to detect pulmonary emboli in rabbits. Clots were formed by re-calcifying rabbit plasma in vitro, and then injected (0.034 ml) into a femoral vein to lodge in the lungs. 131I-r-hirudin (29 +/- 4 microCi/kg) was injected intravenously but emboli could not be detected by gamma camera in real time. Post-mortem analysis of lung tissue showed that 131I-r-hirudin did not associate with emboli prepared with 125I-fibrin. Because of these findings, we used different techniques to look at the binding of hirudin to plasma clots. Clots formed in vitro were incubated with 131I-r-hirudin in the presence of equimolar amounts of 125I-albumin; specific binding of 131I-r-hirudin was not observed. Experiments with immobilized fibrin(ogen) showed that 125I-r-hirudin did not bind to and remain with fibrin-bound 131I-thrombin but did lead to the inactivation and displacement of up to 70% of bound thrombin as r-hirudin-thrombin complex; residual thrombin bound to fibrin remained active. Thus, released r-hirudin-thrombin complex is probably cleared rapidly from the region of the embolus in vivo; radioiodinated r-hirudin may not, therefore, be useful as a marker for detecting emboli.
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PMID:Displacement of fibrin-bound thrombin by r-hirudin precludes the use of 131I-r-hirudin for detecting pulmonary emboli in the rabbit. 783 58

In the absence of prophylaxis, elective orthopedic surgery is associated with a high risk of venous thromboembolic events that are responsible for substantial morbidity and mortality. Despite the publication of articles questioning the significance of fatal pulmonary embolism (PE) following elective hip replacement, recent reports support the need for effective thromboprophylaxis in this indication. These reports also provide evidence of a significant reduction in fatal PE and overall mortality provided by treatment with low-molecular-weight heparin (LMWH), compared with unfractionated heparin. Even with the most effective prophylaxis currently available, however, deep vein thrombosis still develops in a minority of high-risk patients, indicating a need for improved therapies. Desirudin, a novel recombinant hirudin and direct thrombin inhibitor, has been shown to provide more effective prophylaxis than the most widely used LMWH, enoxaparin, in orthopedic surgery patients with multiple thromboembolic risk factors. This benefit was not associated with any increase in bleeding. Regional anesthesia and use of graduated compression stockings may provide additional independent reductions in thromboembolic risk in elective orthopedic surgery.
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PMID:New therapeutic options in DVT prophylaxis. 1087 28

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (s.c.). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received s.c. melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU s.c. once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received s.c. melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the s.c. melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.
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PMID:A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. 1185 82

The first clinical studies evaluating the safety and efficacy of melagatran, a novel, direct thrombin inhibitor, given subcutaneously as prophylaxis for venous thromboembolism (VTE) following total hip (THR) or total knee replacement (TKR) are reported. In Study I, 66 patients received subcutaneous melagatran (1.5-6 mg bid) in a poloxamer depot formulation, and in Study II, 104 patients received subcutaneous melagatran (2-4 mg bid) in saline or as a depot formulation in cyclodextrin. Treatment was given for 8-11 days, with the first dose administered immediately before surgery. Deep vein thrombosis (DVT) was assessed using mandatory bilateral venography on the last day of treatment, and pulmonary scintigraphy was performed if required. Bleeding complications occurred in the only patient who received melagatran 6 mg, and this dose-arm was discontinued. The frequency of VTE was low (12/129=9%, 95% confidence interval [CI]: 5-16%). Eight patients (6%) had distal DVT, three (2%) had proximal DVT, and in one patient (1%) pulmonary embolism (PE) was verified. In conclusion, subcutaneous melagatran 1.5-4.5 mg bid in saline or depot formulation was well tolerated and resulted in a low frequency of VTE.
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PMID:Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from Phase II studies. 1206 37

The phase III trial EXPRESS was a randomised, double-blind comparison of two anticoagulant therapies used as prophylaxis against venous thromboembolism (VTE) during major elective orthopaedic surgery. The investigational treatment was ximelagatran/melagatran (Exanta), a new direct thrombin inhibitor in both its oral and subcutaneously injectable forms; the comparator was the low molecular weight heparin enoxaparin. Results showed ximelagatran/melagatran was highly statistically significantly superior to enoxaparin in preventing VTE with a relative risk reduction in proximal deep vein thrombosis plus pulmonary embolism of 63.3% (p < 0.000002). The relative risk reduction for total VTE was 23.6% (p < 0.0003). There were no differences in clinically important bleeding events (fatal bleeding, critical organ bleeding and bleeding requiring reoperation) but excess bleeding assessed subjectively was more common in the ximelagatran group than in the enoxaparin group.
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PMID:The express study: preliminary results. 1258 45

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, represents a significant source of morbidity and mortality in the United States and worldwide. The pharmacologic management of venous thromboembolic disease has witnessed significant advances since oral anticoagulant and heparin therapies began to gain widespread use more than 50 years ago. Cumulative clinical experience gained from using these 2 classes of antithrombotic agents for the prevention and treatment of venous thromboembolism in high-risk patients pointed to a number of efficacy and safety limitations. This prompted further research and the eventual introduction, in the 1980s, of low-molecular-weight heparin(s) as a potentially superior therapeutic modality. Within the last decade the pace of development of newer classes of antithrombotic agents for venous thromboembolism prevention and treatment (as well as other indications) has accelerated. Among agents at late stages of investigation are ximelagatran (a direct thrombin inhibitor), nematode anticoagulant peptide c2 (a tissue factor VIIa inhibitor), and sodium N-[8(2-hydroxylbenzoyl)amino]caprylate (SNAC)/heparin (a heparin derivative). The most recently approved agents for venous thromboembolism indications include the heparinoid, danaparoid sodium, and the newly introduced selective factor Xa inhibitor, fondaparinux.
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PMID:Management of venous thromboembolism: past, present, and future. 1269 66

Unfractionated heparin, low molecular weight heparin and vitamin K antagonists are anticoagulants currently used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Considerable limitations of these agents, such as a narrow therapeutic window, a variable dose response or lack of oral bioavailability, created the need for new anticoagulants. Numerous new compounds with different mechanisms of action have been developed and some have been already approved for clinical use. Quite recently, fondaparinux, an indirect anti-factor Xa inhibitor, has been licensed in Europe and in the US for prevention of VTE in patients undergoing hip or knee replacement surgery. In addition, lepirudin, a recombinant hirudin derivative, and the heparinoid danaparoid, have been approved in Austria for treatment of heparin-induced thrombocytopenia. Recombinant nematode anticoagulant protein c2, the orally available thrombin inhibitor ximelagatran and ART-123, a recombinant soluble thrombomodulin, are in advanced stages of clinical development. This article reviews mechanisms and sites of action, and the current state of preclinical and clinical research of these and various other agents with respect to the prevention and treatment of venous thromboembolism).
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PMID:Novel anticoagulants for the prevention and treatment of venous thromboembolism. 1464 23

Every year, approximately 2 million people experience a deep venous thrombosis (DVT). Approximately 600,000 of these people are diagnosed with a pulmonary embolism and about 10% of these die. It has been established that surgery, anesthesia, and bed rest increase the risk of DVT, and therefore, patients who undergo a major lower-extremity procedure should receive prophylaxis. During the past 10 years, the choices of pharmacological and mechanical prophylaxis have increased greatly. Warfarin is probably the most widely used prophylactic method in the U.S., but low-molecular-weight heparin (LMWH) use has increased. Also available is a synthetic pentasaccharide that acts as an anti-Xa inhibitor to decrease DVT without increase in bleeding. All but warfarin are given by subcutaneous injection and require no laboratory management to adjust the medication. Another drug in clinical trials is a direct thrombin inhibitor taken orally in a fixed dose that does not require monitoring. Non-pharmacological prophylaxis and/or stacked modalities, although used, have not shown the efficacy of pharmacological prophylaxis. With the incidence of DVT reported in the range of 41% to 85% without prophylaxis in joint replacement and hip-fracture surgery, prophylaxis is warranted in all lower-extremity joint replacement and hip-fracture patients.
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PMID:Advances in DVT prophylaxis and management in major orthopaedic surgery. 1545 36

Patients who undergo orthopaedic surgery are at substantially increased risk for venous thromboembolic events. These include proximal and distal deep vein thrombosis, with the former more likely to lead to pulmonary embolism and fatal complications. Anticoagulants are routinely used for venous thromboembolism prophylaxis in patients undergoing total hip or total knee replacement surgery. Although current treatments offer effective prophylaxis, they have disadvantages. Warfarin is limited by the requirement for coagulation monitoring to ensure effective and safe use. Similarly, low-molecular-weight heparins (LMWHs) have disadvantages, including the need for parenteral administration. This article brings together data from clinical trials of the novel oral direct thrombin inhibitor, ximelagatran, in the prevention of venous thromboembolism in patients undergoing elective total hip or total knee replacement. The ximelagatran clinical trial programme in orthopaedic surgery has focused primarily on five large multicentre studies in Europe (the Melagatran Thromboprophylaxis in Orthopaedic surgery II and III and Expanded Prophylaxis Evaluation Surgery Study studies) and in the United States (the Exanta Used to Lessen Thrombosis A and B studies), which enrolled more than 8000 patients. In addition, the USA clinical trial programme included three other trials that investigated ximelagatran in orthopaedic surgery; two of these studies focused on prevention of venous thromboembolism after total knee replacement, and one study investigated prevention of venous thromboembolism after total hip replacement. These studies compared ximelagatran with the LMWHs dalteparin and enoxaparin and with warfarin, and were designed to reflect regional differences in venous thromboembolism prophylaxis and to build on findings from previous studies. Generally, ximelagatran has been shown to possess comparable or greater efficacy relative to comparators. The timing and dose of ximelagatran have been shown to be important determinants of its efficacy and safety. As ximelagatran can be given in fixed oral dosing without coagulation monitoring, it is an attractive choice for the prevention of venous thromboembolism in major elective orthopaedic surgery.
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PMID:Clinical experience with ximelagatran in orthopaedic surgery. 1558 25

Venous thromboembolism, which is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a significant cause of death, disability, and discomfort. Two million people/year are affected by VTE, making it the third most common cardiovascular disease after coronary heart disease and stroke. The rationale for VTE prophylaxis stems from the clinically silent presentation of the disease and its prevalence among hospitalized patients. At greatest risk are patients undergoing major orthopedic surgery and those admitted to the intensive care unit with acute myocardial infarction, heart failure, ischemic stroke, respiratory disease, systemic infection, or other medical conditions that immobilize patients for 5 days or longer. Several anticoagulant regimens have been effective in reducing the risk of VTE after major orthopedic surgery. For patients undergoing total hip or knee replacement, treatment with adjusted-dose warfarin, low-molecular-weight heparins, or fondaparinux may be used. Warfarin, which has been around for more than 50 years, is the only oral anticoagulant available for VTE prophylaxis. Ximelagatran, a new low-molecular-weight oral prodrug of the direct thrombin inhibitor melagatran, has advantages over warfarin that may make it the drug of choice for prevention of VTE.
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PMID:The role of oral direct thrombin inhibitors in the prophylaxis of venous thromboembolism. 1562 37


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