| 1. |
- Eriksson, Ulf G, et al.
(författare)
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Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran : a population model analysis
- 2003
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Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 42:7, s. 687-701
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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| 2. |
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| 3. |
- Akre [Fall], Katja, 1971-, et al.
(författare)
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Risk for gastric cancer after antibiotic prophylaxis in patients undergoing hip replacement
- 2000
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Ingår i: Cancer Research. - Birmingham, USA : American Asoociation for Cancer Research. - 0008-5472 .- 1538-7445. ; 60, s. 6376-
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Tidskriftsartikel (refereegranskat)abstract
- Despite strong evidence of an association between Helicobacter pylori and gastric cancer, the benefit of eradicating H. pylori infection is unknown. Our aim was to test the hypothesis that exposure to high doses of antibiotics reduces risk for gastric cancer via possible eradication of H. pylori We conducted a nationwide case-control study nested in a cohort of 39,154 patients who underwent hip replacement surgery between 1965 and 1983. Such patients frequently receive prophylactic antibiotic treatment. During follow-up through 1989, we identified 189 incident cases of gastric cancer. For each case, three controls were selected from the cohort. Exposure data were abstracted from hospital records. Blood samples from a separate cohort undergoing hip replacement surgery were analyzed for anti-H. pylori IgG before and after surgery. Both long-term antibiotic treatment before surgery [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7] and prophylactic antibiotic treatment (OR, 0.7; 95% CI, 0.5-1.1) conferred a reduction in gastric cancer risk. The reduction appeared stronger after 5 years (OR, 0.6; 95% CI, 0.3-1.2) than during shorter follow-up after hip replacement (OR, 0.8; 95% CI, 0.4-1.7). There was an apparent decrease in risk with increasing body weight-adjusted doses of antibiotics (P = 0.13). However, the rate of H. pylori antibody disappearance was not strikingly higher in the cohort of patients undergoing hip replacement than in a control cohort. Our findings provide indirect support for the hypothesis that treatment with antibiotics at a relatively advanced age reduces the risk of gastric cancer.
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| 4. |
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| 5. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I
- 2004
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Ingår i: J Thromb Haemost. - 1538-7933. ; 2:9, s. 1573-80
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dabigatran etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). OBJECTIVES: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. METHODS: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. RESULTS: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. CONCLUSIONS: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.
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| 6. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Efficacy of fondaparinux for thromboprophylaxis in hip fracture patients
- 2004
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Ingår i: J Arthroplasty. - 0883-5403. ; 19:7 Suppl 2, s. 78-81
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Tidskriftsartikel (refereegranskat)abstract
- Fondaparinux efficacy for thromboprophylaxis was evaluated in predefined high-risk hip fracture patients. Patients received fondaparinux 2.5 mg for 7 days following surgery; 656 patients were randomized double blind to receive placebo or continue fondaparinux regimen for 21 additional days. Primary efficacy was venous thromboembolism (VTE) based on bilateral venography during the double-blind period. Total VTE was 1.4% (3 of 208 patients) for extended prophylaxis and 35% (77 of 220 patients) for short-term prophylaxis (P = 0.001), relative risk reduction (RRR) of 96%. Major bleeding occurred in 2% (8 of 327 patients) with extended prophylaxis and in 0.6% (2 of 329 patients) with short-term prophylaxis (P =.063). Risk of VTE was continued following short course fondaparinux in hip fracture patients, but was significantly reduced by extending prophylaxis, without significant risk of major bleeding.
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| 7. |
- Eriksson, Bengt I., 1946, et al.
(författare)
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Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors
- 2004
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Ingår i: Drugs. - 0012-6667. ; 64:6, s. 577-95
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Tidskriftsartikel (refereegranskat)abstract
- Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies.Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital.
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| 8. |
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| 9. |
- Johansson, Barbro, et al.
(författare)
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Postischemic housing in an enriched environment influences hippocampal progenitor cell differentiation after focal cortical ischemia
- 2004
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Ingår i: Maturation Phenomenon in Cerebral Ischemia V. - 9783540408741 ; , s. 297-308
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Konferensbidrag (refereegranskat)abstract
- We have tested the hypothesis that environmental factors can influence postischemic progenitor cell survival and differentiation in the dentate gyrus. The proliferation marker bromodeoxyuridine (BrdU) was administered during 7 days starting 24 h after ligation of the right middle cerebral artery. Postoperatively the rats were housed in standard cages or transferred to enriched environment 24 h or 7 days after the ligation. Rats housed in standard cages performed significantly worse than rats housed in an enriched environment in a leg placement and a rotating pole test four weeks after the arterial ligation. Neurogenesis and gliogenesis were determined by triple labeling with antibodies against BrdU, the astrocytic marker glial fibrillary acidic protein (GFAP), and the neuronal markers Calbindin D28k and NeuN. Rats with cortical lesions had a 5- to 6-fold increase in BrdU labeled cells on the ipsilateral side (p<0.001 for the delayed enriched group; p<0.01 for the early enriched and standard groups) and a 2- to 3-fold non-significant increase on the contralateral side with no significant differences between the groups. About 80% of the BrdU-positive cells co-labeled with NeuN and about 70% of the BrdU-positive cells co-labeled with Calbindin D28K. Although housing conditions did not influence neurogenesis it markedly altered gliogenesis. Whereas the standard group did not have more astrocytes than sham-operated rats on the ipsilateral side, the early and delayed enriched group had a 3- to 5-fold increase, respectively, thereby normalizing the severely disturbed neuron to glia ratio in the standard group. We hypothesize that the newly formed neurons in the standard group would have a poor environment in the absence of a concomitant gliogenesis. Astrocytes play an important role in neuronal plasticity, and we propose that more attention should be given to gliogenesis in experimental studies on cell proliferation and differentiation after brain lesions.
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| 10. |
- Lee, A. Y., et al.
(författare)
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Bilateral vs. ipsilateral venography as the primary efficacy outcome measure in thromboprophylaxis clinical trials: a systematic review
- 2004
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Ingår i: J Thromb Haemost. - 1538-7933. ; 2:10, s. 1752-9
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Tidskriftsartikel (refereegranskat)abstract
- Contrast venography, in combination with symptomatic venous thromboembolism (VTE), is the standard efficacy outcome measure in clinical trials of thromboprophylaxis in major orthopedic surgery. It is uncertain whether performing bilateral venography offers any real advantage over venography of the operated leg alone. This study was undertaken to determine the risk of isolated contralateral deep vein thrombosis (DVT) following major orthopedic surgery and to evaluate whether bilateral venography, rather than venography on the operated leg alone, offers any gain in DVT detection and, thereby, improves efficiency in clinical study design. A systematic review of prospective studies that reported DVT incidence as the primary efficacy outcome based on mandatory bilateral venography in patients undergoing elective hip or knee arthroplasty or hip fracture repair was conducted. Based on the use of bilateral venography as a primary efficacy outcome measure, the incidence of any DVT is 16.7% following total hip replacement, 18.8% after hip fracture repair, and 33.8% after total knee replacement. While DVT risk in the operated leg varies depending on the type of surgery, the risk of isolated DVT in the non-operated leg is approximately 4% to 5% in all three procedures. By increasing the detection of any DVT, the use of bilateral venography reduces required sample size by 16% to 25% compared to ipsilateral venography. In clinical trials evaluating the efficacy of thromboprophylaxis in major orthopedic surgery, bilateral venography reduces the risk of undiagnosed DVT in the non-operated leg and improves the efficiency of study design by substantially reducing the sample size requirement.
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| 11. |
- Turpie, A. G., et al.
(författare)
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Fondaparinux
- 2004
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Ingår i: J Am Acad Orthop Surg. - 1067-151X. ; 12:6, s. 371-5
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Turpie, A. G., et al.
(författare)
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Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points
- 2004
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Ingår i: Chest. - 0012-3692. ; 126:2, s. 501-8
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Tidskriftsartikel (refereegranskat)abstract
- STUDY OBJECTIVES: To assess the relevance of various efficacy end points established for thromboprophylaxis trials, we compared the results of the fondaparinux phase III program in major orthopedic surgery using the original primary efficacy end point with those obtained when the efficacy end points recently suggested by the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy and the European Committee for Proprietary Medicinal Products (CPMP) were used. SETTING AND PATIENTS: Fondaparinux was compared with enoxaparin in four multicenter, randomized, double-blind trials of major orthopedic surgery. The original primary efficacy end point consisted of a composite of deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or pulmonary embolism up to day 11. The efficacy end point established by the ACCP Consensus Conference on Antithrombotic Therapy comprises any proximal deep-vein thrombosis, symptomatic proven deep-vein thrombosis or pulmonary embolism, or fatal pulmonary embolism, and that established by the European CPMP comprises any proximal deep-vein thrombosis, symptomatic proven pulmonary embolism, or death from any cause. INTERVENTIONS: Patients were randomized to receive either subcutaneous fondaparinux (2.5 mg once daily) starting postoperatively or approved enoxaparin regimens. RESULTS: Using the original end point of the fondaparinux studies, the incidence of venous thromboembolism was 13.7% (371 of 2,703 patients) in the enoxaparin group compared with 6.8% (182 of 2,682 patients) in the fondaparinux group, with a common odds reduction of 55.2% (p = 10(-17); 95% confidence interval, 45.8% to 63.1%) in favor of fondaparinux. The respective incidences of efficacy end points with enoxaparin and fondaparinux were 3.3% and 1.7%, respectively, according to the ACCP definition, and 3.9% and 2.1%, respectively, according to the CPMP definition. The common odds reduction in favor of fondaparinux was 49.6% (p < 0.001) and 48.0% (p < 0.001), respectively. CONCLUSIONS: Fondaparinux was consistently more effective than enoxaparin in preventing venous thromboembolism in patients undergoing major orthopedic surgery, irrespective of the established composite outcomes used.
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