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- 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. |
- Karlsson, Berndt H, et al.
(författare)
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Metabolic disturbances in male workers with rotating three shift work
- 2003
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 0340-0131 .- 1432-1246. ; 76:6, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- We found a significant association between shift work and lipid disturbances (i.e. low HDL-cholesterol and high triglyceride levels). We did not find any association with hyperglycaemia.
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| 3. |
- Karlsson, Berndt H, et al.
(författare)
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Metabolic disturbances in male workers with rotating three-shift work : results of the WOLF study
- 2003
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 0340-0131 .- 1432-1246. ; 76:6, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of the present study was to investigate the relationship between important metabolic risk factors for coronary heart disease (CHD) and type 2 diabetes in shift workers and day workers.Methods: Cross-sectional data from a sub-population in the WOLF study consisting of 665 day workers and 659 three-shift workers in two plants were analysed.Results: A higher proportion of shift workers than day workers had high triglyceride levels (‡1.7 mmol/l), low levels of HDL-cholesterol (<0.9 mmol/l) and abdominal obesity (waist/hip ratio>0.9). The risk of low HDLcholesterol was doubled in shift workers, (odds ratio (OR): 2.02, 95% confidence interval (95% CI): 1.24– 3.28) after being adjusted for age, socio-economic factors, physical activity, current smoking, social support and job strain. High levels of triglycerides were also significantly associated with shift work (OR: 1.40, 95% CI: 1.08–1.83). The OR for abdominal obesity was 1.19, (95% CI: 0.92–1.56). The prevalence of hyperglycaemia (serum glucose ‡7.0 mmol/l) was similar in day and shift workers. No significant interaction was seen between shift work and abdominal obesity with regard to the associations with triglycerides and HDL-cholesterol.Conclusions: We found a significant association between shift work and lipid disturbances (i.e. low HDL-cholesterol and high triglyceride levels). We did not find any association with hyperglycaemia.
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| 4. |
- Lindell, Monica, et al.
(författare)
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Variable Expression of CYP and Pgp Genes in the Human Small Intestine
- 2003
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 33:6, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. METHODS: The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. RESULTS: Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. CONCLUSIONS: Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.
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