British journal of clinical pharmacology
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Br J Clin Pharmacol · Apr 2004
Blood-brain barrier transport of morphine in patients with severe brain trauma.
In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. ⋯ The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.
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Br J Clin Pharmacol · Mar 2004
Clinical Trial Controlled Clinical TrialThe effect of hypertension and hypercholesterolemia screening with subsequent intervention letter on the use of blood pressure and lipid lowering drugs.
To evaluate the effect of a letter intervention that was send to both the participants of a population screening and their general practitioners. We also tested what predicting variables influenced the GP to actually prescribe blood pressure lowering drugs (BPLD) or lipid lowering drugs (LLD). ⋯ A population survey followed by a letter of intervention to both the patient and GP are effective to improve the use of blood pressure and lipid lowering drugs as a primary prevention in patients with hypertension and hyperlipidemia. Our therapeutic advice however, was followed only in about one of the three subjects with hypertension and one of the four subjects with hyperlipidemia. The levels of blood pressure and plasma total cholesterol are important variables influencing the GP to prescribe a BPLD and/or LLD.
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Br J Clin Pharmacol · Mar 2004
CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes.
To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome p450 enzymes involved, and to predict the in vivo hepatic intrinsic clearance of hydrocodone via these pathways. ⋯ The O-demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity cytochrome p450 enzyme. Norhydrocodone formation was attributed to CYP3A4. Comparison of recalculated published clearance data for hydrocodone, with those predicted in the present work, indicate that about 40% of the clearance of hydrocodone is via non-CYP pathways. Our data also suggest that the genetic polymorphisms of CYP2D6 may influence hydrocodone metabolism and its therapeutic efficacy.
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Br J Clin Pharmacol · Feb 2004
Randomized Controlled Trial Clinical TrialModelling acute tolerance to the EEG effect of two benzodiazepines.
We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. ⋯ Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.
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Br J Clin Pharmacol · Feb 2004
Randomized Controlled Trial Comparative Study Clinical TrialComparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients.
It is well established that there is a wide intra- and interindividual variability in dose requirements for lorazepam and midazolam in intensive care patients. The objective of this study was to compare the population pharmacokinetics of lorazepam and midazolam after long-term continuous infusion in mechanically ventilated critically ill patients. ⋯ The pharmacokinetics of both lorazepam and midazolam were well described by a two-compartment model. Inclusion of alcohol abuse and age as covariates improved both models. PEEP was identified as an additional covariate for lorazepam, and the APACHE score for midazolam. For both drugs there is a large interindividual variability in their pharmacokinetics when used for long-term sedation in critically ill patients. However, the intra-individual variability is much lower for lorazepam.