Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jan 2003
Randomized Controlled Trial Clinical TrialAnalgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers.
Our objective was to quantify the extent and time course of the effects of morphine-6-glucuronide and morphine on pain threshold, pain tolerance, pupil diameter, and side effects. ⋯ Morphine-6-glucuronide clearly produced analgesic effects in healthy volunteers. However, the high amounts of systemic morphine-6-glucuronide needed to produce the same effects as morphine suggest that morphine-6-glucuronide barely contributes to the central nervous opioid effects after administration of analgesic doses of morphine.
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Clin. Pharmacol. Ther. · Dec 2002
Randomized Controlled Trial Clinical TrialPopulation pharmacokinetic and pharmacodynamic modeling of propofol for long-term sedation in critically ill patients: a comparison between propofol 6% and propofol 1%.
A population pharmacokinetic and pharmacodynamic model of propofol for long-term sedation in critically ill patients is described, because limited information is available in these patients. In the models the influence of time-independent covariates, in particular, the propofol formulation (propofol 6% versus propofol 1%), and of time-dependent covariates was investigated. ⋯ The population models in critically ill patients showed no differences in pharmacokinetics or pharmacodynamics between propofol 6% and propofol 1%. TG and T(c) appeared to be significant covariates for elimination clearance. For the pharmacodynamics, when propofol concentrations were between 0.75 and 1.5 mg/L, Ramsay sedation score 6 was most probable (40%-75%) and the probability for Ramsay sedation score 5 was 20% to 40%. Large pharmacodynamic variabilities were observed.
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Clin. Pharmacol. Ther. · Oct 2002
Randomized Controlled Trial Multicenter Study Comparative Study Clinical TrialPharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis.
We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis. ⋯ Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.
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Clin. Pharmacol. Ther. · Oct 2002
Randomized Controlled Trial Comparative Study Clinical TrialPharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.
Inhibition of the tissue factor-factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram-negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades. ⋯ In summary, ASIS effectively and selectively attenuates tissue factor-induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti-inflammatory effects in critically ill patients.
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Clin. Pharmacol. Ther. · Aug 2002
Randomized Controlled Trial Clinical TrialPeripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue injury model.
Nonsteroidal anti-inflammatory drug (NSAID) analgesia is generally attributed to peripheral suppression of cyclooxygenase (COX) enzymes, leading to decreased products of the arachidonic acid cascade. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after systemic or local NSAID administration in a clinical model of tissue injury. ⋯ The temporal profile of PGE(2) and TxB(2) in the immediate postoperative period is consistent with constitutive COX-1 initially, followed by an increase in PGE(2) resulting from expression of COX-2. The temporal association between NSAID analgesia and decreased prostanoids at the site of injury is consistent with a dual COX-1/COX-2 peripheral site of action. The analgesic effects of 1 mg ketorolac tromethamine without a reduction in PGE(2) at the site of injury suggests an additional central site for NSAID analgesia.