British journal of clinical pharmacology
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Br J Clin Pharmacol · Dec 2012
Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery - findings from the ORTHO-TEP registry.
In large randomized trials, thromboprophylaxis with fondaparinux in major orthopaedic surgery (MOS) has been shown to be superior to low molecular weight heparin (LMWH) prophylaxis with comparable safety. However, patients treated under trial conditions are different from unselected patients and efficacy and safety outcomes may be different in unselected patients in daily practice. We performed a retrospective cohort study to compare the efficacy and safety of venous thromboembolism (VTE) prophylaxis with fondaparinux or LMWH in 3896 consecutive patients undergoing major orthopaedic surgery at our centre. ⋯ We conclude that the strict patient selection and surveillance in phase-III trials results in lower VTE and bleeding event rates compared with unselected routine patients. Consequently, the efficacy and safety profile of thromboprophylaxis regimens needs to be confirmed in large registries or phase IV trials of unselected patients.
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Br J Clin Pharmacol · Nov 2012
Controlled Clinical TrialBioactivity of enoxaparin in critically ill patients with normal renal function.
Venous thromboembolism is a frequent complication in critically ill patients that has a negative impact on patient outcomes. Critically ill patients have significantly lower plasma anti-factor-Xa activity levels compared with control patients after administration of subcutaneous heparin. The clinical relevance of the different anti-factor-Xa levels after prophylactic doses of low molecular weight heparin (LMWH) in critically ill patients is not completely understood. ⋯ Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.
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Br J Clin Pharmacol · Nov 2012
Comparative Study Controlled Clinical TrialInhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients.
Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control. ⋯ Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.
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Br J Clin Pharmacol · Nov 2012
Randomized Controlled TrialContribution of CYP2C19 and CYP3A4 to the formation of the active nortilidine from the prodrug tilidine.
The analgesic activity of tilidine is mediated by its active metabolite, nortilidine, which easily penetrates the blood-brain barrier and binds to the µ-opioid receptor as a potent agonist. Tilidine undergoes an extensive first-pass metabolism, which has been suggested to be mediated by CYP3A4 and CYP2C19; furthermore, strong inhibition of CYP3A4 and CYP2C19 by voriconazole increased exposure of nortilidine, probably by inhibition of further metabolism. The novel CYP2C19 gene variant CYP2C19*17 causes ultrarapid drug metabolism, in contrast to the *2 and *3 variants, which result in impaired drug metabolism. ⋯ The sequential metabolism of tilidine is inhibited by the potent CYP3A4 inhibitor, ritonavir, independent of the CYP2C19 genotype, with a twofold increase in the exposure of the active nortilidine.