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Pharmacogenomics and Warfarin therapy

Sat, 31 Dec 2011 13:30:00 GMT

Title: Pharmacogenomics and Warfarin therapy Author: Martin, Jennifer H.; Somogyi, Andrew Alexander

Evaluation of pre-analysis loss of dependent drugs in wastewater: stability and binding assessments

Sat, 31 Dec 2011 13:30:00 GMT

Title: Evaluation of pre-analysis loss of dependent drugs in wastewater: stability and binding assessments Author: Chen, Chang; Kostakis, Chris; Irvine, Rodney James; Felgate, Peter; White, Jason Mark Description: Article first published online: 9 OCT 2012

The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype

Mon, 31 Dec 2012 13:30:00 GMT

Title: The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype Author: Maddison, John Brian; Somogyi, Andrew Alexander; Jensen, Berit P.; James, Heather M.; Gentgall, Melanie Gaye; Rolan, Paul Edward Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS: Using unequivocally pure (R)- and (S)-warfarin we have demonstrated that (R)-warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin. The extent of the interaction is dependent on VKORC1 genotype. AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUCPT((R)-warfarin) : AUCPT((S)-warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Exploring neuroinflammation as a potential avenue to improve the clinical efficacy of opioids

Sat, 31 Dec 2011 13:30:00 GMT

Title: Exploring neuroinflammation as a potential avenue to improve the clinical efficacy of opioids Author: Thomas, Jacob Henry Lloyd; Hutchinson, Mark Rowland Abstract: Opioids are an extremely important part of medical practice, and for thousands of years, continued to provide relief from severe acute and chronic pain. Intriguingly, use of opioids activates endogenous counter-regulatory mechanisms resulting in increased sensitivity to noxious stimuli and the requirement for higher doses of opioids to reach an effective level of analgesia. Until recently, research into the counter regulators of opioid-induced analgesia had been focused on the role of neuronal receptors where the beneficial and detrimental actions of opioids were thought to be inseparable. It is now apparent from molecular and rodent data that opioids have non-neuronal, nonclassic, nonstereoselective sites of action. At these newly recognized sites, opioid activity significantly modifies the pharmacodynamics of opioids by eliciting proinflammatory reactivity from immunocompetent cells of the CNS. This review will examine the nonclassic actions of opioids specifically appreciating the actions of the released immune products.