Clin Pharmacokinet
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Review
Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs.
Many antiarrhythmic drugs introduced into the market during the past three decades have a chiral centre in their structure and are marketed as racemates. Most of these agents, including disopyramide, encainide, flecainide, mexiletine, propafenone and tocainide, belong to class I antiarrhythmics, whereas verapamil is a class IV antiarrhythmic agent. Except for encainide and flecainide, there is substantial stereoselectivity in one or more of the pharmacological actions of chiral antiarrhythmics, with the activity of enantiomers differing by as much as 100-fold or more for some of these drugs. ⋯ Similarly, there is no stereoselectivity in the renal clearance of tocainide, a drug that undergoes tubular reabsorption in addition to glomerular filtration. Overall, substantial stereoselectivity has been observed in both the pharmacokinetics and pharmacodynamics of chiral antiarrhythmic agents. Because the effects of these drugs are related to their plasma concentrations, this information is of special clinical relevance.
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The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. ⋯ Systemic toxicity remains the limiting factor for most methods that use intravascular delivery. This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
The pharmacokinetics of fondaparinux sodium in healthy volunteers.
Fondaparinux sodium is the first in a new class of synthetic factor Xa inhibitors that binds reversibly with high affinity to antithrombin III. It has been investigated for the prevention and treatment of arterial and venous thrombotic disorders and approved for use at a dose of 2.5mg once daily in the prevention of venous thromboembolism in major orthopaedic surgery. The pharmacokinetics of fondaparinux sodium were determined in eight studies in young and elderly healthy volunteers. ⋯ The favourable pharmacokinetic profile of fondaparinux sodium is likely to play an important role in the major advance that the drug represents in the prevention and treatment of thrombotic disorders.
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Randomized Controlled Trial Comparative Study Clinical Trial
Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.
Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. ⋯ Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.
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Randomized Controlled Trial Clinical Trial
Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers.
Fondaparinux sodium is the first of a new class of antithrombotic agents: the selective factor Xa inhibitors. Coadministration with digoxin may occur in clinical practice and both drugs are excreted almost completely by the renal route. In this study we assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers. ⋯ The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.