摘要:

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.The absorption of chiral antiarrhythmics appears to be nonstereoselective. However, their distribution, metabolism and renal excretion usually favour one enantiomer versus the other. In terms of distribution, plasma protein binding is stereoselective for most of these drugs, resulting in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution. For disopyramide, stereoselective plasma protein binding is further complicated by nonlinearity in the binding at therapeutic concentrations.Hepatic metabolism plays a significant role in the elimination of these antiarrhythmics, accounting for >90% of the elimination of mexiletine, propafenone and verapamil. Additionally, in most cases, significant stereoselectivity is observed in different pathways of metabolism of these drugs. For some drugs, such as propafenone and verapamil, the stereoselectivity in metabolism is further complicated by nonlinearity in one or more of the metabolic pathways. Further, the metabolism of a number of chiral antiarrhythmics, such as mexiletine, propafenone, encainide and flecainide, cosegregates with debrisoquine/sparteine hydroxylation phenotype. Therefore, it is not surprising that a wide interindividual variability exists in the metabolism of these drugs.Excretion of the unchanged enantiomers in urine is an important pathway for the elimination of disopyramide, flecainide and tocainide. The renal clearances of both disopyramide and flecainide exceed the filtration rate for these drugs, suggesting the involvement of active tubular secretion. However, the stereoselectivity in the renal clearance of these drugs, if any, is minimal. 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.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Although epilepsy affects men and women equally, there are many women's health issues in epilepsy, especially for women of childbearing age. These issues, which include menstrual cycle influences on seizure activity (catamenial epilepsy), interactions of contraceptives with antiepileptic drugs (AEDs), pharmacokinetic changes during pregnancy, teratogenicity and the safety of breastfeeding, challenge both the woman with epilepsy and the many healthcare providers involved in her care. Although the information in the literature on women's issues in epilepsy has grown steeply in recent years, there are many examples showing that much work is yet to be done. The purpose of this article is to review these issues and describe practical considerations for women of childbearing age with epilepsy. The article addresses the established or ‘first-generation’ AEDs (phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide and valproic acid) and the ‘second-generation’ AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide).Although a relationship between hormones and seizure activity is present in many women, good treatment options for catamenial epilepsy remain elusive. Drug interactions between enzyme-inducing AEDs and contraceptives are well documented. Higher dosages of oral contraceptives or a second contraceptive method are suggested if women use an enzyme-inducing AED. Planned pregnancy and counselling before conception is crucial. This counselling should include, but is not limited to, folic acid supplementation, medication adherence, the risk of teratogenicity and the importance of prenatal care. AED dosage adjustments may be necessary during pregnancy and should be based on clinical symptoms, not entirely on serum drug concentrations.Many groups have turned their attention to women's issues in epilepsy and have developed clinical practice guidelines. Although the future holds promise in this area, many questions and the need for progress remain.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Advances in positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance spectroscopy (MRS), and the ability to label a wide variety of compounds forin vivouse in humans, have created a new technology for making precise physiological and pharmacological measurements. Due to the noninvasive nature of these approaches, repetitive and/or continuous measurements have become possible. Thus far, these techniques have been primarily used for one-time assessments of individuals. However, experience suggests that a major use of this technology will be in the evaluation of new drug therapies. Already, these techniques have been used to measure precisely and noninvasively the pharmacokinetics of a variety of antimicrobial, antineoplastic and CNS agents. In the case of CNS drugs, imaging techniques (particularly PET) have been used to define the classes of neuroreceptors with which the drug interacts. The physiological, pharmacological and biochemical measurements that can be performed noninvasively using modern imaging techniques can greatly facilitate the evaluation of new therapies. These measurements are most likely to be useful during drug development in preclinical studies and in phase I/II human studies. Preclinically, new drugs can be precisely compared with standard therapies, or a series of analogues can be screened for further development on the basis of performance in animal models. In Phase I/II, imaging measurements can be combined with classical pharmacokinetic data to establish optimal administration schedules, evaluate the utility of interventions in specific clinical situations, and aid in the design of Phase III trials.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo investigate the elimination of stabilised hyaluronan following intra-articular injection into the knee joint.DesignThis was a single-centre, single-dose study in healthy human volunteers.ParticipantsSix healthy men, aged 28 to 47 (mean 38) years, were enrolled in the study.MethodsSubjects received a single intra-articular injection (3ml; 20 mg/ml) of131I-labelled non-animal stabilised hyaluronic acid (NASHA). Radioactivity in the knee, blood, urine and over the liver was measured with gamma counters for 3 weeks post-injection; magnetic resonance and gamma camera imaging of the knee were also performed at 24 hours post-injection. Radioactivity uptake data were tested for conformity of fit to different mathematical models.ResultsElimination of131I-labelled NASHA from the knee was characterised by a fast initial phase and a slow late phase, and conformed to a three-exponential-function model with elimination half-lives of 1.5 hours, 1.5 days and 4 weeks. Radioactivity distribution within the knee joint was homogenous, and no local leakage was observed. Hepatic radioactivity uptake was low, but significantly above background levels, for the first 2 days post-injection, before declining to background levels. Visual imaging indicated an increase in intra-articular fluid volume at 24 hours post-injection.ConclusionsThe elimination kinetics of131I-labelled NASHA from the human knee joint were described by three distinct phases, with half-times of 1.5 hours, 1.5 days and 4 weeks. Most likely, the last value reflects the true half-life of NASHA following intra-articular injection since the labelling method used causes minimal modification of hyaluronan.@SUMMARY ORA =

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS