ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Cyclosporin is a unique immunosuppressive agent with a narrow therapeutic range. The pharmacokinetics of the drug present substantial within- and between-patient variability and drug interactions can significantly alter blood cyclosporin concentrations. Monitoring of cyclosporin concentrations in blood is an invaluable and essential aid in adjusting dosage to ensure adequate immunosuppression while minimising toxicity. The principal rationale behind therapeutic monitoring of cyclosporin is the fact that the incidence of rejection is higher at low cyclosporin concentrations and toxicity occurs more often at high concentrations. In renal transplant recipients, cyclosporin concentrations help to discriminate between insufficient immunosuppression and cyclosporin-induced nephrotoxicity.There are several methods available, both specific and nonspecific, for the routine measurement of cyclosporin. Radioimmunoassay and fluorescence polarisation immunoassay are most widely employed, while high performance liquid chromatography remains the reference procedure. The allegedly specific immunoassays tend to slightly overestimate the actual blood cyclosporin concentrations. There is a need for assay systems capable of measuring the biological activity of cyclosporin. Cyclosporin concentrations should be determined by a specific method, using whole blood as the sample matrix. The routine monitoring of individual cyclosporin metabolites is not warranted, but characterising the metabolite pattern of cyclosporin by concomitant use of a nonspecific and a specific assay can be clinically useful in patients with cyclosporinassociated toxicity or impaired liver function.In organ transplantation, measurement of blood cyclosporin concentration should be continued periodically as long as the therapy continues, whereas monitoring is only indicated in special circumstances in patients with autoimmune and other nontransplant diseases. The assessment of a ‘therapeutic window’ for cyclosporin is complicated for several reasons and definite target ranges cannot be given. Cyclosporin concentrations should always be interpreted in conjunction with the recent blood concentration history and other relevant clinical and laboratory data.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs.An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring.Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from otherin vitroandin vivoeffect measurements. These comparisons revealed that changes in the amplitudes in the&bgr;frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines. which reflects their affinity and intrinsic efficacy at the central&ggr;-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function.The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory.Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus.Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants.There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated. Of these, lamotrigine seems the most likely candidate for a pharmacokinetic approach.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

The pharmacokinetics of absorption and distribution of a single bolus dose of sufentanil 150μg for major abdominal surgery were compared in 20 patients after random intravenous or epidural administration. Samples of plasma and cerebrospinal fluid were taken at regular intervals from time zero to 180 min after injection and at the time of tracheal extubation (3.43 to 12.66h). Sufentanil was analysed by radioimmunoassay. The area under the concentration-time curve (AUC) from zero to 1h. 2h. 3h. tracheal extubation and infinity, the absorption and distribution half-lives. maximum plasma and CSF concentrations, time to the peak concentration of sufentanil, and the fraction of sufentanil that reached the central circulation after epidural administration were assessed. Except in the first sample, plasma concentrations of sufentanil were comparable between the 2 groups. The initial transfer of sufentanil from the epidural space to the systemic circulation appeared to be very rapid. Explanations for this phenomenon are given. In only 3 patients could an uptake of sufentanil from the systemic circulation into the CSF be demonstrated. The transfer of sufentanil from the epidural space into the CSF is slower than the transfer into the plasma and it varied interindividually.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS

摘要:

In 2 longitudinal studies with 10 patients each, the stereoselective pharmacokinetics of nitrendipine and the pharmacokinetics of racemic (rac) bisoprolol (both 20mg orally) were investigated during acute febrile infectious diseases and at least 6 weeks later in the healthy state.The area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) ofrac-nitrendipine were increased in the infectious state by 89% [95% confidence interval (CI): 24 to 187%] and 95% (95% CI: 22 to 209%), respectively. Similar increases were observed for bothS- andR-nitrendipine. Nitrendipine exhibited stereoselective pharmacokinetics in both the healthy state and the infectious state, but the mean ratios ofS: RAUC values [healthy: 1.79 (95% CI: 1.36 to 2.11); infectious: 1.87 (95% CI: 1.62 to 2.11)] were not different. The elimination half-life, protein binding and haemodynamic effects of nitrendipine also did not differ between the infectious and the healthy state. The mechanism for the disease effects may be related to suppression of hepatic cytochrome P450 activity by mediators of inflammatory reactions.On the other hand, none of the pharmacokinetic parameters, including nonrenal clearance, ofrac-bisoprolol was changed during febrile infectious disease, indicating specificity in the effects of acute febrile disease on oxidative drug metabolism.

ISSN:0312-5963    

出版商:ADIS    

年代:1992

数据来源: ADIS