ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Background:The processed electroencephalogram (EEG) is a useful surrogate effect measure in estimating opioid potency and latency to peak effect. However, the relationship between EEG determined potency and clinical measures of potency is unclear. The aim of this study was to characterize the relationship between EEG potency and clinical therapeutic windows for fentanyl, alfentanil and sufentanil and then apply this relationship to the new opioid remifentanil.Methods:The fentanyl congener literature published since 1980 was reviewed in detail. Articles reporting EEG or clinically based concentration‐effect relationships were analyzed. The relationship between the EEG potency and clinical measures of potency was examined for consistency and proportionality for all the fentanyl congeners. A generalized ‘fingerprint’ of this relationship was established. This fingerprint was then used to predict clinical therapeutic windows for the new opioid remifentanil. These predicted concentrations were compared to those actually measured in clinical trials.Results:The processed EEG is a reproducible measure of profound opioid effect. Therapeutic windows of the fentanyl congeners estimated in clinical studies relate to the EEG measure of potency in a reproducible, proportional way; that is, clinically determined therapeutic concentration ranges for specific surgical stimuli or drug synergism are a relatively constant fraction of the plasma concentration required to produce 50% of the maximal EEG effect (EC50) for all the fentanyl congeners. The generalized model of this relationship between EEG potency and clinical measures of potency based on data for alfentanil accurately predicted the remifentanil therapeutic windows estimated in clinical studies.Conclusions:The processed EEG is a useful surrogate measure of opioid effect. In addition to estimating potency and latency to peak effect, the EEG surrogate can also be used to estimate the therapeutic concentrations required for a variety of surgical endpoints. Thus, a single combined pharmacokinetic–pharmacodynamic EEG modeling study can yield not only information about potency and latency to peak effect but can also be used to predict the clinical pharmacodynamics of a novel opioid (as was the case in the remifentanil development program). This information can be useful in guiding a novel opioid development program, improving the efficiency of the overall development process.

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

The bioequivalence of encapsulated vs standard (commercial) sumatriptan was assessed before comparative eletriptan–sumatriptan efficacy studies in the acute treatment of migraine were conducted. Commercially acquired sumatriptan was encapsulated to ensure the double‐blind nature of these studies.The pharmacokinetics of three single oral doses of sumatriptan 100 mg – the standard tablet, an encapsulated tablet, and a stressed encapsulated tablet – were compared in an open, randomized, three‐way crossover study. Stressed capsules were produced by storing capsules for 12 weeks at 40°C/75% humidity; conditions chosen to accelerate any effects potentially induced by long‐term storage under normal conditions. Blood samples were obtained from 22 males at baseline and at intervals over 24 h post‐dose. Bioequivalence parameters were calculated as mean ratios and associated 90% confidence intervals, and between‐drug differences were assessed using standard criteria. A priorin vitrodissolution study confirmed similar dissolution of the encapsulated and standard forms; though stressed tablets had decreased dissolution.For standard, encapsulated and stressed encapsulated sumatriptan, the area under the plasma concentration–time curve from 0 to infinity (AUC) values were 201.95, 199.74 and 203.98 ng h/ml, respectively. Maximum observed plasma concentration (Cmax) values were 58.91, 56.09 and 52.56 ng/ml, respectively. The times to the first occurrence ofCmax(Tmax) were 1.69, 1.83 and 1.98 h, respectively. All forms were bioequivalent using the standard range of 80–125%, with the exception of a 1% out of rangeCmaxfor the stressed form. This parameter was within range usingCmax/AUC, a more sensitive absorption rate estimate.These results demonstrate that the encapsulated and stressed sumatriptan used in these studies are bioequivalent to commercial sumatriptan. TheTmaxdata suggest a similar rate of absorption.

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

There have been 13 high‐profile product withdrawals in the United States during the past 4 years. These withdrawals have been due to a limited range of adverse event types, usually associated with relevant antecedent information. Lesser degrees of regulatory action (e.g. specific post‐marketing surveillance requests, labelled warnings, black boxes, and ‘Dear Doctor’ letters) have often preceded product withdrawal. Criticism of regulators has been misdirected because there is no evidence for a chronological trend in the need to withdraw products, nor in the marketed lifespan. The existence of antecedent information is not necessarily a basis for allegations of earlier, prospective grounds for NDA rejection or product withdrawal: In some cases, adverse events have arisen in patients for whom warnings against prescription already existed. Nonetheless, there appears to be scope for improving this situation. Prescribers need to be more familiar with product labels, and to be able to perceive clinically significant adverse event reports from among the mass of information provided. Black boxes are also currently used ambiguously in the United States. Non‐professional constituencies need to understand that relative rather than absolute judgments are required for all drug approvals and withdrawals.

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2001

数据来源: ADIS