Fuzzy Simulation of Pharmacokinetic Models: Case Study of Whole Body Physiologically Based Model of Diazepam

The aim of the present study is to develop and implement a methodology that accounts for parameter variability and uncertainty in the presence of qualitative and semi-quantitative information (fuzzy simulations) as well as when some parameters are better quantitatively defined than others (fuzzy-probabilistic approach). The fuzzy simulations method consists of (i) representing parameter uncertainty and variability by fuzzy numbers and (ii) simulating predictions by solving the pharmacokinetic model. The fuzzy-probabilistic approach includes an additional transformation between fuzzy numbers and probability density functions. To illustrate the proposed method a diazepam WBPBPK model was used where the information for hepatic intrinsic clearance determined by in vitro-in vivo scaling was semi-quantitative. The predicted concentration time profiles were compared with those resulting from a Monte Carlo simulation. Fuzzy simulations can be used as an alternative to Monte Carlo simulation.     

HPLC法测定枸橼酸喷托维林片含量的测量不确定度评定

目的：评定HPLC法测定枸橼酸喷托维林片含量的测量不确定度.方法：建立HPLC法测定含量的数学模型,分析测量不确定度的来源并对各分量进行量化分析和评估,合成标准测量不确定度,给出扩展测量不确定度报告.结果：HPLC法测定枸橼酸喷托维林片含量的扩展测量不确定度为2.4%,测量结果表示为（99.3±2.4）%,k=2.结论：分析产生不确定度的主要来源,为有效地控制该含量测定方法的准确性提供可靠的理论依据.     

Thirteen week toxicity study of dietary l‐tryptophan in rats with a recovery period of 5 weeks

Although l ‐tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l ‐tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague–Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l ‐tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no‐observed‐adverse‐effect level of l ‐tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l ‐tryptophan: 779 mg kg^–1 body weight day^–1 [males] and 1765 mg kg^–1 body weight day^–1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l ‐tryptophan, the no‐observed‐adverse‐effect level of overall l ‐tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l ‐tryptophan: 948 mg kg^–1 body weight day^–1 (males) and 1956 mg kg^–1 body weight day^–1 (females)). We conclude that l ‐tryptophan has a low toxicity profile in terms of human use.     

Overview of pharmacoeconomic modelling methods

In the current climate of burgeoning health care costs, pharmacoeconomics is becoming increasingly important, but knowledge about pharmacoeconomic methods is limited among most clinicians. This review provides an introduction to, and overview of, common methods used in pharmacoeconomic modelling: decision analysis, Markov modelling, discounting and uncertainty analyses via Monte Carlo simulation. It will conclude with a suggested approach to reading and appraising published pharmacoeconomic analyses.     

Uncertainty and certain death: the role of clinical trials in terminal cancer care

We consider uncertainty in relation to clinical trials for terminal non-small cell lung cancer, which is an aggressive and difficult to treat form of cancer. Using grounded theory to analyse 85 clinical interactions between doctors, patients and family members, we argue that uncertainty is a major source of tension for terminally ill patients, with individuals confronting a choice between transitioning to palliative care or volunteering for an experimental/trial medication that might postpone death. Regardless of their efficacy, patients must also consider how such experimental treatments might impact their quality-of-life. We argue that clinical trials produce uncertainty through (i) discussions about the efficacy of clinical trials; (ii) the physiological consequences of clinical trial medications; and (iii) the impact clinical trials have on patient's prognostic understanding of their terminal cancer. Accordingly, while study participants encounter high prognostic certainty (i.e. they have a fatal cancer), they nonetheless experience considerable uncertainty in relation to their participation in clinical trials.     

工作场所空气中盐酸含量测定的不确定度分析

目的分析工作场所空气中盐酸含量测定过程中的不确定度,明确实验中对结果准确性影响较大的环节。方法找出实验过程中各不确定度分量,计算合成标准不确定度以及扩展不确定度。结果在各分量不确定度中,标准溶液配置引入的不确定度和样品定容引入的不确定度对实验结果的不确定度贡献是较大的。结论实验过程中,首先应选择合格的标准物质,配制标准溶液时要细心、准确,其次样品定容时操作要规范,以减少不确定度。     

工作场所空气中镉含量的不确定度分析

目的分析工作场所空气中镉含量测定过程的不确定度,明确实验中对结果准确性影响较大的环节。方法找出实验过程中各不确定度分量,计算合成标准不确定度以及扩展不确定度。结果在各分量不确定度中,样品溶液制备引入的不确定度和标准溶液配置引入的不确定度对实验结果的不确定度贡献较大。结论实验过程中,要注意样品的消化处理以及标准溶液配制等步骤,最大限度地减少测量结果的不确定度,保证实验数据的准确性、可靠性。     

工作场所空气中二甲苯含量的不确定度分析

目的分析工作场所空气中二甲苯含量测定过程的不确定度,明确实验中对结果准确性影响较大的环节。方法按照国标方法对空气中二甲苯进行测定,找出实验过程中各不确定度分量,计算合成标准不确定度以及扩展不确定度。结果在各分量不确定度中,仪器本身引入的不确定度和重复测量引入的不确定度对实验结果的不确定度贡献较大。结论在注重各个环节质量的前提下,选择精密的仪器以及尽可能多的重复测量待测样品,才能得出可靠的实验结果。     

‘You don't get told anything,they don't do anything and nothing changes’. Medicine as a resource and constraint in progressive ataxia

Background

Progressive ataxias are neurological disorders affecting balance, co‐ordination of movement and speech.

Objective

A qualitative study was undertaken to discover patients'' experiences of ataxia and its symptoms.

Participants

Thirty‐eight people with ataxia recruited from patient support groups and two hospital outpatients departments.

Design

Cross‐sectional qualitative study with thematic analysis.

Results

These accounts highlight the limits of medicine in the context of a rare, incurable and disabling disorder, and the embodied uncertainties brought by slowly progressive diseases that lie at the boundaries of mainstream medical knowledge. The existential crises faced by people with ataxia are seemingly magnified by sometimes idiopathic aetiologies and the limited number of inherited conditions identifiable by the available genetic tests. Interviewees were drawn into a medical system that was focused mainly on the diagnosis process, with widely varying results. However, when asked, most had rather valued the provision of disability aids and physical therapies. Only one informant reported overcoming the myriad uncertainties of progressive ataxia, and their account supported the notion of ‘biographical repair’ in chronic illness.

Conclusions

Clinical uncertainties in ataxia constrained people''s attempts to deal with their condition. The construction of the proactive, informed, medical consumer who is assumed to be a partner in care is problematic in the context of a rare and difficult‐to‐diagnose disease for which there is usually no cure. Service providers should be mindful of the need to manage patient expectations in relation to diagnosis and cure. More focus might usefully be placed on the provision of physical therapies and disability aids.