Genetics and diagnostic refinement

For many psychiatric conditions it is speculated that, rather than being single disease entities, they are a set of several disorders sharing clinical features but having (partly) different underlying causes. The possibility of measuring genetic variation on a large scale has given researchers new hope of identifying these disease subtypes that may differ with respect to prognosis, course, and response to treatment. However, although a considerable number of articles have been published suggesting that we may even be on the verge of making genotype-based diagnoses, the reality is that we do not have a good answer to even the most basic question of how measured genes could best be used to refine diagnostic categories. In this article, we show that for common psychiatric disorders, it may not be possible to simply look for similar genetic profiles in groups of patients. Instead, we propose a model assuming that genotypes affect phenotypes through more or less coherent etiological systems or pathogenic processes and argue that these etiological systems may provide a more fruitful basis for defining disease subtypes. Several examples from the literature that support the face validity of different aspects of our model are given. Finally, we argue that, given our limited knowledge of disease etiology, the use of discovery-oriented techniques requiring extensive data collection and (artificial) intelligent computer searches may be imperative, and discuss the prospect of model-based diagnosis to classify etiologically different disease subtypes.     

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product.     

Water Activity and Its Significance in Topical Dosage Forms

Unique properties of thermodynamic activity of solvents in topical semisolids and its effects on in vitro product performance have not been fully understood. Mechanistic investigation was undertaken to demonstrate the significance of thermodynamic potential of solvents [water activity (a_w) or solvent activity (a_s)] on in vitro performance of model topical formulations. Drug transport across synthetic membranes was found to decrease with decreasing water activity of formulations. Similarly, in vitro permeation of model permeant (caffeine) across porcine epidermis was found to decrease with decreasing water activity of formulations. Notably, relatively low water activity formulations (a_w, 0.78) induced dehydration in porcine skin associated with significant structural changes like detachment of individual stratum corneum layers. Inclusion of hydrating agents (propylene glycol) in low water activity (a_w, 0.78) formulations restored hydration levels and structural integrity of porcine skin. Most importantly, incremental inclusion of propylene glycol in low water activity formulations (a_w, 0.78) enhanced in vitro permeation of model permeant (fluorescein sodium). Further investigation revealed that variability in processing conditions (high shear mixing during emulsification step) could modulate water activity in semisolid formulations despite their compositional sameness. In retrospect, water activity was found to be a critical quality attribute of topical semisolid products which impacts overall product performance and drug delivery.     

FDA Breakthrough Therapy Designation: Evaluating the Quality of the Evidence behind the Drug Approvals

The United States Food and Drug Administration (FDA) has created approval pathways and designations to accelerate access to medications indicated for serious or life‐threatening conditions with limited treatment options. Implemented in 2012, the most recent of these is the breakthrough therapy designation (BTD). The purpose of this article was to review the evidence surrounding approval of medications with nononcology indications approved with the BTD designation from 2012 to 2016. Fifteen medications were identified for eight conditions, ranging from conditions that are relatively common, such as chronic hepatitis C infection, to those that are extremely rare, such as lysosomal acid lipase deficiency. The quality of evidence behind these approvals was highly heterogeneous. Much remains unknown about the safety and efficacy of many agents approved through the BTD. Health care professionals should be aware of these limitations to better educate patients and other providers appropriately.     

电子处方警示系统减少门诊重复用药:以台湾289家医院为例

目的:探讨台湾医院门诊应用电子处方警示系统的效果。方法:采集1998-2009年的医保数据库,纳入各年均有数据库数据的259家医院进行分析。根据台湾医院应用门诊电子处方警示系统的发展,12年分为4个阶段:1998—2000年(T1)、2001-2003年(T2)、2004—2006年(T3)、2007—2009年(T4)。重复用药率是计算每个时间段医院门诊重复用药处方数占全部处方数的比例。应用广义估计方程(Generalized Estimating Equation,GEE)分析4个阶段的重复用药率改变。结果 :T1总体门诊重复用药率11.7%,T2减少到10.4%,但T2-T4维持在10. 5%上下。GEE分析发现重复用药率如期呈现下降,但降幅逐渐减小(T2:b=-2.44; T3:b-3.20;T4:b=-3.30;P0.001)。结论:医院门诊重复用药率随电子处方警示系统应用趋势呈现递减后维持平稳,表示系统虽然有效,但仍有需要持续改善之处。     

我国短缺药品监测预警体系中的利益相关者分析

目的:为我国短缺药品监测预警体系更好的运行、实施提供参考。方法:基于利益相关者理论合理界定我国短缺药品监测预警过程中的利益相关者,分析各利益相关者在实现监测预警目标过程中拥有的"资源"及影响监测目标实现的"阻力"。结果:我国短缺药监测预警体系利益相关者主要包括政府部门、医疗机构、生产企业、流通企业、患者等,不同利益相关者之间有不同的"优势"与"劣势",在目标的达成过程中会遇到不同的"阻力"。结论:基于各利益相关者的利益诉求,妥善解决各利益相关者在实施过程中的困难,建立合理的利益平衡机制,才能带来理想的短缺药品监测预警实施效果。     

政府管制与取消管制对药品价格的影响研究——以消化类药品为例

目的:探究政府管制与取消管制对药品价格的影响,为药品定价政策制定提供依据。方法:研究提取全国医药经济信息网数据库中2011年1月-2016年6月64种消化类药品价格水平、用量和费用的月度数据,通过有对照的间断时间序列(interrupted time-series,ITS)模型,分别分析政府管制和取消管制后样本药品的价格水平、用量与费用变化,其中使用固定拉氏价格指数衡量药品价格水平。第一个ITS分析政府管制的影响,利用2011年1月-2015年6月的月度数据,间断点为2012年5月;第二个ITS分析取消管制的影响,利用2014年6月-2016年6月的月度数据,间断点为2015年6月。结果:政府管制政策实施后,短期内干预组药品相比于对照组的价格指数无显著变化(β_6=-0.000 452,P=0.994),但长期增长趋势显著下降(β_7=-0.050 7, P0.001)。在取消管制政策实施后,短期内干预组相较于对照组药品明显下降(β_6=-0.042 7,P=0.005);长期来看,两组药品价格指数变为上升趋势,干预组相较于对照组药品价格指数趋势变化无显著差异(β_7=0.002 83, P=0. 170)。政府管制与取消管制政策实施前后,消化类药品的用量和费用均无显著变化。结论:政府管制可以有效控制药品价格增长趋势,而取消管制在短期可以使药品价格降低,长期来看药品价格仍持续增长,价格管制或取消管制对药品的用量和费用无影响。