试论异常毒性作为药品质量控制指标的合理性

异常毒性最初是一种确保复杂成分制剂生产工艺一致性及安全性的辅助检测手段，后来成为针对外源性毒性污染物的通用安全性检测项，曾在世界范围内被各国药典收载。由于该检测与药品质量、安全性之间的关联性受到质疑，各国药典逐渐在各论及通则中删除该检测项，目前仅《中国药典》保留异常毒性。由于该检测存在设定限值难以统一、给药体积及给药剂量不合理、结果易受干扰且缺乏明确的判定标准等试验原理及设计上的缺陷，导致其试验结果没有实际参考意义。基于对历史数据的回顾分析，国际监管机构及卫生组织对异常毒性有了更为科学的认知，并已逐渐形成统一的监管共识：严格的生产控制措施和有效的质量检测手段，比异常毒性检测更为重要；异常毒性检测结果或与产品质量及污染不具相关性；在异常毒性检查中使用大量动物不符合动物福利和“3R”原则。本文从科学角度试论异常毒性作为药品质量控制指标的合理性，并总结异常毒性修订的科学原则，希望能为我国监管机构、制药行业修订异常毒性相关内容提供思考角度。     

Comparison of guidelines and consensus articles on the management of patients with acne with oral isotretinoin

Guidelines and consensus on the management of patients with acne aim to give evidence-based, expert-group recommendations. This review compares current guidelines and consensus articles to provide a compilation of recommendations on the treatment of acne with oral isotretinoin. Ten common, relevant, clinical questions are addressed, based on published recommendations, including the indications of isotretinoin, the proposed daily dose, the cumulative isotretinoin dose and the laboratory monitoring needed. Recommendations on special considerations are also addressed, including the timing of procedures and the question of an association of depression or inflammatory bowel disease with isotretinoin. A major limitation is the use of different classification systems for acne across guidelines. The recommended daily dose ranges from 0.3 to 0.5 mg/kg in the European guidelines to up to 1 mg/kg in the US guidelines. A specific duration of treatment of at least 6 months is only recommended in the European guidelines. All guidelines report the need of strict pregnancy prevention measures. The European, French and US guidelines recommend to monitor for symptoms of depression. Important clinical questions that are inconsistently addressed in guidelines include the age indication, the recommendation for a cumulative dose, the timing of procedures, the association of isotretinoin with IBD, the recommendation for preventing acne flares and for appropriate laboratory monitoring. These topics should be clearly included in the recommendations of guidelines as they are often raised in everyday clinical practice.     

The Transient Receptor Potential Vanilloid 1 Antagonist Capsazepine Improves the Impaired Lung Mechanics during Endotoxemia

Acute lung injury (ALI) caused by systemic inflammatory response remains a leading cause of morbidity and mortality in critically ill patients. Management of patients with sepsis is largely limited to supportive therapies, reflecting an incomplete understanding of the underlying pathophysiology. Furthermore, there have been limited advances in the treatments for ALI. In this study, lung function and a histological analysis were performed to evaluate the impact of transient receptor potential vanilloid‐1 receptor (TRPV1) antagonist (capsazepine; CPZ) on the lipopolysaccharide (LPS)‐induced lung injury in mice. For this, adult mice pre‐treated with CPZ or vehicle received intraperitoneal injections of LPS or saline and 24 hr after, the mice were anaesthetized, and lung mechanics was evaluated. The LPS‐challenged mice exhibited substantial mechanical impairment, characterized by increases in respiratory system resistance, respiratory system elastance, tissue damping and tissue elastance. The pre‐treatment with CPZ prevented the increase in respiratory system resistance and decreased the increase in tissue damping during endotoxemia. In addition, mice pre‐treated with CPZ had an attenuated lung injury evidenced by reduction on collapsed area of the lung parenchyma induced by LPS. This suggests that the TRPV1 antagonist capsazepine has a protective effect on lung mechanics in ALI during endotoxemia and that it may be a target for enhanced therapeutic efficacy in ALI.     

Vestibular Function Measurement Devices

Vestibular function laboratories utilize a multitude of diagnostic instruments to evaluate a dizzy patient. Caloric irrigators, oculomotor stimuli, and rotational chairs produce a stimulus whose accuracy is required for the patient response to be accurate. Careful attention to everything from cleanliness of equipment to threshold adjustments determine on a daily basis if patient data are going to be correct and useful. Instrumentation specifications that change with time such as speed and temperature must periodically be checked using calibrated instruments.     

Exact confidence intervals for the average causal effect on a binary outcome

Based on the physical randomization of completely randomized experiments, in a recent article in Statistics in Medicine, Rigdon and Hudgens propose two approaches to obtaining exact confidence intervals for the average causal effect on a binary outcome. They construct the first confidence interval by combining, with the Bonferroni adjustment, the prediction sets for treatment effects among treatment and control groups, and the second one by inverting a series of randomization tests. With sample size n, their second approach requires performing O(n⁴)randomization tests. We demonstrate that the physical randomization also justifies other ways to constructing exact confidence intervals that are more computationally efficient. By exploiting recent advances in hypergeometric confidence intervals and the stochastic order information of randomization tests, we propose approaches that either do not need to invoke Monte Carlo or require performing at most O(n²)randomization tests. We provide technical details and R code in the Supporting Information . Copyright © 2016 John Wiley & Sons, Ltd.