Drug discovery strategies for acute radiation syndrome

Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.

Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.

Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

A Reminder of Methylene Blue's Effectiveness in Treating Vasoplegic Syndrome after On-Pump Cardiac Surgery

The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide.We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery.     

床旁多普勒超声引导下经皮气管切开术在重症脑出血患者中的应用

目的探讨床旁多普勒超声引导下经皮气管切开术（PDT）在重症脑出血患者中的应用价值。方法选取2014年1月—2019年4月南方医科大学附属小榄医院重症医学科监护治疗的重症脑出血患者126例，在ICU床旁采用超声引导下行PDT。术前采用超声进行检查，明确气管位置、周围组织及血管情况，确定穿刺部位及深度，指导术前气管导管退管。术中实时超声引导，确保手术安全。术后超声确认气管切开套管位置，筛查排除气胸等相关并发症。观察操作时间（从皮肤穿刺到成功置入气管套管时间）、一针穿刺成功率、置管成功率、气管插管意外脱管率；观察术中及术后并发症：出血量、血管/甲状腺损伤、气管后壁损伤、皮下气肿、气胸、低氧血症发生率等。结果126例患者手术均一次操作成功，一针穿刺成功率及置管成功率均为100%，未发生气管插管意外脱管。操作时间5~12 min，平均操作时间7.5 min。术中及术后未发生难以控制的大出血、严重低氧血症、血管/甲状腺损伤、气管后壁损伤、皮下气肿及气胸等并发症。结论对重症脑出血患者行床旁实时超声引导下行PDT，提高了手术的可视性、操作性和安全性，提高PDT成功率，降低相关并发症，具有良好的临床价值。     

痛泻四神汤腹泻型肠易激综合征的胃肠激素水平变化及临床意义观察

目的:探究痛泻四神汤对腹泻型肠易激综合征胃肠激素水平的影响。方法:选取2017年2月至2018年6月西安市中医医院收治的腹泻型肠易激综合征患者124例作为研究对象,按照就诊顺序编号随机分为对照组和观察组,每组62例。对照组给予西医常规治疗,观察组在对照组基础上加用痛泻四神汤加减治疗,均治疗2周。观察和比较2组治疗前后淋巴细胞指标CD3^+、CD4^+、CD8^+、CD4^+/CD8^+变化,观察并比较2组治疗前后胃肠激素指标血浆胃动素(MOT)、降钙素相关基因肽(CGRP)、血管活性肠肽(VIP)、生长抑素(SS)、一氧化氮(NO)变化;观察并比较2组治疗前后在γ-干扰素(IFN-γ)、5-羟色胺(5-HT)、神经肽Y(NPY)含量变化;观察并比较2组治疗前后临床症状腹痛、腹胀、肠鸣失气、急躁易怒、神疲乏力、纳呆食少症状评分变化;治疗过程中进行不良反应记录,治疗结束后进行统计。结果:1)2组患者治疗前CD3^+、CD4^+、CD8^+、CD4^+/CD8^+比较,差异无统计学意义(P>0.05),治疗后2组CD3^+、CD4^+、CD4^+/CD8^+较治疗前均显著上升,CD8^+显著下降(均P<0.05);治疗后观察组患者CD3^+、CD4^+、CD4^+/CD8^+显著高于对照组,CD8^+显著低于对照组(P<0.05)。2)2组治疗前MOT、CGRP、VIP、SS、NO比较,差异无统计学意义(P>0.05),治疗后2组MOT、NO较治疗前显著升高,CGRP、VIP、SS显著下降(P<0.05);治疗后观察组CGRP、VIP、SS显著低于对照组,MOT、NO显著高于对照组(P<0.05)。3)2组治疗前IFN-γ、5-HT、NPY比较,差异无统计学意义(P>0.05),治疗后2组IFN-γ、5-HT、NPY较治疗前均显著下降(P<0.05);治疗后观察组IFN-γ、5-HT、NPY显著低于对照组(P<0.05)。4)2组治疗前腹痛、腹胀、肠鸣失气、急躁易怒、神疲乏力、纳呆食少积分比较,差异无统计学意义(P>0.05),治疗后2组以上各症状评分较治疗前显著下降(P<0.05);治疗后观察组以上各积分显著低于对照组(P<0.05)。5)2组口干、头痛、皮疹、胃肠道反应发生率比较,差异无统计学意义(P>0.05)。结论:痛泻四神汤能改善腹泻型肠易激综合征胃肠激素水平,改善临床症状,提高机体免疫力,提高疗效。     

The Dangerous Middle: Situational Awareness and Worker Perception of Beetle Kill

ABSTRACT

Forest workers, including loggers, foresters, and wildland firefighters, are regularly exposed to some of the most fatal occupational environments in the United States. These hazardous work environments may become even more complex and dynamic when subject to bark beetle outbreaks that have resulted in significant tree mortality. The impacts of tree death from bark beetles are significant, with the cumulative 17-year (2000–2016) footprint for bark beetle caused tree mortality estimated at 54 million acres. However, how workers think about and act in these environments is understudied. This study, therefore, approaches the issue of beetle kill and forest worker safety by examining the perspectives or workers themselves. Its contribution is to leverage ethnographic research to provide insights that can generate new research questions, better inform outreach, and ultimately improve worker safety outcomes. The resulting insights show that beetle kill was understood by workers as a hazard that increased the complexity and dynamism of the work environment, making situational awareness both more necessary and more difficult to maintain. While much research about situational awareness focuses on hazardous situations, it is suggested that building adequate situational awareness should also include broader considerations of organizational communication, as well as training and experience considered over the course of entire careers.     

OTC drug advertising in Japan: the role of need for cognition and celebrity endorser credibility

Abstract

This research explores how the level of consumers’ need for cognition (NFC) is associated with celebrity endorser credibility and examines its effects on advertising-related attitudes. A 3 (endorser types: actor/actress, athlete, TV personality/talent) × 2 (endorser’s gender) factorial experiment with 435 Japanese consumers was conducted. Concerning Japanese OTC drug advertising, lower NFC individuals perceived celebrity endorsers as more credible in comparison to higher NFC individuals. The main effects of NFC and endorser type on endorser credibility existed; however, no interaction between the two variables was found. The endorser type had an influence on attitudes toward ads and the advertised brand.