Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

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.     

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。     

Medical masks’ and respirators’ pattern of use,adverse effects and errors among Portuguese health care professionals during the COVID-19 pandemic: A cross-sectional study

BackgroundDuring COVID-19 pandemic, a shortage of surgical masks (Mask) and respirators (Resp) was experienced worldwide. We aimed to assess its pattern of use, adverse effects and user errors by Portuguese health care professionals (HCP).MethodsA cross-sectional study was conducted through snowball convenience sample, collected by email/ social media to health care organizations. Participants answered an online anonymous survey in March 2021.ResultsMean age of 3052 respondents was 42.1 years old, 83.6% were female and 77.8% provided direct health care to COVID-19 patients. Mean time of use per shift was 6-8 hours in 40.8% of the participants. 28.0% reported never changing it during their shift. Resp use (vs Mask) was more associated with discomfort (58.2% vs 26.8%), affecting task performance (41.5 vs 18.9%) and communication (55.0 vs 40.9%), dyspnea (36.0 vs 14.4%), skin rash (37.5 vs 19.4%) and headache (37.5 vs 19.4%). Frequent user errors included touching the front while in use (70.1% Mask vs 66.3% Resp) and omitting hand hygiene before (61.8% Mask vs 55.0% Resp) or after use (61.3% Mask vs 57.0% Resp). Average number of errors was higher for Mask (4.3), than for Resp (3.2) (all: P < .001).ConclusionsMost HCP admitted an extended use of Mask/ Resp. Resp were more prone to adverse effects and Mask more prone to errors. Strategies to reinforce good practices should be considered.