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IPEx: A gamification tool for learner application of pharmacologic principles of opioid use, misuse, and addiction. IPEx:一种游戏化工具,用于学习阿片类药物使用、滥用和成瘾的药理学原理。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1141
Kelly Karpa, Josie Ward, Melanie Stegman, Arthur Berg, Shou Ling Leong

Opioids are often prescribed to treat chronic pain ailments, despite lack of evidence for many conditions. Prescriptions frequently become the gateway to opioid misuse and abuse. In response to the opioid crisis, medical school educators in the state of Pennsylvania developed core competencies pertaining to opioids and addiction for which all medical students should demonstrate proficiency before graduation. To enable students to achieve these competencies, we developed a web-based app (IPEx) that delivers a gamified experience for learners in which they are (re)exposed to opioid competencies and practice applying pharmacologic principles in the context of a series of longitudinal patient scenarios. Learning and application are measured by student responses to application questions before and after each of five modules. Prior to launching the IPEx tool broadly, we wished to test the application questions; thus, we invited fourth year medical students to complete a 45 question quiz based on IPEx module content. Students had no specific preparation prior to taking the quiz but had been exposed to all content elsewhere in the curriculum. A total of 45 of 141 medical students (32%) opted to complete the quiz (mean score was 47% ± 13%; range 18%-73%). Cronbach alpha for the instrument was .74. These results suggest that the instrument has internal validity, and medical students have room for growth when it comes to application of opioid related competencies, a situation that the IPEx tool may be uniquely suited to remedy.

阿片类药物通常用于治疗慢性疼痛疾病,尽管缺乏许多疾病的证据。处方经常成为滥用和滥用阿片类药物的途径。为了应对阿片类药物危机,宾夕法尼亚州医学院的教育工作者培养了与阿片类和成瘾相关的核心能力,所有医学生都应在毕业前证明其熟练程度。为了使学生能够实现这些能力,我们开发了一款基于网络的应用程序(IPEx),为学习者提供游戏化体验,让他们(再次)接触阿片类药物能力,并在一系列纵向患者场景中应用药理学原理。学习和应用是通过学生在五个模块之前和之后对应用问题的回答来衡量的。在广泛推出IPEx工具之前,我们希望测试应用程序问题;因此,我们邀请了四年级的医学生完成了一个基于IPEx模块内容的45个问题的测验。学生们在参加测验之前没有做任何具体的准备,但已经接触到了课程中其他地方的所有内容。141名医学生中,共有45人(32%)选择完成测试(平均得分为47% ± 13%;范围18%-73%)。该仪器的克朗巴赫α为.74。这些结果表明,该工具具有内部有效性,医学生在应用阿片类药物相关能力方面有成长空间,IPEx工具可能是唯一适合治疗的情况。
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引用次数: 0
Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation. 致Torsagenic药物影响的心脏离子通道mRNA表达的快速变化影响大鼠心脏对β肾上腺素能刺激诱导的心律失常的易感性。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1134
Katarina Hadova, Jana Kmecova, Katarina Ochodnicka-Mackovicova, Eva Kralova, Gabriel Doka, Lenka Bies Pivackova, Peter Vavrinec, Tatiana Stankovicova, Peter Krenek, Jan Klimas

Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.

药物诱导的长QT综合征(LQTS)和尖端扭转(TdP)是药物开发中的严重问题。尽管大鼠是一种有用的科学工具,但与体型较大的物种不同,它们的心脏通常对致扭转药物没有反应。因此,人们对它们对药物引起的心律失常的抵抗力知之甚少。在这里,我们用抑制快速延迟整流电流(Ikr)的抗生素克拉霉素(CLA)、环路利尿剂呋塞米(FUR)或它们的组合(CLA + FUR),并检查用异丙肾上腺素刺激后的功能和分子异常。克拉霉素和速尿口服给药,间隔12小时,共7天 天。为了评估电不稳定性,在基础条件下以及随后在β肾上腺素能刺激下,使用Langendorff灌注心脏法在体内或离体记录心电图(ECG)。使用实时定量PCR测量左心室组织中的基因表达。事实上,FUR和CLA + FUR大鼠表现出低钾血症。CLA和CLA + FUR治疗导致药物诱导的LQTS,甚至在一个CLA中出现TdP发作 + FUR大鼠。联合治疗失调了几个离子通道亚基的基因表达,包括KCNQ1、钙通道和Na+/K + -ATP酶亚基,而两种单一疗法都没有影响。与CLA内的其他大鼠相比,具有记录的TdP的大鼠在离子通道基因表达方面表现出差异 + FUR集团。在离体灌注心脏中未检测到心电图变化。因此,我们报道了在大鼠中同时给予克拉霉素和呋塞米诱导QT延长的心脏离子通道重编程的快速协调,这可能是它们避免β-肾上腺素能刺激引发心律失常的能力的原因。
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引用次数: 0
Effects of (-)-MBP, a novel 5-HT2C agonist and 5-HT2A/2B antagonist/inverse agonist on brain activity: A phMRI study on awake mice. 新型5-HT2C激动剂和5-HT2A/2B拮抗剂/反向激动剂(-)-MBP对大脑活动的影响:清醒小鼠的phMRI研究。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1144
Preeti K Sathe, Gargi R Ramdasi, Kaylie Giammatteo, Harvens Beauzile, Shuyue Wang, Heng Zhang, Praveen Kulkarni, Raymond G Booth, Craig F Ferris

A novel serotonin ligand (-)-MBP was developed for the treatment of schizophrenia that has 5-HT2A/2B antagonist activity together with 5-HT2C agonist activity. The multi-functional activity of this novel drug candidate was characterized using pharmacological magnetic resonance imaging. It was hypothesized (-)-MBP would affect activity in brain areas associated with sensory perception. Adult male mice were given one of three doses of (-)-MBP (3.0, 10, 18 mg/kg) or vehicle while fully awake during the MRI scanning session and imaged for 15 min post I.P. injection. BOLD functional imaging was used to follow changes in global brain activity. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site-specific information on 132 different brain areas. There was a dose-dependent decrease in positive BOLD signal in numerous brain regions, especially thalamus, cerebrum, and limbic cortex. The 3.0 mg/kg dose had the greatest effect on positive BOLD while the 18 mg/kg dose was less effective. Conversely, the 18 mg/kg dose showed the greatest negative BOLD response while the 3.0 mg/kg showed the least. The prominent activation of the thalamus and cerebrum included the neural circuitry associated with Papez circuit of emotional experience. When compared to vehicle, the 3.0 mg dose affected all sensory modalities, for example, olfactory, somatosensory, motor, and auditory except for the visual cortex. These findings show that (-)-MBP, a ligand with both 5-HT2A/2B antagonist and 5-HT2C agonist activities, interacts with thalamocortical circuitry and impacts areas involved in sensory perception.

开发了一种新的5-羟色胺配体(-)-MBP用于治疗精神分裂症,该配体具有5-HT2A/2B拮抗剂活性和5-HT2C激动剂活性。利用药理学磁共振成像对这种新型候选药物的多功能活性进行了表征。据推测(-)-MBP会影响与感觉相关的大脑区域的活动。成年雄性小鼠接受三种剂量(-)-MBP(3.0,10,18 mg/kg)或载体,同时在MRI扫描期间完全清醒并成像15 注射后分钟。BOLD功能成像用于跟踪整体大脑活动的变化。将每次治疗的数据登记到3D MRI小鼠大脑图谱中,该图谱提供132个不同大脑区域的特定位点信息。在许多大脑区域,特别是丘脑、大脑和边缘皮层,阳性BOLD信号呈剂量依赖性降低。3.0 mg/kg剂量对阳性BOLD的影响最大,而18 mg/kg剂量效果较差。相反,18 mg/kg剂量显示出最大的阴性BOLD反应,而3.0 mg/kg表现最少。丘脑和大脑的显著激活包括与情绪体验的帕佩兹回路相关的神经回路。与车辆相比,3.0 mg剂量影响除视觉皮层外的所有感觉模式,例如嗅觉、体感、运动和听觉。这些发现表明,(-)-MBP是一种同时具有5-HT2A/2B拮抗剂和5-HT2C激动剂活性的配体,与丘脑皮质回路相互作用,并影响与感觉感知有关的区域。
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引用次数: 0
Changes in plasma alpha-1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation. 出血性创伤后血浆α-1酸性糖蛋白的变化:ALM药物治疗在大鼠和猪复苏中剂量差异的可能作用。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1133
Hayley L Letson, Jodie L Morris, Geoffrey P Dobson

Introduction: The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs.

Materials and methods: Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits.

Results: Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period.

Conclusions: We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.

引言:药物与血浆蛋白的结合是药物开发中的一个重要考虑因素。据我们报道,猪失血性休克复苏时使用腺苷、利多卡因和镁(ALM)液的剂量几乎是大鼠的3倍。由于利多卡因能与血清α-1-酸糖蛋白(AGP)强结合,本研究的目的是研究失血性休克对大鼠和猪AGP水平的影响。材料和方法:健康成年雄性Sprague-Dawley大鼠和雌性杂交猪(n = 33个)分别接受尾静脉和耳周静脉血液采样,以收集血浆用于AGP测量。大鼠(n = 17) 和清管器(n = 16) 接受了手术器械治疗,并通过肝切除术控制出血,并接受了3%氯化钠治疗 ± ALM IV推注60 4分钟后 h 0.9%氯化钠 ± ALM IV滴漏。对大鼠进行了72次监测 h,术后采集血样,5.25、24和72 h.对猪进行6次监测 h,术后采集血样,60岁时 最小值和6 h.用大鼠和猪特异性酶联免疫吸附测定试剂盒测定血浆AGP。结果:大鼠AGP基线水平为3.91 μg/mL,显著低于猪的83倍(325 μg/mL)。手术器械与大鼠AGP增加约10倍和猪下降21%有关。大鼠在出血和复苏后AGP水平仍然升高(28-29 μg/mL)。相反,在监测期内,ALM或生理盐水处理的猪的血浆AGP没有发现显著差异。结论:我们得出的结论是,与猪的AGP显著降低相比,单独手术的创伤与大鼠AGP显著升高有关。与大鼠相比,失血性休克前猪血浆AGP水平较高与复苏猪所需的ALM剂量较高一致。
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引用次数: 0
Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study. 胺碘酮的使用对美托洛尔浓度、α-OH美托洛尔的浓度、美托洛尔剂量和心率的影响:一项横断面研究。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1137
Sabrina Robert, Marc-Olivier Pilon, Essaïd Oussaïd, Maxime Meloche, Grégoire Leclair, Martin Jutras, Marie-Josée Gaulin, Ian Mongrain, David Busseuil, Jean-Claude Tardif, Marie-Pierre Dubé, Simon de Denus

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

小型研究表明胺碘酮是细胞色素P450(CYP)2D6的弱抑制剂。CYP2D6的抑制导致酶代谢的药物浓度增加,如美托洛尔。考虑到美托洛尔和胺碘酮都具有β-肾上腺素能阻断特性,并且两种药物之间的适度相互作用会导致美托洛尔浓度增加,这可能会导致更高的心动过缓和房室传导阻滞风险。本研究的主要目的是评估在蒙特利尔心脏研究所医院队列中随机收集的患者的美托洛尔血浆浓度是否有助于确定胺碘酮和美托洛尔之间的适度药代动力学相互作用。我们对一项横断面研究进行了分析,该研究是蒙特利尔心脏研究所医院队列的一部分。所有参与者都是自称“白人”的成年人,美托洛尔是他们日常药物治疗方案的一部分。在接受美托洛尔治疗的999名患者中,36人同时服用胺碘酮。调整不同协变量后,胺碘酮的使用与较高的美托洛尔浓度有关(p = .0132)。一致地,胺碘酮的使用与较低的心率之间的相关性在调整了所有研究的协变量后是明显和显著的(p = .0001)。我们的研究结果强调,可以利用随机采集的单个血液样本来检测适度的药代动力学相互作用。
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引用次数: 0
A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [14 C] encorafenib in healthy male subjects. 一项I期、单中心、开放标签研究,旨在研究单次口服剂量100 mg[14 C]安可非尼用于健康男性受试者。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1140
Lance Wollenberg, Erik Hahn, Jason Williams, Kevin Litwiler

Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [14 C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [14 C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.

安可拉芬尼是BRAF V600E以及野生型BRAF和CRAF的新型激酶抑制剂,并已获得批准与二甲替尼联合治疗BRAF V600 E或V600 K突变阳性的不可切除或转移性黑色素瘤,或与西妥昔单抗联合治疗BRAF-V600 E突变阳性的癌症。通过给药[14C]encorafenib(100 mg含90 μCi)给4名健康男性受试者(NCT01436656)。对健康男性受试者单次口服100 mg剂量[14 C]安可非尼后,四名受试者排泄物中放射性的总体回收率均≥93.9%,表明达到了良好的质量平衡。粪便和尿液中放射性剂量的平均值为47.2%。在粪便(5.0%)和尿液(1.8%)中消除的剂量百分比为未改变的安可芬尼,是很小的。代谢被发现是安可芬尼在人体内的主要清除途径(约为回收放射性剂量的88%),主要通过异丙基氨基甲酸甲酯的N-脱烷基作用介导,形成初级1相直接代谢产物M42.5(LHY746)。根据尿液中回收的放射性剂量(47.2%)和粪便中回收的代谢产物总放射性剂量(39%)估计口服吸收。基于这些值以及安克拉芬尼及其代谢物在粪便中稳定的假设,估计口服吸收率至少为~86%。
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引用次数: 0
Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease. 来自活化小胶质细胞的肿瘤坏死因子的自身分泌正反馈被认为与慢性神经疾病具有广泛的相关性。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1136
Ian A Clark, Bryce Vissel

Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.

十多年来,通过新的椎管外途径给予特异性抗肿瘤坏死因子生物制剂依那西普进行脑卒中后康复的经验与由持续过量的脑肿瘤坏死因子水平引起的广泛的慢性神经功能减退相一致。我们提出,这种TNF的持久性和脑疾病的慢性性在很大程度上源于这种细胞因子的正自分泌反馈回路,允许这些细胞产生的过量TNF引起的小胶质细胞活化的持久性。这些观察结果中的许多似乎从未被用来构建对某些慢性但可逆的神经疾病的广泛理解和治疗。我们提出,这种治疗方法可以让这些慢性激活的小胶质细胞恢复到正常的静止状态,而不是简单地中和这种细胞因子从小胶质细胞释放后的直接有害影响。从逻辑上讲,这也适用于以小胶质细胞活化为特征的各种其他神经疾病的慢性大脑方面。其中包括长期新冠肺炎、莱姆病、卒中后综合征、创伤性脑损伤、慢性创伤性脑病、化疗后、放疗后脑功能障碍、脑瘫、胎儿酒精综合征、肝性脑病、吗啡耐受的抗伤害感受状态和神经源性疼痛。此外,某些精神状态,无论是孤立的还是莱姆病和长期新冠肺炎等传染病的后遗症,都有可能通过这种方法被理解并得到相应的治疗。脊髓周围依那西普通过逆转小胶质细胞产生的过量TNF,有望治疗各种慢性中枢神经系统疾病,无论这些疾病是传染性的还是非传染性的。
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引用次数: 0
Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis. 他克莫司与利特莫韦和唑类抗真菌药物在造血干细胞移植后的相互作用:回顾性观察分析。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-08-01 DOI: 10.1002/prp2.1120
Yuri Shinogi, Toshinori Hirai, Miki Ishibashi, Kazuko Ino, Isao Tawara, Takuya Iwamoto

Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.

他克莫司与莱特莫韦和唑类抗真菌药物相互作用,而莱特莫韦对唑类抗真菌药物的药代动力学影响不均匀。我们回顾性地研究了他克莫司(持续输注)与利特莫韦在成人造血干细胞移植患者中联合使用唑类抗真菌药物的相互作用。研究了他克莫司浓度与体重归一化剂量之比(C/D比)的个体变异程度。分析C/D比值与肾小球滤过率(eGFR)的相关性。35例患者(795分)中,他克莫司联合莱特莫韦组C/D比值高于单用他克莫司组(1234.7 [566.2-2721.0]ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p
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引用次数: 0
Application of physiologically based pharmacokinetic modeling to understand real-world outcomes in patients receiving imatinib for chronic myeloid leukemia. 应用基于生理的药代动力学模型来了解接受伊马替尼治疗慢性髓性白血病患者的实际结果。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-08-01 DOI: 10.1002/prp2.1082
Josephine A Adattini, Jeffry Adiwidjaja, Annette S Gross, Andrew J McLachlan

We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss , Css,min and Css,max for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0-24,ss 51.2 vs. 42.7 μg h mL-1 , p < 0.05; Css,min 1.1 vs. 0.9 μg mL-1 , p < 0.05; Css,max 3.4 vs. 2.8 μg mL-1 , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC0-24,ss 56.1 vs. 45.9 μg h mL-1 , p < 0.05; Css,min 1.2 vs. 1.0 μg mL-1 , p < 0.05; Css,max 3.7 vs. 3.0 μg mL-1 , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α1 -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.

我们的目的是使用基于生理的药代动力学(PBPK)建模和模拟来预测慢性髓性白血病(CML)患者的伊马替尼稳态血浆暴露,以研究结果的变异性。通过验证的伊马替尼PBPK模型(Simcyp Simulator)来预测CML患者(n = 68)的伊马替尼AUCss、Css、min和Css、max。使用Kruskal-Wallis秩和检验,根据临床结果(a)早期分子反应(EMR)的实现和(b)≥3级药物不良反应(adr)的发生来评估伊马替尼暴露的差异。敏感性分析探讨了患者特征和药物相互作用对伊马替尼暴露的影响。模拟伊马替尼暴露在患者明显高于EMR相比,患者没有(几何平均数AUC0-24,党卫军51.2 vs 42.7μg h mL-1 p党卫军,最小1.1 vs 0.9μg mL-1 p党卫军,最大3.4 vs 2.8μg mL-1 p 0-24,党卫军56.1 vs 45.9μg h mL-1 p党卫军,最小1.2 vs 1.0μg mL-1 p党卫军,最大3.7 vs 3.0μg mL-1 p浓度1酸性糖蛋白,肝脏和肾脏功能)和与药物因素(剂量,伴随CYP2C8调节剂)导致伊马替尼暴露的个体间变异性。伊马替尼血浆暴露、EMR实现和不良反应之间的关系支持治疗药物监测的基本原理,以指导伊马替尼给药,以实现CML的最佳结果。
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引用次数: 0
Intravenous ibuprofen in postoperative pain and fever management in adults: A systematic review and meta-analysis of randomized controlled trials. 静脉注射布洛芬治疗成人术后疼痛和发热:随机对照试验的系统回顾和荟萃分析。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-08-01 DOI: 10.1002/prp2.1123
Pengxiang Zhou, Lu Chen, Ente Wang, Lanzhi He, Shuxia Tian, Suodi Zhai

This study aims to evaluate the efficacy and safety of multiple or single-dosage intravenous ibuprofen (IVIB) in managing postoperative pain and fever in adults who are unable to take oral medications. A systematic review and meta-analysis was conducted based on randomized controlled trials (RCTs) comparing IVIB with placebo or other analgesic and antipyretic medications for postoperative pain and fever management. Data were collected from 8 main databases from the inception to June 2022. Risk of bias assessment was performed, and the GRADE methodology was used to assess the certainty of pooled evidence. Primary outcomes included visual analogue scale (VAS) scores within 24 h postoperative and reduction of temperature. Meta-analyses were conducted to calculate the mean difference (MD) or risk ratios (RR) and 95% CIs. As a result, a total of twenty-three RCTs with 3716 participants were included. For postoperative pain, with moderate-to-low certainty evidence, IVIB was associated with lower postoperative VAS scores than placebo, with MD ranging from -3.53 (95% CI, -4.32 to -2.75) at 0 min to -0.96 (95% CI, -1.35 to -0.57) at 24 h. Compared with intravenous acetaminophen, IVIB demonstrated lower VAS scores (MD, -1.54 at 0 min; -0.36 at 24 h). For fever, IVIB showed satisfactory antipyretic efficiency in a short period of time, but no difference was observed between IVIB and intravenous acetaminophen. IVIB was well-tolerated for both pain and fever management. In conclusion, moderate-to-low certainty evidence supports the use of IVIB for adults with postoperative pain and fever who are unable to take oral medications.

本研究旨在评估多次或单次静脉注射布洛芬(IVIB)治疗无法口服药物的成人术后疼痛和发热的疗效和安全性。在随机对照试验(rct)的基础上,对IVIB与安慰剂或其他镇痛和解热药物进行了系统回顾和荟萃分析,以治疗术后疼痛和发烧。数据收集自项目启动至2022年6月期间的8个主要数据库。进行偏倚风险评估,并使用GRADE方法评估合并证据的确定性。主要结果包括术后24 h内视觉模拟评分(VAS)和体温下降。进行meta分析以计算平均差异(MD)或风险比(RR)和95% ci。结果,共纳入23项随机对照试验,共3716名受试者。对于术后疼痛,有中等到低确定性证据表明,IVIB与术后VAS评分相关,其MD范围为0分钟时的-3.53 (95% CI, -4.32至-2.75)至24小时时的-0.96 (95% CI, -1.35至-0.57)。与静脉注射对乙酰氨基酚相比,IVIB的VAS评分较低(MD, 0 min时-1.54;-0.36, 24小时)。对于发热,IVIB在短时间内表现出满意的退热效果,但IVIB与静脉注射对乙酰氨基酚之间无差异。IVIB对疼痛和发热管理均具有良好的耐受性。总之,中等至低确定性证据支持对术后疼痛和发热且无法口服药物的成人使用IVIB。
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Pharmacology Research & Perspectives
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