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No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches. 根据建模方法,二甲双胍或有机阳离子转运体(OCT)1和OCT2以及多药和毒素挤出蛋白(MATE)1/2K与福斯替沙韦联合用药时无需调整剂量。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1238
Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai

Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.

福斯替沙韦是一种已获批准的 gp120 定向附着抑制剂和原药,用于与其他抗逆转录病毒药物(ARVs)联合治疗 1 型人类免疫缺陷病毒感染,适用于对多种药物耐药、不耐受或对当前抗逆转录病毒药物治疗方案存在安全顾虑的重度治疗经验成人。最初的体外研究表明,在测试浓度为100 uM时,fostemsavir的活性分子替米沙韦和其代谢物会抑制有机阳离子转运体(OCT)1、OCT2以及多药和毒素挤压转运体(MATEs),不过,根据食品药品管理局现行的体外药物相互作用(DDI)指南,使用机理静态模型进行的风险评估并未发现对OCTs和MATEs有任何临床相关的抑制作用。然而,EMA 静态模型的预测结果却显示存在 DDI 风险。因此,开发了基于生理学的福斯替沙韦/替米沙韦药代动力学(PBPK)模型,以进一步评估替米沙韦对 OCT 和 MATEs 抑制的 DDI 风险潜力,并预测二甲双胍(一种敏感的 OCT 和 MATEs 底物)暴露量的变化。根据预测,在较宽的替姆沙韦浓度范围内,二甲双胍的浓度不会受到临床相关影响;因此,建议二甲双胍与福斯替沙韦合用时不进行剂量调整。
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引用次数: 0
An open-label study to explore the optimal design of CYP3A drug-drug interaction clinical trials in healthy Chinese people. 一项开放标签研究,探索在健康中国人中进行 CYP3A 药物相互作用临床试验的最佳设计。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1252
Jingcheng Chen, Jiangshuo Li, Jingxuan Wu, Yuqin Song, Lijun Li, Jianxiong Zhang, Ruihua Dong

A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (Cmax), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on Cmax, ~0.18-fold based on AUC0-t, and ~0.18-fold based on AUC0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.

细胞色素P450 3A(CYP3A)药物相互作用(DDI)试验是主要由该酶代谢的药物早期试验的必要组成部分,但CYP3A DDI临床试验并没有标准的设计,尤其是针对中国人。我们旨在为 CYP3A DDI 临床试验设计提供具体建议。这是一项开放式、三周期、自控研究。给健康受试者使用不同的 CYP3A4 致效剂给药策略。在每个周期中,在服用 CYP3A 指示底物咪达唑仑之前和之后 24 小时内采集血样。使用液相色谱串联质谱法测定咪达唑仑和 1-hydroxymidazolam 的血浆浓度。在 CYP3A 抑制方面,根据最大血浆浓度(Cmax)计算,伊曲康唑的负荷剂量可使咪达唑仑的暴露量增加 3.21 倍;根据从零到时间点的曲线下面积(AUC0-t)计算,可使咪达唑仑的暴露量增加 8.37 倍;根据从零到无穷大的曲线下面积(AUC0-∞)计算,可使咪达唑仑的暴露量增加 11.22 倍。伊曲康唑预处理无负荷剂量时的数据类似。就 CYP3A 诱导而言,利福平暴露 7 天后,咪达唑仑的血浆浓度按 Cmax 计算下降了 ~0.27 倍,按 AUC0-t 计算下降了 ~0.18 倍,按 AUC0-∞ 计算下降了 ~0.18 倍。当利福平的预处理时间增加到 14 天时,咪达唑仑的暴露量没有明显变化。本研究表明,伊曲康唑预处理 3 天且不加负荷剂量足以抑制 CYP3A,而利福平预处理 7 天可诱导接近最大的 CYP3A 水平。
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引用次数: 0
Evaluation of intra- and inter-individual variations in plasma belimumab concentrations in adult patients with systemic lupus erythematosus. 评估系统性红斑狼疮成年患者血浆中贝利木单抗浓度的个体内和个体间差异。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1255
Chisato Yoshijima, Yosuke Suzuki, Ryota Tanaka, Hiroyuki Ono, Ayako Oda, Takashi Ozaki, Hirotaka Shibata, Hiroki Itoh, Keiko Ohno

In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra- and interindividual variations in plasma belimumab concentration were evaluated. A single-center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra-high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35-51) years and the median weight was 51.8 (47.0-58.1) kg. A mean of 9.4 (range: 1-13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5-fold difference between patients. On the other hand, the within-patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.

这项研究测量了接受贝利木单抗治疗的系统性红斑狼疮(SLE)患者在治疗过程中的血浆贝利木单抗浓度,并评估了血浆贝利木单抗浓度在个体内和个体间的变化。大分大学医院开展了一项单中心前瞻性研究,评估了13名接受静脉注射贝利木单抗治疗的系统性红斑狼疮患者在治疗过程中的血浆谷浓度。血浆中的贝利木单抗浓度是通过经过验证的超高效液相色谱-串联质谱法测定的。患者的中位年龄为40岁(四分位数间距:35-51岁),中位体重为51.8(47.0-58.1)公斤。每位患者在常规就诊时平均采集了 9.4 份(1-13 份)血液样本。浓度最低的患者血浆中贝利木单抗的平均浓度(± SD)为 33.4 ± 11.9 μg/mL,浓度最高的患者血浆中贝利木单抗的平均浓度(± SD)为 170.0 ± 16.6 μg/mL,表明患者之间存在 5 倍的差异。另一方面,患者内部的变异系数从 7.1% 到 35.7% 不等,显示没有大的变化。血浆中贝利木单抗的浓度与贝利木单抗的剂量(毫克/千克)之间没有发现明显的相关性(Spearman秩相关系数=0.22,p=0.54)。对系统性红斑狼疮患者在治疗过程中的血浆贝利木单抗谷浓度进行的检查显示,个体内差异较小,但个体间差异较大。按批准剂量用药的患者血浆贝利木单抗谷浓度差异很大。
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引用次数: 0
Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function. 对轻度或中度肝功能损害或肝功能正常的参与者进行索替列司他药代动力学和安全性的 1 期研究。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1213
Wei Yin, Pranab Mitra, Veronique Copalu, Thomas C Marbury, Juan Carlos Rondon, Eric J Lawitz, Valerie Lloyd, Mike Baratta, Mahnaz Asgharnejad, Tom Hui, Yasir Khan

This phase 1, open-label, three-arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK-935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child-Pugh B) or mild (Child-Pugh A) hepatic impairment or normal hepatic function (matched to hepatic-impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK-935-G (M3) and M-I were assessed and compared by group. The incidence of treatment-emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M-I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M-I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.

这项1期、开放标签、三臂研究(NCT05098054)比较了肝功能受损患者服用索替列司他(TAK-935)的药代动力学和安全性。与健康匹配的参与者相比,中度肝功能损害者的药代动力学比约高115%,轻度肝功能损害者的药代动力学比约高216%,中度肝功能损害者的药代动力学比约高199%,轻度肝功能损害者的药代动力学比约高45%,轻度肝功能损害者的药代动力学比约高35%,轻度肝功能损害者的药代动力学比约高30%。中度肝功能损害会降低肝脏将索替司他代谢为 M-I 的能力;葡萄糖醛酸化为 M3 的能力也会受到影响。轻度肝功能损害导致血浆 M-I 总暴露量降低,但葡萄糖醛酸化不受影响。各研究臂的 TEAEs 相似且轻微,未观察到新的安全性发现。中度而非轻度肝功能损害患者需要减少索替司他的剂量。
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引用次数: 0
miRNA and leptin signaling in metabolic diseases and at extreme environments. 代谢性疾病和极端环境中的 miRNA 和瘦素信号转导。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1248
Samrita Mondal, Richa Rathor, Som Nath Singh, Geetha Suryakumar

The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.

由于环境和营养之间复杂的相互作用对个体的遗传学和表观遗传学具有重大影响,人们对代谢过程失调的关注与日俱增。因此,由于营养不良、超重、生活方式改变以及暴露于热应激(HS)、冷应激或高海拔(HA)等极端环境,食物摄入调节激素水平的任何异常都可能导致任何年龄组的代谢性疾病的发生。瘦素、脂肪连通素、胃泌素和胆囊收缩素等激素可调节食欲和饱腹感,从而维持能量平衡。瘦素是一种脂肪因子,也是一种多效激素,在调节食物摄入、能量增加和能量消耗方面发挥着重要作用。我们利用硅学方法确定了在瘦素信号通路中发挥关键作用的主要基因(LEP、LEPR、JAK2、STAT3、NPY、POMC、IRS1、SOCS3)。此外,研究人员还从 TargetScan 8.0 数据库中筛选出了 8 个通常靶向这些基因的 miRNA(hsa-miR-204-5p、hsa-miR-211-5p、hsa-miR-30、hsa-miR-3163、hsa-miR-33a-3p、hsa-miR-548、hsa-miR-561-3p、hsa-miR-7856-5p)。这些 miRNA 在调节食欲、能量代谢、代谢性疾病(肥胖、2 型糖尿病、心血管疾病、炎症)以及对抗极端环境方面可能发挥着重要作用,因此应该对它们的作用进行研究。调节瘦素信号转导和食欲的 miRNA 可能有助于开发治疗代谢性疾病的新型疗法。
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引用次数: 0
High prevalence of medication errors in a secondary-level Lithuanian hospital: A prospective cross-sectional observational study. 立陶宛一家二级医院的用药错误高发率:前瞻性横断面观察研究。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1246
J Butauskaite, A Zumbakyte, L Aukstikalne, J Pancere, S Zukaitiene, E Karinauske

As the population continues to age, the occurrence of chronic illnesses and comorbidities that often necessitate the use of polypharmacy has been on the rise. Polypharmacy, among other factors that tend to coincide with chronic diseases, such as obesity, impaired kidney and liver function, and older age, can increase the risk of medication errors (MEs). Our study aims to evaluate the prevalence of MEs in the Internal medicine, Cardiology, and Neurology departments at the secondary-level university hospital. We conducted a prospective observational study of 145 patients' electronic or paper-based data of inpatient prescriptions and patients' pharmacokinetic risk factors, such as an impairment of renal and/or hepatic function, weight, and age. All included patients collectively received 1252 prescribed drugs. The median (Q1; Q3) number of drugs per patient was 8 (7;10). At least one ME was identified in 133 out of the 145 patients, indicating a significantly higher prevalence than hypothesized (91.7% vs. 50%; p < .001). There was moderate, positive correlation between the quantity of prescribed drugs and the number of MEs, meaning that the more drugs are prescribed, the higher the number of identified MEs (Spearman's ρ = 0.428; p < .001). These findings suggest that there is a need for continuous medication education activity for prescribing physicians, continuous evaluation of prescription appropriateness to objectively identify the MEs and to contribute to more rational patient treatment.

随着人口的不断老龄化,慢性疾病和合并症的发生率也在不断上升,这往往需要使用多种药物。除肥胖、肝肾功能受损和高龄等与慢性病相关的因素外,多种药物治疗也会增加用药错误(ME)的风险。我们的研究旨在评估大学二级医院内科、心脏科和神经内科的用药错误发生率。我们对 145 名患者的住院处方电子或纸质数据以及患者的药代动力学风险因素(如肾和/或肝功能损害、体重和年龄)进行了前瞻性观察研究。所有纳入的患者共接受了 1252 种处方药。每名患者的药物数量中位数(Q1; Q3)为 8 (7;10)。在 145 名患者中,有 133 名患者至少发现了一种 ME,这表明其发病率明显高于假设(91.7% 对 50%;P.
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引用次数: 0
Predictors of gentamicin therapy failure in neonates with sepsis. 败血症新生儿庆大霉素治疗失败的预测因素。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1250
Bonifasius Siyuka Singu, Clarissa Hildegard Pieper, Roger Karel Verbeeck, Ene I Ette

Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world-wide. Gram-negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early-onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross-sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C-reactive protein, low birthweight, and low white blood cell count.

败血症是一种常见疾病,在全世界重症监护室的新生儿中发病率和死亡率都很高。革兰氏阴性杆菌是新生儿的主要感染源。庆大霉素是治疗早期败血症最广泛使用的氨基糖苷类抗生素。然而,由于各种因素,可能会导致治疗失败。本研究的目的是确定脓毒症新生儿庆大霉素治疗失败的预测因素。这是一项前瞻性横断面研究,于2019年在温得和克中心医院新生儿重症监护室进行,为期5个月。新生儿静脉注射庆大霉素5毫克/千克/24小时,同时联合使用苄青霉素100 000 IU/千克/12小时或氨苄西林50毫克/千克/8小时。在 50 名新生儿中,有 36% 被归类为庆大霉素治疗失败。治疗时间延长一天,治疗失败的几率就会从 1.0 上升到 2.41。同样,CRP 增加一个单位,庆大霉素治疗失败的几率增加 49%。出生体重每增加 1 公斤,治疗失败的对数几率就会降低 6.848,从而使治疗失败的几率降低 99.9%。白细胞增加一个单位,庆大霉素治疗失败的几率降低 27%。对治疗失败重要预测因素的估计非常精确,得出的几率比在 95% 的置信区间内。本研究发现以下因素可预测新生儿庆大霉素治疗失败:治疗时间过长、C反应蛋白升高、出生体重过轻和白细胞计数过低。
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引用次数: 0
FDA regulatory considerations for oncology drug development. 美国食品及药物管理局对肿瘤药物开发的监管考虑。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1002/prp2.1254
Hanlim Moon, Dae Young Zang, Min-Hee Ryu, YeonSook Seo, Bitna Oh, Sunjin Hwang, Lee Farrand
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引用次数: 0
Involvement of Piezo 1 mechanoceptors in vascular stiffness in isolated small resistance arteries of male and female Dahl salt‐sensitive hypertensive rats Piezo 1 机械感受器参与了雌雄达尔盐敏感高血压大鼠离体小阻力动脉血管僵化的研究
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-22 DOI: 10.1002/prp2.1227
Eric A. Mensah, Noriko Daneshtalab, Reza Tabrizchi
Piezo are mechanosensitive non‐selective cation channels that are suggested to be involved in vascular development and function. The aim of our study was to determine any sex‐specific contributions of the mechanosensitive Piezo 1 channels on blood vessel wall stiffness. Composite Young modulus (CYM) was determined using pressure myograph experimental approach using third‐order mesenteric arteries (intact and denuded) from Dahl salt‐sensitive male and female normotensive and hypertensive rats (n = 6–8). The effects of Piezo 1 agonist (Yoda 1; 10 μM), and antagonist (GsMTx‐4; 2 μM) were studied in intact and denuded vessels. The distribution of Piezo 1 was identified using immunohistochemistry. In intact blood vessels, there were no differences in CYM between the experimental groups, however, removal of the endothelium unmasked significant increases in CYM in normotensive males and female groups compared to hypertensive males. The presence of Yoda 1 did not affect CYM in any groups. In the intact tissues, GsMTx‐4 led to significant increases in CYM in hypertensive females, and normotensive males and females, but not in hypertensive males. In the denuded vessels, GsMTx‐4, produced a significant increase in CYM but only in the female normotensives. Differential expression of Piezo 1 were found in male versus female blood vessels. Our findings support a greater contribution of Piezo 1 mechanoceptors to vascular biomechanics of male hypertensive compared to male normotensive or female groups. The evidence also points to a possible differential vasoregulatory role for Piezo 1 in endothelial versus vascular smooth cells, with a greater contribution in males than females.
压电是一种对机械敏感的非选择性阳离子通道,被认为参与了血管的发育和功能。我们的研究旨在确定机械敏感性 Piezo 1 通道对血管壁僵硬度的贡献是否具有性别特异性。我们使用压力肌电图实验法测定了达氏盐敏感雌雄正常血压大鼠和高血压大鼠(n = 6-8)的三阶肠系膜动脉(完整和剥离)的复合杨氏模量(CYM)。在完整和剥离的血管中研究了 Piezo 1 激动剂(Yoda 1; 10 μM)和拮抗剂(GsMTx-4; 2 μM)的作用。使用免疫组织化学方法确定了 Piezo 1 的分布。在完整的血管中,各实验组之间的 CYM 没有差异,然而,与高血压男性相比,去除内皮后,正常血压男性和女性组的 CYM 明显增加。尤达 1 的存在对各组的 CYM 均无影响。在完整组织中,GsMTx-4 会导致高血压女性、正常血压男性和女性的 CYM 显著增加,但不会影响高血压男性。在剥脱的血管中,GsMTx-4 能使 CYM 显著增加,但仅适用于正常血压的女性。在男性和女性血管中发现了不同的 Piezo 1 表达。我们的研究结果表明,与血压正常的男性或女性相比,Piezo 1 机械感受器对男性高血压患者血管生物力学的贡献更大。证据还表明,Piezo 1 在血管内皮细胞和血管平滑细胞中可能起着不同的血管调节作用,男性的贡献大于女性。
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引用次数: 0
Asciminib, a novel allosteric inhibitor of BCR‐ABL1, shows synergistic effects when used in combination with imatinib with or without drug resistance 阿西米尼是一种新型 BCR-ABL1 异源抑制剂,与伊马替尼联合使用时,无论有无耐药性,都能产生协同效应
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-21 DOI: 10.1002/prp2.1214
Naoki Okamoto, Kenta Yagi, Sayaka Imawaka, Mayu Takaoka, Fuka Aizawa, Takahiro Niimura, Mitsuhiro Goda, Koji Miyata, Kei Kawada, Yuki Izawa‐Ishizawa, Satoshi Sakaguchi, Keisuke Ishizawa
In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.
在慢性髓性白血病(CML)的治疗中,BCR-ABL 抑制剂的耐药性使治疗难以为继,并直接关系到患者的寿命。因此,阿昔米尼作为克服耐药性的有效药物被推向市场。虽然联合使用分子靶向药物有助于避免耐药,但新的 BCR-ABL 抑制剂 asciminib 和传统的 BCR-ABL 抑制剂原则上应作为单一疗法使用。因此,我们研究了阿西米尼和伊马替尼联合用药的协同效应和机制。我们利用人类CML细胞株K562生成了伊马替尼耐药细胞,利用WST-8试验检测了伊马替尼和阿西米尼暴露对细胞存活的影响,并利用RNA-seq和实时PCR全面分析了与耐药性相关的基因变异。在伊马替尼耐药或不耐药的情况下,伊马替尼和阿西米尼联合使用可观察到协同效应。提取了GRRP1、ESPN和NOXA1三个基因作为阿西米尼的作用位点。阿西米尼与BCR-ABL抑制剂联用可提高传统BCR-ABL抑制剂的疗效,并防止耐药性的产生。即使使用不会引起副作用的最小剂量,其剂量也可能有效。这一作用机制还需要进一步验证。此外,BCR-ABL 抑制剂与阿西米尼之间可能会产生交叉耐药性,这需要尽快通过进一步验证加以澄清。
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Pharmacology Research & Perspectives
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