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Progress in the treatment of diabetic cardiomyopathy, a systematic review. 糖尿病心肌病治疗进展,系统回顾。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 DOI: 10.1002/prp2.1177
Yiyi Shou, Xingyu Li, Quan Fang, Aqiong Xie, Yinghong Zhang, Xinyan Fu, Mingwei Wang, Wenyan Gong, Xingwei Zhang, Dong Yang

Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease, valve disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. It is considered a significant and consequential complication of diabetes in the field of cardiovascular medicine. The primary pathological manifestations include myocardial hypertrophy, myocardial fibrosis, and impaired ventricular function, which can lead to widespread myocardial necrosis. Ultimately, this can progress to the development of heart failure, arrhythmias, and cardiogenic shock, with severe cases even resulting in sudden cardiac death. Despite several decades of both fundamental and clinical research conducted globally, there are currently no specific targeted therapies available for DCM in clinical practice, and the incidence and mortality rates of heart failure remain persistently high. Thus, this article provides an overview of the current treatment modalities and novel techniques pertaining to DCM, aiming to offer valuable insights and support to researchers dedicated to investigating this complex condition.

糖尿病心肌病(DCM)是糖尿病患者在没有冠状动脉疾病、瓣膜疾病和其他常规心血管风险因素(如高血压和血脂异常)的情况下发生的一种以心肌功能障碍为特征的疾病。在心血管医学领域,它被认为是糖尿病的重要并发症。其主要病理表现包括心肌肥厚、心肌纤维化和心室功能受损,可导致广泛的心肌坏死。最终会发展为心力衰竭、心律失常和心源性休克,严重者甚至会导致心脏性猝死。尽管全球开展了数十年的基础和临床研究,但目前在临床实践中还没有针对 DCM 的特定靶向疗法,心力衰竭的发病率和死亡率仍然居高不下。因此,本文概述了目前与 DCM 相关的治疗模式和新技术,旨在为致力于研究这一复杂病症的研究人员提供有价值的见解和支持。
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引用次数: 0
Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor. 钙蛋白酶-2抑制剂NA-184的鉴定和神经保护特性
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 DOI: 10.1002/prp2.1181
Michel Baudry, Yubin Wang, Xiaoning Bi, Yun Lyna Luo, Zhijun Wang, Zeechan Kamal, Alexander Shirokov, Ed Sullivan, Dennis Lagasca, Hany Khalil, Gary Lee, Kathy Fosnaugh, Philippe Bey, Shujaath Mehdi, Greg Coulter

Our laboratory has shown that calpain-2 activation in the brain following acute injury is directly related to neuronal damage and the long-term functional consequences of the injury, while calpain-1 activation is generally neuroprotective and calpain-1 deletion exacerbates neuronal injury. We have also shown that a relatively selective calpain-2 inhibitor, referred to as C2I, enhanced long-term potentiation and learning and memory, and provided neuroprotection in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in mice. Using molecular dynamic simulation and Site Identification by Ligand Competitive Saturation (SILCS) software, we generated about 130 analogs of C2I and tested them in a number of in vitro and in vivo assays. These led to the identification of two interesting compounds, NA-112 and NA-184. Further analyses indicated that NA-184, (S)-2-(3-benzylureido)-N-((R,S)-1-((3-chloro-2-methoxybenzyl)amino)-1,2-dioxopentan-3-yl)-4-methylpentanamide, selectively and dose-dependent inhibited calpain-2 activity without evident inhibition of calpain-1 at the tested concentrations in mouse brain tissues and human cell lines. Like NA-112, NA-184 inhibited TBI-induced calpain-2 activation and cell death in mice and rats, both male and females. Pharmacokinetic and pharmacodynamic analyses indicated that NA-184 exhibited properties, including stability in plasma and liver and blood-brain barrier permeability, that make it a good clinical candidate for the treatment of TBI.

我们的实验室已经证明,急性损伤后大脑中的钙蛋白酶-2活化与神经元损伤和损伤的长期功能后果直接相关,而钙蛋白酶-1活化通常具有神经保护作用,钙蛋白酶-1缺失会加剧神经元损伤。我们的研究还表明,一种相对选择性的钙蛋白酶-2抑制剂(称为C2I)可增强小鼠的长期电位、学习和记忆,并在受控皮层冲击(CCI)的创伤性脑损伤(TBI)模型中提供神经保护。利用分子动力学模拟和配体竞争饱和位点识别(SILCS)软件,我们生成了约 130 种 C2I 类似物,并在一系列体外和体内试验中对它们进行了测试。结果发现了两种有趣的化合物:NA-112 和 NA-184。进一步的分析表明,NA-184((S)-2-(3-苄脲基)-N-((R,S)-1-((3-氯-2-甲氧基苄基)氨基)-1,2-二氧代戊烷-3-基)-4-甲基戊酰胺)在小鼠脑组织和人类细胞系中的测试浓度下,可选择性地、剂量依赖性地抑制钙蛋白酶-2的活性,而对钙蛋白酶-1没有明显的抑制作用。与 NA-112 一样,NA-184 也能抑制 TBI 诱导的钙蛋白酶-2 激活和雌雄小鼠和大鼠的细胞死亡。药代动力学和药效学分析表明,NA-184表现出的特性,包括在血浆和肝脏中的稳定性以及血脑屏障渗透性,使其成为治疗创伤性脑损伤的临床候选药物。
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引用次数: 0
Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats. 血管活性物质对雌雄达尔盐敏感大鼠阻力小动脉生物力学的影响
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 DOI: 10.1002/prp2.1180
Eric A Mensah, Noriko Daneshtalab, Reza Tabrizchi

Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex-specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt-sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third-order mesenteric arteries (n = 6). Animals on high-salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle-treated time-control studies. The presence of verapamil (0.3 μM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 μM). BaCl2 (100 μM), ouabain (100 μM), and L-NAME (0.3 μM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 μM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.

血管生物力学的变化导致动脉僵化增加,在循环功能障碍中起着关键作用。我们的目的是研究与生物力学相关的性别特异性药理学变化以及对达尔盐敏感的雌雄大鼠阻力小动脉的结构改变。利用压力肌电图记录测定了复合杨氏模量(CYM),并使用免疫组织化学方法评估了三阶肠系膜动脉(n = 6)的任何结构变化。与普通饮食动物相比,高盐饮食动物患高血压,中心血压和外周血压以及脉搏波速度显著升高。在车辆处理的时间对照研究中,没有观察到任何组别(即雄性和雌性)之间的 CYM 存在明显差异。与车辆相比,维拉帕米(0.3 μM)能显著降低高血压男性的 CYM,而女性则没有变化。苯肾上腺素(0.3 μM)可消除这种效应。与载体相比,BaCl2(100 μM)、uabain(100 μM)和 L-NAME(0.3 μM)合用可明显增加正常血压男性和女性血管中的 CYM,但对高血压男性没有影响。在苯肾上腺素存在的情况下,CYM 的增加被取消。在苯肾上腺素存在的情况下,硝普钠(0.3 μM)可显著降低正常血压男性与高血压男性的 CYM,但女性之间没有差异。在对动脉僵化的生物力学标志物进行免疫组化评估时,观察到男性和女性之间存在明显差异。我们的研究结果表明,压力差异可能是造成生物力学适应性变化以及高血压状态下不同药理反应的原因。
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引用次数: 0
Phenotype versus genotype to optimize cancer dosing in the clinical setting-focus on 5-fluorouracil and tyrosine kinase inhibitors. 表型与基因型在临床中优化癌症用药--聚焦 5-氟尿嘧啶和酪氨酸激酶抑制剂。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-01 DOI: 10.1002/prp2.1182
Jennifer H Martin, Peter Galettis, Alex Flynn, Jennifer Schneider

Cancer medicines often have narrow therapeutic windows; toxicity can be severe and sometimes fatal, but inadequate dose intensity reduces efficacy and survival. Determining the optimal dose for each patient is difficult, with body-surface area used most commonly for chemotherapy and flat dosing for tyrosine kinase inhibitors, despite accumulating evidence of a wide range of exposures in individual patients with many receiving a suboptimal dose with these strategies. Therapeutic drug monitoring (measuring the drug concentration in a biological fluid, usually plasma) (TDM) is an accepted and well validated method to guide dose adjustments for individual patients to improve this. However, implementing TDM in routine care has been difficult outside a research context. The development of genotyping of various proteins involved in drug elimination and activity has gained prominence, with several but not all Guideline groups recommending dose reductions for particular variant genotypes. However, there is increasing concern that dosing recommendations are based on limited data sets and may lead to unnecessary underdosing and increased cancer mortality. This Review discusses the evidence surrounding genotyping and TDM to guide decisions around best practice.

癌症药物的治疗窗口通常很窄;毒性可能很严重,有时甚至致命,但剂量强度不足会降低疗效和生存率。确定每位患者的最佳剂量十分困难,化疗最常用的是体表面积剂量,而酪氨酸激酶抑制剂最常用的是平剂量,尽管有越来越多的证据表明,个体患者的暴露范围很广,许多患者在使用这些策略时接受的剂量并不理想。治疗药物监测(测量生物液体(通常是血浆)中的药物浓度)(TDM)是一种公认的、经过充分验证的方法,用于指导个体患者调整剂量,以改善这种情况。然而,在研究范围之外,在常规护理中实施 TDM 一直很困难。对涉及药物消除和活性的各种蛋白质进行基因分型的技术发展日益突出,一些(但并非所有)指南小组建议对特定的变异基因型降低剂量。然而,越来越多的人担心,剂量建议是基于有限的数据集,可能会导致不必要的剂量不足和癌症死亡率上升。本综述讨论了与基因分型和 TDM 有关的证据,以指导最佳实践决策。
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引用次数: 0
Evaluation of the cardiac safety of parsaclisib, a selective PI3Kδ inhibitor, in patients with previously treated B-cell malignancies: Results from the CITADEL-101 study 评估帕沙利西(一种选择性 PI3Kδ 抑制剂)对既往接受过治疗的 B 细胞恶性肿瘤患者的心脏安全性:CITADEL-101研究的结果
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-02-26 DOI: 10.1002/prp2.1165
Jia Li, Xiaohua Gong, Xing Liu, Xiang Liu, Ke Szeto, Xuejun Chen
Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL-101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non-Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL-101 study. Time-matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose-dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia's method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from −6.83 (−18.8 to 5.19) to 4.75 ms (0.410–9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (−1.75 to 2.48) and 7.87 ms (0.921–14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.
Parsaclisib是一种强效的选择性磷脂酰肌醇3激酶δ抑制剂,已被研究用于治疗B细胞恶性肿瘤,并在自身免疫性疾病和骨髓纤维化患者中进行了研究。CITADEL-101研究(NCT02018861)评估了帕沙利西在复发或难治性非霍奇金淋巴瘤患者中的安全性、耐受性和初步疗效。这项研究根据72例CITADEL-101研究入组患者的数据,评估了帕沙利西作为单药治疗的心脏安全性。69名患者接受了单药治疗,剂量分别为5、10、15、20、30和45毫克,每天一次,在指定时间收集了时间匹配的药代动力学和心电图测量数据。根据离群值分类分析,通过弗里德里西亚法(QTcF)校正心率(HR)后的QT间期、HR或心脏传导的离群值发生率未观察到剂量依赖性影响。根据中心倾向分析,各剂量组的ΔQTcF的最小平方均值(LSMs)(90%置信区间[CI])在-6.83(-18.8至5.19)至4.75毫秒(0.410至9.09)之间(低于20毫秒,大QT效应的阈值),不认为与剂量有关。此外,ΔHR、ΔPR 间期和ΔQRS 间期的 LSM 均很小。从浓度-ΔQTcF分析来看,所有剂量水平的预测ΔQTcF(90% CI)介于0.365(-1.75至2.48)和7.87毫秒(0.921至14.8)之间,CI的最高上限远低于20毫秒,因此,在调查的最高剂量水平(45毫克)之前,排除了较大的QT/QTc效应。总体而言,在所研究的剂量范围内,帕沙利西对QTcF的变化没有显示出浓度依赖性效应,对心率或心脏传导也没有显著影响。
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引用次数: 0
Pharmacology education in the medical curriculum: Challenges and opportunities for improvement. 医学课程中的药理学教育:挑战与改进机会。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-02-01 DOI: 10.1002/prp2.1178
Pius S Fasinu, Teresa W Wilborn

The knowledge and application of pharmacology is essential for safe prescribing and administration of drugs. In this narrative review, the challenges to pharmacology education in the medical curricula were broadly identified to include issues around content and pedagogies. The increasing number of approved drugs and drug targets, expanding field of pharmacology and the often-changing treatment guidelines and board-defined competencies can make pharmacology education in the medical curriculum daunting. There has been a consensus around the deployment of innovative medical curricula with emphasis on vertical and horizontal integration. This strategy, effective as it has been, presents new challenges to pharmacology education. As a discipline often perceived by students to be hard-to-learn, the future of pharmacology education must include heavy reliance on active learning strategies. The continuing utilization of problem-based, team-based and case-based learning can be complemented with personalized learning which aims to identify the learning gaps in individual students. Technology-inspired student engagement can foster pharmacology learning and retention. Early exposure to pharmacology from premedical preparation through an enduring across-the-level integration can be an effective way to enhance pharmacology learning in the medical curricula.

药理学的知识和应用对于安全处方和用药至关重要。在这篇叙述性综述中,我们广泛指出了医学课程中药理学教育所面临的挑战,包括内容和教学方法方面的问题。获批药物和药物靶点的数量不断增加,药理学领域不断扩大,治疗指南和委员会定义的能力经常变化,这些都会使医学课程中的药理学教育变得令人生畏。人们已就创新医学课程的部署达成共识,强调纵向和横向整合。这一策略虽然有效,但也给药理学教育带来了新的挑战。作为一门经常被学生认为难学的学科,药理学教育的未来必须包括对主动学习策略的高度依赖。在继续利用基于问题、基于团队和基于案例的学习的同时,还可以辅之以个性化学习,以找出学生个人的学习差距。由技术激发的学生参与可以促进药理学的学习和保持。在医学课程中,通过持久的跨年级整合,让学生在医学预科准备阶段就尽早接触药理学,是加强药理学学习的有效方法。
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引用次数: 0
Real-world treatment outcomes of immune checkpoint inhibitors used off-label in oncology: A comprehensive cancer institution experience. 免疫检查点抑制剂在肿瘤学中标示外使用的实际治疗效果:综合癌症机构的经验。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1167
Sandra Fontanals, Anna Esteve, Andrea González, Cristina Ibáñez, Ricard Mesía, Ana Clopés

Off-label use (OLU) is quite common in oncology due to the complexity of cancer and the time-consuming regulatory process. However, outcomes of OLU in cancer treatment remain unclear. This study aimed to evaluate the overall survival (OS), event-free survival (EFS), duration of treatment (DOT), and reason for treatment discontinuation in patients receiving immune checkpoint inhibitors (ICI) as OLU for solid tumors from 2011 to 2020. The study collected data on 356 episodes (353 patients), with a median age of 64.4 years, 36.2% women, and 14.6% ECOG ≥ 2. Median OS was 15.7 (11.9-18.7) months, and median EFS was 5.4 (3.8-6.6) months. Men, patients with metastatic disease or ECOG-PS higher than 1, had worse survival outcomes. The findings derived from this study provide valuable information regarding the real-world use of ICI-OLU and contributes to enhancing the decision-making process for individuals with cancer. Further research on immunotherapy outcomes of OLU in cancer is needed.

由于癌症的复杂性和耗时的监管过程,标签外使用(OLU)在肿瘤学中十分常见。然而,OLU 在癌症治疗中的效果仍不明确。本研究旨在评估2011年至2020年期间接受免疫检查点抑制剂(ICI)作为OLU治疗实体瘤患者的总生存期(OS)、无事件生存期(EFS)、治疗持续时间(DOT)和治疗中止原因。该研究收集了356次发病(353名患者)的数据,中位年龄为64.4岁,36.2%为女性,14.6% ECOG≥2。中位 OS 为 15.7(11.9-18.7)个月,中位 EFS 为 5.4(3.8-6.6)个月。男性、患有转移性疾病或ECOG-PS高于1的患者生存率较低。这项研究的结果为ICI-OLU在现实世界中的应用提供了有价值的信息,有助于加强癌症患者的决策过程。我们需要对癌症患者使用 OLU 进行免疫治疗的结果进行进一步研究。
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引用次数: 0
Is pitolisant safe for clinical use? A retrospective pharmacovigilance study focus on the post-marketing safety. 匹多莫德临床使用安全吗?一项以上市后安全性为重点的回顾性药物警戒研究。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1161
Cheng Jiang, Jiancheng Qian, Xin Jiang, Shuohan Zhang, Junxian Zheng, Hongwei Wang

Pitolisant, a novel histamine H3-receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real-world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant-associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant-associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life-threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

Pitolisant 是一种新型组胺 H3 受体拮抗剂,有望治疗嗜睡症。然而,2023年4月3日,一份强调Pitolisant在临床试验中与死亡有关的请愿书将其推向了社会广泛关注的焦点。迄今为止,pitolisant 的临床安全性仍是一个备受争议的话题。本研究旨在全面评估匹多莫德在实际临床环境中的安全性。研究人员从美国食品和药物管理局不良事件报告系统数据库中提取了以匹多莫德为主要可疑药物的不良事件报告。分析了匹多莫德相关不良事件的临床特征和伴随药物。使用四种比例失调分析方法探讨了匹多莫德潜在的不良事件信号。此外,还调查了与匹多莫德相关的不良事件信号在性别、年龄、体重和剂量方面的差异。研究共发现了 526 份报告和 1695 起不良事件,其中匹多莫德是主要的可疑药物。最重要的不良事件信号通常较轻且持续时间较短。匹多莫德的伴随药物非常复杂,主要包括治疗嗜睡症的药物和抗抑郁药。出现了 7 个新的重大不良事件信号。尽管观察到与性别和体重有关的轻微差异,但不同年龄组和不同剂量组的匹多莫德安全性无明显差异。死亡和危及生命的报告结果强调了在使用匹多莫德时加强监测心脏和呼吸系统不良反应的重要性。这项研究使人们对匹多莫德的安全性有了更广泛的了解。
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引用次数: 0
2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats. 雄性大鼠口服 2-脱氧葡萄糖和羟氯喹 HPLC-MS-MS 分析方法和药代动力学相互作用。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1173
Dongxiao Sun, Sangyub Kim, Deepkamal Karelia, Yibin Deng, Cheng Jiang, Junxuan Lü

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax ) and area under the curve (AUC0-4h ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0-8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0-∞ ) of each drug, the combination affected the apparent volume of distribution (Vd ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its Vd . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.

我们之前的研究表明,在动物模型中通过腹腔注射己糖激酶(HK)抑制剂 2-脱氧葡萄糖(2-DG)和自噬抑制剂氯喹(CQ)对 HK2-成瘾的前列腺癌具有协同杀瘤功效。这些口服药物同时口服后的药代动力学(PK)行为尚未见报道。我们开发了高效液相色谱-串联质谱(HPLC-MS-MS)分析 2-DG 和临床首选药物羟氯喹(HCQ)血清样本的方法。我们采用颈静脉封管雄性大鼠模型,在单次灌胃单药或联合用药前后连续采血,研究了这两种药物的 PK 指标,以了解药物之间的相互作用。数据表明,通过 HPLC-MS-MS 多反应监测,2-DG 能从常见单糖中快速、完全地分离出来。将 HPLC-MS-MS 2-DG 和 HCQ 方法应用于 9 只大鼠的血清样本,结果显示 2-DG 单独或与 HCQ 合用后,2-DG 的峰值时间(Tmax)为 0.5 小时,峰值后半衰期约为 1 小时。联合用药后,2-DG 的峰值浓度(Cmax)和曲线下面积(AUC0-4h)分别降低了 53.8% (p = .0004) 和 53.7% (p = .0001),而 HCQ 的 AUC0-8h 则比单药降低了 30.8% (p = .0279)。在不改变每种药物的平均停留时间(MRT0-∞)的情况下,联合用药影响了 2-DG 的表观分布容积(Vd)和清除率(CL),而 HCQ 的清除率不会影响其 Vd。我们观察到同时口服 2-DG 和 HCQ 会产生明显的 PK 负作用,可能是在肠道吸收水平。今后需要对它们的联合用药方案进行优化,以便应用于临床。
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引用次数: 0
Epigenetics in obesity: Mechanisms and advances in therapies based on natural products. 肥胖症的表观遗传学:基于天然产品的疗法的机制和进展。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1171
Peng Chen, Yulai Wang, Fuchao Chen, Benhong Zhou

Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti-obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti-obesity drug targets.

肥胖症是发病和死亡的主要风险因素,因为它与糖尿病、心血管疾病和某些类型的癌症等代谢性疾病关系密切。由于没有药物可用,肥胖症治疗的主要方法仍然是通过运动和调整饮食来改变生活方式。鉴于巨大的疾病负担和未获满足的疗法,我们需要从新的角度看待病理生理学和药物发现。表观遗传学的发展为环境、生活方式和其他风险因素如何导致肥胖症的发病提供了令人信服的理由。此外,表观遗传失调是可以恢复的,据报道,从植物中提取的某些天然产品,如茶多酚、鞣花酸、尿石素、姜黄素、染料木素、异硫氰酸盐和柑橘类异黄酮等,都具有抑制体重增加的作用。这些物质具有巨大的抗氧化潜力,而且还能改变表观遗传机制,因此备受关注。因此,了解表观遗传学修饰,从而锁定肥胖的主要原因,以及某些植物化学物质抗肥胖作用的表观遗传学机制,可以证明是预防肥胖症和开发新型治疗干预措施的合理策略。因此,本综述旨在总结基于天然产品的肥胖症表观遗传学机制和疗法进展,为开发几种潜在的抗肥胖药物靶点提供证据。
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