Fundamental & Clinical Pharmacology最新文献

英文中文

The β2-adrenergic receptor agonist formoterol attenuates necrosis and apoptosis in the rat myocardium under experimental stress-induced cardiac injury β2-肾上腺素能受体激动剂福莫特罗能减轻大鼠心肌在实验应激诱导的心脏损伤中的坏死和凋亡。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-07-02 DOI: 10.1111/fcp.13026

Natalia V. Naryzhnaya, Sergey V. Logvinov, Boris K. Kurbatov, Ivan A. Derkachev, Liliia R. Mustafina, Aleksandr S. Gorbunov, Maria A. Sirotina, Mikhail Kilin, Svetlana V. Gusakova, Leonid N. Maslov

Background

Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that β₂-adrenergic receptor (β₂-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome.

Objectives

The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy.

Methods

Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours.

Results

The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of β₂-AR agonist formoterol (50 μg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels.

Conclusion

Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the β₂-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.

背景：目前，临床上还没有治疗拓扑综合征（应激诱发的人类心脏损伤）的有效疗法。之前有研究表明，β2-肾上腺素能受体（β2-AR）激动剂福莫特罗能减轻实验性拓扑综合征的心肌细胞损伤：本研究旨在探讨福莫特罗是否能预防应激诱导的心肌病中心肌细胞和内皮细胞的凋亡和坏死：方法：将大鼠固定2、6和24小时，诱发应激性心肌损伤：结果：应激大鼠的心肌显示出收缩力下降和心肌细胞损伤的组织学表现：核分裂、心肌细胞和内皮细胞的核周水肿以及微循环障碍随着应激时间的延长而加剧。此外，在应激开始 6 小时后检测到内皮细胞凋亡，并在 24 小时后达到高峰。心肌细胞的凋亡仅在应激暴露 24 小时后才显著增加。这些形态学改变与应激 24 小时后血清肌酸激酶-MB、辛迪加-1 和血栓调节蛋白水平的升高有关。在24小时应激暴露期间，给予β2-AR激动剂福莫特罗（50 μg/kg）四次，可改善心肌肌力，降低组织学特征的严重程度，减少TUNEL阳性心肌细胞的数量，降低血清肌酸激酶-MB、辛迪卡-1和血栓调节蛋白的水平：目前的数据表明，在应激诱导的心脏损伤中，心肌细胞的凋亡和坏死以及内皮细胞的坏死可通过激活β2-AR得到缓解。然而，福莫特罗并不能完全消除应激下的心肌细胞凋亡、组织学改变或内皮损伤标志物。

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引用次数: 0

Sodium-glucose cotransporter-2 inhibitor (SGLT2i) plus glucagon-like peptide type 1 receptor combination is more effective than SGLT2i plus dipeptidyl peptidase-4 inhibitor combination in treating obese mice metabolic dysfunction-associated steatotic liver disease (MASLD) 钠-葡萄糖共转运体-2 抑制剂（SGLT2i）加胰高血糖素样肽 1 型受体组合比 SGLT2i 加二肽基肽酶-4 抑制剂组合治疗肥胖小鼠代谢功能障碍相关性脂肪性肝病（MASLD）更有效。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-06-24 DOI: 10.1111/fcp.13024

Pedro H. Reis-Barbosa, Carlos A. Mandarim-de-Lacerda

Background

Monotherapy to treat obesity-associated liver insult is limited.

Objectives

In diet-induced obese mice showing metabolic dysfunction-associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium-glucose cotransporter-2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase-4 inhibitor (DPP4i, linagliptin, L), and glucagon-like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D).

Methods

Male 3-month-old C57BL/6J mice were fed for 12 weeks in a control (C, n = 10) or high-fat (HF, n = 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n = 10/group).

Results

HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (−60%), insulin (−61%), insulin resistance (−46%), TAG (−61%), and steatosis (−58%), and HF E + D showed lower glucose intolerance (−71%), insulin (−58%), insulin resistance (−62%), TAG (−61%), and steatosis (−82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D.

Conclusion

PCA separated the groups considering the metabolism-related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination.

背景治疗肥胖相关性肝损伤的单一疗法非常有限：在饮食诱导的出现代谢功能障碍相关脂肪性肝病（MASLD）的肥胖小鼠中，我们旨在比较钠-葡萄糖共转运体-2抑制剂（SGLT2i，empagliflozin，E）、二肽基肽酶-4抑制剂（DPP4i，linagliptin，L）和胰高血糖素样肽1型受体激动剂（GLP1RA，dulaglutide，D）的组合：雄性 3 个月大 C57BL/6J 小鼠以对照组（C，n = 10）或高脂组（HF，n = 30）饮食喂养 12 周。然后，再对小鼠进行为期三周的跟踪观察：结果：结果：HF 组与 C 组相比，肝脏三酰甘油（TAG，+82%）、脂肪变性（+850%）、葡萄糖不耐受（+71%）、胰岛素（+98%）和胰岛素抵抗（+68%）均较高。与高频组相比，高频 E + L 组的糖耐量减低（-60%）、胰岛素减低（-61%）、胰岛素抵抗减低（-46%）、TAG 减低（-61%）和脂肪变性减低（-58%），而高频 E + D 组的糖耐量减低（-71%）、胰岛素减低（-58%）、胰岛素抵抗减低（-62%）、TAG 减低（-61%）和脂肪变性减低（-82%）。主成分分析（PCA）将高频组和高频 E + D 组置于两侧，而高频 E + L 组则位于 C 组和高频 E + D 组之间：PCA对代谢相关基因（葡萄糖和脂质）、线粒体生物生成和脂肪变性进行了分组。两种药物组合在治疗肥胖症和 MASLD 方面显示出有益的效果。然而，与 SGLT2i 和 DPP4i 相比，SGLT2i 和 GLP1RA 的组合对 MASLD 有更强的疗效，因此应作为推荐组合。

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引用次数: 0

Population pharmacokinetics of mycophenolate in patients treated for interstitial lung disease (EVER-ILD study) 间质性肺病患者中霉酚酸酯的群体药代动力学（EVER-ILD 研究）。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-06-16 DOI: 10.1111/fcp.13021

Yan-Min Xu, David Ternant, Martine Reynaud-Gaubert, Théodora Bejan-Angoulvant, Sylvain Marchand-Adam

Background

Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of the EVER-ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD.

Methods

Concentrations of MPA were measured during an 8-h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first-order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models.

Results

The pharmacokinetics of MPA was best described using a two-compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC₁₂ = 52.5 mg.h/L in median (interquartile range: 42.2–58.0 mg.h/L).

Conclusion

This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies.

背景：霉酚酸酯（MMF）已被用于治疗间质性肺病（ILD），但霉酚酸酯（MPA）的药代动力学尚未见报道。这项EVER-ILD方案的辅助研究旨在利用群体模型描述MPA在ILD中的药代动力学变异性：采用具有一阶转移和消除速率常数的群体分区模型来描述 MPA 的吸收、分布和消除，同时采用伽马吸收模型来考虑两个吸收峰：结果：采用两室模型和两个伽马吸收模型对 MPA 的药代动力学进行了最佳描述，该模型的性能仍与单伽马吸收模型相似。这种药代动力学似乎明显受到体重、肾功能和炎症状态的影响。MMF两次给药之间的浓度曲线下分布值的中位数为AUC12 = 52.5 mg.h/L（四分位间范围：42.2-58.0 mg.h/L）：结论：这是第一项报道MPA在ILD中药代动力学的研究。结论：这是第一项报告 MPA 在 ILD 中药代动力学的研究，该药代动力学似乎与其他适应症相似，应在今后的研究中进一步探讨。

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引用次数: 0

Pharmacological treatment for mental health illnesses in adults receiving dialysis: A scoping review 接受透析治疗的成人精神疾病的药物治疗：范围综述。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-06-15 DOI: 10.1111/fcp.13022

Jenny Wichart, Peter Yoeun, Tracy Chin, Christopher Evernden, Charlotte Berendonk, Jodi Kerr, Alexandra Birchall, Belinda Boschee, Kimberly Defoe, Jasleen Dhaliwal, Tasia KarisAllen, Megan Kennedy, Alexis McDonald, Monika K. Mierzejewski, Kara Schick-Makaroff

Background

Pharmacologic management of mental health illnesses in patients receiving dialysis is complex and lacking data.

Objective

Our objective was to synthesize published data for the treatment of depression, bipolar and related disorders, schizophrenia or psychotic disorders, and anxiety disorders in adults receiving hemodialysis or peritoneal dialysis.

Methods

We undertook a scoping review, searching the following databases: Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Scopus, and Web of Science. Data on patients who received only short-term dialysis, a kidney transplant, or non-pharmacologic treatments were excluded.

Results

Seventy-three articles were included: 41 focused on depression, 16 on bipolar disorder, 13 on schizophrenia and psychotic disorders, 1 on anxiety disorders, and 2 addressing multiple mental health illnesses. The majority of depression studies reported on selective serotonin reuptake inhibitors (SSRIs) as a treatment. Sertraline had the most supporting data with use of doses from 25 to 200 mg daily. Among the remaining SSRIs, escitalopram, citalopram, and fluoxetine were studied in controlled trials, whereas paroxetine and fluvoxamine were described in smaller reports and observational trials. There are limited published data on other classes of antidepressants and on pharmacological management of anxiety. Data on treatment for patients with bipolar disorder or schizophrenia and related disorders are limited to case reports.

Conclusion

Over half of the studies included were case reports, thus limiting conclusions. More robust data are required to establish effect sizes of pharmacological treatments prior to providing specific recommendations for their use in treating mental health illnesses in patients receiving dialysis.

背景：透析患者精神疾病的药物治疗非常复杂且缺乏数据：我们的目的是综合已发表的有关治疗接受血液透析或腹膜透析的成人抑郁症、双相情感障碍和相关障碍、精神分裂症或精神病性障碍以及焦虑症的数据：我们对以下数据库进行了范围界定研究Medline、Embase、CINAHL、PsycINFO、Cochrane Library、Scopus 和 Web of Science。仅接受短期透析、肾移植或非药物治疗的患者的数据被排除在外：结果：共收录了 73 篇文章：41篇侧重于抑郁症，16篇侧重于躁郁症，13篇侧重于精神分裂症和精神病，1篇侧重于焦虑症，2篇涉及多种精神疾病。大多数抑郁症研究报告都将选择性血清素再摄取抑制剂（SSRIs）作为一种治疗方法。舍曲林的支持性数据最多，每日使用剂量从 25 毫克到 200 毫克不等。在其余的 SSRIs 中，艾司西酞普兰、西酞普兰和氟西汀是在对照试验中研究的，而帕罗西汀和氟伏沙明则是在较小的报告和观察试验中描述的。关于其他类别的抗抑郁药和焦虑症的药物治疗，已发表的数据十分有限。关于治疗双相情感障碍或精神分裂症及相关疾病患者的数据仅限于病例报告：结论：半数以上的研究为病例报告，因此限制了结论的得出。在对透析患者的精神疾病治疗提出具体建议之前，需要更多可靠的数据来确定药物治疗的效果大小。

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引用次数: 0

Oral communication abstracts 法国药理学和治疗学学会年会摘要 2024 年 6 月 11-13 日，法国图尔。