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A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance. 在肾脏清除率增高的重症患者病例系列中对头孢他啶-阿维菌素进行描述性药代动力学/药效学分析。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1163
Ying Xu, Jian Tang, Binbin Yuan, Xuemei Luo, Pei Liang, Ning Liu, Danjiang Dong, Lu Jin, Weihong Ge, Qin Gu

To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.

目的:描述肾清除率增高(ARC)的重症患者2小时输注头孢他啶-阿维菌素(CAZ-AVI)的药代动力学/药效学(PK/PD)。我们对2020年8月至2023年5月期间接受过CAZ-AVI治疗的所有ARC重症患者进行了回顾性研究。患者在接受CAZ-AVI治疗前的12 h肌酐清除率和CAZ-AVI的稳态浓度(Css)均受到监测。根据Css计算CAZ-AVI的游离部分(fCss)。当CAZ的Css/最低抑制浓度(MIC)比值≥4(相当于100% fT > 4 MIC)和AVI的Css/CT比值>1(相当于100% fT > CT 4.0 mg/L)同时达到时,CAZ-AVI的PK/PD联合目标被认为是最佳的;当两个目标中只有一个达到时,则被认为是准最佳的;当两个目标均未达到时,则被认为是次最佳的。评估了PK/PD目标实现、微生物根除和CAZ-AVI临床疗效之间的关系。共纳入了四名患者。只有一名患者达到了最佳的联合 PK/PD 目标,其他三名患者均未达到最佳目标。PK/PD指标达到最佳的患者实现了微生物根除,而其他三名患者则没有,但所有四名患者都取得了良好的临床疗效。标准剂量可能无法使大多数 ARC 重症患者达到 CAZ-AVI 的最佳联合 PK/PD 目标。对 ARC 患者进行 CAZ-AVI 的最佳药物剂量调整需要动态药物浓度监测。
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引用次数: 0
Inhibition of PDE-4 isoenzyme attenuates frequency and overall contractility of agonist-evoked ureteral phasic contractions. 抑制 PDE-4 同工酶可减弱激动剂诱发的输尿管阶段性收缩的频率和总体收缩力。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-02-01 DOI: 10.1002/prp2.1175
Iris Lim, Taishi Masutani, Hikaru Hashitani, Russ Chess-Williams, Donna Sellers

The aim of this study was to investigate the functional role of phosphodiesterase enzymes (PDE) in the isolated porcine ureter. Distal ureteral strips were mounted in organ baths and pre-contracted with 5-HT (100 μM). Upon generation of stable phasic contractions, PDE-4 and PDE-5 inhibitors were added cumulatively to separate tissues. PDE-4 inhibitors, such as rolipram (10 nM and greater) and roflumilast (100 nM and greater), resulted in significant attenuation of ureteral contractile responses, while a higher concentration of piclamilast (1 μM and greater) was required to induce a significant depressant effect. The attenuation effect by rolipram was abolished by SQ22536 (100 μM). PDE-5 inhibitors, such as sildenafil and tadalafil, were not nearly as effective and were only able to suppress the 5-HT-induced contractions at higher concentrations of 1 μM. Rolipram significantly enhanced the depressant effect of forskolin, while sodium nitroprusside-induced attenuation of contractile responses remained unchanged in the presence of tadalafil. In summary, our study demonstrates that PDE-4 inhibitors are effective in attenuating 5-HT-induced contractility in porcine distal ureteral tissues, while PDE-5 inhibitors are less effective. These findings suggest that PDE-4 inhibitors, such as rolipram, may hold promise as potential therapeutic agents for the treatment of ureteral disorders attributable to increased intra-ureteral pressure.

本研究旨在探讨磷酸二酯酶(PDE)在离体猪输尿管中的功能作用。将输尿管远端条带安装在器官槽中,并预先用 5-HT (100 μM)进行收缩。在产生稳定的阶段性收缩后,将 PDE-4 和 PDE-5 抑制剂累积添加到分离的组织中。PDE-4抑制剂,如罗立普仑(10 nM及以上)和罗氟司特(100 nM及以上),可显著减弱输尿管收缩反应,而更高浓度的吡拉米司特(1 μM及以上)则需要诱导显著的抑制作用。SQ22536(100 μM)可消除罗利普仑的衰减效应。PDE-5抑制剂,如西地那非和他达拉非,效果并不明显,只能在1μM的较高浓度下抑制5-HT诱导的收缩。罗利普仑能明显增强福斯可林的抑制作用,而硝普钠诱导的收缩反应减弱作用在他达拉非存在时保持不变。总之,我们的研究表明,PDE-4 抑制剂能有效减弱猪输尿管远端组织中 5-HT 诱导的收缩性,而 PDE-5 抑制剂的效果较差。这些研究结果表明,PDE-4 抑制剂(如罗利普仑)有望成为治疗输尿管内压增高引起的输尿管疾病的潜在治疗药物。
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引用次数: 0
The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload. 磷酸二酯酶-5抑制剂或血管紧张素转换酶抑制剂对慢性容量超负荷导致的心力衰竭患者左右心室重塑的影响。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1172
Tereza Tykvartova, Matus Miklovic, Martin Kotrc, Petra Skaroupkova, Ludmila Kazdova, Jaroslava Trnovska, Vojtech Skop, Michal Kolar, Jiri Novotny, Vojtech Melenovsky

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

虽然磷酸二酯酶-5抑制剂(PED5i)可在实验模型中预防压力过载心脏的肥大和衰竭,但PDE5i对容量过载(VO)诱导的肥大的影响尚不清楚。此外,肥厚的右心室(RV)和左心室(LV)对长期服用 PDE5i 的反应是否不同,以及这种疗法是否会影响肾功能,这些都还不清楚。本研究旨在阐明 PDE5i 治疗对主动脉腔瘘 (ACF) 引起的 VO 的影响,并将 PDE5i 治疗与使用血管紧张素转换酶抑制剂 (ACEi) 的标准心力衰竭 (HF) 治疗进行比较。ACF/sham 手术在 8 周龄的雄性 HanSD 大鼠身上进行。ACF 动物被随机分配接受 PDE5i 西地那非、ACEi 曲托普利或安慰剂治疗。20 周后,对 RV 和 LV 功能(超声心动图、压力-容积分析)、心肌基因表达和肾功能进行研究。对不同组别的大鼠进行了存活率分析。ACF 导致双心室偏心性肥厚(左心室:+68%,右心室:+145%)、搏出功增加(左心室:3.6 倍,右心室:6.7 倍)以及负荷无关收缩功能降低(PRSW,左心室:-54%,右心室:-51%)。两个 ACF 心室都表现出心肌应激和糖代谢基因的上调。ACEi 而非 PDE5i 可减轻肺充血、左心室重塑、白蛋白尿并提高存活率(ACF/ACEi 的中位存活时间为 41 周,ACF/安慰剂的中位存活时间为 35 周,P = .02)。PDE5i 可增加肺部的环鸟苷单磷酸水平,但不会增加左心室、左心室或肾脏的环鸟苷单磷酸水平。与 ACEi 相比,PDE5i 并未改善 ACF 大鼠的存活率以及心脏和肾脏功能。VO诱导的心房颤动对PDE5i疗法无反应。
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引用次数: 0
Human organ chips for regenerative pharmacology. 用于再生药理学的人体器官芯片。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1159
Girija Goyal, Chaitra Belgur, Donald E Ingber

Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions in vitro by recreating multi-cellular and multi-tissue structures and applying in vivo-like biomechanical cues. Human Organ Chips are being used for drug discovery and toxicology testing as an alternative to animal models which are ethically challenging and often do not predict clinical efficacy or toxicity. In this mini-review, we summarize our presentation that reviewed the state of the art relating to these microfluidic culture devices designed to mimic specific human organ structures and functions, and the application of Organ Chips to regenerative pharmacology.

人体器官芯片(器官芯片)是一种小型微流控装置,通过再造多细胞和多组织结构并应用类似于活体的生物力学线索,可使人体细胞在体外执行复杂的器官级功能。人体器官芯片正被用于药物发现和毒理学测试,作为动物模型的替代品,因为动物模型具有伦理挑战性,而且往往不能预测临床疗效或毒性。在这篇微型综述中,我们总结了我们的演讲,回顾了与这些微流体培养装置有关的技术现状,这些装置旨在模拟特定的人体器官结构和功能,以及器官芯片在再生药理学中的应用。
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引用次数: 0
The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity. 阻断 TGF-β 通路可缓解脂肪营养不良而非肥胖症的葡萄糖和脂质代谢异常。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1160
Wen-Dong Xu, Shui-Zheng Lai, Jia Zhao, Shi-Jie Wei, Xue-Ying Fang, Yi-Yi Liu, Xiang-Lu Rong, Jiao Guo

TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.

TGF-β被认为参与早期器官发育的生理功能和实质性器官纤维化的病理变化,而围绕脂肪组织功能和系统性糖脂代谢紊乱的研究仍然很少。本研究采用了两种动物模型:aP2-SREBP-1c小鼠和ob/ob小鼠。在这两种动物模型的腹股沟白色脂肪组织(iWAT)中,TGF-β通路出现上调。TGF-β抑制剂SB431542成功地使腹股沟白色脂肪细胞体积增加了1.5倍以上,并使肝脏、脾脏和肾脏等外周器官的重量分别减少至给药前的73.05%、62.18%和73.23%。iWAT 显示,aP2-SREBP-1c 小鼠的 GLUTs 和脂肪酶表达升高,随后循环中的 GLU、TG、NEFA 和 GLYCEROL 恢复到野生型水平。相反,抑制 TGF-β 对肥胖/ob 小鼠没有类似影响。在体外,经 TGF-β 阻断剂处理的成熟脂肪细胞的甘油和甘油三酯水平大大高于对照组,而 GLUTs 和脂肪酶的表达水平则没有变化。这些研究结果表明,抑制异常上调的 TGF-β 通路只能恢复 iWAT 的扩张,改善脂肪营养不良症而非肥胖症中糖和脂质的整体代谢失调。
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引用次数: 0
Decreased hepatic enzymes reflect the decreased vitamin B6 levels in Parkinson's disease patients. 肝酶的减少反映了帕金森病患者体内维生素 B6 水平的降低。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1174
Kensuke Ikenaka, Yuta Kajiyama, César Aguirre, Chi-Jing Choong, Seira Taniguchi, Junko Doi, Nan Wang, Takahiro Ajiki, Kotaro Ogawa, Keita Kakuda, Yasuyoshi Kimura, Hideki Mochizuki

The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. Furthermore, to evaluate the effect of Opicapone, a catechol-o-methyl-transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa-Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.

该研究旨在调查帕金森病(PD)患者的维生素 B6 水平及其与肝酶的关系,并评估维生素 B6 水平失调与左旋多巴剂量的关系。此外,通过监测左旋多巴-卡比多巴肠溶胶体注射液(LCIG)患者的谷草转氨酶(AST)和谷丙转氨酶(ALT)水平,评估儿茶酚-邻甲基转移酶抑制剂 Opicapone 对维生素 B6 水平的影响。为达到上述目的,对血清维生素 B6 水平进行了测量(PD 72 人,对照组 31 人)。将维生素 B6 水平与左旋多巴总剂量、临床参数以及帕金森病患者血液中的同型半胱氨酸、白蛋白和血红蛋白水平进行了比较。分析了维生素 B6 水平与谷草转氨酶和谷丙转氨酶水平以及谷丙转氨酶/谷丙转氨酶比值之间的相关性。我们分析了接受 LCIG 治疗前后(24 人)以及接受 LCIG + Opicapone 治疗前后(12 人)患者的 AST 和 ALT 水平以及 ALT/AST 的变化。我们发现帕金森病患者的维生素 B6 水平明显较低。左旋多巴总剂量和白蛋白水平与维生素 B6 水平有独立关联。维生素 B6 水平的降低表现为谷草转氨酶(AST)和谷丙转氨酶(ALT)水平以及谷丙转氨酶/谷草转氨酶(ALT/AS)水平的降低。使用 LCIG 治疗可降低谷草转氨酶和谷丙转氨酶水平以及谷丙转氨酶/谷草转氨酶。在使用 LCIG 的同时使用 Opicapone 可改善 ALT 和 ALT/AST 的下降。我们的结论是,ALT和ALT/AST可作为监测维生素B6水平的有用参数,而Opicapone可改善帕金森病患者维生素B6失调的情况。
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引用次数: 0
Role of G protein-coupled receptor kinases (GRKs) in β2 -adrenoceptor-mediated glucose uptake. G 蛋白偶联受体激酶(GRKs)在β2 -肾上腺素受体介导的葡萄糖摄取中的作用。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-02-01 DOI: 10.1002/prp2.1176
Seungmin Ham, Saori Mukaida, Masaaki Sato, Peter Keov, Tore Bengtsson, Sebastian Furness, Nicholas D Holliday, Bronwyn A Evans, Roger J Summers, Dana S Hutchinson

Truncation of the C-terminal tail of the β2 -AR, transfection of βARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β2 -AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant β2 -ARs were generated and receptor affinity for [3 H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β2 -AR agonists, cAMP accumulation, GLUT4 translocation, [3 H]-2-deoxyglucose uptake, and β2 -AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β2 -AR and β-arrestin2 or between β2 -AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β2 -AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β2 -AR agonists occurred in CHO-GLUT4myc cells expressing β2 -ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type β2 -AR. However, β2 -ARs lacking phosphorylation sites failed to recruit β-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β2 -AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.

截短β2 -AR的C端尾巴、转染βARKct或过度表达激酶死亡的GRK突变体都会降低异丙肾上腺素刺激的葡萄糖摄取,这表明GRK对这种反应很重要。我们探讨了 GRK2 对 β2 -AR 的磷酸化是否在葡萄糖摄取中发挥作用,或者这种反应是否与 GRK2 作为支架蛋白的作用有关。生成了表达野生型和突变型 β2 -AR 的 CHO-GLUT4myc 细胞,并测定了受体对 [3 H]-CGP12177A 的亲和力、结合位点的密度以及异丙肾上腺素和 BRL37344 的亲和力。β2-AR激动剂激活受体后,cAMP积累、GLUT4转位、[3 H]-2-deoxyglucose 摄取和β2-AR内化均得到测定。生物发光共振能量转移用于研究 β2 -AR 与 β-restin2 之间或 β2 -AR 与 GRK2 之间的相互作用。测量了 siRNA 敲除或 GRK 抑制剂对 β2 -AR 激动剂反应后的葡萄糖摄取量。BRL37344 在产生 cAMP 方面是一种较差的部分激动剂,但在葡萄糖摄取和 GLUT4 转位方面显示出与异丙肾上腺素相似的效力和功效。这些对 β2 -AR 激动剂的反应发生在表达缺乏 GRK 或 GRK/PKA 磷酸化位点的 β2 -AR 的 CHO-GLUT4myc 细胞以及表达野生型 β2 -AR 的细胞中。然而,缺乏磷酸化位点的β2 -AR不能招募β-arrestin2,也不会内化。GRK2 基因敲除或 GRK2 抑制剂降低了大鼠 L6 骨骼肌细胞中异丙肾上腺素刺激的葡萄糖摄取。因此,β2 -AR的GRK磷酸化与异丙肾上腺素或BRL37344刺激的葡萄糖摄取无关。然而,作为支架蛋白的GRK对葡萄糖摄取很重要,因为GRK2敲除或GRK2抑制降低了异丙肾上腺素刺激的葡萄糖摄取。
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引用次数: 0
Clinical considerations on monkeypox antiviral medications: An overview. 猴痘抗病毒药物的临床考虑因素:概述。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1164
Fariba Pourkarim, Taher Entezari-Maleki

Monkeypox (mpox), a virus belonging to the orthopoxvirus family, can cause a zoonotic infectious disease with morbidity and cosmetic complications. Therefore, effective antiviral drugs with appropriate safety profiles are important for the treatment of patients with mpox. To date, there is no FDA-approved drug for the treatment of mpox. However, tecovirimat, brincidofovir, and cidofovir are the candidate therapies for the management of mpox. Given the safety concerns following the use of these medications, we aimed to review evidence on the clinical considerations of mpox antiviral medications that will be useful to guide clinicians in the treatment approach. Based on the current evidence, tecovirimat has favorable clinical efficacy, safety, and side effect profile and it can be considered as first-line treatment for mpox.

猴痘(mpox)是一种属于正痘病毒科的病毒,可引起人畜共患的传染病,并伴有发病率和外观并发症。因此,具有适当安全性的有效抗病毒药物对于治疗猴痘患者非常重要。迄今为止,美国食品和药物管理局尚未批准用于治疗麻腮风的药物。不过,替考韦利马特、布林昔多韦和西多福韦是治疗水痘的候选疗法。考虑到使用这些药物的安全性问题,我们旨在回顾有关水痘抗病毒药物临床注意事项的证据,以便为临床医生的治疗方法提供指导。根据目前的证据,替考韦瑞(tecovirimat)具有良好的临床疗效、安全性和副作用,可作为水痘的一线治疗药物。
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引用次数: 0
Scopolamine regulates the osteogenic differentiation of human periodontal ligament stem cells through lactylation modification of RUNX2 protein. 东莨菪碱通过乳化修饰RUNX2蛋白调节人牙周韧带干细胞的成骨分化
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1169
Ying Wu, Pan Gong

Periodontal ligament stem cells (PDLSCs) are important mesenchymal stem cells contributing to regenerating lost periodontal tissues and repairing bone defects. Studies on the molecular mechanism affecting the osteogenic differentiation of PDLSCs are necessary. Scopolamine (SCO) is known as a regulator of neural cell damage. The focus of the current study is on unveiling the role of SCO-mediated molecular mechanism in the osteogenic differentiation of PDLSCs. Through CCK-8 assay and LDH detection, we confirmed that SCO enhanced the viability of PDLSCs. Moreover, we determined that SCO induced the PDLSCs osteogenic differentiation, according to data of ALP activity measurement and ARS staining. Mechanistically, we performed western blot and identified that SCO could promote the lactylation of runt-related transcription factor 2 (RUNX2). We also found through rescue assays that knockdown of RUNX2 could reverse the effect of SCO treatment on the osteogenic differentiation of PDLSCs. Further mechanism investigation revealed that lactylation of RUNX2 at K176 site enhances the protein stability of RUNX2 through deubiquitination. Collectively, our present study unveils that SCO stabilizes RUNX2 to promote the osteogenic differentiation of PDLSCs through the lactylation modification of RUNX2.

牙周韧带干细胞(PDLSCs)是重要的间充质干细胞,有助于牙周组织的再生和骨缺损的修复。有必要对影响牙周韧带干细胞成骨分化的分子机制进行研究。东莨菪碱(SCO)是众所周知的神经细胞损伤调节剂。本研究的重点是揭示 SCO 介导的分子机制在 PDLSCs 成骨分化中的作用。通过 CCK-8 试验和 LDH 检测,我们证实 SCO 能增强 PDLSCs 的活力。此外,根据ALP活性测定和ARS染色数据,我们确定SCO诱导了PDLSCs的成骨分化。从机理上讲,我们进行了 Western 印迹分析,发现 SCO 可促进 RUNT 相关转录因子 2(RUNX2)的乳化。我们还通过挽救实验发现,敲除 RUNX2 可以逆转 SCO 对 PDLSCs 成骨分化的影响。进一步的机制研究发现,RUNX2在K176位点的乳酰化可通过去泛素化增强RUNX2的蛋白稳定性。综上所述,本研究揭示了SCO通过对RUNX2的乳化修饰稳定RUNX2,从而促进PDLSCs的成骨分化。
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引用次数: 0
Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells 大麻素对人类卵巢癌细胞诱导的细胞毒性研究
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-15 DOI: 10.1002/prp2.1152
Kartheek Sooda, Simon J. Allison, Farideh A. Javid
Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB1 receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.
研究表明,大麻素能诱导乳腺癌、前列腺癌和脑癌等多种癌细胞产生抗肿瘤活性。本研究旨在探讨大麻素、CBD(大麻二酚)和 CBG(大麻酚)在对化疗药物敏感和耐药的卵巢癌细胞中的抗肿瘤活性。敏感的 A2780 细胞和耐药的 A2780/CP70 癌细胞以及非癌细胞在不同的暴露时间内分别单独或联合暴露于不同浓度的 CBD、CBG、卡铂或 CB1 和 CB2 受体拮抗剂 AM251 和 AM630,并通过 MTT 试验测定细胞毒性。CBD 和 CB 诱导细胞毒性的作用机制通过多种细胞凋亡和细胞周期检测方法进行了研究。CBD 和 CBG 可选择性地、按剂量和时间降低细胞活力并诱导细胞凋亡。在所有测试的细胞系中,CBD 的作用都强于 CBG。在耐药细胞中,CBD 和 CBG 诱导的细胞毒性均强于卡铂。在两种癌细胞中,CBD 诱导的细胞毒性都不依赖于 CB1 或 CB2 受体,但在顺铂耐药癌细胞中,CBG 诱导的细胞毒性可能涉及 CB1 受体的活性。当亚致死剂量的大麻素与卡铂结合使用时,在这两种癌细胞中都观察到了协同效应。凋亡事件可能涉及线粒体膜电位丧失、Annexin V、caspase 3/7、ROS 活性和细胞周期停滞。这些结果能否应用于临床还需要进一步研究。建议使用大麻素与传统癌症治疗方法相结合。
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引用次数: 0
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Pharmacology Research & Perspectives
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