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sGC stimulator (BAY 41-8543) combined with PDE9 inhibitor (BAY 73-6691) reduces renal fibrosis in 5/6 nephrectomized rats sGC 刺激剂(BAY 41-8543)与 PDE9 抑制剂(BAY 73-6691)联合使用可减少 5/6 肾切除大鼠的肾纤维化。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-09 DOI: 10.1111/bcpt.14103
Xin Chen, Denis Delić, Yvonne Liu, Yaochen Cao, Zeyu Zhang, Hongwei Wu, Mohamed M. S. Gaballa, Thomas Klein, Saban Elitok, Bernhard K. Krämer, Berthold Hocher

Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41–8543 (1 mg/kg/day) and/or BAY 73–6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41–8543 in combination with BAY 73–6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41–8543 in combination with BAY 73–6691 had no effect on renal macrophage, CD4 + T-cell and CD8 + T-cell in the late-stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41–8543 in combination with BAY 73–6691 down-regulated the expression of fibrosis-related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down-regulating fibrosis-related gene expression. This novel approach of using low-dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD.

肾脏纤维化与慢性肾脏病(CKD)的预后密切相关。cGMP 的增加可减轻肾脏纤维化。可溶性鸟苷酸环化酶(sGC)和磷酸二酯酶(PDE)是维持 cGMP 水平的关键酶。BAY 41-8543(1 毫克/千克/天)和/或 BAY 73-6691(1 毫克/千克/天)用于治疗 5/6 肾切除大鼠,为期 13 周。5/6 肾切除术导致胱抑素 C 增加、蛋白尿、肾小球硬化和肾间质纤维化。单独刺激 sGC 或抑制 PDE9 都不能改善肾功能和肾脏形态,而 BAY 41-8543 与 BAY 73-6691 联用可减轻肾间质纤维化。血压和肾脏免疫系统的改变无法解释这种有益作用。在 5/6 肾切除术后期,BAY 41-8543 联合 BAY 73-6691 对肾巨噬细胞、CD4 + T 细胞和 CD8 + T 细胞没有影响。RNA 测序显示,BAY 41-8543 联合 BAY 73-6691 可下调纤维化相关基因的表达,如胶原 I 型 Alpha 1、胶原 III 型 Alpha 1 链和胶原 XIV 型 Alpha 1 链。这种使用低剂量联合疗法的新方法在保持疗效的同时将副作用降至最低,为治疗慢性肾功能衰竭提供了一种前景广阔的策略。
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引用次数: 0
Dichloroacetate, a pyruvate dehydrogenase activator, alleviates high-fat-induced impairment of myogenic differentiation in skeletal muscles 丙酮酸脱氢酶激活剂二氯乙酸可减轻高脂肪引起的骨骼肌成肌分化障碍。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-06 DOI: 10.1111/bcpt.14102
Chuang-Yen Huang, I-Shan Han, Po-Shiuan Hsieh, Min-Chien Tsai, Hung-Che Chien

Obesity-induced impairment of myogenic differentiation leads to muscle loss and sarcopenia. Pyruvate dehydrogenase (PDH) plays a crucial role in glucose metabolism and is associated with muscle differentiation. However, the effect of dichloroacetate (DCA), a PDH activator, on obesity-induced impairment of myogenic differentiation remains unknown. Here, we evaluated the effects of DCA treatment on high-fat intake-induced impairment of myogenic differentiation in C2C12 cells and C57BL/6 mice. In C2C12 cells, DCA treatment improved PDH activity that was reduced by palmitate (PAL) and decreased the lactate concentrations in the media. Additionally, DCA reversed PAL- and high-fat diet (HFD)-induced decrease in the expression of myoblast determination protein 1 (MyoD), myogenin (MyoG) and myosin heavy chain (MyHC) in C2C12 cells and C57BL/6 mice. To explore the possible mechanism, DCA treatment restored the levels of p-Akt, p-FoxO1, p-FoxO3a and p-p38 MAPK levels in PAL-treated C2C12 cells. Moreover, the protective effects of DCA were reversed by treatment with the Akt inhibitor MK2206 in C2C12 cells. In summary, DCA treatment alleviated high-fat intake-induced impairment of myogenic differentiation via Akt signalling, suggesting its potential in treating obesity-associated muscle loss and sarcopenia.

肥胖引起的肌肉分化障碍会导致肌肉流失和肌肉疏松症。丙酮酸脱氢酶(PDH)在葡萄糖代谢中起着关键作用,并与肌肉分化有关。然而,丙酮酸脱氢酶激活剂二氯乙酸(DCA)对肥胖诱导的肌肉分化损伤的影响仍然未知。在此,我们评估了 DCA 处理对高脂肪摄入诱导的 C2C12 细胞和 C57BL/6 小鼠肌原分化损伤的影响。在 C2C12 细胞中,DCA 处理提高了因棕榈酸酯(PAL)而降低的 PDH 活性,并降低了培养基中的乳酸浓度。此外,DCA还能逆转棕榈酸盐和高脂饮食(HFD)引起的C2C12细胞和C57BL/6小鼠中肌母细胞决定蛋白1(MyoD)、肌原蛋白(MyoG)和肌球蛋白重链(MyHC)表达的减少。为了探索可能的机制,DCA处理可恢复PAL处理的C2C12细胞中p-Akt、p-FoxO1、p-FoxO3a和p-p38 MAPK的水平。此外,用 Akt 抑制剂 MK2206 处理 C2C12 细胞可逆转 DCA 的保护作用。总之,DCA 处理可通过 Akt 信号缓解高脂肪摄入诱导的肌原分化损伤,这表明它具有治疗肥胖相关肌肉损失和肌肉疏松症的潜力。
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引用次数: 0
A nationwide Swedish retrospective study on poisoning deaths between the years 2000 and 2022 瑞典全国范围内对 2000 年至 2022 年间中毒死亡事件的回顾性研究。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-05 DOI: 10.1111/bcpt.14097
Elin Lindqvist, Jacob Hollenberg, Mattias Ringh, Per Nordberg, Henrik Druid, Leif Svensson, Sune Forsberg

Background

Approximately 1% of Sweden's 90 000 annual deaths were reported caused by poisoning. In this study, we aim to describe this poisoning population's characteristics, autopsy frequency and results of toxicology testing.

Method

A national cohort study based on Swedish national registers. All deceased subjects older than 18 years with poisoning as the cause of death registered between 1 January 2000 and 31 December 2021 were included. Causes of death according to primary ICD-10 code were analysed along with the substances found in forensic chemistry testing.

Results

There were 27 057 poisonous deaths during the study periods 2 018 495 adult deaths. Subjects deceased due to poisoning had a median age of 53 years, and 18 838 (70%) were men. A private home was the most reported location of death (52%). In total, 23 260 (87%) did undergo some sort post-mortem examination. Drugs (synthetic narcotics, opioids, heroin) caused 12 448 (46%) deaths, and alcohols explained 9056 cases (33%). Positive toxicological tests were found in 22 550 (83%) of the subjects. The most common separate substances were ethanol, zopiclone and nordazepam.

Conclusion

Poisoning caused 1.3% of Swedish deaths. Men in their 50s were the most common victims, and their deaths were often cause by synthetic narcotics, other opioids or alcohol. The autopsy frequency was lower than expected for poisonous deaths.

背景:据报道,在瑞典每年 9 万例死亡病例中,约有 1%是由中毒引起的。本研究旨在描述中毒人群的特征、尸检频率和毒理学检测结果:方法:一项基于瑞典国家登记册的全国性队列研究。研究对象包括 2000 年 1 月 1 日至 2021 年 12 月 31 日期间登记的以中毒为死因的所有 18 岁以上死者。根据 ICD-10 主要代码对死因和法医化学检验中发现的物质进行分析:研究期间共有 27 057 例中毒死亡 2 018 495 例成人死亡。中毒死亡者的中位年龄为 53 岁,其中 18 838 人(70%)为男性。私人住宅是报告最多的死亡地点(52%)。共有 23 260 人(87%)接受了某种尸检。毒品(合成麻醉剂、阿片类药物、海洛因)导致 12 448 人死亡(占 46%),酒精导致 9056 人死亡(占 33%)。在 22 550 例(83%)受试者中发现了阳性毒物检测结果。最常见的单独物质是乙醇、佐匹克隆和去甲西泮:结论:中毒导致的死亡占瑞典死亡人数的 1.3%。50多岁的男性是最常见的受害者,他们的死亡通常是由合成麻醉剂、其他阿片类药物或酒精造成的。尸检频率低于中毒死亡的预期。
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引用次数: 0
Population pharmacokinetic modelling of cetirizine concentrations in human breast milk—A contribution from the ConcePTION project 母乳中西替利津浓度的群体药代动力学模型--来自 ConcePTION 项目的贡献。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-04 DOI: 10.1111/bcpt.14100
Erik Melander, Elisabet I. Nielsen, Annika Lindqvist, Markus Hovd, Peggy Gandia, Alice Panchaud, Monia Guidi, Pieter Annaert, Pawel Baranczewski, Olav Spigset, Hedvig Nordeng

Cetirizine is an antihistamine commonly used to treat allergic rhinitis and other allergic conditions. Cetirizine is often prescribed to breastfeeding mothers although there is limited information on infant exposure via breast milk. The aim of this study was to develop a popPK model based on data from a lactation study to predict cetirizine breast milk concentrations and estimate the relative infant dose (RID) in a breastfed infant. A popPK model was developed in NONMEM on data from a human lactation study including 35 women using cetirizine or levocetirizine while breastfeeding. Serial samples of breast milk were collected (n = 205) and the cetirizine concentrations quantified using a validated LC–MS/MS method. A one-compartment model of cetirizine in breast milk was developed and employed to calculate the relative infant dose (RID). Covariates related to the maternal characteristics and breastfeeding patterns were evaluated in the model; only milk sampling pumping duration was found to be a significant covariate, with an increasing pumping duration leading to an increased apparent milk volume of distribution (Vm). The mean RID was 1.99% with the highest RID being 3.36% at Cmax. PopPK modelling could be used to estimate infant exposure to cetirizine via breast milk. The low predicted exposure in infants supports that cetirizine is compatible with breastfeeding.

西替利嗪是一种抗组胺药,常用于治疗过敏性鼻炎和其他过敏性疾病。尽管有关婴儿通过母乳接触西替利嗪的信息有限,但母乳喂养的母亲经常会服用西替利嗪。本研究的目的是根据哺乳期研究的数据开发一个 popPK 模型,以预测西替利嗪的母乳浓度,并估算母乳喂养婴儿的相对婴儿剂量 (RID)。根据一项人类哺乳期研究的数据,在 NONMEM 中建立了一个 popPK 模型,该研究包括 35 位在哺乳期使用西替利嗪或左西替利嗪的妇女。研究人员收集了连续的母乳样本(n = 205),并使用经过验证的 LC-MS/MS 方法对西替利嗪的浓度进行了定量。建立了西替利嗪在母乳中的单室模型,并用于计算婴儿相对剂量(RID)。该模型评估了与母体特征和母乳喂养模式相关的协变量;发现只有抽奶持续时间是一个重要的协变量,抽奶持续时间越长,表观乳汁分布容积(Vm)越大。平均 RID 为 1.99%,最高 RID 为 Cmax 时的 3.36%。PopPK 模型可用于估算婴儿通过母乳摄入西替利嗪的情况。预测的婴儿西替利嗪暴露量较低,证明西替利嗪可用于母乳喂养。
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引用次数: 0
Effect of bariatric surgery on the pharmacokinetics of drugs used for attention-deficit hyperactivity disorder—A case series 减肥手术对治疗注意力缺陷多动障碍药物药代动力学的影响--病例系列。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-04 DOI: 10.1111/bcpt.14099
Hege-Merete Krabseth, Magnus Strømmen, Arne Helland, Olav Spigset

Background

Changes in gastrointestinal physiology following bariatric surgery may affect the pharmacokinetics of drugs. Data on the impact of bariatric surgery on drugs used for attention-deficit/hyperactivity disorder (ADHD) are limited.

Methods

In patients treated with ADHD medication and undergoing bariatric surgery, serial drug concentrations were measured for 24 h preoperatively and one, six and 12 months postoperatively. Primary outcome was change in area under the concentration-time curve from 0 to 24 h (AUC0–24), with other pharmacokinetic variables as secondary outcomes.

Results

Eight patients treated with lisdexamphetamine (n = 4), dexamphetamine (n = 1), methylphenidate (n = 1) and atomoxetine (n = 2) were included. In total, 409 samples were analysed. Patients underwent sleeve gastrectomy (n = 5) and Roux-en-Y gastric bypass (n = 3). AUC0–24 and Cmax of dexamphetamine increased after surgery in those using the prodrug lisdexamphetamine. There was no clear-cut reduction in tmax postoperatively. For ritalinic acid and atomoxetine, no changes in AUC0–24 were observed, but for atomoxetine, a higher Cmax and a shorter tmax were observed postoperatively.

Conclusion

Bariatric surgery may increase the systemic exposure of dexamphetamine after intake of lisdexamphetamine. Patients using lisdexamphetamine should be followed with regard to adverse drug reactions after bariatric surgery, and, if available, therapeutic drug monitoring should be considered.

背景:减肥手术后胃肠道生理机能的变化可能会影响药物的药代动力学。有关减肥手术对治疗注意力缺陷/多动症(ADHD)药物影响的数据还很有限:方法:对接受减肥手术的注意力缺陷多动障碍(ADHD)患者进行术前24小时、术后1个月、6个月和12个月的连续药物浓度测量。主要结果是0至24小时浓度-时间曲线下面积(AUC0-24)的变化,其他药代动力学变量为次要结果:结果:共纳入了8名接受过利司地苯丙胺(4人)、右旋苯丙胺(1人)、哌醋甲酯(1人)和阿托西汀(2人)治疗的患者。总共分析了 409 份样本。患者接受了袖状胃切除术(5 例)和 Roux-en-Y 胃旁路术(3 例)。手术后,使用原研药利血平的患者体内右旋苯丙胺的AUC0-24和Cmax均有所增加。术后 tmax 没有明显下降。利他林酸和阿托西汀的 AUC0-24 没有变化,但阿托西汀的 Cmax 增加,术后 tmax 缩短:结论:减肥手术可能会增加摄入利血平后体内的地塞米松暴露量。使用利血平的患者在减肥手术后应注意药物不良反应,如有条件,应考虑进行治疗药物监测。
{"title":"Effect of bariatric surgery on the pharmacokinetics of drugs used for attention-deficit hyperactivity disorder—A case series","authors":"Hege-Merete Krabseth,&nbsp;Magnus Strømmen,&nbsp;Arne Helland,&nbsp;Olav Spigset","doi":"10.1111/bcpt.14099","DOIUrl":"10.1111/bcpt.14099","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Changes in gastrointestinal physiology following bariatric surgery may affect the pharmacokinetics of drugs. Data on the impact of bariatric surgery on drugs used for attention-deficit/hyperactivity disorder (ADHD) are limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In patients treated with ADHD medication and undergoing bariatric surgery, serial drug concentrations were measured for 24 h preoperatively and one, six and 12 months postoperatively. Primary outcome was change in area under the concentration-time curve from 0 to 24 h (AUC<sub>0–24</sub>), with other pharmacokinetic variables as secondary outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eight patients treated with lisdexamphetamine (<i>n</i> = 4), dexamphetamine (<i>n</i> = 1), methylphenidate (<i>n</i> = 1) and atomoxetine (<i>n</i> = 2) were included. In total, 409 samples were analysed. Patients underwent sleeve gastrectomy (<i>n</i> = 5) and Roux-en-Y gastric bypass (<i>n</i> = 3). AUC<sub>0–24</sub> and C<sub>max</sub> of dexamphetamine increased after surgery in those using the prodrug lisdexamphetamine. There was no clear-cut reduction in t<sub>max</sub> postoperatively. For ritalinic acid and atomoxetine, no changes in AUC<sub>0–24</sub> were observed, but for atomoxetine, a higher C<sub>max</sub> and a shorter t<sub>max</sub> were observed postoperatively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Bariatric surgery may increase the systemic exposure of dexamphetamine after intake of lisdexamphetamine. Patients using lisdexamphetamine should be followed with regard to adverse drug reactions after bariatric surgery, and, if available, therapeutic drug monitoring should be considered.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"136 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neurodegenerative disorders: Advances in neurobiology and new treatment perspectives 神经退行性疾病:神经生物学的进展和新的治疗前景。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-30 DOI: 10.1111/bcpt.14098
Sâmia Joca
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引用次数: 0
An extended substrate spectrum of the proton organic cation antiporter and relation to other cation transporters 质子有机阳离子反转运体的扩展底物谱及其与其他阳离子转运体的关系。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-21 DOI: 10.1111/bcpt.14090
Cauzar Ali Khan, Nicolai Kirsch, Jürgen Brockmöller, Kyra-Elisa Maria Redeker

Most central nervous system (CNS) active drugs are organic cations, which need carrier proteins for efficient transfer through the blood–brain barrier (BBB). A genetically still unidentified proton organic cation (H+/OC) antiporter is found in several tissues, including endothelial cells of the BBB. We characterized the substrate spectrum of the H+/OC antiporter and the overlap in substrate spectrum with OCTN1, OCTN2 or OCT3 by screening 87 potential substrates for transport activity. Based on high antiport rates, 45 of the tested substances were substrates of the H+/OC antiporter. They included antidepressants (like tranylcypromine or nortriptyline), antipsychotics (like levomepromazine) and local anaesthetics. Concentration-dependent transport was confirmed for 38 of the substrates. Transport uptake depending on a pH gradient across the cell membrane confirmed that 43 drugs were indeed substrates of the H+/OC antiporter. However, the patterns of pH dependence differed between the substrates, possibly indicating different modes of transport or the existence of multiple antiporter proteins. The substrate overlap between the H+/OC antiporter and OCTN1, OCTN2 or OCT3 was minimal, indicating that the latter three are not the proteins underlying the H+/OC antiporter activity. Overall, about 50% of positively charged drugs may be substrates of the antiporter, which may be the most important membrane transport protein for many drugs.

大多数中枢神经系统(CNS)活性药物都是有机阳离子,它们需要载体蛋白才能有效地通过血脑屏障(BBB)。一种基因上仍未确定的质子有机阳离子(H+/OC)反转运体存在于多种组织中,包括血脑屏障的内皮细胞。我们通过筛选 87 种具有转运活性的潜在底物,确定了 H+/OC拮抗剂的底物谱以及与 OCTN1、OCTN2 或 OCT3 的底物谱重叠情况。根据高反转运率,45 种受测物质是 H+/OC 反转运体的底物。这些物质包括抗抑郁药(如氨酰环丙胺或去甲替林)、抗精神病药(如左美普马嗪)和局部麻醉剂。其中 38 种底物的转运证实了浓度依赖性。根据细胞膜上的 pH 梯度进行的转运吸收证实,43 种药物确实是 H+/OC 反转运体的底物。不过,不同底物的 pH 依赖性模式各不相同,这可能表明存在不同的转运模式或多种拮抗剂蛋白。H+/OC 拮抗剂与 OCTN1、OCTN2 或 OCT3 之间的底物重叠极少,这表明后三者不是 H+/OC 拮抗剂活性的基础蛋白。总体而言,约 50% 带正电荷的药物可能是拮抗剂的底物,而拮抗剂可能是许多药物最重要的膜转运蛋白。
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引用次数: 0
The active ingredient of Evodia rutaecarpa reduces inflammation in knee osteoarthritis rats through blocking calcium influx and NF-κB pathway Evodia rutaecarpa 的活性成分通过阻断钙离子流入和 NF-κB 通路,减轻膝骨关节炎大鼠的炎症反应。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-21 DOI: 10.1111/bcpt.14096
Yan Gao, Sixiang Wang, Yuehong Gao, Li Yang

Chronic inflammation significantly contributes to the progression of osteoarthritis (OA), and an anti-inflammatory small molecule derived from medicinal herbs could be a potential drug candidate for OA. Herein, we investigated the function and mechanism of Evodiamine (EAE), the active ingredient from Evodia rutaecarpa, in chondrocytes and macrophages in vitro and in vivo. The cytotoxicity of EAE was determined using an MTT assay. And the anti-inflammatory and anti-extracellular matrix (ECM) degradation effects of EAE were investigated using qRT-PCR, western blot (WB), immunofluorescence (IF). Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES), Fluo-4 AM, IF and AutoDock were used to elucidate the molecular mechanisms and signalling pathways of the reducing-inflammatory properties of EAE on chondrocytes in vitro. Moreover, the effect of EAE on macrophage polarization was detected by IF and flow cytometry (FC). Ultimately, we explored the in vivo therapeutic efficacy of EAE in an anterior cruciate ligament transection (ACLT)-induced OA model. The finding demonstrated that EAE blocked the phosphorylation of IKBα and Ca2+ influx, thereby curbing inflammation and ECM degradation. Additionally, EAE can prevent the polarization towards the M1 phenotype. Thus, our findings suggest that EAE has great potential as a therapeutic drug for the treatment of OA.

慢性炎症是导致骨关节炎(OA)恶化的重要原因,而从药草中提取的抗炎小分子可能是治疗OA的潜在候选药物。在此,我们研究了Evodiamine(EAE)在体外和体内软骨细胞和巨噬细胞中的功能和机制,EAE是从Evodia rutaecarpa中提取的活性成分。EAE 的细胞毒性是通过 MTT 试验测定的。使用 qRT-PCR、Western 印迹(WB)和免疫荧光(IF)研究了 EAE 的抗炎和抗细胞外基质(ECM)降解作用。利用电感耦合等离子体原子发射光谱(ICP-AES)、Fluo-4 AM、IF和AutoDock阐明了EAE对体外软骨细胞消炎作用的分子机制和信号通路。此外,我们还通过 IF 和流式细胞术(FC)检测了 EAE 对巨噬细胞极化的影响。最后,我们在前交叉韧带横断(ACLT)诱导的 OA 模型中探讨了 EAE 的体内疗效。研究结果表明,EAE能阻断IKBα的磷酸化和Ca2+的流入,从而抑制炎症和ECM降解。此外,EAE 还能阻止向 M1 表型的极化。因此,我们的研究结果表明,EAE 作为一种治疗药物在治疗 OA 方面具有巨大潜力。
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引用次数: 0
Efficacy of weekly versus daily cholecalciferol for repleting serum vitamin D (25(OH)D) deficiency: A systematic review and meta-analysis of randomized controlled trials 每周与每天服用胆钙化醇补充血清维生素 D (25(OH)D) 缺乏症的疗效:随机对照试验的系统回顾和荟萃分析。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-13 DOI: 10.1111/bcpt.14092
Émilie Bortolussi-Courval, Connor Prosty, Jimin J. Lee, Lisa M. McCarthy, Emily G. McDonald, Todd C. Lee

Background/rationale

Weekly cholecalciferol can replace daily supplementation to reduce pill burden in patients with complex medication regimens and hypovitaminosis D, but evidence supporting this switch is unclear.

Objective

We aimed to determine whether weekly cholecalciferol was superior to daily cholecalciferol to replete patients with hypovitaminosis D.

Methods

We conducted a systematic review of randomized controlled trials involving participants with baseline hypovitaminosis D (<30 ng/ml) comparing weekly versus daily cholecalciferol dosing and where serum cholecalciferol was measured within 120 days of starting treatment. We searched MEDLINE, CINAHL and EMBASE from inception to 7 May 2024. A random-effects meta-analysis evaluated the odds ratio for repletion of serum vitamin D levels.

Findings

Eight trials involving 542 patients were included in the analysis. Weekly and daily cholecalciferol were not significantly different in correcting hypovitaminosis D (OR = 1.5, 95% CI = 0.3–6.9, p = 0.6, favouring weekly dosing, I2 = 85.3%). A sensitivity analysis excluding otherwise healthy patients had similar findings (OR = 0.8, 95% CI = 0.3–2.1, p = 0.6). Most studies were at risk of bias; the different doses being compared increased the heterogeneity.

Conclusions

Limited direct evidence supports a switch from daily to weekly cholecalciferol dosing; however, weekly supplementation was not demonstrably worse at repleting levels and decreased a patient's daily pill burden.

背景/原理:每周补充胆钙化醇可替代每日补充,以减轻用药方案复杂和维生素D缺乏症患者的药片负担,但支持这种转换的证据尚不明确:我们旨在确定每周补充胆钙化醇是否优于每天补充胆钙化醇,以补充维生素 D 缺乏症患者的营养:我们对涉及基线维生素 D 缺乏症患者的随机对照试验进行了系统回顾(结果:共纳入 8 项试验,涉及 542 名患者):八项涉及 542 名患者的试验被纳入分析。每周服用胆钙化醇和每天服用胆钙化醇在纠正维生素 D 过低方面没有显著差异(OR = 1.5,95% CI = 0.3-6.9,P = 0.6,倾向于每周服用,I2 = 85.3%)。一项排除其他健康患者的敏感性分析也得出了类似的结果(OR = 0.8,95% CI = 0.3-2.1,p = 0.6)。大多数研究存在偏倚风险;不同剂量的比较增加了异质性:有限的直接证据支持将胆钙化醇剂量从每天一次改为每周一次;但是,每周一次的补充并不会明显降低补充水平,而且还能减轻患者的日常用药负担。
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引用次数: 0
Phase I clinical trial evaluating the safety, tolerance, pharmacokinetics and pharmacodynamics of HSK21542 injection in healthy volunteers I 期临床试验,评估 HSK21542 注射液在健康志愿者中的安全性、耐受性、药代动力学和药效学。
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-13 DOI: 10.1111/bcpt.14094
Rong Shao, Hai-ying Wang, Zou-rong Ruan, Bo Jiang, Dan-dan Yang, Yin Hu, Yi-chao Xu, Jin-ting Yang, Wei Gao, Wan-yun Zhao, Min Yan, Honggang Lou

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2–3.375 μg/kg, 15-min infusion) and different infusion durations (0.2 and 1 μg/kg, 2- or 15-min infusion). The area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose-linear among 0.2–3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half-life (t1/2) of 1.5 h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1–2 h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2 h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions.

HSK21542 注射液是一种新型外周卡巴阿片受体(KOR)激动剂。为评估其安全性、耐受性、药代动力学和药效学,该研究在健康志愿者中进行,包括两部分:单次升剂量(0.2-3.375 μg/kg,15 分钟输注)和不同输注持续时间(0.2 和 1 μg/kg,2 或 15 分钟输注)。HSK21542 的血浆浓度曲线下面积(AUC)和峰值浓度(Cmax)在 0.2-3.375 μg/kg 之间呈剂量线性关系。静脉注射后,HSK21542迅速消除,半衰期(t1/2)为1.5小时,大部分剂量(48.02%)通过尿液排出,未发生变化。药效学结果显示,HSK21542 可增加催乳素的释放,并在给药后 1-2 小时达到峰值,但对血管加压素水平无明显影响。在用药后最初 2 小时内,尿量会短暂增加。HSK21542 的耐受性良好;试验组的大多数不良反应(AEs)为 1 级,只有 2 例(4.0%)为 2 级。主要的不良反应是麻痹,试验组中有 42% 的患者(21/50)出现了麻痹。未观察到严重不良事件(SAE)。没有受试者因不良反应而提前退出。这些结果表明,HSK21542可能是一种治疗疼痛和瘙痒症的潜在药物。
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Basic & Clinical Pharmacology & Toxicology
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