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Genes ingenuity pathway analysis unveils smoothelin‐like 1 (SMTNL1) as a key regulatory protein involved in sodium pentobarbital‐induced growth inhibition in breast cancer 基因独创性通路分析揭示SMTNL1是一个关键的调节蛋白,参与戊巴比妥钠诱导的乳腺癌生长抑制
4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-09 DOI: 10.1002/prp2.1153
Bingwei Li, Xiaoyan Zhang, Xueting Liu, Ailing Li, Jianqun Han
Abstract We previously reported that sodium pentobarbital inhibited the growth of the breast cancer associated with the normalization of microcirculatory hemodynamics and oxygenation. Here, we aimed to screen the key regulatory proteins involved in pentobarbital‐induced normalization of microcirculatory hemodynamics in the breast cancer tissues. A nude mice model of xenograft was established using triple negative breast cancer cell line MDA‐MB‐231. After tumor cell implantation, the mice were subcutaneously injected with 50 mg/kg/day of sodium pentobarbital or an equal volume of solvent adjacent to the tumor for 14 days. Liquid chromatography linked to tandem mass spectrometry (LC–MS/MS) was used to analyze the difference in protein expression profile between the two groups. Ingenuity pathway analysis (IPA) was used to perform the canonical pathway analysis, upstream regulators analysis, and protein–protein interaction networks analysis. Screened proteins were confirmed by real‐time quantitative polymerase chain reaction (RT–qPCR) and Western blot analysis. A total of 101 differentially expressed proteins were revealed between groups. Canonical pathway analysis suggested that acute phase response signaling ( z = 1, p = .00208), dilated cardiomyopathy signaling pathway ( z = −2, p = .00671), and ILK signaling ( z = 1, p = .0172) were key pathways with highlight associations. The mRNA and protein expressions of SMTNL1 were found significantly decreased in pentobarbital‐treated tumor tissues compared with those in controls (both p < .01). Nine important protein–protein interaction networks were identified, and of which, two contained multiple downstream regulatory proteins of SMTNL1. In conclusion, SMTNL1 is revealed as a key protein involved in pentobarbital‐induced growth inhibition signaling in breast cancer. SMTNL1 may become a new potential target for tumor microcirculation research.
我们之前报道过戊巴比妥钠抑制与微循环血流动力学和氧合正常化相关的乳腺癌生长。在这里,我们旨在筛选戊巴比妥诱导乳腺癌组织微循环血流动力学正常化的关键调节蛋白。采用三阴性乳腺癌细胞系MDA‐MB‐231建立了裸鼠异种移植瘤模型。肿瘤细胞植入后,小鼠在肿瘤旁皮下注射戊巴比妥钠50 mg/kg/d或等体积的溶剂,持续14 d。采用液相色谱-串联质谱(LC-MS /MS)分析两组蛋白表达谱的差异。匠心途径分析(Ingenuity pathway analysis, IPA)用于典型途径分析、上游调控因子分析和蛋白质相互作用网络分析。筛选的蛋白通过实时定量聚合酶链反应(RT-qPCR)和Western blot分析证实。组间共发现101个差异表达蛋白。典型信号通路分析表明,急性期反应信号通路(z = 1, p = 0.00208)、扩张型心肌病信号通路(z = - 2, p = 0.00671)和ILK信号通路(z = 1, p = 0.0172)是具有突出相关性的关键信号通路。与对照组相比,戊巴比妥治疗的肿瘤组织中SMTNL1的mRNA和蛋白表达均显著降低(p <. 01)。鉴定出9个重要的蛋白-蛋白相互作用网络,其中2个含有SMTNL1的多个下游调节蛋白。综上所述,SMTNL1是参与戊巴比妥诱导的乳腺癌生长抑制信号传导的关键蛋白。SMTNL1可能成为肿瘤微循环研究新的潜在靶点。
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引用次数: 0
Biochemical and genetic biomarkers associated with nicotine dependence in Mexican smokers. 与墨西哥吸烟者尼古丁依赖相关的生化和遗传生物标志物。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1142
Gissela Borrego-Soto, Yadira Xitlalli Perez-Paramo, Francisco Hernández-Cabrera, Fatima Miroslaba Alvarado-Monroy, Gilberto Borrego, Alejandro Robles-Zamora, Philip Lazarus, Augusto Rojas-Martinez

Cigarette smoking remains an important health concern and is still a leading cause of preventable mortality. Nicotine is the substance responsible for sustained tobacco use and dependence. Identification of biomarkers underlying nicotine dependence behavior is important to identify people at risk for this dependence. In the present study, we identified biochemical and genetic biomarkers of nicotine dependence detected by the Fagerström Test for Nicotine Dependence (FTDN) in Mexican smokers. The nicotine metabolites nicotine-N'-oxide, trans-3'-hydroxycotinine-glucuronide (3HC-O-Gluc), and nicotine-N-Gluc (Gluc) were useful to differentiate nicotine-dependent from non-dependent subjects (p < .0001) with an area under the curve (AUC) of 0.7818. Genetic variants in CYP2A6, FMO3, and UGT2B7 (rs2431413, rs28363545, and rs7439326, respectively) were associated with nicotine dependence (p = .03, p = .01, p = .01, respectively). Variations in the enzymatic activity of CYP2A6 were associated with altered nicotine-N'-oxide and 3HC-O-Gluc levels. Decreased urinary levels of 3HC-O-Gluc and increased nicotine-N'-oxide were associated with a decrease in the functional activity of CYP2A6. A strong positive correlation was observed between the ratio of urinary 3HC/cotinine, a measure of CYP2A6 activity, and the levels of 3HC-O-Gluc (p < .0001, r = .6835), while a strong negative correlation was observed with nicotine-N'-oxide (p < .0001, r = .6522) in nicotine-dependent subjects. No correlations were observed in non-nicotine-dependent subjects. These data suggest that particular urinary nicotine metabolites and genetic variants involved in nicotine metabolism are useful to identify subjects with nicotine dependence in the Mexican population.

吸烟仍然是一个重要的健康问题,也是可预防死亡的主要原因。尼古丁是造成烟草持续使用和依赖的物质。识别尼古丁依赖行为的生物标志物对于识别有这种依赖风险的人很重要。在本研究中,我们确定了通过Fagerström尼古丁依赖性测试(FTDN)在墨西哥吸烟者中检测到的尼古丁依赖的生化和遗传生物标志物。尼古丁代谢产物烟碱-N’-氧化物、反式-3’-羟基可替宁葡萄糖醛酸(3HC-O-Gluc)和烟碱-N-Guc(Gluc
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引用次数: 0
Neuroprotective effect of Kurarinone against corticosterone-induced cytotoxicity on rat hippocampal neurons by targeting BACE1 to activate P13K-AKT signaling - A potential treatment in insomnia disorder. Kurarinone通过靶向BACE1激活P13K-AKT信号对皮质酮诱导的大鼠海马神经元细胞毒性的神经保护作用——失眠障碍的潜在治疗方法。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1132
Guoqing Wu, Yanyan Wu

The hippocampus has been implicated in the pathogenesis of insomnia disorder (ID) and the purpose of this study was to investigate the neuroprotective mechanism of the natural flavone Kurarinone (Kur) on hippocampal neurotoxicity as a potential treatment of ID. The effect of Kur on hippocampal neuronal cell (HNC) viability and apoptosis were assessed by Cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Then, the effect of Kur on β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), brain-derived neurotrophic factor (BDNF), and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) phosphorylation level were measured by Western blot. Further, SwissTargetPrediction analysis and molecular docking experiments were used to detect a potential target of Kur. Then, the p-chlorophenylalanine (PCPA) model was established in vivo to further study the effect of BACE1 expression on Kur and HNC. As a result, HNC viability was only significantly decreased by 2 μM of Kur. Kur reversed the impacts of corticosterone upon inhibiting viability (0.25-1 μM), PI3K (0.5-1 μM)/AKT phosphorylation, and BDNF (1 μM) level, and enhancing the apoptosis (0.25-1 μM) and BACE1 expression (1 μM) in HNCs. BACE1 was a potential target of Kur. Notably, Kur (150 mg/kg) attenuated PCPA-induced upregulation of BACE1 expression in rat hippocampal tissues as ZRAS (0.8 g/kg). The effects of Kur (1 μM) on corticosterone-treated HNCs were reversed by BACE1 overexpression. Collectively, Kur downregulates BACE1 level to activate PI3K/AKT, thereby attenuating corticosterone-induced toxicity in HNCs, indicating that Kur possibly exerted a neuroprotective effect, which providing a new perspective for the treatment of insomnia disorders.

海马与失眠障碍(ID)的发病机制有关,本研究的目的是探讨天然黄酮Kurarinone(Kur)对海马神经毒性的神经保护机制,作为治疗ID的潜在药物。分别通过细胞计数试剂盒-8(CCK-8)法和流式细胞术评估Kur对海马神经元细胞(HNC)活力和凋亡的影响。然后,通过蛋白质印迹法测定Kur对β-位点淀粉样蛋白前体蛋白裂解酶1(BACE1)、脑源性神经营养因子(BDNF)和磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(AKT)磷酸化水平的影响。此外,SwissTargetPrediction分析和分子对接实验被用于检测Kur的潜在目标。然后,在体内建立对氯苯丙氨酸(PCPA)模型,进一步研究BACE1表达对Kur和HNC的影响。结果,HNC活力仅显著降低2 μM的Kur。Kur逆转皮质酮对抑制生存能力的影响(0.25-1 μM),PI3K(0.5-1 μM)/AKT磷酸化和BDNF(1 μM)水平,并增强细胞凋亡(0.25-1 μM)和BACE1表达(1 μM)。BACE1是Kur的潜在靶点。值得注意的是,库尔(150 mg/kg)作为ZRAS(0.8 g/kg)。库尔(1 μM)通过BACE1过表达逆转。总之,Kur下调BACE1水平以激活PI3K/AKT,从而减轻皮质酮诱导的HNCs毒性,表明Kur可能发挥神经保护作用,这为治疗失眠障碍提供了新的视角。
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引用次数: 0
Suspected oncologic adverse reactions associated with interleukin-23 inhibitors in EudraVigilance: Comparative study and gender distribution. EudraVigilance中与白细胞介素-23抑制剂相关的疑似肿瘤不良反应:比较研究和性别分布。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1130
Fabrizio Calapai, Carmen Mannucci, Luigi Cardia, Mariaconcetta Currò, Gioacchino Calapai, Emanuela Esposito, Ilaria Ammendolia

Psoriasis is a chronic inflammatory skin disease characterized by plaque formation. Interleukin (IL)-23 is upregulated in psoriatic lesions and is thought to be a major regulator of the Th17 pathway in psoriasis pathogenesis. Three monoclonal antibodies targeting the IL-23p19 subunit, guselkumab, tildrakizumab, and risankizumab, have been approved for psoriasis therapy. The balance between cytokines IL-23 and IL-12 can affect antitumor and pro-tumor immune activities, and patients with psoriasis may have higher rates of cancer than the general population. Moreover, a chronic inflammatory state typical of psoriasis may induce protumorigenic effects, however, the potential risk of malignancy in patients taking these drugs remains largely unknown. This study investigated the occurrence of malignancies as suspected adverse reactions (SARs) potentially associated with IL-23 inhibitors by analyzing real-world data from the European EudraVigilance database. Although indicatory, these real-world data seem to confirm the potential association between the IL-23 inhibitors risankizumab and tildrakizumab, and the occurrence of SARs linked to cancer in patients with psoriasis and, according to a gender perspective, they show that this relationship is asymmetrically distributed between women and men, with a clear prevalence of oncologic SARs in men.

银屑病是一种以斑块形成为特征的慢性炎症性皮肤病。白细胞介素(IL)-23在银屑病病变中上调,被认为是银屑病发病机制中Th17通路的主要调节因子。三种靶向IL-23p19亚基的单克隆抗体,即古selkumab、tildrakizumab和risankizumab,已被批准用于银屑病治疗。细胞因子IL-23和IL-12之间的平衡可以影响抗肿瘤和促肿瘤免疫活性,银屑病患者的癌症发病率可能高于普通人群。此外,银屑病典型的慢性炎症状态可能会引起促肿瘤作用,然而,服用这些药物的患者患恶性肿瘤的潜在风险在很大程度上仍然未知。本研究通过分析欧洲EudraVigilance数据库的真实世界数据,调查了恶性肿瘤作为可能与IL-23抑制剂相关的疑似不良反应(SAR)的发生情况。尽管具有指示性,但这些真实世界的数据似乎证实了白细胞介素-23抑制剂利桑基珠单抗和替拉基珠单抗与银屑病患者中与癌症相关的严重急性呼吸系统综合征的发生之间的潜在关联,根据性别观点,他们表明这种关系在女性和男性之间不对称分布,男性中肿瘤严重急性呼吸综合征的患病率明显。
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引用次数: 1
Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain. 加巴喷丁和曲马多在儿童慢性疼痛患者中的剂量原理。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1138
Paul Healy, Luka Verrest, Mariagrazia Felisi, Adriana Ceci, Oscar Della Pasqua

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.

尽管标签外使用,加巴喷丁和曲马多在儿科患者中的疗效和安全性(3 月至0-8)约35 mg/L*小时(1200 mg/天成人剂量当量)。曲马多的中位稳态浓度在200和300之间 2-5次给药后达到ng/mL mg/kg,但浓度表现出较高的个体间变异性。模拟场景显示,考虑到两种药物的安全性,需要滴定步骤来探索治疗相关的剂量范围。加巴喷丁可按7-63至5-45的剂量静脉注射使用 mg/kg,用于接受加巴喷丁称重的患者
{"title":"Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain.","authors":"Paul Healy,&nbsp;Luka Verrest,&nbsp;Mariagrazia Felisi,&nbsp;Adriana Ceci,&nbsp;Oscar Della Pasqua","doi":"10.1002/prp2.1138","DOIUrl":"10.1002/prp2.1138","url":null,"abstract":"<p><p>Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC<sub>0-8</sub> ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41162386","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
A randomized, double-blind, comparative study of the pharmacodynamics and pharmacokinetics of GP40141 (romiplostim biosimilar) and reference romiplostim in healthy male volunteers. GP40141(romipostim生物类似物)和参比romipostin在健康男性志愿者中的药效学和药代动力学的随机、双盲、比较研究。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1125
Igor Makarenko, Artem Dorotenko, Sergey Noskov, Veniamin Banko, Valeria Saparova, Alexandr Khokhlov, Evgeniia Zoreeva, Andrey Nedorubov, Bella Zinnatulina, Maria Gefen, Roman Drai

Aims: The pharmacodynamic (PD) similarity between GP40141, a proposed romiplostim biosimilar, and reference romiplostim was evaluated. Pharmacokinetics and safety were also assessed.

Methods: In this phase 1, randomized, double-blind, single-dose, crossover comparative study with an adaptive design, 56 healthy male volunteers were randomized 1:1 to receive a 3 ug × kg-1 subcutaneous dose of GP40141 and reference romiplostim. The PD similarity between GP40141 and the reference romiplostim was determined using the standard equivalence criteria (80%-125%) for the area under the platelet count-time curve from time 0 to the time of the last sampling for PD (AUCplt ) and the maximum observed platelet count (Pmax ).

Results: GP40141 and the reference romiplostim exhibited similar PD profiles. 90% CI for the geometric mean ratios for the primary PD parameters (AUCplt, Pmax ) for GP40141 (T) and the reference romiplostim (R) were fully contained within the predefined equivalence limits of 80%-125%: 98.13%-102.42% for AUCplt and 97.56%-105.80% for Pmax . The pharmacokinetic profiles of GP40141 and the reference romiplostim were well described. No adverse events were observed during the clinical trial after the administration of GP40141 and the reference romiplostim.

Conclusion: This study demonstrates the PD similarity of GP40141 to the reference romiplostim. Both treatments had comparable safety profiles (NCT05652595).

目的:评价拟用罗匹司汀生物类似物GP40141与参考罗匹司亭之间的药效学(PD)相似性。还评估了药物动力学和安全性。方法:在这项采用适应性设计的1期随机、双盲、单剂量、交叉比较研究中,56名健康男性志愿者被1:1随机分配接受3μg × kg-1皮下剂量的GP40141和参比罗米司汀。使用标准等效标准(80%-125%)确定GP40141和参考romipostim之间的PD相似性,该标准等效标准用于从时间0到PD最后一次采样时的血小板计数-时间曲线下面积(AUCplt)和最大观察到的血小板计数(Pmax)。结果:GP40141和对照品romipostim表现出相似的PD图谱。GP40141(T)和参考romiplastim(R)的主要PD参数(AUCplt,Pmax)的几何平均比的90%CI完全包含在80%-125%的预定义等效限内:AUCplt为98.13%-102.42%,Pmax为97.56%-105.80%。对GP40141和参比罗密普司汀的药代动力学特征进行了详细描述。在给药GP40141和参考romipostim后的临床试验期间未观察到不良事件。结论:本研究证明了GP40141与参比药物romipostim的PD相似性。两种治疗方法的安全性相当(NCT05652595)。
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引用次数: 0
Evaluating adverse events in databases. 评估数据库中的不良事件。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1129
Katie Lovell, Steven R Feldman
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引用次数: 0
Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects. 在健康受试者中,采用鸡尾酒法,选择性食欲素-1受体拮抗剂尼瓦松(ACT-539313)在体外和体内对多种细胞色素P450探针底物的影响。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1143
Benjamin Berger, Priska Kaufmann, Matthias Berse, Alexander Treiber, Nathalie Grignaschi, Jasper Dingemanse

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

Nivasorexant是一种选择性食欲素-1受体拮抗剂,最近被评估用于治疗人类暴饮性饮食障碍。在此,评估了尼瓦松对细胞色素P450(CYPs)2C9、2C19和3A4的抑制潜力。在体外评估人肝微粒体/重组CYP酶。在体内,对健康成年人进行了一项单中心、开放标签、固定序列的研究,以探索100 mg nivasorexant,每日两次(b.i.d.)对氟比洛芬(50 mg,CYP2C9),奥美拉唑(20 mg,CYP2C19),咪唑安定(2 mg、CYP3A4)。在24小时内进行血浆PK取样 第1天的h(单独的鸡尾酒)、第8天(鸡尾酒+nivasorexant)和第15天(稳定状态下的鸡尾酒+niwasorexat)。对受试者的CYP进行基因分型,同时评估安全性和耐受性。在体外,nivasorexant在竞争性抑制试验中抑制CYP2C9、2C19和3A4,IC50值分别为8.6、1.6和19-44 μM,同时显示出显著的时间依赖性CYP2C19抑制。在22名受试者中,与单独给药的鸡尾酒底物相比,咪达唑仑在伴随单次给药(即,血浆浓度-时间曲线下面积[AUC]比分别增加1.04倍、2.05倍和1.56倍)和重复给药(AUC比分别增加1.47倍、6.84倍和3.71倍)期间通常更高。最常见的不良事件是嗜睡。根据监管指南,nivasorexant在1天后被分类为中度CYP2C19和弱CYP3A4抑制剂,在8天后被归类为弱CYP2C9、强CYP2C19或中度CYP3A4抑制物 100天 mg b.i.d.给药。Clinicaltrials.gov ID:NCT05254548。
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引用次数: 0
Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106. 通过I类HDAC抑制剂TC-H 106表达VMAT2来保护多巴胺能细胞和减轻神经精神疾病症状。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1135
Heejin Lee, Hye-Ji Kim, Dong-Kyu Choi, Eu N-A Ko, Jae-Hyeog Choi, Yohan Seo, Sion Lee, Soong-Hyun Kim, Sejin Jung, Minwoo Kim, Dongwan Kang, Chun-Young Im, Gi-Hun Bae, Sung-Cherl Jung, Oh-Bin Kwon

The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+ ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.

膀胱单胺类转运蛋白2(VMAT2)在多巴胺调节中的重要性目前正在研究中,多巴胺调节被认为对神经精神疾病至关重要。此外,使用组蛋白脱乙酰酶(HDAC)抑制剂(HDACi)治疗疾病的开发在各个领域都取得了积极进展。最近,对调节神经精神障碍的可能性进行了研究。在这项研究中,我们评估了HDACi增加的VMAT2表达是否可以微调神经精神行为,如注意力缺陷多动障碍(ADHD),并通过氧化多巴胺保护细胞免受细胞毒性。首先,将大约300种候选HDACi化合物添加到SH-SY5Y多巴胺能细胞系中,以确定VMAT2表达水平的可能变化,这是使用定量聚合酶链式反应测量的。结果表明,用一类I类HDACi庚二酸二苯胺106(TC-H 106)处理,增加了SH-SY5Y细胞和小鼠脑中VMAT2的表达。TC-H 106诱导的VMAT2表达增加减轻了归因于6-羟基多巴胺(6-OHDA)或1-甲基-4-苯基吡啶鎓(MPP+)和游离多巴胺处理的细胞毒性。此外,细胞内和突触体中的多巴胺浓度都因VMAT2表达的增加而显著升高。这些结果表明,TC-H 106诱导的VMAT2表达对多巴胺浓度的调节可以改变几个相关的行为方面,多动症和冲动性的减弱证实了这一点,这是表现出多动症样行为的动物模型的主要特征。这些结果表明,HDACi增加的VMAT2表达对氧化应激诱导的多巴胺能细胞死亡提供了足够的保护。因此,表观遗传学方法可以被认为是神经精神疾病调节的候选治疗方法。
{"title":"Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.","authors":"Heejin Lee,&nbsp;Hye-Ji Kim,&nbsp;Dong-Kyu Choi,&nbsp;Eu N-A Ko,&nbsp;Jae-Hyeog Choi,&nbsp;Yohan Seo,&nbsp;Sion Lee,&nbsp;Soong-Hyun Kim,&nbsp;Sejin Jung,&nbsp;Minwoo Kim,&nbsp;Dongwan Kang,&nbsp;Chun-Young Im,&nbsp;Gi-Hun Bae,&nbsp;Sung-Cherl Jung,&nbsp;Oh-Bin Kwon","doi":"10.1002/prp2.1135","DOIUrl":"10.1002/prp2.1135","url":null,"abstract":"<p><p>The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP<sup>+</sup> ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3f/19/PRP2-11-e01135.PMC10517640.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41128472","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
Effects of pharmacological doses of niacin on subacute glucocorticoid-induced testicular damage in rats. 烟酸药物剂量对亚急性糖皮质激素诱导的大鼠睾丸损伤的影响。
IF 2.6 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1002/prp2.1128
E Azimi Zangabad, Tahoora Shomali, L Roshangar

Glucocorticoid excess adversely affects male reproduction. This study evaluates effects of pharmacological doses of niacin on testicular structure and function in dexamethasone-treated rats. Adult rats (48) were randomly assigned to 6 equal groups: (1) Negative control (NC): normal rats; (2) Positive control (PC): dexamethasone at 7 mg/kg/day by intraperitoneal injections for 7 days; groups 3-6 (N50, N100, N200, and N400): dexamethasone and concomitant treatment with niacin at 50, 100, 200, and 400 mg/kg/day by oral gavages. Testicular weight and volume of PC rats were significantly lower than the NC group (p < .05). Testicular volume of rats in the N50 and N200 groups was statistically similar to the NC group. Significant decreases in serum testosterone with a slight LH increase were detected in the PC group. Nacin at 50 mg/kg reversed serum testosterone to NC levels and increased serum LH concentration. Niacin only slightly increased epididymal spermatozoa number while all groups of niacin-treated rats had significantly higher percentages of motile spermatozoa compared with the PC group. Hypospermatogenesis, germ cell degeneration and depletion, epithelial vacuolization, and degenerated Leydig cells were observed in PC rats. Lesions were relatively milder in niacin-treated rats. Johnsen scores were also significantly higher in niacin-treated rats. Niacin reduced apoptosis as shown by TUNEL assay. In conclusion, niacin administration at pharmacological doses dose-dependently ameliorates the destructive effects of dexamethasone on sperm motility, Johnsen score, and testicular cell apoptosis in rats with the latter can be considered a decisive mechanism for its positive effects on testis.

糖皮质激素过量会对男性生殖产生不利影响。本研究评估了药物剂量烟酸对地塞米松治疗大鼠睾丸结构和功能的影响。成年大鼠(48只)随机分为6组:(1)阴性对照组(NC):正常大鼠;(2) 阳性对照(PC):地塞米松7 mg/kg/天,腹膜内注射7次 天;第3-6组(N50、N100、N200和N400):地塞米松和烟酸联合治疗50、100、200和400 mg/kg/天。PC大鼠睾丸重量和体积显著低于NC组(p
{"title":"Effects of pharmacological doses of niacin on subacute glucocorticoid-induced testicular damage in rats.","authors":"E Azimi Zangabad,&nbsp;Tahoora Shomali,&nbsp;L Roshangar","doi":"10.1002/prp2.1128","DOIUrl":"10.1002/prp2.1128","url":null,"abstract":"<p><p>Glucocorticoid excess adversely affects male reproduction. This study evaluates effects of pharmacological doses of niacin on testicular structure and function in dexamethasone-treated rats. Adult rats (48) were randomly assigned to 6 equal groups: (1) Negative control (NC): normal rats; (2) Positive control (PC): dexamethasone at 7 mg/kg/day by intraperitoneal injections for 7 days; groups 3-6 (N50, N100, N200, and N400): dexamethasone and concomitant treatment with niacin at 50, 100, 200, and 400 mg/kg/day by oral gavages. Testicular weight and volume of PC rats were significantly lower than the NC group (p < .05). Testicular volume of rats in the N50 and N200 groups was statistically similar to the NC group. Significant decreases in serum testosterone with a slight LH increase were detected in the PC group. Nacin at 50 mg/kg reversed serum testosterone to NC levels and increased serum LH concentration. Niacin only slightly increased epididymal spermatozoa number while all groups of niacin-treated rats had significantly higher percentages of motile spermatozoa compared with the PC group. Hypospermatogenesis, germ cell degeneration and depletion, epithelial vacuolization, and degenerated Leydig cells were observed in PC rats. Lesions were relatively milder in niacin-treated rats. Johnsen scores were also significantly higher in niacin-treated rats. Niacin reduced apoptosis as shown by TUNEL assay. In conclusion, niacin administration at pharmacological doses dose-dependently ameliorates the destructive effects of dexamethasone on sperm motility, Johnsen score, and testicular cell apoptosis in rats with the latter can be considered a decisive mechanism for its positive effects on testis.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/b8/PRP2-11-e01128.PMC10433454.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10048839","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}
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Pharmacology Research & Perspectives
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