Fundamental & Clinical Pharmacology最新文献_第6页

Latest advances in the reversal strategies for direct oral anticoagulants 直接口服抗凝剂逆转策略的最新进展。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-13 DOI: 10.1111/fcp.12992

Jean Escal, Julien Lanoiselée, Géraldine Poenou, Paul Zufferey, Silvy Laporte, Patrick Mismetti, Xavier Delavenne

Background

Since the late 2000s, Europe has granted approval for various thrombotic risk-related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident.

Objectives

The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development.

Methods

For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar.

Results

In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility.

Conclusion

With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice.

背景：自 2000 年代末以来，欧洲已批准直接口服抗凝剂（DOACs）的各种血栓风险相关用途。与传统抗凝药不同，DOACs 无需进行常规凝血监测。然而，临床实践中经常会遇到与这些药物相关的出血事件，因此显然需要有效的逆转策略：本研究旨在对目前 DOACs 的逆转策略进行评估，尤其侧重于已经开发或正在开发的最新化合物：方法：我们参考了 ClinicalTrials 网站、PubMed 和 Google Scholar，以获取有关当前逆转策略和正在开发的化合物的信息：结果：2024 年，有两种针对 DOAC 的特效解毒剂已获得批准，用于因危及生命或出血无法控制而需要逆转抗凝时的治疗：可逆转达比加群作用的 idarucizumab 和旨在对抗阿哌沙班和利伐沙班等活化因子 X 抑制剂的 andexanet alfa。此外，一种潜在的通用逆转剂 ciraparantag 目前正处于临床开发的后期阶段。对于特定逆转剂的安全性，尤其是血栓形成的风险，仍存在担忧。此外，这些解毒剂的成本仍然很高。因此，包括活性炭、血液透析和凝血因子浓缩物在内的非特异性抗凝药物解毒策略仍有用武之地：结论：随着特异性和非特异性解毒剂的验证，DOAC 可取代传统的口服抗凝剂。这一进展标志着抗凝疗法的重大进步。然而，要解决 DOACs 特异性逆转剂在临床实践中仍然存在的安全问题，持续的研究至关重要。

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引用次数: 0

Population pharmacokinetics and pharmacodynamics of nirmatrelvir in Chinese patients with COVID-19 中国 COVID-19 患者服用尼尔马特韦的群体药代动力学和药效学。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-11 DOI: 10.1111/fcp.12989

Liyan Zeng, Rui Chen, Xuhua Jiang, Feng Li, Zhaoqin Zhu, Zheng Jiao, Yun Ling, Lijun Zhang

Background

The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of nirmatrelvir (NMV) are unknown in Chinese patients with COVID-19.

Objectives

To understand the PK, as well as PK–PD characteristics of NMV for optimizing the dose in Chinese patients with COVID-19.

Methods

We enrolled 141 participants who received NMV 300 mg/ritonavir (RTV) 100 mg b.i.d. for 5 days. The NMV concentrations were analyzed using 251 blood samples. PK/PD of NMV was investigated in these COVID-19 patients using a nonlinear mixed-effects model.

Results

The patients had a mean age of 82 years (range, 34–97). The absorption rate constant and apparent clearance of NMV in this Chinese cohort were 0.253 h⁻¹ and 6.83 L/h, respectively, similar to Caucasian patients. No covariates affected NMV clearance. Predicted peak (C_max) and trough concentration (C_min) under 300 mg NMV/100 mg RTV b.i.d. were 4004 and 1498 ng/mL, respectively. Although higher AUC and C_min were weakly associated with a slight increase in the number of cycle threshold (CT) of viral genes, no significant correlation was found, indicating a weak relationship between drug exposure and efficacy (CT).

Conclusions

In all, our findings suggest no ethnic PK differences, a weak and clinically insignificant relationship between drug exposure and efficacy, suitable dosage for Chinese patients (including the elderly) based on PK parameters, and the need for further studies to determine optimal regimens for high-risk patients due to inter-individual variability.

背景：中国COVID-19患者的药代动力学（PK）和药效学（PD）特征尚不清楚：在中国的COVID-19患者中，nirmatrelvir（NMV）的药代动力学（PK）和药效学（PD）特征尚不清楚：目的：了解NMV的PK以及PK-PD特征，以优化COVID-19中国患者的剂量：方法：我们招募了141名参与者，他们接受了NMV 300 mg/ritonavir (RTV) 100 mg b.i.d.治疗，共5天。对251份血样进行了NMV浓度分析。采用非线性混合效应模型对这些 COVID-19 患者的 NMV PK/PD 进行了研究：结果：患者的平均年龄为 82 岁（34-97 岁）。中国患者对 NMV 的吸收率常数和表观清除率分别为 0.253 h-1 和 6.83 L/h，与白种人相似。没有协变量影响 NMV 的清除率。在 300 毫克 NMV/100 毫克 RTV 条件下，预测的峰浓度（Cmax）和谷浓度（Cmin）分别为 4004 纳克/毫升和 1498 纳克/毫升。虽然较高的AUC和Cmin与病毒基因周期阈值（CT）的轻微增加有微弱关联，但没有发现显著的相关性，表明药物暴露与疗效（CT）之间的关系不大：总之，我们的研究结果表明，没有种族间的 PK 差异，药物暴露量与疗效之间的关系较弱且在临床上不显著，根据 PK 参数确定适合中国患者（包括老年人）的剂量，由于个体间的差异性，需要进一步研究确定高危患者的最佳治疗方案。

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引用次数: 0

Ursodeoxycholic acid for preventing parenteral nutrition-associated cholestasis in neonates: A systematic review and meta-analysis 熊去氧胆酸用于预防新生儿肠外营养相关性胆汁淤积症：系统综述和荟萃分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-11 DOI: 10.1111/fcp.12993

Rajendra Prasad Anne, Srikanth Puttaiah Kadyada, Abhishek Somasekhara Aradhya, Tejo Pratap Oleti

Background

While ursodeoxycholic acid is used in treating parenteral nutrition-associated cholestasis (PNAC) in neonates, its role in prevention is unclear.

Objectives

In this systematic review and meta-analysis, we attempted to determine the role of ursodeoxycholic acid in preventing PNAC in neonates.

Methods

PubMed, Embase, Cochrane Library, Scopus, and CINAHL databases were searched on September 16, 2023, for interventional studies comparing ursodeoxycholic acid with placebo.

Results

Of the 6180 unique records identified, five studies were eligible for inclusion (three randomised and two nonrandomised). Evidence from randomised trials showed that ursodeoxycholic acid prophylaxis did not reduce cholestasis, mortality, sepsis, and necrotising enterocolitis. Ursodeoxycholic acid prophylaxis reduced feed intolerance (RR 0.23 (0.09, 0.64); 1 RCT, 102 neonates), peak conjugated bilirubin levels (MD −0.13 (−0.22, −0.04) mg/dL; 1 RCT, 102 neonates), and time to full enteral feeds (MD −2.7 (−5.09, −0.31) days; 2 RCTs, 76 neonates). There was no decrease in hospital stay and parenteral nutrition duration. Data from nonrandomised studies did not show benefit in any of the outcomes. The certainty of the evidence was low to very low.

Conclusion

Because of the very low-quality evidence and lack of evidence on critical outcomes, definitive conclusions could not be made on using ursodeoxycholic acid to prevent parenteral nutrition-associated cholestasis in neonates.

背景：熊去氧胆酸可用于治疗新生儿肠外营养相关性胆汁淤积症（PNAC），但其预防作用尚不明确：在本系统综述和荟萃分析中，我们试图确定熊去氧胆酸在预防新生儿 PNAC 中的作用：2023 年 9 月 16 日，我们在 PubMed、Embase、Cochrane Library、Scopus 和 CINAHL 数据库中检索了熊去氧胆酸与安慰剂比较的干预性研究：结果：在已确定的 6180 条唯一记录中，有五项研究符合纳入条件（三项随机试验和两项非随机试验）。随机试验的证据显示，熊去氧胆酸预防性治疗并不能减少胆汁淤积、死亡率、败血症和坏死性小肠结肠炎。熊去氧胆酸预防可减少喂养不耐受（RR 0.23 (0.09, 0.64)；1 项随机试验，102 例新生儿）、结合胆红素峰值（MD -0.13 (-0.22, -0.04) mg/dL；1 项随机试验，102 例新生儿）和完全肠内喂养时间（MD -2.7 (-5.09, -0.31) 天；2 项随机试验，76 例新生儿）。住院时间和肠外营养时间没有缩短。来自非随机研究的数据未显示任何结果的益处。证据的确定性为低至极低：由于证据质量极低，且缺乏关键结果方面的证据，因此无法就使用熊去氧胆酸预防新生儿肠外营养相关性胆汁淤积症得出明确结论。

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引用次数: 0

Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database 两种抗甲状腺药物引起的粒细胞减少症和抗中性粒细胞胞浆抗体相关性血管炎的比较：利用世界卫生组织国际数据库进行的药物警戒研究。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-11 DOI: 10.1111/fcp.12991

Ji Yun Han, Jun Myong Lee, Se Yong Jung, Min Seo Kim, Seung Won Lee, Andreas Kronbichler, Kalthoum Tizaoui, Ai Koyanagi, Eun Young Kim, Kyungchul Song, Hyun Wook Chae, Dong Keon Yon, Jae Il Shin, Lee Smith

Background

Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database.

Methods

We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV.

Results

Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake.

Conclusions

This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.

背景：甲巯咪唑（MMI）和丙基硫氧嘧啶（PTU）是甲状腺毒症患者的常用药物。粒细胞减少症和抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）与高发病率和高死亡率相关，需要适当的干预措施。在本研究中，我们利用真实世界的大型药物警戒数据库比较了与 MMI 和 PTU 相关的药物不良反应：我们从 VigiBase 中检索了 1967 年至 2021 年 6 月 2 日期间所有与 MMI 和 PTU 相关的个人病例安全报告。我们进行了比例失调分析（病例/非病例分析），以分析抗甲状腺药物（病例）和整个数据库（非病例）之间报告的药物不良反应（ADR）的差异。我们进一步分析了粒细胞减少症和 AAV 病例的信息：在服用 MMI 后报告的 11 632 例 ADR 中，1633 例出现粒细胞减少，41 例出现 AAV。在摄入 PTU 后报告的 5055 例 ADR 中，459 例出现粒细胞减少，110 例出现 AAV。粒细胞减少发生在摄入 PTU 后的中位数为 28 天后，而摄入 MMI 后的中位数为 33 天。超过 95% 的粒细胞减少病例被归类为严重病例，但其中大多数病例（65.1% 的 PTU 和 70.4% 的 MMI）在采取去挑战行动（主要是停药）后均已痊愈。AAV 发生在摄入 PTU 后的中位数 668 天后，MMI 的中位数为 1162 天后：这是一项药物流行病学研究，调查了 MMI 和 PTU 引起的粒细胞减少症和 AAV。通过这项研究，我们可以为在现实环境中安全处方抗甲状腺药物提供更具体的见解。

{"title":"Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database","authors":"Ji Yun Han, Jun Myong Lee, Se Yong Jung, Min Seo Kim, Seung Won Lee, Andreas Kronbichler, Kalthoum Tizaoui, Ai Koyanagi, Eun Young Kim, Kyungchul Song, Hyun Wook Chae, Dong Keon Yon, Jae Il Shin, Lee Smith","doi":"10.1111/fcp.12991","DOIUrl":"10.1111/fcp.12991","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 4","pages":"780-788"},"PeriodicalIF":2.1,"publicationDate":"2024-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139717507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anticancer effect of propranolol on diethylnitrosamine-induced hepatocellular carcinoma rat model 普萘洛尔对二乙基亚硝胺诱导的肝细胞癌大鼠模型的抗癌作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-07 DOI: 10.1111/fcp.12990

Yomna M. Tamim, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail

Background

Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non-selective β-blocker propranolol demonstrated antiproliferative activity in many cancer types.

Objective

This investigation aimed to evaluate the anticancer effect of propranolol against DEN-induced HCC in rats.

Methods

Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10 weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10 weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks.

Results

HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α-fetoprotein (AFP), total- and direct-bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF-1α, IL-8, NF-κB, PGE2, TGF-β1, VEGF, and CD8, but significant decline of GSH, and IL-10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG-3 were up-regulated. Moreover, the protein expression of p-PKC was up-regulated, while that of PD-1 and PD-L1 were down-regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group.

Conclusion

Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD-1/PD-L1 and LAG-3 signals participated in the anti-tumor effect of propranolol on HCC.

背景：肝细胞癌（HCC）是最常见的原发性肝癌类型。二乙基亚硝胺（DEN）是一种具有肝毒性的致肝癌化合物，可用于诱导动物模型中的 HCC。非选择性β-受体阻滞剂普萘洛尔在许多癌症类型中都具有抗增殖活性：本研究旨在评估普萘洛尔对 DEN 诱导的大鼠 HCC 的抗癌作用：方法：将 30 只成年雄性大鼠分为以下几组：方法：将30只成年雄性大鼠分为以下几组：I组（C，对照组）；II组（HCC组）；接受DEN诱导HCC，每周一次，每次70 mg/kg体重，共10周；III组（HCC/普萘洛尔组）；接受DEN诱导HCC，共10周，然后腹腔注射20 mg/kg体重的普萘洛尔，连续4周：结果：大鼠肝脏发生了 HCC，并通过肝脏结构的显著变化、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、α-胎儿蛋白（AFP）、总胆红素和直接胆红素（Bil）活性的显著升高以及血清中白蛋白（ALB）水平的下降证实了这一点。HCC 组的丙二醛（MDA）、一氧化氮（NO）、HIF-1α、IL-8、NF-κB、PGE2、TGF-β1、VEGF 和 CD8 水平升高，但 GSH 和 IL-10 水平显著下降，抗氧化酶活性受到抑制。此外，肝脏诱导型一氧化氮合酶（iNOS）和 LAG-3 的基因表达上调。此外，HCC 组肝脏组织中 p-PKC 蛋白表达上调，而 PD-1 和 PD-L1 蛋白表达下调。然而，普萘洛尔能改善HCC/Prop组的相关指标：结论：普萘洛尔具有抗癌作用，因此可被视为一种治疗 HCC 的有效方法。阻断 PD-1/PD-L1 和 LAG-3 信号参与了普萘洛尔对 HCC 的抗肿瘤作用。

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引用次数: 0

Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart—The signaling mechanism 血管紧张素 1-7 增加心脏对缺血/再灌注的耐受性并减轻心脏的不良重塑--信号机制

IF 2.9 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-04 DOI: 10.1111/fcp.12983

Ivan A. Derkachev, Sergey V. Popov, Leonid N. Maslov, Alexandr V. Mukhomedzyanov, Natalia V. Naryzhnaya, Alexander S. Gorbunov, Artur Kan, Andrey V. Krylatov, Yuri K. Podoksenov, Ivan V. Stepanov, Svetlana V. Gusakova, Feng Fu, Jian-Ming Pei

Background

The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1–7 has some promise in this regard.

Objective

The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1–7.

Methods

PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study.

Results

Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1–7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1–7. Angiotensin 1–7 alleviates Ca²⁺ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1–7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1–7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1–7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1–7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1–7. However, the specific end-effector of the cardioprotective impact of angiotensin 1–7 remains unknown.

Conclusion

The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1–7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal K_ATP channel or the mitochondrial K_ATP channel.

急性心肌梗死（AMI）患者的高死亡率仍然是现代心脏病学最紧迫的问题。在过去 10 年中，急性心肌梗死患者的死亡率一直没有显著下降。显而易见，治疗急性心肌梗死急需开发全新的药物。在这方面，血管紧张素 1-7 具有一定的前景。

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引用次数: 0

Effect of spermidine on long non-coding RNAs MALAT1 in a rotenone induced-rat model of Parkinson's disease 在鱼藤酮诱导的帕金森病大鼠模型中，亚精胺对长非编码 RNA MALAT1 的影响

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-26 DOI: 10.1111/fcp.12986

Noha Mohamed Badae, Doaa A. Abdelmonsif, Rania Gaber Aly, Amira M. Omar, Mai S. Shoela, Eman M. Omar

Background

Spermidine is a natural biologically active substance that has widespread influences on the body.

Objective

This study aims to enhance our understanding of the potential effect of spermidine on long non-coding RNA MALAT1 and explore the underlying mechanism in the rotenone-induced rat model of Parkinson's disease.

Methods

Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers.

Results

Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non-treated group.

Conclusion

Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine-induced autophagy pathway.

背景：精胺是一种天然生物活性物质，对人体具有广泛的影响：本研究旨在进一步了解亚精胺对长非编码 RNA MALAT1 的潜在影响，并探讨其在鱼藤酮诱导的帕金森病大鼠模型中的作用机制：方法：大鼠在运动行为测试后被处死。方法：大鼠在运动行为测试后被处死，纹状体组织用于评估 MALAT1、氧化应激标记物和自噬标记物的表达：我们的研究发现，在诱导模型期间使用亚精胺治疗 2 周，与未治疗组相比，可显著改善行为评估和多巴胺水平，并减轻帕金森病的组织病理学变化：我们的初步研究证实了亚精胺对自噬激活的保护作用及其抗氧化特性。部分抗氧化活性是由于抑制了 MALAT1。然而，MALAT1与亚精胺诱导的自噬途径并不相关。

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引用次数: 0

Role of biomarkers and molecular signaling pathways in acute lung injury 生物标志物和分子信号通路在急性肺损伤中的作用。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-26 DOI: 10.1111/fcp.12987

Pakter Niri, Achintya Saha, Subramanyam Polopalli, Mohit Kumar, Sanghita Das, Pronobesh Chattopadhyay

Background

Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS).

Objectives

Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI.

Methods

The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination.

Results

This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs).

Conclusion

However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing.

背景：急性肺损伤（ALI）是由细菌、真菌和病毒感染引起的。当病原体侵入肺部时，免疫系统会产生细胞因子、趋化因子和干扰素，以促进吞噬细胞的浸润。细胞因子、趋化因子和干扰素的过量产生会导致过度活跃的免疫反应和病理性高炎症状态，从而引发 ALI。迄今为止，尽管已知有中性粒细胞胞外捕获物（NETs）和活性氧（ROS）等炎症介质，但仍没有治疗 ALI 的特效药物：因此，本综述的主要目的是提供关于控制中性粒细胞胞外捕获物（NETs）、活性氧（ROS）形成的机制以及 ALI 发病过程中其他相关过程的清晰概述。此外，我们还讨论了上皮和内皮损伤指标的重要性以及与 ALI 相关的几种分子信号通路：方法：我们从 Web of Science、Scopus、PubMed 和 Google Scholar 上查阅了有关 ALI、NETs、ROS、炎症、生物标志物、Toll 和核苷酸结合寡聚域（NOD）样受体、肺泡损伤、促炎细胞因子以及上皮/内皮损伤的单独或组合的文献：本综述总结了 ALI 的主要临床表现，包括上皮和内皮生物标志物、NETs、ROS 和模式识别受体（PRRs）的调节和不同功能：然而，目前还没有针对 ALI 的特定药物（包括疫苗）。此外，目前还缺乏有效的诊断工具，现有治疗生物标志物的预测合理性也很差。因此，需要开展广泛而精确的研究，通过应用人工智能技术、基于结构的药物设计、硅内方法和药物再利用，加快药物测试和开发进程。

{"title":"Role of biomarkers and molecular signaling pathways in acute lung injury","authors":"Pakter Niri, Achintya Saha, Subramanyam Polopalli, Mohit Kumar, Sanghita Das, Pronobesh Chattopadhyay","doi":"10.1111/fcp.12987","DOIUrl":"10.1111/fcp.12987","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, <i>in-silico</i> approaches, and drug repurposing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 4","pages":"640-657"},"PeriodicalIF":2.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139566975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Arterial hypertension associated with PARPi: A meta-analysis of 41 placebo randomized controlled trials combined with a World Health Organization's pharmacovigilance study 与 PARPi 相关的动脉高血压：41 项安慰剂随机对照试验与世界卫生组织药物警戒研究的荟萃分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-25 DOI: 10.1111/fcp.12984

Clémence Blaize, Ellina Surtouque, Jonaz Font, Charles Dolladille, Sophie Postel-Vinay, Angélique Da Silva, Joachim Alexandre, Pierre-Marie Morice

Background

Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP-ribose) polymerase inhibitor (PARPi).

Objective

In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice.

Methods

We performed a systematic review and meta-analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi-associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022.

Results

In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68–0.86], P < 0.01; I² = 19%, χ² P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76–4.57], P < 0.01; I² = 66%, χ² P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23–25.50). In real-life setting, niraparib-associated hypertension occurs within 20 days and was serious in 66%. Co-prescription of at least one antihypertensive or therapy-induced hypertension was reported in 20.5% or 14.4% of cases, respectively.

Conclusions

In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival.

背景：最近，评估聚（ADP-核糖）聚合酶抑制剂（PARPi）的随机对照试验（RCT）报告了动脉高血压：在越来越多地使用 PARPi 的情况下，正确评估这一不良事件的风险和发生率对于临床实践至关重要：截至 2023 年 1 月 4 日，我们在 MEDLINE、Cochrane CENTRAL 和 ClinicalTrials.gov 上进行了系统回顾和荟萃分析，并持续监测至 2023 年 6 月 7 日。如果报告了高血压，则纳入在实体瘤成年患者中比较 PARPi 和安慰剂的 RCT。主要结果是安慰剂 RCT 中 PARPi 类任何高血压的总风险比 (RR，含 95% CIs)。次要结果是每种 PARPi 的高血压总风险和发病率。为了提供 PARPi 相关高血压的临床特征，我们独立查询了世界卫生组织的药物警戒数据库（截至 2022 年 9 月 1 日）：结果：共纳入 41 项安慰剂 RCT（n = 15 264 名成年患者）。与安慰剂相比，PARPi 类药物与高血压风险增加无关。在单项分析中，奥拉帕利的高血压风险低于安慰剂（RR 0.77 [95% CI：0.68-0.86]，P 2 = 19%，χ2 P = 0.26）。尼拉帕利单药治疗会增加任何高血压的风险（RR 2.84 [95% CI：1.76-4.57]，P 2 = 66%，χ2 P = 0.01），总发生率为 19.87%（95% CI：15.23-25.50）。在现实生活中，尼拉帕利相关高血压发生在 20 天内，66% 的患者病情严重。据报道，20.5%或14.4%的病例同时服用了至少一种降压药或治疗引起的高血压：结论：在对尼拉帕利联合用药进行广泛评估的背景下，这些数据强化了密切监测这一不良事件的必要性，以保持其对患者生存的临床益处。

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引用次数: 0

Sodium hypochlorite accident diagnosis and management: Analysis from the literature and the French pharmacovigilance database 次氯酸钠事故的诊断和处理：文献和法国药物警戒数据库分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-24 DOI: 10.1111/fcp.12985

Zahoua Kartit, Céline Delacroix, Céline Clement, Mathilde Beurrier, Claudie Mouton-Faivre, Nadine Petitpain

Purpose

Sodium hypochlorite (NaOCl) is considered as the reference irrigation solution in endodontics. However, NaOCl-related accidents may occur, and non-dentist health professionals might under-recognize this rare adverse effect although it is potentially severe, with possible medical and aesthetic sequelae. We performed a literature review to provide to non-dentist healthcare professionals a large picture of symptoms, management and potential consequences of NaOCl accidents.

Methods

We queried PubMed and the French Pharmacovigilance database and retrieved 76 cases for analysis (70 from 57 published articles, and six from the database).

Results

The analysis showed that patients were mostly women (79%), aged around of 42 years, undergoing upper jawbone (74%) endodontic procedure. NaOCl concentration ranged from 1% to 10%, with 0.5 to 30 mL injected. Most cases (86%) corresponded to an accidental extrusion beyond the root apex to the periapical tissues, followed by tissular injection by error (8%) and extrusion into the maxillary sinus (3%). Local symptoms always occurred within 24 h, mostly pain (99%), edema (89%) and/or ecchymosis (61%). Complications were mainly neurological (29%), necrotic (22%) and cutaneous (9%). Most of patients (76%) fully recovered after medical management but 18 (24%) required surgical management.

Conclusion

Any healthcare professional should be aware of the classical symptomatic triad of NaOCl accident with sudden pain, haemorrhage/ecchymosis and swelling, to start or recommend adequate management. Patients should be reassured, but a close follow-up is necessary to avoid delayed complication.

目的：次氯酸钠（NaOCl）被认为是牙髓病学的参考灌洗溶液。然而，与次氯酸钠相关的事故可能会发生，非牙科医生保健专业人员可能对这种罕见的不良反应认识不足，尽管这种不良反应可能很严重，并可能带来医疗和美学后遗症。我们进行了一次文献综述，旨在为非牙科医生的医疗保健专业人员提供有关 NaOCl 事故的症状、处理方法和潜在后果的全面信息：我们查询了 PubMed 和法国药物警戒数据库，并检索了 76 个病例进行分析（其中 70 例来自 57 篇发表的文章，6 例来自数据库）：分析结果显示，患者多为女性（79%），年龄在 42 岁左右，正在接受上颌骨牙髓治疗（74%）。NaOCl 浓度从 1%到 10%不等，注射量从 0.5 毫升到 30 毫升不等。大多数病例（86%）是由于意外挤出根尖至根尖周围组织，其次是组织注射错误（8%）和挤入上颌窦（3%）。局部症状总是在 24 小时内出现，主要是疼痛（99%）、水肿（89%）和/或瘀斑（61%）。并发症主要是神经系统（29%）、坏死（22%）和皮肤（9%）。大多数患者（76%）在接受内科治疗后完全康复，但有18名患者（24%）需要接受外科治疗：任何医护人员都应了解 NaOCl 事故的典型症状三联征，即突然疼痛、出血/瘀斑和肿胀，以便开始或建议适当的治疗。患者应得到安抚，但有必要进行密切随访，以避免延误并发症的发生。

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引用次数: 0