Basic & Clinical Pharmacology & Toxicology最新文献

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7,8-Dihydroxyflavone Suppresses Experimental Pulmonary Fibrosis by Inhibiting Fibroblast-to-Myofibroblast Transformation and Epithelial–Mesenchymal Transition 7,8-二羟黄酮通过抑制成纤维细胞向肌成纤维细胞转化和上皮-间质转化抑制实验性肺纤维化。

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-05 DOI: 10.1111/bcpt.70158

Yu-chen Song, Qing-liu Li, Ru-jin Liang, Jia-tong Yao, Zhen Tian, Yu-wei Hu, Ting-ting Tan, Dong-xu Jia, Dan-dan Guo, Hua Zhu, Jing Zhao, Peng-zhou Hang

Pulmonary fibrosis (PF) is a chronic and progressive fibrotic disease with limited treatment options, which highlights the urgent need for novel therapeutic strategies. Fibroblast-to-myofibroblast transformation (FMT) and epithelial–mesenchymal transition (EMT) are central mechanisms driving fibrosis progression. This study investigated the therapeutic potential and mechanisms of 7,8-dihydroxyflavone (7,8-DHF), a selective tropomyosin receptor kinase B (TrkB) agonist, in experimental PF models in vitro and in vivo. Human lung fibroblast cells (MRC-5) and mouse lung epithelial cells (MLE-12) were stimulated with transforming growth factor-β1 (TGF-β1). 7,8-DHF suppressed the migration, proliferation and differentiation of TGF-β1-induced MRC-5 cells as well as reduced the protein levels of fibrotic markers including α-smooth muscle actin, connective tissue growth factor, collagen I and fibronectin. Moreover, 7,8-DHF attenuated the migration and EMT of TGF-β1-induced MLE-12 cells. Additionally, 7,8-DHF alleviated bleomycin-induced PF in mice. Mechanistically, 7,8-DHF inhibited the TGF-β1/Smad2/3 signalling pathway in both models. Notably, the anti-fibrotic effects were not reversed by the selective TrkB inhibitor ANA-12, suggesting TrkB-independent action. Instead, 7,8-DHF suppressed Akt activity in MRC-5 and MLE-12 cells. These findings demonstrate that 7,8-DHF alleviates PF by targeting FMT and EMT via TGF-β1/Smad2/3 signalling and Akt inhibition. These results highlight 7,8-DHF as a promising therapeutic candidate for PF.

肺纤维化（PF）是一种慢性进行性纤维化疾病，治疗方案有限，迫切需要新的治疗策略。成纤维细胞到肌成纤维细胞转化（FMT）和上皮-间充质转化（EMT）是驱动纤维化进展的主要机制。本研究探讨了选择性原肌球蛋白受体激酶B （TrkB）激动剂7,8-二羟黄酮（7,8- dhf）在PF模型中的治疗潜力和机制。转化生长因子-β1 （TGF-β1）刺激人肺成纤维细胞（MRC-5）和小鼠肺上皮细胞（MLE-12）。7,8- dhf抑制TGF-β1诱导的MRC-5细胞的迁移、增殖和分化，降低α-平滑肌肌动蛋白、结缔组织生长因子、I型胶原和纤维连接蛋白等纤维化标志物的蛋白水平。此外，7,8- dhf可减弱TGF-β1诱导的MLE-12细胞的迁移和EMT。此外，7,8- dhf可减轻博莱霉素诱导的小鼠PF。在机制上，7,8- dhf在两种模型中均抑制TGF-β1/Smad2/3信号通路。值得注意的是，抗纤维化作用不会被选择性TrkB抑制剂ANA-12逆转，表明其作用与TrkB无关。相反，7,8- dhf抑制MRC-5和MLE-12细胞中的Akt活性。这些研究结果表明，7,8- dhf通过TGF-β1/Smad2/3信号通路和Akt抑制作用靶向FMT和EMT，从而缓解PF。这些结果强调7,8- dhf是一种有希望的PF治疗候选药物。

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引用次数: 0

Hyperfiltration and Metabolism Before and After a Low-Calorie, Pre-Gastric Bypass Surgery Diet: Significance for Concentrations of Hydrophilic and Lipophilic Drugs 低热量胃旁路手术前饮食前后的超滤过和代谢：对亲水和亲脂药物浓度的意义

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70138

Magnus A. B. Axelsson, Susanna M. Wallerstedt

Psychotropic drug concentrations increase/decrease with hydrophilicity/lipophilicity after a low-calorie pre-bariatric surgery diet. To investigate underlying mechanisms, body weight and serum creatinine/cystatin C changes over the diet period were characterized and suggested to reflect changes in glomerular filtration and metabolic capacity, respectively. The greater the individual weight loss, the greater the concentration increase in hydrophilic drugs that undergo glomerular filtration, for example, pregabalin and gabapentin, suggesting that this reflects decreased glomerular hyperfiltration. By contrast, for highly lipophilic drugs, for example, mirtazapine and sertraline, the greater the individual creatinine and cystatin C loss, the greater the decrease in drug concentration, interpreted as increased drug metabolism based on decreased liver inflammation and steatosis. Venlafaxine/O-desmethylvenlafaxine displayed a complicated pattern suggesting the involvement of both glomerular filtration and metabolism. Serum concentrations of modestly lipophilic drugs, for example, duloxetine and (es)citalopram, were not significantly affected by the diet. In conclusion, hydrophilicity- and lipophilicity-related changes in drug concentrations over the diet period covary with markers of changes in hyperfiltration and metabolism, respectively. This implies that weight and creatinine/cystatin C changes could provide quantitative indications regarding expected drug concentration changes following fasting for hydrophilic and lipophilic drugs, respectively, which could be of value when therapeutic drug monitoring is not available.

低热量减肥手术前饮食后，精神药物浓度随亲水性/亲脂性增加/减少。为了研究其潜在的机制，我们对体重和血清肌酐/胱抑素C在饮食期间的变化进行了表征，并认为它们分别反映了肾小球滤过和代谢能力的变化。个体体重减轻越大，经肾小球滤过的亲水性药物（如普瑞巴林和加巴喷丁）的浓度增加越大，提示这反映了肾小球高滤过减少。相比之下，对于高度亲脂性药物，如米氮平和舍曲林，个体肌酐和胱抑素C损失越大，药物浓度下降越大，这可以解释为基于肝脏炎症和脂肪变性减少的药物代谢增加。文拉法辛/ o -去甲基文拉法辛表现出复杂的模式，表明肾小球滤过和代谢都参与其中。中度亲脂性药物（如度洛西汀和西酞普兰）的血清浓度不受饮食的显著影响。总之，与亲水性和亲脂性相关的药物浓度在饮食期间的变化分别与超滤和代谢的变化标志物相关。这意味着体重和肌酐/胱抑素C的变化可以分别提供亲水性和亲脂性药物禁食后预期药物浓度变化的定量指标，这在治疗药物监测不可用时可能有价值。

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引用次数: 0

Managing Delayed or Missed Doses of Prolonged-Release Tacrolimus in Transplant Recipients: Implications for Drug Exposure and Recovery Strategies 移植受者延迟或错过他克莫司缓释剂量的管理：对药物暴露和恢复策略的影响

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70157

S. Arraki Zava, F. Maizaud, H. Sayadi, Y. Fromage, P. Marquet, J. B. Woillard, C. Monchaud

In lifelong immunosuppressive therapy, missed doses of prolonged-release tacrolimus are almost inevitable and may reduce drug exposure, compromising transplant outcomes. Using pharmacokinetic models, we simulated delayed and missed doses in virtual kidney and liver transplant recipients. Our simulations showed that a missed dose significantly lowers exposure, with recovery taking 2–4 days. For delays shorter than 12 h, the full dose should be taken immediately; for delays between 12 and 24 h, half the dose should be administered; for a missed dose, 150% should be given at the next intake. These strategies may help maintain therapeutic exposure and preserve transplant outcomes.

在终身免疫抑制治疗中，错过缓释他克莫司的剂量几乎是不可避免的，并且可能减少药物暴露，影响移植结果。使用药代动力学模型，我们模拟了虚拟肾和肝移植受者的延迟和错过剂量。我们的模拟显示，错过的剂量显著降低了暴露，恢复需要2-4天。如果延迟时间小于12小时，应立即服用全剂量；如果延迟12至24小时，应给予一半剂量；对于漏服的剂量，应在下次服用时给予150%的剂量。这些策略可能有助于维持治疗暴露和保持移植结果。

引用次数: 0

Retrospective Analysis of the Use of Oral Ivermectin and 5% Permethrin Cream in Galicia (Spain) 西班牙加利西亚地区口服伊维菌素和5%氯菊酯乳膏使用情况回顾性分析

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70152

S. Vazquez-Prieto, A. Vaamonde, E. Paniagua

引用次数: 0

Epigallocatechin-3-Gallate Provides Hepatoprotection Through Endoplasmic Reticulum Stress/TXNIP/NLRP3 Axis in Paracetamol-Induced Acute Liver Injury 表没食子儿茶素-3-没食子酸酯通过内质网应激/TXNIP/NLRP3轴在扑热息痛诱导的急性肝损伤中提供肝保护

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70155

Nagihan Demirtas, Busra Sahin Mazlumoglu, Nevra Aydemir Celep, Elif Cadirci, Zekai Halici, Saziye Sezin Palabiyik-Yucelik

Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound with strong antioxidant properties and is abundantly found in green tea. We investigated how EGCG affects the liver injury of high-dose paracetamol in this study. In our study, 56 rats were divided into seven groups (n = 8): healthy control, EGCG (100 mg/kg), paracetamol (2 g/kg), paracetamol + EGCG 25 (2 g/kg + 25 mg/kg), paracetamol + EGCG 50 (2 g/kg + 50 mg/kg), paracetamol + EGCG 100 (2 g/kg + 100 mg/kg) and paracetamol + N-acetyl cysteine (NAC, 2 g/kg + 140 mg/kg). Our findings suggest that high-dose paracetamol induces liver injury through endoplasmic reticulum (ER) stress and that EGCG alleviates liver injury by attenuating ER stress-induced inflammasome signalling.

表没食子儿茶素-3-没食子酸酯（EGCG）是一种多酚化合物，具有很强的抗氧化特性，在绿茶中含量丰富。本研究探讨EGCG对大剂量扑热息痛肝损伤的影响。将56只大鼠分为7组（n = 8）：健康对照组、EGCG （100 mg/kg）、扑热息痛（2 g/kg）、扑热息痛+ EGCG 25 （2 g/kg + 25 mg/kg）、扑热息痛+ EGCG 50 （2 g/kg + 50 mg/kg）、扑热息痛+ EGCG 100 （2 g/kg + 100 mg/kg）和扑热息痛+ n -乙酰半胱氨酸（NAC, 2 g/kg + 140 mg/kg）。我们的研究结果表明，大剂量扑热息痛通过内质网（ER）应激诱导肝损伤，而EGCG通过减弱内质网应激诱导的炎症小体信号传导来减轻肝损伤。

引用次数: 0

Reducing Anticholinergic Burden in Hospitalised Older Adults: Analysis From the INFAR Study 减轻住院老年人抗胆碱能负担：来自INFAR研究的分析

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70160

Romana Santos Gama, Luiz Carlos Passos, Welma Wildes Amorim, Renato Morais Souza, Marcio Galvão Oliveira

This study aimed to evaluate the effectiveness of pharmacist-led medication reviews in reducing the anticholinergic burden of hospitalised patients with cardiovascular diseases (CVDs), to identify which anticholinergic medications were most frequently prescribed or discontinued during hospitalisation and to investigate factors associated with an elevated anticholinergic burden via secondary analysis of the INFAR study. An uncontrolled before-and-after design was used, and medication reviews were performed for all patients so that the anticholinergic burden of medications prescribed to older adults during their hospital stay could be examined. The mean age of the 319 patients was 68.9 years (±6.2), and upon hospital admission, 40.4% were classified as having a high anticholinergic burden, decreasing to 22.6% at discharge. Multivariate analysis at admission indicated that polypharmacy (PR = 2.00; 95% CI = 1.47–2.72) and potentially inappropriate medication (PR = 4.47; 95% CI = 2.10–9.53) were independently associated with a higher anticholinergic burden; however, only inappropriate medication was significantly associated with a high burden (PR = 2.39; 95% CI = 1.54–3.71) at discharge. The results indicate that a clinical pharmacist-led medication review may reduce the anticholinergic burden in older adults with CVD, highlighting the importance of such a review in promoting safer prescribing practices during hospitalisation.

本研究旨在评估药师主导的药物评价在减少心血管疾病（cvd）住院患者抗胆碱能负担方面的有效性，确定住院期间最常开具或停药的抗胆碱能药物，并通过对INFAR研究的二次分析调查与抗胆碱能负担升高相关的因素。采用不受控制的前后对照设计，并对所有患者进行药物评价，以便检查老年人住院期间处方的抗胆碱能药物负担。319例患者的平均年龄为68.9岁（±6.2岁），入院时40.4%的患者被归为抗胆碱能负荷高，出院时降至22.6%。入院时的多因素分析显示，多药（PR = 2.00, 95% CI = 1.47-2.72）和可能不适当的用药（PR = 4.47, 95% CI = 2.10-9.53）与较高的抗胆碱能负担独立相关；然而，只有用药不当与出院时的高负担显著相关（PR = 2.39; 95% CI = 1.54-3.71）。结果表明，临床药师主导的药物审查可能会减少老年心血管疾病患者的抗胆碱能负担，强调了这种审查在促进住院期间更安全的处方实践中的重要性。

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引用次数: 0

Gadoteric Acid Induces Dose-Dependent DNA Damage and Enzyme Binding in Fibroblast Cells gadoteracid诱导成纤维细胞剂量依赖性DNA损伤和酶结合

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70150

İbrahim Halil Kenger

Gadolinium-based contrast agents, widely used in magnetic resonance imaging, raise safety concerns due to their potential cytotoxic and genotoxic effects, especially at high doses or repeated exposures. In this study, the cytogenotoxic potential of gadoteric acid in NIH3T3 fibroblast cells was evaluated using in vitro and in silico approaches. NIH3T3 cells were treated with increasing concentrations of gadoteric acid. Cytotoxicity was evaluated by MTS assay and genotoxicity by comet assay; hydrogen peroxide (75 μM) was used as a positive control. In addition, the interaction of gadoteric acid with DNA topoisomerase IIα, DNA topoisomerase IIβ, DNA polymerase β, and B-DNA was examined by molecular docking. MTS assay results showed a dose-dependent decrease in cell viability with an IC₅₀ of 28.19 mM. Comet assay revealed significant DNA damage only at the highest concentration (56.38 mM) (p < 0.05), which also caused marked cytotoxicity. Thus, the observed DNA damage likely resulted from cytotoxicity stress rather than direct strand breaks. In silico docking predicted a high binding affinity of gadoteric acid for DNA polymerase β (−11.7 kcal/mol) and other DNA-related targets. However, these predictions require experimental validation. Overall, gadoteric acid exhibited dose-dependent cytotoxicity and limited genotoxicity at high concentrations, suggesting that DNA damage occurs secondary to cytotoxic effects rather than a direct genotoxic mechanism.

钆基造影剂广泛应用于磁共振成像，由于其潜在的细胞毒性和基因毒性作用，特别是在高剂量或重复暴露时，引起了安全性问题。在本研究中，采用体外和计算机方法评估了钆乙酸对NIH3T3成纤维细胞的细胞基因毒性潜力。NIH3T3细胞用浓度增加的钆处理。MTS法测定细胞毒性，comet法测定遗传毒性；过氧化氢（75 μM）作为阳性对照。此外，通过分子对接研究了牛乳酸与DNA拓扑异构酶i α、DNA拓扑异构酶i β、DNA聚合酶β和B-DNA的相互作用。MTS实验结果显示细胞活力呈剂量依赖性下降，IC50为28.19 mM。彗星试验显示，仅在最高浓度（56.38 mM）时DNA损伤显著（p < 0.05），并引起显著的细胞毒性。因此，观察到的DNA损伤可能是由细胞毒性应激而不是直接链断裂引起的。在硅对接预测gadoteracid对DNA聚合酶β (- 11.7 kcal/mol)和其他DNA相关靶点具有高结合亲和力。然而，这些预测需要实验验证。总的来说，gadoteracid在高浓度下表现出剂量依赖性的细胞毒性和有限的遗传毒性，这表明DNA损伤是继发于细胞毒性作用，而不是直接的遗传毒性机制。

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引用次数: 0

Proton Pump Inhibitors and Biomarkers of Haemostasis in Postmenopausal Women: The Buffalo OsteoPerio Study 绝经后妇女血液止血的质子泵抑制剂和生物标志物：水牛骨手术研究

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-04 DOI: 10.1111/bcpt.70156

Ahmed I. Soliman, Jean Wactawski-Wende, Amy E. Millen, Kathleen M. Hovey, Michael J. LaMonte

Aims

Examine the association between proton pump inhibitor (PPI) use and plasma levels of four biomarkers of haemostasis: fibrinogen, von Willebrand factor (vWF), high-sensitivity CRP (hs-CRP) and plasminogen activator inhibitor-1 (PAI-1) in postmenopausal women.

Methods

We conducted a cross-sectional analysis on 200 women in the Buffalo Osteoporosis and Periodontitis study Year 17 visit. PPI use was assessed using medication inventories, and biomarkers were measured using frozen plasma samples. Linear regression was used to estimate mean differences for each biomarker according to PPI use (yes/no) and duration (≤ 1 year, > 1 year). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for having a high versus low level of each biomarker. Models were adjusted for major cardiovascular risk factors to account for potential confounding.

Results

PPI users had non-statistically significant higher levels of vWF (mean difference = 52.9 mIU/mL, p = 0.38) and log hs-CRP (mean difference = 0.1 mg/L, p = 0.5) compared to non-users. PPI users for > 1 year had non-statistically significant higher odds of having a high level of vWF (OR = 1.08, 95% CI: 0.51–2.31) and hs-CRP (OR = 1.16, 95% CI: 0.58–2.33) compared to non-users.

Conclusions

There was no significant association between PPI use and measured plasma haemostatic markers.

目的探讨绝经后妇女血浆中纤维蛋白原、血管性血友病因子（vWF）、高敏CRP （hs-CRP）和纤溶酶原激活物抑制剂-1 （PAI-1）水平与质子泵抑制剂（PPI）使用的关系。方法我们对布法罗骨质疏松和牙周炎研究17年访问的200名妇女进行了横断面分析。使用药物清单评估PPI使用情况，使用冷冻血浆样本测量生物标志物。根据PPI使用情况（是/否）和持续时间（≤1年，>； 1年），采用线性回归估计每个生物标志物的平均差异。使用逻辑回归来估计每种生物标志物高水平与低水平的比值比（OR）和95%置信区间（95% CI）。对模型进行了主要心血管危险因素调整，以考虑潜在的混杂因素。结果PPI使用者的vWF水平（平均差值为52.9 mIU/mL, p = 0.38）和log hs-CRP水平（平均差值为0.1 mg/L, p = 0.5）高于非PPI使用者，无统计学意义。PPI使用者1年的vWF （OR = 1.08, 95% CI: 0.51-2.31）和hs-CRP （OR = 1.16, 95% CI: 0.58-2.33）高于非PPI使用者，无统计学意义。结论PPI的使用与血浆止血指标之间无显著相关性。

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引用次数: 0

BCPT 2026 Policy for Experimental and Clinical Studies BCPT 2026实验与临床研究政策。

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-03 DOI: 10.1111/bcpt.70159

Pernille Tveden-Nyborg, Troels K. Bergmann, Niels Jessen, Ulf Simonsen, Jens Lykkesfeldt

引用次数: 0

Significant Antispastic Effect of Combined Fasudil and Isosorbide Dinitrate on Internal Mammary Artery in Coronary Artery Bypass Grafting 法舒地尔联合硝酸异山梨酯对冠状动脉搭桥术中乳腺内动脉的显著抗痉挛作用

IF 3.3 4区医学 Q2 PHARMACOLOGY & PHARMACY

Basic & Clinical Pharmacology & Toxicology

Pub Date : 2025-12-03 DOI: 10.1111/bcpt.70148

You-Feng Zhang, Hai-Tao Hou, Qin Yang, Guo-Wei He

Background

Vasospasm of arterial grafts remains a critical problem in coronary artery bypass grafting (CABG), contributing to perioperative ischemia and graft failure. This study evaluates the antispastic effects of combining the ROCK inhibitor fasudil and isosorbide dinitrate (ISDN) on the human internal mammary artery (IMA).

Methods

IMA rings (n = 208) from 94 CABG patients were investigated in a myograph. Relaxation to fasudil (−3.5 log M), ISDN (−4 log M) and their combination (FI solution) was assessed after precontraction with potassium chloride (KCl 30 mM) or U46619 (10⁻⁸ M). The preventive effects of FI solution on the contraction induced by KCl or U46619 were studied. ROCK2 protein and cGMP levels were measured using Western blot and ELISA.

Results

FI solution demonstrated superior relaxation compared to either drug alone against KCl or U46619 (p < 0.001). Pretreatment with FI inhibited the contraction by KCl and U46619, significantly higher than that with either drug alone (p < 0.0001). FI also reduced ROCK2 expression (p = 0.0001) and elevated cGMP levels (p = 0.0002).

Conclusions

The combination of fasudil and ISDN effectively prevents and relieves IMA vasospasm mediated by both voltage-operated and receptor-operated calcium channels, with a long-lasting vasorelaxing effect. The FI solution offers a novel approach for preventing and relieving IMA spasm in CABG.

背景在冠状动脉旁路移植术（CABG）中，血管痉挛仍然是一个关键问题，导致围手术期缺血和移植失败。本研究评价了ROCK抑制剂法舒地尔和硝酸异山梨酯（ISDN）联合应用对人乳腺内动脉（IMA）的抗痉挛作用。方法对94例冠脉搭桥患者的IMA环（208个）进行肌图检查。用氯化钾（KCl 30 mM）或U46619（10−8 M）预收缩后，评估法舒地尔（−3.5 log M）、ISDN（−4 log M）及其组合（FI溶液）的松弛度。研究了FI溶液对KCl和U46619诱导的收缩的预防作用。Western blot和ELISA检测各组小鼠ROCK2蛋白和cGMP水平。结果与单独使用KCl或U46619的药物相比，FI溶液表现出更好的松弛作用（p < 0.001）。FI预处理对KCl和U46619的收缩抑制作用显著高于单独用药（p < 0.0001）。FI还降低了ROCK2的表达（p = 0.0001），升高了cGMP水平（p = 0.0002）。结论法舒地尔联合ISDN可有效预防和缓解电压型和受体型钙通道介导的IMA血管痉挛，并具有持久的血管舒张作用。FI解决方案为预防和缓解CABG的IMA痉挛提供了一种新的方法。

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