Fundamental & Clinical Pharmacology最新文献_第2页

Body mass index affects imatinib exposure: Real-world evidence from TDM with adaptive dosing 体重指数影响伊马替尼暴露：适应性给药TDM的真实证据。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-01-03 DOI: 10.1111/fcp.13049

Paul Maroselli, Raphaelle Fanciullino, Julien Colle, Laure Farnault, Pauline Roche, Geoffroy Venton, Régis Costello, Joseph Ciccolini

Background

Imatinib is the treatment of elderly or frail patients with chronic myeloid leukemia (CML). Trough levels of around 1000 ng/ml are considered as the target exposure.

Objectives

We searched for baseline parameters associated with imatinib pharmacokinetics, and studied the clinical impact of subsequent adaptive dosing.

Methods

We present data from 60 adult CML patients upon imatinib with therapeutic drug monitoring (TDM) and adaptive dosing.

Results

Mean trough levels after treatment initiation were 994.2 ± 560.6 ng/ml with 56% inter-patient variability). Only 29% of patients were in the therapeutic range. Body weight, height, body surface area, body mass index (BMI), and age were associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with imatinib trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI < 18.5 kg/m², with exposure +61.5% higher than in patients with 18.5 < BMI ≤ 24.9 and +76.3% higher than in patients with BMI ≥ 25. After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg. No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing.

Conclusion

Our data suggest that low BMI has a significant impact on imatinib exposure but that pharmacokinetically-guided dosing limits its clinical impact in patients.

背景：伊马替尼是老年或体弱慢性髓性白血病（CML）患者的治疗药物。约1000纳克/毫升的谷水平被认为是目标暴露。目的：我们寻找与伊马替尼药代动力学相关的基线参数，并研究后续适应性给药的临床影响。方法：我们报告了60名接受伊马替尼治疗的成人CML患者的数据，并进行了治疗药物监测（TDM）和适应性给药。结果：治疗开始后的平均低谷水平为994.2±560.6 ng/ml，患者间差异为56%。只有29%的患者在治疗范围内。单变量分析显示，体重、身高、体表面积、体重指数（BMI）和年龄与伊马替尼血浆水平相关。在多变量分析中，年龄和BMI仍然是与伊马替尼低谷水平相关的唯一参数。由于此前曾报道过使用标准伊马替尼治疗的低BMI患者的严重毒性，因此我们评估了低BMI可能导致血浆过度暴露的程度。我们发现BMI为2的患者伊马替尼过药水平差异有统计学意义，暴露量比BMI为18.5的患者高61.5%。结论：我们的数据表明，低BMI对伊马替尼暴露有显著影响，但药代动力学指导给药限制了其对患者的临床影响。

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引用次数: 0

A novel naphthylchalcone ([E]-4-(3-[naphthalen-2-yl]-3-oxoprop-1-en-1-yl) induces intrinsic and extrinsic apoptosis in human acute leukemia cell lines 一种新型萘查尔酮([E]-4-（3-[萘-2-基]-3-氧丙基-1-烯-1-基）诱导人急性白血病细胞内源性和外源性凋亡。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-01-03 DOI: 10.1111/fcp.13047

Amanda V. Jacques, Natália M. Stefanes, Laura O. Walter, Stephanie M. Syracuse, Alisson Bigolin, Louise D. Chiaradia-Delatorre, Luiz F. S. de Souza, Ana C. R. de Moraes, Ricardo J. Nunes, Maria C. Santos-Silva

Background

Chalcones have been described in the literature as promising antineoplastic compounds.

Objectives

Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562).

Methods

Cytotoxicity assessment was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry.

Results

The most cytotoxic chalcone (R32) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). R32 demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase-3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl-2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis-inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI-67 cell proliferation marker.

Conclusion

These findings suggest R32 as a potential compound for the development of novel drugs for the treatment of AL.

背景：查尔酮在文献中被描述为有前途的抗肿瘤化合物。目的：本研究的目的是分析23种合成查尔酮对人急性白血病（AL）细胞株Jurkat和K562的细胞毒性。方法：采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）法进行细胞毒性评价。采用荧光显微镜、DNA片段化技术和流式细胞术评估细胞死亡情况。结果：细胞毒性最强的查尔酮（R32）对外周血单个核细胞（PBMC）无细胞毒性。它没有溶血活性，不会改变二磷酸腺苷（ADP）和肾上腺素刺激后的血小板聚集，也不会影响凝血酶原时间（PT）和活化的部分凝血活素时间（APTT）。R32通过诱导内源性和外源性细胞凋亡，导致caspase-3活化和DNA断裂，显示出细胞毒性活性。在Jurkat和K562细胞中，细胞凋亡与线粒体膜电位（MMP）的变化有关。Bcl-2表达降低，Bax表达升高，survivin表达降低，凋亡诱导因子（AIF）表达升高。在两种细胞系中也观察到外源性凋亡的参与，其特征是Fas受体的表达增加。此外，Jurkat细胞表现出KI-67细胞增殖标志物的表达降低。结论：R32是开发新型AL治疗药物的潜在化合物。

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引用次数: 0

Knockdown of RFC3 enhances the sensitivity of colon cancer cells to oxaliplatin by inducing ferroptosis RFC3基因敲低可通过诱导铁凋亡增强结肠癌细胞对奥沙利铂的敏感性。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2025-01-03 DOI: 10.1111/fcp.13044

Youyi Wu, Tingting Chen, Songsong Wu, Yiwei Huang, Fuyao Li

Background

The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug-induced apoptosis.

Objective

To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.

Methods

siRNA-mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β-catenin/GPX4 axis.

Results

RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β-catenin/GPX4 axis.

Conclusion

Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.

背景：对奥沙利铂耐药的发展是一个多方面的过程，通常涉及药物转运、DNA修复机制的改变以及细胞逃避药物诱导的凋亡的能力。目的：评估敲除RFC3是否促进结直肠癌（CRC）细胞对奥沙利铂的敏感性，可能为对抗耐药提供新的途径。方法：在结直肠癌细胞系中采用sirna介导的RFC3敲低来评估对奥沙利铂反应性的影响。通过细胞活力测定、克隆存活测定和流式细胞术评估其对细胞生长和凋亡的影响。此外，使用免疫印迹分析来仔细检查Wnt/β-catenin/GPX4轴上关键蛋白表达的表达变化。结果：RFC3在结直肠癌组织中高表达，且与预后相关。敲除RFC3可增强CRC细胞对奥沙利铂的敏感性。此外，RFC3的减少通过诱导铁下垂促进化疗耐药肿瘤细胞对奥沙利铂的易感性。此外，RFC3的敲低会破坏Wnt/β-catenin/GPX4轴。结论：RFC3缺失通过诱导铁凋亡增强CRC细胞对奥沙利铂的敏感性。

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引用次数: 0

Breastfeeding and contrast agents—A critical review and presentation of new aspects 母乳喂养和造影剂——一个重要的回顾和新方面的介绍。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-11-28 DOI: 10.1111/fcp.13045

Sina Lemmenmeier, Ingrid Boehm

Background

There are discrepancies between guidelines of scientific societies and information of the package inserts of contrast media concerning breastfeeding following the application of a contrast agent to the mother.

Objectives

The contents of different review articles reflect the opinion of scientific societies. Consequently, in clinical routine settings it is difficult to find the optimal advice for a breastfeeding woman and her baby.

Methods

Therefore, the paper carefully summarized important information dealing with the topic ‘breastfeeding and contrast media’ from the literature. Among other things, the paper focuses on topics that are not yet taken into account in other reviews (e.g. approval for breastfeeding women, contrast agents that have been analysed in human breast milk).

Results

In this way, the review shows new aspects. It has been revealed that data concerning the amount of contrast agents in human breast milk as well as contrast medium absorption by the infants' intestine are sparse. Instead of them, a lot of speculations and incorrect conclusions do exist in the literature. Because studies are rare or missing, contrast media are not approved for breastfeeding women (off-label-use).

Conclusion

Although breastfeeding women 100% prefers a break from breastfeeding, in current decision-making processes, their preference plays a minor role. However, this should change in the future. In addition, it would be very important to inform breastfeeding women in the future about the missing data concerning ‘breastfeeding and contrast media’.

背景：科学学会的指南和造影剂说明书上关于母亲使用造影剂后母乳喂养的信息存在差异。目的：不同综述文章的内容反映了科学学会的意见。因此，在临床常规设置是很难找到母乳喂养的妇女和她的婴儿的最佳建议。方法：因此，本文仔细总结了文献中有关“母乳喂养与造影剂”主题的重要信息。除其他事项外，该文件侧重于其他审查尚未考虑到的主题（例如，对母乳喂养妇女的批准，在人类母乳中分析的造影剂）。结果：综述呈现出新的方面。研究表明，关于人类母乳中造影剂的含量以及婴儿肠道对造影剂的吸收的数据很少。相反，文献中确实存在许多猜测和不正确的结论。由于研究很少或缺失，造影剂不被批准用于母乳喂养妇女（标签外使用）。结论：虽然母乳喂养妇女100%倾向于中断母乳喂养，但在当前的决策过程中，她们的偏好只起了很小的作用。然而，这在未来应该会改变。此外，将来告知母乳喂养妇女关于“母乳喂养和造影剂”的缺失数据将是非常重要的。

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引用次数: 0

The synergy between alkylating agents and ERCC1–XPF inhibitors is p53 dependent 烷化剂与 ERCC1-XPF 抑制剂之间的协同作用取决于 p53。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-11-08 DOI: 10.1111/fcp.13043

Gloria Ciniero, Tiago Marques Pedro, Charles Dumontet, Ahmed H. Elmenoufy, Frederick G. West, Michael Weinfeld, Francesco Gentile, Jack A. Tuszynski, Emeline Cros-Perrial, Lars Petter Jordheim

Background

DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.

Objectives

Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair.

Methods

We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities.

Results

We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53.

Conclusion

Our results confirm the mechanism of action of our ERCC1–XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs.

背景：DNA 修复在维持基因组稳定性方面发挥着重要作用，从而限制了正常细胞向癌细胞的转化。然而，在使用 DNA 靶向药物治疗的癌症患者中，DNA 修复可通过消除此类分子产生的损伤（诱导药理活性所需的损伤）而降低疗效。因此，抑制 DNA 修复是在这种情况下增强化疗活性的一种有趣方法：在此，我们继续研究核苷酸切除修复的两个关键蛋白--切除修复交叉互补Rrodent修复缺陷互补组1（ERCC1）和色素沉着病F组（XPF）（B9）之间相互作用的抑制剂的特性：方法：我们利用各种细胞系和共孵育研究来测定细胞存活和 DNA 修复能力：结果：我们发现，与之前描述的其他铂衍生物相比，它具有协同作用，而且在不表达 ERCC1 或 XPF 的细胞中缺乏协同作用。最后，一系列实验表明，只有在表达野生型 p53 的细胞中才能观察到增效作用：我们的研究结果证实了我们的 ERCC1-XPF 抑制剂的作用机制，并为这种增强现有抗癌药物活性的方法提供了重要的补充数据。

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引用次数: 0

Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models Capivasertib 在临床前小细胞肺癌模型中通过抑制 Akt 增强化疗效果。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-11-05 DOI: 10.1111/fcp.13042

Cheng Long, Hui Shen, Hui Li, Lan Han

Background

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy.

Objectives

To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms.

Methods

SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role.

Results

Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib.

Conclusion

Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.

背景：小细胞肺癌（SCLC小细胞肺癌（SCLC）是一种侵袭性极强的肺癌，铂类化疗是其标准疗法。尽管这种疗法最初会产生反应，但患者最终会对化疗产生耐药性：研究卡匹伐他汀这种已获批准的晚期乳腺癌药物在临床前SCLC模型中增强顺铂疗效的潜力，并探索其潜在机制：方法：用capivasertib和顺铂单独或联合处理SCLC细胞系，以评估细胞活力、增殖、集落形成和凋亡。接着，在 SCLC 小鼠模型中评估了卡非伐他汀单独或与顺铂联合使用的效果。机理研究的重点是Akt和MYC信号转导，用组成性活性Akt过表达来评估其作用：结果：Capivasertib对各种SCLC细胞系均有活性，不受细胞来源和遗传特征的影响，IC50在临床可达到的范围内。特别是，capivasertib能抑制SCLC细胞的增殖和锚定依赖性集落形成，并诱导细胞凋亡。在所有测试的细胞系中，它都能明显增强顺铂的抑制作用。重要的是，无毒剂量的卡非伐他汀能有效延缓小鼠的SCLC生长，与顺铂联用几乎能完全抑制肿瘤生长。机理研究证实，卡必伐替抑制了Akt和MYC信号转导，此外，组成型活性Akt的过表达逆转了卡必伐替的抗SCLC活性：我们的研究首次揭示了抑制Akt可以增强SCLC的化疗效果，capivasertib是SCLC治疗手段的有益补充。

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引用次数: 0

New ways to repurpose salmeterol in an animal model of fibromyalgia 在纤维肌痛动物模型中重新利用沙美特罗的新方法。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-11-04 DOI: 10.1111/fcp.13041

Mena Z. Shafiek, Hala F. Zaki, Ahmed F. Mohamed

Background

Fibromyalgia (FM) is a syndrome of pervasive chronic pain accompanied by low mood, sleep disorders, and cognitive decline. The dysfunction of central pain processing systems along with neurotransmitter disturbances are possible contributing mechanisms. Genetic polymorphism of the 𝛽2 adrenergic receptors is reported in FM patients. It is reported that chronic β2 agonists administration is effective for neuropathic pain alleviation. No current information, however, exists on their potential to alleviate nociplastic pain, such as FM. Therefore, the purpose of the current study is to examine salmeterol's potential antiallodynic effects in experimentally produced FM and explore some of the possible contributing mechanisms.

Methods

Thirty rats are allocated into three groups (n = 10): a normal group, a reserpine group that received reserpine (1 mg/kg; s.c.) for 3 days, and a reserpine + salmeterol group that received salmeterol (1 mg/kg; i.p.) for 21 consecutive days following last reserpine injection.

Results

Reserpine administration resulted in behavioral and biochemical changes consistent with FM, including thermal and mechanical hyperalgesia, depressive behavior, and motor incoordination. This is coupled with disturbed spinal monoamine levels, depressed cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, disturbed mitochondrial function/dynamics, and compromised blood-nerve barrier integrity. Treatment with salmeterol conceivably reversed these effects.

Conclusion

β2 receptor agonists such as salmeterol could be regarded as a promising strategy for the management of FM.

背景：纤维肌痛（FM）是一种普遍存在的慢性疼痛综合征，同时伴有情绪低落、睡眠障碍和认知能力下降。中枢疼痛处理系统功能障碍和神经递质紊乱是可能的致病机制。有报告称，FM 患者的肾上腺素 2 受体存在遗传多态性。据报道，长期服用β2激动剂可有效缓解神经性疼痛。然而，目前还没有关于其缓解非痉挛性疼痛（如 FM）潜力的信息。因此，本研究的目的是考察沙美特罗在实验性 FM 中的潜在镇痛作用，并探索一些可能的作用机制：将 30 只大鼠分为三组（n = 10）：正常组、连续 3 天注射 1 毫克/千克瑞舍平（s.c.）的瑞舍平组以及在最后一次注射瑞舍平之后连续 21 天注射 1 毫克/千克沙美特罗（i.p.）的瑞舍平 + 沙美特罗组：结果：瑞舍平注射会导致与 FM 一致的行为和生化变化，包括热和机械痛觉减退、抑郁行为和运动不协调。与此同时，脊髓单胺水平紊乱、环磷酸腺苷（cAMP）/蛋白激酶A（PKA）信号传导受抑、线粒体功能/动力学紊乱以及血液-神经屏障完整性受损。结论：沙美特罗等β2受体激动剂可被视为治疗FM的一种有前途的策略。

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引用次数: 0

Induction of Ca2+ signaling and cytotoxic responses of human lung fibroblasts upon an antihistamine drug oxatomide treatment and evaluating the protective effects of Ca2+ chelating 抗组胺药物奥沙米特处理人肺成纤维细胞时诱导 Ca2+ 信号传导和细胞毒性反应，并评估 Ca2+ 螯合剂的保护作用。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-10-21 DOI: 10.1111/fcp.13040

Wei-Zhe Liang, Kai-Wei Hsieh, Zong-Da Yang, Gwo-Ching Sun

Background

Oxatomide, an antihistamine drug of the diphenylmethylpiperazine family, has anti-inflammatory effects in airway disease. Because oxatomide was shown to cause diverse physiological responses in several cell models, the impact of oxatomide on Ca²⁺ signaling and its related physiological effects has not been explored in IMR-90 human fetal lung fibroblasts.

Objectives

This study assessed the effect of oxatomide on cell viability and intracellular free Ca²⁺ concentrations ([Ca²⁺]_i) and examined whether oxatomide-induced cytotoxicity through Ca²⁺ signaling in IMR-90 cells.

Methods

Cell viability was measured by the cell proliferation reagent (WST-1). [Ca²⁺]_i was measured by the Ca²⁺-sensitive fluorescent dye fura-2.

Results

Oxatomide (10–40 μM) concentration dependently reduced cell viability and induced [Ca²⁺]_i rises in IMR-90 cells. This cytotoxic effect was reversed by chelation of cytosolic Ca²⁺ with BAPTA-AM. In terms of Ca²⁺ signaling, oxatomide-caused Ca²⁺ entry was inhibited by modulators of store-operated Ca²⁺ channels (2-APB and SKF96365) and protein kinase C (PKC) inhibitor (GF109203X). Furthermore, oxatomide-induced Ca²⁺ influx was confirmed by Mn²⁺-induced quench of fura-2 fluorescence. In a Ca²⁺-free medium, preincubation with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin inhibited oxatomide-evoked [Ca²⁺]_i rises. Conversely, treatment with oxatomide abolished thapsigargin-induced [Ca²⁺]_i rises. Inhibition of phospholipase C (PLC) with U73122 also inhibited oxatomide-caused [Ca²⁺]_i rises.

Conclusion

In IMR-90 cells, oxatomide-induced cytotoxicity by preceding [Ca²⁺]_i rises involving PKC-sensitive store-operated Ca²⁺ entry and PLC-dependent Ca²⁺ release from the endoplasmic reticulum. BAPTA-AM, with its Ca²⁺ chelating effects, may be a potential compound for preventing oxatomide-induced cytotoxicity.

背景：奥沙米特是一种二苯基甲基哌嗪类抗组胺药物，对气道疾病具有抗炎作用。由于奥沙托酰胺在多个细胞模型中被证明可引起多种生理反应，因此尚未在 IMR-90 人胎肺成纤维细胞中探讨奥沙托酰胺对 Ca2+ 信号转导的影响及其相关生理效应：本研究评估了草铵膦对 IMR-90 细胞活力和细胞内游离 Ca2+ 浓度（[Ca2+]i）的影响，并考察了草铵膦是否通过 Ca2+ 信号转导诱导细胞毒性：方法：用细胞增殖试剂（WST-1）测量细胞活力。方法：用细胞增殖试剂（WST-1）测量细胞活力，用 Ca2+ 敏感荧光染料 fura-2 测量 [Ca2+]i：结果：奥沙托胺（10-40 μM）浓度依赖性地降低了 IMR-90 细胞的存活率，并诱导[Ca2+]i 上升。用 BAPTA-AM 螯合细胞膜 Ca2+ 可逆转这种细胞毒性效应。在 Ca2+ 信号转导方面，贮存操作的 Ca2+ 通道调节剂（2-APB 和 SKF96365）和蛋白激酶 C（PKC）抑制剂（GF109203X）抑制了草甘膦引起的 Ca2+ 进入。此外，氧胺诱导的 Ca2+ 流入通过 Mn2+ 诱导的 fura-2 荧光淬灭得到证实。在无 Ca2+ 的培养基中，预孵育内质网 Ca2+ 泵抑制剂硫司加精可抑制氧胺诱导的 [Ca2+]i 上升。相反，用奥沙利酰胺处理则可消除硫司加精诱导的[Ca2+]i 上升。用 U73122 抑制磷脂酶 C（PLC）也能抑制奥沙米德引起的[Ca2+]i 上升：结论：在 IMR-90 细胞中，氧胺诱导的细胞毒性是在[Ca2+]i 上升之前发生的，其中涉及 PKC 敏感的贮存操作 Ca2+ 进入和 PLC 依赖的内质网 Ca2+ 释放。具有 Ca2+ 螯合作用的 BAPTA-AM 可能是一种潜在的化合物，可用于防止氧胺诱导的细胞毒性。

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引用次数: 0

Nociceptive TRP channels function as molecular target for several antifungal drugs 痛觉 TRP 通道是几种抗真菌药物的分子靶点。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-10-17 DOI: 10.1111/fcp.13039

Shota Okabe, Kenji Takahashi, Miho Hashimoto, Toshio Ohta

Background/objectives

Topically applied antifungal agents can induce adverse effects, such as pain and irritation. The transient receptor potential (TRP) channels—TRPA1 and TRPV1—mainly expressed in sensory neurons, act as sensors for detecting irritants. This study aims to evaluate the involvement of nociceptive channels in topical antifungal-induced pain and irritation. We tested nine topical antifungals belonging five classes: isoconazole, econazole, miconazole, clotrimazole, and ketoconazole as imidazoles; liranaftate as a thiocarbamate; terbinafine as an allylamine; amorolfine as a morpholine; and butenafine as a benzylamine.

Methods

Intracellular calcium concentrations ([Ca²⁺]_i) and membrane currents in response to antifungals were measured to estimate channel activity using heterologously expressing cells and isolated mouse sensory neurons.

Results

In mouse TRPA1-expressing cells, all the tested drugs induced an increase in [Ca²⁺]_i, which was abrogated or reduced by a TRPA1 blocker. Although many drugs evoked the TRPA1-nonspecific [Ca²⁺]_i response at high concentrations, responses to clotrimazole, ketoconazole, and liranaftate were TRPA1 specific and elicited current responses in TRPA1-expressing cells. In mouse TRPV1-expressing cells, clotrimazole and ketoconazole elicited [Ca²⁺]_i and current responses. In mouse sensory neurons, liranaftate-induced increase in [Ca²⁺]_i was abrogated by a TRPA1 blocker and Trpa1 deletion. Responses to ketoconazole were inhibited by TRPA1 and TRPV1 blockers and by the genetic deletion of either channel.

Conclusion

These results suggest that topical antifungal-induced pain and irritation are attributable to the activation of nociceptive TRPA1 and/or TRPV1 channel/s. Consequently, caution should be exercised in the use of topical antifungals with symptoms of pain.

背景/目的：局部使用抗真菌剂会引起疼痛和刺激等不良反应。瞬时受体电位（TRP）通道--TRPA1 和 TRPV1--主要在感觉神经元中表达，是检测刺激物的传感器。本研究旨在评估局部抗真菌引起的疼痛和刺激中痛觉通道的参与情况。我们测试了属于五类的九种外用抗真菌药：咪唑类的异康唑、益康唑、咪康唑、克霉唑和酮康唑；硫代氨基甲酸酯类的利拉那酯；烯丙基胺类的特比萘芬；吗啉类的阿莫罗芬；以及苄胺类的丁烯那芬：方法：使用异源表达细胞和分离的小鼠感觉神经元测量细胞内钙浓度（[Ca2+]i）和膜电流对抗真菌药物的反应，以估计通道活性：结果：在小鼠 TRPA1 表达细胞中，所有测试药物都会诱导[Ca2+]i 的增加，而 TRPA1 阻断剂会减弱或降低[Ca2+]i 的增加。虽然许多药物在高浓度下会诱发 TRPA1 非特异性 [Ca2+]i 反应，但克霉唑、酮康唑和利拉那酯对 TRPA1 的反应是特异性的，并在表达 TRPA1 的细胞中诱发电流反应。在小鼠表达 TRPV1 的细胞中，克霉唑和酮康唑引起[Ca2+]i 和电流反应。在小鼠感觉神经元中，TRPA1 阻断剂和 Trpa1 基因缺失可抑制利拉伐酸诱导的[Ca2+]i 增加。对酮康唑的反应受到 TRPA1 和 TRPV1 阻断剂以及任一通道基因缺失的抑制：这些结果表明，局部抗真菌引起的疼痛和刺激可归因于痛觉 TRPA1 和/或 TRPV1 通道的激活。因此，出现疼痛症状时应谨慎使用外用抗真菌药。

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引用次数: 0

In vitro evidence that the vasorelaxant effects of 2-nitro-1-phenyl-1-propanol on rat coronary arteries involve cyclic nucleotide pathways 体外证据表明，2-硝基-1-苯基-1-丙醇对大鼠冠状动脉的血管舒张作用涉及环核苷酸途径。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-10-04 DOI: 10.1111/fcp.13038

Alfredo Augusto Vasconcelos-Silva, Suliana Mesquita Paula, Karine Lima-Silva, Kalinne Kelly Lima de Gadelha, Rodrigo José Bezerra de Siqueira, Armenio Aguiar dos Santos, Saad Lahlou, Ricardo de Freitas Lima, Pedro Jorge Caldas Magalhães

The synthetic nitro-alcohol 2-nitro-1-phenyl-1-propanol (NPP) has endothelium-independent relaxing properties in isolated preparations of rat aorta and mesenteric artery. In this study, we investigated whether the vasodilator effects occur in coronary vessels and explored whether hyperpolarization is involved in the underlying mechanism of NPP-induced smooth muscle relaxation. The relaxing responses were studied in isolated preparations of the left anterior descending coronary (ADC) and the septal coronary (SC) arteries, which had been previously maintained under sustained contraction induced by the thromboxane A₂ analogue U-46619. Administered cumulatively, NPP elicited concentration-dependent vasorelaxation with similar potency in both vessels. The relaxant effect remained unaffected by the nitric oxide synthase inhibitor L-NAME, the protein kinase C inhibitor bisindolylmaleimide IV and the Rho-associated protein kinase inhibitor Y-27632. However, it was significantly diminished by the adenylyl cyclase inhibitor MDL-12,330A, the guanylyl cyclase inhibitor ODQ, as well as the K⁺ channel inhibitors tetraethylammonium and CsCl. In ADC preparations impaled with intracellular micropipettes, NPP hyperpolarized the vascular preparation. When the isolated preparation was precontracted by 5-hydroxytryptamine or 80 mM KCl, NPP-induced relaxation with lower pharmacological potency compared to the vessels contracted by U-46619. In conclusion, NPP exhibits vasorelaxant effects on rat coronary arteries, likely involving pathways that include cyclic nucleotide production and membrane hyperpolarization.

合成硝基酒精 2-硝基-1-苯基-1-丙醇（NPP）在大鼠主动脉和肠系膜动脉离体制备物中具有不依赖于内皮的松弛特性。在这项研究中，我们探讨了冠状动脉血管中是否存在血管扩张效应，并探讨了超极化是否参与了 NPP 诱导平滑肌松弛的基本机制。我们在左前降支冠状动脉（ADC）和室间隔冠状动脉（SC）的离体制备物中研究了松弛反应，这些制备物之前一直处于血栓素 A2 类似物 U-46619 诱导的持续收缩状态下。累积给药后，NPP 在两种血管中都能引起浓度依赖性血管舒张，且效力相似。一氧化氮合酶抑制剂 L-NAME、蛋白激酶 C 抑制剂双吲哚马来酰亚胺 IV 和 Rho- 相关蛋白激酶抑制剂 Y-27632 均不会影响其松弛作用。然而，腺苷酸环化酶抑制剂 MDL-12,330A、鸟苷酸环化酶抑制剂 ODQ 以及 K+ 通道抑制剂四乙基铵和氯化铯则会明显减弱这种作用。在用细胞内微量移液管插入的 ADC 制备中，NPP 使血管制备超极化。当用 5-hydroxytryptamine 或 80 mM KCl 预收缩离体制剂时，NPP 诱导的松弛药效低于 U-46619 收缩的血管。总之，NPP 对大鼠冠状动脉具有血管舒张作用，可能涉及的途径包括环核苷酸生成和膜超极化。

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引用次数: 0