Arhiv za Farmaciju最新文献_第7页

Cadmium levels in human breast tissue and estradiol serum levels: Is there a connection? 人乳腺组织中的镉水平和血清雌二醇水平:有联系吗?

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-34280

Aleksandra Buha-Đorđević, Milena Anđelković, Elena Kačavenda, D. Javorac, Evica Antonijević-Miljaković, Đ. Marić, K. Baralić, Danijela Đukić-Ćosić, M. Ćurčić, B. Antonijević, Z. Bulat

Cadmium (Cd), one of the most abundant environmental pollutants, is considered to have endocrine disrupting properties. However, data on the dose-response relationship between Cd dose and levels of hormones have been insufficiently studied, especially in human data sets. Thus, the aim of this study was to determine the possibility of analyzing data obtained from a case-control study in female patients with benign/malignant breast tumors, using the Benchmark dose (BMD) concept. The collected data on Cd levels in breast tissue and estrogen serum levels were processed in PROAST software using different variables. The dose-response relationship between the internal dose of Cd and estradiol levels in the serum was investigated and BMD intervals were calculated. The dose-response relationship between the Cd concentration in breast tissue and the estradiol serum level was shown, indicating lower estradiol serum levels as a consequence of higher Cd concentrations in breast tissue. As one of the few studies analyzing human data using the BMD approach, these findings could have a pivotal role in dose response analysis of data collected from human studies.

镉(Cd)是最丰富的环境污染物之一，被认为具有内分泌干扰特性。然而，关于Cd剂量与激素水平之间的剂量-反应关系的数据尚未得到充分研究，特别是在人体数据集中。因此，本研究的目的是确定使用基准剂量(BMD)概念分析女性乳腺良/恶性肿瘤患者病例对照研究数据的可能性。收集的乳腺组织Cd水平和血清雌激素水平数据在PROAST软件中使用不同的变量进行处理。研究Cd内剂量与血清雌二醇水平的量效关系，计算BMD间隔。乳腺组织中Cd浓度与血清雌二醇水平之间的剂量-反应关系得到了证实，表明乳腺组织中Cd浓度升高导致血清雌二醇水平降低。作为少数使用BMD方法分析人体数据的研究之一，这些发现可能对从人体研究中收集的数据的剂量反应分析具有关键作用。

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引用次数: 9

Testicular dysgenesis syndrome and phthalate exposure: A review of literature 睾丸发育不良综合征与邻苯二甲酸盐暴露:文献综述

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-34438

P. Erkekoğlu, A. Özyurt, Anıl Yırün, D. Çakır

Endocrine disruptors are chemicals that interfere with the body's endocrine system and cause adverse effects in biological systems. Phthalates are a group of man-made chemicals which are mainly used as plasticizers and classified as endocrine disruptors. They are also used in cosmetic and personal care products as color or smell fixators. Moreover, phthalates are present in inks, adhesives, sealants, automobile parts, tools, toys, carpets, medical tubing and blood storage bags, and food packages. Pathological condition known as "testicular dysgenesis syndrome" (TDS) or "phthalate syndrome" is usually linked to phthalate exposure and is coined to describe the rise in alterations in reproductive health in men, such as reduced semen quality (decrease in sperm counts, sperm motility and increase in abnormal sperms), hypospadias, cryptorchidism, reduced anogenital distance and early-life testicular cancer. Phthalates are suggested to cause direct effect on gonadal and non-gonadal tissues, impair the differentiation and morphogenesis of seminiferous tubules and accessory sex organs and testicular cells (both Sertoli and Leydig cells), alter estradiol and/or testosterone levels, decrease insulin-like 3 (INSL3) peptide production, impair spermatogenesis and lead to epigenetic alterations, all of which may lead to TDS. This review will mainly focus on phthalates as causes of TDS and their mechanisms of action.

内分泌干扰物是指干扰人体内分泌系统并对生物系统造成不良影响的化学物质。邻苯二甲酸酯是一类人造化学物质，主要用作增塑剂，并被列为内分泌干扰物。它们也用于化妆品和个人护理产品中作为颜色或气味固定剂。此外，邻苯二甲酸盐存在于油墨、粘合剂、密封剂、汽车零部件、工具、玩具、地毯、医用管道和血液储存袋以及食品包装中。被称为“睾丸发育不良综合征”(TDS)或“邻苯二甲酸盐综合征”的病理状况通常与邻苯二甲酸盐暴露有关，并被用来描述男性生殖健康变化的增加，如精液质量下降(精子数量减少、精子活力下降和异常精子增加)、尿道下裂、隐睾、肛门生殖器距离缩短和早期睾丸癌。邻苯二甲酸盐可直接影响性腺和非性腺组织，损害精小管、附属性器官和睾丸细胞(包括支持细胞和睾丸间质细胞)的分化和形态发生，改变雌二醇和/或睾酮水平，减少胰岛素样3 (INSL3)肽的产生，损害精子发生并导致表观遗传改变，这些都可能导致TDS。本文将重点介绍邻苯二甲酸盐引起TDS的原因及其作用机制。

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引用次数: 2

Can probiotics win the battle against environmental endocrine disruptors? 益生菌能战胜环境内分泌干扰物吗?

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-34237

Çiğdem Sevİm, M. Kara

Compounds that have negative effects on the endocrine system are called endocrine disrupting compounds (EDCs). There are several different types of compounds, with several different usage areas in the environment, which can be classified as EDCs. These chemicals have a wide range of negative health effects in organisms, depending on their target hormone system. EDCs are among the most popular topics of scientific research, as they are widely used and organisms are frequently exposed to these chemicals. There are various exposure routes for EDCs, such as oral, inhalation and dermal exposure. Parabens, phenolic compounds, phthalates, and pesticides are the most common EDCs. Nowadays, intestinal microorganism distribution, probiotics, and food supplements that regulate these microorganisms and their protective effects against various harmful chemicals attract attention. For this reason, many studies have been carried out in this field and certain diet schemes have been created according to the results of these studies. In fact, probiotics are preferred in order to reduce and eliminate the negative effects of harmful chemicals and to ensure that the organism reacts strongly in these conditions. In this review, we will focus on EDCs, their health effects and positive effects of probiotics on EDCs exposure conditions.

对内分泌系统有负面影响的化合物被称为内分泌干扰化合物(EDCs)。有几种不同类型的化合物，在环境中有几种不同的使用领域，它们可以被归类为EDCs。这些化学物质对生物体的健康有广泛的负面影响，这取决于它们的目标激素系统。EDCs是科学研究中最受欢迎的主题之一，因为它们被广泛使用，生物体经常暴露于这些化学物质。EDCs有多种接触途径，如口服、吸入和皮肤接触。对羟基苯甲酸酯、酚类化合物、邻苯二甲酸酯和杀虫剂是最常见的EDCs。目前，肠道微生物的分布、益生菌以及调节这些微生物的食品补充剂及其对各种有害化学物质的保护作用引起了人们的关注。因此，在这一领域进行了许多研究，并根据这些研究的结果制定了某些饮食计划。事实上，为了减少和消除有害化学物质的负面影响，并确保生物体在这些条件下产生强烈的反应，益生菌是首选。在本文中，我们将重点介绍EDCs及其对健康的影响以及益生菌对EDCs暴露条件的积极影响。

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引用次数: 1

Endocrine-disrupting activity of mancozeb. 代森锰锌的内分泌干扰作用。

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-34359

Anatoly Skalny, Michael Aschner, Monica Paoliello, Abel Santamaria, Natalia Nikitina, Vladimir Rejniuk, Yueming Jiang, João Rocha, Alexey Tinkov

The objective of the present study was to review the existing data on the mechanisms involved in the endocrine disrupting activity of mancozeb (MCZ) in its main targets, including thyroid and gonads, as well as other endocrine tissues that may be potentially affected by MCZ. MCZ exposure was shown to interfere with thyroid functioning through impairment of thyroid hormone synthesis due to inhibition of sodium-iodine symporter (NIS) and thyroid peroxidase (TPO) activity, as well as thyroglobulin expression. Direct thyrotoxic effect may also contribute to thyroid pathology upon MCZ exposure. Gonadal effects of MCZ involve inhibition of sex steroid synthesis due to inhibition of P450scc (CYP11A1), as well as 3β-HSD and 17β-HSD. In parallel with altered hormone synthesis, MCZ was shown to down-regulate androgen and estrogen receptor signaling. Taken together, these gonad-specific effects result in development of both male and female reproductive dysfunction. In parallel with clearly estimated targets for MCZ endocrine disturbing activity, namely thyroid and gonads, other endocrine tissues may be also involved. Specifically, the fungicide was shown to affect cortisol synthesis that may be mediated by modulation of CYP11B1 activity. Moreover, MCZ exposure was shown to interfere with PPARγ signaling, being a key regulator of adipogenesis. The existing data also propose that endocrine-disrupting effects of MCZ exposure may be mediated by modulation of hypothalamus-pituitary-target axis. It is proposed that MCZ neurotoxicity may at least partially affect central mechanisms of endocrine system functioning. However, further studies are required to unravel the mechanisms of MCZ endocrine disrupting activity and overall toxicity.

本研究的目的是审查有关代谢物(MCZ)在其主要目标(包括甲状腺和性腺)以及可能受MCZ潜在影响的其他内分泌组织中内分泌干扰活性的机制的现有数据。MCZ暴露通过抑制钠碘同调体(NIS)和甲状腺过氧化物酶(TPO)活性以及甲状腺球蛋白表达而导致甲状腺激素合成受损，从而干扰甲状腺功能。直接的甲状腺毒性作用也可能导致MCZ暴露后的甲状腺病理。MCZ对性腺的影响包括通过抑制P450scc (CYP11A1)以及3β-HSD和17β-HSD来抑制性类固醇合成。在改变激素合成的同时，MCZ被证明可以下调雄激素和雌激素受体信号。综上所述，这些性腺特异性影响导致了男性和女性生殖功能障碍的发展。在明确估计MCZ内分泌干扰活动的目标，即甲状腺和性腺的同时，其他内分泌组织也可能受到影响。具体来说，杀菌剂被证明可以影响皮质醇的合成，这可能是通过调节CYP11B1活性介导的。此外，MCZ暴露被证明会干扰PPARγ信号，而PPARγ是脂肪形成的关键调节因子。现有数据还表明MCZ暴露的内分泌干扰效应可能是通过调节下丘脑-垂体-靶轴介导的。提示MCZ神经毒性至少部分影响内分泌系统功能的中枢机制。然而，MCZ的内分泌干扰活性和整体毒性机制尚需进一步研究。

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引用次数: 2

Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice 群体药代动力学和药代动力学/药效学模型在药物开发和临床实践中的概念和应用

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-32901

M. Roganović, A. Homšek, Marija Jovanović, Valentina Topić-Vučenović, M. Ćulafić, B. Miljković, K. Vučićević

Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.

由于临床试验失败频繁，新药获批较少，基于模型的药物开发在一定程度上满足了改进药物开发的需要。药物计量学是药理学的一部分，它基于不同的模型(药代动力学- PK、药效学- PD、PK/PD模型等)和模拟来量化药物行为、治疗反应和疾病进展。监管机构(欧洲药品管理局，食品和药物管理局)鼓励使用建模和模拟，以促进整个药物开发阶段的决策。此外，确定导致变异的因素为常规临床实践中的剂量个体化提供了基础。这篇综述总结了目前关于药物计量学在药物开发和临床实践中的应用的知识，重点是人口建模方法。

引用次数: 1

Concentrations of persistent organic pollutants in blood of the Spanish population: Temporal trend 西班牙人口血液中持久性有机污染物的浓度:时间趋势

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-33765

Neus González, J. Domingo

The present article reviews the human biomonitoring studies conducted in Spain to assess exposure to persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), polybrominated diphenyl ethers (PBDEs), and per- and poly-fluoroalkyl substances (PFAS). In general terms, important variations in POPs concentrations between Spanish regions and specific populations were observed, while no associations between exposure to POPs and adverse health outcomes were found. Moreover, occupational exposure seems not to be a risk factor with regards to POPs exposure in the Spanish population. The present review highlights the importance of conducting human biomonitoring studies to find possible associations between POPs and adverse health effects.

本文回顾了在西班牙开展的人体生物监测研究，以评估暴露于持久性有机污染物(POPs)，如多氯联苯(PCBs)、多氯二苯并对二恶英(pcdd)和多氯二苯并呋喃(pcdf)、多溴联苯醚(PBDEs)以及全氟和多氟烷基物质(PFAS)。总体而言，观察到西班牙各区域和特定人群之间持久性有机污染物浓度存在重大差异，但未发现接触持久性有机污染物与不良健康结果之间存在关联。此外，就西班牙人口接触持久性有机污染物而言，职业接触似乎不是一个风险因素。本审查强调进行人体生物监测研究以发现持久性有机污染物与不利健康影响之间可能存在的联系的重要性。

引用次数: 1

Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma 同时定量人血浆中舍曲林、艾司西酞普兰、利培酮和帕利培酮含量的快速简便色谱方法的验证

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-31163

A. Jeremić, F. Milosavljević, S. Vladimirov, B. Batinić, B. Marković, M. Jukic

Simultaneous quantification of multiple psychiatric drugs is important for the therapeutic drug monitoring of psychiatric patients. In addition, it would be highly advantageous if the method could be simple, straightforward, and not time-consuming. A 200 µl plasma sample was deproteinized, drugs were separated by a ZORBAX Eclipse XDB-Phenyl column with the mobile phase composed of acetonitrile and 0.1 % formic acid in water (60:40, v/v), and recorded in the MRM mode by using a positive electrospray source with tandem mass spectrometry detection. The dynamic range was 2-256 ng/ml for all the analyzed drugs, except escitalopram (8-256 ng/ml). Quality control samples were prepared in quintuplicates in three relevant concentrations for each drug. Coefficients of determination (R2 ) were higher than 0.99, while the relative difference between nominal and measured concentrations (RE) and CV were lower than 15% for all targets. High performance liquid chromatography coupled with the mass detector (HPLC-MS/MS) method for simultaneous determination of sertraline, escitalopram, risperidone and paliperidone in human plasma was validated with respect to selectivity, linearity, accuracy, precision, matrix effect and stability. This method has significant advantages in terms of low sample volume (200 µl), short preparation time (3 hours) and short runtime per sample (4 minutes).

多种精神科药物的同时定量对精神科患者的治疗药物监测具有重要意义。此外，如果该方法简单、直接且不耗时，那将是非常有利的。取200µl血浆样品脱蛋白，用ZORBAX Eclipse XDB-Phenyl色谱柱分离药物，流动相为乙腈和0.1%甲酸水溶液(60:40,v/v)，采用正电喷雾源，串联质谱检测，MRM模式记录。除艾司西酞普兰(8 ~ 256 ng/ml)外，所有分析药物的动态范围均为2 ~ 256 ng/ml。每种药物以三种相关浓度制备五份质控样品。测定系数(R2)均大于0.99，标称浓度与实测值(RE)和CV之间的相对差异均小于15%。建立了高效液相色谱-质谱联用(HPLC-MS/MS)同时测定人血浆中舍曲林、艾司西酞普兰、利培酮和帕利培酮的选择性、线性度、准确度、精密度、基质效应和稳定性的方法。该方法具有样品体积小(200µl)、制备时间短(3小时)、每个样品运行时间短(4分钟)等显著优势。

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引用次数: 0

The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development 基于生理的药代动力学/生物药剂学建模在制剂开发中的新兴作用

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-32479

S. Cvijić, Jelisaveta Ignjatović, J. Parojčić, S. Ibrić

Computer-based (in silico) modeling & simulation tools have been embraced in different fields of pharmaceutics for a variety of applications. Among these, physiologically-based pharmacokinetic/biopharmaceutics modeling (PBPK/PBBM) emerged as a particularly useful tool in formulation development. PBPK/PBBM facilitated strategies have been increasingly evaluated over the past few years, as demonstrated by several reports from the pharmaceutical industry, and a number of research and review papers on this subject. Also, the leading regulatory authorities have recently issued guidance on the use of PBPK modeling in formulation design. In silico PBPK models can comprise different dosing routes (oral, intraoral, parenteral, inhalation, ocular, dermal etc.), although the majority of published examples refer to modeling of oral drugs performance. In order to facilitate the use of PBPK modeling tools, a couple of companies have launched commercially available software such as GastroPlus™, Simcyp™ PBPK Simulator and PK-Sim®. This paper highlights various application fields of PBPK/PBBM modeling, along with the basic principles, advantages and limitations of this approach, and provides relevant examples to demonstrate the practical utility of modeling & simulation tools in different stages of formulation development.

基于计算机的(硅片)建模和仿真工具已被广泛应用于制药的不同领域。其中，基于生理的药代动力学/生物药剂学建模(PBPK/PBBM)在制剂开发中成为一个特别有用的工具。制药行业的几份报告以及关于这一主题的一些研究和评论论文表明，在过去几年中，PBPK/PBBM促进战略得到了越来越多的评价。此外，主要监管机构最近发布了关于在配方设计中使用PBPK模型的指导。在计算机中，PBPK模型可以包括不同的给药途径(口服、口服、肠外、吸入、眼内、皮肤等)，尽管大多数已发表的例子是指口服药物性能的建模。为了方便PBPK建模工具的使用，几家公司已经推出了商用软件，如GastroPlus™，Simcyp™PBPK模拟器和PK-Sim®。本文重点介绍了PBPK/PBBM建模的各种应用领域，以及该方法的基本原理、优点和局限性，并通过相关实例说明建模仿真工具在配方开发的不同阶段的实际应用。

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引用次数: 3

'In silico' toxicology methods in drug safety assessment 药物安全评价中的“计算机”毒理学方法

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-32966

Danijela Đukić-Ćosić, K. Baralić, D. Jorgovanović, K. Živančević, D. Javorac, N. Stojilković, B. Radović, Đ. Marić, M. Ćurčić, Aleksandra Buha-Đorđević, Z. Bulat, Evica Antonijević-Miljaković, B. Antonijević

While experimental animal investigation has historically been the most conventional approach conducted to assess drug safety and is currently considered the main method for determining drug toxicity, these studies are constricted by cost, time, and ethical approvals. Over the last 20 years, there have been significant advances in computational sciences and computer data processing, while knowledge of alternative techniques and their application has developed into a valuable skill in toxicology. Thus, the application of in silico methods in drug safety assessment is constantly increasing. They are very complex and are grounded on accumulated knowledge from toxicology, bioinformatics, biochemistry, statistics, mathematics, as well as molecular biology. This review will summarize current state-of-the-art scientific data on the use of in silico methods in toxicity testing, taking into account their shortcomings, and highlighting the strategies that should deliver consistent results, while covering the applications of in silico methods in preclinical trials and drug impurities toxicity testing.

虽然实验动物研究历来是评估药物安全性的最传统方法，目前被认为是确定药物毒性的主要方法，但这些研究受到成本、时间和伦理批准的限制。在过去的20年里，计算科学和计算机数据处理取得了重大进展，而替代技术及其应用的知识已经发展成为毒理学中的一项宝贵技能。因此，计算机方法在药品安全性评价中的应用不断增加。它们非常复杂，并以毒理学、生物信息学、生物化学、统计学、数学以及分子生物学积累的知识为基础。本综述将总结目前关于在毒性试验中使用计算机方法的最新科学数据，考虑到它们的缺点，并强调应该提供一致结果的策略，同时涵盖计算机方法在临床前试验和药物杂质毒性试验中的应用。

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引用次数: 0

Endocrine disruption by PFAS: A major concern associated with legacy and replacement substances PFAS对内分泌的干扰:与遗留和替代物质相关的主要问题

Q4 Pharmacology, Toxicology and Pharmaceutics

Arhiv za Farmaciju

Pub Date : 2021-01-01 DOI: 10.5937/arhfarm71-34197

E. Panieri, Aleksandra Buha-Đorđević, L. Saso

Perand poly-fluorinated alkyl substances (PFAS) have been used for decades in a great variety of processes and products by virtue of their exceptional properties, versatility and chemical stability. Nevertheless, it is increasingly recognized that these substances can represent a serious hazard to human health and living organisms due to their persistence, long-range transport potential and tendency to accumulate in biota. For this reason, some efforts have been made across the EU to identify alternative molecules, with a shorter carbon chain and theoretically safer profile, that might replace the previous generation of legacy PFAS. Unfortunately, this strategy has not been entirely successful and serious concerns are still posed by PFAS in different human populations. Among others, an emerging aspect is represented by the adverse effects that both legacy and alternative PFAS can exert on the human endocrine system, with respect to vulnerable target subpopulations. In this review we will briefly summarize PFAS properties, uses and environmental fate, focusing on their effects on human reproductive capacity and fertility, body weight control and obesity as well as thyroid function.

数十年来，Perand多氟烷基物质(PFAS)凭借其卓越的性能、多功能性和化学稳定性，在各种工艺和产品中得到了广泛应用。然而，人们日益认识到，由于这些物质的持久性、远距离转运潜力和在生物群中积累的趋势，它们可能对人类健康和生物体构成严重危害。出于这个原因，整个欧盟都在努力寻找碳链更短、理论上更安全的替代分子，以取代上一代的传统PFAS。不幸的是，这一策略并未完全成功，PFAS在不同人群中仍然引起严重关注。在其他方面，一个新出现的方面是遗留的和替代的PFAS可以对人体内分泌系统施加不利影响，相对于脆弱的目标亚群。本文将简要介绍PFAS的性质、用途和环境命运，重点介绍其对人类生殖能力和生育能力、体重控制和肥胖以及甲状腺功能的影响。

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引用次数: 2