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Minimizing the Risk of Ethylene Glycol and Diethylene Glycol Poisoning in Medications: A Regulatory and Pharmacopoeial Response. 将药物中乙二醇和二甘醇中毒的风险降至最低:监管和药典对策》。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-18 DOI: 10.1016/j.yrtph.2024.105741
Pawan Kumar, Shruti Rastogi, Pawan Kumar Saini, Saurabh Sahoo, Rajeev Singh Raghuvanshi, Gaurav Pratap Singh Jadaun

Pharmaceutical and personal care products, including syrups and toothpastes, extensively use glycerin, sorbitol, and propylene glycol. However, past incidents of ethylene glycol (EG) and diethylene glycol (DEG) contamination in these products have raised serious health concerns. Recently, several child deaths linked to contaminated cough syrup consumption have heightened concerns regarding the safety of Indian pharmaceuticals. In response, Indian drug regulatory authorities and the Indian Pharmacopoeia have implemented several measures to enhance the quality, safety, and efficacy of pharmaceuticals manufactured in India. These measures encompass risk-based inspections of manufacturing facilities, rigorous quality control checks of medicinal products intended for export, and increased transparency in the supply chain of excipients prone to EG and DEG contamination. Further, the Indian Pharmacopoeia has updated monographs for five high-risk excipients: glycerin, propylene glycol, sorbitol solution (70%, both crystallizing and non-crystallizing), and liquid maltitol. These efforts are consistent with global regulatory standards and aim to ensure the overall quality and safety of pharmaceuticals produced in India.

包括糖浆和牙膏在内的医药和个人护理产品广泛使用甘油、山梨醇和丙二醇。然而,过去这些产品中出现的乙二醇(EG)和二甘醇(DEG)污染事件引起了严重的健康问题。最近,几起儿童死亡事件与饮用受污染的止咳糖浆有关,这加剧了人们对印度药品安全性的担忧。对此,印度药品监管机构和印度药典已采取多项措施,以提高印度生产的药品的质量、安全性和有效性。这些措施包括对生产设施进行基于风险的检查,对准备出口的医药产品进行严格的质量控制检查,以及提高易受 EG 和 DEG 污染的辅料供应链的透明度。此外,印度药典还更新了五种高风险辅料的各论:甘油、丙二醇、山梨醇溶液(70%,包括结晶型和非结晶型)和液体麦芽糖醇。这些努力符合全球监管标准,旨在确保印度生产的药品的整体质量和安全。
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引用次数: 0
Response to Letter to Editors submitted by PE Rasmussen, P Huntsman, TM Singer, MN Jacobs, and CC Trevithick-Sutton (Aug 2024). 对 PE Rasmussen、P Huntsman、TM Singer、MN Jacobs 和 CC Trevithick-Sutton 提交的致编辑信的回复(2024 年 8 月)。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-16 DOI: 10.1016/j.yrtph.2024.105740
Adriana Oller, João Barroso, Pilar Prieto, Violaine Verougstraete, Katherine Heim, Rayetta Henderson
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引用次数: 0
A framework for categorizing sources of uncertainty in in silico toxicology methods: Considerations for chemical toxicity predictions 硅学毒理学方法中不确定性来源的分类框架:对化学毒性预测的考虑。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-14 DOI: 10.1016/j.yrtph.2024.105737
Jerry Achar , James W. Firman , Mark T.D. Cronin , Gunilla Öberg
Improving regulatory confidence and acceptance of in silico toxicology methods for chemical risk assessment requires assessment of associated uncertainties. Therefore, there is a need to identify and systematically categorize sources of uncertainty relevant to the methods and their predictions. In the present study, we analyzed studies that have characterized sources of uncertainty across commonly applied in silico toxicology methods. Our study reveals variations in the kind and number of uncertainty sources these studies cover. Additionally, the studies use different terminologies to describe similar sources of uncertainty; consequently, a majority of the sources considerably overlap. Building on an existing framework, we developed a new uncertainty categorization framework that systematically consolidates and categorizes the different uncertainty sources described in the analyzed studies. We then illustrate the importance of the developed framework through a case study involving QSAR prediction of the toxicity of five compounds, as well as compare it with the QSAR Assessment Framework (QAF). The framework can provide a structured (and potentially more transparent) understanding of where the uncertainties reside within in silico toxicology models and model predictions, thus promoting critical reflection on appropriate strategies to address the uncertainties.
要提高监管机构对用于化学品风险评估的硅学毒理学方法的信心和接受程度,就需要对相关的不确定性进行评估。因此,有必要对与方法及其预测相关的不确定性来源进行识别和系统分类。在本研究中,我们分析了对常用硅学毒理学方法的不确定性来源进行定性的研究。我们的研究显示,这些研究涵盖的不确定性来源的种类和数量各不相同。此外,这些研究使用了不同的术语来描述类似的不确定性来源;因此,大多数不确定性来源存在很大重叠。在现有框架的基础上,我们开发了一个新的不确定性分类框架,对所分析研究中描述的不同不确定性源进行了系统整合和分类。然后,我们通过一个涉及五种化合物毒性 QSAR 预测的案例研究来说明所开发框架的重要性,并将其与 QSAR 评估框架 (QAF) 进行比较。该框架可以让人们有条理地(并有可能更加透明地)理解硅毒理学模型和模型预测中的不确定性所在,从而促进对解决不确定性的适当策略进行批判性思考。
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引用次数: 0
The definition of chemical contaminants in food: ambiguity and consequences. 食品中化学污染物的定义:模糊性和后果。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-13 DOI: 10.1016/j.yrtph.2024.105739
Ivonne M C M Rietjens, Michelangelo Pascale, Gloria Pellegrino, Daniel Ribera, Armando Venâncio, Danlei Wang, Konrad Korzeniowski

Consumers may be exposed via foods to a diverse range of substances that could be considered as contaminants. However, it is not always straightforward to understand the definition of a 'contaminant'. The present review evaluates how various categories of food-relevant substances are considered in terms of being 'contaminants'. To this end these categories of food borne constituents are evaluated against the various criteria encountered in the available definitions of a food contaminant, including unintentional presence, harmful, existence of regulatory limits, and stakeholder perception. The categories of chemicals considered include: phytotoxins, mycotoxins, (heavy) metals, persistent organic pollutants (POPs), processing aids, process related contaminants, food contact materials (FCMs), pesticides and veterinary drugs. The evaluation revealed that usage of the term appears complex, and may differ between stakeholders. A common proposed definition of the term 'contaminant' could be 'a substance considered to require control measures due to the unacceptability of its context within a food'. Use of a dimension of harm results in equivocal outcomes because risk depends on the level of exposure. As the term 'contaminant' has influence on risk management including public policy, the motivations for applying the term should be subject to more detailed analysis and understanding.

消费者可能会通过食品接触到各种可被视为污染物的物质。然而,要理解 "污染物 "的定义并非总是那么简单。本综述从 "污染物 "的角度评估了各类食品相关物质。为此,我们根据现有食品污染物定义中的各种标准,包括无意存在、有害、存在监管限制和利益相关者的看法,对这些类别的食源性成分进行了评估。考虑的化学品类别包括:植物毒素、霉菌毒素、(重)金属、持久性有机污染物、加工助剂、加工相关污染物、食品接触材料、杀虫剂和兽药。评估显示,该术语的用法似乎很复杂,而且利益相关者之间可能存在差异。污染物 "一词的常见拟议定义可以是 "由于其在食品中的不可接受性而被认为需要采取控制措施的物质"。使用危害维度会导致结果不明确,因为风险取决于暴露程度。由于 "污染物 "一词会对包括公共政策在内的风险管理产生影响,因此应更详细地分析和理解使用该词的动机。
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引用次数: 0
Mode of action Criteria for selection of the critical effect and safe dose range for PFOA by the Alliance for risk assessment 风险评估联盟选择 PFOA 临界效应和安全剂量范围的作用模式标准。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-13 DOI: 10.1016/j.yrtph.2024.105738
Harvey Clewell
In response to the current disparity in risk assessment values for PFOA from different agencies and countries, an international effort facilitated by the Alliance for Risk Assessment (ARA) was recently undertaken to characterize the range of scientifically supportable safe dose estimates. In this assessment (Burgoon et al., 2023), an evaluation of the evidence regarding the potential modes of action (MOA) for PFOA toxicity was performed first, so that it could be used to inform subsequent decisions regarding potential critical effects and studies. This review describes the evidence considered in the MOA evaluations that were performed as part of the ARA effort. The overall conclusions of this evaluation are that the available mechanistic data do not support any conclusion that reported epidemiological associations of blood concentrations of PFOA as low as 10 ng/mL with various health effects should be considered causal. It is more likely that the reported associations may instead reflect reverse causality/pharmacokinetic confounding. These conclusions are consistent with the opinions of the World Health Organization (WHO, 2022).
针对目前不同机构和国家对全氟辛烷磺酸风险评估值的差异,风险评估联盟(ARA)最近推动了一项国际工作,以确定科学上可支持的安全剂量估算范围。在这项评估(Burgoon 等人,2023 年)中,首先对有关 PFOA 毒性的潜在作用模式 (MOA) 的证据进行了评估,以便为后续有关潜在关键效应和研究的决策提供信息。本综述介绍了作为 ARA 工作一部分的 MOA 评估所考虑的证据。本次评估的总体结论是,现有的机理数据并不支持任何结论,即所报告的血液中低至10纳克/毫升的全氟辛烷磺酸浓度与各种健康影响之间的流行病学关联应被视为因果关系。更有可能的情况是,报告的关联可能反映了反向因果关系/药代动力学混杂。这些结论与世界卫生组织(WHO 2022)的意见一致。
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引用次数: 0
Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice 对新型抗疟药物进行量身定制的非临床安全性测试的重要性:行业最佳实践。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-06 DOI: 10.1016/j.yrtph.2024.105736
Philip Hewitt , Andreas Hartmann , Belen Tornesi , Sandrine Ferry-Martin , Jean-Pierre Valentin , Paul Desert , Stephanie Gresham , Claudia Demarta-Gatsi , Vinay Kumar Venishetty , Carine Kolly
Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate.
We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs.
In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients.
疟疾是一种使人衰弱的急性寄生虫病。2022 年,全球疟疾病例达 2.49 亿例,造成 60.8 万人死亡,其中 76% 为 5 岁以下儿童。这种疾病的特殊性(复发导致再次治疗,多个器官系统受到影响)、特定的临床治疗方案、依从性差以及受影响人群的多样性(主要是儿科、育龄妇女、孕妇和哺乳期妇女),往往使得标准检测方法不充分,而量身定制的安全性评估更为合适。我们根据公司的经验为抗疟药物的非临床安全性评估提供最佳实践建议,重点是小分子药物,因为它们代表了该疾病的大多数候选药物。我们将重点放在重复剂量毒性研究的具体测试注意事项上,包括组合毒性评估,因为新药治疗方案通常会考虑缩短治疗时间,以提高依从性(即 1 天),并通过组合化合物来提高疗效和限制潜在的耐药性。由于目标人群的原因,生殖、发育和幼年毒性研究的时间可能早于其他小分子药物的一般测试路线图。总之,本文提出的主要建议应能使开发路径更有效、更高效,同时保护临床试验参与者和患者。
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引用次数: 0
Updated assessment of the genotoxic potential of titanium dioxide based on reviews of in vitro comet, mode of action and cellular uptake studies, and recent publications 根据对体外彗星、作用模式和细胞吸收研究的审查以及最近的出版物,对二氧化钛的遗传毒性潜力进行最新评估。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-02 DOI: 10.1016/j.yrtph.2024.105734
David Kirkland , Arne Burzlaff , Andreas Czich , Shareen H. Doak , Paul Fowler , Stefan Pfuhler , Leon F. Stankowski
In 2021 the European Food Safety Authority (EFSA) concluded that “A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out.”. A detailed review of the genotoxicity of titanium dioxide (TiO2) was subsequently published by Kirkland et al. (2022) using a comprehensive weight of evidence (WoE) approach in which test systems and endpoints were allocated different levels of relevance. At that time only 34 publications met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity, and based on these it was concluded that the existing evidence did not support a direct DNA damaging mechanism for TiO2. Recently a number of regulatory opinions have been published, in which papers were cited that described in vitro DNA damage (mainly comet), mode of action, and cellular uptake studies that were not discussed in Kirkland et al. (2022). Furthermore, a number of additional papers have been published recently or have been identified from the regulatory opinions as a result of using extended search criteria. A total of 70 publications not previously reviewed in Kirkland et al. (2022) have been reviewed here, and again show that the published data on the genotoxicity of TiO2 are inconsistent, often of poor quality, and in some cases difficult to interpret. The cellular uptake studies show some evidence of cytoplasmic uptake, particularly in cells treated in vitro, but there is no convincing evidence of nuclear uptake. In terms of genotoxicity, the conclusions of Kirkland et al. (2022) that existing evidence does not support a direct DNA damaging mechanism for titanium dioxide (including nano forms), and that the main mechanism leading to TiO2 genotoxicity is most likely indirect damage to DNA through generation of reactive oxygen species (ROS), are still valid.
2021 年,欧洲食品安全局(EFSA)得出结论:"因此不能排除 E 171 中可能存在的二氧化钛微粒的遗传毒性问题"。随后,Kirkland 等人(2022 年)采用综合证据权重法(WoE),对二氧化钛(TiO2)的基因毒性进行了详细审查。当时,只有 34 篇出版物符合与遗传毒性评估最相关的可靠性和质量标准,并据此得出结论,现有证据并不支持二氧化钛的直接 DNA 损伤机制。最近发表了一些监管意见,其中引用的论文描述了 Kirkland 等人(2022 年)未讨论的体外 DNA 损伤(主要是彗星)、作用模式和细胞吸收研究。此外,最近还发表了一些其他论文,或通过使用扩展搜索标准从监管意见中发现了一些其他论文。本文共审查了 70 篇未在 Kirkland 等人(2022 年)中审查过的论文,这些论文再次表明,已发表的有关二氧化钛遗传毒性的数据并不一致,通常质量较差,在某些情况下难以解释。细胞摄取研究显示了一些细胞质摄取的证据,特别是在体外处理的细胞中,但没有令人信服的核摄取证据。就遗传毒性而言,Kirkland 等人(2022 年)的结论仍然有效,即现有证据不支持二氧化钛(包括纳米形式)的直接 DNA 损伤机制,导致二氧化钛遗传毒性的主要机制很可能是通过产生活性氧 (ROS) 间接损伤 DNA。
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引用次数: 0
Endocrine-disrupting chemicals – pesticide regulatory issues from the EU perspective 干扰内分泌的化学品--欧盟视角下的农药监管问题。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-11-02 DOI: 10.1016/j.yrtph.2024.105735
Monika Liszewska, Katarzyna Czaja, Wojciech Korcz, Radosław Lewiński, Paweł Struciński
Endocrine-disrupting chemicals (EDCs), including substances used in plant protection products (PPPs), are a source of ongoing concern for the EU society. Under the EC Regulation 1107/2009, the endocrine-disrupting (ED) properties of active substances, safeners, and synergists used in PPPs shall be investigated. The scientific criteria established by the Regulation (EU) 2018/605 and the joint guidance of the European Chemicals Agency (ECHA)/European Food Safety Authority (EFSA) provide the basis for this assessment. Data requirements for the approval of safeners and synergists have been recently published in Commission Regulation (EU) 2024/1487, allowing a consistent assessment of these substances. The approach to assessing co-formulant hazards is currently a subject of EU-wide discussion. It outlines the necessity to take into account information or evaluation data from other than pesticides' EU regulatory frameworks, such as REACH or SCCS applications for cosmetic ingredients. This paper outlines: a) current EU approach applied for identification of endocrine disrupting properties of pesticides; b) issues related to European regulations that may have an indirect impact on the safe use of plant protection products and c) an analysis of the European Commission's activities aimed to limit exposure to EDCs associated with use of PPPs in the society.
干扰内分泌的化学品(EDCs),包括植物保护产品(PPPs)中使用的物质,是欧盟社会持续关注的问题。根据欧盟委员会第 1107/2009 号法规,应调查植保产品中使用的活性物质、安全剂和增效剂的内分泌干扰(ED)特性。法规(EU)2018/605 制定的科学标准以及欧洲化学品管理局(ECHA)/欧洲食品安全局(EFSA)的联合指南为这一评估提供了依据。欧盟委员会法规(EU)2024/1487 最近公布了安全剂和增效剂审批的数据要求,以便对这些物质进行一致的评估。评估共配制剂危害的方法目前是欧盟范围内讨论的主题。它概述了考虑来自农药以外的欧盟监管框架的信息或评估数据的必要性,如 REACH 或化妆品成分的 SCCS 申请。本文概述了:a) 当前欧盟用于识别农药内分泌干扰特性的方法;b) 可能会对植物保护产品的安全使用产生间接影响的欧洲法规相关问题;c) 对欧盟委员会旨在限制社会中与使用植物保护产品相关的 EDCs 暴露的活动进行分析。
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引用次数: 0
Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation 虚拟对照组在非啮齿动物毒性研究中的统计应用:初步评估。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-31 DOI: 10.1016/j.yrtph.2024.105733
Dingzhou Li , Jeonifer Garren , Raja Mangipudy , Matthew Martin , Lindsay Tomlinson , Nichole R. Vansell
Utilization of data from historical control animals to form virtual control groups (VCGs) is an innovative approach to embody the 3Rs (reduce, refine, and replace use of control animals) principle in research. However, there is no available systematic comparison of statistical performance between concurrent control groups (CCGs) and VCGs in nonrodent safety assessment. The optimal selection criteria and combination of VCGs and CCGs also remain unclear. This study retrospectively evaluated VCGs’ statistical performance to detect test article effects on body weight and clinical pathology endpoints in dog and nonhuman primate (NHP) systemic toxicity studies. Body weight and six clinical pathology endpoints were analyzed against the reported study findings from a cohort of 22 previously reported nonrodent 1-month oral gavage toxicity using three different methods of generating VCGs. When the fold change from baseline was used, VCGs yielded a similar or higher statistical sensitivity to detect test article relatedness than CCGs. Compared to simple random sampling or using fixed criteria, the propensity score matching by BW, age, and year of study initiation yielded higher sensitivities. Our analysis supports the hypothesis that VCGs can be a viable instrument in nonrodent toxicity studies.
利用历史对照动物的数据组成虚拟对照组(VCGs)是一种创新方法,可在研究中体现 3R(减少、完善和替代对照动物的使用)原则。然而,在非啮齿动物安全性评估中,目前还没有系统地比较同期对照组(CCGs)和虚拟对照组的统计性能。VCGs和CCGs的最佳选择标准和组合也仍不明确。本研究回顾性地评估了VCGs在狗和非人灵长类动物(NHP)全身毒性研究中检测试验品对体重和临床病理学终点影响的统计性能。使用三种不同的 VCG 生成方法,对照先前报告的 22 项非啮齿类动物 1 个月口服灌胃毒性的研究结果,对体重和六项临床病理终点进行了分析。当使用与基线相比的折叠变化时,VCGs 在检测测试物相关性方面的统计灵敏度与 CCGs 相似或更高。与简单随机抽样或使用固定标准相比,按体重、年龄和研究开始年份进行倾向评分匹配的灵敏度更高。我们的分析支持这样的假设,即在非啮齿动物毒性研究中,VCGs 是一种可行的工具。
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引用次数: 0
Opportunities and challenges for use of minipigs in nonclinical pharmaceutical development: Results of a follow-up IQ DruSafe survey 在非临床药物开发中使用迷你猪的机遇与挑战:IQ DruSafe 调查的后续结果。
IF 3 4区 医学 Q1 MEDICINE, LEGAL Pub Date : 2024-10-30 DOI: 10.1016/j.yrtph.2024.105729
David O. Clarke , Kaushik Datta , Kevin French , Michael W. Leach , Drew Olaharski , Susanne Mohr , Devon Strein , Jeanine Bussiere , Bianca Feyen , Beatrice E. Gauthier , Michael Graziano , Joanna Harding , Kenneth Hershman , Binod Jacob , Shaofei Ji , Robert Lange , Smita Salian-Mehta , Brian Sayers , Nicole Thomas , Thierry Flandre
Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&D.
与狗或非人灵长类动物 (NHP) 相比,迷你猪是有效的非啮齿类动物物种,很少被用于药物研发 (R&D)。2022 年 IQ DruSafe 调查显示,与 2014 年的上一次调查相比,制药公司使用迷你猪的情况略有增加,主要用于开发口服小分子药物和肠外蛋白分子药物。一些公司考虑更频繁地使用迷你猪,原因是NHP短缺以及使用NHP和狗的地区伦理问题。然而,对于大多数制药公司而言,迷你猪仍占其非啮齿动物使用量的 ≤5%。公司指出,更广泛采用迷你猪所面临的主要挑战是试验品要求高、历史对照数据有限以及缺乏相关试剂或检测方法。此外,一些公司对合同研究组织 (CRO) 的能力和经验表示不确定,而受访的 CRO 并不认同这种看法。最新调查结果显示,2014 年发现的许多问题依然存在。调查还包括几个案例研究,以说明微型机器人的扩大应用领域以及阻碍更广泛应用的挑战。为解决已发现或感知到的挑战而采取的持续、集中和全行业范围的举措,可能会促使在制药研发中更频繁或更常规地考虑将迷你猪作为试验物种。
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引用次数: 0
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Regulatory Toxicology and Pharmacology
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