目的分析斑马鱼模型在药源性肾损伤评价中的应用价值。方法检索PubMed、Web of Science、中国知网(CNKI)数据库中斑马鱼模型在药物及化学品诱导肾毒性研究中的文献,检索时限为各数据库自建库起至2023年12月31日,归纳其方法学、评价指标...目的分析斑马鱼模型在药源性肾损伤评价中的应用价值。方法检索PubMed、Web of Science、中国知网(CNKI)数据库中斑马鱼模型在药物及化学品诱导肾毒性研究中的文献,检索时限为各数据库自建库起至2023年12月31日,归纳其方法学、评价指标、毒性机制及在中医药评价中的具体实践,展望其在新领域的应用潜力。结果斑马鱼因与人类高度的遗传与生理相似性、早期胚胎透明、繁殖快速等特点,在肾毒性评价中展现出独特优势,可作为补充模型。斑马鱼模型肾损伤评价指标包括表型和组织病理形态学指标、滤过功能相关指标、细胞生物学过程和生化指标、肾损伤细胞标志物,涵盖从整体表型到分子标志物的多层次检测体系。化学品诱导斑马鱼模型肾毒性的主要机制包括细胞凋亡、细胞死亡、纤维化、炎性反应、氧化应激等。该模型已成功应用于马兜铃酸等中药毒性物质的评价及大黄酸、大豆苷等潜在肾保护成分的筛选,但未来仍需进一步明确斑马鱼模型在化学品毒性筛选中的地位,考察其对药物毒性动力学、实验操作及结果评价的重现性和标准,并加快高端配套设备的研发。结论斑马鱼模型可作为衔接体外筛选与哺乳动物体内实验、进行药物肾毒性快速评价与机制研究的一种重要补充模型,且在复杂的中医药体系安全性评价中具有潜力。展开更多
透皮贴剂作为应用广泛但开发复杂的仿制药剂型,其临床生物等效性试验开展难度较高,针对此,监管机构鼓励采用生理药代动力学(physiologically based pharmacokinetic,PBPK)模型引导研发,以降低成本并提升成功率。透皮贴剂的PBPK建模关键...透皮贴剂作为应用广泛但开发复杂的仿制药剂型,其临床生物等效性试验开展难度较高,针对此,监管机构鼓励采用生理药代动力学(physiologically based pharmacokinetic,PBPK)模型引导研发,以降低成本并提升成功率。透皮贴剂的PBPK建模关键影响因素包括药物特性、制剂系统与机体差异。药物因素方面,定量结构-性质关系(quantitative structure-property relationship,QSPR)模型基于相对分子质量、脂水分配系数(LogP)等参数预测分配与扩散系数;机制模型通过解析多层皮肤结构阐明渗透动力学过程。制剂系统中,骨架型与储库型贴剂的释放差异可通过多相多层皮肤吸收机制(multiphase multilayered mechanistic dermal absorption,MPML MechDermA)模型模拟,涵盖溶出、沉淀及载体蒸发等关键过程。机体差异上,皮肤厚度、pH值、附属器密度及病理状态等显著影响渗透效率,模型需结合年龄、性别、种族等变量校准。模型整合基于菲克定律构建隔室间药物转运方程,支持体外-体内外推(in vitro to in vivo extrapolation,IVIVE)。本文系统综述透皮贴剂开发的PBPK建模方法及其影响因素,有望减少动物实验并加速临床转化。展开更多
Genetic hypoparathyroidism(HP),achondroplasia(ACH),and primary growth hormone deficiency(GHD)are listed as rare diseases in the second List of Rare Diseases in China in 2023.Numerous studies have explored optimal ther...Genetic hypoparathyroidism(HP),achondroplasia(ACH),and primary growth hormone deficiency(GHD)are listed as rare diseases in the second List of Rare Diseases in China in 2023.Numerous studies have explored optimal therapies for certain rare endocrine diseases,and the development of long-acting therapeutic agents has been considered a key strategy for improving treatment outcomes,especially given the challenges associated with daily subcutaneous injections.However,limited attention has been given to the potential of"transient conjugation"(TransCon)technology,a platform designed to convert drugs into prodrug forms,thereby extending their half-lives and reducing dosing frequency,which demonstrates promise as a more convenient treatment option for these conditions.This is the first study to review the research progress of TransCon technology in the treatment of HP,ACH,and GHD,focusing on its pharmacokinetic properties,efficacy,safety,tolerability,and patient-reported outcomes in comparison with conventional therapies,in order to provide a reference for formulation development and clinical management of these rare endocrine diseases.展开更多
文摘目的分析斑马鱼模型在药源性肾损伤评价中的应用价值。方法检索PubMed、Web of Science、中国知网(CNKI)数据库中斑马鱼模型在药物及化学品诱导肾毒性研究中的文献,检索时限为各数据库自建库起至2023年12月31日,归纳其方法学、评价指标、毒性机制及在中医药评价中的具体实践,展望其在新领域的应用潜力。结果斑马鱼因与人类高度的遗传与生理相似性、早期胚胎透明、繁殖快速等特点,在肾毒性评价中展现出独特优势,可作为补充模型。斑马鱼模型肾损伤评价指标包括表型和组织病理形态学指标、滤过功能相关指标、细胞生物学过程和生化指标、肾损伤细胞标志物,涵盖从整体表型到分子标志物的多层次检测体系。化学品诱导斑马鱼模型肾毒性的主要机制包括细胞凋亡、细胞死亡、纤维化、炎性反应、氧化应激等。该模型已成功应用于马兜铃酸等中药毒性物质的评价及大黄酸、大豆苷等潜在肾保护成分的筛选,但未来仍需进一步明确斑马鱼模型在化学品毒性筛选中的地位,考察其对药物毒性动力学、实验操作及结果评价的重现性和标准,并加快高端配套设备的研发。结论斑马鱼模型可作为衔接体外筛选与哺乳动物体内实验、进行药物肾毒性快速评价与机制研究的一种重要补充模型,且在复杂的中医药体系安全性评价中具有潜力。
文摘透皮贴剂作为应用广泛但开发复杂的仿制药剂型,其临床生物等效性试验开展难度较高,针对此,监管机构鼓励采用生理药代动力学(physiologically based pharmacokinetic,PBPK)模型引导研发,以降低成本并提升成功率。透皮贴剂的PBPK建模关键影响因素包括药物特性、制剂系统与机体差异。药物因素方面,定量结构-性质关系(quantitative structure-property relationship,QSPR)模型基于相对分子质量、脂水分配系数(LogP)等参数预测分配与扩散系数;机制模型通过解析多层皮肤结构阐明渗透动力学过程。制剂系统中,骨架型与储库型贴剂的释放差异可通过多相多层皮肤吸收机制(multiphase multilayered mechanistic dermal absorption,MPML MechDermA)模型模拟,涵盖溶出、沉淀及载体蒸发等关键过程。机体差异上,皮肤厚度、pH值、附属器密度及病理状态等显著影响渗透效率,模型需结合年龄、性别、种族等变量校准。模型整合基于菲克定律构建隔室间药物转运方程,支持体外-体内外推(in vitro to in vivo extrapolation,IVIVE)。本文系统综述透皮贴剂开发的PBPK建模方法及其影响因素,有望减少动物实验并加速临床转化。
文摘Genetic hypoparathyroidism(HP),achondroplasia(ACH),and primary growth hormone deficiency(GHD)are listed as rare diseases in the second List of Rare Diseases in China in 2023.Numerous studies have explored optimal therapies for certain rare endocrine diseases,and the development of long-acting therapeutic agents has been considered a key strategy for improving treatment outcomes,especially given the challenges associated with daily subcutaneous injections.However,limited attention has been given to the potential of"transient conjugation"(TransCon)technology,a platform designed to convert drugs into prodrug forms,thereby extending their half-lives and reducing dosing frequency,which demonstrates promise as a more convenient treatment option for these conditions.This is the first study to review the research progress of TransCon technology in the treatment of HP,ACH,and GHD,focusing on its pharmacokinetic properties,efficacy,safety,tolerability,and patient-reported outcomes in comparison with conventional therapies,in order to provide a reference for formulation development and clinical management of these rare endocrine diseases.
