An open label, randomized, single-dose, two-sequence, two-period, crossover comparative bioavailability study to assess the pharmacokinetic and safety profile of Dofetilide intravenous solution compared to Tikosyn® (Dofetilide) oral capsule in healthy subjects under fasting conditions.

开始日期2024-07-22

申办/合作机构

Hyloris Developments SA

NCT04508491

/ CompletedN/AIIT

The Best Treatment Strategy for the Reservation of Cognitive Function in Patients With Persisted Atrial Fibrillation

Compare the difference of cognitive function between different treatment strategy in patients with persistent atrial fibrillation

开始日期2020-11-30

申办/合作机构

国立台湾大学医学院附设医院

NCT04128878

/ CompletedN/AIIT

Improvement in Endothelial Dysfunction After Initiation of Anti-arrhythmic Therapy in Atrial Fibrillation Patients

This is a prospective, observational study that will examine endothelial dysfunction in atrial fibrillation before and after treatment with anti-arrhythmic agents and the extent to which baseline endothelial dysfunction improves after treatment.

开始日期2019-05-01

申办/合作机构

University of Pittsburgh

100 项与多菲菜德相关的临床结果

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100 项与多菲菜德相关的转化医学

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100 项与多菲菜德相关的专利（医药）

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1,279

项与多菲菜德相关的文献（医药）

2026-09-01·BIOMEDICINE & PHARMACOTHERAPY

Amsacrine modifies action potential configuration without its prolongation via the blockade of multiple ion currents in canine ventricular cells

Article

作者: Magyar, János ; Óvári, József ; Kovács, Zsigmond Máté ; Horváth, Balázs ; Bányász, Tamás ; Szentandrássy, Norbert ; Nánási, Péter P ; Varga, Zoltan

Amsacrine is an antineoplastic agent for acute lymphoblastic leukemia. It contains methanesulfonamide group -similar to hERG/I_Kr inhibitors like E-4031 and dofetilide-therefore may exert cardiac arrhythmias. Although amsacrine inhibits expressed hERG channels, its effects on native cardiac electrophysiology remain unclear. We investigated the effects of 1 and 10 µM amsacrine on action potentials (APs) and underlying ionic currents in isolated canine ventricular cardiomyocytes. Amsacrine reduced phase 0 parameters: maximal upstroke velocity (∼50-60%), action potential amplitude (∼15%), and peak potential (∼55%), suggesting inhibition of sodium current. Moreover, the maximal rates of phase 1 and 3 repolarizations, and plateau potentials were reduced, suggesting effects on multiple ionic currents. Despite these, AP duration (APD₂₀-APD₉₀) remained unaffected. AP voltage-clamp analysis revealed a complex amsacrine-sensitive current consisting of an early inward component consistent with sodium current inhibition, a second early outward component suggesting transient outward current suppression, a mid-plateau inward component likely reflecting inhibition of inward plateau currents, and a late outward component compatible with I_Kr inhibition. 10 µM amsacrine reduced L-type calcium, transient outward potassium and expressed Na_V1.5 channel currents by 22, 38, and 10%, respectively. Native I_Kr was also reduced in a concentration-dependent manner (152 nM IC₅₀ and 1.21 Hill coefficient). These findings demonstrate that amsacrine modulates multiple cardiac ion currents. The lack of AP prolongation despite I_Kr inhibition can be due to concomitant suppression of inward currents. As the tested concentrations overlap with therapeutic plasma levels (3-18 µM), amsacrine may carry a non-negligible risk of cardiac electrophysiological effects, particularly in susceptible patients.

2026-08-01·HeartRhythm case reports

Safety evaluation of dofetilide administration per enteral tube

Article

作者: LaBreck, Megan E ; Badin, Auroa ; Crawford, Katherine ; Nemer, David M ; Amin, Anish

2026-08-01·JACC-Clinical Electrophysiology

Safety of Dofetilide Initiation Following a Shortened Amiodarone Washout Period

Article

作者: Kapa, Suraj ; Siontis, Konstantinos C ; Asirvatham, Samuel J ; Sugrue, Alan M ; Noseworthy, Peter A ; Del-Carpio Munoz, Freddy ; Deshmukh, Abhishek J ; Burright, Isaac T ; Killu, Ammar M

BACKGROUND:

Dofetilide, a class III antiarrhythmic for atrial fibrillation, frequently requires dose reduction or discontinuation for QT interval prolongation or ventricular arrhythmias. Food and Drug Administration guidelines mandate a 3-month amiodarone washout or serum amiodarone <0.3 mcg/mL before dofetilide initiation, potentially prolonging therapy interruption.

OBJECTIVES:

This study aimed to evaluate the safety of a shortened amiodarone to dofetilide transition by assessing dose reduction, drug discontinuation, and arrhythmic events.

METHODS:

Mayo Clinic patients transitioned from amiodarone to dofetilide in <90 days with ≥12 weeks of amiodarone therapy and serum concentration ≥0.3 mcg/mL if measured were identified. The primary end point was ventricular arrhythmias requiring dofetilide discontinuation.

RESULTS:

The final cohort included 66 patients (mean age 65 ± 14 years; 74.2% of the patients were men). Atrial fibrillation classification was 33.3% paroxysmal, 54.5% persistent, and 12.1% long-standing persistent. A total of 22.7% had implantable cardioverter-defibrillators. The median transition period was 43 days; 16 patients (24%) transitioned within 30 days (5 [8%] within 14 days), 20 (30%) between 31 and 45 days, 16 (24%) between 46 and 60 days, and 14 (21%) between 61 and 90 days. Dose reduction occurred in 24.2% and discontinuation in 10.6%, with no difference between ≤30- and >30-day transitions (dose reduction: 12.5% vs 28.0%, P = 0.319; discontinuation: 6.3% vs 12.0%, P = 1). No torsades de pointes (TdP) occurred during inpatient dofetilide initiation/loading. One TdP episode (339 days after dofetilide initiation, 419 days postamiodarone) was associated with intercurrent illness and additional QT-prolonging medication exposure.

CONCLUSIONS:

In this cohort, dofetilide initiation within 90 days of amiodarone discontinuation was not associated with TdP during inpatient loading, supporting the feasibility of monitored, expedited transitions in select patients.

项与多菲菜德相关的新闻（医药）

2026-09-08

·今日头条

综合性体外致心律失常风险评估的研究进展

药源性心脏毒性不仅严重危害人类健康，由其所引发的药物撤市也给研发机构带来巨大的财力与人力损失，已成为新药研发领域广泛关注的重要问题。自1969年以来，大量药物因上市后出现不良反应，被迫撤市或修改说明书，其中因诱发心血管相关不良反应而采取上述措施的药物达40种，占比达8.7%，在所有类别中位居第2位[1-2]。现有的体外心脏毒性评价模型主要有离体动物组织模型和二维细胞系模型。离体心脏组织是心脏安全性评价的重要工具，但其应用存在通量低、实验周期长、种属差异、对实验技术要求高等显著瓶颈[3-4]。除离体心脏组织外，以中国仓鼠卵巢细胞（CHO）为代表的二维细胞系，也是当前体外促心律失常风险评估中广泛使用的模型[5]，但其非心脏特异性细胞系，其离子通道表达谱、亚型构成及电生理特性与人心肌细胞存在固有差异，与人心脏存在显著的生理性差异[6]。针对以上问题，美国食品药品监督管理局（FDA）于2003年将人类ether-à-go-go相关基因（hERG）钾电流试验确立为临床前药物心脏毒性检测的新标准[7]，以期通过这一试验减少相关药物召回事件的发生。2005年，人用药品注册技术要求国际协调理事会（ICH）发布了《人用药品延迟心室复极化（QT间期延长）潜在作用的非临床评价指导原则》（S7B）[8]，及《非抗心律失常药物致QT/QT间期延长以及潜在致心律失常作用的临床评价指导原则》（E14）[9]。2014年，我国参照ICH S7B制定了《药物QT间期延长潜在作用非临床研究技术指导原则》。上述指导原则的核心目的是在药物研发早期借助hERG试验和动物体内QT间期实验，评估药物是否具有QT间期延长风险，从而预测其致心律失常风险。然而，这一评估方法存在明显局限。由于hERG试验仅检测药物对单一钾离子通道的影响，其局限性主要体现在2方面：一是假阳性问题，即部分无心脏毒性的药物（例如临床长期使用的钙离子拮抗剂维拉帕米等）可能显示阳性结果，导致有潜力的候选药物被错误淘汰，在一定程度上阻碍新药研发进程；二是假阴性问题，即某些具有心脏毒性的药物可能通过评估，实际却仍具有致心律失常风险，这也解释了为何2003年后仍持续出现因心脏毒性引发的药物召回事件[10-11]。此外，动物模型与人类之间的生理差异，也使得临床前实验结果在推演至人体时存在不确定性。为优化药物心脏毒性检测方法，FDA于2013年启动了综合性体外致心律失常风险评估（CiPA）项目，致力于构建更为系统、可靠的临床前药物心血管风险评估体系及标准。CiPA的最终目标是通过修订相关指南，提升临床前药物心脏安全性筛选的准确性与效率，并使大多数新药得以免于开展以QT间期为核心的人体临床试验，从而显著降低新药研发的整体成本。近年来，随着该评估体系在实践中的持续优化与标准化，CiPA不仅提升了心脏安全性评价的准确性、降低了药物研发成本，还为ICH E14/S7B Q＆A的发布提供了理论及数据支持。这一标准的建立与推广，将使新药的试验与审批过程更安全、更高效，助力更多安全有效的药物早日上市服务于全球患者。本文将对近年来CiPA取得的突破性进展进行综述。 1 CiPA研究现状 CiPA包含4个核心工作组：（1）离子通道工作组：测定药物对与心律失常相关的7种关键离子通道的阻断程度，并将其划分为高、中、低3个风险等级；（2）计算机模拟（in silico）工作组：通过人源干细胞来源的心肌细胞（hSC-CMs）电生理模型，将通道阻断数据导入模型以定量评估药物的尖端扭转性室性心动过速（TdP）风险；（3）干细胞工作组：借助体外hSC-CMs模型，识别可能干扰风险评估的额外电生理效应，并对计算机模拟结果进行验证；（4）临床心电图（ECG）工作组：研究新的生物标志物，以确定与临床前离子通道数据相比，人类是否存在意外的离子通道效应。 1.1 离子通道工作组 CiPA体系突破了传统仅针对hERG钾离子通道检测的局限，拓展至涵盖7种关键心脏离子通道的综合性评价，包括hERG、Nav1.5、CaV1.2、NaV1.5-Late、Kv4.3、Kir2.1以及IKs通道。通过同步检测药物对这些通道的作用，系统反映药物对心脏复极化过程中多离子通道的综合影响，从而更真实地模拟人体心脏的电生理反应。这种多通道协同评估的策略，有助于显著降低单一通道检测导致的假阳性与假阴性风险，提升心脏安全性预测的全面性和可靠性。基于膜片钳的离子通道研究，当前CiPA离子通道工作组已标准化了手动和全自动膜片钳操作方案[12]。但多项基于CiPA的研究显示，非临床数据与临床观察之间存在不一致现象。例如，氯喹、洛匹那韦及利托那韦所引发的心电图变化提示存在CaV1.2与NaV1.5通道阻滞作用[13]，而用于指导临床研究的离子通道实验数据却未显示这些药物对上述通道有明显影响。为增强非临床数据在监管决策中的可信度，需明确非临床-临床不一致性的来源，并填补相关代谢物数据缺口。Alvarez等[14]进一步研究了氯喹、洛匹那韦、利托那韦及范诺沙林对hERG、CaV1.2和NaV1.5通道的影响。结果表明，在采用更贴近生理条件的实验方案、并纳入药物活性代谢物作用考量后，离子通道阻滞曲线与药物诱发的心电图变化及早期心律失常表现之间的对应关系被显著优化。考虑到生理温度等对实验结果的影响，ICH S7B Q＆A草案[15]（2020年8月27日版）第2.1节中对离子通道研究的最佳实践考量方案进行了说明，包括以下几方面：（1）阳性对照，即需为每种电流设置阳性对照，且药物浓度范围应覆盖20%～80%的抑制效果；（2）实验温度，应在生理温度37 ℃或接近生理温度35～37 ℃下进行；（3）电压控制，在生理温度下，NaV1.5和CaV1.2电流的峰值出现速度极快，因此在开始实验前应先在记录细胞中建立电流-电压关系，例如从−60 mV到40 mV，以5 mV为增量，以排除电压逃逸现象。hERG实验电压方案需每5秒重复1次，电压“斜坡下降”阶段持续100 ms，从40 mV降至−80 mV。2024年，Johnson等[16]采用修订后的CiPA最佳实践方案，在生理温度下评估了维拉帕米对hERG钾通道的抑制效应，测得半数抑制浓度（IC50）为225 nmol·L−1，与修订前结果（252 nmol·L−1）相近，但实验成功率从5%提升至25%，较原方案提高了5倍，更符合生理学研究的成功率要求。此外，Annie等[17]通过7个离子通道的膜片钳检测评估了氯喹和羟氯喹介导的QT延长及TdP的风险，成功评估了氯喹和羟氯喹对部分钾、钠和钙电流的抑制作用。但此前FDA也提出了一些担忧，目前尚无开放数据格式来促进离子通道原始数据的共享，为了解决这一问题，2021年在CiPA倡议下，业界、学术界和FDA的研究人员组成团队，并由健康与环境科学研究所（HESI）协调，制定了CiPA开放数据（COD）格式草案。为了将现有数据导出为COD格式，FDA分团队还开发了一种基于电子表格的格式—表格化实验数据（TED）格式[18]。 1.2 in silico 工作组 CiPA体系引入了计算机模拟技术，通过构建心室动作电位的虚拟模型，预测药物在人体内潜在的致心律失常风险。这一方法不仅显著提升了风险评估的准确性，还有助于研究人员更深入地解析药物对心脏电生理的影响机制。 2019年，Li等[19]基于CiPA工作组提供的体外离子通道数据，将药物对关键电流（IKr、INa、INaL、ICaL等）的阻滞参数输入计算机系统，选用O’Hara-Rudy动态模型（ORd）进行优化，开发出CiPAORdv1.0模型。该模型考虑了生理温度对离子通道功能的影响，并采用16种CiPA药物验证其预测性能。结果显示，该模型对药物TdP风险的预测具有较高的准确性。既往研究通常提取动作电位复极化90%时程（APD90）、净离子电荷的指标（qNet）或内向电流的指标（qInward）等单一指标并通过二分类方法将其作为预测致心律失常风险的生物标志物。然而，Logistic回归等分类方法属于简单的算法，无法完全有效进行风险分类。因此，2021年Yoo等[20]提出了人工神经网络模型（ANN），利用9个多重输入特征（包括动作电位形态、钙瞬态形态和电荷特征），以进一步提升药物毒性评估的性能。通过不确定性定量技术，将28种药物的膜片钳实验数据补充至2 000条。通过将这些数据应用于修改后的ORD模型，使用12种药物的数据进行训练，并使用剩余16种药物的数据进行测试。结果显示评估准确率相较于2019年Li等[19]的研究提高了6.4%。此外，使用单一的计算机模拟功能（比如以qNet作为TdP风险评估生物标志物的回归模型）无法在整个动作电位（AP）中反映与TdP相关的全部特性。2022年，Jeong等[21]建立了一种深度卷积神经网络模型（CNN），采用“Adam”优化算法和类别交叉熵损失函数进行训练，从而实现了无需使用动态模型即可进行高效药物分类。对CiPA药物风险分类结果显示，高、中、低风险药物的分类准确率分别为98%、94%、89%，准确率优于使用qNet的传统模型。上述模型依赖于ORD模型中单一生物标志物，且未将hERG动态作为单个机器学习模型输入，在捕捉影响药物诱导TdP风险的综合因素复杂性方面存在局限。为弥补这一局限，2024年，Fuadah等[22]构建了集成机器学习模型，融合来自CiPAORdv1.0模型的计算机生物标志物与hERG动态特性，并成功用于多种药物在高临床暴露下的风险分类，相较传统单生物标志物方法更为全面，并仍保持高预测准确性，且在多种临床条件下具有稳健性。2025年，研究人员又运用可解释的人工智能（XAI）机器学习模型开发了心脏毒性药物智能发现平台（CUPID）[23]，旨在预测与hERG、Nav1.5和Cav1.2通道相关的心脏毒性。该框架使用最新的跨物种实验数据集进行训练，在五重分层交叉验证分析中，风险评估准确率达到约80%。CUPID提供了早期心脏毒性全面的风险评估，关键突破在于其可解释性：预测以清晰的适用领域信息加以注释，与心脏毒性风险相关的化学亚结构则通过夏普利加性解释（SHAP）值突出显示。但此模型目前还处于前期开发验证阶段，后续应用还需采用阳性药物进行跨实验室验证。 1.3 干细胞工作组 CiPA干细胞工作组采用hSC-CMs作为关键实验模型，具有更接近人类心脏生理特性的优势，可提供更为准确和真实的药物电生理效应评估。与传统评价模型相比，hSC-CMs模型在预测药物心脏毒性方面展现出更高的相关性和可靠性，有助于提升临床前心脏安全性评估的预测准确性与转化价值。尽管人诱导多能干细胞来源的心肌细胞（hiPSC-CM）应用于致心律失常风险评估具有较大潜力，但近年来业界对于实验可重复性、细胞成熟度等的担忧也一直存在。2024年Guerrelli等[24]通过微电极阵列（MEA）研究了时间变化、多孔板位置差异等因素对hiPSC-CM电生理特征的影响，发现心脏相关终点的测量结果受细胞培养持续时间影响。提示，为提高实验可重复性、确保数据解释一致性，建立标准化操作流程并详细报告关键实验条件（如细胞系、培养时间、平衡时间、电刺激参数及原始数据等）是十分必要的。而传统的MEA电极密度较低，这在一定程度上限制了MEA技术的通量，为解决这一问题，2024年，Lee等[25]在前期开发的高密度微电极阵列（HD-MEAs）基础上开发了CardioMEA平台，可实现在2 mm×4 mm的范围内集成26 400个电极，2个电极间距仅17.4 μm，几乎跟单个细胞一样大小，且可用于高级可视化分析。除了其核心功能外，CardioMEA还集成了旨在识别患病和健康hiPSC-CMs之间关键电生理特征的模块。但此平台目前还在研究阶段，后续还需大规模验证，以进一步应用于电生理评估中。基于光学电压传感技术（VSO）的心律失常风险评估，通量方面也存在相对局限，2020年，Bedut等[26]基于VSO开发了Hamamatsu FDSS系统，结果显示使用该高通量系统对96孔内hSC-CMs的兴奋性、传导速度和晚期复极化阶段的适度电生理紊乱具有更高的检测能力。除此之外，其团队还进一步优化了成像设备帧率，这代表着基于多孔光学记录电生理信号的高通量药物筛选在信息丰度上取得了新进展。研究人员在细胞模型优化方面也在不断努力。为进一步提升心肌细胞成熟度与预测能力，Li等[27]将动波与MEA相结合，构建出hiPSC衍生的闭环心脏组织模型。该模型可自发启动动波并进行快速起搏，促进了心肌细胞的结构与功能成熟，从而改善了hiPSC-CMs常见的不成熟表现。在给予奎尼丁和哌莫齐特后，该系统检测到的心律失常发生率高于传统hiPSC-CMs模型，突出了其在CiPA框架中用于药物心脏安全性评价的潜在价值。然而，仅依赖场电位时程（FPD）测量进行电生理评估，可能无法完全评估药物诱导的心脏毒性全机制，不同药物可能通过不同机制影响心肌细胞。因此，结合场电位和收缩力测量的全面评估方法，对实现准确的毒性评估至关重要。2024年Kanade等[28]推出的一种集成机械电生理平台解决了这些问题，该平台可实现同时对心肌细胞的收缩力和场电位的进行实时监测。研究人员通过6种作用机制不同的心脏毒性药物展开验证，结果表明该平台能够成功识别药物作用机制，并准确评估毒性特征，包括不抑制钾通道的药物。除了对单药致心律失常风险展开评估外，2025年1项基于hiPSC-CMs的药物联用研究，实现了临床前药物联用致TdP风险的评估，结果显示，可比司他（QT缩短药）和莫西沙星（QT延长药）联合使用导致相较于对照组和单用莫西沙星组，场电位时程校正值（FPDcF）呈浓度依赖性地缩短，且通过局部胞外动作电位检测到莫西沙星诱导的心律失常在联用后被消除[29]。在向FDA提交新药临床试验申请（IND）的过程中，hiPSC-CMs数据曾被作为支持性证据提交，与其他非临床数据共同支撑心脏安全性评估，体现了该类模型在药物研发早期识别潜在风险、指导临床开发策略中的实际应用价值。索磷布韦于2013年获批用于治疗慢性丙型肝炎病毒感染，当索磷布韦与抗心律失常药物胺碘酮联合使用时，曾出现严重症状性心动过缓的意外病例报告。后研究人员采用hiPSC-CMs进行了机制研究[30]。结果显示，在hiPSC-CMs中，索磷布韦在胺碘酮存在条件下可抑制L型钙通道，而在胺碘酮缺失时无此效应[31]，该结果与索磷布韦和胺碘酮对离体豚鼠心脏房室结传导的协同作用一致。 1.4 临床 ECG 工作组 ECG工作组的核心目标是开发并验证新型ECG生物标志物，以捕捉非临床离子通道数据未能预测的人体心脏电生理反应。由于并非所有hERG阻断及QT间期校正值（QTc）延长的药物均会引发TdP，因此QTc延长不能作为临床上心律失常风险评估的唯一指标。实际风险需通过区分以下2种情形进行评估：（1）单纯hERG阻断药物（高TdP风险）表现为QTc延长伴随J-Tpeakc延长；（2）平衡型多离子通道阻断药物（低TdP风险）虽可能出现QTc延长，但J-Tpeakc不延长甚至缩短。平衡型多离子通道阻断药物因同时阻断内向电流，可能不引起明显QT间期变化，故TdP风险较低，但这一特性也可能增加风险评估的复杂性，影响对药物真实致心律失常潜力的准确判断[32]。为验证平衡型多通道阻滞剂是否存在心率校正后的J-Tpeakc延长现象，CiPA研究选取平衡型阻滞剂洛匹那韦、多非利特及雷诺嗪开展临床试验，通过对J-Tpeakc进行浓度-反应分析，证实基于QTc与J-Tpeakc的浓度-效应关系，可有效区分以hERG阻滞为主的QT延长药物与具备平衡性离子通道阻滞特征的药物[33]。然而，该研究样本量较小（仅10例受试者），可能不足以充分表征部分多通道阻滞药物的完整浓度-效应关系。ECG工作组进一步对28种训练药物与16种验证药物，在Ⅰ期临床试验中采集的24 h连续12导联心电图进行分析，结果显示，J-Tpeakc对多离子通道失衡的检测灵敏度较Fridericia-QTc高出18%，且不受进食或体位变化干扰。基于此，2024年10月发布的联合白皮书已将J-Tpeakc列为CiPA框架下“推荐用于机制验证的心电图生物标志物”。同年1项CiPA验证子研究（n＝48）也表明，对于同时抑制hERG与晚钠电流（late-INa）的药物代谢物，J-Tpeakc延长幅度可被“抵消”显示，而QTc仍呈现假性延长；这一发现为ICH S7B Q＆A新增“代谢物心电图评估应采用J-Tpeakc”的条款提供了实验基础[14]。尽管如此，相关研究仍存在一定局限性：受预设剂量与固定时间点ECG采集的限制，研究可能忽略药物血药浓度动态变化及活性代谢产物的影响，从而在一定程度上限制了QT间期评估的全面性。据此，2024年国家药品监督管理局（NMPA）发布《药物浓度-QTc临床研究技术指导原则（征求意见稿）》[34]，阐述了采用药物浓度-QTc（C-QTc）研究替代标准的全面QT间期（TQT）研究的相关考虑，以指导创新药C-QTc研究高质量和高效率地实施、完成以及评估。在人工智能（AI）高速发展的当下，2021年研究人员探索了基于AI驱动的ECG临床决策支持工具是否能够实现射血分数（EF）的早期诊断。在该试验中，120个团队被分组随机分配到干预组（AI干预）或对照组（常规护理）。数据采集从22 641名无既往心力衰竭的成人中获得，主要结局为ECG 90 d内新诊断EF低（≤50%）。结果显示，试验符合预先设定的主要终点，表明干预措施提高了整体队列中低EF的诊断率。总体队列中，两组超声心动图利用率相似。这些结果表明，基于AI的ECG临床监测可以在常规初级保健环境中实现低EF的早期诊断[35]。 2 CiPA的机遇与挑战近年来，CiPA通过整合多学科技术，实现了对药物心脏安全性评估范式的革新。其核心进展体现在以下4个层面：（1）多离子通道系统评估，引入生理温度和标准电压等最佳实践，弥合了非临床与临床数据的差异，并改善了离子通道原始数据的共享与分析效率；（2）in silico工作组在生理温度下，通过虚拟重建药物对人心室肌细胞动作电位的动态影响，实现致心律失常风险的定量预测与分级，并不断优化模型与算法，通过引入多维度输入条件实现更全面的风险评估，并保持高预测准确性；（3）基于hSC-CMs的评价体系在细胞来源逐步标准化与成熟化的基础上，实验了通量与重复性同步提升；（4）ECG工作组推动使用以J-Tpeakc为代表的新型ECG标志物，这类指标对多离子通道失衡具有更高的敏感性，且受食物、体位等混杂因素影响较小，标志着临床心脏安全性评估正从单一的QT间期监测，迈向基于电生理机制、更具特异性的生物标志物新阶段。CiPA也为指导原则的优化提供了实验基础，ICH于2022年通过了E14/S7B Q&A的新修订版本[36]，其中就参考了CiPA内容，包括引入机制性定量风险指标，标准化体外测试，针对离子通道测试提出了最佳实践建议（包括温度、电压方案等）以提升数据的可重复性与可比较性，对hSC-CMs来源、培养条件、记录质量以及灵敏度验证要求进行建议等[37-38]。 CiPA从科研成果向监管指南的转化，经历了从学术倡议到监管认可的系统性演进过程。自2013年FDA牵头启动CiPA倡议以来，各工作组通过大规模阳性药物验证、跨实验室验证、标准化实验方案等[19]，逐步构建了致心律失常风险预测框架。2022年，ICH发布E14/S7B Q&A第一阶段文件，提出“双阴性”非临床场景下的简化评估路径，标志着CiPA核心理念和框架正式融入ICH S7B和E14的修订进程，目前CiPA范式已通过ICH指南在全球范围内实施[37]。这一转化历程深刻诠释了“创新-验证-协调”的3阶段演进范式：从基础研究的科学假说提出，到多中心验证数据的循证积累，再到国际监管框架的制度化嵌入。未来，CiPA将不断完善，第二阶段Q&A预计将进一步细化对“非双阴性”化合物的评估建议。尽管CiPA的不断优化已然代表了药物心脏安全评估领域的重大进步，但其全面实施仍面临一系列关键挑战（表1）。在技术层面，不同实验室间细胞系、培养条件与设备的差异导致数据可比性不足，1项基于30种CiPA药物的验证结果表明，不同实验室测得的Cav1.2通道IC50可能相差数十倍甚至上千倍[13]，导致同一药物在不同实验室被归入完全不同的风险类别，这直接影响风险评估模型在不同实验系统中的通用性与普适性。此外，现有体系仅支持单一离子通道检测，难以充分模拟多离子通道协同调控作用，Mangala等[40]揭示了离子通道共表达网络对心脏电稳定性的保护作用，进一步说明单一通道检测难以全面评估致心律失常风险；同时，现有模型缺乏对血管化结构及多器官交互作用的模拟能力，难以真实还原包含血供、免疫浸润及器官间信号交流在内的体内微环境。在应用层面，CiPA研究主要基于单药效应，缺乏针对联合用药的标准评估框架，研究表明，联合用药会以高度非线性方式改变APD90等电生理参数，最终影响药物风险等级的评定，如2个低风险药物维拉帕米与雷诺嗪联用的风险评定结果则为高风险[41]。此外，现有临床验证研究通常将老年群体排除在外，Bourgeois等[42]评估了839项针对心脏病药物研究中排除老年人的情况，在这些试验中，有53%的研究明确排除了老年人，这进一步加剧了非临床预测结果与老年患者实际用药安全之间的“证据断层”[43]。在AI与生物医学深度融合的背景下，药物安全评估正步入一个挑战与机遇并存的新阶段。针对实验室间差异性问题，已有研究提出可通过AI量化各实验室数据的相对不确定性，自动识别出与其他实验室存在系统性偏差的异常实验室，并在此基础上构建出多实验室间的共识值[44]。目前，国内外正积极推动类器官技术的发展。FDA已明确将逐步取消对单克隆抗体等部分药物开展动物实验，转而采纳类器官等更为高效、更贴近人体生理特征的“新方法”（NAMs）作为替代策略[45]。在FDA发布的roadmap[39]中，也进一步强调了类器官的应用前景。因此针对现有模型无法完全模拟人体心脏的血管化、多离子通道等特征，可通过构建血管化心脏类器官模型，整合单细胞数据与三维类器官数据，以更真实地模拟体内多离子通道调控机制以及体内微环境[46]。值得注意的是，可尝试将构建心脏类器官与其他器官共发育模型，并与AI深度融合，模拟人体内复杂的多器官交互作用[47]。此外，针对老龄化及联合用药等局限性，一方面可构建年龄特异性的“虚拟人群”模型，另一方面可建立标准化的药物相互作用模型，从而形成可量化的风险评估指标。总而言之，CiPA标志着心脏安全性评价实现了从经验性、简化性向机制性、系统性的重要转型。该范式通过整合多离子通道电生理分析、计算模型动态模拟、人源心肌细胞实验以及新型ECG生物标志物，构建了一套更具预测力与机制解释力的闭环评估体系，为降低药物研发损耗、加速安全有效新药上市提供了新的机遇。然而，CiPA要广泛应用于实践，仍需持续应对若干核心挑战，包括实验模型的标准化、数据来源的一致性、药物代谢物影响的系统评估等。展望未来，CiPA的发展必将是一个动态演进的过程：一方面需依赖技术进步，不断提升各环节的精度与可靠性；另一方面，也需要通过监管机构与学术界的协作，推动其稳健融入全球药物研发与审评体系。唯有如此，CiPA才能真正成为保障患者心脏安全、促进医药创新的基石性工具。来源：曾芸茜，赵琪，杨浩，程之凯，侯敏博，杨淑雯，汪溪洁．综合性体外致心律失常风险评估的研究进展 [J]. 药物评价研究, 2026, 49(7): 2536-2544.

引进/卖出申请上市

2026-08-28

·allsci.com

FDA approves Gilead's Bixlenvo to simplify complex HIV regimens

The US FDA has approved Bixlenvo (bictegravir 75 mg/lenacapavir 50 mg), a once-daily single-tablet regimen (STR) for HIV-1 treatment in virologically suppressed adults — including, for the first time, those on complex multi-tablet regimens who could not previously use an STR. Gilead Sciences (Nasdaq: GILD) said the combination is the smallest oral STR and the first approved STR option for virologically suppressed patients on complex regimens who are unable to use existing STRs because of factors including historical resistance or tolerability. Bixlenvo is indicated as a complete regimen for adults with HIV-1 RNA below 50 copies per mL on a stable antiretroviral regimen, with no known or suspected resistance to either component. Initiation requires a two-day loading period with Sunlenca (lenacapavir) co-administered alongside Bixlenvo, after which Bixlenvo is taken alone once daily. Contraindications include co-administration with dofetilide and strong CYP3A inducers. Approval rested on two Phase III trials — ARTISTRY-1 (NCT05502341) and ARTISTRY-2 (NCT06333808) — both evaluating virologic suppression maintenance at Week 48 after switching to Bixlenvo. ARTISTRY-1 enrolled a notably treatment-experienced population: median age 60 years, median 28 years on antiretroviral therapy, 67% with nucleoside reverse transcriptase inhibitor (NRTI) resistance, and 81% on complex regimens due to resistance. Both trials reported comparable efficacy to prior regimens and no new safety signals; the most common adverse reactions were headache (4%), nausea (3%), and diarrhea (2%). ARTISTRY-1 results were published in The Lancet and ARTISTRY-2 in Lancet HIV. Bictegravir is an integrase strand transfer inhibitor (INSTI) that blocks insertion of viral cDNA into the host genome. Lenacapavir, a first-in-class capsid inhibitor also marketed as Sunlenca, disrupts capsid-dependent processes across multiple stages of the HIV lifecycle — nuclear import, uncoating, and virion assembly — with no cross-resistance to other approved antiretroviral classes. The approval adds another option to an increasingly competitive HIV switch market that includes ViiV Healthcare's Dovato (dolutegravir/lamivudine), long-acting injectable Cabenuva (cabotegravir/rilpivirine), and Merck's recently approved Idvynso (doravirine/islatravir). Bixlenvo is differentiated by its ability to simplify treatment for some heavily treatment-experienced patients currently requiring complex multi-tablet regimens. Spot something wrong? Report an issue with this article

临床3期上市批准临床结果临床研究寡核苷酸

2026-08-27

·BioSpace

U.S. FDA Approves Gilead’s Bixlenvo™, a New Once-Daily Single Tablet Option for Virologically Suppressed Adults With HIV, Including Those on Complex Regimens

– Novel Daily Oral Tablet Combines Bictegravir, a Guideline-Recommended INSTI with a High Barrier to Resistance, with Lenacapavir, a First-in-Class Capsid Inhibitor with No Cross-Resistance to Other Existing Antiretrovirals – – Bixlenvo Now the Smallest STR; First and Only STR for Most People on Complex HIV Treatment Regimens – FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) approved Bixlenvo ™ (bictegravir 75 mg/lenacapavir 50 mg), the smallest once-daily single tablet regimen (STR) for the treatment of HIV in adults who are virologically suppressed. Bixlenvo is now the first and only STR option for virologically suppressed people with HIV who are on complex regimens and unable to take currently available STRs. This novel HIV treatment pairs bictegravir, a global guideline-recommended integrase strand transfer inhibitor (INSTI) with a high barrier to resistance, with lenacapavir, a first-in-class capsid inhibitor that has a novel mechanism of action with no cross-resistance to other antiretrovirals. “Bixlenvo offers a new once-daily STR designed for the evolving needs of people with HIV,” said Chloe Orkin, MD, lead primary investigator for ARTISTRY-1 and Clinical Professor of Infection and Inequities at Queen Mary University of London. “The approval is a significant advancement in HIV treatment, especially for individuals unable to benefit from guideline-recommended STRs due to challenges like pre-existing resistance or tolerability. It expands tailored, simplified dosing to people whose needs were not fully met by existing single tablet therapies." The FDA approval is based on results from the Phase 3 ARTISTRY-1 ( NCT05502341 ) and ARTISTRY-2 ( NCT06333808 ) trials, with data presented during late-breaker sessions at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI 2026). The trials evaluated Bixlenvo in adults with HIV who are virologically suppressed, including those who switched from complex multi-tablet regimens or from Biktarvy ® (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg). In both trials, Bixlenvo demonstrated comparable efficacy in maintaining virologic suppression at Week 48 and was generally well tolerated, with no significant or new safety concerns identified. Most common adverse reactions reported in at least 2% of participants across the ARTISTRY program were headache, nausea, and diarrhea. Detailed ARTISTRY-1 results were published in The Lancet , and ARTISTRY-2 results were published in Lancet HIV . “Bixlenvo continues Gilead's long-term commitment to innovation in HIV. Bringing together bictegravir with our first-in-class capsid inhibitor, lenacapavir, Bixlenvo offers a novel choice to people with HIV looking to switch or simplify their treatment regimen,” said Daniel O’Day, Chairman and Chief Executive Officer of Gilead Sciences. “Our goal at Gilead is to provide multiple options for HIV treatment and prevention and with a pipeline of potential daily, weekly and longer acting options, today’s approval could be the first of many in the years ahead.” ARTISTRY-1 enrolled the oldest study population in a Phase 3 registrational trial for HIV-1 treatment to date, with a median participant age of 60 years. Participants were taking between two and 11 pills per day at baseline, with approximately 40% taking antiretroviral therapy more than once daily. Additionally, the trial participants had extensive HIV treatment experience, with a median treatment duration of 28 years, a high level of historical antiretroviral resistance (67% with NRTI resistance) and a high proportion of participants on a complex regimen because of antiretroviral resistance (81%). The Phase 3 results demonstrated that switching from complex multi-tablet regimens to Bixlenvo was associated with improvements in certain fasting lipid parameters and participant-reported treatment satisfaction. ARTISTRY-2 showed that switching to Bixlenvo had no significant impact on weight. Bixlenvo requires a two-day initiation dose with Sunlenca ® (lenacapavir), thereafter only Bixlenvo is taken orally once a day. Bictegravir and lenacapavir in combination are not approved by any regulatory authority outside of the United States. There is currently no cure for HIV or AIDS. Please see below for the U.S. Indication and Important Safety Information for Bixlenvo. About Bixlenvo Bixlenvo is a once-daily, single tablet regimen that combines bictegravir, a global guideline-recommended integrase strand transfer inhibitor (INSTI) with a high barrier to resistance, and lenacapavir, a first-in-class capsid inhibitor with a multi-stage mechanism of action. Together, bictegravir and lenacapavir target multiple stages of the HIV life cycle. Developed for adults with HIV who are virologically suppressed, including those on complex regimens, Bixlenvo expands treatment choice with a simple daily oral option supported by results from the Phase 3 ARTISTRY clinical program. For more information, visit . U.S. Indication for Bixlenvo Bixlenvo is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known or suspected resistance to the individual components of Bixlenvo. IMPORTANT SAFETY INFORMATION Contraindications Coadministration: Concomitant administration of Bixlenvo is contraindicated with dofetilide and strong CYP3A inducers. Warnings and precautions See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during Bixlenvo therapy and monitor for adverse reactions. Adverse reactions Most common adverse reactions (incidence > 2%; all grades) reported in clinical trials were headache (4%), nausea (3%), and diarrhea (2%). Drug interactions Prescribing Information: Consult the full Prescribing Information for Bixlenvo for more information on contraindications, warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that are both a strong inducer of CYP3A and induce UGT1A1 can substantially decrease the concentration of components of Bixlenvo. Drugs that are strong or moderate inducers of CYP3A may significantly decrease the concentrations of components of Bixlenvo. Drugs that are both a strong CYP3A inhibitor and a UGT1A1 inhibitor, or combined P-gp, UGT1A1, and strong CYP3A inhibitors can significantly increase concentrations of components of BIXLENVO. Dosage and administration Dosage: Two-day initiation regimen of Bixlenvo 1 tablet plus Sunlenca 2 tablets taken orally daily, followed by a maintenance regimen of Bixlenvo 1 tablet orally once daily. Tablets may be taken with or without food. Day 1: Bixlenvo 1 tablet of 75 mg/50 mg orally and Sunlenca 2 tablets of 300 mg orally (600 mg dose) Day 2: Bixlenvo 1 tablet of 75 mg/50 mg orally and Sunlenca 2 tablets of 300 mg orally (600 mg dose) Day 3 and once daily thereafter: Bixlenvo 1 tablet of 75 mg/50 mg orally once daily Missed dose: If the initiation doses of Bixlenvo or Sunlenca are missed, patients should take them as soon as possible. Patients should not take both Day 1 and Day 2 doses of Sunlenca on the same day. Patients should take missed maintenance doses as soon as possible. If more than 7 days have elapsed since the last maintenance dose, restart initiation dosage regimen from Day 1, if clinically appropriate to continue treatment. Pregnancy and lactation Pregnancy: Lower exposures of bictegravir were observed in clinical studies with a bictegravir-containing regimen; therefore, viral load should be monitored closely in pregnant individuals. An Antiretroviral Pregnancy Registry (APR) has been established. Lactation: Individuals with HIV-1 should be informed of the potential risks of breastfeeding. About Gilead HIV For almost 40 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 13 HIV medications, including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce new HIV infections, and the first long-acting injectable HIV prevention medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Gilead is committed to continued scientific innovation to provide solutions for the evolving needs of people affected by HIV around the world. Through partnerships , collaborations and charitable giving, the company also aims to improve education, expand access and address barriers to care, with the goal of ending the HIV epidemic worldwide. Gilead has been repeatedly recognized as the top two leading philanthropic funders of HIV-related programs in a report released by Funders Concerned About AIDS. Discover more about Gilead’s unique collaborations worldwide and the work to help end the HIV epidemic. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. In 2025, Gilead announced a planned $32 billion investment to further strengthen its U.S. footprint to power the next era of discovery, job creation and public health preparedness – while continuing to invest globally to ensure patients everywhere benefit from its scientific innovation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, Calif. Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving bictegravir and lenacapavir (such as ARTISTRY-1 and ARTISTRY-2); uncertainties relating to regulatory applications and related filing and approval timelines, including potential applications for programs and/or indications currently under evaluation, and the risk that any regulatory approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of these programs and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; the risk that physicians and patients may not see the advantages of Bixlenvo for the treatment of HIV in adults who are virologically suppressed; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2026, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Bixlenvo ™ , Sunlenca ® , Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies. U.S. Prescribing Information for Bixlenvo is available at . For more information about Gilead, please visit the company’s website at , follow Gilead on X ( @Gilead Sciences ) and LinkedIn , or contact Gilead Public Affairs. Contacts Priscilla White, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

临床3期临床结果上市批准

100 项与多菲菜德相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D00647	多菲菜德	C01BD04	DB00204

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适应症	国家/地区	公司	日期
心房颤动	美国	Pfizer Inc.	1999-10-01
心房扑动	美国	Pfizer Inc.	1999-10-01

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适应症	最高研发状态	国家/地区	公司	日期
心房颤动和扑动	临床1期	保加利亚	Hyloris Developments SA	2024-07-22

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ESC2026	N/A	心房颤动	2,187	Dofetilide	壓糧膚衊遞齋願餘廠鑰(顧鏇膚齋範衊網鏇觸鑰) = 衊齋顧獵鏇餘觸獵艱糧憲顧築窪顧築壓餘選繭 (壓襯鹽憲選鹹選遞獵顧 ) 更多	积极	2026-04-13
				Amiodarone	壓糧膚衊遞齋願餘廠鑰(顧鏇膚齋範衊網鏇觸鑰) = 蓋壓廠窪觸憲齋糧鹹繭憲顧築窪顧築壓餘選繭 (壓襯鹽憲選鹹選遞獵顧 ) 更多
NCT03070470 (CTgov)	临床1期	长QT综合征	60	Ranolazine (Ranolazine)	憲觸網獵選壓網淵鑰選(廠鹹夢憲鑰窪蓋憲構繭) = 簾窪簾鹽壓鏇願簾製鏇膚網窪顧艱蓋襯製淵鏇 (製憲齋襯鹽艱齋夢襯廠, 窪艱艱遞餘憲選鹽鹹膚 ~ 鬱襯鬱鏇齋鹹廠積膚網) 更多	-	2020-01-18
				Verapamil (Verapamil)	憲觸網獵選壓網淵鑰選(廠鹹夢憲鑰窪蓋憲構繭) = 餘選繭網網選壓鏇壓觸膚網窪顧艱蓋襯製淵鏇 (製憲齋襯鹽艱齋夢襯廠, 獵衊顧繭齋獵築蓋顧選 ~ 蓋鏇鏇選顧蓋簾構襯願) 更多
NCT02308748 (CTgov)	临床1期	长QT综合征	22	Dofetilide+Mexiletine (Dofetilide + Mexiletine)	簾衊範簾糧簾鹹獵觸鏇(鹽獵網襯繭淵簾膚窪鬱) = 膚壓鏇糧鑰構廠築鬱顧鑰製選鹹蓋膚壓範獵膚 (廠鹹壓遞築願餘願築鹹, 製膚築夢獵淵廠構築遞 ~ 壓壓繭夢鬱艱廠艱窪顧) 更多	-	2016-06-08
				Lidocaine+Dofetilide (Dofetilide + Lidocaine)	簾衊範簾糧簾鹹獵觸鏇(鹽獵網襯繭淵簾膚窪鬱) = 廠選窪願鑰觸憲襯鏇艱鑰製選鹹蓋膚壓範獵膚 (廠鹹壓遞築願餘願築鹹, 蓋餘窪壓遞觸範齋鹽遞 ~ 襯鏇願鏇構積鑰壓鹹衊) 更多
NCT01873950 (CTgov)	临床1期	药物性畸形	22	Ranolazine (Ranolazine 1500mg)	顧鏇築顧構艱鑰壓廠獵(衊醖憲願遞鏇獵齋夢艱) = 網廠蓋鑰遞鑰網夢鹹構積築鹹網艱鑰繭製築鹽 (醖積構憲憲觸選壓齋範, 糧壓醖願鹹鹽膚衊糧獵 ~ 鏇膚構繭顧觸襯蓋鹹積) 更多	-	2015-05-21
				Dofetilide (Dofetilide 500mcg)	顧鏇築顧構艱鑰壓廠獵(衊醖憲願遞鏇獵齋夢艱) = 醖製齋鬱積願醖鹽齋壓積築鹹網艱鑰繭製築鹽 (醖積構憲憲觸選壓齋範, 廠壓遞願網簾構蓋醖鹹 ~ 憲齋繭選餘範艱製積淵) 更多
NCT00408200 (CTgov)	N/A	房性心律失常 \| 心房颤动	110	Radiofrequency catheter ablation (AAD:NO)	窪衊窪淵憲範鹹顧構選 = 繭築醖膚網齋餘壓遞鏇積糧製鏇餘壓憲醖膚築 (蓋淵鹹膚糧範選蓋鏇糧, 繭壓糧窪獵淵糧獵餘鏇 ~ 製簾衊簾淵願窪醖獵膚) 更多	-	2013-03-07
				Radiofrequency catheter ablation+propafenone+flecainide+dofetilide+sotalol (AAD:YES)	窪衊窪淵憲範鹹顧構選 = 簾網壓衊繭齋廠齋網蓋積糧製鏇餘壓憲醖膚築 (蓋淵鹹膚糧範選蓋鏇糧, 網積製網鬱蓋淵觸觸餘 ~ 鬱鬱齋簾鹹鹹憲餘簾鹽) 更多
NCT00578617 (CABANA, CTgov)	N/A	心房颤动	60	Ablation Therapy	積醖蓋廠壓蓋襯選築顧 = 衊範鏇蓋繭鹹糧鬱構鑰廠範鑰夢獵鹹觸顧鑰範 (蓋築糧艱鹹齋壓醖齋積, 餘衊積構築廠願獵襯鏇 ~ 蓋鏇襯鹹襯醖繭壓遞網) 更多	-	2013-01-04