This research will determine if: 1) Oral progesterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in postmenopausal women 50 years of age or older, and 2) Transdermal testosterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in men 65 years of age or older. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Men 65 years of age or older. Study 1: Each postmenopausal woman will take progesterone or placebo capsules for 1 week. After a 14-day "washout" (no progesterone or placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1 week. After 7 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be compared. Study 2: Each man 65 years of age or older will apply transdermal testosterone or transdermal placebo gel for 3 days. After a 7-day "washout" (no testosterone or placebo) each subject will then apply the alternative therapy (testosterone or placebo gel) for 1 week. After 3 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the testosterone and placebo phases will be compared.

开始日期2021-09-02

申办/合作机构

Indiana University

[+4]

NCT03834883

/ Completed临床4期IIT

Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

This research will determine if oral progesterone attenuates drug-induced QT interval lengthening in a) Postmenopausal women 50 years of age or older, and b) Premenopausal women studied during the ovulation phase of the menstrual cycle. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Premenopausal women. Each subject will take progesterone or placebo capsules for 1 week. After a two-week "washout" (no progesterone or placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1 week. After 7 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be compared

开始日期2019-03-26

申办/合作机构

Indiana University

[+2]

NCT03370536

/ TerminatedN/AIIT

Panoramic ECGi to Guide Ablation of Non-Paroxysmal AF: Effect of Ibutilide on AF Source Location and Organization

This is a prospective, multi-center, non-randomized, un-blinded, observational trial.

开始日期2017-11-01

申办/合作机构

Icahn School of Medicine at Mount Sinai

[+1]

100 项与富马酸伊布利特相关的临床结果

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100 项与富马酸伊布利特相关的转化医学

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100 项与富马酸伊布利特相关的专利（医药）

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390

项与富马酸伊布利特相关的文献（医药）

2025-01-01·INTERNATIONAL JOURNAL OF CARDIOLOGY

Drug-induced increase in dispersion of ventricular repolarization in patients with heart failure with preserved ejection fraction

Article

作者: Alhurayri, Fatimah ; Kovacs, Richard J ; Overholser, Brian R ; Sowinski, Kevin M ; Tisdale, James E ; Jaynes, Heather A

BACKGROUND:

Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with enhanced response to drug-induced QT interval lengthening. We determined the influence of HFpEF on drug-induced lengthening of dispersion of repolarization, a measure of proarrhythmic risk.

METHODS:

We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched controls without HF. Twelve‑lead electrocardiograms were obtained prior to ibutilide and serially for 8 h post-ibutilide. Tpeak-Tend, a measure of dispersion of ventricular repolarization, and heart rate-corrected J-Tpeak (J-Tpeakc), representing early repolarization, were measured by an investigator blinded to study groups.

RESULTS:

Baseline (pre-ibutilide) Tpeak-Tend and J-Tpeakc were not significantly different in the HFpEF and control groups. Maximum Tpeak-Tend was longer in the HFpEF group than in the control group (85 ± 10 vs 73 ± 8 ms, p = 0.01). Additionally, % change from baseline in Tpeak-Tend was greater in the HFpEF group [median (IQR) 17 (11) vs 8 (3)%, p = 0.003]. The area under the effect curve from 0 to 8 hours following ibutilide (including the 10-minute infusion) (AUEC_0-8.17) for Tpeak-Tend was also larger in the HFpEF group (600 ± 42 vs. 543 ± 49 ms•hr, p = 0.03). Maximum J-Tpeakc, % change from baseline in J-Tpeakc and AUEC_0-8.17 for J-Tpeakc in the two groups were not significantly different.

CONCLUSION:

HFpEF is associated with enhanced response to drug-induced increases in dispersion of repolarization.

2025-01-01·JACC-Clinical Electrophysiology

Effect of the Membrane Environment on Pharmacologic Inhibition of hERG K+ Channel Activity

Article

作者: Fiore, Chase M ; Vorobyov, Igor ; Clancy, Colleen E ; Quigley, Kate ; Harvey, Robert D

BACKGROUND:

hERG encodes K_V11.1 voltage-gated K⁺ channels, which generate the rapidly activating delayed rectifier K⁺ current that contributes to repolarization of the cardiac action potential. In addition to being targeted by many class III antiarrhythmic agents, these channels are also inhibited by a multitude of other pharmacological compounds, which can produce acquired long QT syndrome, leading to polymorphic ventricular tachycardia. While most drugs are thought to interact with a hydrophilic binding site in the channel pore, it has been postulated that some compounds act by perturbing the membrane environment or acting at hydrophobic sites accessed through the plasma membrane.

OBJECTIVES:

Because hERG channels reside in cholesterol rich lipid raft domains, we hypothesized that disrupting the membrane environment by depleting cholesterol might alter inhibition of channel activity by certain drugs.

METHODS:

We tested our hypothesis by examining the effect that depleting membrane cholesterol with methyl-β-cyclodextrin has on the ability of several compounds to inhibit hERG channels expressed in HEK293 cells.

RESULTS:

We found that cholesterol depletion significantly increased the sensitivity of the whole cell current to inhibition by ibutilide, while decreasing the currents sensitivity to dofetilide and amiodarone at negative membrane potentials.

CONCLUSIONS:

These results support the idea that the lipid environment of the plasma membrane plays a role in the ability of certain drugs to inhibit hERG channel activity. Differences in membrane cholesterol content may affect the ability of some hERG channel blockers to produce arrhythmogenic behavior.

2024-12-30·Indian Journal of Critical Care Medicine

Clinical Efficacy and Safety of Ibutilide in Cardioversion of Atrial Fibrillation or Flutter in Indian Patients: A Multicenter Study

Article

作者: Chaudhary, Janaki ; Dewan, Bhupesh ; Navale, Sanjaykumar ; Shinde, Siddheshwar

Aim and background:

To assess the efficacy and safety of Ibutilide infusion for cardioversion of atrial fibrillation (AF) or flutter (AFL) to sinus rhythm.

Materials and methods:

This open-label, multicenter phase IV study was conducted at six sites across India. The study enrolled 120 patients (108 with AF, 12 with AFL), each receiving up to two, 10-minute intravenous doses of 1.0 mg Ibutilide. The primary endpoints were the proportion of patients achieving cardioversion and the mean time taken to achieve cardioversion. Secondary endpoints included the proportion of patients maintaining sinus rhythm at 24 hours and the incidence of adverse events.

Results:

The cardioversion rate at 4 hours post-Ibutilide infusion among 120 patients was 65.83% (n = 79), with an average conversion time of 35.12 ± 36.71 minutes. At 24 hours, 85 patients (70.8%) had successful cardioversion, with a mean time of 107.24 minutes. The majority of patients (71.76%) had achieved cardioversion within 30 minutes. Of the 85 patients who achieved successful conversion, 82 (68.3%) maintained sinus rhythm at 24 hours. A total of 66 patients (55%) achieved cardioversion with the first bolus whereas 19 (15.8%) needed a second bolus. Atrial fibrillation patients had a higher conversion rate (75%) compared to AFL patients (33%). A total of 10 adverse events were recorded in eight patients (6.67%), including nausea, headache, palpitations, and bradycardia. Three severe cardiac events, one case of ventricular tachycardia, and two of tachycardia necessitated discontinuation of Ibutilide. No fatalities or serious adverse events (SAE) were reported.

Conclusion:

Ibutilide was found to be effective and well-tolerated for rapid restoration of sinus rhythm in patients with AF or AFL.

Clinical Trial Registry of India:

CTRI/2018/01/011248.

How to cite this article:

Dewan B, Navale S, Shinde S, Chaudhary J. Clinical Efficacy and Safety of Ibutilide in Cardioversion of Atrial Fibrillation or Flutter in Indian Patients: A Multicenter Study. Indian J Crit Care Med 2025;29(1):45-51.

项与富马酸伊布利特相关的新闻（医药）

2025-03-23

·微信

CardioGenAI：基于机器学习的药物再设计框架，以降低 hERG 风险

买科研服务（代计算、代测试、超算机时），送老李校长“科研理工男士情感课” 第一性原理计算解决50年悬而未决难题：半导体中铜为何扩散更快？ Ab initio及第一性原理入门参考书介绍《海贼王》告诉你，做科研为什么不能闭门造车…… 985博导亲测：用DeepSeek写国自然本子，3天完成30天工作量来自公众号：AIDD Pro 本文以传播知识为目的，如有侵权请后台联系我们，我们将在第一时间删除。在新药研发过程中， hERG 通道抑制与 QT 间期延长及心律失常密切相关，许多潜在药物因此被迫终止开发。为了解决这一问题，耶鲁大学和辉瑞公司的研究团队开发了一个基于机器学习的框架CardioGenAI，能够精准预测化合物对hERG、NaV1.5和CaV1.2离子通道的影响，设计在降低hERG风险的同时保留原有药理活性的分子。CardioGenAI作为一个开放源码工具，不仅可用于优化潜在药物的心脏安全性，挽救因hERG毒性受限的研发项目，还能作为高效的虚拟筛选方案，助力新药设计，加速从计算机模拟到临床应用的转化。 CardioGenAI框架概述 CardioGenAI框架结合了生成模型与判别模型，用于重新设计具有hERG活性的化合物，以减少其对hERG通道的抑制作用，同时保留原有的药理活性。该框架采用Transformer解码器模型，基于一个包含约500万条有效SMILES字符串的数据集进行训练。该数据集来源于ChEMBL33、GuacaMolv1、MOSES和BindingDB等公开数据库。训练后的模型能够在指定的分子骨架和物理化学性质条件下生成有效化合物。对于输入的 hERG 活性化合物，生成过程会依据其骨架和物理化学属性进行优化（图1）。随后，生成的化合物将根据其对 hERG、NaV1.5 和 CaV1.2 通道的活性进行筛选。具体而言，框架通过分类模型筛选出 hERG 非抑制剂（pIC50 ≤ 5.0），或利用回归模型筛选出活性处于特定 pIC50 值范围内的化合物。所有筛选后的候选化合物都会经过进一步的结构冗余性处理。首先，利用RDKit描述符模块计算每个化合物的209个二维化学描述符，并通过计算每对描述符之间的互信息来去除冗余描述符。随后，计算输入分子与每个筛选后候选化合物之间的余弦相似度，从而识别出与输入化合物在化学结构上最相似的候选分子。图1 CardioGenAI框架辨别模型如图2所示，每个化合物通过三种不同的表征方式进行处理：首先，使用双向Transformer从SMILES字符串中提取256维特征向量，捕捉分子结构的语法信息；其次，采用摩根算法生成1024位扩展连接指纹（ECFP4），以表示分子的拓扑结构；最后，将化合物转化为图表示，其中节点代表原子，边代表化学键。每个节点的特征包括原子类型、极性、氢键受体/供体、芳香性等信息。SMILES特征向量和ECFP4指纹分别通过两层前馈神经网络进行处理，而图表示则通过图注意力网络（Graph Attention Network, GAT）进行处理，节点特征通过自注意力机制进行加权聚合。所有表征后的特征会被拼接在一起，并通过两层前馈神经网络进行最终预测。图2 分子表征方式与其他已有的预测模型相比，该模型在hERG基准测试的二分类任务中表现更优，验证了其在CardioGenAI框架中的优势。同时，该模型在NaV1.5和CaV1.2的基准测试中也展现出良好性能。作者进一步利用DrugCentral数据库中的FDA批准药物对模型进行评估，在1692种药物中，模型预测504种为hERG阻滞剂、764种为NaV1.5阻滞剂、400种为CaV1.2阻滞剂，且预测结果与已知药物的作用机制高度一致。此外，模型鉴定出11种hERG pIC50预测值超过7.0的药物，其中大多数预测值与实验结果一致，仅少数因训练集中高pIC50样本不足而存在偏差。虽然CardioGenAI 框架的判别模型具备良好预测性能，但受实验数据差异和训练数据偏倚影响，可能存在预测精度上限及泛化能力限制。表1 分类模型与其他现有模型在hERG、NaV1.5和CaV1.2上的评估结果生成模型训练数据集结合了来自ChEMBL33、GuacaMol v1、MOSES和BindingDB的所有有效SMILES字符串，最终数据集包含约550万条SMILES字符串。组合后的数据集最初包含196个唯一标记的词汇表。去除了包含至少一个在数据集中出现次数少于1000次的token（元素）的SMILES字符串，这些通常包含稀有过渡金属或同位素。99.99%的SMILES包含133个或更少的tokens，为提高计算效率，删除超过133个tokens的SMILES，少于133个SMILES则使用填充token进行补齐，并添加了开始token“[CLS]”和结束token“[EOS]”。数据集被随机划分为训练集（95%）和验证集（5%）。生成模型包括自回归Transformer和双向Transformer。自回归Transformer考虑了SMILES字符串、分子骨架和物理化学属性，而双向Transformer仅考虑SMILES字符串。案例分析 Pimozide是FDA批准的抗精神病药物，主要用于治疗Tourette综合症及其他精神疾病。尽管具有药效，但pimozide会引起QT间期延长和室性心律失常，且与患者的突发死亡事件相关。研究表明，pimozide对hERG通道具有较高的亲和力，IC50值约为18nM，提示它可能通过与心脏钾离子通道结合导致不良心脏反应。因此，开发更安全的替代药物，降低其hERG活性，同时保留药效，成为亟待解决的挑战。本研究采用CardioGenAI框架，通过重新设计pimozide分子来减少其对hERG的抑制作用。作者以pimozide的分子骨架和物理化学特性为基础，生成了一系列新的化合物，并通过PCA分析确认这些化合物在物理化学性质上与pimozide高度相似，但hERG活性显著降低。最终筛选出100个符合条件的化合物，其hERGpIC50值范围从4.64到6.00，平均值为5.59，成功实现了降低hERG活性的目标（图3）。图3 CardioGenAI 框架应用于Pimozide的优化进一步的数据库比对发现，筛选出的100个化合物中，有一个名为fluspirilene的化合物，如图4所示，其属于与Pimozide相同类别的药物（苯基甲烷类），在hERG pIC50值上显著低于Pimozide，实验值为5.638，进一步验证了CardioGenAI框架在药物优化中的巨大潜力，能够在保持药物药理特性的同时，显著降低hERG活性。图4 fluspirilene与Pimozide性质对比除了pimozide，作者还将CardioGenAI框架应用于nintedanib、ibutilide、halofantrine和astemizole等药物，结果表明，该框架能够针对每种药物成功生成理化性质相似且hERG通道活性显著降低的化合物。此外，考虑到调控NaV1.5和CaV1.2通道活性可能有助于缓解hERG通道阻滞引发的致心律失常风险，作者评估了CardioGenAI框架在调控NaV1.5和CaV1.2通道活性方面的能力。通过针对不同药物设定四种优化目标（提高或降低NaV1.5/CaV1.2活性），结果显示，该框架能够成功优化心脏离子通道活性至少一个数量级，同时保持化合物的理化性质不变（图5）。图5 CardioGenAI 框架应用于NaV1.5和CaV1.2的优化参考文献 Kyro GW, Martin MT, Watt ED, Batista VS. CardioGenAI: a machine learning-based framework for re-engineering drugs for reduced hERG liability. J Cheminform. 2025;17(1):30. Published 2025 Mar 5. doi:10.1186/s13321-025-00976-8 数据和代码 https://github.com/gregory-kyro/CardioGenAI

2023-03-14

·蒲公英Ouryao

参比制剂目录（第65批）正式发布！

‍‍‍‍转自：国家药监局编辑：wangxinglai20042023年03月14日，国家药监局发布了第65批次仿制药一致性评价参比制剂目录，其中新增品种67个、变更及增加持证商品种21个。通知原文经国家药品监督管理局仿制药质量和疗效一致性评价专家委员会审核确定，现发布仿制药参比制剂目录（第六十五批）。涉及品种：非那雄胺片、阿伐替尼片、布美他尼片、尼索地平缓释片、盐酸地尔硫卓缓释胶囊、吲哚美辛搽剂、雌二醇醋酸炔诺酮片、利伐沙班口崩片、低钙腹膜透析液（乳酸盐-G1.5%）、低钙腹膜透析液（乳酸盐-G2.5%）、注射用头孢唑肟钠、普伐他汀钠片、马来酸噻吗洛尔滴眼液、孟鲁司特钠咀嚼片、氯沙坦钾氢氯噻嗪片、卡波姆滴眼液、氯化镭[223Ra]注射液、注射用硫酸艾沙康唑、琥珀酰明胶电解质醋酸钠注射液、普拉左米星注射液、注射用盐酸曲拉西利、克拉考特酮乳膏、富马酸伊布利特注射液、木聚硫钠胶囊、米拉贝隆缓释干混悬剂、硫酸艾沙康唑胶囊、醋酸地非法林注射液、盐酸赛洛唑啉鼻用喷雾剂、盐酸多沙普仑注射液、聚乙烯醇滴眼液、丙酸交沙霉素糖浆剂、甲苯磺酸妥舒沙星片、布地奈德缓释胶囊、曲安奈德鼻喷雾剂、盐酸他喷他多片、氯化钾缓释胶囊、恩格列净利格列汀片、硫酸镁钠钾口服用浓溶液、盐酸奥昔布宁缓释片、二甲双胍恩格列净片等；仿制药参比制剂目录（第65批）（扫描二维码下载附件）仿制药参比制剂目录（第65批）‍‍

一致性评价

100 项与富马酸伊布利特相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00648	富马酸伊布利特	C01BD05	DB00308

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
心律失常	中国	蚌埠丰原涂山制药有限公司	2006-06-06
心房颤动	美国	Pfizer Inc.	1995-12-28
心房扑动	美国	Pfizer Inc.	1995-12-28

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临床结果

适应症

分期

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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


ATS2023	N/A	心房颤动一线	156	Ibutilide	襯繭壓淵糧網糧選壓獵(襯願衊衊廠鑰繭積鑰遞) = 餘觸製遞廠餘鬱積鏇獵構廠餘膚壓鏇築鑰餘構 (壓壓餘壓蓋簾網鑰淵餘 )	积极	2023-05-21
NCT01014741 (MAGIC-AF, CTgov)	N/A	心房颤动	200	Ibutilide (Ibutilide Arm)	壓鏇製膚衊積窪餘製廠 = 獵獵襯鏇鏇膚鏇醖鹽觸鑰網廠憲築願積選製齋 (蓋艱齋獵膚壓蓋鑰積鏇, 製鹽餘選網鹽鑰鹹夢觸 ~ 網膚膚蓋遞蓋窪艱膚鑰) 更多	-	2017-05-24
				Placebo (Placebo Arm)	壓鏇製膚衊積窪餘製廠 = 獵襯齋觸簾願艱憲築壓鑰網廠憲築願積選製齋 (蓋艱齋獵膚壓蓋鑰積鏇, 醖積獵積願簾鹽憲簾糧 ~ 繭觸獵窪積壓鑰廠遞構) 更多
NCT01447862 (Pubmed \| Europace)	临床4期	心房颤动	100	Vernakalant	蓋構鹽願築糧壓廠餘遞(簾衊蓋窪繭蓋壓憲淵範) = 遞鹽積窪蓋鏇襯醖網簾廠襯觸醖艱淵觸製膚鬱 (鹽築願窪鑰網膚壓範獵 ) 更多	积极	2017-02-01
				Ibutilide	蓋構鹽願築糧壓廠餘遞(簾衊蓋窪繭蓋壓憲淵範) = 鹹廠鹽蓋鹹憲鹹艱網鬱廠襯觸醖艱淵觸製膚鬱 (鹽築願窪鑰網膚壓範獵 ) 更多
NCT01014741 (Pubmed \| Eur Heart J)	N/A	心房颤动维持	200	Ibutilide	夢積製鬱膚築廠築窪鬱(衊廠範糧製網糧艱淵壓) = 鹹製廠鏇膚鹹簾襯願獵積範廠廠繭餘範積夢獵 (簾網選餘窪製淵繭蓋膚 )	-	2016-05-21
				Placebo	夢積製鬱膚築廠築窪鬱(衊廠範糧製網糧艱淵壓) = 簾憲範憲獵構膚壓鹽膚積範廠廠繭餘範積夢獵 (簾網選餘窪製淵繭蓋膚 )