A randomized, double blind, placebo-controlled, parallel, international multicenter study assessing the efficacy of S066913 in patients with paroxysmal atrial fibrillation Double-blind, International study AssessinG efficacy of S 066913 in paRoxysmal Atrial Fibrillation – IKur inhibitor (DIAGRAF - IKUR) - DIAGRAF-IKur

开始日期2015-02-17

申办/合作机构

Institut de Recherches Intern Servier

EUCTR2013-004456-38-GB / Not yet recruitingN/A

A double blind, randomised, placebo-controlled, crossover study assessing the use of XEN D0103 in patients with paroxysmal atrial fibrillation and implanted pacemakers allowing continuous beat-to-beat monitoring of drug efficacy

开始日期2014-04-11

申办/合作机构

Xention Ltd.

NCT02390258 / Completed临床1期

A Single Centre, Randomised, Double-blind, Placebo-controlled, Fed-fasted, Single and Multiple Ascending Dose Trial of XEN-D0103 in Healthy Subjects

This study is an evaluation of the safety and tolerability of XEN-D0103 in healthy subjects. Part 1 assesses the safety, tolerability and blood levels of the ascending single doses of XEN-D0103. Blood levels of XEN-D0103 will be assessed when administered with food and also without food in Part 2. The safety, tolerability and blood levels of XEN-D0103 will be assessed following dosing for 10 days in Part 3.

开始日期2011-07-01

申办/合作机构

Xention Ltd.

100 项与 XEN-D0103 相关的临床结果

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100 项与 XEN-D0103 相关的转化医学

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100 项与 XEN-D0103 相关的专利（医药）

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项与 XEN-D0103 相关的文献（医药）

2022-02-21·Cardiovascular Research1区 · 医学

Novel insights into the electrophysiology of murine cardiac macrophages: relevance of voltage-gated potassium channels

1区 · 医学

Article

作者: Schneider-Warme, Franziska ; Fernández, Marbely C ; Simon-Chica, Ana ; Ravens, Ursula ; Wülfers, Eike M ; Hilgendorf, Ingo ; Seemann, Gunnar ; Kohl, Peter ; Lother, Achim

AbstractAimsMacrophages (MΦ), known for immunological roles, such as phagocytosis and antigen presentation, have been found to electrotonically couple to cardiomyocytes (CM) of the atrioventricular node via Cx43, affecting cardiac conduction in isolated mouse hearts. Here, we characterize passive and active electrophysiological properties of murine cardiac resident MΦ, and model their potential electrophysiological relevance for CM.Methods and resultsWe combined classic electrophysiological approaches with 3D florescence imaging, RNA-sequencing, pharmacological interventions, and computer simulations. We used Cx3cr1eYFP/+ mice wherein cardiac MΦ are fluorescently labelled. FACS-purified fluorescent MΦ from mouse hearts were studied by whole-cell patch-clamp. MΦ electrophysiological properties include: membrane resistance 2.2±0.1 GΩ (all data mean±SEM), capacitance 18.3±0.1 pF, resting membrane potential −39.6±0.3 mV, and several voltage-activated, outward or inwardly rectifying potassium currents. Using ion channel blockers (barium, TEA, 4-AP, margatoxin, XEN-D0103, and DIDS), flow cytometry, immuno-staining, and RNA-sequencing, we identified Kv1.3, Kv1.5, and Kir2.1 as channels contributing to observed ion currents. MΦ displayed four patterns for outward and two for inward-rectifier potassium currents. Additionally, MΦ showed surface expression of Cx43, a prerequisite for homo- and/or heterotypic electrotonic coupling. Experimental results fed into development of an original computational model to describe cardiac MΦ electrophysiology. Computer simulations to quantitatively assess plausible effects of MΦ on electrotonically coupled CM showed that MΦ can depolarize resting CM, shorten early and prolong late action potential duration, with effects depending on coupling strength and individual MΦ electrophysiological properties, in particular resting membrane potential and presence/absence of Kir2.1.ConclusionOur results provide a first electrophysiological characterization of cardiac resident MΦ, and a computational model to quantitatively explore their relevance in the heterocellular heart. Future work will be focussed at distinguishing electrophysiological effects of MΦ–CM coupling on both cell types during steady-state and in patho-physiological remodelling, when immune cells change their phenotype, proliferate, and/or invade from external sources.

2019-01-01·European Heart Journal - Cardiovascular Pharmacotherapy1区 · 医学

A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation

1区 · 医学

Article

作者: Vandzhura, Victoria ; Ni, Yongbin ; Maison-Blanche, Pierre ; Kowey, Peter R ; Hohnloser, Stefan H ; Dorian, Paul ; Tyl, Benoît ; Camm, A John ; Sanders, Prashanthan ; de Melis, Mirko

AimsAntiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects.Methods and resultsA randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up.ConclusionsDIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.

2018-04-01·Journal of Interventional Cardiac Electrophysiology4区 · 医学

A double-blind, randomised, placebo-controlled, cross-over study assessing the use of XEN-D0103 in patients with paroxysmal atrial fibrillation and implanted pacemakers allowing continuous beat-to-beat monitoring of drug efficacy

4区 · 医学

Article

作者: Sugihara, Conn ; Sulke, Neil ; Shunmugam, S R ; Furniss, Steve ; Freemantle, Nick ; Round, Patrick

PURPOSEThe ultrarapid delayed rectifier current (I_Kur) carried by Kv1.5 channels, which are solely expressed in the atrium, is a potential target for safer treatment of paroxysmal atrial fibrillation (PAF). XEN-D0103 is a nanomolar ion channel blocker that selectively inhibits potassium ion flux through the Kv1.5 ion channel. The efficacy of XEN-D0103 in reducing AF burden was assessed in patients with DDDRp permanent pacemakers (PPMs) and PAF.METHODSA double-blind, placebo-controlled, cross-over study was performed in patients with PAF and DDDRp PPMs with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up. All anti-arrhythmic drugs were withdrawn before randomised treatment. After baseline assessment, patients were randomly assigned to two treatment periods of placebo then XEN-D0103 50 mg bd, or XEN-D0103 50 mg bd then placebo.RESULTSFifty-four patients were screened and 21 patients were eligible and included in the randomised trial. All 21 patients completed both treatment periods. The primary endpoint was change in AF burden assessed by PPM. There was no significant difference in AF burden on treatment with XEN-D0103 versus placebo. There was a reduction in the mean frequency of AF episodes (relative reduction 0.72, 95% CI 0.66 to 0.77; p < 0.0001). XEN-D0103 was safe and well tolerated, and there were no serious adverse events. XEN-D0103 did not have any apparent effect on heart rate compared to placebo.CONCLUSIONSXEN-D0103 did not reduce AF burden in patients with PAF and dual chamber pacemakers providing beat-to-beat monitoring. XEN-D0103 was well tolerated and did not have any apparent effect on heart rate. Although single-ion channel blockade with XEN-D0103 did not affect AF in this study, there might be a potential for this agent to be used in combination with other atrially specific drugs in the treatment of AF.EUDRACT TRIAL REGISTRATION NUMBER2013-004456-38.

100 项与 XEN-D0103 相关的药物交易

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研发状态

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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	临床2期	波兰	-	-
心房颤动	临床2期	英国	Xention Ltd.	-
心房颤动	临床2期	荷兰	-	-
心房颤动	临床2期	-	Xention Pharma Ltd.	-
心房颤动	临床2期	丹麦	-	-
心房颤动	临床2期	斯洛伐克	-	-
心房颤动	临床2期	瑞典	-	-
心房颤动	临床2期	捷克	-	-