Delving into the Latest Updates on Xention Ltd. with Synapse

The purpose of this study is to compare the pharmacokinetics of capsule and tablet formulations of TA-8995 in healthy male subjects aged 18 to 55 years.

开始日期2015-07-01

申办/合作机构

Xention Ltd.

NCT02408055 / Completed临床1期

A Phase I Study to Assess the Mass Balance Recovery, Pharmacokinetics, Metabolism and Excretion of 14C-TA-8995 in Healthy Male Subjects

A study to measure the absorption, metabolism and excretion of a single dose of radiolabelled TA-8995 (10mg) in healthy male subjects.

开始日期2015-06-01

申办/合作机构

Xention Ltd.

NCT02241772 / Completed临床1/2期

A Study on the Effects of TA-8995 on Lp(a) in Subjects With Elevated Lp(a)

A study in males and females with elevated Lp(a) to look at the effects of TA-8995 on Lp(a) levels.

开始日期2014-09-01

申办/合作机构

Xention Ltd.

100 项与 Xention Ltd. 相关的临床结果

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18

项与 Xention Ltd. 相关的文献（医药）

2022-02-01·Heart Rhythm O2

Pharmacological inhibition of acetylcholine-regulated potassium current (IK,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events

Article

作者: Saljic, Arnela ; Linz, Benedikt ; Linz, Dominik ; Jespersen, Thomas ; Thostrup, Anne Hauge ; Milnes, James ; Rombouts, Karlijn ; Tfelt-Hansen, Jacob ; Hohl, Mathias ; Hertel, Julie Norup

BACKGROUNDIn obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.OBJECTIVETo investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (I _K,ACh) activated by the M₂ receptor.METHODSIn sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced I _K,ACh activation, protein levels of protein kinase C (PKC_Ɛ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an I _K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.RESULTSIn vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKC_Ɛ content relative to cytosolic levels. Upon INAP recovery, ratio of PKC_Ɛ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.CONCLUSIONShort-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKC_Ɛ translocation to LA membrane. Pharmacological I _K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I _K,ACh in the transient arrhythmogenic AF substrate in OSA.

2021-01-01·Journal of Biological Chemistry2区 · 生物学

A benzopyran with antiarrhythmic activity is an inhibitor of Kir3.1-containing potassium channels

2区 · 生物学

Article

作者: Noujaim, Sami F ; Logothetis, Diomedes E ; Thakur, Ganesh A ; Plant, Leigh D ; Masotti, Meghan ; Cantwell, Lucas ; Eptaminitaki, Giasemi C ; Alhamshari, Yaser ; Cui, Meng ; Chang, Mengmeng ; Abou-Assali, Obada ; Milnes, James ; Ei-Haou, Said ; Xu, Keman ; Tan, Haozhou

Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia and is associated with increased morbidity and mortality. Currently approved AF antiarrhythmic drugs have limited efficacy and/or carry the risk of ventricular proarrhythmia. The cardiac acetylcholine activated inwardly rectifying K⁺ current (I_KACh), composed of Kir3.1/Kir3.4 heterotetrameric and Kir3.4 homotetrameric channel subunits, is one of the best validated atrial-specific ion channels. Previous research pointed to a series of benzopyran derivatives with potential for treatment of arrhythmias, but their mechanism of action was not defined. Here, we characterize one of these compounds termed Benzopyran-G1 (BP-G1) and report that it selectively inhibits the Kir3.1 (GIRK1 or G1) subunit of the K_ACh channel. Homology modeling, molecular docking, and molecular dynamics simulations predicted that BP-G1 inhibits the I_KACh channel by blocking the central cavity pore. We identified the unique F137 residue of Kir3.1 as the critical determinant for the I_KACh-selective response to BP-G1. The compound interacts with Kir3.1 residues E141 and D173 through hydrogen bonds that proved critical for its inhibitory activity. BP-G1 effectively blocked the I_KACh channel response to carbachol in an in vivo rodent model and displayed good selectivity and pharmacokinetic properties. Thus, BP-G1 is a potent and selective small-molecule inhibitor targeting Kir3.1-containing channels and is a useful tool for investigating the role of Kir3.1 heteromeric channels in vivo. The mechanism reported here could provide the molecular basis for future discovery of novel, selective I_KACh channel blockers to treat atrial fibrillation with minimal side effects.

2020-08-01·Heart Rhythm O2

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Article

作者: McNiff, Cameron ; Choisy, Stéphanie C ; Cheng, Hongwei ; Milnes, James T ; James, Andrew F ; Mann, Brendan ; Caves, Rachel E ; Hancox, Jules C ; Clennell, Ben ; Carpenter, Alexander

BACKGROUNDAtrial-ventricular differences in voltage-gated Na⁺ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na⁺ channel blocker ranolazine that has been shown to be safe and well tolerated in patients.OBJECTIVEThe present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na⁺ currents.METHODSThe fast and late components of whole-cell voltage-gated Na⁺ currents (respectively, I _Na and I _NaL) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes.RESULTSAtrial I _Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I _Na. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I _NaL activated by 3 nM ATX-II (IC₅₀s ∼200 nM). Eleclazine (10 μM) inhibited I _Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I _Na from inactivation in both cell types.CONCLUSIONSDifferences exist between rat atrial and ventricular myocytes in the biophysical properties of I _Na. The more negative voltage dependence of I _Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

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