A Phase I, Randomised, Open, Single-centre Study to Evaluate the Pharmacokinetics of Different Extended-release Formulations of AZD1305 When Given as Single and Repeated Oral Doses to Healthy Male Volunteers

The purpose of this study is to evaluate the pharmacokinetics of different extended-release formulations of AZD1305 when given as single and multiple oral doses to healthy male volunteers.

Start Date01 Aug 2009

Sponsor / Collaborator

AstraZeneca PLC

NCT00935025 / TerminatedPhase 1

A Single-center, Single-blind, Randomized, Placebo-controlled, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics After Single and Multiple Ascending Oral Doses of AZD1305 Extended-release Capsules in Healthy Male Japanese and Caucasian Subjects

This is a phase I, single-blind, randomized, placebo-controlled single and repeated ascending dose study to assess the safety, tolerability and pharmacokinetics with oral doses of AZD1305 extended-release capsules in healthy male Japanese and Caucasian subjects. Three (or four if needed) dose levels will be given to Japanese subjects and one of the doses will also be given to Caucasian subjects.

Start Date01 Jul 2009

Sponsor / Collaborator

AstraZeneca PLC

EUCTR2009-009862-15-CZ / Not yet recruitingNot Applicable

A double-Blind, Randomised, Placebo-Controlled, Multicentre, Dose-Escalating Study of AZD1305 Given Intravenoulsy for Cardioversion of Atrial Fibrillation

Start Date16 Jun 2009

Sponsor / Collaborator-

100 Clinical Results associated with VGKCs x VDCCs x SCNA

100 Translational Medicine associated with VGKCs x VDCCs x SCNA

0 Patents (Medical) associated with VGKCs x VDCCs x SCNA

152

Literatures (Medical) associated with VGKCs x VDCCs x SCNA

01 Dec 2024·Developmental Biology

Voltage-gated ion channel’s gene expression in the myocardium of embryo and adult chickens

Article

Author: Gonotkov, M A ; Lebedeva, E A ; Velegzhaninov, I O ; Furman, A A

The functioning of the cardiovascular system is critical for embryo survival. Cardiac contractions depend on the sequential activation of different classes of voltage-gated ion channels. Understanding the fundamental features of these interactions is important for identifying the mechanisms of pathologies development in the myocardium. However, at present there is no consensus on which ion channels are involved in the formation of automaticity in the early embryonic stages. The aim of this study was to elucidate the expression of genes encoding various types of ion channels that are involved in the generation of electrical activity chicken heart at different stages of ontogenesis. We analyzed the expression of 14 genes from different families of ion channels. It was revealed that the expression profiles of ion channel genes change depending on the stages of ontogenesis. The HCN4, CACNA1D, SCN1A, SCN5A, KCNA1 genes have maximum expression at the tubular heart stage. In adult, a switch occurs to the higher expression of CACNA1C, KCNH6, RYR and SLC8A1 genes. This data correlated with the results obtained by the microelectrode method. It can be assumed that the automaticity of the tubular heart is mainly due to the mechanism of the «membrane-clock» (hyperpolarization-activated current (I_f), Ca²⁺-current L-type (I_CaL), Na⁺-current (I_Na) and the slow component of the delayed rectifier K⁺-current (I_Ks)). Whereas in adult birds, the mechanism for generating electrical impulses is determined by both «membrane- clock» and «Ca²⁺-clock».

01 Oct 2024·Biomedicine & Pharmacotherapy

Nuciferine analogs block voltage-gated sodium, calcium and potassium channels to regulate the action potential and treat arrhythmia

Article

Author: Li, Peng ; Wang, Wen Ping ; Zhou, Ying Xun ; Hou, An Guo ; Ke, Jin ; Chen, Lin Yun ; Ma, Yun Shu ; Bin Jin, Wen ; Ou, Hui Ping

Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the I_Na and I_Ca without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC₅₀ values of 6a against Nav1.5 and Cav1.2 were 4.98 μM and 4.62 μM, respectively. Furthermore, 6a (10 μM) blocked I_Ks, I_K1, and I_to with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl₂ and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.

01 Sep 2024·International Journal of Biological Macromolecules

MultiCBlo: Enhancing predictions of compound-induced inhibition of cardiac ion channels with advanced multimodal learning

Article

Author: Wang, Tao ; Yao, Xiaojun ; Zou, Quan ; Zhuo, Linlin ; Du, Zhenya ; Fu, Xiangzheng

Predicting compound-induced inhibition of cardiac ion channels is crucial and challenging, significantly impacting cardiac drug efficacy and safety assessments. Despite the development of various computational methods for compound-induced inhibition prediction in cardiac ion channels, their performance remains limited. Most methods struggle to fuse multi-source data, relying solely on specific dataset training, leading to poor accuracy and generalization. We introduce MultiCBlo, a model that fuses multimodal information through a progressive learning approach, designed to predict compound-induced inhibition of cardiac ion channels with high accuracy. MultiCBlo employs progressive multimodal information fusion technology to integrate the compound's SMILES sequence, graph structure, and fingerprint, enhancing its representation. This is the first application of progressive multimodal learning for predicting compound-induced inhibition of cardiac ion channels, to our knowledge. The objective of this study was to predict the compound-induced inhibition of three major cardiac ion channels: hERG, Cav1.2, and Nav1.5. The results indicate that MultiCBlo significantly outperforms current models in predicting compound-induced inhibition of cardiac ion channels. We hope that MultiCBlo will facilitate cardiac drug development and reduce compound toxicity risks. Code and data are accessible at: https://github.com/taowang11/MultiCBlo. The online prediction platform is freely accessible at: https://huggingface.co/spaces/wtttt/PCICB.

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