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 x Potassium channel

100 Translational Medicine associated with VGKCs x VDCCs x SCNA x Potassium channel

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

164

Literatures (Medical) associated with VGKCs x VDCCs x SCNA x Potassium channel

30 Mar 2025·Circulation Journal

Clinical Impact of Genetic Testing for Long QT Syndrome　― Evidence From a Nationwide LQTS Registry in Japan ―

Article

Author: Yoshida, Yoko ; Ueno, Michihiko ; Ninomiya, Yumiko ; Fukuyama, Megumi ; Kaneko, Yoshiaki ; Takamuro, Motoki ; Horigome, Hitoshi ; Kato, Koichi ; Kosho, Tomoki ; Takegami, Misa ; Kato, Yoshiaki ; Nishimura, Kunihiro ; Hayashi, Kenshi ; Shimizu, Wataru ; Aiba, Takeshi ; Hayabuchi, Yasunobu ; Inden, Yasuya ; Otsuki, Sou ; Nakajima, Tadashi ; Yoshinaga, Masao ; Sakaguchi, Heima ; Ohno, Seiko ; Yagihara, Nobue ; Murakami, Takashi ; Sumitomo, Naokata ; Takahashi, Tatsunori ; Morita, Hiroshi ; Sonoda, Keiko ; Asano, Yoshihiro ; Watanabe, Shigeo ; Shimamoto, Keiko ; Muraji, Shota ; Horie, Minoru ; Ida, Kazufumi ; Makiyama, Takeru ; Ohta, Kunio ; Kusano, Kengo ; Nabeshima, Taisuke

BACKGROUNDGenetic testing for long QT syndrome (LQTS) is useful for diagnosis, risk stratification, and therapeutic strategies. This study investigated the clinical impact of genetic testing for LQTS patients.METHODS AND RESULTSTotal 3,851 patients (proband: 2,316 [60%]; female: 2,283 [59%]; median age: 14 years [interquartile range 9-36 years]) diagnosed with LQTS (LQTS score ≥3.5, QTc ≥500 ms, pathogenic variants in LQTS-associated genes, or unexplored syncope with QTc 480-499 ms) were enrolled in this study. Of these patients, 1,146 (29.8%) experienced syncope and 322 (8.5%) experienced ventricular fibrillation (VF) or cardiopulmonary arrest (CPA) at ≤70 years of age. Genetic testing using a next-generation sequencing panel and/or Sanger sequencing was performed for 3,770 (98%) patients, genotype was then identified in the following LQTS-associated genes: KCNQ1 (45%), KCNH2 (34%), SCN5A (8%), KCNE1 (0.1%), KCNE2 (0.03%), KCNJ2 (2.7%), CACNA1C (1.2%), and CALM1,2 (0.3%). Forty-seven (1.2%) patients had double or compound heterozygous variants in LQTS-associated genes, whereas the genotype remained unknown in 220 (5.8%) patients. When comparing phenotype with genotype, QTc was significantly longer in CALM1,2 patients than in others except for CACNA1C, whereas QTc was almost normal in KCNJ2 patients. The incidence of the first cardiac event (syncope, VF/CPA) differed among the genotypes, and prognosis was significantly worse for CALM1,2 patients.CONCLUSIONSComprehensive genetic testing, including non-major LQTS genes, is important for diagnosis and risk stratification of LQTS.

01 Feb 2025·Toxicological Sciences

In vitro human ion channel assays predictive of drug-induced seizure

Article

Author: Sharma, Ashok K ; Cohen, Jennifer D ; Cai, Beibei ; You, Dahea ; Sales, Vicencia T ; Takai, Takafumi ; Hara, Hideto ; Yukawa, Tomoya

AbstractSeizure is among the most severe FDA black box warnings of neurotoxicity reported on drug labels. Gaining a better mechanistic understanding of off-targets causative of seizure will improve the identification of potential seizure risks preclinically. In the present study, we evaluated an in vitro panel of 9 investigational (Cav2.1, Cav3.2, GlyRA1, AMPA, HCN1, Kv1.1, Kv7.2/7.3, NaV1.1, Nav1.2) and 2 standard (GABA-A, NMDA) ion channel targets with strong correlative links to seizure, using automated electrophysiology. Each target was assessed with a library of 34 preclinical compounds and 10 approved drugs with known effects of convulsion in vivo and/or in patients. Cav2.1 had the highest frequency of positive hits, 20 compounds with an EC30 or IC30 ≤ 30 µM, and the highest importance score relative to the 11 targets. An additional 35 approved drugs, with categorized low to frequent seizure risk in patients, were evaluated in the Cav2.1 assay. The Cav2.1 assay predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 52% and specificity of 78%, and approved drugs to cause seizure in nonclinical species or in patients with a sensitivity of 48% or 54% and specificity of 71% or 78%, respectively. The integrated panel of 11 ion channel targets predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 68%, specificity of 56%, and accuracy of 65%. This study highlights the utility of expanding the in vitro panel of targets evaluated for seizurogenic activity, in order to reduce compound attrition early on in drug discovery.

01 Feb 2025·Apoptosis

The gut microbial metabolite phenylacetylglutamine increases susceptibility to atrial fibrillation after myocardial infarction through ferroptosis and NLRP3 inflammasome

Article

Author: Lu, Shimin ; Gong, Yang ; Yang, Hongjie ; Kong, Bin ; Shuai, Wei ; Wang, Guangji ; He, Qin

Myocardial infarction (MI) is an important risk factor for the development of atrial fibrillation (AF), and the gut microbial metabolite phenylacetylglutamine (PAGln) is strongly associated with the prognosis of MI patients. However, whether PAGln is involved in the regulation of AF after MI is currently unknown. Therefore, the present study aimed to explore the effect of PAGln on the susceptibility to AF after MI. MI model was constructed by surgically ligating the left anterior descending branch of the coronary artery. PAGln was administered by intraperitoneal injection for 7 consecutive days starting after surgery and then investigated by histopathologic, molecular biological, and electrophysiologic studies. Myocardial ischemia resulted in intestinal barrier dysfunction and significantly increased circulating levels of PAGln. Compared with the myocardial ischemia group, administration of PAGln significantly exacerbated atrial fibrosis and atrial electrical remodeling in mice after myocardial ischemia, as evidenced by shortening of the ERP (at varying pacing cycle lengths of 40, 60, 80, and 100), ion channel remodeling (Nav1.5, Cav1.2, and Kv1.5), and decreased expression of CX40, which led to an increase in the susceptibility to AF (54.5% vs. 90.9%, P < 0.05). In addition, administration of PAGln further exacerbated MI-induced intestinal barrier dysfunction compared with the MI group. Mechanistically, PAGln may affect atrial remodeling and AF susceptibility after MI by modulating ferroptosis and NLRP3 inflammasome. The present study preliminarily reveals that the gut microbial metabolite PAGln exacerbates post-MI AF remodeling and AF susceptibility, possibly through ferroptosis and activation of NLRP3 inflammasome.

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