A Randomized, Double-Blind, Placebo-Controlled, Multiple Continuous Intravenous Injection, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of M201-A in Healthy Japanese Subjects

This Phase I is designed to evaluate the safety, tolerability and pharmacokinetics of multiple ascending doses of M201-A administered by multiple continuous intravenous injection in Healthy Japanese subjects.

Start Date30 Mar 2020

Sponsor / Collaborator

Kitasato University

[+1]

NCT04609059 / Unknown statusPhase 2IIT

First-in-Patient Study for Sing le Dose of M201-A Hydrochloride Injection in Japanese Patients With Paroxysmal Atrial Fibrillation

First-in-Patient Study for sing le dose of M201-A hydrochloride injection in Japanese patients with paroxysmal atrial fibrillation.

Start Date07 May 2019

Sponsor / Collaborator

Kitasato University

[+1]

NCT03055403 / CompletedPhase 1IIT

A Randomized, Double-Blind, Placebo-Controlled, Single Continuous Intravenous Injection, Dose Escalation, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of M201-A in Healthy Japanese Subjects

This Phase I first-in-human is designed to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of M201-A administered by single continuous intravenous injection in Healthy Japanese subjects.

Start Date17 Feb 2017

Sponsor / Collaborator

Kitasato University

[+1]

100 Clinical Results associated with RYR1 x RYR2 x RYR3

100 Translational Medicine associated with RYR1 x RYR2 x RYR3

0 Patents (Medical) associated with RYR1 x RYR2 x RYR3

122

Literatures (Medical) associated with RYR1 x RYR2 x RYR3

12 Mar 2023·International journal of molecular sciences

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.

Article

Author: Gaburjakova, Marta ; Gaburjakova, Jana

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. The therapeutic effect of dantrolene is the result of a direct inhibitory action on the RyR1 channel, thus suppressing aberrant Ca²⁺ release from the sarcoplasmic reticulum. Despite the almost identical dantrolene-binding sequence exits in all three mammalian RyR isoforms, dantrolene appears to be an isoform-selective inhibitor. Whereas RyR1 and RyR3 channels are competent to bind dantrolene, the RyR2 channel, predominantly expressed in the heart, is unresponsive. However, a large body of evidence suggests that the RyR2 channel becomes sensitive to dantrolene-mediated inhibition under certain pathological conditions. Although a consistent picture of the dantrolene effect emerges from in vivo studies, in vitro results are often contradictory. Hence, our goal in this perspective is to provide the best possible clues to the molecular mechanism of dantrolene's action on RyR isoforms by identifying and discussing potential sources of conflicting results, mainly coming from cell-free experiments. Moreover, we propose that, specifically in the case of the RyR2 channel, its phosphorylation could be implicated in acquiring the channel responsiveness to dantrolene inhibition, interpreting functional findings in the structural context.

01 Dec 2022·Biochemical and Biophysical Research Communications

Hippocampal dendritic spines express the RyR3 but not the RyR2 ryanodine receptor isoform

Article

Author: Lobos, Pedro ; Vega-Vásquez, Ignacio ; Toledo, Jorge ; Paula-Lima, Andrea ; Hidalgo, Cecilia ; Adasme, Tatiana

The hippocampus is a brain region implicated in synaptic plasticity and memory formation; both processes require neuronal Ca²⁺ signals generated by Ca²⁺ entry via plasma membrane Ca²⁺ channels and Ca²⁺ release from the endoplasmic reticulum (ER). Through Ca²⁺-induced Ca²⁺ release, the ER-resident ryanodine receptor (RyR) Ca²⁺ channels amplify and propagate Ca²⁺ entry signals, leading to activation of cytoplasmic and nuclear Ca²⁺-dependent signaling pathways required for synaptic plasticity and memory processes. Earlier reports have shown that mice and rat hippocampus expresses mainly the RyR2 isoform, with lower expression levels of the RyR3 isoform and almost undetectable levels of the RyR1 isoform; both the RyR2 and RyR3 isoforms have central roles in synaptic plasticity and hippocampal-dependent memory processes. Here, we describe that dendritic spines of rat primary hippocampal neurons express the RyR3 channel isoform, which is also expressed in the neuronal body and neurites. In contrast, the RyR2 isoform, which is widely expressed in the neuronal body and neurites of primary hippocampal neurons, is absent from the dendritic spines. We propose that this asymmetric distribution is of relevance for hippocampal neuronal function. We suggest that the RyR3 isoform amplifies activity-generated Ca²⁺ entry signals at postsynaptic dendritic spines, from where they propagate to the dendrite and activate primarily RyR2-mediated Ca²⁺ release, leading to Ca²⁺ signal propagation into the soma and the nucleus where they activate the expression of genes that mediate synaptic plasticity and memory.

01 Jul 2022·Translational Cancer Research

Ryanodine receptor (RYR) mutational status correlates with tumor mutational burden, age and smoking status and stratifies non-small cell lung cancer patient prognosis

Article

Author: Xiong, Jian ; Xu, Zheyuan ; Chen, Yun ; Xu, Lele ; Wang, Yang ; Zhang, Libin ; Cheng, Changfu

BackgroundThe ryanodine receptors (RYRs) have been implicated in many muscular, cardiac and neurological diseases. However, there are almost no studies so far focusing on RYR genetic alterations and its roles in cancer, especially in non-small cell lung cancer (NSCLC).MethodsThe whole-exome sequencing (WES) data, demographic and clinical data of 1,052 NSCLC patients was downloaded from The Cancer Genome Atlas (TCGA) database and analyzed using the corresponding packages of the R software. Mutational profile was established and its correlation with tumor mutational burden (TMB), prognosis, age and smoking status was analyzed and compared.ResultsRYR mutations were found in 502 NSCLC patients, in which mutations of RYR1, RYR2 and RYR3 were found in 17.3% (182/1,052), 40.0% (421/1,052) and 21.3% (224/1,052) of patients, respectively. Random distribution of mutations without hotspot mutations were observed with all three RYR isoforms. Significant co-mutations were found between RYR1 and RYR3, while mutual exclusive mutations were found between RYR1 and RYR2, and between RYR2 and RYR3. Significant correlation was found between cumulative number of mutations and cumulative TMB for all three RYR isoforms, and patients with RYR mutations exhibited significantly higher TMB than those without RYR mutations. Significant correlation was also found between mutational status and age in RYR2 and RYR3, and between mutational status and smoking history grading in all three isoforms, and between mutational status and number of pack years in RYR3. More interestingly, significant stratification of patient survival was revealed by RYR2 mutational status, which was found to be one of the independent risk factors for patient prognosis in multivariate Cox analysis.ConclusionsThe mutational profile of RYR in NSCLC has been characterized for the first time. Strong correlation was found between RYR mutational status and TMB, age and smoking status. RYR2 mutational status was an independent risk factor for NSCLC patient prognosis.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis