A pilot single-centre double-blind randomised controlled trial of centhaquine in the treatment of vasodilatory hypotension in adults admitted to the intensive care unit

开始日期2024-10-07

申办/合作机构

Austin Health

CTRI/2023/12/060444 / Recruiting临床2/3期

A randomized, double-blind, placebo-controlled pilot study to evaluate the effect of centhaquine on cardiovascular parameters in patients with hypovolemic shock. - NIL

开始日期2023-12-15

申办/合作机构-

NCT05956418 / Recruiting临床4期

A Prospective, Multi-centric, Open-labeled, Phase-IV Study to Assess Safety and Efficacy of LYFAQUIN™ (Centhaquine Citrate) as a Resuscitative Agent for Hypovolemic Shock to be Used as an Adjuvant to Standard Treatment of Shock

This is a prospective, multi-centric, open-labeled, phase-IV clinical study to evaluate the safety and efficacy of centhaquine citrate (LYFAQUIN™), a first-in-class drug for treating hypovolemic shock, a life-threatening condition caused by severe blood or fluid loss. Centhaquine has been found to be an effective resuscitative agent in rat, rabbit, and swine models of hemorrhagic shock. It has demonstrated the ability to decrease blood lactate levels, increase mean arterial pressure, enhance cardiac output, and reduce mortality rates. The increase in cardiac output during resuscitation is primarily attributed to an augmentation in stroke volume. Centhaquine exerts its effects by acting on the venous α2B-adrenergic receptors, which enhances venous return to the heart. Additionally, it produces arterial dilation by targeting central α2A-adrenergic receptors, thereby reducing sympathetic activity and systemic vascular resistance.

开始日期2021-08-13

申办/合作机构

Pharmazz, Inc.

100 项与 α2A-AR x α2B-AR 相关的临床结果

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100 项与 α2A-AR x α2B-AR 相关的转化医学

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项与 α2A-AR x α2B-AR 相关的文献（医药）

2024-07-01·Archives of Toxicology

Patulin alters alpha-adrenergic receptor signalling and induces epigenetic modifications in the kidneys of C57BL/6 mice

Article

作者: Ghazi, Terisha ; Mazibuko, Makabongwe ; Chuturgoon, Anil

AbstractPatulin (PAT) is a food-borne mycotoxin produced by Penicillium and Byssochlamys species. It is widely known for its mutagenic, carcinogenic, and genotoxic effects and has been associated with kidney injury; however, the mechanism of toxicity remains unclear. To address this gap, we conducted a study to explore the changes in α-adrenergic receptor signalling pathways and epigenetic modifications induced by PAT in the kidneys of C57BL/6 mice during acute (1 day) and prolonged (10 days) exposure. The mice (20–22 g) were orally administered PAT (2.5 mg/kg; at 1 and 10 days), and post-treatment, the kidneys were harvested, homogenised and extracted for RNA, DNA, and protein. The relative gene expression of the α-adrenergic receptors (ADRA1, ADRA2A, ADRA2B) and associated signalling pathways (MAPK, MAPK14, ERK, PI3K, and AKT) was assessed by qPCR. The protein expression of ERK1/2 and MAPK was determined by western blot. The impact of PAT on DNA methylation was evaluated by quantifying global DNA methylation; qPCR was used to determine gene expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and demethylase (MBD2). PAT downregulated the expression of ADRA1, ADRA2A, ADRA2B, PI3K, and AKT and upregulated ERK1/2 and MAPK protein expression. Furthermore, PAT induced alterations in DNA methylation patterns by upregulating DNMT1 and MBD2 expressions and downregulating DNMT3A and DNMT3B expressions, resulting in global DNA hypomethylation. In conclusion, PAT disrupts α-1 and α-2 adrenergic receptor signalling pathways and induces epigenetic modifications, that can lead to kidney injury.

2024-06-27·Journal of Medicinal Chemistry

Structure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine

Article

作者: Česnek, Michal ; Kužmová, Erika ; Dvořáková, Alexandra ; Dračínský, Martin ; Brož, Břetislav ; Chayka, Artem ; Kozák, Jaroslav ; Strmeň, Timotej ; Janeba, Zlatko ; Mertlíková-Kaiserová, Helena ; Osifová, Zuzana ; Tloušt'ová, Eva

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.

2024-05-17·ACS Synthetic Biology

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

Article

作者: Pinho, Pedro ; Keasling, Jay D ; Bradley, Samuel A ; Courdavault, Vincent ; Adhikari, Khem B ; Jensen, Emil D ; Hansen, Lea G ; Hansson, Frederik G ; Birer Williams, Caroline ; Marc, Jillian ; Ma, Xin ; Besseau, Sébastien ; Zhang, Jie ; Jensen, Michael K ; Gautron, Nicolas ; Koudounas, Konstantinos ; Lehka, Beata J ; Volkova, Daria ; Peng, Huadong ; Rago, Daniela ; Muyo Abad, Sergi ; Holtz, Maxence ; Haidar, Ahmad K ; Mélin, Céline

Monoterpene indole alkaloids (MIAs) make up a highly bioactive class of metabolites produced by a range of tropical and subtropical plants. The corynanthe-type MIAs are a stereochemically complex subclass with therapeutic potential against a large number of indications including cancer, psychotic disorders, and erectile dysfunction. Here, we report yeast-based cell factories capable of de novo production of corynanthe-type MIAs rauwolscine, yohimbine, tetrahydroalstonine, and corynanthine. From this, we demonstrate regioselective biosynthesis of 4 fluorinated derivatives of these compounds and de novo biosynthesis of 7-chlororauwolscine by coexpression of a halogenase with the biosynthetic pathway. Finally, we capitalize on the ability of these cell factories to produce derivatives of these bioactive scaffolds to establish a proof-of-principle drug discovery pipeline in which the corynanthe-type MIAs are screened for bioactivity on human drug targets, expressed in yeast. In doing so, we identify antagonistic and agonistic behavior against the human adrenergic G protein-coupled receptors ADRA2A and ADRA2B, and the serotonergic receptor 5HT4b, respectively. This study thus demonstrates a proto-drug discovery pipeline for bioactive plant-inspired small molecules based on one-pot biocatalysis of natural and new-to-nature corynanthe-type MIAs in yeast.