A Multicenter, Randomized, Single-blind, Etomidate-controlled, Phase II Clinical Trial to Evaluate the Efficacy and Safety of Methoxyethyl Etomidate Hydrochloride for Sedation/Anesthesia During Gastroscopy/Colonoscopy.

A total of 78 subjects undergoing gastroscopy/colonoscopy were randomly assigned to the methoxetomidate hydrochloride group and the etomidate group according to the ratio of 1:1:1 with etomidate as the control group, 26 cases in each group. All subjects were blinded to treatment allocation. Screening assessments for all subjects will be completed within D-14 to D-2 before the first dose. For all subjects who received the investigational drug, they were required to return to the research center on D2-5 to complete the corresponding examination before being discharged from the group. To preliminarily evaluate the efficacy and safety of ET-26 in gastroscopy/colonoscopy.

Start Date15 Nov 2024

Sponsor / Collaborator

Jinzhou Ahon Pharmaceutical Co., Ltd.

CTR20233784 / CompletedPhase 1

注射用甲氧依托咪酯盐酸盐在非老年与老年受试者中单次给药的药代动力学研究

[Translation] Pharmacokinetics of methoxyetomidate hydrochloride for injection after single administration in non-elderly and elderly subjects

主要研究目的：1. 评价健康非老年/老年受试者单次静脉注射ET-26-HCl，ET-26的药代动力学特征，为ET-26-HCl临床应用提供指导。次要研究目的：1. 评价健康非老年/老年受试者单次静脉注射ET-26-HCl的药效动力学和安全性；2. 评价健康非老年/老年受试者单次静脉注射ET-26-HCl，依托咪酯酸的药代动力学特征。探索性研究目的：1. 探索CYP2C19基因多态性对ET-26及依托咪酯酸药代动力学参数的影响。

[Translation]

Main study objectives: 1. To evaluate the pharmacokinetic characteristics of ET-26-HCl and ET-26 after a single intravenous injection in healthy non-elderly/elderly subjects, and to provide guidance for the clinical application of ET-26-HCl. Secondary study objectives: 1. To evaluate the pharmacodynamics and safety of a single intravenous injection of ET-26-HCl in healthy non-elderly/elderly subjects; 2. To evaluate the pharmacokinetic characteristics of ET-26-HCl and etomidate acid after a single intravenous injection in healthy non-elderly/elderly subjects. Exploratory study objectives: 1. To explore the effect of CYP2C19 gene polymorphism on the pharmacokinetic parameters of ET-26 and etomidate acid.

Start Date25 Dec 2023

Sponsor / Collaborator

Horgos Consulting Co., Ltd.

[+2]

NCT06176716 / RecruitingPhase 1

Phase I Clinical Study to Evaluate the Pharmacokinetics, Pharmacokinetics, and Safety of Intravenous Administration of Methoxyethyl Etomidate Hydrochloride for Injection in Subjects With Mild, Moderate, and Normal Hepatic Dysfunction.

A Phase I clinical study to compare the pharmacokinetics, pharmacokinetics, and safety of intravenous administration of methoxyetomidate hydrochloride for injection in subjects with mild hepatic insufficiency (Child-pugh A), moderate hepatic insufficiency (Child-Pugh B), and normal hepatic function.Main OBJECTIVE: To evaluate the pharmacokinetic characteristics of metoetomidate hydrochloride for injection in subjects with mild liver dysfunction (Child-Pugh A), moderate liver dysfunction (Child-Pugh B) and normal liver function, and to provide evidence for the clinical application of metoetomidate hydrochloride in patients with liver dysfunction.Secondary objective: To evaluate the safety and pharmacokinetics of metoetomidate hydrochloride for injection in subjects with mild hepatic insufficiency (Child-Pugh A), moderate hepatic insufficiency (Child-Pugh B), and normal hepatic dysfunction.Exploratory objective: To investigate and analyze the relationship between the pharmacokinetic index (MOAA/S, BIS) and the pharmacokinetic parameters of metoetomidate hydrochloride in subjects with different liver function states in this study.The CYP2C19 genotype of the subjects in the study was analyzed, and the influence of gene polymorphism on pharmacokinetic parameters of metoetomidate hydrochloride was explored according to the data of CYP2C19 genotype.The relationship between in vivo exposure to methoxyetomidate hydrochloride and liver injury was analyzed.

Start Date06 Dec 2023

Sponsor / Collaborator

Jinzhou Ahon Pharmaceutical Co., Ltd.

100 Clinical Results associated with Methoxyetomidate Hydrochloride

100 Translational Medicine associated with Methoxyetomidate Hydrochloride

100 Patents (Medical) associated with Methoxyetomidate Hydrochloride

Literatures (Medical) associated with Methoxyetomidate Hydrochloride

01 Oct 2024·British Journal of Anaesthesia

Phase 1 single-centre placebo- and etomidate-controlled study in healthy volunteers to assess safety, tolerability, clinical effects, and pharmacokinetics of intravenous methoxyethyl etomidate hydrochloride (ET-26)

Article

Author: Liu, Jin ; Yin, Qinqin ; Yang, Xiaoran ; Zhang, Wensheng ; Li, Lize ; Diao, Lei ; Sun, Yi ; Yang, Yang ; Deng, Xiaoqian

BACKGROUNDMethoxyethyl etomidate hydrochloride (ET-26) is a novel etomidate analogue. This is the first-in-human study of a bolus i.v. formulation of ET-26 to assess its safety, tolerability, hypnotic effects, and pharmacokinetics.METHODSWe enrolled 58 subjects in a dose-escalating study (stage 1a, 10 cohorts, ET-26 0.05-2.8 mg kg^-1) and 40 subjects in a head-to-head study (stage 1b, four cohorts). Safety estimates included vital signs, adverse events, physical examination, and laboratory tests. Hypnotic effects were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale, bispectral index, loss of eyelash reflex, and response to pain. Adrenocortical function was assessed using plasma total cortisol (PTC), and area above the PTC baseline (AUC_PTC) after adrenocorticotropic hormone stimulation. Pharmacokinetics of plasma ET-26 concentrations were investigated.RESULTSNo severe adverse events occurred; the most common adverse events were myoclonus (53.8%) and injection pain (47.4%), which were transient and resolved spontaneously. Vital signs remained stable. ET-26 produced rapid-onset, short-duration unconsciousness. At the 95% effective dose (ED₉₅, 0.8 mg kg^-1), ET-26 produced unconsciousness with a similar onset time (1.9 [0.6] min vs 2.1 [1.3] min) and slightly shorter duration (2.9 [0.9] vs 4.8 [1.8]) compared with etomidate 0.3 mg kg^-1, and resulted in higher AUC_PTC (614 [454] vs -932 [555] nmol h^-1). ET-26 showed linear pharmacokinetics, and a two-compartment model best described the pharmacokinetics.CONCLUSIONSET-26 was tolerated in healthy volunteers up to 2.8 mg kg^-1. It produced rapid-onset, short-acting unconsciousness with stable cardiovascular and respiratory properties. Adrenocortical function was better preserved compared with etomidate 0.3 mg kg^-1.CLINICAL TRIAL REGISTRATIONChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525).

01 Dec 2019·BMC Pharmacology and ToxicologyQ4 · MEDICINE

Behavioral and steroidogenic pharmacology of phenyl ring substituted etomidate analogs in rats

Q4 · MEDICINE

ArticleOA

Author: Raines, Douglas E ; Hofmann, Alissa ; McGrath, Megan

BACKGROUNDCushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABA_A receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABA_A receptor modulatory activities.METHODSIn the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg^- 1 min^- 1) of either etomidate or an etomidate analog.RESULTSAll rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80-84% and 68-94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations.CONCLUSIONSOur studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.

01 Feb 2018·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Dimethoxy-etomidate: A Nonhypnotic Etomidate Analog that Potently Inhibits Steroidogenesis

Q3 · MEDICINE

Article

Author: Ma, Celena ; Raines, Douglas E ; McGrath, Megan

Cushing's syndrome is characterized by the overproduction of adrenocortical steroids. Steroidogenesis inhibitors are mainstays of medical therapy for Cushing's syndrome; unfortunately, adverse side effects and treatment failures are common with currently available drugs. The general anesthetic induction agent etomidate is among the most potent inhibitors of adrenocortical steroidogenesis. However, its use as a treatment of Cushing's syndrome is complicated by its sedative-hypnotic activity and ability to produce myoclonus, central nervous system actions thought to be mediated by the GABA_A receptor. Here, we describe the pharmacology of the novel etomidate analog (R)-ethyl 1-(1-(3,5-dimethoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (dimethoxy-etomidate). In contrast to etomidate, dimethoxy-etomidate minimally enhanced GABA-evoked GABA_A receptor-mediated currents even at a near-saturating aqueous concentration. In Sprague-Dawley rats, dimethoxy-etomidate's potency for producing loss of righting reflexes-an animal model of sedation/hypnosis-was 2 orders of magnitude lower than that of etomidate, and it did not produce myoclonus. However, similar to etomidate, dimethoxy-etomidate potently suppressed adrenocortical steroid synthesis primarily by inhibiting 11β-hydroxylase. [³H]etomidate binding to rat adrenocortical membranes was inhibited by dimethoxy-etomidate in a biphasic manner with IC₅₀ values of 8.2 and 3970 nM, whereas that by etomidate was monophasic with an IC₅₀ of 22 nM. Our results demonstrate that, similar to etomidate, dimethoxy-etomidate potently and dose-dependently suppresses adrenocortical steroid synthesis by inhibiting 11β-hydroxylase. However, it is essentially devoid of etomidate's GABA_A receptor positive modulatory and sedative-hypnotic activities and produces no myoclonus, providing proof of concept for the design of etomidate analogs without important central nervous system actions for the pharmacologic treatment of Cushing's syndrome.

100 Deals associated with Methoxyetomidate Hydrochloride

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Anesthesia	Phase 3	CN	Jinzhou Ahon Pharmaceutical Co., Ltd.	11 Oct 2023
Anesthesia	Phase 3	CN	West China Hospital	11 Oct 2023
Anesthesia	Phase 3	CN	Horgos Consulting Co., Ltd.	11 Oct 2023
Anesthesia	Phase 3	CN	Chengdu List Pharmaceutical Co., Ltd.	11 Oct 2023
Sedation	Phase 2	CN	West China Hospital	07 Nov 2024
Sedation	Phase 2	CN	Chengdu List Pharmaceutical Co., Ltd.	07 Nov 2024

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