Phase I, Single Centre, Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous AZD3043 After a Single Ascending Bolus Dose Followed by a Single Infusion Dose in Elderly (=65 Years) Healthy Volunteers

Phase I, Single Centre, Open Label Study to Assess the Safety, Tolerability,Pharmacokinetics and Pharmacodynamics of Intravenous AZD3043 after aSingle Ascending Bolus Dose Followed by a Single Infusion Dose in Elderly(=65 years) Healthy Volunteers

开始日期2010-03-01

申办/合作机构

AstraZeneca PLC

NCT01028040 / Completed临床1期

Phase I, Single Centre, Open Label Study to Access The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous AZD3043 After A) a Single Ascending Bolus Dose and B) a Single Ascending Bolus Dose Followed by a Single Infusion Dose in Healthy Japanese Volunteers (Age Range 20-45 Years)

This is a single centre, open label, non-randomised study to access the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD3043 following a single dose administration to Japanese subjects.

开始日期2009-12-01

申办/合作机构

AstraZeneca PLC

NCT00984880 / Completed临床1期

Phase I, Single Centre, Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous AZD3043 After a Single Ascending Bolus Dose, and a Single Ascending Bolus Dose Followed by a Single Infusion Dose in Healthy Volunteers

The primary purpose of this study is to assess the safety and tolerability of AZD3043 following administration of single ascending bolus doses (Part A) and single ascending bolus doses followed by infusion (Part B).

开始日期2009-09-01

申办/合作机构

AstraZeneca PLC

100 项与 AZD-3043 相关的临床结果

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100 项与 AZD-3043 相关的转化医学

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100 项与 AZD-3043 相关的专利（医药）

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项与 AZD-3043 相关的文献（医药）

2018-11-18·Journal of Biomolecular Structure and Dynamics

Possible binding sites and interactions of propanidid and AZD3043 within the γ-aminobutyric acid type A receptor (GABA_AR)

Article

作者: Li, Xi ; Qiu, Ling ; Wang, Shanshan ; Lin, Jianguo ; Liu, Qingzhu ; Zhao, Xueyu

Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the γ-aminobutyric acid type A receptors (GABA_ARs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABA_AR. The predicted active region located in the transmembrane domain (TMD) of GABA_AR was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (-39.69 and -39.44 kcal/mol, respectively) and the largest binding energy (-88.478 and -78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABA_AR was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABA_AR were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead-like molecules.

2015-10-01·Anesthesia & Analgesia2区 · 医学

A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers

2区 · 医学

Article

作者: Simonsson, Ulrika S. H. ; Norberg, Aake ; Bjoernsson, Marcus A. ; Kalman, Sigridur

BACKGROUNDAZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers.METHODSArterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM.RESULTSA recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations.CONCLUSIONSAZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half-life led to a fast onset and offset of effects.

2015-10-01·Anesthesia & Analgesia2区 · 医学

First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043

2区 · 医学

Article

作者: Kanes, Stephen J. ; Kalman, Sigridur ; Ahlen, Kjell ; Koch, Pauline ; Norberg, Aake ; Bjoernsson, Marcus A. ; Barassin, Stephane

BACKGROUNDAZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile.METHODSOur primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index.RESULTSFifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone.CONCLUSIONSAZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

100 项与 AZD-3043 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12576

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
镇静	临床2期	-	AstraZeneca PLC	2010-03-01
麻醉	临床1期	英国	AstraZeneca PLC	-
麻醉	临床1期	-	Theravance Biopharma, Inc.	-
麻醉	临床1期	-	阿斯利康制药有限公司	-
麻醉	临床1期	瑞典	AstraZeneca PLC	-