A Phase 1, Single Centre, Single Dose, Double-Blind, Double-Dummy, Four-Way Crossover, Placebo-Controlled, Randomized Study to Investigate the Effects of AZD6280 on Sedation, Cognition and EEG in Comparison With Lorazepam in Healthy Male Volunteers
The purpose of the study is to determine the effects of AZD6280 compared to lorazepam on sleepiness, concentration and brain activity.
A Phase I, Single-Center, Randomized, Double-Blind, Placebo-Controlled, Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD6280 When Given in Multiple Ascending Oral Doses in Healthy Male and Healthy Female Subjects of Non-child Bearing Potential
This is a study to evaluate safety, tolerability, PK and PD effects of orally administered AZD6280 after single and repeated ascending doses.
2021-02-01·Journal of labelled compounds & radiopharmaceuticals4区 · 医学
The impact of radiochemistry in drug projects: The use of C-14 label in the AZD8529, AZD7325, and AZD6280 projects.
4区 · 医学
作者: Lee Kingston ; Chungang Gu ; Jian Guo ; Steve Swallow ; Charles S Elmore
Understanding the metabolic transformations of a potential drug molecule is important to understanding the safety profile of a drug candidate. Liquid chromatography-mass spectrometry is a standard method for detecting metabolites in the drug discovery stage, but this can lead to an incomplete understanding of the molecule's metabolism. In this manuscript, we highlight the role radiolabeling played in determining the metabolism and in quantifying the metabolites of AZD8529, AZD7325, and AZD6280. A quantitative whole-body autoradiography study can detect covalent adducts in vivo as was the case with AZD5248 in which the compound was bound to the aorta. Ultimately another compound free of aortic binding was developed, AZD7986.
GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans
3区 · 医学
作者: Jucaite, Aurelija ; Cselenyi, Zsolt ; Lappalainen, Jaakko ; McCarthy, Dennis J. ; Lee, Chi-Ming ; Nyberg, Svante ; Varnaes, Katarina ; Stenkrona, Per ; Halldin, Christer ; Cross, Alan ; Farde, Lars
Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects.
The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability.
Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests.
The [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively.
High GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.
2015-03-01·Clinical Pharmacology in Drug Development4区 · 医学
The effects of the nonselective benzodiazepine lorazepam and the α2/α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280 on plasma prolactin levels
4区 · 医学
作者: te Beek, Erik T. ; Chen, Xia ; Jacobs, Gabriel E. ; Nahon, Kimberly J. ; de Kam, Marieke L. ; Lappalainen, Jaakko ; Cross, Alan J. ; van Gerven, Joop M. A. ; Hay, Justin L.
Compounds with selectivity for GABAA receptor subtypes may differ significantly from nonselective benzodiazepines in their dopaminergic effects in vivo. To explore the exact role of the GABAA receptor subtypes in the regulation of prolactin secretion and the differential effects of selective and nonselective GABA receptor modulators, the effects of the nonselective benzodiazepine lorazepam, as well as two novel α2 /α3 subunit-selective GABAA receptor modulators AZD7325 and AZD6280, on prolactin levels were measured in healthy male volunteers. Following administration of lorazepam at 2 mg doses and AZD6280 at 10 mg and 40 mg doses, prolactin levels increased significantly compared with placebo (difference 42.0%, 19.8%, and 32.8%, respectively), suggesting that the α2 and/or α3 receptor subtypes are involved in GABAergic modulation of prolactin secretion, although possible roles of the α1 and α5 receptor subtypes are not excluded. The increases in prolactin levels after administration of AZD7325 at 2 mg and 10 mg doses (difference 7.6% and 10.5%, respectively) did not reach statistical significance, suggesting that doses of AZD7325 or intrinsic efficacy at the α2 and α3 receptor subtypes may have been too low.