Propofol and AZD3043 Inhibit Adult Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes
Propofol is a widely used general anaesthetic with muscle relaxant properties. Similarly as propofol， the new general anaesthetic AZD3043 targets the GABAA receptor for its anaesthetic effects， but the interaction with nicotinic acetylcholine receptors (nAChRs) has not been investigated. Notably， there is a gap of knowledge about the interaction between propofol and the nAChRs found in the adult neuromuscular junction. The objective was to evaluate whether propofol or AZD3043 interact with the α1β1δε， α3β2， or α7 nAChR subtypes that can be found in the neuromuscular junction and if there are any differences in affinity for those subtypes between propofol and AZD3043. Human nAChR subtypes α1β1δε， α3β2， and α7 were expressed into Xenopus oocytes and studied with an automated voltage-clamp. Propofol and AZD3043 inhibited ACh-induced currents in all of the nAChRs studied with inhibitory concentrations higher than those needed for general anaesthesia. AZD3043 was a more potent inhibitor at the adult muscle nAChR subtype compared to propofol. Propofol and AZD3043 inhibit nAChR subtypes that can be found in the adult NMJ in concentrations higher than needed for general anaesthesia. This finding needs to be evaluated in an in vitro nerve-muscle preparation and suggests one possible explanation for the muscle relaxant effect of propofol seen during higher doses.
目的：观察蒙药尼达金德格治疗功能失调性子宫出血的效果。方法：选择42例功能失调性子宫出血患者，以蒙药尼达金德格治疗15天，观察出血缓解速度和疗 效。结果：治疗5天后停止流血的15例、10天后停止流血的10例、15天后停止流血的10例、症状好转的7例。结论：蒙药尼达金德格具有治疗功能失调性 子宫出血疾病的特殊功效，可以在临床推广应用。
A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers.
BACKGROUND： AZD3043 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 ar ...
Feng, Z. et al. The regulation of AMPK 1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 67, 3043-3053
The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division， and responds by initiating cell cycle arrest， senescence， or apoptosis. This study explores four p53-regulated gene products， the β1 and β2 subunits of the AMPK， which are shown for the first time to be regulated by the p53 protein， TSC2， PTEN， and IGF-BP3， each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle， heart， white fat， liver， and kidney). In addition， these genes are regulated by p53 in a stress signal–specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts， AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts， a p53-mediated apoptosis ensues. Thus， there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways. [Cancer Res 2007;67(7)：3043–53]
A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.
BACKGROUND： AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is
摘 要： 目的根据2007-2009年德格县鼠疫监测结果，对德格县鼠疫流行危险进行分析，并提出预警。方法按照＂全国鼠疫总体规划＂和＂四川省鼠疫监测方案＂及实施细则进行监测，危险性分析从危害性认定和流行病学危害两个角度展开。结果德格县鼠疫监测结果显示2007-2009年旱獭密度分别为0.24只/ha、0.22只/ha、0.39只/ha，旱獭细菌检测阳性率分别为12.12%、8.74%和16.00%。结论德格县疫源地旱獭密度和旱獭细菌检出率均呈增高趋势，动物鼠疫控制难度增大，人间鼠疫发生危险性增高。 ...全文
3043 Clinicopathological features of patients with ROS1-rearranged advanced non-small cell lung cancer: LC-SCRUM-Japan
3043 Clinicopathological features of patients with ROS1-rearranged advanced non-small cell lung cancer： LC-SCRUM-Japan
First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers.
AZD3043 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.Our 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.Fifty-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.AZD3043 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.