Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel.

BACKGROUND AND PURPOSE: We aimed to characterize the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded K(+) channel (Kv 11.1). EXPERIMENTAL APPROACH: Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology. KEY RESULTS: AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 µM respectively. At 100 µM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at -30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv 4.3-hKChIP2.2, hCav 3.2 and hKv 1.5 and activated hCav 1.2/ß2/α2δ channels. CONCLUSION AND IMPLICATIONS: The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome.

Cognitive assessment of unipolar depression: measuring products, processes and structures.

In this article we survey current and emerging approaches to the cognitive assessment of affective disorder. Our review begins with an evaluation of the role of cognition in prevailing multidimensional models of unipolar depression. Within this framework, we distinguish three classes of cognitive variables that are operative in depression, and review strategies for assessing them. First, we consider methods of measuring cognitive product variables in depression (e.g. automatic thoughts, attributions, negative self-evaluations). Next, we focus on the assessment of cognitive and social cognitive mechanisms (e.g. irrational thought processes, social comparison processes) thought to play a proximal role in the development and maintenance of depressive phenomenology. Third, we review strategies for measuring the content and organization of the knowledge structures (i.e. schemas) postulated to underlie both products and processes. We conclude with a discussion of general issues and future directions for research.

Dreaming during anaesthesia in patients at high risk of awareness.

Dreaming during anaesthesia is commonly reported but remains poorly understood. In this study, adult surgical patients at high risk of awareness were randomly assigned to receive bispectral index (BIS)-guided anaesthesia or routine care, and were interviewed about dreaming three times postoperatively. Dreaming patients (n = 134) were compared with all other patients who were interviewed at least once (n = 2251). Intraoperative dreaming was reported by 4.2%, 3.9% and 3.4% of patients at 2-4 h, 24-36 h and 30 days after surgery, respectively. Fewer BIS-monitored patients reported intra-operative dreaming at 2-4 h than control patients (2.7% vs. 5.7%; p = 0.004). Reports of dreaming were similar in the two groups at 24-36 h and 30 days. Dreaming patients were younger (p = 0.001); healthier (p < 0.001) and more likely to be women (p < 0.001), and were less satisfied with anaesthetic care (p = 0.004) than other patients.

Recovery from bispectral index-guided anaesthesia in a large randomized controlled trial of patients at high risk of awareness.

Electroencephalographic monitors of anaesthetic depth are reported to assist anaesthetists in reducing recovery times. We explored the effect of bispectral index (BIS) monitoring on recovery times in a double-blind, randomized controlled trial of 2,463 patients at high risk of awareness. Patients were randomized to BIS-guided anaesthesia or routine care. In the BIS group, anaesthesia was adjusted to maintain a BIS value of 40-60 from the commencement of laryngoscopy to the start of wound closure, and 55-70 during wound closure. In the routine care group, anaesthesia was adjusted according to traditional clinical signs. In multivariate models, BIS monitoring, female gender, lower American Society of Anesthesiologists' physical status and shorter duration of anaesthesia predicted faster time to eye-opening after anaesthesia, and faster time to post-anaesthesia care unit discharge. BIS monitoring did not affect times to tracheal extubation among patients admitted to the intensive care unit. We conclude that BIS monitoring has statistically significant, but clinically modest, effects on recovery times in high risk surgical patients.