Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919).

RATIONALE: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. OBJECTIVE: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. RESULTS: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. CONCLUSION: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways.

Radiofrequency surgery of the tongue base in the treatment of snoring--a pilot study.

In a previously published study, a significant reduction of snoring was reported after treatment with radiofrequency surgery of the tongue base in patients suffering from obstructive sleep apnea syndrome. The aim of this study was to investigate the efficacy of radiofrequency surgery of the tongue base in the treatment of primary snoring. Twenty patients suffering from primary snoring (AHI < 10/h, body mass index < 32 kg/m(2)) and an isolated hypertrophic tongue base at clinical examination were enrolled in this clinical trial. The patients underwent bipolar radiofrequency surgery of the tongue base under local anaesthesia. Pre- and post-operative body weight, daytime sleepiness (Epworth sleepiness scale) and snoring scores (visual analogue scales) were evaluated by the patients and their bed partners, respectively. Postoperative follow-up data was collected 6-8 weeks after treatment. A statistically significant reduction of the preoperative snoring levels from 7.5 +/- 2.4 to 6.1 +/- 2.8 was seen after treatment (p < 0.001). Body weight and daytime sleepiness remained unaffected. Only 3 out of 20 patients were satisfied with the result as defined by VAS < 3. Despite statistically significant reduction of the subjective snoring scores after radiofrequency of the tongue base, only minimal clinical improvement was achieved. Only 3 out of 20 patients were satisfied with the results. With regard to the clearly beneficial effect seen in patients with obstructive sleep apnea, this result indicates different pathophysiological principles in the generation of snoring.