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The story of modern tranquilliser drugs
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
During the 1980s, a lot of interest was shown in the potential use of drugs acting on the serotonergic system for the treatment of anxiety disorders and insomnia. The only drug to have been marketed as a result of this programme has been buspirone (Rickels, 1990), a 5-HT1A receptor agonist used for the treatment of generalised anxiety disorders. Buspirone has clear anxiolytic properties, but, unlike benzodi-azepines, has a delayed onset of action (around two weeks) that makes it less interesting in this indication than benzodiazepine anxiolytics that act immediately. Ritanserin, a 5-HT2A receptor antagonist, received extensive investigation for the treatment of both anxiety and sleep disorders. However, unequivocal demonstration of efficacy was lacking and this agent has never been marketed. Interest in drugs acting at serotonin receptors has now been on the wane for several years, although this may change if deramciclane, a 5-HT2 receptor antagonist currently in clinical development for the treatment of anxiety disorders, demonstrates interesting efficacy.
New and Emerging Therapies for Anxiety
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
David J. Nutt, Spilios V. Argyropoulos
Deramciclane is a 5HT2C antagonist with anxiolytic properties that is now in phase III trials. Animal data show that it does not potentiate the effects of alcohol, yet it improves sleep [7,16]. Another 5HT2C antagonist in development for depression, and possibly for anxiety, is agomelatine [61]. This compound has both melatonin agonist and 5HT2C antagonist properties in the same molecule and shows anxiolytic properties in animal models.
Three-dimensional liver models: state of the art and their application for hepatotoxicity evaluation
Published in Critical Reviews in Toxicology, 2020
Xihui Zhang, Tianyan Jiang, Dandan Chen, Qi Wang, Leshuai W. Zhang
Drug hepatotoxicity was previously investigated using isolated primary hepatocytes from rats to compare with the results from human hepatocytes. Monostory et al. demonstrated that rat primary hepatocytes are closer to humans than mouse, dog and rabbit primary hepatocytes when studying the biotransformation of deramciclane, likely because of the similarity of phase I enzyme activities between rat and human hepatocytes (Monostory et al. 2005). When human liver can be obtained from organ donation, fresh isolated or cryopreserved PHH becomes the gold standard for drug metabolism and DILI studies. PHH can maintain higher expression and activity than HepG2 cell line with respect to CYP3A4, a type of human specific cytochrome P450 enzyme (Wilkening et al. 2003). Although pre-clinical studies using rats and primates can partially reflect the drug induced hepatotoxicity, species variation is the major obstacle that impedes the transformation of the drug candidates to clinical trials during the development of investigational drugs. Therefore, PHH is currently the major cell type for hepatotoxicity prediction highly suggested by US FDA. The largest vendors providing PHH in the world are BioIVT, Lonza and Corning Life Sciences, which will be also specified in Section 5.1.