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Benzodiazepines as anxiolytics
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
Bretazenil appears to be a highly efficacious anxiolytic agent in GAD, showing similar activity to diazepam (5 mg) in a large double-blind placebo-controlled trial (Pieri et al, 1988). Some rebound effects were reported for both bretazenil and diazepam. In this study, the frequency of adverse events (including sedation) was no different from placebo, and lower than for diazepam. However, in the two studies of bretazenil in panic attacks referred to below sedative side-effects were reported. There is little published information on possible sedative effects of bretazenil in healthy volunteers: in a comparative study aimed at evaluating abuse potential (Busto et al, 1994), decreases in psychomotor performance and subjective impressions of sedation, were observed after bretazenil but these were less marked than for the two full agonists tested and the dose-response curve was shallow. The duration of action of bretazenil is relatively short (T1/2 in man was found to be around 2.5 h: Pieri et al, 1988), and not ideal for use in the day-to-day treatment of anxiety; this unsatisfactory pharmacokinetic profile is one of the factors that has contributed to the stopping of the clinical development of this compound.
GABAA receptor subtype modulators in medicinal chemistry: an updated patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Letizia Crocetti, Gabriella Guerrini
The granted patent filed by Regents of University of California reports in [73] methods for mitigation of epileptic seizure tetramethylenedisulfotetramine (TETS)-induced (a nerve agent that causes seizures by inducing Ca2+ dysregulation and modifying electrical activity), using a composition of benzodiazepine and neurosteroid in subtherapeutic dose (in the range of 0.3–3.0 pg/kg for benzodiazepine and 5–50 mg/kg for neurosteroid). It is claimed that in adult male NIH Swiss mice, the administration of drugs combination immediately after the second clonic seizure TETS-induced, rescued the 100% of TETS-intoxicated animals. They used bretazenil, clonazepam, diazepam, lorazepam, midazolam, nitrazepam, clobazam (full agonist) as ‘benzodiazepine drug’ whereas the neurosteroid is allopregnanolone; the association of drugs is administered by aerosol or intrapulmonary and the particles have a diameter ranging from 1 to 3 μm.