The status of these and other BZ site compounds with claimed, but often not explicitly stated, GABA(A) subtype selectivity (such as ELB-139 and ocinaplon) will be reviewed in relation to their development as non-sedating anxiolytics for the treatment of generalised anxiety disorder.Ītack JR The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. On the other hand, subtype-selective efficacy relies on a compound binding to all subtypes but having different efficacies at various subtypes (relative selective efficacy, for example SL654198 or pagoclone) or having efficacy at some subtypes but none at others (absolute selective efficacy for example, L-838417). Selective affinity relies on a compound binding with higher affinity to the alpha2/alpha3 compared with alpha1 subtypes, but to date no such compounds have been described. In order to achieve selectivity for the alpha2/alpha3 subtypes relative to alpha1, two approaches may be used selective affinity or selective efficacy. More specifically, the alpha2- and/or alpha3-containing GABA(A) receptors play a role in anxiety whereas the alpha1 subtype is involved in sedation, raising the possibility of a compound that selectively modulates alpha2- and/or alpha3-containing receptors but does not affect alpha1-containing receptors would be a non-sedating anxiolytic. However, the advent of molecular genetic and pharmacological approaches has begun to delineate which GABA(A) receptor subtypes are associated with the various pharmacological effects of the non-selective BZs. Unfortunately, these compounds failed, for a variety of reasons, to translate into clinical benefit, and as the public perception of BZs deteriorated interest in the area waned.
Their reduced intrinsic efficacy relative to full agonists such as diazepam resulted in an improved preclinical pharmacological profile in that there was a large window between anxiolytic and sedative doses and their dependence and abuse liabilities were much lower. In the late 1980s and early 1990s a number of non-selective partial agonists, exemplified by bretazenil, pazinaclone and abecarnil, were described.
However, despite their proven clinical anxiolytic efficacy, such compounds possess a relatively narrow window between doses that produce anxiolysis and those that cause sedation, and are also associated with physical dependence and a potential for abuse. Non-selective benzodiazepine (BZ) binding-site full agonists, exemplified by diazepam, act by enhancing the inhibitory effects of GABA at GABA(A) receptors containing either an alpha1, -2, -3 or -5 subunit. Product label Diazepam Auto-injector Last revised: September 1997 by a syringe (operated manually) indicates that the mean percent availability of the drug from the autoinjector is 100% of that obtained from the syringe. Injection of 10 mg of diazepam in the mid-anterior/lateral thigh by the autoinjector versus 10 mg I.M. A study performed in 24 healthy male subjects comparing the I.M. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use. Diazepam was found to have transient cardiovascular depressor effects in dogs, Long-term experiments in rats revealed no disturbances of endocrine function.
However, animals treated with diazepam do have a transient ataxia at higher doses.
Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects. In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Evidence-based medicine for Chemical Defense - including efficacy and safety A. The anticonvulsant diazepam has been used therapeutically in the treatment of both convulsant (e.g., picrotoxin, hydrazine, strychnine, tetramethylenedisulfotetramine) and cholinergic (e.g., sarin (GB), soman (GD), cyclosarin (GF), tabun (GA), VX, and organophosphorus pesticides) agents to enhance the inhibitory effect of gamma-aminobutyric acid at GABA(a) receptors and limit excess central nervous system excitation and seizures. Chemical Defense therapeutic area(s) - including key possible uses Name of Chemical Defense therapeutic agent/deviceĭiazepam 2.