Disorders of Consciousness
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Sedative/hypnotic drug use disorder (e.g. benzodiazepines, barbiturates, opiates, phenothiazines, and tricyclic antidepressants alone or in combination): Elderly and those with mild cognitive impairment (MCI), pre-MCI, and dementia are particularly sensitive.Naloxone may be given diagnostically and therapeutically in suspected opiate toxicity. However, its half-life is comparatively shorter than most opioids, and prolonged monitoring is required.Flumazenil may acutely reverse suspected benzodiazepine toxicity although it carries a risk of provoking seizures and should be avoided in most circumstances.
Interaction of the benzodiazepines with the GABAA receptor
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
The original 5-phenyl-1,4-benzodiazepines all appear to be agonists with similar efficacy: they potentiate GABAA receptor-activated currents by increasing the probability of channel opening in response to a given GABA stimulus. In vivo, these compounds are sedative, anxiolytic, anticonvulsant and myorelaxant. However, compounds also exist that bind potently to the benzodiazepine binding site without modulating GABAA receptor activity. These are the benzodiazepine antagonists, of which the first to be identified was flumazenil, or Ro 15-1788 (Hunkeler et al, 1981), the structure of which is shown in Figure 2.4. This compound has nanomolar affinity for the benzodiazepine binding site, no overt benzodiazepine-like behavioural properties, and will reverse all the biological effects of classical benzodiazepines, both in vitro and in vivo. As a pharmacological tool, flumazenil has been indispensible not only in characterising the effects of benzodiazepines but also exploring benzodiazepine receptor sensitivity changes. Flumazenil is used therapeutically to control benzodiazepine anaesthesia. Its effects and uses in animals and man will be discussed in Chapters 6 and 10.
Toxicology
Anthony FT Brown, Michael D Cadogan in Emergency Medicine, 2020
Flumazenil, a specific benzodiazepine receptor antagonist, is rarely if ever indicated. Flumazenil may induce VT, elevate intracranial pressure, precipitate benzodiazepine withdrawal in chronic abusers, and may invoke seizures, particularly with co-ingestion of TCAs.Potential role for flumazenil is thus restricted to: reversal of excessive benzodiazepine sedative effect following procedural sedation, particularly in the elderly.
Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014–2017
Published in Clinical Toxicology, 2019
Joseph E. Carpenter, Brian Patrick Murray, Camille Dunkley, Ziad N. Kazzi, Melissa H. Gittinger
It is interesting to note that 9 subjects (3%) had received flumazenil, none of whom suffered a seizure. The incidence of both adverse events and serious adverse events are significantly increased with the routine use of flumazenil [17], although there is disagreement about the clinical interpretation of benefits and risks from that data [18]. In this study, 48/234 (23%) subjects overall, and 2/9 (22%) subjects that received flumazenil, reported an acute-on-chronic or chronic exposure to a designer benzodiazepine. Data regarding the effectiveness of flumazenil in reversing CNS and/or respiratory depression was not available in this data set. Given the relatively small number of subjects receiving flumazenil in this retrospective study, we do not feel this is sufficient evidence to make conclusions regarding safety of flumazenil administration in this population. Further study is required in order to determine the safety and efficacy of flumazenil in the setting of designer benzodiazepine exposure.
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ming-Xia Song, Xian-Qing Deng
Amongst all pharmacodynamic models suggested for binding to the benzodiazepine receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance. Also, the presence of a second out-of-plane, aromatic ring could potentiate binding to the receptor. Abbas Shafiee and his team launched a project to design simple non-rigid structures with benzodiazepine activity based on the proposed SAR. A series of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives (29, Figure 6), with a simple non-rigid structure, were designed, which had all the suggested requirements for binding to the benzodiazepine receptors. Their benzodiazepine effects and anticonvulsant activity were evaluated. Among the tested compounds, compound 29a with dichloro-substituent showed the best anticonvulsant activity with an ED50 of 12.0 mg/kg in the PTZ models. To clarify whether the designed compounds could mimic the structure of a benzodiazepine agonist, conformational analysis on designed molecules as well as a known benzodiazepine agonist estazolam was performed followed by superimposition of energy minima conformers. The results showed that the main proposed pharmacofores were well matched. In addition, the activity of the compounds is significantly reduced by flumazenil, a benzodiazepine antagonist, which further confirms that this effect is mediated through benzodiazepine receptors.
Carbon-11 patents (2012–2022): synthetic methodologies and novel radiotracers for PET imaging
Published in Expert Opinion on Therapeutic Patents, 2022
Sridhar Goud Nerella, Priti Singh, Sanam Tulja
A few routinely used carbon-11 radiotracers include [11C]methionine; it is an amino acid mainly involved in the amino acid transport, protein synthesis, which is used in multiple cancer diagnosis. [11C]flumazenil is a ligand for brain GABAA benzodiazepine receptors to study neurological conditions. [11C]choline is the precursor to acetylcholine neurotransmitter synthesis, the activity of which is impaired in most neurodegenerative diseases. [11C]raclopride is a specific D2, and D3 receptors antagonist, used for the diagnosis of Parkinson’s disease, 11C(carbonyl)-estramustine phosphate is a estrogen receptors agonist for cancer diagnosis, [11C]NS14492 is a α7-subtype nicotinic acetylcholine receptor agonist for cognitive disturbances, [11C]Tanaproget is a selective progesterone receptor modulator for cancer diagnosis, [11C]thymidine is a pyrimidine derivative for DNA synthesis for cancer diagnosis, and [11C]citalopram is a selective serotonin reuptake inhibitor for depression [29,30]. Unfortunately, there are no carbon-11 patent reviews available till date, hence we have reviewed all the available carbon-11 patents with a decade search from 2012 to 2022 to provide a good useful information to the nuclear medicine scientific community about different new synthetic methodologies as well as novel patented carbon-11 radiotracers for PET molecular imaging, whereas other positron emitters, such as the fluorine-18 and gallium-68 patent reviews are available to study their novel patented radiotracers [31–33].
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