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Palliative Care and Social Practice 2020Midazolam is a commonly used benzodiazepine in palliative care and is considered one of the four essential drugs needed for the promotion of quality care in dying... (Review)
Review
Midazolam is a commonly used benzodiazepine in palliative care and is considered one of the four essential drugs needed for the promotion of quality care in dying patients. Acting on the benzodiazepine receptor, it promotes the action of gamma-aminobutyric acid. Gamma-aminobutyric acid action promotes sedative, anxiolytic, and anticonvulsant properties. Midazolam has a faster onset and shorter duration of action than other benzodiazepines such as diazepam and lorazepam lending itself to greater flexibility in dosing than other benzodiazepines. The kidneys excrete midazolam and its active metabolite. Metabolism occurs in the liver by the P450 system. This article examines the pharmacology, pharmacodynamics, and clinical uses of midazolam in palliative care.
PubMed: 32215374
DOI: 10.1177/2632352419895527 -
CNS Drugs Sep 2022Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and... (Review)
Review
Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA) receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.
Topics: Anticonvulsants; Benzodiazepines; Clonazepam; Diazepam; Humans; Lorazepam; Midazolam; Seizures; Status Epilepticus; gamma-Aminobutyric Acid
PubMed: 35971024
DOI: 10.1007/s40263-022-00940-2 -
Proceedings of the National Academy of... Dec 2022We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the...
We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D () and metabotropic receptor 4 () and downregulation of the GABA-A receptor associated protein () mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.
Topics: Humans; Female; Male; Animals; Mice; Mice, Inbred C57BL; Glutamic Acid; Aspartame; Receptors, GABA-A; Drinking Water; Anxiety; Amygdala; Diazepam; RNA, Messenger; Gene Expression; gamma-Aminobutyric Acid
PubMed: 36459641
DOI: 10.1073/pnas.2213120119 -
The Korean Journal of Gastroenterology... Aug 2020Alcohol withdrawal syndrome (AWS) is the most common and well-known condition occurring after intentional or unintentional cessation or decreasing heavy drinking.... (Review)
Review
Alcohol withdrawal syndrome (AWS) is the most common and well-known condition occurring after intentional or unintentional cessation or decreasing heavy drinking. Approximately 5-10% of these people are suffering from serious medical and psychiatric problems, withdrawal seizures, perceptual disturbances, and delirium tremens. Despite acute medical conditions with the high mortality of severe AWS, proper management could decrease the severity and mortality of AWS. The Clinical Institute withdrawal assessment for alcohol-revised version is a valid, reliable, and sensitive instrument for assessing the clinical course and the treatment monitoring of alcohol withdrawal. Benzodiazepine is the pharmacotherapy of choice for alcohol withdrawal. Diazepam or lorazepam treatment is best initiated early in the course of alcohol withdrawal to prevent progression to more severe withdrawal. There are three strategies for the pharmacotherapy of AWS. After the treatment of AWS, most patients should be managed or treated by the continuing care, including the psychosocial treatments, community-based management, and programs for preventing recurrence of AWS.
Topics: Alcoholism; Benzodiazepines; Diazepam; Humans; Hypnotics and Sedatives; Psychotherapy; Severity of Illness Index; Substance Withdrawal Syndrome
PubMed: 32839369
DOI: 10.4166/kjg.2020.76.2.71 -
Nature Sep 2020Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity...
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity in the brain. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
Topics: Allosteric Regulation; Anesthetics, General; Barbiturates; Benzodiazepines; Bicuculline; Binding Sites; Binding, Competitive; Cryoelectron Microscopy; Diazepam; Electrophysiology; Etomidate; Flumazenil; GABA-A Receptor Antagonists; Humans; Ligands; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Phenobarbital; Picrotoxin; Propofol; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 32879488
DOI: 10.1038/s41586-020-2654-5 -
Neuropharmacology Dec 2020Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties...
Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, αβγ, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.
Topics: Animals; Anticonvulsants; Antidepressive Agents; Binding Sites; Brain; Diazepam; Drug Synergism; Electroencephalography; GABA Modulators; GABA-A Receptor Agonists; Hippocampus; Humans; Male; Mice; Pregnanes; Pyrazoles; Rats, Sprague-Dawley; Receptors, GABA; Seizures; Steroids; gamma-Aminobutyric Acid
PubMed: 32976892
DOI: 10.1016/j.neuropharm.2020.108333 -
Addiction (Abingdon, England) Oct 2022There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of pharmacotherapies for AW.
METHODS
Six databases were searched for randomized clinical trials through November 2021. Trials were included after a blinded review by two independent reviewers. Outcomes included incident seizures, delirium tremens, AW severity scores, adverse events, dropouts, dropouts from adverse events, length of hospital stay, use of additional medications, total benzodiazepine requirements, and death. Effect sizes were pooled using frequentist random-effects network meta-analysis models to generate summary ORs and Cohen's d standardized mean differences (SMDs).
RESULTS
Across the 149 trials, there were 10 692 participants (76% male, median 43.5 years old). AW severity spanned mild (n = 32), moderate (n = 51), and severe (n = 66). Fixed-schedule chlormethiazole (OR, 0.16; 95% CI, 0.04-0.65), fixed-schedule diazepam (OR, 0.16; 95% CI, 0.04-0.59), fixed-schedule lorazepam (OR = 0.19; 95% CI, 0.08-0.45), fixed-schedule chlordiazepoxide (OR = 0.21; 95% CI, 0.08-0.53), and divalproex (OR = 0.22; 95% CI, 0.05-0.86) were superior to placebo at reducing incident AW seizures. However, only fixed-schedule diazepam (OR, 0.19; 95% CI, 0.05-0.76) reduced incident delirium tremens. Oxcarbazepine (d = -3.69; 95% CI, -6.21 to -1.17), carbamazepine (d = -2.76; 95% CI, -4.13 to -1.40), fixed-schedule oxazepam (d = -2.55; 95% CI, -4.26 to -0.83), and γ-hydroxybutyrate (d = -1.80; 95% CI, -3.35 to -0.26) improved endpoint Clinical Institute Withdrawal Assessment for Alcohol-Revised scores over placebo. Promazine and carbamazepine were the only agents significantly associated with greater dropouts because of adverse events. The quality of evidence was downgraded because of the substantial risk of bias, heterogeneity, inconsistency, and imprecision.
CONCLUSIONS
Although some pharmacotherapeutic modalities, particularly benzodiazepines, appear to be safe and efficacious for reducing some measures of alcohol withdrawal, methodological issues and a high risk of bias prevent a consistent estimate of their comparative performance.
Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Carbamazepine; Diazepam; Female; Humans; Male; Network Meta-Analysis; Seizures; Substance Withdrawal Syndrome
PubMed: 35194860
DOI: 10.1111/add.15853