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Neuropsychopharmacology : Official... Mar 2023Benzodiazepines and 'Z-drugs' (including zolpidem and zopiclone) are GABA receptor (GABAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or...
Benzodiazepines and 'Z-drugs' (including zolpidem and zopiclone) are GABA receptor (GABAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or anxiety. However, alongside sedation, augmenting GABAR function may also alter coordinated neuronal activity during sleep, thereby influencing sleep-dependent processes including memory consolidation. We used simultaneous recordings of neural population activity from the medial prelimbic cortex (PrL) and CA1 of the dorsal hippocampus (dCA1) of naturally sleeping rats to detail the effects of zolpidem on network activity during the cardinal oscillations of non-REM sleep. For comparison, we also characterized the effects of diazepam and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP/gaboxadol), which acts predominantly at extra-synaptic GABARs. Zolpidem and THIP significantly increased the amplitudes of slow-waves, which were attenuated by diazepam. Zolpidem increased hippocampal ripple density whereas diazepam decreased both ripple density and intrinsic frequency. While none of the drugs affected thalamocortical spindles in isolation, zolpidem augmented the temporal coordination between slow-waves and spindles. At the cellular level, analyses of spiking activity from 523 PrL and 579 dCA1 neurons revealed that zolpidem significantly enhanced synchronized pauses in cortical firing during slow-wave down states, while increasing correlated activity within and between dCA1 and PrL populations. Of the drugs compared here, zolpidem was unique in augmenting coordinated activity within and between hippocampus and neocortex during non-REM sleep. Zolpidem's enhancement of hippocampal-prefrontal coupling may reflect the cellular basis of its potential to modulate offline memory processing.
Topics: Animals; Rats; Diazepam; Electroencephalography; gamma-Aminobutyric Acid; Hippocampus; Receptors, GABA-A; Sleep; Zolpidem
PubMed: 35717464
DOI: 10.1038/s41386-022-01355-9 -
Ceska a Slovenska Farmacie : Casopis... 2019Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by... (Review)
Review
Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patients comfort during this process. Patients are typically afraid of switching to a more suitable long-acting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.
Topics: Benzodiazepines; Diazepam; Drug Administration Schedule; Humans; Inactivation, Metabolic; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 31822106
DOI: No ID Found -
Journal of Analytical Toxicology May 2020Diazepam abuse is widespread all over the word, leading to an increasing number of forensic cases such as suicide, drug-driving and robbery, but relevant studies are...
Diazepam abuse is widespread all over the word, leading to an increasing number of forensic cases such as suicide, drug-driving and robbery, but relevant studies are limited regarding the extraction of diazepam and its metabolites in oral fluid. This study aimed to investigate the pharmacokinetics of diazepam and its metabolites in oral fluid after a single oral dose in healthy volunteers. There was a total of 28 volunteers, and each ingested 5 mg diazepam orally, then ~2 mL oral fluid were collected from each participant at post-consumption time-points of prior (zero), 1, 2, 4, 8, 12, 24 h and 2, 3, 6, 12 and 15 days, respectively. All samples were extracted with solid-phase extraction and analyzed with high-performance liquid chromatography-tandem mass spectrometry method, and diazepam and nordazepam were detected in the oral fluid of volunteers. Pharmacokinetics of diazepam in oral fluid conformed to a two-compartment model, and k01_HL, k12_HL, k10_HL were 0.7 ± 1.1, 31.4 ± 68.5, 12.1 ± 11.6 h, respectively, nordazepam conformed to an one-compartment model, and k01_HL, k10_HL were 41.5 ± 44.8, 282.3 ± 365.5 h, respectively. Both diazepam and nordazepam could be detected continuously for 15 days, although there were individual differences, and the results regarding diazepam detecting in oral fluid will be of much help in forensic science and drug screening filed.
Topics: Adult; Chromatography, High Pressure Liquid; Diazepam; Healthy Volunteers; Humans; Nordazepam; Saliva; Solid Phase Extraction
PubMed: 31965188
DOI: 10.1093/jat/bkz101 -
Critical Reviews in Toxicology Mar 2021Designer benzodiazepines are a part of the recently discovered abuse synthetic drugs called Novel Psychoactive Substances (NPS) which need to be controlled due to their... (Review)
Review
Designer benzodiazepines are a part of the recently discovered abuse synthetic drugs called Novel Psychoactive Substances (NPS) which need to be controlled due to their constantly growing market. Most of them are derived from the medically approved benzodiazepines used nowadays yet, may possess stronger effects, more toxicity, and longer durations of action. Some differences have also been observed in their detection and characteristics, in addition to the variations discovered in postmortem redistribution and drug stability. All these major alterations in features can result from only minor structural modifications. For example, a classic benzodiazepine (BZD) like diazepam only lacks one fluorine atom which exists in its derivatized designer drug, diclazepam, making substantial differences in activity. For this reason, it is essential to study the designer drugs in order to identify their dangers and distinguish them thus rule out their abuse and control the spread of such drugs. This review would highlight the distinct characteristics of some of the most commonly abused designer benzodiazepine analogies in relation to their original prescription BZD compounds.
Topics: Benzodiazepines; Designer Drugs; Diazepam; Humans; Prescriptions
PubMed: 34038656
DOI: 10.1080/10408444.2021.1907303 -
Journal of Analytical Toxicology Sep 2016To interpret postmortem toxicology results, reference concentrations for non-toxic and toxic levels are needed. Usually, measurements are performed in blood, but because... (Review)
Review
To interpret postmortem toxicology results, reference concentrations for non-toxic and toxic levels are needed. Usually, measurements are performed in blood, but because of postmortem redistribution phenomena this may not be optimal. Rather, measurement in the target organ of psychoactive drugs, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug-metabolite ratios were similar in brain and blood for most compounds. Duplicate measurements of brain samples showed that the pre-analytical variation in brain (5.9%) was relatively low, supporting the notion that brain tissue is a suitable postmortem specimen. The reported concentrations in both brain and blood can be used as reference values when evaluating postmortem cases.
Topics: Alprazolam; Blood-Brain Barrier; Bromazepam; Chlordiazepoxide; Diazepam; Forensic Toxicology; Humans
PubMed: 27416838
DOI: 10.1093/jat/bkw059 -
Journal of Child Neurology May 2023Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray...
Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).
Topics: Child; Humans; Anticonvulsants; Brain Diseases; Diazepam; Epilepsy; Epilepsy, Generalized; Lennox Gastaut Syndrome; Nasal Sprays; Seizures
PubMed: 37455404
DOI: 10.1177/08830738231185424 -
Revista Da Associacao Medica Brasileira... 2015to compare clinical and cost effectiveness of midazolam and diazepam for urgent intubation. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
to compare clinical and cost effectiveness of midazolam and diazepam for urgent intubation.
METHODS
patients admitted to the Central ICU of the Santa Casa Hospital Complex in Porto Alegre, over the age of 18 years, undergoing urgent intubation during 6 months were eligible. Patients were randomized in a single-blinded manner to either intravenous diazepam or midazolam. Diazepam was given as a 5 mg intravenous bolus followed by aliquots of 5 mg each minute. Midazolam was given as an intravenous bolus of 5 mg with further aliquots of 2.5 mg each minute. Ramsay sedation scale 5-6 was considered adequate sedation. We recorded time and required doses to reach adequate sedation and duration of sedation.
RESULTS
thirty four patients were randomized, but one patient in the diazepam group was excluded because data were lost. Both groups were similar in terms of illness severity and demographics. Time for adequate sedation was shorter (132 ± 87 sec vs. 224 ± 117 sec, p = 0.016) but duration of sedation was similar (86 ± 67 min vs. 88 ± 50 min, p = 0.936) for diazepam in comparison to midazolam. Total drug dose to reach adequate sedation after either drugs was similar (10.0 [10.0-12.5] mg vs. 15.0 [10.0-17.5] mg, p = 0.248). Arterial pressure and sedation intensity reduced similarly overtime with both drugs. Cost of sedation was lower for diazepam than for midazolam (1.4[1.4-1.8] vs. 13.9[9.4-16.2] reais, p <0.001).
CONCLUSIONS
intubation using intravenous diazepam and midazolam is effective and well tolerated. Sedation with diazepam is associated to a quicker sedation time and to lower costs.
Topics: Deep Sedation; Diazepam; Female; Humans; Hypnotics and Sedatives; Injections, Intravenous; Intensive Care Units; Intubation, Intratracheal; Male; Midazolam; Middle Aged; Single-Blind Method
PubMed: 25909205
DOI: 10.1590/1806-9282.61.01.030 -
Frontiers in Endocrinology 2023Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is...
OBJECTIVE
Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.
DESIGN/METHODS
Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of was measured in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.
RESULTS
Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized β=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mRNA expression in different tissues of CKD mice or in indoxyl sulfate-treated adipocytes .
CONCLUSIONS
Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.
Topics: Mice; Humans; Animals; Diazepam Binding Inhibitor; Indican; Carrier Proteins; Kidney; Diazepam; RNA, Messenger; Malnutrition
PubMed: 37288304
DOI: 10.3389/fendo.2023.1152444 -
The American Journal of Emergency... Jun 2021Front-loaded diazepam is used to rapidly control agitation in patients with severe alcohol withdrawal syndrome (AWS). Our institution began using front-loaded lorazepam... (Comparative Study)
Comparative Study
BACKGROUND
Front-loaded diazepam is used to rapidly control agitation in patients with severe alcohol withdrawal syndrome (AWS). Our institution began using front-loaded lorazepam in August 2017 secondary to a nation-wide shortage of intravenous (IV) diazepam. Currently, there are no studies comparing lorazepam to diazepam for frontloading in severe AWS.
METHOD
Retrospective cohort study of all adults presenting to the emergency department with a diagnosis of AWS and prescribed the institution's alcohol withdrawal agitated delirium protocol 8 months pre and post shortage of IV diazepam were eligible inclusion for the study. Of these, 106 patients were front-loaded with diazepam and 70 patients were front-loaded with lorazepam.
RESULTS
There was no difference in the mean change in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised scores 24 h pre and post front-loading in the two groups (-13.9 ± -8.08 vs. -13.1 ± -8.91, p = 0.534). Patients who received front-loaded lorazepam had an increased incidence of ICU-delirium (positive for the Confusion Assessment Method in the ICU: 75% with lorazepam vs. 52.6% with diazepam, p = 0.009) and a higher risk of over-sedation, but this did not reach statistical significance (Richmond Agitation-Sedation Scale score < -1: 32.1% with lorazepam vs. 18.2% with diazepam, p = 0.063).
CONCLUSION
Front-loaded lorazepam was similar to front-loaded diazepam in controlling AWS symptoms. Lorazepam's delayed onset of action should be considered when determining how quickly repeat doses are administered to avoid the potential for adverse drug events.
Topics: Alcohol Withdrawal Delirium; Biomarkers; Diazepam; Emergency Service, Hospital; Female; Humans; Hypnotics and Sedatives; Lorazepam; Male; Middle Aged; Retrospective Studies; Vital Signs
PubMed: 32402500
DOI: 10.1016/j.ajem.2020.04.095 -
Journal of Oral and Maxillofacial... May 2020
Topics: Anxiety; Diazepam; Midazolam; Nitrous Oxide; Research Design
PubMed: 32081691
DOI: 10.1016/j.joms.2020.01.017