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Ugeskrift For Laeger Jun 2022In this case report we describe a life-threatening episode of delirium in a 51-year-old man. The condition was triggered by an abrupt withdrawal of benzodiazepines. The...
In this case report we describe a life-threatening episode of delirium in a 51-year-old man. The condition was triggered by an abrupt withdrawal of benzodiazepines. The patient had been taking multiple sedatives for several years but a large proportion of the drugs were not available in Denmark. His general practitioner substituted and prescribed oxazepam and zolpidem for ten days. Afterwards the patient did not have access to benzodiazepines and developed a severe benzodiazepine withdrawal delirium. He was treated with diazepam and olanzapine with gradual dose reduction.
Topics: Alcohol Withdrawal Delirium; Benzodiazepines; Delirium; Diazepam; Humans; Male; Middle Aged; Oxazepam; Substance Withdrawal Syndrome
PubMed: 35703059
DOI: No ID Found -
Proceedings of the National Academy of... Oct 2022Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that...
Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible knockout or a constitutive mutation that abolishes ACBP/DBI binding to the GABA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of . Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.
Topics: Animals; Mice; Acetaminophen; Antibodies, Monoclonal; Antioxidants; Autoantibodies; Autophagy; Carbon Tetrachloride; Carrier Proteins; Choline; Coenzyme A; Concanavalin A; Diazepam; Diazepam Binding Inhibitor; Fatty Acids; Fibrosis; Inflammation; Methionine; Receptors, GABA-A
PubMed: 36191214
DOI: 10.1073/pnas.2207344119 -
ACS Chemical Neuroscience May 2021Opioids and benzodiazepines have complex drug-drug interactions (DDIs), which serve as an important source of adverse drug effects. In this work, we predicted the DDI...
Opioids and benzodiazepines have complex drug-drug interactions (DDIs), which serve as an important source of adverse drug effects. In this work, we predicted the DDI between oxycodone (OXY) and diazepam (DZP) in the human body by applying pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation. First, we studied the PK interaction between OXY and DZP with a physiologically based pharmacokinetic (PBPK) model. Second, we applied molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energy method to predict the PD-DDI between these two drugs. The PK interaction between OXY and DZP predicted by the PBPK model was not obvious. No significant interaction was observed between the two drugs at normal doses, though very high doses of DZP demonstrated a non-negligible inhibitory effect on OXY metabolism. On the contrary, the molecular modeling study shows that DZP has potential to compete with OXY at the same binding pocket of the active μ-opioid receptor (MOR) and κ-opioid receptor (KOR). MD simulation and MM-PBSA calculation results demonstrated that there is likely a synergetic effect between OXY and DZP binding to opioid receptors, as OXY is likely to target the active MOR while DZP selectively binds to the active KOR. Thus, pharmacokinetics contributes slightly to the DDI between OXY and DZP although an overdose of DZP has been brought to attention. Pharmacodynamics is likely to play a more important role than pharmacokinetics in revealing the mechanism of DDI between OXY and DZP.
Topics: Computer Simulation; Diazepam; Drug Interactions; Humans; Models, Biological; Molecular Docking Simulation; Oxycodone; Pharmaceutical Preparations
PubMed: 33950681
DOI: 10.1021/acschemneuro.0c00810 -
Neuron Oct 2022Earlier work has implicated the neurotransmitter GABA in controlling forebrain progenitor proliferation. In this issue of Neuron, Everlien et al. (2022) demonstrate...
Earlier work has implicated the neurotransmitter GABA in controlling forebrain progenitor proliferation. In this issue of Neuron, Everlien et al. (2022) demonstrate that diazepam binding inhibitor acts to keep the neurogenesis-promoting effect of GABA at bay.
Topics: Diazepam; Diazepam Binding Inhibitor; Neurogenesis; Neurons; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 36202087
DOI: 10.1016/j.neuron.2022.08.030 -
The Turkish Journal of Pediatrics 2023Catatonia is a complex neuropsychiatric disorder involving stupor, waxy flexibility, and mutism lasting more than 1 hour. It has arisen mostly from mental and neurologic...
BACKGROUND
Catatonia is a complex neuropsychiatric disorder involving stupor, waxy flexibility, and mutism lasting more than 1 hour. It has arisen mostly from mental and neurologic disorders. Organic causes are more prominent in children.
CASE
A 15-year-old female who had refused to eat and drink for 3 days, had not talked, and had stood in a fixed position for long periods was admitted to the inpatient clinic, and she was diagnosed with catatonia. Her maximum score on the Bush-Francis Catatonia Rating Scale (BFCRS) was 15/69 on day 2 of her stay. On neurologic examination, the patient`s cooperation was limited, and she was apathetic to her surroundings and stimuli and inactive. Other neurologic examination findings were normal. To investigate catatonia etiology, her biochemical parameters, thyroid hormone panel, and toxicology screening were conducted but all parameters were normal. Cerebrospinal fluid examination and autoimmune antibodies were negative. Sleep electroencephalography showed diffuse slow background activity, and brain magnetic resonance imaging was normal. As a first-line treatment for catatonia, diazepam was started. With her poor response to diazepam, we continued to evaluate the cause and found the transglutaminase levels were 153 U/mL (normal values, < 10 U/mL). The patient`s duodenal biopsies showed changes consistent with Celiac disease (CD). Catatonic symptoms did not benefit from a gluten-free diet or oral diazepam for 3 weeks. Then, diazepam was replaced with amantadine. With amantadine, the patient recovered within 48 hours, and her BFCRS retreated to 8/69.
CONCLUSIONS
Even without gastrointestinal manifestations, CD may present with neuropsychiatric symptoms. According to this case report, CD should be investigated in patients with unexplained catatonia, and that CD may only present with neuropsychiatric symptoms.
Topics: Child; Female; Humans; Adolescent; Catatonia; Celiac Disease; Amantadine; Biopsy; Diazepam
PubMed: 36866995
DOI: 10.24953/turkjped.2022.411 -
Toxicology Reports 2020Diazepam is a medicine of the family benzodiazepine, used to treat various CNS disorders. To date, no study is available for biochemical analysis of diazepam in cardiac...
Diazepam is a medicine of the family benzodiazepine, used to treat various CNS disorders. To date, no study is available for biochemical analysis of diazepam in cardiac dysfunction. This study aimed to determine the effect of diazepam in stress-induced cardiac dysfunctions in rats. Male Wistar Albino rats were divided into four groups with six animals in each group for 90 days of the experimental protocol. Group1 served as a Normal Control (NC), Groups 2, as a Disease Control (DC), Group 3 as a Diazepam Control (DIC), and Group 4 as a Disease + Diazepam Treatment (DDT). Disease Control and Disease + Diazepam Treatment animals exposed to regular stress by forced swimming exercise method for 3 months. Diazepam Control and Disease + Diazepam Treatment received 5 mg/kg/p.o the daily dose of diazepam. At the end of the protocol, animals were sacrificed, heart preserved, blood collected, and utilized for biochemical estimations. Heart weight was increased in DC as compared to NC. Serum levels of cardiac biomarkers, creatine phosphokinase (CPK), creatine kinase-MB (CPK-MB), lactate dehydrogenase (LDH), High sensitivity C-reactive protein (hs-CRP) and troponin I (TnI) were significantly increased in DC as compared to NC. Heart tissue examined for histological changes. The altered serum levels of CPK, CPK-MB, LDH, hs-CRP, and TnI were significantly restored by the treatment of diazepam. Serum levels of Sodium, Potassium, Calcium, and Magnesium was increased in DC animals as compared to NC. The altered ionic level was also restored by the treatment of diazepam. Level of various cardiac markers and ions in the plasma were also slightly elevated in DIC. Histopathological studies are also in agreement with serological examinations and bonafide cardioprotective influences of diazepam in cardiac dysfunction. Conclusively research findings endorse the cardioprotective effect of diazepam in stress-induced cardiac dysfunction in rats.
PubMed: 32642445
DOI: 10.1016/j.toxrep.2020.06.004 -
The Cochrane Database of Systematic... Oct 2016Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane review first published in 2013, and previously updated in 2014.
OBJECTIVES
To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke.
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (accessed March 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 3, part of the Cochrane Library (accessed March 2016), MEDLINE (from 1949 to March 2016), Embase (from 1980 to March 2016), CINAHL (from 1982 to March 2016), AMED (from 1985 to March 2016), and 11 Chinese databases (accessed March 2016). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias.
MAIN RESULTS
We included five trials with 3838 participants (3758 analyzed). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. Four trials (N = 2909) measured death and dependency at three months for chlormethiazole versus placebo; pooled results did not find a significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11). One trial (N = 849) measured this outcome for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; N = 2527) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; N = 2527).
AUTHORS' CONCLUSIONS
This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.
Topics: Acute Disease; Chlormethiazole; Diazepam; Disorders of Excessive Somnolence; GABA Agonists; Humans; Neuroprotective Agents; Randomized Controlled Trials as Topic; Rhinitis; Stroke
PubMed: 27701753
DOI: 10.1002/14651858.CD009622.pub4 -
BMC Neuroscience Dec 2019The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these...
BACKGROUND
The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons.
METHOD
We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase.
RESULTS
While both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p < 0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p < 0.05, Kolmogorov-Smirnov test).
CONCLUSION
Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.
Topics: Action Potentials; Animals; Central Nervous System Depressants; Diazepam; Ethanol; Female; GABA Modulators; Male; Neocortex; Neurons; Rats, Sprague-Dawley; Tissue Culture Techniques
PubMed: 31823754
DOI: 10.1186/s12868-019-0540-6 -
Epilepsy & Behavior : E&B Jul 2023People with epilepsy may experience episodes of frequent seizure activity (seizure clusters, acute repetitive seizures), and benzodiazepines are the cornerstone of...
People with epilepsy may experience episodes of frequent seizure activity (seizure clusters, acute repetitive seizures), and benzodiazepines are the cornerstone of rescue treatment. Cannabidiol (CBD) can be used as an adjunctive treatment for epilepsy, and it may interact with other antiseizure drugs, such as benzodiazepines. Here, we examined the safety and effectiveness of intermittent use of diazepam nasal spray in patients with seizure clusters who also received CBD treatment. This analysis included data from patients aged 6 to 65 years enrolled in a phase 3, long-term safety study of diazepam nasal spray. Age- and weight-based dosing of diazepam nasal spray were administered during a 12-month treatment period. Concomitant CBD use was recorded, and treatment-emergent adverse events (TEAEs) were collected. Of 163 treated patients, 119 (73.0%) did not receive CBD, 23 (14.1%) received the US Food and Drug Administration-approved highly purified CBD and 21 (12.9%) received another form of CBD. On average, patients receiving highly purified CBD were younger and more likely to have epileptic encephalopathies, including Dravet syndrome or Lennox-Gastaut syndrome, than patients who received another CBD preparation or no CBD. Rates of TEAEs and serious TEAEs were greater in patients who received any form of CBD (90.9% and 45.5%, respectively) compared with no CBD (79.0% and 26.1%, respectively). However, the lowest rates of TEAEs attributed to diazepam nasal spray were reported in patients who received highly purified CBD (13.0%), and this result was maintained in those who received concomitant clobazam. Use of second doses of diazepam nasal spray, a proxy for effectiveness, was lowest in the highly purified-CBD group (8.2%) compared with the no-CBD (11.6%) and other-CBD groups (20.3%). These results suggest that CBD does not alter the safety and effectiveness of diazepam nasal spray and supports concomitant use in appropriate patients.
Topics: Humans; Anticonvulsants; Cannabidiol; Diazepam; Epilepsy; Nasal Sprays; Seizures; Treatment Outcome
PubMed: 37210793
DOI: 10.1016/j.yebeh.2023.109248 -
JPMA. the Journal of the Pakistan... Feb 2021To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children.
OBJECTIVE
To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children.
METHODS
The comparative study was conducted in the paediatric neurological emergency unit of The Children's Hospital and the Institute of Child Health, Multan, Pakistan, from December 15, 2018, to May 14, 2019, and comprised paediatric patients of status epilepticus seizures which were divided into Diazepam and Midazolam groups. Data was analysed using Graph-Pad Prism 5.
RESULTS
Of the 164 patients, 82(50%) were in each of the two groups. There was no significant difference between the groups in terms of weight, age, residence area of patients and mean duration of seizures (p>0.05). Status epilepticus seizures subsided after intravenous midazolam administration in 77(93.90%) cases, while success in the diazepam group 64(78.05%) (p<0.05). Mean time taken by midazolam to halt seizures was significantly shorter than diazepam (p<0.05) and less cases of treatment failure were observed with intravenous midazolam (p<0.05). Somnolence was observed after diazepam administration in 47(57.3%) cases (p=0.0001).
CONCLUSION
Intravenous midazolam was found to be superior in efficacy than intravenous diazepam in controlling status epilepticus seizures.
Topics: Anticonvulsants; Child; Diazepam; Humans; Midazolam; Pakistan; Status Epilepticus
PubMed: 33941951
DOI: 10.47391/JPMA.843