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The Cochrane Database of Systematic... Sep 2014Status epilepticus is a medical emergency associated with significant mortality and morbidity that requires immediate and effective treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Status epilepticus is a medical emergency associated with significant mortality and morbidity that requires immediate and effective treatment.
OBJECTIVES
(1) To determine whether a particular anticonvulsant is more effective or safer to use in status epilepticus compared to another and compared to placebo.(2) To delineate reasons for disagreement in the literature regarding recommended treatment regimens and to highlight areas for future research.
SEARCH METHODS
For the latest update of this review, the following electronic databases were searched on 15/08/2013: the Cochrane Epilepsy Group's Specialized Register, CENTRAL The Cochrane Library July 2013, Issue 7, and MEDLINE (Ovid) 1946 to 15/08/2013.
SELECTION CRITERIA
Randomised controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion, assessed trial quality and extracted data.
MAIN RESULTS
Eighteen studies with 2755 participants were included. Few studies used the same interventions. Intravenous diazepam was better than placebo in reducing the risk of non-cessation of seizures (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.57 to 0.92), requirement for ventilatory support (RR 0.39, 95% CI 0.16 to 0.94), or continuation of status epilepticus requiring use of a different drug or general anaesthesia (RR 0.73, 95% CI 0.57 to 0.92). Intravenous lorazepam was better than placebo for risk of non-cessation of seizures (RR 0.52, 95% CI 0.38 to 0.71) and for risk of continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.52, 95% CI 0.38 to 0.71). Intravenous lorazepam was better than intravenous diazepam for reducing the risk of non-cessation of seizures (RR 0.64, 95% CI 0.45 to 0.90) and had a lower risk for continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.63, 95% CI 0.45 to 0.88). Intravenous lorazepam was better than intravenous phenytoin for risk of non-cessation of seizures (RR 0.62, 95% CI 0.45 to 0.86). Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures (RR 0.43 95% CI 0.30 to 0.62)For pre-hospital treatment, intramuscular midazolam is at least as effective as (probably more effective than) intravenous lorazepam in control of seizures (RR1.16, 95% CI 1.06 to 1.27) and frequency of hospitalisation (RR 0.88, 95% CI 0.79 to 0.97) or intensive care admissions (RR 0.79, 95% CI 0.65 to 0.96). It was uncertain whether Intravenous valproate was better than intravenous phenytoin in reducing risk of non-cessation of seizures (RR 0.75, 95% CI 0.28 to 2.00). Both levetiracetam and lorazepam were equally effective in aborting seizures (RR 0.97, 95% CI 0.44 to 2.13). Results for other comparisons of anticonvulsant therapies were uncertain due to single studies with few participants.The body of randomised evidence to guide clinical decisions is small. It was uncertain whether any anticonvulsant therapy was better than another in terms of adverse effects, due to few studies and participants identified. The quality of the evidence from the included studies is not strong but appears acceptable. We were unable to make judgements for risk of bias domains incomplete outcome reporting (attrition bias) and selective outcome reporting (selection bias) due to unclear reporting by the study authors.
AUTHORS' CONCLUSIONS
Intravenous lorazepam is better than intravenous diazepam or intravenous phenytoin alone for cessation of seizures. Intravenous lorazepam also carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia compared with intravenous diazepam. Both intravenous lorazepam and diazepam are better than placebo for the same outcomes. For pre hospital management, midazolam IM seemed more effective than lorazepam IV for cessation of seizures, frequency of hospitalisation and ICU admissions however,it was unclear whether the risk of recurrence of seizures differed between treatments. The results of other comparisons of anticonvulsant therapies versus each other were also uncertain. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. Results for other comparisons of anticonvulsant therapies were uncertain due to single studies with few participants.
Topics: Anticonvulsants; Diazepam; Humans; Injections, Intravenous; Lorazepam; Midazolam; Phenobarbital; Phenytoin; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 25207925
DOI: 10.1002/14651858.CD003723.pub3 -
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 -
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 -
Behavioural Brain Research Jan 2016Drug residue contamination in aquatic ecosystems has been studied extensively, but the behavioral effects exerted by the presence of these drugs are not well known....
Drug residue contamination in aquatic ecosystems has been studied extensively, but the behavioral effects exerted by the presence of these drugs are not well known. Here, we investigated the effects of acute stress on anxiety, memory, social interaction, and aggressiveness in zebrafish exposed to fluoxetine and diazepam at concentrations that disrupt the hypothalamic-pituitary-interrenal (HPI) axis. Stress increased the locomotor activity and time spent in the bottom area of the tank (novel tank). Fluoxetine and diazepam prevented these behaviors. We also observed that stress and fluoxetine and diazepam exposures decreased social interaction. Stress also increased aggressive behavior, which was not reversed by fluoxetine or diazepam. These data suggest that the presence of these drugs in aquatic ecosystems causes significant behavioral alterations in fish.
Topics: Aggression; Animals; Behavior, Animal; Diazepam; Disease Models, Animal; Female; Fluoxetine; GABA Modulators; Male; Motor Activity; Selective Serotonin Reuptake Inhibitors; Stress, Psychological; Zebrafish
PubMed: 26403161
DOI: 10.1016/j.bbr.2015.09.027 -
Journal of Clinical Pharmacology Oct 2022Benzodiazepines induce a series of clinical effects by modulating subtypes of γ-aminobutyric acid type A receptors in the central nervous system. The brain...
Benzodiazepines induce a series of clinical effects by modulating subtypes of γ-aminobutyric acid type A receptors in the central nervous system. The brain concentration-time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4-benzodiazepines diazepam and nordiazepam was developed from plasma concentration-time courses with PK-Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration-time profiles correlated with diazepam pharmacodynamic end points. With a 30-mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant γ-aminobutyric acid type A receptors composed of α1β2γ2s, α2β2γ2s, and α5β2γ2s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10-mg peroral administrations of diazepam delivered every 24 hours, steady-state peak and trough unbound interstitial brain diazepam concentrations are 22.3 ± 7.5 and 9.3 ± 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13- to 30-Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.
Topics: Benzodiazepines; Brain; Diazepam; Humans; Nordazepam; gamma-Aminobutyric Acid
PubMed: 35533144
DOI: 10.1002/jcph.2071 -
ASN Neuro 2023Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory...
Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65 kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.
Topics: Rats; Animals; Glucose; Ventromedial Hypothalamic Nucleus; Hypoglycemic Agents; Rats, Sprague-Dawley; Diazepam Binding Inhibitor; Glucokinase; Glycogen; Hypoglycemia; RNA, Messenger; RNA, Small Interfering; Diazepam
PubMed: 38031405
DOI: 10.1177/17590914231214116 -
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 -
Drug and Alcohol Dependence Jul 2022Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABA receptor resulting in hyperpolarisation. BZDs are often a difficult... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABA receptor antagonist, may be a useful agent to allow for rapid detoxification.
AIM
To collect pilot data on the safety and efficacy of low-dose subcutaneous flumazenil to reduce BZD use, withdrawal symptoms, and craving in participants taking above and below the therapeutic maximum diazepam equivalent of 30 mg to inform on sample size for future trials.
METHOD
In a randomised double-blinded crossover study design, participants received low-dose flumazenil first (4 mg/24 h for approximately eight days) or placebo first. Groups were divided into those taking < 30 mg diazepam equivalent and ≥ 30 mg diazepam equivalent at baseline. Main outcome measures were percentage reduction in daily diazepam use, withdrawal symptoms, and craving scores from baseline, difference in diazepam use across the placebo first group, and flumazenil related adverse events.
RESULTS
Twenty-eight participants were recruited and randomised to flumazenil first (n = 14) and placebo first (n = 14). In participants taking ≥ 30 mg diazepam equivalent at baseline (n = 15), flumazenil significantly reduced diazepam use by 30.5% (p = 0.024) compared to placebo.
CONCLUSION
Low-dose flumazenil may aid in BZD detoxification in participants taking daily diazepam equivalent doses greater than or equal to the therapeutic maximum (≥30 mg) by reducing the need for diazepam.
Topics: Benzodiazepines; Cross-Over Studies; Diazepam; Double-Blind Method; Flumazenil; GABA-A Receptor Antagonists; Humans; Inactivation, Metabolic; Pilot Projects; Receptors, GABA-A; Substance Withdrawal Syndrome
PubMed: 35644071
DOI: 10.1016/j.drugalcdep.2022.109501 -
Journal of Biomolecular Structure &... 2023Anxiety and epilepsy affect millions of people worldwide, and the treatment of these pathologies involves the use of Benzodiazepines, drugs that have serious adverse...
Anxiety and epilepsy affect millions of people worldwide, and the treatment of these pathologies involves the use of Benzodiazepines, drugs that have serious adverse effects such as dependence and sedation, so the discovery of new anxiolytic and antiepileptic drugs are necessary. Many routes for synthesizing ibuprofen derivatives have been developed, and these derivatives have shown promising pharmacological effects. Therefore, this study aims to evaluate its anxiolytic and anticonvulsant effect against the adult Zebrafish animal model of Ibuprofen (IBUACT) and its interaction with the GABAergic receptor through in silico studies. The light/dark preference test (Scototaxis test) was used to evaluate the anxiolytic behavior of adult Zebrafish acutely treated with IBUACT and Diazepam, and their anticonvulsant effects were investigated through the pentylenetetrazol (PTZ)-induced seizure model. Animals treated with IBUACT showed anxiolytic behavior similar to Diazepam, and pretreatment with flumazenil reversed this behavior. PTZ-induced seizures were delayed by IBUACT in all three stages and were shown to bind strongly in the Diazepam region of GABA. In addition, this work presents evidence of new pharmacological applications of ibuprofen derivative in pathologies of the central nervous system (CNS), opening the horizon for new studies.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Animals; Anti-Anxiety Agents; Anticonvulsants; Zebrafish; Ibuprofen; Diazepam; Seizures
PubMed: 36695084
DOI: 10.1080/07391102.2023.2170915 -
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