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Emergency Medicine Journal : EMJ Jul 2023Acute low back pain (LBP) is a common complaint in the emergency department and achieving effective analgesia can be challenging. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute low back pain (LBP) is a common complaint in the emergency department and achieving effective analgesia can be challenging.
METHODS
In this multicentre randomised double-blind clinical trial conducted at three EDs in Iran from August to November 2020, we assessed the efficacy and adverse effects of two muscle relaxants in patients aged 18 years or older who suffered LBP in the last 6 weeks. Group 1 received intravenous methocarbamol and group 2 received intravenous diazepam followed by a weight-based dose of intravenous morphine in both groups. Exclusion criteria mainly included non-spine aetiologies, cord compression, acute gastrointestinal bleeding, renal/hepatic insufficiency, pregnancy, breast feeding and unstable vital signs. Pain scores and adverse events were measured by a Numeric Rating Scale (NRS) at baseline and after 30 and 60 min by one of the researchers who was not involved with patient visits and was blinded to the intervention. We used -test to assess the mean difference of NRS at 30 and 60 min.
RESULTS
Out of 101 enrolled patients, 50 participants received methocarbamol and 51 diazepam. The baseline mean pain scores and demographic characteristics were not different between the study groups. Pain scores were reduced by both agents after 60 min, with slightly greater pain reductions in the diazepam group in comparison with methocarbamol (mean difference -6.1, 95% CI -6.5 to -5.7 vs mean difference -5.2, 95% CI -5.7 to -4.7, respectively, p<0.001). ED length of stay of patients did not differ between the groups (methocarbamol 5.9 vs diazepam 4.8 hours, p=0.365). Patients receiving diazepam were more likely to report drowsiness (2 (4.0%) vs 15 (29.4%), p=0.001).
CONCLUSIONS
In patients with LBP, the pain was relieved in the methocarbamol and diazepam groups after 60 min. Although diazepam was more effective, its use was associated with a slightly higher risk of drowsiness.
TRIAL REGISTRATION NUMBER
The protocol of this clinical trial was prospectively registered in the irct.ir (IRCTID: IRCT20151113025025N4; https://irct.ir/trial/50148) .
Topics: Humans; Methocarbamol; Diazepam; Low Back Pain; Treatment Outcome; Acute Pain; Emergency Service, Hospital; Double-Blind Method
PubMed: 37068928
DOI: 10.1136/emermed-2021-211485 -
International Journal of Legal Medicine Jan 2017Only sporadic data are available on hair concentrations of diazepam and some of its metabolites (nordazepam, oxazepam, and temazepam) following a single controlled dose....
Only sporadic data are available on hair concentrations of diazepam and some of its metabolites (nordazepam, oxazepam, and temazepam) following a single controlled dose. The aim of this study was to investigate the deposition of diazepam and its metabolites in human hair after eight healthy volunteers (four women and four men, ages 24-26, East Asian) consumed 10 mg of diazepam. Hair was collected from all volunteers 1 month after exposure, and also 2 months post-exposure from men and 10 months post-exposure from women. Diazepam and the complete metabolite profile, including oxazepam glucuronide and temazepam glucuronide, were measured by ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with limits of quantifications (LOQs) of 0.5-2.5 pg/mg for diazepam, nordazepam, oxazepam, and temazepam, and of 10 pg/mg for oxazepam glucuronide and temazepam glucuronide. There were no differences by gender in the amounts of diazepam or metabolites found. The concentration of the main metabolite nordazepam was consistently higher than that of diazepam at both 1 and 2 months after consumption. Oxazepam and temazepam traces were found in some volunteers' hair, but the glucuronides were not detected. Diazepam and nordazepam levels at 10 months post-exposure were extremely low (near the LOQ), indicating drug loss by personal hygiene and physical handling. To our knowledge, this is the first single-dose diazepam study using black hair and the first study to include measurements of oxazepam glucuronide and temazepam glucuronide in human hair.
Topics: Adult; Asian People; Chromatography, Liquid; Diazepam; Female; Hair; Healthy Volunteers; Humans; Hypnotics and Sedatives; Male; Nordazepam; Oxazepam; Tandem Mass Spectrometry; Temazepam; Young Adult
PubMed: 27534563
DOI: 10.1007/s00414-016-1429-x -
Analytical Biochemistry Dec 2021A high-throughput quantitative analytical method based on Direct Analysis in Real Time tandem mass spectrometry (DART-MS/MS) has been developed and validated for the...
A high-throughput quantitative analytical method based on Direct Analysis in Real Time tandem mass spectrometry (DART-MS/MS) has been developed and validated for the determination of diazepam in rat plasma, whereby analyzing of each sample needs merely 25 μL plasma, simple solid phase extraction sample preparation and 15 s acquisition time. The multiple reaction monitoring (MRM) transitions at m/z 285.2 → 193.1 and 316.0 → 270.0 were selected for the monitoring of diazepam and its internal standard clonazepam respectively. A good linearity within the range of 10-2000 ng/mL, an intra- and inter-day precisions within <7.78% as to an accuracy ranging from 1.04% to 7.92% have been achieved. The method has been successfully applied to the pharmacokinetic study of diazepam in rats' plasma after a single intragastric administration at a dose of 10 mg/kg. The results indicate that this method fulfills the requirements of the bioanalysis in sensitivity and accuracy. It shows considerable promise for application of DART-MS to the quantitative investigation of other drugs.
Topics: Animals; Diazepam; Female; High-Throughput Screening Assays; Male; Molecular Structure; Rats; Tandem Mass Spectrometry; Time Factors
PubMed: 34715069
DOI: 10.1016/j.ab.2021.114435 -
Journal of Analytical Toxicology Mar 2023Etizolam is a benzodiazepine (BZD). Etizolam is structurally different from BZDs as a thiophene replaces the benzene ring and a triazole ring is fused to the diazepine... (Review)
Review
Etizolam is a benzodiazepine (BZD). Etizolam is structurally different from BZDs as a thiophene replaces the benzene ring and a triazole ring is fused to the diazepine ring, but etizolam's pharmacological profile is similar. Etizolam has been used to treat anxiety and panic disorders, to reduce depressive and somatization symptoms and to induce muscle relaxation. Etizolam is used recreationally due to its reinforcing and sedative effects. Etizolam is available in tablet or powder form or administered on blotter paper that can be placed on the tongue for oral absorption. Etizolam metabolizes into two major metabolites: α-hydroxyetizolam and 8-hydroxyetizolam, and all three compounds can be detected in different biological specimens using various common analytical techniques such as immunoassay, chromatography and mass spectrometry. Etizolam is a controlled drug in many countries around the globe but is approved for medical use in some countries, such as Japan, South Korea and Italy. This work is a collation and review of available literature on etizolam to help improve the fundamental understanding of its toxicology, outline best analytical practice, and aid interpretation of toxicology results.
Topics: Benzodiazepines; Diazepam; Mass Spectrometry; Republic of Korea
PubMed: 36477341
DOI: 10.1093/jat/bkac096 -
Epilepsia Mar 2020The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The study assesses the bioavailability of diazepam after intranasal administration (diazepam nasal spray) in healthy volunteers. Comparative agents were diazepam rectal gel, which served as the regulatory reference product; and oral diazepam, a product with decades of clinical use. Tolerability of diazepam nasal spray was also assessed.
METHODS
This was a phase 1, open-label, randomized, single-dose, three-treatment, three-period, six-sequence crossover study in 48 healthy adult subjects that consisted of a screening period, a baseline period, and an open-label treatment period. Interperiod intervals were at least 28 days.
RESULTS
Forty-eight healthy volunteer subjects were enrolled, two of whom discontinued before receiving study medication. For all routes of administration, the onset of diazepam absorption was rapid, with measurable concentrations of drug present by the first sample time point. The t (time to reach maximum plasma concentration) was similar for diazepam nasal spray and diazepam rectal gel, both of which were slower than oral diazepam in fasted individuals. Variability (as defined by % coefficient of variation of geometric mean) in peak plasma concentration and area under the curve was lowest with oral diazepam, followed by diazepam nasal spray, with diazepam rectal gel showing the greatest variability. Overall, 131 treatment-emergent adverse events (TEAEs) were considered mild (42 subjects, 91.3%), four TEAEs were considered moderate (four subjects, 8.3%), and no TEAEs were considered severe. The most commonly reported TEAE was somnolence at 56.5% (26/46) during diazepam nasal spray treatment, 89.1% (41/46) with the rectal diazepam gel treatment, and 82.6% (38/46) with oral diazepam treatment. No nasal irritation was observed for the majority of the subjects at any time point after administration, with no score higher than 2 ("minor bleeding that stops within 1 minute").
SIGNIFICANCE
Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).
Topics: Administration, Intranasal; Administration, Oral; Administration, Rectal; Adolescent; Adult; Biological Availability; Diazepam; Female; Gels; Healthy Volunteers; Humans; Male; Middle Aged; Nasal Sprays; Sleepiness; Young Adult
PubMed: 32065672
DOI: 10.1111/epi.16449 -
Journal of Child Neurology Aug 2016Midazolam, lorazepam, and diazepam were recommended as emergent initial therapy for status epilepticus. However, there are no current studies to confirm the best agent... (Comparative Study)
Comparative Study Meta-Analysis Review
Midazolam, lorazepam, and diazepam were recommended as emergent initial therapy for status epilepticus. However, there are no current studies to confirm the best agent for pediatric status epilepticus. We compared the efficacy of midazolam, lorazepam, and diazepam in treating pediatric status epilepticus using a network meta-analysis method. In total, 16 randomized controlled trials containing 1821 patients were included. Nonintravenous midazolam, intravenous lorazepam, and intravenous diazepam were more successful in achieving seizure cessation when compared with nonintravenous diazepam (odds ratio = 2.23, 95% credibility interval: 1.62, 3.10; odds ratio = 2.71, 95% credibility interval: 1.25, 5.89; odds ratio = 2.65, 95% credibility interval: 1.12, 6.29; respectively). Among lorazepam, midazolam, and diazepam, midazolam had the highest probability (surface under the cumulative ranking area [SUCRA] = 0.792) of achieving seizure cessation, and lorazepam had the largest probability (surface under the cumulative ranking area = 0.4346) of being the best treatment in reduction of respiratory depression. In conclusion, nonintravenous midazolam and intravenous lorazepam were superior to intravenous or nonintravenous diazepam, and intravenous lorazepam was at least as effective as nonintravenous midazolam in treating pediatric status epilepticus.
Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Diazepam; Humans; Infant; Lorazepam; Midazolam; Network Meta-Analysis; Status Epilepticus; Young Adult
PubMed: 27021145
DOI: 10.1177/0883073816638757 -
Journal of Applied Toxicology : JAT Aug 2018Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse... (Review)
Review
Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.
Topics: Animals; Antidotes; Antioxidants; Atropine; Cholinesterase Reactivators; Diazepam; Humans; Organophosphate Poisoning; Oxidative Stress; Oximes
PubMed: 29516527
DOI: 10.1002/jat.3605 -
Brain Research Oct 2023Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of... (Meta-Analysis)
Meta-Analysis
Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of anxiety and post-traumatic stress disorder. However, the neural mechanisms of AA extinction and its relationship to anxiety remain unclear. We examined AA extinction during three extinction training sessions in two-way active avoidance paradigm and tested the effect of anxiolytic on AA extinction. Then we performed a meta-analysis of rodent studies, identified anxiolytic diazepam facilitates AA acquisition, and tested the same treatment in AA extinction. Diazepam-treated rats significantly reduced avoidance in the first two extinction training, compared with the saline-treated rats, and the reduction in avoidance remained in the third drug-free session. Then we explored extinction associated hippocampal and amygdala activity in saline-and diazepam-treated rats using c-Fos immunostaining following the last extinction session. The density of c-Fos positive cells was higher in dorsal CA3 of the diazepam group than in that of saline-treated animals, and was also higher in the central and basolateral amygdala regions of diazepam-treated rats than in that of saline-treated animals. Combined, these results suggest anxiolytics promotes AA extinction associated with dorsal CA3 and amygdala activity changes.
Topics: Rats; Animals; Diazepam; Anti-Anxiety Agents; Extinction, Psychological; Amygdala; Anxiety; Proto-Oncogene Proteins c-fos; Avoidance Learning
PubMed: 37429455
DOI: 10.1016/j.brainres.2023.148481 -
Physiological Reports Sep 2023The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form...
The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form of diclofenac, and frequently used clinically for inflammatory process by inhibiting cyclooxygenase enzyme (COX). Wistar rats aged 2-4 months were divided into Epilepsy, Diazepam, Diclofenac potassium, and Diazepam+diclofenac potassium groups. Diazepam and diclofenac potassium were administered intraperitoneally 30 min after the epileptiform activity was created with penicillin injected intracortically under anesthesia. After the electrophysiological recording was taken in the cortex for 125 min, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated by the ELISA in the serums. No change was observed between the groups in serum IL-1β, IL-6, and TNF-α values. It was observed that the co-administration of diclofenac potassium and diazepam at 51-55, 56-60, 61-65, 111-115, and 116-120 min was more effective in reducing spike amplitude than diclofenac potassium alone (p < 0.05). Single-dose diclofenac potassium did not have an anti-inflammatory effect in epileptiform activity but both diazepam and diclofenac potassium reduced the epileptiform activity.
Topics: Rats; Animals; Rats, Wistar; Diclofenac; Interleukin-6; Tumor Necrosis Factor-alpha; Cyclooxygenase 2; Diazepam; Anti-Inflammatory Agents
PubMed: 37688418
DOI: 10.14814/phy2.15800 -
Medical Science Monitor : International... Dec 2021BACKGROUND Being refractory to drugs remains an urgent treatment problem in status epilepticus (SE). The fact that γ-aminobutyric acid A receptors (GABAARs) become...
BACKGROUND Being refractory to drugs remains an urgent treatment problem in status epilepticus (SE). The fact that γ-aminobutyric acid A receptors (GABAARs) become internalized and inactive, N-methyl-D-aspartate receptors (NMDARs) become externalized and active during SE may explain the refractoriness to benzodiazepine. However, the real-time dynamic efficacy of antiepileptic drugs remains unclear. Therefore, we propose a hypothesis that diazepam monotherapy or diazepam-ketamine dual therapy could terminate seizures and reduce mortality in the SE model at different time points during ongoing SE. MATERIAL AND METHODS An SE model was established in adult Sprague-Dawley rats with lithium and pilocarpine. The GABAAR agonist diazepam was injected at 5, 10, 20, or 30 min when SE continued. In addition, diazepam and the NMDAR antagonist ketamine were injected at 10 to 60 min at 6 different time points. We measured seizure-free rates, seizure duration, degree of behavioral seizure, and mortality. RESULTS Diazepam monotherapy at 5 min and 10 min from the beginning of SE was able to terminate seizures and improved survival rates. Diazepam-ketamine dual therapy at 10 min, 20 min, and 30 min from the beginning of SE terminated seizures and achieved high survival rates. CONCLUSIONS In this parallel randomized controlled trial with a rat model, we found that diazepam monotherapy was an effective antiepileptic strategy at the early stage of SE less than 10 min after SE onset. If SE lasts more than 10 min but less than 30 min, the diazepam-ketamine dual therapy strategy may be an appropriate choice.
Topics: Analgesics; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Female; Ketamine; Male; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Treatment Outcome
PubMed: 34866132
DOI: 10.12659/MSM.934043