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Neurology Aug 2023The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory convulsive status epilepticus (RSE) in children.
METHODS
An observational case-control study was conducted comparing pediatric patients (1 month-21 years) with convulsive SE whose seizures stopped after benzodiazepine (BZD) and a single second-line antiseizure medication (ASM) (responsive established status epilepticus [rESE]) with patients requiring more than a BZD and a single second-line ASM to stop their seizures (RSE). These subpopulations were obtained from the pediatric Status Epilepticus Research Group study cohort. We explored clinical variables that could be acquired early after presentation to emergency medical services with univariate analysis of the raw data. Variables with < 0.1 were retained for univariable and multivariable regression analyses. Multivariable logistic regression models were fit to age-matched and sex-matched data to obtain variables associated with RSE.
RESULTS
We compared data from a total of 595 episodes of pediatric SE. Univariate analysis demonstrated no differences in time to the first BZD (RSE 16 minutes [IQR 5-45]; rESE 18 minutes [IQR 6-44], = 0.068). Time to second-line ASM was shorter in patients with RSE (RSE 65 minutes; rESE 70 minutes; = 0.021). Both univariable and multivariable regression analyses revealed a family history of seizures (OR 0.37; 95% CI 0.20-0.70, = 0.0022) or a prescription for rectal diazepam (OR 0.21; 95% CI 0.078-0.53, = 0.0012) was associated with decreased odds of RSE.
DISCUSSION
Time to initial BZD or second-line ASM was not associated with progression to RSE in our cohort of patients with rESE. A family history of seizures and a prescription for rectal diazepam were associated with a decreased likelihood of progression to RSE. Early attainment of these variables may help care for pediatric rESE in a more patient-tailored manner.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that patient and clinical factors may predict RSE in children with convulsive seizures.
Topics: Humans; Child; Anticonvulsants; Case-Control Studies; Retrospective Studies; Status Epilepticus; Benzodiazepines; Seizures; Drug Resistant Epilepsy; Diazepam
PubMed: 37295955
DOI: 10.1212/WNL.0000000000207472 -
Biomedicine & Pharmacotherapy =... Dec 2023Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular...
Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.
Topics: Rats; Animals; Basolateral Nuclear Complex; Anti-Anxiety Agents; Lipoylation; Motor Activity; Anxiety; Diazepam
PubMed: 37948993
DOI: 10.1016/j.biopha.2023.115859 -
Neuropharmacology Jun 2023Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A...
Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.
Topics: Mice; Male; Female; Animals; Ethanol; Propofol; Mice, Inbred C57BL; Cyclic Nucleotide Phosphodiesterases, Type 4; Hypnotics and Sedatives; Phosphodiesterase 4 Inhibitors; Ataxia; Diazepam
PubMed: 36935006
DOI: 10.1016/j.neuropharm.2023.109508 -
Nature Neuroscience Mar 2022Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause...
Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.
Topics: Animals; Benzodiazepines; Cognition; Diazepam; Mice; Microglia; Mitochondrial Proteins; Receptors, GABA
PubMed: 35228700
DOI: 10.1038/s41593-022-01013-9 -
Epilepsy Research Sep 2023Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE.
METHODS
This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders.
RESULTS
We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups.
CONCLUSIONS
Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.
Topics: Humans; Adult; Valproic Acid; Anticonvulsants; Follow-Up Studies; Treatment Outcome; Status Epilepticus; Phenobarbital; Diazepam
PubMed: 37467704
DOI: 10.1016/j.eplepsyres.2023.107187 -
Phytotherapy Research : PTR May 2023Anxiety disorders are prevalent conditions in the world population, whose standard approaches include pharmacotherapy, psychotherapy, and combinations of these... (Review)
Review
Anxiety disorders are prevalent conditions in the world population, whose standard approaches include pharmacotherapy, psychotherapy, and combinations of these interventions. Different classes of psychopharmaceuticals are recommended as the first line of drugs to treat these disorders, which can have several adverse effects, treatment resistance, dependence, and drug-drug interactions making it necessary to search for new therapeutic agents. In particular, diazepam (DZP), a prototype drug from the group of benzodiazepines, has been commonly used and evaluated for its efficacy and safety in different anxiety disorders in clinical trials. DZP is also the most widely used reference standard in in vivo pharmacological assays of natural compounds. However, translating the results obtained in different rodent species and physiological anxiety tests instead of psychopathological animal models that can be of clinical application remains challenging. A systematic review of scientific articles published between 2010 and 2020 that included in vivo pre-clinical tests to define the anxiolytic, sedative and/or hypnotic effect of flower extracts is proposed. PRISMA and Rayyan were used for the selection of studies using four databases (Pubmed, Scopus, Web of Science, and QInsight), using the keywords: "Animals," "Anxiolytic," "Diazepam," "Elevated Plus Maze," "Flower Extracts," "Insomnia," "In vivo," "Mice," "Open Field Test," "Pre clinical" and "Sedative." The characteristics of anxiety studies in animal models, other studies related to locomotor activity, and the hypnotic effect of the extracts were compiled. Twenty-four articles were included, 21 of them performed the animal model of anxiety-like behavior of the elevated plus maze, seven the open field test, and six the light-dark box test. The locomotor activity was evaluated in 10 studies after the administration of the extracts to the animals to define their sedative effect, where only one defined that the extract (Matricaria chamomilla) had a sedative effect. The plants declared with this type of activity were Achyranthes aspera, Alcea aucheri, Brassica nigra, Cananga odorata, Carthamus tinctorius, Chrysanthemum indicum, Citrus aurantium, Couroupita guianensis, Echium amoenum, Erythrina berteroana, Gardenia jasminoides, Hibiscus tilliaceus, Lavandula officinalis, Lawsonia inermis, Matricaria chamomilla, Melia azedarach, Nerium oleander, Passiflora incarnata, Plumeria rubra, Salix aegyptiaca, Syzygium aromaticum, Tagetes erecta, Tilia americana. Although this review showed that some flower extracts have an anxiolytic effect as effective as diazepam, their therapeutic utility in anxiety disorders remains to be extensively demonstrated. Hence, more reliable and predictive behavioral tests and appropriate strategies for the experimental designs are needed to obtain more conclusive evidence with clinical significance.
Topics: Mice; Animals; Anti-Anxiety Agents; Hypnotics and Sedatives; Research Design; Plant Extracts; Anxiety; Diazepam; Oils, Volatile; Maze Learning; Flowers; Behavior, Animal
PubMed: 37039741
DOI: 10.1002/ptr.7830 -
The Veterinary Record Nov 2022Idiopathic generalised tremor syndrome (IGTS) causes tremor and often vestibulocerebellar signs. Previous publications on IGTS in dogs are restricted to case reports or...
BACKGROUND
Idiopathic generalised tremor syndrome (IGTS) causes tremor and often vestibulocerebellar signs. Previous publications on IGTS in dogs are restricted to case reports or lack exclusion of structural causes.
METHODS
Medical records of 75 dogs diagnosed with IGTS that had undergone magnetic resonance imaging (MRI) of the brain were collected retrospectively.
RESULTS
Crossbreeds were affected most commonly (41.3%), followed by West Highland white terriers (14.7%) and cocker spaniels (10.7%). A higher proportion of females were affected than males (68.0%). Median age of the affected dogs was 17 months (range 6-121 months), and median bodyweight was 9.15 kg (range 2.9-26 kg). All dogs presented with tremors and most experienced concomitant neurological signs (93.3%). Seventeen (22.7%) were hyperthermic and 31 (41.3%) had gastrointestinal signs. MRI of the brain was normal in most of the cases, and cerebrospinal fluid analysis frequently revealed mild pleocytosis. All animals were treated with prednisolone, and 39 (51.3%) also received diazepam. Median follow-up time was 13 months (range 0-134 months). The overall outcome was good, although 16 (21.3%) patients were reported to have relapsing clinical signs and 10 (13.2%) patients experienced persistent mild clinical signs.
CONCLUSIONS
IGTS should be suspected in any dog with generalised tremor and vestibulocerebellar signs with younger and smaller dogs more commonly affected.
Topics: Male; Female; Animals; Dogs; Tremor; Dog Diseases; Retrospective Studies; Prednisolone; Diazepam; Syndrome
PubMed: 35700269
DOI: 10.1002/vetr.1734 -
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 -
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