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Schizophrenia Research Jan 2024The effect of lorazepam in the treatment of catatonia is outstanding and almost immediate. Clinicians are familiar with its effects: mute patients can speak again,... (Review)
Review
The effect of lorazepam in the treatment of catatonia is outstanding and almost immediate. Clinicians are familiar with its effects: mute patients can speak again, akinetic patients can move again and patients with negativism can eat and drink again within usually a short duration of about 10 min to 1-2 h. Fear is often gone after lorazepam administration. While not always effective, the introduction of lorazepam into clinical practice represented a breakthrough and was often life-saving for many patients suffering from catatonia. It is rare to observe such rapid therapeutic effects in other domains of psychiatry. In this narrative review we will briefly look at the past, present and future of lorazepam in the treatment of catatonia. It is gratifying to reflect on the fact that clinicians using the age-old medical practice of observation and empirical treatment succeeded in advancing the management of catatonia 40 years ago. The present evidence shows that the clinical effect of lorazepam in catatonia treatment is excellent and more or less immediate although it remains to be explicitly tested against other substances such as diazepam, zolpidem, clozapine, quetiapine, amantadine, memantine, valproate and dantrolene in randomized clinical trials. In addition, future studies need to answer the question how long lorazepam should be given to patients with catatonia, months or even years? This narrative review promotes the rapid use of lorazepam in the treatment of acute catatonic patients and stipulates further scientific examination of its often impressive clinical effects.
Topics: Humans; Adult; Lorazepam; Catatonia; Diazepam; Clozapine; Valproic Acid
PubMed: 36805317
DOI: 10.1016/j.schres.2023.02.015 -
Science Advances Dec 2023Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying...
Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type-specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type-specific vulnerability to ELA.
Topics: Humans; Mice; Animals; Transcriptome; Adverse Childhood Experiences; Stress, Psychological; Hippocampus; Mental Disorders
PubMed: 38039370
DOI: 10.1126/sciadv.adj3793 -
Toxicology Letters Jun 2024Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research,...
Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.
Topics: Animals; Swine, Miniature; Swine; Male; Diazepam; Atropine; Nerve Agents; Dose-Response Relationship, Drug; Injections, Intramuscular; Half-Life; Heart Rate; Telemetry; Models, Animal; Pralidoxime Compounds
PubMed: 38703967
DOI: 10.1016/j.toxlet.2024.04.014 -
Epilepsy Research Jan 2024Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS), also referred to as electrical status epilepticus during sleep (ESES)...
INTRODUCTION
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS), also referred to as electrical status epilepticus during sleep (ESES) or epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS or EE-CSWS), is a spectrum of rare childhood epileptic encephalopathies that can lead to long-term cognitive impairment. Despite the importance of early diagnosis and intervention for D/EE-SWAS, there is a paucity of well-controlled clinical trial data to inform treatment, and no approved treatments are available. To assess correlations between diagnosis, treatment, and outcomes in D/EE-SWAS, we carried out a systematic review of the literature.
METHODS
In August 2020, we conducted comprehensive database searches using search terms including "electrical status epilepticus," "ESES," "CSWS," and "Landau-Kleffner syndrome." Two or more independent reviewers screened titles, abstracts, and full-text articles for those that met the following criteria: prospective studies (randomized controlled trials [RCTs] or open-label trials), retrospective studies (drug evaluations or observational studies/chart reviews), and case series with ≥ 10 participants. Both interventional and non-interventional studies were included (i.e., drug intervention was not an inclusion criterion). Articles published before 2012, review articles, animal studies, and studies of surgical or dietary interventions were excluded. Standardized data extraction templates were used to capture data on study design, patient characteristics, interventions, and outcomes from each of the selected publications. Study quality was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale (NOS) or the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for retrospective, observational studies.
RESULTS
A total of 34 studies were included for full data extraction, most of which were uncontrolled and observational. Interpretation of study outcomes was limited by small study populations, variability in inclusion criteria, and inconsistency in methods of assessment and reporting of outcomes, which resulted in large heterogeneity in patients and their presenting symptoms. Despite these limitations, some patterns could be discerned. Several studies found that longer duration of ESES and younger age at onset were correlated with more severe language and cognitive deficits. In addition, several studies reported an association between improvement in cognitive outcomes and reduction in electroencephalogram (EEG) abnormalities and/or seizure frequency. In the 16 prospective or retrospective studies that evaluated drug treatments (e.g., antiseizure medications, corticosteroids, and high-dose diazepam), there was some improvement in EEG, seizure, and/or cognitive outcomes, although the specific outcomes and rates of improvement reported varied from study to study.
CONCLUSION
Long-term cognitive deficits remain common in D/EE-SWAS, and data gaps exist in the literature that preclude an evidence-based approach to managing this complex epilepsy indication. Early intervention with more effective medications is needed to optimize long-term outcomes. Sufficiently powered, randomized, double-blind, controlled trials with standardized methods and predefined primary and secondary outcomes are needed.
Topics: Child; Humans; Cognition Disorders; Electroencephalography; Epilepsy, Generalized; Landau-Kleffner Syndrome; Randomized Controlled Trials as Topic; Sleep; Status Epilepticus
PubMed: 38157757
DOI: 10.1016/j.eplepsyres.2023.107278 -
Food Science & Nutrition May 2024Allium species are consumed extensively as folkloric medicine and dietary elements, but limited studies have been conducted on them. In this study, the effects of an...
Allium species are consumed extensively as folkloric medicine and dietary elements, but limited studies have been conducted on them. In this study, the effects of an ethanol-water extract obtained from the underground bulb of (Kollmann) Özhatay, B. Mathew & Şiraneci (AT) on the behavioral, antioxidant, and metabolite parameters in rats were evaluated. AT was administered orally once a day at doses of 100 and 400 mg/kg to male Wistar albino rats for 10 consecutive days. The elevated plus maze, rotarod, and hotplate tests were used to examine anxiety-like behaviors, locomotor activities, and pain perception in the rats, respectively. Additionally, untargeted metabolomic analyses were performed on plasma samples and AT extracts using two orthogonal analytical platforms. The phenolic components, mainly fumaric acid, malic acid, vanillic acid, quercetin-3-arabinoside, hydrocinnamic acid, and gallocatechin, were determined in the extract. In addition, arbutin, salicylic acid, trehalose, and nicotinic acid were analyzed in the extract for the first time. The AT extract did not decrease the catalase, glutathione peroxidase, or superoxide dismutase levels; however, diazepam decreased some of those parameters significantly in the brain, liver, and kidney. Although both the AT and diazepam treatments resulted in an increase in anxiolytic-like effects compared to the control group, no significant differences were observed ( > .05). In the metabolomic analysis, significant changes were observed in the rats treated with AT and diazepam, and they caused significant changes in some metabolic pathways, including amino acid and fatty acid metabolism, compared to the control.
PubMed: 38726412
DOI: 10.1002/fsn3.4022 -
Patient Preference and Adherence 2024In the US, 3 rescue treatment options are approved for patients with seizure clusters (ie, acute repetitive seizures), which are intermittent increases of seizure... (Review)
Review
In the US, 3 rescue treatment options are approved for patients with seizure clusters (ie, acute repetitive seizures), which are intermittent increases of seizure activity. This narrative PubMed review of these 3 treatments examines newer intranasal options that are well suited for adolescent and adult patients who may desire a transition from rectal treatment. Diazepam rectal gel is indicated for patients ≥2 years, diazepam nasal spray for those ≥6 years, and midazolam nasal spray for those ≥12 years. Approvals for diazepam rectal gel and midazolam nasal spray were based on safety and efficacy comparisons with placebo. Approval for diazepam nasal spray was based on results from long-term safety and tolerability studies in addition to its comparable bioavailability to diazepam rectal gel, while also showing less interpatient variability. The safety profiles of diazepam rectal gel and nasal spray are similar, and the medications share safety, warning, and precaution labeling. Thus, patients ≥6 years could be introduced to intranasal diazepam, allowing for continuity of familiar treatment while improving access and comfort. Intranasal midazolam also has a well-characterized safety profile. A proxy for effectiveness is the number of seizure clusters that were treated with a single dose, and these differed in separate, noncomparative studies. The safety and effectiveness of diazepam nasal spray have been examined in multiple subpopulations, whereas patient/caregiver experiences with both approved intranasal formulations have been characterized. Users may prefer nasal administration because it is noninvasive and effective, and provides social advantages, comfort, ease of use, and less variability compared with rectal gel. Nasal sprays are portable and convenient for use in the community (school, work, travel), and self-administration was reported in one study, with patients as young as 11 years old self-administering diazepam nasal spray. These newer, intranasal rescue treatments for seizure clusters provide an alternative to the rectal route.
PubMed: 38344151
DOI: 10.2147/PPA.S447028 -
Surgical Technology International Dec 2023To systematically evaluate cases of local anaesthetic systemic toxicity (LAST) in adult urological patients.
OBJECTIVE
To systematically evaluate cases of local anaesthetic systemic toxicity (LAST) in adult urological patients.
METHODS
A search of the Cochrane, Embase, and Medline databases as well as grey literature from 1 January 1974 to 1 February 2023 was performed using reported methods. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Eligible studies were published in English, described LAST secondary to local anaesthetic administration by urological medical staff to an adult patient, and reported >1 symptom of LAST.
RESULTS
One hundred fifty-seven publications were screened, and six eligible studies (all case reports) were identified, representing six cases of LAST in adult urological patients. Patients were aged 29-54 years and one was female. Cases occurred secondary to penile dorsal nerve block (two cases), scrotal self-injection (two), circumcision (one) or trans-vaginal tape insertion (one). Causative drugs were lidocaine (three patients; median dose 600mg) and bupivacaine (three; 200mg). While one patient was found deceased at home and received no treatment, five experienced LAST as inpatients and were discharged with no deficit. Three patients (50%) experienced a state of reduced consciousness or seizures, one experienced psychosis and one had asymptomatic tachyarrhythmia. Management consisted of supportive management (five patients), intravenous lipid emulsion (three) or intravenous thiopental and diazepam (one). Recommended tools suggested that two of these studies were at moderate or high risk of bias.
CONCLUSION
LAST is seen only rarely in adult urology. Most iatrogenic cases occur due to penile dorsal nerve block and most patients have no long-term sequelae. Urologists should be familiar with its presentation and management, and minimise risk by adhering to local anaesthetic maximum safe dose ranges.
PubMed: 38237111
DOI: 10.52198/23.STI.43.UR1725 -
Epilepsy & Behavior : E&B Aug 2023Limited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may...
OBJECTIVE
Limited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may reduce the need for emergency care, intermittent intranasal benzodiazepine formulations are expensive and rectal diazepam administration is often socially unacceptable. We determined whether caregivers could use sublingual lorazepam oral concentrate solution effectively as acute treatment for adults with prolonged and repetitive seizures.
METHODS
Patients prescribed sublingual lorazepam solution at the Johns Hopkins Epilepsy Center for acute seizure treatment during a 5-year period (2012-2017) were screened. We determined clinical history of seizure patterns and number of antiseizure medications (ASMs) through patient and caregiver surveys, and we verified this history in patients' medical records and charts. During a 2-year span (2017-2018), patients and caregivers were surveyed on responses to their most recent use of sublingual lorazepam solution, including seizure cessation (prolonged seizure stopping <5 minutes or ≤1 repetitive seizure), presence of sedation and adverse events within 24 hours of administration, and whether refrigeration limited use.
RESULTS
In total, 52 patients used sublingual lorazepam for treatment of acute seizures during the study period (median dose 1 mg, range 0.5 to 2 mg). Of them, 48 patients participated in treatment survey interviews. Family caregivers usually administered lorazepam (88%); 3 self-administered. Patients were surveyed on responses to their most recent use of sublingual lorazepam treatment: 66% (23/35) of patients with repetitive seizures reported no further seizure activity after administering treatment; 70% (7/10) with prolonged seizures reported seizure activity ceased within 5 minutes of treatment. Three patients treated auras and had no seizures. There were no serious adverse events during most recent use: 31% of patients developed moderate/severe sedation. Of note, 98% refrigerated lorazepam, often with coolers; 44%, however, said this limited treatment access. There was high treatment satisfaction; 79% reported that having the emergency treatment available made them feel safer.
SIGNIFICANCE
This patient survey and retrospective chart review demonstrates that home treatment with sublingual lorazepam solution may be effective for interrupting prolonged and repetitive seizures. No patients had sedation complications with home doses of 0.5 to 2 mg, and patients report high satisfaction with the treatment.
Topics: Humans; Adult; Lorazepam; Anticonvulsants; Retrospective Studies; Emergencies; Diazepam; Status Epilepticus; Epilepsy
PubMed: 37406555
DOI: 10.1016/j.yebeh.2023.109294 -
Metabolic Brain Disease Oct 2023Aggression, a highly prevalent behavior among all the psychological disorders having strong association with psychiatric imbalance, neuroendocrine changes and...
Aggression, a highly prevalent behavior among all the psychological disorders having strong association with psychiatric imbalance, neuroendocrine changes and neurological disturbances (including oxidative stress & neuroinflammation) require both pharmacological and non-pharmacological treatments. Focusing the preclinical neuroendocrine determinants of aggression, this interventional study was designed to elucidate the curative effect of antioxidants on aggression in male mice. Adult albino male mice (n = 140) randomly divided into two main treatment groups for α-lipoic acid (ALA) and silymarin with 5 subgroups (n = 10) for each curative study, namely control, disease (aggression-induced), standard (diazepam, 2.5 mg/kg), low dose (100 mg/kg) and high dose (200 mg/kg) treatment groups of selected antioxidants. Resident-intruder paradigm and levodopa (L-dopa 375 mg/kg, p.o.) induced models were used for aggression. Effect of antioxidant treatment (i.e., 21 days bid) on aggression was assessed by evaluating the changes in aggressive behavior, oxidative stress biomarkers superoxide dismutase, catalase, glutathione, nitrite and malondialdehyde (SOD, CAT, GSH, nitrite & MDA), neurotransmitters (dopamine, nor-adrenaline and serotonin), pro-inflammatory cytokines tumor necrosis factor-α and interleukin- 6 (TNF-α & IL-6) along with serum testosterone examination. This study showed potential ameliorative effect on aggressive behavior with both low (100 mg/kg) and high (200 mg/kg) doses of antioxidants (ALA & silymarin). Resident-intruder or L-dopa induced aggression in male mice was more significantly tuned with ALA treatment than silymarin via down regulating both oxidative stress and inflammatory biomarkers. ALA also exhibited notable effects in managing aggression-induced disturbances on plasma testosterone levels. In conclusion, ALA is more effective than silymarin in attenuating aggression in mice.
Topics: Male; Mice; Animals; Thioctic Acid; Antioxidants; Silymarin; Levodopa; Nitrites; Oxidative Stress; Glutathione; Aggression; Biomarkers; Testosterone
PubMed: 37458892
DOI: 10.1007/s11011-023-01258-8 -
Neuroscience Letters Jul 2023Benzodiazepines are among the most prescribed drug class worldwide to treat disorders such as anxiety, insomnia, muscle spasticity, and convulsive disorders, and to...
Diazepam-Induced Down-Regulation of the GABA receptor α1 Subunit, as mediated by the activation of L-Type Voltage-Gated calcium Channel/Ca/Protein kinase a signaling cascade.
Benzodiazepines are among the most prescribed drug class worldwide to treat disorders such as anxiety, insomnia, muscle spasticity, and convulsive disorders, and to induce presurgical sedation. Although benzodiazepines exhibit a high therapeutic index and low toxicity in short-term treatments, prolonged administration induces tolerance to most of their therapeutic actions. The mechanism of this tolerance remains unclear. The central actions of benzodiazepines are mediated by binding to GABA receptors, which mediate most fast inhibitory transmission in the brain. The majority of GABA receptors are composed of two α-(1-6), two β-(1-3) and one γ-subunits (1-3). In a previous report, we demonstrated that the prolonged exposure of cerebrocortical neurons to diazepam produces a transcriptional repression of the GABA receptor α1 subunit gene via a mechanism dependent on the activation of L-type voltage-gated calcium channels (L-VGCCs). The results reported here confirm that the diazepam-induced downregulation of the α1 subunit is contingent upon calcium influx from extracellular space. In addition, this regulatory mechanism involves the activation of protein kinase A (PKA) and is accompanied by the activation of two transcription factors, the cAMP-response element-binding protein (CREB) and the inducible cAMP early repressor (ICER). Together, our results suggest that diazepam s activation of an L-VGCC/Ca/PKA/CREB-ICER signaling pathway is responsible for the regulation of GABA receptors. This elucidation of the intracellular signaling cascade activated by a prolonged benzodiazepine exposure, itself potentially involved in the development of tolerance, may contribute to locating molecular targets for future therapeutic interventions.
Topics: Diazepam; Receptors, GABA-A; Down-Regulation; Benzodiazepines; Signal Transduction; Calcium Channels; gamma-Aminobutyric Acid; Cyclic AMP-Dependent Protein Kinases
PubMed: 37356564
DOI: 10.1016/j.neulet.2023.137358