A case of lethal suicidal intoxication with propafenone and diazepam.

Diazepam poisoning is a common emergency situation, but propafenone poisoning is relatively rare. We reported a case of propafenone poisoning combined with diazepam. An 18-year-old female patient was admitted to our hospital with an overdose of oral propafenone and diazepam. The patient was treated with medication that proved to be useful, but the sinus rhythm could not be recovered, and cardiac arrest occurred. A bipolar temporary pacemaker and extracorporeal membrane oxygenation (ECMO) were installed. However, even with multiple electrode positions, effective capture could not be achieved. The patient eventually died. We should be alert to the possibility of co-poisoning.

Risk of suicide attempts and intentional self-harm on alprazolam.

BACKGROUND: From 2000-2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. METHODS: An exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. FINDINGS: Alprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59). INTERPRETATION: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.

Polysaccharide-rich extract of Genipa americana leaves protects seizures and oxidative stress in the mice model of pentylenetetrazole-induced epilepsy.

Plant polysaccharides have biological activities in the brain and those obtained from Genipa americana leaves present antioxidant and anticonvulsant effects in the mice model of pentylenetetrazole (PTZ)-induced acute seizures. This study aimed to evaluate the polysaccharide-rich extract of Genipa americana leaves (PRE-Ga) in the models of acute seizures and chronic epilepsy (kindling) induced by PTZ. In the acute seizure model, male Swiss mice (25-35 g) received PRE-Ga (1 or 9 mg/kg; intraperitoneal- IP), alone or associated with diazepam (0.01 mg/kg), 30 min before induction of seizures with PTZ (70 mg/kg; IP). In the chronic epilepsy model, seizures were induced by PTZ (40 mg/kg) 30 min after treatment and in alternated days up to 30 days and evaluated by video. Brain areas (prefrontal cortex, hippocampus, striatum) were assessed for inflammatory and oxidative stress markers. Diazepam associated to PRE-Ga (9 mg/kg; i.p.) increased the latency of seizures in acute (222.4 ± 47.57 vs. saline: 62.00 ± 4.709 s) and chronic models (6.267 ± 0.502 vs. saline: 4.067 ± 0.407 s). In hippocampus, PRE-Ga (9 mg/kg) inhibited TNF-α (105.9 ± 5.38 vs. PTZ: 133.5 ± 7.62 pmol/g) and malondialdehyde (MDA) (473.6 ± 60.51) in the chronic model. PTZ increased glial fibrillar acid proteins (GFAP) and Iba-1 in hippocampus, which was reversed by PRE-Ga (GFAP: 1.9 ± 0.23 vs PTZ: 3.1 ± 1.3 and Iba-1: 2.2 ± 0.8 vs PTZ: 3.2 ± 1.4). PRE-Ga presents neuroprotector effect in the mice model of epilepsy induced by pentylenetetrazole reducing seizures, gliosis, inflammatory cytokines and oxidative stress.

Correlation between serum galanin and neuron-specific enolase levels with EEG abnormalities in pediatric convulsive status epilepticus and the efficacy of triple drug therapy.

OBJECTIVE: This study aimed to investigate the association between serum galanin (GAL) and neuron-specific enolase (NSE) levels in children with convulsive status epilepticus (CSE) and their relationship with abnormal electroencephalogram (EEG) patterns. Additionally, the study assessed the effectiveness of a combination therapy involving midazolam, diazepam, and phenobarbital in treating CSE. PATIENTS AND METHODS: The research involved 100 children diagnosed with CSE and included a control group of 50 healthy children. Serum GAL and NSE levels were measured, and EEGs were analyzed for abnormalities in the CSE group. Comparisons were made between the healthy control group and the CSE group, particularly within the first 24 hours after persistent seizures. The severity of EEG abnormalities was correlated with GAL and NSE levels. The treatment consisted of an observation group that received the triple therapy of midazolam, diazepam, and phenobarbital, while a control group received diazepam and phenobarbital. Clinical efficacy, symptom improvement, Status Epilepticus Severity Score (STESS), and adverse reactions were evaluated. RESULTS: The results indicated elevated levels of GAL and NSE in the CSE group, with higher levels noted within 24 hours after persistent seizures. Furthermore, a positive correlation was observed between the severity of EEG abnormalities and GAL and NSE levels. The group receiving the triple therapy demonstrated superior efficacy, faster resolution of seizures and fever, reduced STESS scores, and fewer adverse reactions than the control group. In conclusion, this study highlights the positive correlation between serum GAL and NSE levels and the severity of EEG abnormalities in pediatric CSE. The triple therapy approach is effective in treating CSE, leading to improved clinical symptoms, reduced brain damage, and enhanced safety. CONCLUSIONS: The study concludes that serum GAL and NSE levels in children with convulsive status epilepticus are positively correlated with the degree of EEG abnormalities. The combination therapy involving midazolam, diazepam, and phenobarbital is effective in treating children with convulsive status epilepticus, significantly improving clinical symptoms, reducing brain damage, and ensuring safety.

Status epilepticus resulted in rhabdomyolysis-induced AKI associated with hepatotoxicity induced by synergistic carbamazepine and diazepam: A case report.

RATIONALE: Rhabdomyolysis is a serious complication of status epilepticus (SE) caused by muscle cell damage and can lead to a life-threatening acute kidney injury (AKI). PATIENT CONCERNS: A 35-year-old man with a history of seizures treated with 3 different antiepileptic drugs (carbamazepine, lamotrigine, and levetiracetam) presented with SE. The patient received 5 doses of diazepam to control the SE in another hospital and was transferred to our emergency due to AKI. DIAGNOSES: Laboratory tests corresponded with rhabdomyolysis-induced AKI and disseminated intravascular coagulation. Thereafter, the decrease in renal excretion of both drugs (diazepam and carbamazepine) caused acute liver injury and neurotoxicity. The carbamazepine concentration was 16.39 mcg/mL, which considered in toxic level, despite using the usual dose. INTERVENTIONS: The patient was treated with hydration and sodium bicarbonate, however; severe AKI mandated a hemodialysis session. OUTCOMES: The diuresis started to increase, kidney and liver functions improved, and altered mental status reversed. LESSONS: This case alerts physicians to consider the synergistic drug side effects and interactions, especially when patients present with impaired liver or kidney functions. The reduction in metabolism or excretion of drugs can cause an increase in serum concentrations and induce toxicity, even when the drug intake at the usual dose.

Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Anticonvulsant effect of (±) citronellal possibly through the GABAergic and voltage-gated sodium channel receptor interaction pathways: In vivo and in silico studies.

This study aimed to investigate the anticonvulsant effects of citronellal (CIT) and possible underlying mechanisms through an isoniazid (INH)-induced seizure (convulsion) via in vivo and in silico studies. For this, convulsions were induced by the oral administration of INH (300 mg/kg) to the mice. The animals were treated orally with different doses of CIT (50, 100, and 200 mg/kg). Vehicle served as a negative control (NC), while diazepam (DZP) (2 mg/kg) and carbamazepine (CAR) (80 mg/kg) were provided (p.o.) as positive controls (PC). A combination therapy of CIT (middle dose) with DZP and CAR was also given to two separate groups of animals to estimate the synergistic or antagonistic effects. Molecular docking and visualization of ligand-receptor interactions are also estimated through different computational tools. The results of the in vivo study showed that CIT dose-dependently significantly (p < 0.05) exhibited a higher onset of seizures while reducing the frequency and duration of seizures in mice compared to the NC group. Besides these, in combination therapy, CIT significantly antagonized the activity of CAR and DZP, leading to a reduction in the onset of seizures and an increase in their frequency and duration compared to treatment with CAR and DZP alone. Additionally, molecular docking revealed that the CIT exhibited a moderate binding affinity (-5.8 kcal/mol) towards the GABAA receptor and a relative binding affinity (-5.3 kcal/mol) towards the voltage-gated sodium channel receptor by forming several bonds. In conclusion, CIT showed moderate anticonvulsant activity in INH-induced convulsion animals, possibly by enhancing GABAA receptor activity and inhibiting the voltage-gated sodium channel receptor.

Intranasal administration of antiseizure medications in chronic and emergency treatment: Hopes and challenges.

Despite the availability of many antiseizure medications (ASMs), 30 % of patients experience pharmacoresistant seizures. High-throughput screening methods undoubtedly remain one of the most important approaches for discovering new molecules to treat seizures. However, the costly and time-consuming nature of drug development prompts us to explore alternative strategies to counteract drug-resistant seizures. One such approach is to consider intranasal administration of known molecules for seizure treatment. In the case of treating epileptic seizures, administering ASMs intranasally may enhance treatment effectiveness and minimize adverse effects. A good example of changes in drug administration is the intranasal administration of fentanyl, which has become a clinical standard in the emergency setting to treat moderate to severe pain in adults and children. This review discusses the utilization of intranasally administered ASMs for both acute and chronic seizures. It addresses various targeted pharmacokinetic approaches, challenges and prospects associated with these regimens. Brief neuroanatomical and molecular rationale for nose-to-brain drug transport is also presented. Furthermore, recent preclinical studies validating the efficacy and brain distribution following intranasal administration of the most commonly used drugs in chronic treatment are also discussed.

Lorazepam in catatonia - Past, present and future of a clinical success story.

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.

Febrile seizure in children with COVID-19 during the Omicron variant-predominant era: A single-center study.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has significantly impacted medical services worldwide. During the Omicron variant-predominant era, febrile seizure (FS) in patients with COVID-19 increased compared to that in the pre-Omicron variant era. Therefore, this study aimed to demonstrate the clinical characteristics of FS in patients with COVID-19. METHODS: We surveyed patients aged < 16 years who presented with FS to the emergency room of Tottori University Hospital. The patients were divided into two groups: FS patients with COVID-19 (FS with COVID-19 group) and FS patients without COVID-19 (FS without COVID-19 group) as per the results of the respiratory multiplex array test. Patients with positive results for both SARS-CoV-2 and other microorganisms were excluded. We obtained data on the patients' clinical backgrounds, symptoms, seizure duration, type of FS (simple or complex), diagnostic examinations, laboratory test results, and treatment. We compared the data between the FS with and without COVID-19 groups. RESULT: A total of 128 patients with FS met the inclusion criteria. Of these, 18 patients and 110 patients were included in the FS with COVID-19 group and without COVID-19 group, respectively. The late FS onset (>60 months) were significantly more common in the FS with COVID-19 group than that in the FS without COVID-19 group. Moreover, patients in the FS with COVID-19 group had significantly longer seizure durations than those in the FS without COVID-19 group. A diazepam (DZP) suppository was administered to 72% of FS patients with COVID-19 after the first seizure during a febrile episode. CONCLUSION: FS patients with COVID-19 had different distributions of age at onset and seizure duration than those without COVID-19. The use of DZP suppositories was more frequent in FS patients with COVID-19 compared to those without COVID-19.

Assessment of the anxiolytic, antidepressant, and antioxidant potential of Parquetina nigrescens (Afzel.) Bullock in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The recent growing concerns about the multisystemic nature of mental health conditions in the global population are facilitating a new paradigm involving alternative natural, nutritional, and complementary therapies. Herbal remedies despite accounts in literature of their ethnobotanical as alternative remedies for diverse ailments, remain underexplored for psychiatric disorders like anxiety, depression, and insomnia. AIM OF THE STUDY: Hence, the anxiolytic, antidepressant, and antioxidant properties of a hydro-ethanolic leaf extract of Parquetina nigrescens (PN) in male Wistar rats were investigated. MATERIALS AND METHODS: The sedative effect was evaluated using the Diazepam sleeping time test while anxiety was induced with a single intraperitoneal injection of 20 mg/kg pentylenetetrazol (PTZ). This was after pre-treatment with 100, 150, and 250 mg/kg of PN or the standard drugs (1 mg/kg diazepam and 30 mg/kg imipramine) for 14 consecutive days. Behavioral tests (Open Field test, Elevated Plus-Maze test, and Forced Swim test) were performed on days 1 and 14, to evaluate the antidepressant and anxiolytic activities of PN. Oxidative stress and neurochemical markers were determined in the brain homogenates of the animals. RESULTS: The duration of sleep was significantly (p < 0.001) increased in the PN-administered group compared to the control. The behavioral models showed that PN exhibited antidepressant and anxiolytic properties in PTZ-induced animals. Significant reductions were observed in GSH level and SOD activity while MDA, nitrite, and GPx levels were significantly increased in PTZ-induced rats. However, treatment with PN significantly improved brain antioxidant status by ameliorating the PTZ-induced oxidative stress. Dopamine, cortisol, and acetylcholine esterase activity levels were significantly (p < 0.05) elevated while serotonin and brain-derived neurotrophic factors were reduced in PTZ-induced rats compared with the control. CONCLUSION: The PN demonstrated neurotransmitter modulatory ability by ameliorating the PTZ-induced neurochemical dysfunction. Findings from this study showed that PN exhibited sedative, antidepressant, and anxiolytic activities in rats.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Behavioral and electrophysiological (ECoG) effects of haplophyllum robustum and TRPA1 antagonist in adult male wistar rats.

This article aimed to investigate the effects of Haplophyllum robustum hydroalcoholic extract on animals' behavioral and electrocorticographic changes. This plant is mainly found in Turkey, Iran, and Central Asia, and is reported to have convulsive effects. In this article, we worked on the effects of its hydroalcoholic extract on electrocorticography (ECoG), along with changes induced by intracerebroventricular administration of GABAA antagonists. Furthermore, the effects of low doses of this extract on behavioral depression were examined. Four animal sets were used to compare ECoG in Wistar rats. A group of negative control, a group of positive control (PTZ), and two groups received an injection of plant extract (500 mg/kg, ip), with or without administration of Diazepam (5 mg/kg). Also, three sets were applied to compare receiving and not receiving intracerebroventricular (icv) injection of Transient receptor potential ankyrin 1 antagonist (HC-030031) (2 µg/kg) on plant-induced seizure delay and animal death. Two groups of control and a group with plant extract together with TRPA1 antagonist were administrated. Furthermore, in the present study, the forced swimming test (FST) was used as a model of depression. The behaviors of animals in three groups of negative control and positive control (Fluoxetine) and plant extract (200 mg/kg, ip) were compared. According to the ECoG, high doses of extract of plants led to seizures similar to PTZ, which were then reduced by diazepam injection. At this dose, injection of TRPA1 antagonist did not significantly delay the onset of seizures or the death of the animals. Further, a subconvulsive dose of hydroalcoholic plant extracts was equally effective in treating depression as Fluoxetine injections.

A Comparative Analysis of Prehospital Emergency Treatments: Midazolam Intramuscularly, Diazepam Enema, and Chloral Hydrate Enema for Pediatric Convulsions.

Objective: This study aimed to compare the effectiveness of prehospital emergency treatments using midazolam (MDL) intramuscularly, diazepam (DZP) enema, and chloral hydrate (CH) enema in managing pediatric convulsions. Methods: A comparative observational study was conducted, and a total of 140 children with acute convulsions treated with prehospital anti-convulsions at Qinhuangdao First Hospital's emergency department between June 2015 and May 2019 were included in this study. The children were categorized based on the prehospital anti-convulsion measures received: group M (n = 48) received MDL intramuscularly, group D (n = 46) received DZP enema, and group C (n = 46) received CH enema. The emergency effects of the three treatment groups were compared. Results: 1. Group M showed significantly shorter treatment preparation time and total rescue time compared to groups C and D (both P < .05); no significant difference was observed between groups C and D (both P > .05), including convulsion control time in the effective cases (45 in group M, 42 in group C, and 43 in group D) (all P > .05 Group M had effective rates of 93.75%, while group C and group D had rates of 91.3% and 93.48%, respectively (all P > .05); Group M had more controlled cases at 1 min, 3 min, 5 min, and 10 min than group C and group D (all P > .05). Group M had significantly fewer relapses, cases requiring intravenous maintenance treatment, and faster convulsion control after intravenous maintenance compared to groups C and D (P < .05), with no significant differences between groups C and D in time to recovery of consciousness and length of hospitalization (P > .05). 4. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory (R) frequency, and peripheral oxygen saturation (SpO2) showed no significant differences before and 10 minutes after medication in all three groups (P > .05); SBP and DBP levels fluctuated within the normal range, while HR decreased, R frequency decreased, and SpO2 increased significantly 10 minutes after medication compared to before treatment (P < .05). 5. No significant adverse effects were observed in the three patient groups. Conclusions: MDL intramuscular injection, DZP enema, and CH enema were effective prehospital treatments for pediatric acute convulsions. MDL intramuscular injection demonstrated advantages such as fast onset, reliable efficacy, ease of use, and high safety, making it more suitable for the prehospital treatment of pediatric convulsions.

Flumazenil Treatment for Diazepam-Associated Neurological Signs in a Cat With a Portosystemic Shunt.

A 7-month-old female spayed domestic short hair cat was presented for evaluation of inadequate clinical response to medical management for hepatic encephalopathy (HE). An abdominal computed tomography (CT) was to be performed but the cat developed 2 grand mal seizures shortly after presentation. Minimal handling and no drugs had been administered before the seizures. A single dose of diazepam (0.3 mg/kg, IV) was administered after each seizure. Another seizure occurred 24 hours after hospitalization and diazepam (0.5 mg/kg, IV) was once again administered. Seizures ceased but neurological signs worsened and included head pressing, loss of menace response, and a stuporous mentation. Due to unresponsiveness to treatment that included administration of intravenous fluids, levetiracetam, ampicillin/sulbactam, and retention enemas (water with lactulose), a dose of flumazenil (0.01 mg/kg) was administered IV and resulted in immediate but transient improvement of clinical signs. The stuporous state returned after 60 min post-treatment and an additional dose of IV flumazenil (0.01 mg/kg) was administered with the same outcome. Based on this positive clinical response, IV infusion of flumazenil was initiated at 0.01 mg/kg/h following a loading dose of 0.005 mg/kg. Due to minimal improvement in neurological signs, flumazenil IV infusion was increased gradually until reaching the effective dose of 0.1 mg/kg/h. Flumazenil IV infusion was continued for 24 hours with improvements in neurological signs, which did not return upon gradual decrease of the flumazenil dose. This is the first report describing the use of a flumazenil IV infusion to improve neurological signs in a cat with a PSS and HE treated with diazepam.

The effects of continuous administration of diazepam on the recovery of lesion-induced nystagmus in unilaterally labyrinthectomised rats.

BACKGROUND: Diazepam, a gamma-aminobutyric acid type A receptor agonist, is classified as a vestibular suppressant and is effective in treating acute vertigo. However, its effects on vestibular compensation (VC) remain unclear. OBJECTIVES: We examined the effects of continuous administration of diazepam on the frequency of spontaneous nystagmus (SN) after unilateral labyrinthectomy (UL) as an index of the initial process of VC in rats. MATERIALS AND METHODS: Diazepam was continuously administered at doses of 3.5 and 7.0 mg/kg/day, intraperitoneally, via an osmotic minipump. The frequency of SN beating against the lesion side after UL was measured. Potassium chloride (KCl) solution (1 M) was injected intratympanically to induce SN beating to the injection side. RESULTS: Continuous administration of diazepam significantly and dose-dependently decreased the frequency of SN after UL, and also reduced the x intercept of the nonlinear regression curve of the decline in UL-induced SN with time in rats. However, the continuous administration of diazepam did not affect the frequency of intratympanic KCl-induced SN in the rats. CONCLUSION: These findings suggested that continuous administration of diazepam accelerates the initial process of VC; however, it does not suppress the nystagmus-driving mechanisms in rats.

Baclofen during alcohol detoxification reduces the need for additional diazepam: a randomized placebo-controlled trial.

Baclofen may reduce the symptoms of alcohol withdrawal, as an alternative or as an adjuvant for benzodiazepines, but the available data are insufficient to support baclofen-assisted alcohol withdrawal. This study investigated the need for diazepam during acute alcohol withdrawal in patients receiving baclofen. In a single-blind, dose-dependent randomized controlled trial with three study arms, 63 patients with alcohol use disorder, starting in-patient benzodiazepine-assisted alcohol detoxification, were randomly assigned to receive placebo (n = 18), baclofen 30 mg/day (N = 20), or baclofen 60 mg/day (N = 25) for 7 days. Diazepam was provided as needed based on the withdrawal symptoms stated by Clinical Institute Withdrawal Assessment for Alcohol-revised. The primary outcome measure was the number of patients in need of diazepam during alcohol detoxification. Secondary outcome measure included the between-group difference in the amount of diazepam needed during alcohol detoxification. Using baclofen 60 mg/day, 32% of patients needed additional diazepam compared to 35% on baclofen 30 mg/day and compared to 72% on placebo (P = .013). The median total amount of diazepam needed was significantly lower in patients receiving baclofen 60 mg/day (0 ± 10 mg diazepam) and baclofen 30 mg/day (0 ± 10 mg diazepam) compared to placebo (10 ± 43 mg diazepam; P = .017). Adverse events were comparable between patients on baclofen and placebo. Baclofen can reduce the withdrawal symptoms during alcohol detoxification. Baclofen was well tolerated and may be considered for the management of alcohol withdrawal syndrome, especially useful in situations where benzodiazepines should be withheld, such as patients with liver impairment.

Sublingual lorazepam as rescue therapy for seizure emergencies in adults.

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.

Utilization of Antiseizure Medications in Women of Childbearing Age With Epilepsy and Nonepilepsy Indications: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic drugs in women of childbearing age. Limited data exist on utilization patterns across different indications for therapy and for the newer-generation ASMs in this population. Thus, we assessed the pattern of ASM use in women of childbearing age with epilepsy and nonepilepsy indications (pain and psychiatric disorders). METHODS: We conducted a retrospective analysis of deidentified administrative data submitted to the Optum Clinformatics database. Eligible participants included women aged 12-50 years who filled ASMs between year 2011 and 2017. Participants were followed from date of index prescription filled to study end or insurance disenrollment, whichever came first. For the overall cohort and potential therapy indications, we assessed the type and frequency of ASMs filled; proportion of participants on monotherapy, polytherapy, or treatment switching; and duration of continuous use. Trends were characterized using annual percent change from study start to study end. RESULTS: Our analysis included 465,131 participants who filled 603,916 distinct ASM prescriptions. At baseline, most of the participants had chronic pain (51.0%) and psychiatric disorders (32.7%), with epilepsy the least common (0.9%). The most frequently dispensed were diazepam (24.3%), lorazepam (20.1%), gabapentin (17.4%), clonazepam (12.7%), topiramate (11.3%), and lamotrigine (4.6%). Significant linear increase in trends were observed with gabapentin (annual percent change [95% CI]: 8.4 [7.3-9.4]; p < 0.001) and levetiracetam (3.4 [0.7-6.2]; p = 0.022) and decreasing trends for diazepam (-3.5 [-2.4 to 4.5]; p < 0.001) and clonazepam (-3.4 [-2.3 to 4.5]; p = 0.001). No significant change in trend was observed with valproate (-0.4 [-2.7 to 1.9]; p = 0.651), while nonlinear changes in trends were observed with lorazepam, topiramate, lamotrigine, and pregabalin. DISCUSSION: Decreasing trends were observed with older ASMs in the overall cohort and across the potential indications for therapy. Conversely, increasing trends were seen with the newer ASMs. Considering the risk of teratogenicity associated with the newer medications largely unknown, counseling and education in addition to a careful consideration of the benefits vs potential risks should remain pivotal when prescribing ASMs for women of childbearing age.

Lestaurtinib (CEP-701) reduces the duration of limbic status epilepticus in periadolescent rats.

BACKGROUND: The timely abortion of status epilepticus (SE) is essential to avoid brain damage and long-term neurodevelopmental sequalae. However, available anti-seizure treatments fail to abort SE in 30% of children. Given the role of the tropomyosin-related kinase B (TrkB) receptor in hyperexcitability, we investigated if TrkB blockade with lestaurtinib (CEP-701) enhances the response of SE to a standard treatment protocol and reduces SE-related brain injury. METHODS: SE was induced with intra-amygdalar kainic acid in postnatal day 45 rats under continuous electroencephalogram (EEG). Fifteen min post-SE onset, rats received intraperitoneal (i.p.) CEP-701 (KCEP group) or its vehicle (KV group). Controls received CEP-701 or its vehicle following intra-amygdalar saline. All groups received two i.p. doses of diazepam, followed by i.p. levetiracetam at 15 min intervals post-SE onset. Hippocampal TrkB dimer to monomer ratios were assessed by immunoblot 24 hr post-SE, along with neuronal densities and glial fibrillary acid protein (GFAP) levels. RESULTS: SE duration was 50% shorter in the KCEP group compared to KV (p < 0.05). Compared to controls, SE induced a 1.5-fold increase in TrkB dimerization in KV rats (p < 0.05), but not in KCEP rats which were comparable to controls (p > 0.05). The KCEP group had lower GFAP levels than KV (p < 0.05), and both were higher than controls (p < 0.05). KCEP and KV rats had comparable hippocampal neuronal densities (p > 0.05), and both were lower than controls (p < 0.05). CONCLUSIONS: Given its established human safety, CEP-701 is a promising adjuvant drug for the timely abortion of SE and the attenuation of SE-related brain injury.