Explore the vast range of titles available.

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted.SettingNeonatal intensive care unit.PatientsTerm neonates with electrographically confirmed seizures.InterventionsIn NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction.Main outcome measuresClearance (CL) and volume of distribution (Vd) were determined. Covariates that significantly affected LEV disposition were identified.ResultsPrimary outcome: The median initial LEV level was 57 µg/mL (range 19–107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and Vd were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and Vd were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and Vd (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%.ConclusionsLEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.Trial registration number NCT01720667.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06–9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19–3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11–7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.

In this single-center trial involving term infants with in utero opioid exposure, the use of sublingual buprenorphine resulted in a shorter duration of treatment and length of hospital stay than the use of oral morphine. The neonatal abstinence syndrome is defined as the occurrence of signs and symptoms of neonatal withdrawal after in utero drug exposure. 1 Among drug exposures, opioids cause severe symptoms, including autonomic instability, tremor, irritability, poor feeding, and loose stool. Measures that improve symptom control include minimization of stimulation, rooming in, 2 breast-feeding, 3 and frequent calorically dense feedings. Approximately two thirds of infants with this condition do not have a response to behavioral approaches and ultimately require pharmacologic therapy for control of symptoms. 4 The administration of an opioid at an appropriate dose for symptom control with subsequent weaning has been identified as an . . .

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30–4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (OR 2·41, 95% CI 1·33–4·38; p=0·0055) and oxcarbazepine at doses of 75–4500 mg/day (2·37, 1·17–4·80; p=0·0169). Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. European Community's Seventh Framework Programme.

Alcohol withdrawal syndrome (AWS) is a serious complication of alcohol use disorder. Although benzodiazepines are the mainstay of treatment, some patients may be resistant to them, requiring rapidly escalating doses. Phenobarbital has emerged as an effective adjunct therapy in severe alcohol withdrawal, but studies have yielded inconsistent results and carry safety risks. The purpose of our study was to examine the effectiveness and the potential harm of phenobarbital in AWS. In this multi-center, retrospective cohort study, patients who were admitted for AWS and received phenobarbital with benzodiazepine were compared to patients who received benzodiazepine monotherapy. The primary outcome was time to AWS resolution. Other secondary and safety outcomes included length of stay (LOS), rate of mechanical ventilation, and incidence of aspiration pneumonia. The phenobarbital group received significantly higher doses of benzodiazepines compared to the benzodiazepine monotherapy group (660 mg vs 340 mg, p < 0.0001). After adjustment, the use of phenobarbital was associated with significantly reduced time to AWS resolution (141.65 h vs 165.72 h, p < 0.0001). However, the use of phenobarbital was associated with the likelihood of mechanical ventilation (19.42 %vs. 0.96 %, p < 0.0001), aspiration pneumonia (22.33 % vs 5.77 %, p = 0.0006), and increased hospital LOS (8 days vs. 6 days, p = 0.0197). In the combination group, earlier phenobarbital initiation (within 24 h) was associated with significantly lower cumulative benzodiazepine dose (530 mg vs 887.50 mg, p = 0.002) and hospital LOS (6 days vs 10 days, p = 0.0017). In our study, patients who received phenobarbital in combination with benzodiazepines had a quicker resolution of AWS but also had a higher incidence of mechanical ventilation, prolonged hospital LOS, and an increased risk of aspiration pneumonia. For patients at high risk of severe alcohol withdrawal, earlier initiation of phenobarbital appeared to yield the most optimal benefit.

Abstract Phenobarbital (PB) is an antiseizure medication widely used in dogs that is metabolized by hepatic cytochrome P450 (CYP) enzymes. Fluconazole, a commonly prescribed antifungal medication, inhibits several CYP isoenzymes and can impair PB metabolism. Genetic polymorphisms such as the CYP2C41 gene deletion can alter CYP activity and influence drug interactions, although not well characterized in dogs. We describe two epileptic dogs on chronic PB treatment that developed marked sedation and ataxia, and increased serum PB concentrations after receiving fluconazole. Both dogs were homozygous for the CYP2C41 deletion. Discontinuation of fluconazole resulted in decreased PB concentrations and resolution of clinical signs. These findings suggest fluconazole can inhibit PB metabolism, leading to clinically relevant toxicity, and this interaction does not require CYP2C41 enzyme expression. Monitoring PB concentrations during fluconazole co-administration is advised. Further characterization of the role of CYP enzymes in PB metabolism in dogs is needed to better predict drug interactions.

Background Phenobarbital is an effective treatment for epilepsy but concerns remain over its potential neurocognitive toxicity. This prospective study evaluated the effects of phenobarbital treatment on cognition and mood in people with epilepsy in rural China. Methods We recruited 144 adults with convulsive seizures and 144 healthy controls from six sites in rural China. People with epilepsy were treated with phenobarbital monotherapy for 12 months. At baseline, and at 3, 6 and 12 months, cases and controls were evaluated with a battery of neuropsychological tests: the Mini-Mental State Examination, the Hamilton Depression Rating Scale, a digit span test, a verbal fluency test, an auditory verbal learning test and a digit cancellation test. Efficacy of phenobarbital treatment was evaluated at the end of follow-up for those with epilepsy. Results Cognitive test scores and mood ratings were available for 136 (94%) people with epilepsy and 137 (95%) controls at the 12 month follow-up. Both groups showed slightly improved performance on a number of neuropsychological measures. The people with epilepsy showed greater performance gains (p=0.012) in verbal fluency. Nine people with epilepsy complained of memory problems during the treatment period. Conclusion In this study, phenobarbital was not found to have a major negative impact on cognitive function of people with convulsive seizures and some cognitive gains were observed, possibly due to improved seizure control.

Background Phenobarbital (PB) has long been considered the standard first-line therapy for neonatal seizures, despite suboptimal efficacy and concerns about neurotoxicity and adverse cardiopulmonary effects. Levetiracetam (LEV), a newer antiseizure medication with a more favorable safety profile, has emerged as a potential alternative. This systematic review and meta-analysis aimed to compare the efficacy and safety of LEV versus PB when used as first-line treatment for neonatal seizures. Methods A systematic search of PubMed, Scopus, and Web of Science from inception to September 2025 identified eligible randomized controlled trials (RCTs) and observational studies comparing first-line LEV with PB in neonates. Data were pooled using random-effects models to calculate risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity, publication bias, and potential effect modifiers were explored through subgroup, and meta-regression analyses. Results Twenty-six studies (13 RCTs and 13 observational cohorts) including 9,854 neonates (LEV = 1,601; PB = 8,253) were analyzed. The overall rate of seizure control did not differ significantly between LEV and PB (RR = 0.92, 95% CI 0.82–1.03; p  = 0.16). Subgroup analyses by study design yielded consistent findings. LEV was associated with significantly fewer adverse events (RR = 3.59, 95% CI 1.85–6.95; I² = 86%), particularly lower risks of hypotension (RR = 3.90, 95% CI 1.94–7.87) and respiratory depression (RR = 2.06, 95% CI 1.23–3.47) compared with PB. Mortality rates were similar between groups (RR = 1.27, 95% CI 0.84–1.91). Meta-regression revealed that higher gestational age and birth weight were associated with better seizure control, whereas older age at seizure onset predicted poorer response. Conclusion LEV and PB demonstrate comparable efficacy for first-line treatment of neonatal seizures; however, LEV provides a more favorable safety and tolerability profile, particularly with respect to cardiopulmonary stability. These findings support the consideration of LEV as an alternative first-line agent, especially in neonates at risk for hemodynamic or respiratory compromise. Further large, high-quality RCTs with standardized EEG confirmation and long-term neurodevelopmental follow-up are warranted.