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Frontiers in Pharmacology 2024Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs...
Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72 h later-at time at which drug is expected to be cleared. We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers and , and increased the marker of activated microglia, and the astrocyte- associated gene . These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.
PubMed: 38606173
DOI: 10.3389/fphar.2024.1340691 -
Veterinary World Feb 2024Dogs with idiopathic epilepsy (IE) experience a shortened lifespan, neurobehavioral changes, and an increased risk of comorbidities during the interictal period. There...
BACKGROUND AND AIM
Dogs with idiopathic epilepsy (IE) experience a shortened lifespan, neurobehavioral changes, and an increased risk of comorbidities during the interictal period. There have been several reports of sudden death in humans with epilepsy, suggesting changes in cardiac rhythm secondary to seizures. In veterinary medicine, there are still no such conclusive studies. The present study aimed to evaluate blood pressure values, electrocardiographic findings, and laboratory parameters in dogs with IE treated with phenobarbital and to correlate these findings with possible cardiac alterations.
MATERIALS AND METHODS
Twenty-one dogs were divided into 11 healthy dogs and 10 idiopathic epileptic dogs for blood analysis, computerized electrocardiogram, and oscillometer-based blood pressure measurement.
RESULTS
QRS complex and S-T interval values differed significantly between groups, but blood pressure values were not significantly different.
CONCLUSION
IE can occur with alterations in cardiac conduction and is a pathological condition.
PubMed: 38595650
DOI: 10.14202/vetworld.2024.356-360 -
Italian Journal of Pediatrics Apr 2024Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area,...
BACKGROUND
Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental.
CASE PRESENTATION
A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases.
CLINICAL OUTCOMES
spastic cerebral palsy, microcephaly, treatment-refractory epilepsy.
CONCLUSIONS
Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.
Topics: Infant, Newborn; Infant; Pregnancy; Female; Child; Humans; Asphyxia; Brain; Hypoxia-Ischemia, Brain; Asphyxia Neonatorum; Seizures; Epilepsy
PubMed: 38594715
DOI: 10.1186/s13052-024-01633-w -
BMC Pregnancy and Childbirth Apr 2024Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.
BACKGROUND
Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome.
METHODS
This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam.
RESULTS
Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644).
CONCLUSIONS
Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome.
TRIAL REGISTRATION
The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.
Topics: Infant, Newborn; Infant; Female; Humans; Neonatal Abstinence Syndrome; Levetiracetam; Intensive Care Units, Neonatal; Phenobarbital; Hospitalization; Substance-Related Disorders; Plant Extracts
PubMed: 38580935
DOI: 10.1186/s12884-024-06433-y -
Epilepsia Open Jun 2024Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the...
OBJECTIVE
Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate.
METHODS
A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration.
RESULTS
The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period.
SIGNIFICANCE
Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load.
PLAIN LANGUAGE SUMMARY
Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.
Topics: Humans; Anticonvulsants; Carbamates; Drug Resistant Epilepsy; Spain; Drug Therapy, Combination; Chlorophenols; Consensus; Adult; Epilepsies, Partial; Seizures; Delphi Technique; Tetrazoles
PubMed: 38573131
DOI: 10.1002/epi4.12936 -
Cancer Management and Research 2024Large animal models are still used in many studies because of their likeness to humans. It has not been documented that regular-sized conventional farm-breed pigs,...
PURPOSE
Large animal models are still used in many studies because of their likeness to humans. It has not been documented that regular-sized conventional farm-breed pigs, generally bred for meat production, can be used to generate hepatocellular carcinoma (HCC) animal models. The goal of this study was to investigate how N-diethylnitrosamine (DENA) and phenobarbital (PB) together can generate HCC in ordinary farmed pigs.
MATERIALS AND METHODS
Conventional domestic swine () were used. DENA 15 mg/kg was intraperitoneally injected weekly for 12 weeks, while PB tablets (4 mg/kg) were also administered through food for 16 weeks. Blood testing and ultrasonography evaluation were performed to monitor the progress. Subsequently, computed tomography was conducted in cases with suspected nodules, followed by histopathological examination to confirm the diagnosis.
RESULTS
Ten swine (seven males, three females; age: 2 months; weight: 9-15 kg) were included in the study and followed up for 25 months; nine were experimental, and one was control for ethical considerations. The maximum weight of animals during this study reached 162-228 kg. The weight gain seen in the intervention swine was predominantly lower than that documented in the control. The laboratory analysis revealed no notable abnormalities in liver function markers but did demonstrate statistically significant changes in urea (p = 0.028) and creatinine (p = 0.003) levels. Ultrasonography and computed tomography showed multiple liver nodules with characteristics resembling HCC. Serial imaging screening and more extended observations revealed that all animals eventually developed tumors. Histopathological confirmation at 15-22 weeks post-induction revealed that all intervened swine developed multiple nodules of well-differentiated HCC and some with hepatic angiosarcoma.
CONCLUSION
This study successfully generated HCC in conventional domestic swine with a DENA and PB combination. This investigation required at least 15 months to develop tumors. This model will be beneficial for future investigations of HCC in large animals.
PubMed: 38560662
DOI: 10.2147/CMAR.S439787 -
PloS One 2024This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy...
This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Lamotrigine; Pregnant Women; Retrospective Studies; Stillbirth; Brazil; Anticonvulsants; Seizures; Epilepsy; Phenobarbital; Status Epilepticus
PubMed: 38558080
DOI: 10.1371/journal.pone.0291190 -
Clinical Chemistry and Laboratory... Jun 2024Primidone is an anticonvulsive drug used in the treatment of epilepsy and essential tremor. It offers beneficial effects in controlling seizures, but its usage is...
An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of primidone in human serum and plasma.
OBJECTIVES
Primidone is an anticonvulsive drug used in the treatment of epilepsy and essential tremor. It offers beneficial effects in controlling seizures, but its usage is also associated with possible side effects. To ensure optimal therapy, it is crucial to measure its concentration through accurate quantification methods. Therefore, our main goal was to develop and validate a new reference measurement procedure (RMP) for accurately measuring primidone levels in human serum and plasma.
METHODS
In our study, we focused on the separation of primidone from both known and unknown interferences using a C18 column. To achieve accurate sample preparation, we developed a protocol involving protein precipitation followed by a high dilution step. The validation of the assay and determination of measurement uncertainty were carried out following guidelines from organizations such as the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. These rigorous validation processes ensure the reliability and accuracy of our method for quantifying primidone levels in human serum and plasma samples.
RESULTS
The RMP was shown to be highly selective and specific, with no evidence of matrix interference. It can be used to quantify primidone in the range of 0.150-30.0 μg/mL. Intermediate precision was less than 4.0 %, and repeatability CV ranged from 1.0 to 3.3 % across all concentration levels. The relative mean bias ranged from 0.1 to 3.9 % for native serum levels, and from -2.6 to 2.8 % for lithium-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment were 1.5-4.1 % and 0.9-1.0 %, respectively.
CONCLUSIONS
In this study, we introduce an innovative LC-MS/MS-based candidate RMP specifically designed for primidone in human serum and plasma. Our RMP offers a traceable platform, facilitating the standardization of routine assays and enabling the evaluation of clinically relevant samples. With this novel approach, we aim to enhance the accuracy and reliability of primidone measurements, ultimately benefiting the field of clinical research and patient care.
Topics: Humans; Tandem Mass Spectrometry; Primidone; Chromatography, Liquid; Reference Standards; Reproducibility of Results; Indicator Dilution Techniques; Limit of Detection; Anticonvulsants; Liquid Chromatography-Mass Spectrometry
PubMed: 38549258
DOI: 10.1515/cclm-2023-1032 -
Genes Mar 2024Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by mutation. Symptoms usually occur...
INTRODUCTION
Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by mutation. Symptoms usually occur in the infantile age with macrocephaly, developmental deterioration, progressive quadriparesis, and seizures as the most characteristic features. In this case report, we provide a detailed clinical description of the neonatal type of AxD.
METHOD
Next-Generation Sequencing (NGS), including a panel of 49 genes related to Early Infantile Epileptic Encephalopathy (EIEE), was carried out, and then Whole Exome Sequencing (WES) was performed on the proband's DNA extracted from blood.
CASE DESCRIPTION
In the first weeks of life, the child presented with signs of increased intracranial pressure, which led to ventriculoperitoneal shunt implementation. Recurrent focal-onset motor seizures with secondary generalization occurred despite phenobarbital treatment. Therapy was modified with multiple anti-seizure medications. In MRI contrast-enhanced lesions in basal ganglia, midbrain and cortico-spinal tracts were observed. During the diagnostic process, GLUT-1 deficiency, lysosomal storage disorders, organic acidurias, and fatty acid oxidation defects were excluded. The NGS panel of EIEE revealed no abnormalities. In WES analysis, missense heterozygous variant NM_002055.5: c.1187C>T, p.(Thr396Ile) was detected, confirming the diagnosis of AxD.
CONCLUSION
AxD should be considered in the differential diagnosis in all neonates with progressive, intractable seizures accompanied by macrocephaly.
Topics: Child; Infant, Newborn; Humans; Alexander Disease; Glial Fibrillary Acidic Protein; Drug Resistant Epilepsy; Hyponatremia; Spasms, Infantile; Bone Diseases; Demyelinating Diseases; Lysosomal Storage Diseases; Megalencephaly
PubMed: 38540409
DOI: 10.3390/genes15030350