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Iranian Journal of Child Neurology 2023Indicatively, phenobarbital can impair thyroid function in adults and children. The present research aims to evaluate the thyroid hormone levels in preterm neonates who...
OBJECTIVES
Indicatively, phenobarbital can impair thyroid function in adults and children. The present research aims to evaluate the thyroid hormone levels in preterm neonates who had received phenobarbital treatment.
MATERIALS &METHODS
This study was conducted on preterm neonates who weighed less or equal to 2500 g when phenobarbital was prescribed for treatment in the first 15 days of life. TSH and total T4 measurements were performed before and three months after initiation of phenobarbital.
RESULTS
In this study, the sum of preterm neonates stood at 94, of which 53 were girls, with a mean birth weight of 2004.41 ± 315.41g. Weight of 8.5% were under 1500 g. The mean gestational age was estimated at 33.64 ± 2.01 weeks. Mean T4 levels were 12.24 ± 1.96 and 12.07 ± 1.95 (p=0.334), and mean TSH levels were 5.34 ± 2.14 and5.15 ± 2.15 (p=0.376) before and after prescribing phenobarbital, respectively. The same results were compared based on sex, gestational age, birth weight, and height for T4 and TSH and T4 based on head circumference. The only significant difference was TSH in preterm infants with head circumference <32 cm before and after prescribing phenobarbital (p=0.030).
CONCLUSION
In preterm newborns that had less than 2500 g birth weight, phenobarbital did not significantly alter the serum thyroid hormone levels.
PubMed: 38074926
DOI: 10.22037/ijcn.v17i4.42583 -
The Lancet Regional Health. Europe Mar 2024The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs)...
BACKGROUND
The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain.
METHODS
This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age.
FINDINGS
We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small.
INTERPRETATION
Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction.
FUNDING
The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).
PubMed: 38476755
DOI: 10.1016/j.lanepe.2024.100849 -
RSC Advances Mar 2024An innovative molecularly imprinted polymer membrane (MIPM) was prepared with polyvinylidene difluoride (PVDF) as the support, phenytoin (PHT) as the single template,...
Fabrication of a surface molecularly imprinted polymer membrane based on a single template and its application in the separation and extraction of phenytoin, phenobarbital and lamotrigine.
An innovative molecularly imprinted polymer membrane (MIPM) was prepared with polyvinylidene difluoride (PVDF) as the support, phenytoin (PHT) as the single template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross-linking reagent, azobisisobutyronitrile as the initiator, and acetonitrile-dimethylformamide (1 : 1.5, v/v) as the porogen. These materials were characterized scanning electron microscopy, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller measurements and X-ray photoelectron spectroscopy. Their adsorption performances were evaluated through a series of experiments including isothermal adsorption, kinetic adsorption, selective adsorption, adsorption-desorption, reusability, and preparation reproducibility. Additionally, the application was explored by investigating the extraction recovery of MIPMs towards PHT, phenobarbital (PHB) and lamotrigine (LTG) in different matrices including methanol, normal saline (NS), phosphate buffer solution (PBS) and plasma. The results showed that MIPMs with rough and porous surfaces were successfully constructed, which offered good preparation reproducibility, reusability and selectivity. The adsorption capacities of MIPMs towards PHT, PHB and LTG were 2.312, 2.485 and 2.303 mg g, respectively, while their corresponding imprinting factors were 8.538, 12.122 and 4.562, respectively. The adsorption equilibrium of MIPMs was achieved within 20 min at room temperature without stirring or ultrasonication. The extraction recoveries of MIPMs for PHT, PHB or LTG in methanol, NS and PBS were more than 80% with an RSD% value of less than 3.64. In the case of plasma, the extraction recovery of MIPMs for PHT and PHB was more than 80% with an RSD% value of less than 2.41, while that of MIPMs for LTG was more than 65% with an RSD% value of less than 0.99. All the results indicated that the preparation method for MIPMs was simple, stable, and reliable, and the prepared MIPMs possessed excellent properties to meet the extraction application of PHT, PHB and LTG in different matrices.
PubMed: 38469200
DOI: 10.1039/d4ra00294f -
Neurotherapeutics : the Journal of the... Apr 2024Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical... (Observational Study)
Observational Study
Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022. The effectiveness of each triple regimen was evaluated by the seizure-free rate and within-patient ratio of the seizure frequency (a seizure frequency ratio [SFR]<1 indicated superior efficacy). The independent t-test or Mann-Whitney U test was used for effectiveness analysis, and P values were adjusted by the Benjamini-Hochberg method for multiple comparisons. A total of 511 triple trials comprising 76 different regimens were conducted among 323 enrolled patients. Among these triple regimens, lamotrigine (LTG)/valproic acid (VPA)/topiramate (TPM) was the most frequently prescribed (29.4%, n = 95). At the last clinical visit, 14.9% (n = 48) of patients achieved seizure freedom after receiving triple therapy. LTG/VPA/TPM and LTG/VPA/levetiracetam (LEV) exhibited the highest seizure-free rates at 17.9% and 12.8%, respectively. These two regimens also had significantly lower median SFRs of 0.48 (interquartile range [IQR], 0.17-0.85; adjusted P < 0.001) and 0.63 (IQR, 0.21-1.04; adjusted P < 0.01), respectively. LTG/VPA/perampanel (PER) was another promising regimen that showed marginal effectiveness (median SFR = 0.67; adjusted P = 0.053). LTG/VPA/phenobarbital had the highest incidence of regimen-specific side effects (40.0%, 4/10), while the incidence of side effects from LTG/VPA/LEV was minimal (5.1%, 2/39). In conclusion, LTG/VPA/TPM and LTG/VPA/LEV exhibited superior efficacy and good tolerability in treating patients with DRE. Our results provide preliminary insights into the selection of ASMs for three-drug combination therapies in this clinically challenging population.
Topics: Humans; Anticonvulsants; Male; Female; Drug Therapy, Combination; Adult; Epilepsies, Partial; Lamotrigine; Middle Aged; Drug Resistant Epilepsy; Longitudinal Studies; Treatment Outcome; Topiramate; Valproic Acid; Young Adult; Adolescent
PubMed: 38490875
DOI: 10.1016/j.neurot.2024.e00345 -
Basic and Clinical Neuroscience 2023Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide...
INTRODUCTION
Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods.
METHODS
Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed.
RESULTS
The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14.
CONCLUSION
The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.
PubMed: 38628829
DOI: 10.32598/bcn.2022.3904.1 -
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 -
Revista Brasileira de Epidemiologia =... 2023To describe the profile of dispensation of mental health drugs by analyzing trends in use before and during the COVID-19 pandemic within the Unified Health System...
OBJECTIVE
To describe the profile of dispensation of mental health drugs by analyzing trends in use before and during the COVID-19 pandemic within the Unified Health System (Sistema Único de Saúde [SUS]).
METHODS
Pharmacoepidemiological study based on the retrospective analysis of records regarding the dispensation of psychotropic medicines in the SUS database in the state of Minas Gerais between 2018 and 2021, considering the periods before (2018-2019) and during the COVID-19 pandemic (2020-2021). A database with the records of dispensation of municipalities was created, and the consistency of releases was verified using the Analysis of Variance (ANOVA) test. Medicine consumption was measured in a defined daily dose (DDD) per 1,000 inhabitants/day for SUS, and the difference between periods was evaluated using Student's t-test.
RESULTS
During the COVID-19 pandemic, there was an increase in the consumption of psychotropic drugs in SUS-MG. The most consumed medicines were fluoxetine hydrochloride, diazepam and phenobarbital sodium (DDD=5.89; 3.42; 2.49) in the Basic Pharmaceutical Services Component(CBAF), and olanzapine, risperidone and quetiapine hemifumarate (DDD=0.80; 0.47; 0.38) in the Specialized Pharmaceutical Services Component (CEAF). The highest percentage increase in consumption was attributed to clonazepam (75.37%) and lithium carbonate (35.35%), in CBAF, and levetiracetam (3,000.00%) and memantine hydrochloride (340.0%) in CEAF.
CONCLUSION
The change in the psychotropic drug dispensation profile during the COVID-19 pandemic highlights the need to produce more studies to complete, confirm or rule out this profile and monitor the use of psychotropic drugs by the population in the post-pandemic context.
Topics: Humans; Pandemics; Brazil; Retrospective Studies; COVID-19; Psychotropic Drugs
PubMed: 38088718
DOI: 10.1590/1980-549720230059 -
Pediatric Research Jan 2024Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and...
BACKGROUND
Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs.
METHODS
Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC).
RESULTS
Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies.
CONCLUSIONS
There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms.
IMPACT
There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.
Topics: Infant, Newborn; Humans; Midazolam; Phenobarbital; Anticonvulsants; Electroencephalography; Hypothermia, Induced
PubMed: 37752246
DOI: 10.1038/s41390-023-02779-9 -
The Journal of Trauma and Acute Care... Mar 2024Alcohol withdrawal syndrome (AWS) represents significant cost to the hospitalized trauma population from a clinical and financial perspective. Historically, AWS has been...
BACKGROUND
Alcohol withdrawal syndrome (AWS) represents significant cost to the hospitalized trauma population from a clinical and financial perspective. Historically, AWS has been managed with benzodiazepines. Despite their efficacy, benzodiazepines carry a heavy adverse effect profile. Recently, benzodiazepine-sparing protocols for the prophylaxis and treatment of AWS have been used in medical patient populations. Most existing benzodiazepine-sparing protocols use phenobarbital, while ours primarily uses gabapentin and clonidine, and no such protocol has been developed and examined for safety and efficacy specifically within a trauma population.
METHODS
In December of 2019, we implemented our benzodiazepine-sparing protocol for trauma patients identified at risk for alcohol withdrawal on admission. Trauma patients at risk for AWS admitted to an academic Level 1 trauma center before (conventional) and after (benzodiazepine-sparing [BS]) protocol implementation were compared. Outcomes examined include morphine milligram equivalent dosing rates and lorazepam equivalent dosing rates as well as the Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) scores, hospital length of stay, intensive care unit length of stay, and ventilator days.
RESULTS
A total of 387 conventional and 134 benzodiazepine sparing patients were compared. Injury Severity Score (13 vs. 16, p = 0.10) and admission alcohol levels (99 vs. 149, p = 0.06) were similar. Patients in the BS pathway had a lower maximum daily CIWA-Ar (2.7 vs. 1.5, p = 0.04). While mean morphine milligram equivalent per day was not different between groups (31.5 vs. 33.6, p = 0.49), mean lorazepam equivalents per day was significantly lower in the BS group (1.1 vs. 0.2, p < 0.01). Length of stay and vent days were not different between the groups.
CONCLUSION
Implementation of a benzodiazepine-sparing pathway that uses primarily clonidine and gabapentin to prevent and treat alcohol withdrawal syndrome in trauma patients is safe, reduces the daily maximum CIWA-Ar, and significantly decreases the need for benzodiazepines. Future studies will focus on outcomes affected by avoiding AWS and benzodiazepines in the trauma population.
LEVEL OF EVIDENCE
Therapeutic/Care Management; Level IV.
Topics: Humans; Benzodiazepines; Substance Withdrawal Syndrome; Alcoholism; Lorazepam; Gabapentin; Clonidine; Alcohol Withdrawal Delirium; Retrospective Studies; Ethanol; Morphine Derivatives
PubMed: 37934662
DOI: 10.1097/TA.0000000000004188 -
Frontiers in Veterinary Science 2023Phenobarbital has been used for many decades in both human and veterinary epileptic patients. Many formulations for a particular drug exist, most of which are marketed...
INTRODUCTION
Phenobarbital has been used for many decades in both human and veterinary epileptic patients. Many formulations for a particular drug exist, most of which are marketed for humans. Recently a veterinary specific phenobarbital product has been introduced to the market in the United States. Utilizing a specific formulation to treat patients may help decrease the issue of bioequivalence between one pharmaceutical product to another. Therefore, the goal of this study was to determine single and multiple dosing pharmacokinetics and tolerability of a veterinary specific phenobarbital product over a 4-week time period.
MATERIALS AND METHODS
8 Healthy dogs from a canine research colony were used in the study.
RESULTS
Overall, this phenobarbital formulation was well tolerated in the dogs in this study. Cmax, Tmax, half-life, and AUC after single 12 mg/kg oral dose were 23.5 μg/mL, 4.2 h, 94 h, and 2,758 h*μg/mL. Following chronic dosing, these parameters were 29.1 μg/mL, 3.4 h, 70 h, and 2,971 h*μg/mL, respectively.
DISCUSSION
This formulation demonstrated a mean absolute bioavailability of 100%, with similar pharmacokinetic properties to previously published data.
PubMed: 38249559
DOI: 10.3389/fvets.2023.1307888