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Epilepsy & Behavior : E&B Jun 2024This review aims to summarize existing evidence on the adverse pregnancy outcomes and seizure control effects of using lamotrigine (LTG) monotherapy in pregnancy women... (Review)
Review
OBJECTIVE
This review aims to summarize existing evidence on the adverse pregnancy outcomes and seizure control effects of using lamotrigine (LTG) monotherapy in pregnancy women with epilepsy (WWE) during pregnancy.
METHODS
A comprehensive search was conducted in various databases including Cochrane, Web of Science, CBM, PubMed, Embase, CNKI, and Pregnancy Registration Center databases to identify relevant studies. The search was concluded up to January 2024. Studies comparing LTG with other antiseizure medications (ASMs) for treating epilepsy in pregnant women were included, with no language or regional restrictions.
RESULTS
A total of 19 studies were included for analysis, with 16 studies reporting adverse pregnancy outcomes and 6 studies reporting seizure control outcomes. Meta-analysis showed that compared to monotherapy with carbamazepine (CBZ), sodium valproate (VPA), and levetiracetam (LEV), LTG monotherapy had a slightly weaker ability to control seizures during pregnancy, with ORs and 95 %CIs of 0.65 (0.57-0.75; CBZ), 0.50 (0.32-0.79; VPA), and 0.55 (0.36-0.84; LEV). Regarding adverse pregnancy outcomes, the occurrence rate of LTG monotherapy was significantly lower than that of CBZ, VPA, phenytoin (PHT), and phenobarbital (PHB), with ORs and 95 %CIs ranging from 0.30 (0.25-0.35; VPA) to 0.68 (0.56-0.81; CBZ).
CONCLUSION
Based on meta-analysis, LTG and LEV appear to be preferred medications for controlling seizures during pregnancy. This review provides further support for the use of LTG monotherapy in pregnant WWE, building upon existing evidence for clinical practitioners.
PubMed: 38945077
DOI: 10.1016/j.yebeh.2024.109924 -
The American Journal of Emergency... Jun 2024Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs. (Review)
Review
BACKGROUND
Status epilepticus (SE) is potentially life-threatening, however, it is unclear which antiepileptic drugs (AEDs) should be used as second-line AEDs.
OBJECTIVE
We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing multiple second-line AEDs for SE to investigate the efficacy of AEDs.
METHODS
We searched MEDLINE, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal and included RCTs for patients aged ≥15 years with SE on December 31, 2023. We compared multiple second-line AEDs for SE including fosphenytoin (fPHT), lacosamide (LCM), levetiracetam (LEV), phenytoin (PHT), phenobarbital (PHB), and valproate (VPA). The primary and secondly outcomes were termination of seizures integrating the absence of seizure recurrence at 30 min and 60 min, and adverse events associated with AEDs, respectively, with expressing as relative risk (RR) with a 95% confidence interval (CI). We conducted a NMA using frequentist-based approach with multivariate random effects, and assessed the certainty based on the Grading of Recommendations, Assessment, Development, and Evaluations framework.
RESULTS
Seven RCTs (n = 780) were included, and statistically significant difference was detected between VPA vs. PHB (RR, 0.67; 95% CI, 0.53-0.85; very low certainty), fPHT vs. PHB (RR, 0.66; 95% CI, 0.48-0.90; very low certainty), LCM vs. PHB (RR, 0.62; 95% CI, 0.41-0.93; very low certainty), and LEV vs. PHB (RR, 0.69; 95% CI, 0.51-0.94; very low certainty). Moreover, PHB was the highest in the ranking for termination of seizures. For adverse events, no significant reduction was observed owing to the selection of AEDs, although the ranking of PHB was the lowest.
CONCLUSIONS
PHB may have been the most effective for seizure termination as second-line AEDs in adult patients with SE. However, the certainty of almost all comparisons was "very low", and careful interpretation is essential.
PubMed: 38941904
DOI: 10.1016/j.ajem.2024.06.019 -
Current Pediatric Reviews Jun 2024An off-label medication involves the use of an approved drug for an unapproved indication, population, route of administration, or dosage.The physiological state of...
Awareness, Practice, and Views of Pediatricians, General Physicians, and Pharmacists about Prescribing Off-label Medication in Pediatric Patients in Eastern Province, Saudi Arabia.
BACKGROUND
An off-label medication involves the use of an approved drug for an unapproved indication, population, route of administration, or dosage.The physiological state of children differs from that of adults, making the adult formulation potentially dangerous to children. Off-label prescribing is quite common in children due to challenges in the development of pediatric formulations. The current study was conducted to determine the awareness, practice, and views of pediatricians, general physicians, and pharmacists about prescribing Off-label medication to pediatric patients in Eastern Province, Saudi Arabia.
METHODS
A cross-sectional study based on a questionnaire was conducted among pediatricians, general physicians, and pharmacists (clinical and community) in Eastern Province, Saudi Arabia. Statistical analysis was conducted using the data exported from Google Forms (Mountain View, California, USA) and Microsoft Excel (Version 2016) and then exported into Statistical Package for Social Sciences (SPSS) version 26.0 (IBM, Inc., Armonk, NY, USA). Chi-square was deemed suitable. The level of significance was set at 0.05.
RESULTS
Among the study participants, 53(35.09%) were pharmacists, followed by 24(15.89%) others, 22(14.565) pediatricians, 19(12.58%) other specialists, 17(11.25%) general physicians, and 16(10.59%) were clinical pharmacist. About 73(48.34%) described the definition of off-label correctly. About 114(75.49%) believed that parents and guardians must be informed about off-label medicine prescribed to their children. About 52(34.43%) had concerns about the safety of the medication, and 98(64.90%) believed they should be tested in pediatrics during clinical trials. Further, 97(64.23%) considered themselves not enough knowledgeable about off-label medications. The barriers reported by the participants were as follows: 89(58.945%) said lack of information resources, 71(47.01%) said lack of training, 56(37.08%) said lack of information on the safety of excipients used in pediatrics, 47(31.12%) said lack of formulary, 44(29.13%) said lack of guidelines, and 58(5.29%) said lack of information related to the safety of excipient concentration in pediatrics. The proportion of healthcare professionals who agreed that excipients in adult medication may be harmful to pediatrics was 103(68.21%). The drugs most often prescribed as off-label were paracetamol 54(21.68%), followed by Phenobarbital 35(14%), and Amoxicillin 33(13.25%).
CONCLUSION
There are a considerable number of healthcare professionals unaware of the description of off-label medication. The majority have concerns over the safety and efficacy of the off-label drugs and believe that most frequently used off-label drugs in pediatrics must be tested in pediatrics during clinical trials. In addition, excipient safety data are of considerable importance to ensure off-label drug safety in pediatrics, who believe their knowledge is inadequate and need proper guidelines and training on this issue.
PubMed: 38934287
DOI: 10.2174/0115733963298903240614072717 -
Veterinary Sciences Jun 2024Seizures are a common presentation seen in small animal practices. Seizures require prompt management including initial interventions for triage, stabilization, and... (Review)
Review
Seizures are a common presentation seen in small animal practices. Seizures require prompt management including initial interventions for triage, stabilization, and treatment with first-line anticonvulsant (AC) drugs like benzodiazepines. Concurrently, ruling out metabolic or extracranial causes with point-of-care diagnostics can help guide further diagnostics and treatments. Analysis of the history and a physical exam are also necessary to rule out common "look-alikes" that require specific diagnostic workup and treatments. Typically, causes of seizures can be grouped into intracranial and extracranial causes, with the latter being easier to diagnose with commonly available tests. This review presents a systematic approach to the diagnosis and treatment of single seizures, cluster seizures, and status epilepticus in dogs and cats.
PubMed: 38922024
DOI: 10.3390/vetsci11060277 -
Pediatric Neurology Jun 2024Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month....
BACKGROUND
Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures.
METHODS
A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects.
RESULTS
A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted.
CONCLUSIONS
LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.
PubMed: 38917517
DOI: 10.1016/j.pediatrneurol.2024.05.019 -
Drug Metabolism and Disposition: the... Jun 2024Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology,...
Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy (HIE), disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs - midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM), were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), hypoxia + TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (pre-dose), and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, 24 hours post-drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and non-compartmental PK analysis (NCA). The study showed a statistically significant decrease in FNT clearance (CL, 66% decrease) with approximately 3-fold longer half-life (t) in the TH group. The H+TH group showed a 17% reduction in FNT CL with a 62% longer t compared to the C group, however non-statistically significant. Trends towards lower CL and longer t were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared to controls. The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK, using four model drugs. Such insights can subsequently be used to inform and develop a physiologically-based pharmacokinetic (PBPK) model, which is useful for drug exposure prediction in human neonates.
PubMed: 38906699
DOI: 10.1124/dmd.124.001677 -
Archives of Disease in Childhood Jun 2024To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.
OBJECTIVES
To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.
DESIGN
Pharmacokinetic 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.
SETTING
Neonatal intensive care unit.
PATIENTS
Term neonates with electrographically confirmed seizures.
INTERVENTIONS
In 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 MEASURES
Clearance (CL) and volume of distribution (V) were determined. Covariates that significantly affected LEV disposition were identified.
RESULTS
Primary 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 V 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 V were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and V (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%.
CONCLUSIONS
LEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates.
TRIAL REGISTRATION NUMBER
NCT01720667.
PubMed: 38902005
DOI: 10.1136/archdischild-2022-324952 -
ACS Pharmacology & Translational Science Jun 2024Drug-resistant epilepsy is a prominent challenge in chronic neurological disorders. Valproate, commonly used to treat epilepsy, can fail due to various side effects and...
Unlocking the Therapeutic Potential: Sitagliptin's Multifaceted Approach in Drug-Resistant Epilepsy through a Novel Mechanism Inhibiting Protein Kinase C-γ and a Long-Term Potentiation Pathway.
Drug-resistant epilepsy is a prominent challenge in chronic neurological disorders. Valproate, commonly used to treat epilepsy, can fail due to various side effects and interactions, necessitating the exploration of alternative treatments. Our study primarily investigated sitagliptin's potential as a therapeutic agent for drug-resistant epilepsy. Employing computational modeling and enzyme assay testing, three lead compounds, emixustat, sitagliptin, and distigmine bromide, were evaluated against the target enzyme protein kinase C-γ. , experiments on a pentylenetetrazolium-induced lamotrigine-resistant epilepsy model were conducted to test sitagliptin's antiseizure effects, compared with the standard phenobarbital treatment. Emixustat and sitagliptin showcased strong inhibitory properties, while distigmine bromide was less effective in the enzyme assay. Mechanistic insights revealed sitagliptin's ability to modulate the seizure grade and first myoclonic jerk latency via oxidative stress markers, like reduced glutathione and glutathione peroxidase emphasizing its antioxidative role in epilepsy. Additionally, it demonstrated anti-inflammatory effects by significantly reducing proinflammatory markers interleukin-1β and interleukin-6. The modulation of key genes of the long-term potentiation pathway, particularly protein kinase C-γ and metabotropic glutamate receptor 5, was evident through mRNA expression levels. Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-γ.
PubMed: 38898950
DOI: 10.1021/acsptsci.4c00073 -
Journal of Veterinary Internal Medicine Jun 2024Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy.
BACKGROUND
Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy.
HYPOTHESIS/OBJECTIVES
Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs.
ANIMALS
Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam.
METHODS
Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction.
RESULTS
The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified.
CONCLUSION AND CLINICAL IMPORTANCE
Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.
PubMed: 38888491
DOI: 10.1111/jvim.17128 -
Frontiers in Veterinary Science 2024Zonisamide is used in dogs for the treatment of epileptic seizures. It is predominantly metabolised by CYP450 hepatic enzymes. When used concurrently with phenobarbital...
Zonisamide is used in dogs for the treatment of epileptic seizures. It is predominantly metabolised by CYP450 hepatic enzymes. When used concurrently with phenobarbital (PB), zonisamide clearance is increased and its elimination half-life decreases. However, the effect that zonisamide may have on serum PB concentrations in dogs has not been previously described. Eight dogs diagnosed with idiopathic epilepsy and two dogs with structural epilepsy commenced zonisamide at 8.0 mg/kg/12 h [7.4-10 mg/kg/12 h] following an increase in the frequency of epileptic seizures. Nine dogs were receiving PB every 12 h (4.2 mg/kg/12 h [3.8-6 mg/kg/12 h]), and one dog was receiving PB every 8 h (6 mg/kg/8 h). Following the addition of zonisamide and despite no increase in PB dosage, an increase in phenobarbital serum PB concentration was observed in 9 out of 10 dogs in subsequent measurements. In five dogs, phenobarbital serum concentrations were raised to concentrations higher than the reported hepatotoxic concentrations (trough>35 mg/L). This required a reduction in daily doses of PB. This case series suggests that zonisamide affects the metabolism of PB and causes an increase in PB serum concentrations over time.
PubMed: 38868500
DOI: 10.3389/fvets.2024.1389615