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CPT: Pharmacometrics & Systems... Feb 2022Oxcarbazepine (OXZ) and levetiracetam (LEV) are two new generation anti-epileptic drugs, often co-administered in children with enzyme-inducing antiepileptic drugs...
Oxcarbazepine (OXZ) and levetiracetam (LEV) are two new generation anti-epileptic drugs, often co-administered in children with enzyme-inducing antiepileptic drugs (EIAEDs). The anti-epileptic effect of OXZ and LEV are linked to the exposure of OXZ's active metabolite 10-monohydroxy derivative (MHD) and (the parent) LEV, respectively. However, little is known about the confounding effect of age and EIAEDs on the pharmacokinetics (PKs) of MHD and LEV. To address this knowledge gap, physiologically-based pharmacokinetic (PBPK) modeling was performed in the PK-Sim software using literature data from children greater than or equal to 2 years of age. Age-related changes in clearance (CL) of MHD and LEV were characterized, both in the presence (group 1) and absence (group 2) of concomitant EIAEDs. The drug-drug interaction effect of EIAEDs was estimated as the difference in CL estimates between groups 1 and 2. PBPK modeling suggests that bodyweight normalized CL (ml/min/kg) is higher in younger children than their older counterparts (i.e., due to an influence of age). Concomitant EIAEDs further increase MHD's CL to a fixed extent of 25% at any age, but EIAEDs' effect on LEV's CL increases with age from 20% (at 2 years) to 30% (at adolescence). Simulations with the maximum recommended doses (MRDs) revealed that children between 2 and 4 years and greater than 4 years, who are not on EIAEDs, are at risk of exceeding the reference exposure range for OXZ and LEV, respectively. This analysis demonstrates the use of PBPK modeling in understanding the confounding effect of age and comedications on PKs in children and adolescents.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Interactions; Epilepsy; Humans; Levetiracetam; Oxcarbazepine
PubMed: 34816634
DOI: 10.1002/psp4.12750 -
International Journal of Molecular... Jun 2024The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and...
The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.
Topics: Animals; Oxcarbazepine; Mice; Anticonvulsants; Electroshock; Male; Disease Models, Animal; Seizures; Brain; Memory, Long-Term; Carbamazepine; Avoidance Learning
PubMed: 38928457
DOI: 10.3390/ijms25126751 -
Seizure Dec 2020
Topics: Anticonvulsants; Carbamazepine; Dibenzazepines; Humans
PubMed: 33334544
DOI: 10.1016/j.seizure.2020.10.026 -
Brain Sciences Jul 2021Carbamazepine and oxcarbazepine are used for behavioral disorders following organic diseases. After severe acquired brain injury, patients may develop frontal symptoms....
Carbamazepine and oxcarbazepine are used for behavioral disorders following organic diseases. After severe acquired brain injury, patients may develop frontal symptoms. In our neurological rehabilitation routine, oxcarbazepine is used for better safety over carbamazepine, although its efficacy is not clarified. We aimed to improve knowledge on this use of oxcarbazepine, by probing clinical factors associated with response. We retrospectively examined the clinical records of our patients, collecting clinical variables and outcomes of efficacy, both clinician-rated and caregiver/self-rated. We described the distribution of clinical variables and examined their associations via logistic regressions. Patients in our cohort were predominantly pediatric, with frontal lobe damage and irritable/reactive. With an oxcarbazepine median dose of 975 mg, almost half of patients improved. We found several clinical factors associated with clinician-rated efficacy: absence of frontal damage and absence of irritability/reactivity symptoms; clinical factors associated with caregivers/patients-rated efficacy were: higher DRS score at baseline and higher patient age. In this retrospective study, we observed that oxcarbazepine was differentially efficacious in patients with specific characteristics. Our study could not examine drug therapy separately from neuropsychological therapy, nor the influence of dose. Our associative results should be verified experimentally, also assessing causality and establishing dose-related efficacy and safety.
PubMed: 34356183
DOI: 10.3390/brainsci11070949 -
Cephalalgia : An International Journal... Feb 2024Short-lasting unilateral neuralgiform headache attacks (SUNHA) have the features of both short-lasting unilateral neuralgiform pain, such as trigeminal neuralgia or... (Review)
Review
BACKGROUND
Short-lasting unilateral neuralgiform headache attacks (SUNHA) have the features of both short-lasting unilateral neuralgiform pain, such as trigeminal neuralgia or stabbing headache, and associated trigeminal autonomic symptoms, such as paroxysmal hemicrania or cluster headache. Recognizing and adequately treating SUNHA is essential but current treatment methods are ineffective in treating SUNHA.
METHODS
We reviewed the changes in the concept of short-lasting unilateral neuralgiform headache attacks and provide a narrative review of the current medical and surgical treatment options, from the first choice of treatment for patients to treatments for selective intractable cases.
RESULTS
Unlike the initial impression of an intractable primary headache disorder affecting older men, SUNHA affects both sexes throughout their lifespan. One striking feature of SUNHA is that the attacks are triggered by cutaneous or intraoral stimulation. The efficacy of conventional treatments is disappointing and challenging, and preventive therapy is the mainstay of treatment because of highly frequent attacks of a very brief duration. Amongst them, lamotrigine is effective in approximately two-third of the patients with SUNHA, and intravenous lidocaine is essential for the management of acute exacerbation of intractable pain. Topiramate, oxcarbazepine and gabapentin are considered good secondary options for SUNHA, and botulinum toxin can be used in selective cases. Neurovascular compression is commonly observed in SUNHA, and surgical approaches, such as neurovascular compression, have been reported to be effective for intractable cases.
CONCLUSIONS
Recent advances in the understanding of SUNHA have improved the recognition and treatment approaches for this unique condition.
Topics: Male; Female; Humans; Aged; SUNCT Syndrome; Headache; Anticonvulsants; Gabapentin; Lamotrigine; Neuralgia; Trigeminal Autonomic Cephalalgias
PubMed: 38415675
DOI: 10.1177/03331024241232256 -
Clinical and Translational Allergy Jan 2022Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA)...
BACKGROUND
Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre-stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre-stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs.
METHODS
We analyzed the incidence and the risk of ADRs for selected HLA alleles (, , , , , , , and ) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre-stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus.
RESULTS
Among 11,988 HLA-tested transplant patients, 4092 (34.1%) had high-risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09-2.13], = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19-22.69], < 0.001). Higher risks of type B ADR and SCARs were observed in patients taking carbamazepine or oxcarbazepine if they had one of , , or alleles. Vancomycin and dapsone use in and carriers, respectively, showed trends toward increased risk of type B ADRs.
CONCLUSION
Utilization of pre-stored HLA data can prevent type B ADRs including SCARs by screening high-risk patients.
PubMed: 35070271
DOI: 10.1002/clt2.12098 -
Frontiers in Pharmacology 2021To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was...
To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE ( = 0.002, = 0.04). HLA-B*38:02 was associated with CBZ-MPE ( 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE ( = 0.02 and = 0.04, respectively). analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.
PubMed: 34122097
DOI: 10.3389/fphar.2021.671572 -
Tremor and Other Hyperkinetic Movements... 2023There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin... (Review)
Review
BACKGROUND
There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review.
METHODS
We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents.
RESULTS
Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties.
DISCUSSION
Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.
Topics: Humans; Anticonvulsants; Restless Legs Syndrome; Carbamazepine; Gabapentin; Glutamates
PubMed: 36873914
DOI: 10.5334/tohm.739 -
Frontiers in Pediatrics 2022Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological...
BACKGROUND
Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases.
METHODS
We enrolled 10 children with mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed.
RESULTS
Ten children with gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was (P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that gene expression levels were significantly lower in children and parent carriers than the control group. The gene expression level of affected children was significantly lower ( ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures.
CONCLUSION
Mutation of led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.
PubMed: 36467477
DOI: 10.3389/fped.2022.997088 -
Pediatric Neurology Jul 2023Knowledge on antiseizure medication (ASM) use and retention for children with epilepsy is limited, partly because of extensive off-label use of newer drugs with limited...
BACKGROUND
Knowledge on antiseizure medication (ASM) use and retention for children with epilepsy is limited, partly because of extensive off-label use of newer drugs with limited registration. We used prescription data to study prescription patterns on a population-wide scale and compared the proportion of patients remaining on monotherapy of ASMs with and without formal indication for different age groups.
METHODS
A total of 14,681 individuals aged <18 years were included, using cross-referenced Swedish registers from 2007 to 2020. Kaplan-Meier retention rates were calculated for all ASMs. The most common pathways of the first three medications per patient were analyzed.
RESULTS
In children older than one month and up to age one year, monotherapy retention rates were the highest for oxcarbazepine, valproic acid, and carbamazepine. Among children aged one to five years, oxcarbazepine and levetiracetam were among ASMs that do not have a monotherapy indication in Sweden but still had high retention rates. In the age group five to 12 years, lamotrigine and oxcarbazepine had the highest retention rate. In males aged 12 to 18 years, valproic acid was the most common choice followed by lamotrigine, whereas lamotrigine was the first choice of ASM for females, exceeding the second and third most common options levetiracetam and oxcarbazepine by a factor of two and three, respectively.
CONCLUSION
Off-label medication is common in children with epilepsy but does not seem to be associated with lower retention. The restrictions regarding valproic acid for females of childbearing age seem to have been well implemented in Swedish neuropediatric care.
Topics: Male; Female; Humans; Child; Infant; Child, Preschool; Lamotrigine; Oxcarbazepine; Levetiracetam; Sweden; Valproic Acid; Triazines; Epilepsy; Anticonvulsants
PubMed: 37116405
DOI: 10.1016/j.pediatrneurol.2023.03.016