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International Journal of Molecular... Dec 2023Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications... (Review)
Review
Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications (ASMs) in rodents, oxcarbazepine, tiagabine and lamotrigine being the exceptions. Clinical data based on low numbers of patients support the experimental results by showing that caffeine (ingested in high quantities) may sharply increase seizure frequency, considerably reducing the quality of patients' lives. In contrast, this obviously negative activity of caffeine was not found in clinical studies involving much higher numbers of patients. ASMs vulnerable to caffeine in experimental models of seizures encompass carbamazepine, phenobarbital, phenytoin, valproate, gabapentin, levetiracetam, pregabalin and topiramate. An inhibition of R-calcium channels by lamotrigine and oxcarbazepine may account for their resistance to the trimethylxanthine. This assumption, however, is complicated by the fact that topiramate also seems to be a blocker of R-calcium channels. A question arises why large clinical studies failed to confirm the results of experimental and case-report studies. A possibility exists that the proportion of patients taking ASMs resistant to caffeine may be significant and such patients may be sufficiently protected against the negative activity of caffeine.
Topics: Humans; Lamotrigine; Oxcarbazepine; Caffeine; Topiramate; Anticonvulsants; Seizures; Calcium Channels
PubMed: 38139396
DOI: 10.3390/ijms242417569 -
CNS Drugs Aug 2023Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with...
BACKGROUND
Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown.
OBJECTIVE
The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients.
METHODS
We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment.
RESULTS
Patients had a mean valproate intravenous loading dose of 34.5 mg/kg and a mean maintenance dose of 15.3 mg/kg/d (1078 mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p = 0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone).
CONCLUSION
Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.
Topics: Adult; Humans; Anticonvulsants; Brain Diseases; Hyperammonemia; Status Epilepticus; Valproic Acid
PubMed: 37466895
DOI: 10.1007/s40263-023-01024-5 -
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 -
Iranian Journal of Child Neurology 2024Jaundice occurs in 60% of full-term and 80% of pre-term newborns. This study compared the effect of phototherapy with and without phenobarbital on icteric newborns.
OBJECTIVES
Jaundice occurs in 60% of full-term and 80% of pre-term newborns. This study compared the effect of phototherapy with and without phenobarbital on icteric newborns.
MATERIALS & METHODS
This study is a randomized clinical trial conducted from July until March 2018 at Imam Reza Hospital, Mashhad University of Medical Science, Iran. Full-term and near-term neonates with more than 2000 grams who were hospitalized in the mentioned period for jaundice were entered into the study. The newborns were divided into two groups using block randomization. Data were analyzed by SPSS version 19.
RESULTS
The average gestational age was 36.4 weeks (SD 2.39) in the intervention group and 36.9 weeks (SD 2.16) in the control group, with no significant difference between them. The mean hospital stay for the intervention group was 72 hours (SD 1.66), compared to 55 hours (SD 1.88) for the control group. At discharge, the serum bilirubin level in the intervention group was 11.53 mg/dL (SD 0.77), while it was 10.80 mg/dL (SD 1.09) in the control group, a statistically significant difference.
CONCLUSION
According to this study, phototherapy with phenobarbital is not more effective than phototherapy alone in neonatal hyperbilirubinemia.
PubMed: 38617400
DOI: 10.22037/ijcn.v18i2.36848 -
Chemistry of Materials : a Publication... Aug 2023We present an approach for the rational development of stimuli-responsive ionogels which can be formulated for precise control of multiple unique ionogel features and...
We present an approach for the rational development of stimuli-responsive ionogels which can be formulated for precise control of multiple unique ionogel features and fill niche pharmaceutical applications. Ionogels are captivating materials, exhibiting self-healing characteristics, tunable mechanical and structural properties, high thermal stability, and electroconductivity. However, the majority of ionogels developed require complex chemistry, exhibit high viscosity, poor biocompatibility, and low biodegradability. In our work, we overcome these limitations. We employ a facile production process and strategically integrate silk fibroin, the biocompatible ionic liquids (ILs) choline acetate ([Cho][OAc]), choline dihydrogen phosphate ([Cho][DHP]), and choline chloride ([Cho][Cl]), traditional pharmaceutical excipients, and the model antiepileptic drug phenobarbital. In the absence of ILs, we failed to observe gel formation; yet in the presence of ILs, thermoresponsive ionogels formed. Systems were assessed via visual tests, transmission electron microscopy, confocal reflection microscopy, dynamic light scattering, zeta potential and rheology measurements. We formed diverse ionogels of strengths ranging between 18 and 642 Pa. Under 25 °C storage, formulations containing polyvinylpyrrolidone (PVP) showed an ionogel formation period ranging over 14 days, increasing in the order of [Cho][DHP], [Cho][OAc], and [Cho][Cl]. Formulations lacking PVP showed an ionogel formation period ranging over 32 days, increasing in the order of [Cho][OAc], [Cho][DHP] and [Cho][Cl]. By heating from 25 to 60 °C, immediately following preparation, thermoresponsive ionogels formed below 41 °C in the absence of PVP. Based on our experimental results and density functional theory calculations, we attribute ionogel formation to macromolecular crowding and confinement effects, further enhanced upon PVP inclusion. Holistically, applying our rational development strategy enables the production of ionogels of tunable physicochemical and rheological properties, enhanced drug solubility, and structural and energetic stability. We believe our rational development approach will advance the design of biomaterials and smart platforms for diverse drug delivery applications.
PubMed: 37576585
DOI: 10.1021/acs.chemmater.3c00303 -
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 -
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 -
Journal of Veterinary Internal Medicine 2023We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug.
CASE DESCRIPTION
We describe a case of presumptive acquired systemic lupus erythematosus secondary to phenobarbital administration in a dog, which resolved with withdrawal of the drug.
CLINICAL FINDINGS
A 3.5 year-old poodle presented to a veterinary teaching hospital for Tier 1 idiopathic epilepsy and was treated with phenobarbital. The dog experienced fever, multiple cytopenias, and proteinuria in conjunction with a positive antinuclear antibody (ANA) titer.
DIAGNOSTICS
Serial CBCs, urine protein : creatinine ratios, and sternal bone marrow aspirates were performed to evaluate improvement.
TREATMENT AND OUTCOME
Phenobarbital was withdrawn and levetiracetam initiated. All abnormalities resolved with supportive care, without initiation of immunosuppressive drugs. All cytopenias and proteinuria resolved and ANA test results became negative within 3 months. The patient recovered and did well clinically.
CLINICAL RELEVANCE
Systemic lupus erythematosus is a disease of multiple autoimmune syndromes occurring concurrently or sequentially in conjunction with the presence of circulating ANA. It has been well described in dogs as an idiopathic condition, but in human medicine may occur secondary to drug reactions (drug-associated lupus) including as a reaction to phenobarbital. The findings in our case are consistent with the criteria for drug-induced lupus in humans and we suggest it as the first report of phenobarbital-induced lupus in a dog.
Topics: Dogs; Humans; Animals; Hospitals, Animal; Hospitals, Teaching; Lupus Erythematosus, Systemic; Phenobarbital; Proteinuria; Dog Diseases
PubMed: 37737539
DOI: 10.1111/jvim.16882 -
Epilepsia Open Sep 2023Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions...
Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q -Q ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.
Topics: Humans; Anticonvulsants; Pharmacogenetics; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Pilot Projects; Cytochrome P-450 CYP2C9; Saliva; Epilepsy; Phenytoin; Clobazam; Phenobarbital
PubMed: 36840436
DOI: 10.1002/epi4.12717 -
Journal of Veterinary Internal Medicine 2024Evidence-based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures...
BACKGROUND
Evidence-based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures remain inadequately controlled by administration of phenobarbital alone or for cats that cannot safely receive phenobarbital.
OBJECTIVE
To compare seizure frequency in cats before and after oral administration of zonisamide and describe adverse clinical or clinicopathologic effects in this cohort.
ANIMALS
Fifty-seven cats with a history of seizures.
METHODS
Multicenter, retrospective study. Median number of seizures per month and number of seizure days per month were compared before and after administration of zonisamide in all cats, a subgroup of cats with idiopathic epilepsy (IE), and a subgroup of cats receiving zonisamide as sole therapy. Clinical and clinicopathologic adverse effect data were also reported.
RESULTS
A median decrease of 1 (P = .001, 95% confidence interval (CI) [-1.0, -0.5]) seizure per month, and 1 (P = .003, 95% CI [-1.5, -0.2]) seizure days per month was found across all cats after oral administration of zonisamide. The subgroup with IE showed median decreases of 1 (P = .03, 95% CI [-2.0, -0.5]) and 2 (P = .01, 95% CI [-2.5, -1.0]), respectively. The most common clinical adverse effects were sedation (17%), ataxia (11%), hyporexia (17%), and emesis (5%). One cat developed mild nonregenerative anemia, 2 cats developed mild metabolic acidosis, and 6 cats showed mild increases in ALT and ALP.
CONCLUSION
Zonisamide was well tolerated and efficacious in controlling seizure activity in most cats.
Topics: Animals; Cats; Anticonvulsants; Cat Diseases; Epilepsies, Partial; Epilepsy; Phenobarbital; Retrospective Studies; Seizures; Zonisamide
PubMed: 38240116
DOI: 10.1111/jvim.16984