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The Turkish Journal of Pediatrics 2018Acar T, Alkan G, Çaksen H, Ertekin B, Ergin M, Koçak S, Cander B. Phenytoin induced dystonia. Turk J Pediatr 2018; 60: 111-112. The abnormalities of dopaminergic...
Acar T, Alkan G, Çaksen H, Ertekin B, Ergin M, Koçak S, Cander B. Phenytoin induced dystonia. Turk J Pediatr 2018; 60: 111-112. The abnormalities of dopaminergic activity in the basal ganglia have been emphasized to be effective in dystonia. We hereby report a case of a 2.5-year-old male patient who presented with tonic-clonic sezures and who developed dystonia after being given phenytoin. Biperidene hydrochloride was administered intramuscularly; primidone was added to the treatment regimen. After a 7-day-follow-up at the hospital, the patient had no dystonia and was discharged.
Topics: Anticonvulsants; Child, Preschool; Dystonia; Epilepsy; Humans; Male; Phenytoin; Primidone
PubMed: 30102491
DOI: 10.24953/turkjped.2018.01.019 -
Current Pharmaceutical Design 2017Progressive myoclonus epilepsies (PMEs) are a group of rare inherited diseases featuring a combination of myoclonus, seizures and variable degree of cognitive... (Review)
Review
BACKGROUND
Progressive myoclonus epilepsies (PMEs) are a group of rare inherited diseases featuring a combination of myoclonus, seizures and variable degree of cognitive impairment. Despite extensive investigations, a large number of PMEs remain undiagnosed. In this review, we focus on the current pharmacological approach to PMEs.
METHODS
References were mainly identified through PubMed search until February 2017 and backtracking of references in pertinent studies.
RESULTS
The majority of available data on the efficacy of antiepileptic medications in PMEs are primarily anecdotal or observational, based on individual responses in small series. Valproic acid is the drug of choice, except for PMEs due to mitochondrial diseases. Levetiracetam and clonazepam should be considered as the first add-on treatment. Zonisamide and perampanel represent promising alternatives. Phenobarbital and primidone should be reserved to patients with resistant disabling myoclonus or seizures. Lamotrigine should be used with caution due to its unpredictable effect on myoclonus. Avoidance of drugs known to aggravate myoclonus and seizures, such as carbamazepine and phenytoin, is paramount. Psychiatric (in particular depression) and other comorbidities need to be adequately managed. Although a 3- to 4-drug regimen is often necessary to control seizures and myoclonus, particular care should be paid to avoid excessive pharmacological load and neurotoxic side effects. Target therapy is possible only for a minority of PMEs.
CONCLUSIONS
Overall, the treatment of PMEs remains symptomatic (i.e. pharmacological treatment of seizures and myoclonus). Further dissection of the genetic background of the different PMEs might hopefully help in the future with individualised treatment options.
Topics: Animals; Anticonvulsants; Humans; Myoclonic Epilepsies, Progressive
PubMed: 28799509
DOI: 10.2174/1381612823666170809114654 -
Cell Death and Differentiation May 2021The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1...
The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.
Topics: Animals; COVID-19; Cell Death; HEK293 Cells; HT29 Cells; Humans; Inflammation; Jurkat Cells; Mice; NIH 3T3 Cells; Primidone; Receptor-Interacting Protein Serine-Threonine Kinases; SARS-CoV-2; U937 Cells; COVID-19 Drug Treatment
PubMed: 33273695
DOI: 10.1038/s41418-020-00690-y -
ELife Jan 2023TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo...
TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function . Here, we report a further 10 patients carrying one of seven additional heterozygous missense variants. These patients present with a broad spectrum of neurodevelopmental symptoms, including global developmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain perception. We describe a cerebellar phenotype with ataxia or severe hypotonia, nystagmus, and cerebellar atrophy in more than half of the patients. All disease-associated variants exhibited a robust gain-of-function phenotype, characterized by increased basal activity leading to cellular calcium overload and by enhanced responses to the neurosteroid ligand pregnenolone sulfate when co-expressed with wild-type TRPM3 in mammalian cells. The antiseizure medication primidone, a known TRPM3 antagonist, reduced the increased basal activity of all mutant channels. These findings establish gain-of-function of TRPM3 as the cause of a spectrum of autosomal dominant neurodevelopmental disorders with frequent cerebellar involvement in humans and provide support for the evaluation of TRPM3 antagonists as a potential therapy.
Topics: Animals; Humans; Gain of Function Mutation; Neurosteroids; Neurodevelopmental Disorders; Epilepsy; Ion Channels; TRPM Cation Channels; Mammals
PubMed: 36648066
DOI: 10.7554/eLife.81032 -
Epilepsy Research Jul 2020Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam... (Review)
Review
Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes. The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug-drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment, and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug-drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam. The strong enzyme-inducing AEDs carbamazepine, phenytoin and phenobarbital/primidone have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent CYP inducer, rifampin. Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John's wort. In summary, brivaracetam (50-200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug-drug interactions.
Topics: Anticonvulsants; Brain; Carbamazepine; Drug Interactions; Humans; Pyrrolidinones; Seizures
PubMed: 32361205
DOI: 10.1016/j.eplepsyres.2020.106327 -
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 -
Progress in Neuro-psychopharmacology &... Jun 2023Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a...
OBJECTIVE
Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a series of matrices from combined samples of pregnant/breastfeeding women treated with anticonvulsants or lithium.
METHODS
We conducted a systematic literature search in PubMed/EMBASE for studies with concentrations of anticonvulsants/lithium from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal concentrations. When data from multiple studies were available, we calculated combined penetration ratios, weighting studies' mean by study size.
RESULTS
Ninety-one eligible studies for brivaracetam, carbamazepine, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, lithium, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproate, vigabatrin and zonisamide were identified. For amniotic fluid, the highest penetration ratios were estimated for levetiracetam (mean 3.56, range 1.27-5.85, n = 2) and lowest for valproate (mean 0.11, range 0.02-1.02, n = 57). For umbilical cord plasma, oxcarbazepine had the highest ratio (mean 1.59, range 0.11-4.33, n = 12) with clonazepam having the lowest (mean 0.55, range 0.52-0.59, n = 2). For breast milk, the highest ratios were observed for oxcarbazepine (mean 3.75, range 0.5-7.0, n = 2), whereas the lowest were observed for valproate (mean 0.04, range 0.01-0.22, n = 121).
DISCUSSION
We observed substantial variability between anticonvulsants and lithium regarding their ability to enter fetal/newborn circulation. Assessing concentrations of anticonvulsants and lithium in maternal samples can provide a surrogate of fetal/infant exposure, although patterns of concentration-dependent effects for maternal/neonatal safety are lacking.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Amniotic Fluid; Anticonvulsants; Fetal Blood; Lithium; Maternal-Fetal Exchange; Milk, Human
PubMed: 36805301
DOI: 10.1016/j.pnpbp.2023.110733 -
Signal Transduction and Targeted Therapy Dec 2023Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to...
Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1 mice and ALS patients. SOD1 mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Biomarkers; Interleukin-8; Mice, Transgenic; Motor Neurons; Neurodegenerative Diseases; Primidone; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 38086800
DOI: 10.1038/s41392-023-01713-z -
Revista de Neurologia Jul 2019In clinical practice, it is common to find cases of epileptic women being treated with antiepileptic drugs (AEDs) whom we have to advise on the compatibility of these... (Review)
Review
INTRODUCTION
In clinical practice, it is common to find cases of epileptic women being treated with antiepileptic drugs (AEDs) whom we have to advise on the compatibility of these AEDs with breastfeeding.
AIMS
In order to offer correct guidance, we must be well informed about the pharmacokinetic characteristics of the different AEDs, in addition to being aware of the clinical experience in this regard. This review stems from the paucity of information on this topic.
DEVELOPMENT
The World Health Organisation recommends that breastfeeding should be the norm for all women, even in epileptic mothers that are taking AEDs, who must always be given special attention in order to watch for the appearance of adverse effects in the infant, and always avoiding sudden weaning in order to avoid withdrawal symptoms.
CONCLUSIONS
Very few AEDs are incompatible with breastfeeding. The decision to breastfeed should take into account not only the AED, but also its number, dose, serum levels, transmission and elimination rates in the infant, and the conditions of the newborn infant. Ethosuximide and felbamate are probably high risk and incompatible with breastfeeding. Lamotrigine, phenobarbital, pregabalin, primidone, tiagabine, eslicarbazepine, brivaracetam, perampanel, zonisamide, lacosamide or the sporadic use of benzodiazepines in low doses are considered quite safe, with a low risk for breastfeeding. The other AEDs present a very low risk for breastfeeding.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Humans; Infant, Newborn
PubMed: 31287150
DOI: 10.33588/rn.6902.2019037 -
Journal of Clinical Neurology (Seoul,... Oct 2020Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and... (Review)
Review
Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and ethosuximide were developed in the early 20th century. More than 10 types of antiepileptic drugs have been developed since the 1990s, and there are now more than 20 antiepileptic drugs in active clinical use. The choice of antiepileptic drugs is based on the clinical features of the seizure types, electroencephalogram findings, epileptic syndrome, and drug stability. Currently there are 19 antiepileptic drugs approved by the Korean Food and Drug Administration, 18 of which (with the exclusion of brivaracetam) are covered by the National Health Insurance Service in Korea. We reviewed the selection of antiepileptic drugs according to the classification of epileptic seizures.
PubMed: 33029959
DOI: 10.3988/jcn.2020.16.4.547