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3.
Cochrane Database Syst Rev ; 1: CD003032, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475151

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2019. Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web, 22 September 2020) and MEDLINE (Ovid, 1946 to September 21, 2020). CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: 1. proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; 2. individuals with a 50% or greater reduction in seizure frequency; 3. normalisation of EEG and/or negative hyperventilation test; and 4. adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence for the outcomes derived from all included studies. MAIN RESULTS: On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials (RCTs) to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, seizure freedom was higher in patients taking ethosuximide (70/154, 45%) than in patients taking lamotrigine (31/146, 21%; P < 0.001), with no difference between valproate (64/146, 44%) and ethosuximide (70/154, 45%; P > 0.05). In this study, the frequency of treatment failures due to intolerable adverse events was significantly different among the treatment groups, with the largest proportion of adverse events in the valproic acid group (48/146, 33%) compared to the ethosuximide (38/154, 25%) and the lamotrigine (29/146, 20%) groups (P < 0.037). Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. This study provided high certainty of the evidence for outcomes for which data were available. However, the certainty of the evidence provided by the other included studies was low, primarily due to risk of bias and imprecise results because of the small sample sizes. Hence, conclusions regarding the efficacy of ethosuximide, valproic acid and lamotrigine derive mostly from this single study. AUTHORS' CONCLUSIONS: Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Lamotrigina/uso terapêutico , Ácido Valproico/uso terapêutico , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Epilepsia Tipo Ausência/prevenção & controle , Etossuximida/efeitos adversos , Feminino , Humanos , Lamotrigina/efeitos adversos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/prevenção & controle , Falha de Tratamento , Ácido Valproico/efeitos adversos
4.
Acta Neurol Scand ; 142(4): 317-322, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33378111

RESUMO

OBJECTIVES: The aim of the study was to assess whether, male patients with epilepsy, switching from valproic acid (VPA) to levetiracetam (LEV) or lamotrigine (LMG) critically improves sperm counts and parameters, increasing chance of patients' female partners to spontaneously conceive. MATERIALS AND METHODS: This is an observational prospective study recruiting all consecutive infertile male patients with epilepsy followed up at the outpatient Epilepsy Clinic of University Hospital of Ioannina, Northwest Greece. Infertile couples were referred to the Laboratory of Assisted Reproduction and Treatment of the University Hospital of Ioannina to conduct semen analysis. The first sample was collected while the patients were receiving VPA, and the second semen sample was collected after the patients were switched to LEV or LMG. RESULTS: Seventeen infertile male patients were recruited in the study. Nine patients were switched to LEV, and eight patients were switched to LMG. The mean sperm count increased after VPA withdraw P = .06. Motility was improved with an increase of total motility and non-progressive motility (P = .02 and P = .03, accordingly), whether sperm defects were decreased, mainly head defects (P = .03). Differences between patients switched to LEV or LMG were minimal and showed no significant findings. Spontaneous pregnancies were reported in three of the patients' partners, without any other clinical intervention offered to the couple. CONCLUSION: Switching from valproic acid to levetiracetam or lamotrigine improved sperm counts and other sperm parameters in subfertile male patients and increased the chance of spontaneously conceiving in subfertile couples.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Infertilidade Masculina/induzido quimicamente , Espermatozoides/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Adulto , Substituição de Medicamentos , Feminino , Grécia , Humanos , Lamotrigina/uso terapêutico , Levetiracetam/uso terapêutico , Masculino , Gravidez , Taxa de Gravidez , Estudos Prospectivos , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos
5.
Yakugaku Zasshi ; 140(10): 1199-1206, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999198

RESUMO

Potential risks to the fetus or infant should be considered prior to medication during pregnancy and lactation. It is essential to evaluate the exposure levels of drugs and their related factors in addition to toxicological effects. Epilepsy is one of the most common neurological complications in pregnancy; some women continue to use antiepileptic drugs (AEDs) to control seizures. Benzodiazepines (BZDs) are widely prescribed for several women who experience symptoms such as anxiety and insomnia during the postpartum period. In this review, we describe the 1) transport mechanisms of AEDs across the placenta and the effects of these drugs on placental transporters, and 2) the transfer of BZDs into breast milk. Our findings indicated that carrier systems were involved in the uptake of gabapentin (GBP) and lamotrigine (LTG) in placental trophoblast cell lines. SLC7A5 was the main contributor to GBP transport in placental cells. LTG was transported by a carrier that was sensitive to chloroquine, imipramine, quinidine, and verapamil. Short-term exposure to 16 AEDs had no effect on folic acid uptake in placental cells. However, long-term exposure to valproic acid (VPA) affected the expression of folate carriers (FOLR1, SLC46A1). Furthermore, VPA administration changed the expression levels of various transporters in rat placenta, suggesting that sensitivity to VPA differed across gestational stages. Lastly, we developed a method for quantifying eight BZDs in human breast milk and plasma using LC/MS/MS, and successfully applied it to quantify alprazolam in breast milk and plasma donated by a lactating woman.


Assuntos
Anticonvulsivantes/metabolismo , Benzodiazepinas/metabolismo , Transporte Biológico/genética , Aleitamento Materno , Gabapentina/metabolismo , Lactação/metabolismo , Lamotrigina/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/fisiologia , Troca Materno-Fetal , Leite Humano/metabolismo , Placenta/metabolismo , Ácido Valproico/metabolismo , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Linhagem Celular , Epilepsia/tratamento farmacológico , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Gabapentina/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Humanos , Lamotrigina/efeitos adversos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , Ácido Valproico/efeitos adversos
6.
J Clin Psychiatry ; 81(5)2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32841553

RESUMO

OBJECTIVE: Lithium is an important mood disorder treatment; however, the renal risks of its use in older adults are unclear. We wished to determine in older adults (1) whether lithium is associated with increased risk of renal decline compared to valproate and (2) whether this association differs with higher vs lower baseline serum lithium concentrations. METHOD: We conducted a population-based cohort study using linked health care databases (Ontario, Canada). The cohort consisted of older adults (mean age 71 years) accrued 2007-2015; 3,113 lithium users were propensity-score matched 1:1 to 3,113 valproate users. Users with higher (> 0.7 mmol/L) or lower concentration of serum lithium were further examined. The primary outcome was ≥ 30% loss in estimated glomerular filtration rate from baseline. RESULTS: Matched lithium users and valproate users demonstrated similar indicators of baseline health over a median (maximum) follow-up of 3.1 (8.3) years. Lithium was associated with increased risk of renal function loss compared to valproate (674/3,113 [21.7%] vs 584/3,113 [18.8%]; 6.5 vs 5.7 events per 100 person years; hazard ratio = 1.14 [95% CI = 1.02-1.27]). When baseline serum lithium concentrations were > 0.7 mmol/L, the risk of renal decline compared to valproate use was 1.26 (95% CI = 1.06-1.49); when baseline lithium concentrations were ≤ 0.7 mmol/L, the risk was 1.06 (95% CI = 0.92-1.22). CONCLUSION: In older adults, lithium use is associated with a statistically significant increased risk of renal decline compared to valproate use, although the decline is less than previously reported. Further studies should confirm whether this effect is primarily in patients with higher serum lithium concentrations.


Assuntos
Antimaníacos/uso terapêutico , Lítio/uso terapêutico , Insuficiência Renal/induzido quimicamente , Idoso , Antimaníacos/efeitos adversos , Antimaníacos/sangue , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Lítio/efeitos adversos , Lítio/sangue , Estudos Longitudinais , Masculino , Pontuação de Propensão , Fatores de Risco , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico
9.
Arch Gerontol Geriatr ; 89: 104091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413690

RESUMO

INTRODUCTION: The neuroprotective effect of valproic acid has been observed in the animal models of neurodegeneration, which suggests it as a potential candidate for clinical trials. In this paper, we aimed to systematically analyze the efficacy and safety of valproic acid in the treatment of dementia. METHODS: We searched the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure until March 2020 for the eligible randomized controlled trials, as well as the unpublished and ongoing trials. We pooled the results using a random-effects model. RESULTS: We included seven studies with 770 randomized patients with dementia, which compared valproic acid with placebo. Indeed, there were no significant differences found in the scores of Mini-mental State Examination, Cohen-Mansfield Agitation Inventory and number of patients with adverse events. Valproic acid is generally well-tolerated in patients with dementia, even in long-term therapy for 24 months. CONCLUSION: Insufficient evidences are found to support valproic acid in the treatment of dementia for cognitive, psychiatric symptoms or disease-modifying. The anticipations for a success in the trial of valproic acid for dementia in the future look not optimistic based on the available evidence.


Assuntos
Demência , Inibidores Enzimáticos , Ácido Valproico , Demência/tratamento farmacológico , Inibidores Enzimáticos/efeitos adversos , Humanos , Agitação Psicomotora , Ácido Valproico/efeitos adversos
10.
Toxicol Appl Pharmacol ; 399: 115033, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387339

RESUMO

N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.


Assuntos
Amidas/efeitos adversos , Amidas/farmacologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Pentanos/efeitos adversos , Pentanos/farmacologia , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacologia , Animais , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Eletrochoque/métodos , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Pentilenotetrazol/efeitos adversos , Pentilenotetrazol/farmacologia , Gravidez , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo
13.
Epilepsia ; 61(5): 944-950, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32314363

RESUMO

OBJECTIVE: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. METHODS: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. RESULTS: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR 0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. SIGNIFICANCE: Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Complicações na Gravidez/tratamento farmacológico , Ácido Valproico/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Austrália/epidemiologia , Epilepsia/tratamento farmacológico , Feminino , Humanos , Gravidez , Sistema de Registros , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Convulsões/prevenção & controle , Ácido Valproico/administração & dosagem , Ácido Valproico/uso terapêutico
15.
Sultan Qaboos Univ Med J ; 20(1): e104-e108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32190378

RESUMO

Proximal muscle weakness is a common presentation in paediatric-orthopaedic clinics and is frequently paired with a vitamin D deficiency diagnosis. Recently, side effects of the extensive use of antiepileptic and antipsychotic drugs such as sodium valproate in childhood disorders are being documented. Sodium valproate causes a time-dependent, drug-induced proximal myopathy. We report a 13-year-old female patient who presented at the Orthopaedic Outpatient Department at Lady Hardinge Medical College, New Delhi, India, in 2019 with an abnormal gait. The patient was taking a combination therapy of sodium valproate, risperidone and trihexyphenidyl for absence seizures and a mood disorder. Following clinical investigations, the patient was diagnosed with proximal myopathy. As a result of elevated serum alkaline phosphatase and creatine kinase myocardial band levels, sodium valproate was replaced with ethosuximide and a carnitine supplementation was prescribed. The patient fully recovered and regained full mobility. Proximal myopathy had been incorrectly managed and assumed to be caused by a vitamin D deficiency.


Assuntos
Anticonvulsivantes/efeitos adversos , Antipsicóticos/efeitos adversos , Transtornos Neurológicos da Marcha/induzido quimicamente , Doenças Musculares/induzido quimicamente , Ácido Valproico/efeitos adversos , Adolescente , Quimioterapia Combinada , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/psicologia , Feminino , Marcha/efeitos dos fármacos , Humanos , Índia , Transtornos do Humor/complicações , Transtornos do Humor/tratamento farmacológico , Risperidona/efeitos adversos , Triexifenidil/efeitos adversos , Deficiência de Vitamina D
16.
Lancet ; 395(10231): 1217-1224, 2020 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-32203691

RESUMO

BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.


Assuntos
Anticonvulsivantes/administração & dosagem , Levetiracetam/administração & dosagem , Fenitoína/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lactente , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Ácido Valproico/efeitos adversos , Adulto Jovem
17.
Epilepsia ; 61(4): 610-616, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32162687

RESUMO

OBJECTIVE: Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital. METHODS: We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications. RESULTS: From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group. SIGNIFICANCE: The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.


Assuntos
Anticonvulsivantes/efeitos adversos , Elementos de Dados Comuns , Registros Eletrônicos de Saúde , Epilepsia/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Lamotrigina/efeitos adversos , Levetiracetam/efeitos adversos , Oxcarbazepina/efeitos adversos , Topiramato/efeitos adversos , Ácido Valproico/efeitos adversos
18.
J Pharmacol Sci ; 143(1): 23-29, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32139333

RESUMO

Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ácido Elágico/farmacologia , Fígado/efeitos dos fármacos , Ácido Valproico/toxicidade , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Elágico/administração & dosagem , Ácido Elágico/uso terapêutico , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Ratos Sprague-Dawley , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversos
19.
Mol Pharmacol ; 97(5): 314-323, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32098797

RESUMO

Farnesoid X receptor (FXR), or NR1H4, protects the liver from insults of various etiologies. A role of FXR in drug-induced liver injury has also been hypothesized yet only marginally investigated. The aim of this study was to assess the effect of FXR activation on gene expression and phenotype of the liver of mice treated with valproic acid (VPA), or 2-propylpentanoic acid, a prototypical hepatotoxic drug. Obeticholic acid (OCA) was used to activate FXR both in mice and in human hepatocellular carcinoma (Huh-7) cells. Next-generation sequencing of mouse liver tissues was performed from control, VPA, and VPA + OCA-treated mice. Pathway analysis validation was performed using real-time reverse-transcription polymerase chain reaction, Western blotting, immunohistochemistry, and fluorometric assays. FXR activation induced antioxidative pathways, which was confirmed by a marked reduction in VPA-induced lipid peroxidation and endoplasmic reticulum stress. In vitro, VPA-induced oxidative stress was independent of lipid accumulation, stemmed from the cytoplasm, and was mitigated by OCA. In the liver of the mice treated with OCA, the levels of cytochrome P450 potentially involved in VPA metabolism were increased. The hepatic lipid-lowering effect observed in animals cotreated with VPA and OCA in comparison with that of animals treated with VPA was associated with regulation of the genes involved in the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) pathway. In conclusion, pronounced antioxidant activity, repression of the PPARγ pathway, and higher expression of P450 enzymes involved in VPA metabolism may underlie the hepatoprotective of FXR activation during VPA treatment. SIGNIFICANCE STATEMENT: Valproic acid-induced oxidative stress occurs in absence of lipid accumulation and is not of mitochondrial origin. Valproic acid exposure induces the expression of the steatogenic nuclear receptor peroxisome proliferator-activated γ (PPARγ) and its downstream target genes. Constitutive activation of the farnesoid X receptor (FXR) reduces PPARγ hepatic expression and induces hepatic antioxidant activity. The variability in FXR expression level/activity, for instance in individuals carrying loss-of-function genetic variants of the FXR gene, could contribute to valproic acid pharmacokinetic and toxicokinetic profile.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Estresse Oxidativo , Ácido Valproico/efeitos adversos , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/fisiopatologia , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transcriptoma/genética
20.
J Stroke Cerebrovasc Dis ; 29(5): 104644, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32081495

RESUMO

BACKGROUND: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy. METHODS: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups. RESULTS: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups. CONCLUSIONS: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors.


Assuntos
Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Mediadores da Inflamação/sangue , Lamotrigina/uso terapêutico , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Ácido Valproico/uso terapêutico , Idoso , Anticonvulsivantes/efeitos adversos , Biomarcadores/sangue , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Regulação para Baixo , Quimioterapia Combinada , Epilepsia/sangue , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Proteína HMGB1/sangue , Humanos , Interleucina-6/sangue , Lamotrigina/efeitos adversos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Ácido Valproico/efeitos adversos
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