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1.
Expert Opin Drug Saf ; 19(2): 131-138, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31914330

RESUMO

Introduction: Lacosamide has been used in epilepsy patients in the United States, Europe and Asia since it was approved by the FDA in 2008. Many patients have benefited from this drug as a new generation of sodium channel blocker. With the worldwide use of this drug, its adverse effects have gradually emerged, especially some rare adverse events.Areas covered: The present review aims to summarize the adverse effects of lacosamide reported in the literature in recent years to promote the safe clinical application of the drug.Expert opinion: In more than 10 years of experience in drug usage, adverse reactions of lacosamide have also been gradually discovered. The review showed that lacosamide is safe and effective in antiepileptic treatment, and its common side effects are dizziness, headache, drowsiness, diplopia, and cardiovascular abnormalities. Skin rashes, hematotoxicity and heart damage, psychological symptoms and suicide risk have also been reported and emphasized.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Lacosamida/efeitos adversos , Animais , Anticonvulsivantes/administração & dosagem , Humanos , Lacosamida/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
2.
AAPS PharmSciTech ; 21(2): 39, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897724

RESUMO

The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs via direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-ß-cyclodextrin (HPßCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ-an antiepileptic and anticonvulsant drug-may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPßCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an in vitro disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Carbamazepina/administração & dosagem , Carbamazepina/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Comprimidos , Difração de Raios X
3.
Clin Biochem ; 74: 24-30, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31672648

RESUMO

BACKGROUND: In some clinical situations (pregnancy, aging, drug resistance, toxicity), measurements of lamotrigine plasma levels may be reliable. Limited studies indicate that saliva and hair could be alternative sources for monitoring lamotrigine therapy. The drug content in hair can also be used to assess the history of drug therapy and to ascertain long-term patient compliance. The aims of this study were to 1) determine the correlations among plasma, saliva, and hair lamotrigine concentrations, 2) evaluate saliva as an alternative matrix for monitoring drug levels and 3) evaluate hair as a source of information on adherence to antiepileptic treatment and on the correlation of hair concentrations with clinical outcomes in patients with epilepsy. METHODS: Plasma, saliva, and hair lamotrigine concentrations were measured by liquid chromatography-tandem mass spectrometry in positive ionization mode. The study group (n = 85) was recruited among the epileptic patients at the Institute of Psychiatry and Neurology, Warsaw, Poland. RESULTS: Plasma concentrations were not influenced by sex, age, or the concomitant use of other antiepileptic drugs. Lamotrigine saliva and plasma concentrations were strongly correlated (r = 0.82, p < 0.001). Lamotrigine hair concentrations were correlated with the plasma concentrations (r = 0.53, p < 0.001) and daily dose in mg/kg (r = 0.23, p = 0.024). The analysis revealed no significant correlation between lamotrigine hair levels and the number of seizures in the previous 3 months (r = -0.1, p > 0.05). CONCLUSIONS: The lamotrigine saliva concentration is strongly correlated with its plasma level, and saliva can be used as an alternative matrix to plasma for monitoring. Lamotrigine can also be successfully measured in hair, and the drug levels in hair tend to be correlated with the levels in plasma. However, lamotrigine levels in hair may not correspond to clinical outcomes (i.e., seizure episodes).


Assuntos
Anticonvulsivantes/análise , Monitoramento de Medicamentos/métodos , Cabelo/química , Lamotrigina/análise , Saliva/química , Adolescente , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Cromatografia Líquida , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lamotrigina/administração & dosagem , Lamotrigina/sangue , Lamotrigina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polônia , Convulsões/sangue , Convulsões/tratamento farmacológico , Espectrometria de Massas em Tandem , Adulto Jovem
4.
AAPS PharmSciTech ; 20(8): 332, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31705211

RESUMO

Individualized dosing is often required in pharmacotherapy, particularly for pediatric and geriatric patients and adjustment of drugs that demand dose adaptation. This study aimed to evaluate critical quality attributes (CQAs) of doses obtained by distinct approaches for achieving individual dosing. Approaches were evaluated as follows: subdivision of tablets by splitter and hand (haloperidol) and delivery by plastic dropper bottle (haloperidol), glass dropper bottle (clonazepam), dosing cup (sodium valproate), and dosing syringe (carbamazepine), including brand name, generic, and similar marketed products. Measuring devices were packaged with their respective product. Drug content uniformity was assessed to each substance according to pharmacopeial methods. Tablets subdivided by splitter had the poorest performance among all approaches, in which doses ranged around 60% of the labeled amount (Acceptance Value = 58.1 and RSD = 23.2%). The greatest performances were observed for the dosing syringe which fulfilled all the requirements for dose precision and for the glass dropper bottle. There were significant differences in dose delivery between manufacturers of the same medicine when measuring the same volume or number of drops. High drug content variability is extremely harmful to pharmacotherapy and may result in therapeutic failure or toxicity. It is crucial that measuring devices and scoring of tablets be checked for functionality and standardized for different manufacturers of the same medicine. Part of the approaches for achieving individual dosing did not meet the quality needs for drug content and uniformity. Yet, our findings show that more accurate and precise dosing can be accessed when using the dosing syringe and glass dropper bottle.


Assuntos
Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/normas , Formas de Dosagem/normas , Sistemas de Liberação de Medicamentos/métodos , Controle de Qualidade , Seringas/normas , Administração Oral , Idoso , Criança , Relação Dose-Resposta a Droga , Humanos , Comprimidos
5.
Medicine (Baltimore) ; 98(42): e17171, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626082

RESUMO

Mesial temporal lobe epilepsy (MTLE) is a common epilepsy syndrome often refractory to antiepileptic drug (AED) treatment. The purpose of this study was to evaluate the effectiveness and tolerability of perampanel (PER) as add-on treatment for patients of MTLE.We pooled retrospective data from adult patients with MTLE, from a tertiary center in Taiwan, who were prescribed PER between March 2016 and December 2016. The retention, responder, and seizure-free rate as well as the treatment emergent adverse events were assessed after 6 months of PER adjunctive treatment in this single-center postmarketing study.Review of medical records revealed that adequate data were available for 44 patients who were being administered PER (mean age: 42.0 ±â€Š13.3 years, 24 females; baseline mean seizure frequency: 5.4 per 28 days). Twelve patients exhibited hippocampal sclerosis (HS). Open-label PER was added to ongoing medications. Twelve patients withdrew because of ineffectiveness (n = 6) or adverse effects (n = 6). The retention rate was 72.7% at 6 months. On final evaluation, with a mean PER dose of 5.7 mg/day for 6 months, a ≥50% reduction in seizure frequency was observed in 46.9% of the patients, and 5 patients became seizure-free. The effectiveness was similar for patients with or without HS. Twenty-three patients (52.3%) experienced adverse effects. The most common adverse effects were dizziness, ataxia, and irritability.Our results suggest that PER, at doses of 2 to 12 mg/day, reduces seizure frequency effectively with acceptable safety profiles for adults with MTLE.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Anticonvulsivantes/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Piridonas/efeitos adversos , Estudos Retrospectivos , Taiwan , Resultado do Tratamento
7.
Gac Med Mex ; 155(4): 417-422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31486780

RESUMO

Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Ácido Valproico/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Neoplasias/patologia , Ácido Valproico/farmacologia
8.
Rev. neurol. (Ed. impr.) ; 69(5): 181-189, 1 sept., 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-184455

RESUMO

Objetivo. Evaluar la adecuación y el efecto del tratamiento antiepiléptico preventivo en pacientes adultos con una primera crisis epiléptica en cuanto a resultados adversos a los 30 días del alta del servicio de urgencias hospitalario (SUH). Pacientes y métodos. ACESUR fue un registro observacional de cohortes multipropósito, prospectivo y multicéntrico con un muestreo sistemático. Se realizó seguimiento telefónico a los 30 días. Se recogieron variables clínicas en la visita índice y de resultado en seguimiento. La variable principal fue "tratamiento preventivo adecuado según indicaciones", y la de resultado, "algún resultado adverso" (recurrencia de crisis epiléptica, revisita a SUH, hospitalización o muerte) a los 30 días del alta de urgencias. Se realizó un modelo de regresión logística para aislar el efecto del tratamiento preventivo adecuado. Resultados. Se incluyó a 151 (22,7%) pacientes con una media de 55 años con primera crisis epiléptica, dados de alta de 18 SUH con datos de seguimiento. El tratamiento preventivo se consideró adecuado en 128 (84,8%) pacientes. Cuarenta y un (27,2%) pacientes presentaron algún resultado adverso a los 30 días del alta. Tras la regresión logística, el tratamiento preventivo adecuado al alta del SUH ejerce un efecto protector sobre la variable "algún resultado adverso a 30 días". Conclusiones. En el registro ACESUR, el tratamiento preventivo fue adecuado en la mayoría de los pacientes y su efecto resultó, de forma independiente, protector a los 30 días. Por tanto, el tratamiento preventivo adecuado podría mejorar los resultados a corto plazo de pacientes adultos dados de alta con una primera crisis epiléptica del SUH


Aim. To evaluate the adequacy and effect of preventive antiepileptic treatment in adult patients with the first epileptic seizure in adverse outcomes at 30 days after discharge from the hospital emergency department (HED). Patients and methods. ACESUR was an observational registry of multipurpose, prospective and multicentric cohorts with a systematic sampling. Phone follow-up was done at 30 days. Clinical variables were collected in the index visit and the follow-up result. The main variable was "adequate preventive treatment according to indications" and the result of "some adverse outcome" (recurrence of epileptic seizure, revisits to HED, hospitalization or death) 30 days after discharge from HED. A logistic regression model was used to isolate the effect of adequate preventive treatment. Results. 151 (22.7%) patients with a mean age of 55 years old were included with first epileptic seizure discharged from 18 HED with follow-up data. Preventive treatment was considered adequate in 128 (84.8%) patients. 41 (27.2%) patients presented some adverse outcome 30 days after discharge. After the logistic regression, the appropriate preventive treatment to the discharge of the HED exerts a protective effect on the variable "some adverse outcome to 30 days". Conclusions. In the ACESUR registry, preventive treatment was adequate for most patients and its effect was independent protective at 30 days. Therefore, adequate preventive treatment could improve the short-term results of adult patients discharged with the first epileptic seizure of the HED


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Anticonvulsivantes/administração & dosagem , Serviço Hospitalar de Emergência , Anticonvulsivantes/efeitos adversos , Convulsões/prevenção & controle , Epilepsia/tratamento farmacológico , Estudos Prospectivos , Seguimentos
9.
Expert Opin Pharmacother ; 20(13): 1563-1574, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31373526

RESUMO

Introduction: Lennox-Gastaut syndrome (LGS) is a chronic, epileptic encephalopathy, characterized by multiple seizure types, distinctive slow spike-wave patterns in the electroencephalogram (EEG), and severe cognitive and behavioral comorbidities. Seizures are typically refractory and long-term prognosis is poor. No antiseizure drug (ASD) is fully effective as a monotherapy. Clobazam (CLB) was licensed in the United States in 2011 as an adjunctive therapy for seizures in LGS. In 2018, a new formulation, CLB oral soluble film (COSF) (AQST-120), was approved by the Federal Drug Administration (FDA) for the same indication. Areas covered: The authors summarize current pharmacological options and guidelines for the management of seizures in LGS and efficacy and safety findings from phase II and III randomized controlled trials of adjunctive CLB in patients with LGS. An open-label extension trial is also considered. A pharmacokinetic comparison of COSF and CLB tablets is also undertaken. Expert opinion: CLB is partly effective as an add-on therapy in treating seizures in LGS. Adverse effects, pharmacokinetic interactions and the potential for tolerance with long-term treatment should be weighed against the clinical benefit when considering the introduction of CLB in this population. COSF has a similar pharmacokinetic profile to CLB tablets and may help to improve adherence to treatment.


Assuntos
Anticonvulsivantes/administração & dosagem , Clobazam/administração & dosagem , Síndrome de Lennox Gastaut/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Clobazam/efeitos adversos , Tolerância a Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológico , Comprimidos
10.
J Enzyme Inhib Med Chem ; 34(1): 1465-1473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411081

RESUMO

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Desenho de Drogas , Imidas/química , Imidas/farmacologia , Tiazóis/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidas/síntese química , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/efeitos dos fármacos , Óxidos/química , Técnicas de Patch-Clamp , Espectroscopia de Prótons por Ressonância Magnética
11.
Neurology ; 93(11): 500-509, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31413170

RESUMO

OBJECTIVE: To provide updated evidence-based recommendations for migraine prevention using pharmacologic treatment with or without cognitive behavioral therapy in the pediatric population. METHODS: The authors systematically reviewed literature from January 2003 to August 2017 and developed practice recommendations using the American Academy of Neurology 2011 process, as amended. RESULTS: Fifteen Class I-III studies on migraine prevention in children and adolescents met inclusion criteria. There is insufficient evidence to determine if children and adolescents receiving divalproex, onabotulinumtoxinA, amitriptyline, nimodipine, or flunarizine are more or less likely than those receiving placebo to have a reduction in headache frequency. Children with migraine receiving propranolol are possibly more likely than those receiving placebo to have an at least 50% reduction in headache frequency. Children and adolescents receiving topiramate and cinnarizine are probably more likely than those receiving placebo to have a decrease in headache frequency. Children with migraine receiving amitriptyline plus cognitive behavioral therapy are more likely than those receiving amitriptyline plus headache education to have a reduction in headache frequency. RECOMMENDATIONS: The majority of randomized controlled trials studying the efficacy of preventive medications for pediatric migraine fail to demonstrate superiority to placebo. Recommendations for the prevention of migraine in children include counseling on lifestyle and behavioral factors that influence headache frequency and assessment and management of comorbid disorders associated with headache persistence. Clinicians should engage in shared decision-making with patients and caregivers regarding the use of preventive treatments for migraine, including discussion of the limitations in the evidence to support pharmacologic treatments.


Assuntos
Academias e Institutos/normas , Transtornos de Enxaqueca/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto/normas , Sociedades Médicas/normas , Adolescente , Analgésicos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Criança , Cefaleia/tratamento farmacológico , Cefaleia/epidemiologia , Cefaleia/prevenção & controle , Humanos , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/prevenção & controle , Relatório de Pesquisa/normas , Resultado do Tratamento , Estados Unidos/epidemiologia
12.
Pan Afr Med J ; 33: 78, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31448040

RESUMO

Nearly 75% of patients with metastatic melanoma develop brain metastases. We here report the case of an 83 year-old woman hospitalized for secondarily generalized clonic seizures of the left leg with partial convulsive seizures in the Resuscitation Department. Melanoma resection of the left ankle had been performed 6 months before her admission. Neurological examination showed left ataxic crural monoparesis. Electro-encephalogram showed central and right frontal focus with left-sided dissemination. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed multiple supratentorial and subtentorial encephalic lesions with varying size and shape, with T1 hypersignal (A and A'), haemorrhage on T2*-weighted sequences (B and B'), gadolinium-enhancing T1 with perilesional edema on Flair sequences. Positron emission tomography (PET) showed multiple lymph node and bone metastases. Lymph node biopsy was negative for VE1 antibody with no BRAFV600E mutation by immunohistochemistry. An increase in the number of metastatic lesions was observed during control brain CT scan despite 10 brain radiotherapy sessions motivating palliative care. Epileptic seizures were controlled with levetiracetam. In patient with multiple hemorrhagic and spontaneous brain lesions, it is essential to obtain informations on patient's history of melanoma and to perform a thorough dermatologic examination in order to investigate its cause and to establish adequate therapeutic treatment.


Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Encefálicas/diagnóstico , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso de 80 Anos ou mais , Anticonvulsivantes/administração & dosagem , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Feminino , Humanos , Levetiracetam/administração & dosagem , Metástase Linfática , Imagem por Ressonância Magnética , Melanoma/patologia , Tomografia por Emissão de Pósitrons , Convulsões/tratamento farmacológico , Convulsões/etiologia , Neoplasias Cutâneas/patologia
13.
Neurology ; 93(12): e1212-e1226, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31462582

RESUMO

OBJECTIVE: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS: In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. RESULTS: Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). CONCLUSIONS: Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER: NCT01921205. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.


Assuntos
Anticonvulsivantes/administração & dosagem , Lacosamida/administração & dosagem , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Adolescente , Anticonvulsivantes/sangue , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Lacosamida/sangue , Masculino , Estudos Prospectivos , Convulsões/sangue , Resultado do Tratamento
14.
BMJ Case Rep ; 12(8)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451475

RESUMO

A 62-year-old previously healthy male was admitted with new onset generalised tonic-clonic seizures. Treatment was initiated with the antiepileptic levetiracetam and he had no further episodes of seizures. Creatine kinase (CPK) level was 1812 IU/L 12-hour postadmission. Despite good hydration, his CPK levels continued to rise dramatically and reached a level of 19 000 IU/L on day 5. This rise was unexplained as he did not have any further seizures and had a normal renal function. In the absence of other risk factors, the rare possibility of levetiracetam being responsible for the disproportionately high CPK was considered. Within 12 hours of withdrawal of levetiracetam, there was a downward trend in the CPK levels, with a 10-fold decrease in CPK levels over the next 4 days. This is only the ninth case reported in literature regarding this rare and potentially serious adverse effect of levetiracetam.


Assuntos
Creatina Quinase/sangue , Substituição de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Levetiracetam , Rabdomiólise , Convulsões/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Levetiracetam/administração & dosagem , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Fenitoína/administração & dosagem , Rabdomiólise/sangue , Rabdomiólise/induzido quimicamente , Rabdomiólise/diagnóstico , Rabdomiólise/terapia , Convulsões/diagnóstico , Resultado do Tratamento
15.
Cien Saude Colet ; 24(8): 3129-3140, 2019 Aug 05.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31389559

RESUMO

This descriptive, ecological study of clonazepam consumption in Rio de Janeiro State (RJ) estimated use prevalence from 2009 to 2013 using data from the National Controlled Product Management System operated by Brazil's health surveillance agency, Anvisa. Consumption was measured by total population and by population over 18 years old, using the standardised Daily Defined Doses of 8 mg (anticonvulsant) and 1 mg (sedative-hypnotic). The municipalities of the Rio de Janeiro Metropolitan Region were grouped by Human Development Index (HDI) and GINI index, subjected to cluster analysis and ranked by clonazepam consumption. From 2009 to 2013, consumption in the state rose from 0.35 to 1.97 DDD/1000 population, but the figures are higher for individuals over 18 years of age. A DDD of 1 mg instead of 8mg returns consumption in 2013 of 21 DDD/1000 population over 18 years of age. Consumption in 2013 was highest - 3.38 and 4.52 DDD, respectively - in Rio de Janeiro and Niterói, which have the highest HDIs. This suggests that up to 2% of the adult population uses clonazepam, possibly as a sedative-hypnotic. This broad use and use outside therapeutic indications deserves attention, given clonazepam's potential for abuse and adverse reactions.


Assuntos
Anticonvulsivantes/administração & dosagem , Clonazepam/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Padrões de Prática Médica/tendências , Adulto , Brasil , Análise por Conglomerados , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino
16.
J Neurol ; 266(10): 2554-2559, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31267208

RESUMO

BACKGROUND: Once adults with long-standing idiopathic generalised epilepsy have achieved stable seizure remission, patients or physicians may attempt to discontinue their antiepileptic drug treatment. To date, risk of subsequent seizure relapse across the four idiopathic generalised epilepsy syndromes is largely unknown, and so are the clinical variables associated. METHODS: For this retrospective observational study, 256 adult outpatients with idiopathic generalised epilepsy were evaluated. Data were obtained from outpatient charts and, if possible, from additional telephone or mail interviews. RESULTS: In 84 patients (33%), antiepileptic medication was discontinued at least once. Median patient age at antiepileptic drug withdrawal was 33 years, and median duration of subsequent follow-up was 20 years. Seizures recurred in 46% of patients after a median latency of 11 months. Following multivariable analysis, seizure relapse was independently associated with short duration of seizure remission beforehand. If medication was withdrawn after < 5 years of seizure freedom, two-thirds of patients had a seizure relapse, while among those in remission for ≥ 5 years, only one-third relapsed. CONCLUSIONS: Discontinuation of antiepileptic drug treatment can be successful in every other adult with long-standing idiopathic generalised epilepsy. Short duration of prior seizure remission appears to be a relevant predictor of seizure recurrence.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia Generalizada/tratamento farmacológico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo
17.
Eur J Pharm Sci ; 137: 104988, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291598

RESUMO

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ±â€¯1.57 nm), narrow size distribution (polydispersity index 0.195 ±â€¯0.002) and efficient entrapment (entrapment efficiency 92.2 ±â€¯2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.


Assuntos
Alcaloides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Benzodioxóis/administração & dosagem , Epilepsia/tratamento farmacológico , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Administração Oral , Alcaloides/química , Alcaloides/farmacocinética , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Benzodioxóis/química , Benzodioxóis/farmacocinética , Disponibilidade Biológica , Liberação Controlada de Fármacos , Embrião não Mamífero , Masculino , Camundongos , Nanopartículas/química , Piperidinas/química , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual , Peixe-Zebra
18.
J Toxicol Sci ; 44(7): 459-469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270302

RESUMO

Phenobarbital (PB) and Di (2-ethylhexyl) phthalate (DEHP), an anti-epileptic drug and a plasticizer used in flexible polyvinylchloride formulations, respectively, are well-known typical hepatotoxicants. This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDP-glucuronosyltransferase in liver were observed in both the PB and DEHP groups. One of the assumed mechanisms inducing thyroid effects is predictable to be secondary changes based on the enhancement in thyroid hormone metabolism via the induction of hepatic microsomal enzymes. No reproductive system-related changes in organ weights, histopathology, and sexual maturation were observed in both groups. Lower testosterone level was observed in the PB group. CYP2B and CYP3A, which are involved in testosterone metabolism, were induced in liver of the PB group. There was no change of 17ß-hydroxysteroid dehydrogenase activity in testis of both groups. Lower testosterone level in the PB-treated male rats was attributed to an indirect, hepatotoxicity-associated effect on the reproductive system and not to direct effects on testis such as the antiandrogenic activity and the inhibition of steroidogenesis. These results did not indicate that PB or DEHP exposure affects the endocrine system directly.


Assuntos
Anticonvulsivantes/toxicidade , Dietilexilftalato/toxicidade , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/patologia , Fenobarbital/toxicidade , Plastificantes/toxicidade , Animais , Animais Recém-Nascidos , Anticonvulsivantes/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Fígado/enzimologia , Masculino , Fenobarbital/administração & dosagem , Ratos Sprague-Dawley , Testosterona/metabolismo , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Fatores de Tempo
19.
J Pharm Pharmacol ; 71(10): 1488-1496, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313838

RESUMO

OBJECTIVES: This study aimed to investigate the clearance pathways of lamotrigine (LTG)-loaded micelles by intranasal administration and intracerebral injection in the brain and whether nanoparticles can induce the inflammation promoted by interleukin-6 (IL-6), accelerating the phagocytosis of drug particles in the brain and drainage through lymphatics. METHODS: The drug concentrations in the deep cervical lymph node, superficial cervical lymph node, brain tissues and jugular vein, the pharmacokinetic parameters, and the concentrations of IL-6 in deep cervical lymph node and brain tissues were investigated following UPLC/MS, DAS3.0, ELISA statistically analysed. KEY FINDINGS: The AUC0- t of deep cervical lymph node after intranasal and intracerebral injection was 1.93, 2.77, 1.34 times and 3.06, 16.4, 3.34 times higher compared with the superficial cervical lymph node, jugular vein and brain tissue, respectively. After intranasal administration of lamotrigine-loaded micelles for 30 min, the IL-6 concentrations in deep cervical lymph node and brain tissue were significantly increased (P < 0.05). CONCLUSIONS: These results suggested that lamotrigine micelles were primarily cleared from the brain by lymphatics rather than blood clearance. Also, the nanoparticle induced the increase in IL-6 level after entering the brain suggested that nanoparticles might induce the inflammation promoted by IL-6 in the brain, accelerating the clearance of drug particles in the brain and drainage through lymphatics.


Assuntos
Encéfalo/metabolismo , Lamotrigina/administração & dosagem , Lamotrigina/metabolismo , Sistema Linfático/metabolismo , Administração Intranasal , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/metabolismo , Drenagem/métodos , Linfonodos/metabolismo , Micelas , Nanopartículas/administração & dosagem , Ratos , Ratos Sprague-Dawley
20.
Mar Drugs ; 17(7)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340514

RESUMO

Thirty-four new benzo[d]thiazol derivatives 2a-2i, 3a-3r, and 4a-4g were synthesized and investigated for their potential antidepressant and anticonvulsant effects. In a forced swimming test, 2c and 2d showed the highest antidepressant and anticonvulsant effects. 2c and 2d displayed a higher percentage decrease in immobility duration (89.96% and 89.62%, respectively) than that of fluoxetine (83.62%). In the maximal electroshock seizure test, 3n and 3q showed the highest anticonvulsant effect, with ED50 values of 46.1 and 64.3 mg kg-1, and protective indices of 6.34 and 4.11, respectively, which were similar to those of phenobarbital or valproate. We also found that the mechanism for the antidepressant activity of 2c and 2d may be via increasing the concentrations of serotonin and norepinephrine.


Assuntos
Anticonvulsivantes/administração & dosagem , Antidepressivos/administração & dosagem , Benzotiazóis/administração & dosagem , Produtos Biológicos/farmacologia , Depressão/tratamento farmacológico , Convulsões/tratamento farmacológico , Animais , Regiões Antárticas , Anticonvulsivantes/síntese química , Antidepressivos/síntese química , Organismos Aquáticos/química , Benzotiazóis/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/uso terapêutico , Depressão/etiologia , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrochoque/efeitos adversos , Fluoxetina/administração & dosagem , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Penicillium/química , Convulsões/etiologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Testes de Toxicidade , Resultado do Tratamento , Ácido Valproico/administração & dosagem
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