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1.
Cell Physiol Biochem ; 54(2): 180-194, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32068980

RESUMO

BACKGROUND/AIMS: Still in 1999 the first hints were published for the pharmacoresistant Cav2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Cav2.3) and alpha1G (Cav3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Cav2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, γ-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Cav2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Cav2.3-competent but increases it in Cav2.3-deficient mice. In vivo, Cav2.3 must be under tight control by endogenous trace metal cations (Zn2+ and Cu2+). The dyshomeostasis of either of them, especially of Cu2+, may alter the regulation of Cav2.3 severely and its activity for Ca2+ conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation. METHODS: To investigate by telemetric EEG recordings the mechanism of generating hyperexcitation by kainate, mice were tested for their sensitivity of changes in neuronal (intracerebroventricular) concentrations of the trace metal cation Zn2+. As the blood-brain barrier limits the distribution of bioavailable Zn2+ or Cu2+ into the brain, we administered micromolar Zn2+ ions intracerebroventricularly in the presence of 1 mM histidine as carrier and compared the effects on behavior and EEG activity in both genotypes. RESULTS: Kainate seizures are more severe in Cav2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Cav2.3-deficient mice. Surprisingly, Zn2+ plus histidine resembles the kainate only control with more seizure severity in Cav2.3-competent than in deficient mice. CONCLUSION: Cav2.3 represents one important Zn2+-sensitive target, which is useful for modulating convulsive seizures.


Assuntos
Canais de Cálcio Tipo R/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Convulsões/tratamento farmacológico , Zinco/uso terapêutico , Animais , Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histidina/farmacologia , Íons/química , Ácido Caínico/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Convulsões/induzido quimicamente , Convulsões/patologia , Índice de Gravidade de Doença , Zinco/farmacologia , Ácido gama-Aminobutírico/metabolismo
2.
J Clin Neurophysiol ; 37(1): 2-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895184

RESUMO

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy, and those with epileptic encephalopathy can be particularly challenging to treat. The endocannabinoid system can modulate the physiologic processes underlying epileptogenesis. The anticonvulsant properties of several cannabinoids, namely Δ-tetrahydrocannabinol and cannabidiol (CBD), have been demonstrated in both in vitro and in vivo studies. Cannabis-based therapies have been used for millennia to treat a variety of diseases including epilepsy. Several studies have shown that CBD, both in isolation as a pharmaceutical-grade preparation or as part of a CBD-enriched cannabis herbal extract, is beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy. Overall, cannabis herbal extracts appear to provide greater efficacy in decreasing seizure frequency, but the studies assessing cannabis herbal extract are either retrospective or small-scale observational studies. The two large randomized controlled studies assessing the efficacy of pharmaceutical-grade CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to other anticonvulsants. Lack of data regarding appropriate dosing and pediatric pharmacokinetics continues to make authorization of cannabis-based therapies to children with treatment-resistant epilepsy challenging.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Canabinoides/uso terapêutico , Cannabis , Criança , Epilepsia Generalizada/tratamento farmacológico , Humanos , Estudos Retrospectivos , Convulsões/tratamento farmacológico
3.
J Clin Neurophysiol ; 37(1): 9-14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895185

RESUMO

Marijuana is the dried leaves, stems, and flowers of a 1- to 5-m weed originating from Central Asia. The most common varieties are Cannabis sativa and Cannabis indica. It is usually inhaled as smoke but can also be used as a vapor, taken by mouth as a spray, ingested in tea or as butter in baked goods, or in capsule form and used as an oil. Cannabis has been widely used to treat many medical conditions such as multiple sclerosis symptoms, mood disorders, pain, sleep disorders, and seizures among others. Preclinical and clinical studies have been done over the past decade, among them there are few randomized placebo-controlled trials. In the last few years, Cannabis has been proposed as a potential therapy for patients with drug-resistant epilepsy. This review analyzes the best information about the use of cannabis in adult patients, reviewing aspects of efficacy and safety.


Assuntos
Epilepsia/tratamento farmacológico , Maconha Medicinal/efeitos adversos , Adulto , Cannabis , Humanos , Maconha Medicinal/uso terapêutico , Convulsões/tratamento farmacológico
5.
Lancet ; 394(10216): 2243-2254, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31862249

RESUMO

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Administração Oral , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Fenfluramina/administração & dosagem , Fenfluramina/efeitos adversos , Humanos , Masculino , Estudos Observacionais como Assunto , Placebos , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento
6.
Eur J Med Chem ; 185: 111824, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708184

RESUMO

In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca2+ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED50 values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD50/ED50) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABAA receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Atividade Motora/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/toxicidade , Células Cultivadas , Relação Dose-Resposta a Droga , Descoberta de Drogas , Eletrochoque , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pentilenotetrazol , Substâncias Protetoras/química , Substâncias Protetoras/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Triazóis/química , Triazóis/toxicidade
7.
Acta Neurol Scand ; 141(1): 65-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618439

RESUMO

OBJECTIVES: Antiepileptic drug (AED) tapering in persons with epilepsy (PWE) after 2-3 years of seizure freedom is still debatable because of the risk of seizure recurrence. Tapering patterns have wide variability and could impact seizure recurrence; this study aimed to find out the correlation between them. MATERIAL AND METHODS: This prospective, observational independent assessor study enrolled PWE undergoing AED tapering in a tertiary care hospital. Data collected included demography, seizure history, AED treatment, and investigational findings. Tapering pattern was assessed based on seizure-free period and AED dose before onset of tapering, dose reduction percentage and frequency, duration of tapering, and follow-up. These variables were compared among the PWE with seizure recurrence and no seizure recurrence. RESULTS: Among 408 enrolled PWE, 181 were on AED monotherapy: levetiracetam (73), valproate (45), carbamazepine (44), phenytoin (16), and clobazam (3). With a minimum 19 (maximum 41 months) follow-up, seizure recurrence was reported in 119 (29.2%) PWE. The seizure recurrence was not significantly different in-between mono and polytherapy groups; however, among monotherapy groups seizure recurrence was significantly higher (P = .023) in valproate (35.5%) followed by levetiracetam (28.8%) group. Parameters having significant association with seizure recurrence were duration of epilepsy (P = .03), frequency of seizures before control (P = .002), history of previously failed tapering (P = .04), and history of smoking/alcoholic/tobacco intake (P = .003). CONCLUSIONS: There is a wide variation in AEDs tapering pattern and seizure recurrence risk can be minimized by considering the risk factors like history of smoking/alcoholic/tobacco, longer duration of epilepsy, frequency of seizures before control, and previously failed tapering.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões , Suspensão de Tratamento , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Recidiva , Fatores de Risco , Convulsões/tratamento farmacológico
8.
Medicine (Baltimore) ; 98(51): e18075, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860957

RESUMO

RATIONALE: Dyke-Davidoff-Masson syndrome (DDMS) is a rare syndrome commonly occurring in children and characterized by cerebral hemiatrophy, hypertrophy of the skull, epilepsy, and mental retardation. However, few have been reported in China, especially in teenagers. This case investigated its possible cause and explored a relative effective solution. PATIENT CONCERNS: A 24-year-old female came to department having experienced recurrent seizures for 12 years. DIAGNOSIS: DDMS was diagnosed from its manifestations, biochemistry indexes, and imaging (computed tomography angiography, magnetic resonance venography, and so on). INTERVENTIONS: Several drugs are used to treat the disease, including valproate, carbamazepine, topiramate, and ginkgo biloba extract. OUTCOMES: Under the medicine treatment of magnesium valproate with carbamazepine, the patient experienced partial seizures approximately once per month that lasted 30 to 60 seconds each without any complications observed during a follow-up period of 24 months. CONCLUSION: The imaging and clinical features of DDMS in this teenager were similar to those in classic infantile-onset cases. A potential cause of the disease could be brain trauma, which impaired the middle cerebral artery and reduced cerebral blood supply, leading to epilepsy and hemiatrophy. LESSONS: It was concluded early diagnosis and pharmacotherapy are the keys to preventing intellectual decline in DDMS patients. Moreover, the combination of magnesium valproate and carbamazepine could significantly reduce the frequency and duration of seizures, despite not eliminating them completely.


Assuntos
Encefalopatias/diagnóstico por imagem , Deficiência Intelectual/diagnóstico , Imagem por Ressonância Magnética/métodos , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Carbamazepina/uso terapêutico , China , Doença Crônica , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Prognóstico , Recidiva , Medição de Risco , Índice de Gravidade de Doença , Síndrome , Tomografia Computadorizada por Raios X/métodos , Ácido Valproico , Adulto Jovem
9.
Yakugaku Zasshi ; 139(11): 1397-1402, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685736

RESUMO

Patients with epilepsy are often affected by not only seizures but also a variety of cognitive and psychiatric comorbidities that further impair their quality of life. However, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning, using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice displayed impaired motor coordination (in the rotarod test), and social approach impairment (in the three-chamber social test) compared with vehicle mice. Intraperitoneal ABT-418 treatment (0.05 mg/kg) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 subunit of the α4ß2 nicotinic acetylcholine receptor in the piriform cortex was significantly decreased in PTZ-kindled mice. In contrast, expression of the synaptic adhesion molecule neuroligin 3 (NLG3) was significantly higher in the piriform cortex of PTZ-kindled mice compared with vehicle mice. Collectively, our findings suggest that attention deficit/hyperactivity disorder (ADHD)-like or autistic-like behavioral abnormalities associated with epilepsy are closely linked to downregulation of the α4 subunit of the α4ß2 receptor and upregulation of NLG3 in the mouse piriform cortex. In summary, this study indicates that ABT-418 is a good candidate for the treatment of patients with epilepsy complicated by psychiatric symptoms such as autism and ADHD.


Assuntos
Epilepsia/psicologia , Excitação Neurológica , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Pentilenotetrazol , Receptores Nicotínicos/metabolismo , Convulsões/psicologia , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Córtex Piriforme/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Qualidade de Vida , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/etiologia , Comportamento Social
10.
BMC Neurol ; 19(1): 292, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31739779

RESUMO

BACKGROUND: Antiepileptic drug (AED) induced dyskinesia is an unusual manifestation in the medical field. In the previous case reports describing first generation-AED related involuntary movements, the authors suggested that a plausible cause is pharmacokinetic interactions between two or more AEDs. To date, development of dyskinesia after levetiracetam (LEV) has not been reported. CASE PRESENTATION: A 28-year-old woman with a history of brain metastasis from spinal cord glioblastoma presented with several generalized tonic-clonic seizures without restored consciousness. LEV was administered intravenously. Thereafter no more clinical or electroencephalographic seizures were noted on video-EEG monitoring, while chorea movement was observed in her face and bilateral upper limbs. DISCUSSION AND CONCLUSIONS: To our knowledge, there is no case report of dyskinesia after administration of LEV. Considering the temporal relationship and absence of ictal video-EEG findings, we suggest that development of choreoathetosis was closely associated with the undesirable effects of LEV. We propose that dopaminergic system dysregulation and genetic susceptibility might underlie this unusual phenomenon after LEV treatment.


Assuntos
Anticonvulsivantes/efeitos adversos , Coreia/induzido quimicamente , Levetiracetam/efeitos adversos , Adulto , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/secundário , Feminino , Glioblastoma/complicações , Glioblastoma/secundário , Humanos , Convulsões/tratamento farmacológico , Convulsões/etiologia , Neoplasias da Medula Espinal/secundário
11.
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
12.
J Vet Emerg Crit Care (San Antonio) ; 29(6): 674-679, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31642158

RESUMO

OBJECTIVE: To describe the use of extracorporeal therapy (ECT) to treat severe cannabinoid intoxication in a dog with severe hyperlipidemia. CASE SUMMARY: A 7-month-old female intact Labrador Retriever presented with seizures and severe hyperesthesia that were refractory to multiple anticonvulsant medications and required induction of general anesthesia with propofol and mechanical ventilation. The dog's urine yielded a strong positive signal for delta-9-tetrahydrocannabinol (THC) on urine drug test and exposure to THC oil was confirmed by the owner. Bloodwork revealed severe hyperlipidemia such that IV lipid emulsion was considered contraindicated. The dog was treated with a 3-hour ECT session, using charcoal hemoperfusion and hemodialysis in series. Neurologic signs improved during the session and mechanical ventilation was discontinued. Immediately after the session, the dog's mentation was significantly improved and seizures and hyperesthesia had ceased, although the dog remained moderately ataxic. The dog was hospitalized for 36 hours following the ECT session for continued monitoring. The dog fully recovered and was successfully discharged. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first published report to document ECT to treat THC intoxication in veterinary medicine. ECT may be considered as a treatment option for severe THC intoxication that is refractory to standard therapy or where severe hyperlipidemia precludes use of IV lipid emulsions.


Assuntos
Canabinoides/toxicidade , Doenças do Cão/induzido quimicamente , Hemoperfusão/veterinária , Diálise Renal/veterinária , Respiração Artificial/veterinária , Convulsões/veterinária , Animais , Anticonvulsivantes/uso terapêutico , Carvão Vegetal/uso terapêutico , Doenças do Cão/terapia , Cães , Feminino , Propofol/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
13.
N Engl J Med ; 381(17): 1644-1652, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31597037

RESUMO

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).


Assuntos
Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do Genoma
14.
Acta Neurol Scand ; 140(6): 422-428, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31498422

RESUMO

OBJECTIVE: To assess the effectiveness and tolerability of eslicarbazepine acetate (ESL) monotherapy in routine clinical practice for the treatment of focal-onset seizures. METHODS: Multicenter, retrospective, observational study conducted in patients older than 16 years treated with ESL as first-line monotherapy or converted to ESL monotherapy from polytherapy or other monotherapy. Outcomes included 1-year retention rate, seizure-free rates after 6 and 12 months of monotherapy treatment, and safety/tolerability issues. RESULTS: A total of 256 patients were included (106 first-line and 150 conversion to monotherapy; 56 patients aged >65 years). Overall, the 1-year retention rate was 79% (72.7% in the ≥65 years subgroup) and seizure-free rates at 6 and 12 months were 59.3% and 55.3% (72.2% and 67.3% in the ≥65 years subgroup), without significant differences when comparing first-line vs conversion-to-ESL monotherapy groups (P = .979). However, the conversion group was heterogeneous and included 43 (29.1%) patients that were seizure free the year prior ESL introduction. A substantially higher proportion of patients remained seizure free for the entire follow-up among those who initiated ESL due to tolerability problems compared with those treated due to inadequate seizure control (71.4% vs 37.3%). Overall, 62 of 256 (24.2%) patients reported AEs (39.3% in >65 years subgroup) and led to discontinuation in 20/256 (7.8%) patients (12.5% in >65 years subgroup). Commonly reported AEs were somnolence (6.6%), dizziness (6.3%), and headache (4.3%). Hyponatremia was recorded in five patients, the majority (4/5) of whom were older than 65 years. CONCLUSIONS: Eslicarbazepine acetate was effective and well-tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal-onset seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 566-571, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484623

RESUMO

Epilepsy has high incidence and complex etiologies,and its treatment remains challenging.For around 70% of people with epilepsy,seizures can be controlled after proper antiepileptic treatment.The availability of some new antiepileptic drugs in recent years has offered new options for epileptic patients.A solid knowledge on the pharmacokinetics,efficacy,and tolerability profiles of these new antiepileptic drugs will help to provide safe,proper,reasonable,and standardized treatment for patients.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Convulsões/tratamento farmacológico
16.
BMJ Case Rep ; 12(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31399414

RESUMO

Streptococcus agalactiae (group B streptococcus or GBS) is the most common cause of bacterial meningitis in infants, but is rarely the cause in adults. Across all non-pregnant adults it comprises 7% of bacterial meningitis cases, with a mortality rate of 56% in the elderly. Therefore, while rare, GBS should be a part of a patient's differential when initiating antibiotics in adults with chronic illnesses. We report a 78-year-old diabetic female admitted to the hospital with suspected meningitis. Lumbar puncture revealed grossly purulent cerebrospinal fluid (CSF) and she was started on antibiotics for empiric treatment of expected Streptococcus pneumoniae Thirty-one hours post-sampling, the CSF culture results returned positive for beta haemolytic GBS and treatment was altered accordingly. The case was complicated by concomitant periodic lateralising epileptiform discharges which were treated simultaneously. After 14 days of hospitalisation, the patient was discharged to a skilled nursing facility for further recovery.


Assuntos
Meningites Bacterianas/diagnóstico , Infecções Estreptocócicas/diagnóstico , Idoso , Antibacterianos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Ceftriaxona/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Eletroencefalografia , Feminino , Humanos , Levetiracetam/uso terapêutico , Meningites Bacterianas/líquido cefalorraquidiano , Meningites Bacterianas/tratamento farmacológico , Convulsões/complicações , Convulsões/tratamento farmacológico , Infecções Estreptocócicas/líquido cefalorraquidiano , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus agalactiae/isolamento & purificação
17.
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
18.
J Stroke Cerebrovasc Dis ; 28(11): 104338, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31444045

RESUMO

A 57-year-old male presented with generalized seizure who received red blood cell (RBC) transfusion for the treatment of iron deficiency anemia (IDA). Neuroradiological findings revealed cerebral venous thrombosis (CVT) on the left frontal vein. He received anticoagulants, anticonvulsants, and iron supplements. He discharged without any neurological deficit. It should be noted that RBC transfusion might increase the risk of CVT in patients with IDA.


Assuntos
Anemia Ferropriva/terapia , Transfusão de Eritrócitos/efeitos adversos , Trombose Intracraniana/etiologia , Trombose Venosa/etiologia , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Anticoagulantes/uso terapêutico , Anticonvulsivantes/uso terapêutico , Suplementos Nutricionais , Humanos , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Convulsões/etiologia , Resultado do Tratamento , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/tratamento farmacológico
19.
Arch Pharm (Weinheim) ; 352(10): e1900106, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364202

RESUMO

A series of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5-(4-Chlorophenyl)-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6c) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED50 ) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine-binding site on gamma-aminobutyric acid A (GABAA ) receptors. The results of in vivo GABA estimation and bicuculline-induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.


Assuntos
Anticonvulsivantes/síntese química , Piridinas/síntese química , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrochoque , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos Wistar , Teste de Desempenho do Rota-Rod , Convulsões/metabolismo , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/metabolismo
20.
Epileptic Disord ; 21(4): 366-369, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366451

RESUMO

Recently, decanoic acid (C10), a medium-chain fatty acid, was shown to be a direct inhibitor of the AMPA receptor. Accordingly, C10 has been suggested as a potential anticonvulsant factor in the ketogenic diet (KD) or the medium-chain triglyceride KD. Here, we tested whether C10 serum levels correlate with the response to KD in five children (1.5 ± 0.6 years of age) with epilepsy. The serum levels of C10 were measured before and after KD initiation (n=2 at one month, n=3 at three months, and n=1 at six months after initiation) by gas chromatography-mass spectrometry. After three months on KD, two patients were found to be responders. The mean serum level before KD initiation was 63.2 µM. Only one patient, who was a non-responder, showed an increase (5%) in C10 serum level after a month of KD. The remaining four patients (two responders) showed a decrease in the C10 level from -5.3% to -75.5%. Our preliminary data show that KD does not lead to an increase in C10 serum levels, suggesting that increased concentration of C10 might not be directly involved in the anticonvulsant effects of classic KD.


Assuntos
Ácidos Decanoicos/sangue , Dieta Cetogênica , Epilepsia/sangue , Convulsões/sangue , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Dieta Cetogênica/métodos , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Feminino , Humanos , Masculino , Convulsões/diagnóstico , Convulsões/tratamento farmacológico
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