Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.466
Filtrar
2.
Medicina (B Aires) ; 79 Suppl 3: 48-53, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603844

RESUMO

Antiepileptic drugs are the first treatment option in patients with epilepsy. Drugs developed after 2000 are known as third generation antiepileptic drugs. These medications offer new mechanisms of action and favorable pharmacokinetics, decreasing the occurrence of side effects and drug-drug interactions. Broad spectrum antiepileptic drugs, such as brivaracetam and clobazam are good choices for generalized tonic colonic seizures and are well tolerated.New sodium channel blockers such as lacosamide and eslicarbazepine, have a more "benign" side effect profile than the first or second generation of sodium channel blockers. These new drugs are useful therapies in patients with epilepsy of difficult control. Cannabidiol and fenfluramine are useful in the treatment of Dravet or Lennox Gastaut syndrome. Allopregnenolona and ganaxolone showed good efficacy in status epilepticus and could play an important future role in this clinical scenario.


Assuntos
Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Anticonvulsivantes/classificação , Interações de Medicamentos , Humanos , Estado Epiléptico/tratamento farmacológico
3.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
4.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416290

RESUMO

Neuroleptics and antiepileptics are excreted in saliva, which can, therefore, be very useful in determining their concentration in the body. This study presents a method developed to simultaneously identify five neuroleptics-olanzapine, quetiapine, risperidone, aripiprazole, and clozapine-and the antiepileptic carbamazepine together with their metabolites: N-demethyl olanzapine, norquetiapine, 9-OH-risperidone, dehydroaripiprazole, N-desmethylclozapine, and carbamazepine-10,11 epoxide. Chlordiazepoxide was used as the internal standard. Strata-X-C columns were used for isolation of the compounds. Chromatographic analysis was carried out using UHPLC with a diode array detector (DAD). A mixture of acetonitrile and water with the addition of formic acid and 0.1% triethylamine was used as the mobile phase. The developed method was validated by determining the linearity for all analytes in the range 10-1000 ng/mL and the value of R2 > 0.99. Intra- and inter-day precision were also determined, and the relative standard deviation (RSD) value in both cases did not exceed 15%. To determine the usefulness of the developed method, saliva samples were collected from 40 people of both sexes treated with the tested active substances both in monotherapy and in polypragmasy. In all cases, the active substances tested were identified.


Assuntos
Anticonvulsivantes/farmacologia , Antipsicóticos/farmacocinética , Cromatografia Líquida de Alta Pressão , Saliva/metabolismo , Anticonvulsivantes/química , Antipsicóticos/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Reprodutibilidade dos Testes
5.
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
6.
Handb Clin Neurol ; 160: 161-170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31277845

RESUMO

Ambulatory electroencephalography (aEEG) is a technique of continuous EEG recording while ensuring maximum mobility of the patient in a more naturalistic setting. The initial technological drawbacks of aEEG have been circumvented by incorporating digital and computer technology. Some of the current devices provide the facility of synchronous video recording. Low cost, convenience, higher diagnostic yield, and the ability to capture circadian patterns are the main advantages of aEEG. It is a useful tool in the diagnosis of epilepsy and nonepileptic paroxysmal disorders. Ambulatory EEG is superior to routine EEG in capturing interictal epileptiform abnormalities particularly in relation to natural sleep. However, the use of aEEG in presurgical workup is still unclear and more research is needed. At present, the place of EEG in the decision making for antiepileptic drug withdrawal is unclear and aEEG is an ideal tool to study this research question. Well-designed studies are needed to evaluate the use of aEEG in the assessment of response to antiepileptic therapy and occupational safety. Ambulatory EEG is an underutilized tool and more research is needed to expand the horizon of its applications in clinical practice.


Assuntos
Eletroencefalografia/métodos , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Monitorização Ambulatorial/métodos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ritmo Circadiano/fisiologia , Eletroencefalografia/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Humanos
7.
Acta Pharm ; 69(3): 321-344, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259739

RESUMO

There are several limited approaches to treat epilepsy in hospitals, for example, using medicines, surgery, electrical stimulation and dietary interventions. Despite the availability of all these new and old approaches, seizure is particularly difficult to manage. The quest for new antiepileptic molecules with more specificity and less CNS toxicity continues for medicinal chemists until a new and ideal drug arrives. This review covers new antiseizure molecules of different chemical classes, the exact mode of action of which is still unidentified. Newer agents include sulfonamides, thiadiazoles, semi- and thiosemicarbazones, pyrrolidine-2,5-diones, imidazoles, benzothiazoles and amino acid deriva tives. These new chemical entities can be useful for the design and development of forthcoming antiseizure agents.


Assuntos
Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Animais , Epilepsia/tratamento farmacológico , Humanos , Convulsões/tratamento farmacológico
8.
Pak J Pharm Sci ; 32(3): 997-1003, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278712

RESUMO

The aim of this study was to investigate the antiepileptic effects of duloxetine in the maximal electroshock test and convulsions induced by four compounds: Pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide, and bicuculline. Duloxetine exhibited moderate anticonvulsive activity with an ED50 (median effective dose) of 48.21 mg/kg in the maximal electroshock test in mice. The anticonvulsive action of duloxetine was also confirmed in chemical-induced seizure tests, where this drug decreased tonic convulsions. Single administration of duloxetine (6.25-25 mg/kg) significantly increased the anticonvulsant effects of valproate, carbamazepine, and oxcarbazepine in the maximal electroshock test. Furthermore, pretreatment with thiosemicarbazide (an inhibitor of GABA synthesis enzyme) significantly increased the ED50 of duloxetine, suggesting the GABAergic system may contribute to the anticonvulsive action of duloxetine. These results support the use of duloxetine in the treatment of coexisting depression and epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Cloridrato de Duloxetina/farmacologia , Epilepsia/tratamento farmacológico , Ácido 3-Mercaptopropiônico/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Antidepressivos/farmacologia , Carbamazepina/farmacologia , Depressão/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Cloridrato de Duloxetina/administração & dosagem , Cloridrato de Duloxetina/efeitos adversos , Eletrochoque/efeitos adversos , Fenclonina/farmacologia , GABAérgicos/farmacologia , Masculino , Camundongos , Síndromes Neurotóxicas/etiologia , Oxcarbazepina/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Semicarbazidas/farmacologia , Ácido Valproico/farmacologia
9.
Molecules ; 24(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323993

RESUMO

Epilepsy is one of the most common neurological disorder in the world. Many antiepileptic drugs cause multiple adverse effects. Moreover, multidrug resistance is a serious problem in epilepsy treatment. In the present study we evaluated the safety profile of three (1-3) new chiral N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol demonstrating anticonvulsant activity. Our aim was also to determine differences between the enantiomeric compounds with respect to their safety profile. The results of the study indicated that compounds 1-3 are non-cytotoxic for astrocytes, although they exhibit cytotoxic activity against human glioblastoma cells. Moreover, 1-3 did not affect the viability of HepG2 cells and did not produce adducts with glutathione. Compounds 1-3 demonstrated no mutagenic activity either in the Salmonella typhimurium or in Vibrio harveyi tests. Additionally, the compounds displayed a strong or moderate antimutagenic effect. Finally, the P-glycoprotein (P-gp) ATPase assay demonstrated that both enantiomers are potent P-gp inhibitors. To sum up, our results indicate that the newly synthesized derivatives may be considered promising candidates for further research on anticonvulsant drug discovery and development. Our study indicated the similar safety profile of the enantiomeric N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol, although in the previous studies both enantiomers differ in their biotransformation pathways and pharmacological activity.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Cicloexanóis/química , Cicloexanóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ativação Metabólica/efeitos dos fármacos , Anticonvulsivantes/toxicidade , Antimutagênicos/química , Antimutagênicos/farmacologia , Biotransformação/efeitos dos fármacos , Cicloexanóis/toxicidade , Relação Dose-Resposta a Droga , Humanos , Fígado/efeitos dos fármacos , Estrutura Molecular , Mutagênicos/química , Mutagênicos/farmacologia
10.
Eur J Med Chem ; 180: 134-142, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31302446

RESUMO

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.


Assuntos
Acetamidas/farmacologia , Anticonvulsivantes/farmacologia , Quinolinas/farmacologia , Convulsões/tratamento farmacológico , Acetamidas/síntese química , Acetamidas/química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
11.
Cell Mol Biol (Noisy-le-grand) ; 65(5): 59-63, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31304908

RESUMO

Epilepsy is a common chronic disease of the central nervous system that can last for years or even decades, causing serious adverse effects on the body, mind, and psychology of patients. Traditional antiepileptic drugs can effectively control seizures, but because of large individual differences, serious adverse reactions, narrow therapeutic window and other shortcomings, more effective, new treatment drugs are looked for. Streptocaulon griffithii is a plant of Asclepiadaceae. 16-O-acetyldigitoxigenin (ACE) is a strong cardiac glycoside isolated from methanol extract of Streptocaulon griffithii. The aim of this study was to investigate the antiepileptic effect of ACE on Pilocarpine (Pilo) induced epilepsy in mice, and to explore the effect of mTOR signaling pathway on its antiepileptic effect. The results showed that ACE had antiepileptic and neuroprotective effects on Pilo induced epilepsy mice. ACE attenuates Pilo induced seizures by inhibiting the activation of p-mTOR/p-70S6K pathway, and inhibits Pilocarpine induced brain damage by inhibiting mTOR signaling pathway. These results suggest that ACE has a promising future in the treatment of epilepsy and other nervous system diseases.


Assuntos
Anticonvulsivantes/farmacologia , Digitoxigenina/análogos & derivados , Digitoxigenina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Apocynaceae/química , Caspase 3/metabolismo , Digitoxigenina/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pilocarpina/administração & dosagem , Pilocarpina/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
12.
Chem Pharm Bull (Tokyo) ; 67(7): 699-706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257325

RESUMO

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).


Assuntos
Anticonvulsivantes/síntese química , Nitrilos/química , Receptores de AMPA/antagonistas & inibidores , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/veterinária , Relação Estrutura-Atividade
13.
Oxid Med Cell Longev ; 2019: 7897584, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31198493

RESUMO

Bombyx batryticatus is a known traditional Chinese medicine (TCM) utilized to treat convulsions, epilepsy, cough, asthma, headaches, and purpura in China for thousands of years. This study is aimed at investigating the antiepileptic effects of protein-rich extracts from Bombyx batryticatus (BBPs) on seizure in mice and exploring the protective effects of BBPs against H2O2-induced oxidative stress in PC12 cells and their underlying mechanisms. Maximal electroshock-induced seizure (MES) and pentylenetetrazole- (PTZ-) induced seizure in mice and the histological analysis were carried out to evaluate the antiepileptic effects of BBPs. The cell viability of PC12 cells stimulated by H2O2 was determined by MTT assay. The apoptosis and ROS levels of H2O2-stimulated PC12 cells were determined by flow cytometry analysis. Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione (GSH) in PC12 cells were assayed by ELISA and expressions of caspase-3, caspase-9, Bax, Bcl-2, PI3K, Akt, and p-Akt were evaluated by Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) assays. The results revealed that BBPs exerted significant antiepileptic effects on mice. In addition, BBPs increased the cell viability of H2O2-stimulated PC12 cells and reduced apoptotic cells and ROS levels in H2O2-stimulated PC12 cells. By BBPs treatments, the levels of MDA and LDH were reduced and the levels of SOD and GSH-Px were increased in H2O2-stimulated PC12 cells. Moreover, BBPs upregulated the expressions of PI3K, Akt, p-Akt, and Bcl-2, whereas they downregulated the expressions of caspase-9, caspase-3, and Bax in H2O2-stimulated PC12 cells. These findings suggested that BBPs possessed potential antiepileptic effects on MES and PTZ-induced seizure in mice and protective effects on H2O2-induced oxidative stress in PC12 cells by exerting antioxidative and antiapoptotic effects via PI3K/Akt signaling pathways.


Assuntos
Anticonvulsivantes/farmacologia , Bombyx/química , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Insetos/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose , Sobrevivência Celular , Convulsivantes/toxicidade , Eletrochoque/efeitos adversos , Peróxido de Hidrogênio/toxicidade , Proteínas de Insetos/farmacologia , Masculino , Malondialdeído/metabolismo , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Pentilenotetrazol/toxicidade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Convulsões/etiologia , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais
14.
Paediatr Drugs ; 21(4): 283-290, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179531

RESUMO

BACKGROUND: A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy. OBJECTIVE: The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children's Hospital in Rome, Italy. METHODS: This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98-99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2-5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects. RESULTS: Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required. CONCLUSIONS: These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Adolescente , Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
15.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248209

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that is the main cause of dementia in the elderly. The aggregation of ß-amyloid peptides is one of the characterizing pathological changes of AD. Topiramate is an antiepileptic drug, which in addition, is used in the treatment of many neuropsychiatric disorders. In this study, the therapeutic effects of topiramate were investigated in a transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). Before, during, and after topiramate treatment, behavioral tests were performed. Following a treatment period of 21 days, topiramate significantly ameliorated deficits in nest-constructing capability as well as in social interaction. Thereafter, brain sections of mice were analyzed, and a significant attenuation of microglial activation as well as ß-amyloid deposition was observed in sections from topiramate-treated APP/PS1 mice. Therefore, topiramate could be considered as a promising drug in the treatment of human AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Topiramato/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/patologia , Animais , Anticonvulsivantes/química , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Topiramato/química
16.
Paediatr Drugs ; 21(4): 291-301, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250322

RESUMO

OBJECTIVE: This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of brivaracetam oral solution in children aged 1 month to < 16 years with epilepsy. METHODS: This was a phase IIa, open-label, single-arm, fixed three-step dose escalation trial of 3-weeks duration (N01263; NCT00422422). Patients were taking one to three concomitant antiepileptic drugs. Brivaracetam oral solution dosage, in two divided daily doses, was increased each week: approximately 0.8, 1.6, and 3.2 mg/kg/day for patients aged ≥ 8 years, and 1.0, 2.0, and 4.0 mg/kg/day for patients aged < 8 years. RESULTS: Of the 100 patients enrolled, 90 (90.0%) completed the trial. The safety population comprised 99 patients. Treatment-emergent adverse events (TEAEs) considered drug related by the investigator were reported by 32/99 (32.3%) patients, most commonly (≥ 5%) somnolence (7.1%) and decreased appetite (6.1%). TEAEs were reported by 66/99 (66.7%) patients, most commonly (≥ 5%) convulsion, irritability, pyrexia, somnolence, and decreased appetite. In patients with a history of focal seizures with or without secondary generalization and no primary generalized seizures aged 4 to < 16 years (n = 34), drug-related TEAEs and TEAE incidences were 47.1% and 67.6%, respectively. Steady-state trough brivaracetam and brivaracetam metabolite plasma concentrations increased proportionally with dose. The ≥ 50% responder rates (all seizure types) were 21.3% (all patients, n = 80) and 36.4% (patients with focal seizures, aged 4 to < 16 years, n = 22). CONCLUSIONS: This open-label trial in pediatric patients with epilepsy provides preliminary information that short-term, adjunctive brivaracetam treatment is well tolerated and effective. Plasma concentrations of brivaracetam and metabolites increased with increasing dose.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Adolescente , Anticonvulsivantes/farmacologia , Criança , Pré-Escolar , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Pirrolidinonas/farmacologia , Resultado do Tratamento
17.
Pak J Pharm Sci ; 32(2): 675-681, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31081782

RESUMO

Epilepsy remains a major chronic neurological disorder with significantly higher refractory seizure rate. Based on the folk medicine literature, we explored the anticonvulsant and antiepileptogenic activity of aqueous ethanolic extracts of Fumaria indica, Euphorbia lactea, Euphorbia helioscopia, Neurada procumbens, and Euphorbia nivulia. The acute anticonvulsant activity of the extracts was determined at different concentrations in different groups of Swiss albino mice. Among all the materials tested, the ethanolic extracts of Euphorbia nivulia (eth-EN) alone was found to exhibit concentration-dependent anticonvulsant effects when evaluated against the acute convulsant dose of Pentylenetetrazole (PTZ, 90mg/kg, s.c.). eth-EN extract at 100mg/kg i.p concentration showed maximum protection against the PTZ induced mortality (P<0.05). eth-EN (100mg/kg) treated animals also showed significant reduction in the progression of epileptogenesis (P<0.05) when tested against the PTZ-induced (50mg/kg s.c.) chemical kindling model of epilepsy. The FT-IR spectra of this extract showed both known and unknown spectral peaks from which the presence of the functional groups; i.e. aromatics, diketones, alkenes, carbonyls, carboxylic acids and amide compounds were confirmed. The unknown peaks strongly suggested the presence of novel compounds that may be responsible for its anticonvulsant and antiepileptogenic activity.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Euphorbia/química , Extratos Vegetais/farmacologia , Animais , Anticonvulsivantes/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Epilepsia/induzido quimicamente , Fumaria/química , Excitação Neurológica/efeitos dos fármacos , Masculino , Camundongos , Pentilenotetrazol/toxicidade , Extratos Vegetais/química , Plantas Medicinais/química , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Espectroscopia de Infravermelho com Transformada de Fourier
18.
Eur J Pharmacol ; 855: 175-182, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31063770

RESUMO

New, more effective pharmacologic treatments for epilepsy are needed, as a substantial portion of patients (>30%) are refractory to currently available anti-epileptic drugs. Cenobamate (YKP3089) is an investigational anti-epileptic drug in clinical development. Two completed adequate and well-controlled studies demonstrated a significant reduction in focal seizures with cenobamate in patients with epilepsy. In this study, we characterized the effects of cenobamate on voltage-gated Na+ channels in acutely isolated rat hippocampal CA3 neurons using a whole-cell patch-clamp technique. While cenobamate had little effect on the peak component of transient Na+ current (INaT) induced by brief depolarizing step pulses, it potently inhibited the non-inactivating persistent component of INa (INaP). In addition, cenobamate potently inhibited the current by slow voltage-ramp stimuli. Cenobamate significantly shifted the steady-state fast inactivation relationship toward a hyperpolarizing range, indicating that cenobamate binds to voltage-gated Na+ channels at the inactivated state with a higher affinity. Cenobamate also accelerated the development of inactivation and retarded recovery from inactivation of voltage-gated Na+ channels. In current clamp experiments, cenobamate hyperpolarized membrane potentials in a concentration-dependent manner, and these effects were mediated by inhibiting the INaP. Cenobamate also increased the threshold for generation of action potentials, and decreased the number of action potentials elicited by depolarizing current injection. Given that the INaP plays a pivotal role in the repetitive and/or burst generation of action potentials, the cenobamate-mediated preferential blockade of INaP might contribute to anti-epileptic activity.


Assuntos
Anticonvulsivantes/farmacologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Feminino , Cinética , Masculino , Neurônios/citologia , Ratos , Sódio/metabolismo
19.
J Enzyme Inhib Med Chem ; 34(1): 1078-1082, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31124389

RESUMO

3-Methylpentyl(4-sulphamoylphenyl)carbamate (MSPC) came as the most potent compound out of a new series of carbamates composed of phenyl-ethanol or branched aliphatic alcohols, and 4-benzenesulphonamide-carbamic acid. In this study, the anticonvulsant activity and pharmacokinetics (PKs) of MSPC-two individual enantiomers were comparatively analysed in rats as well as their carbonic anhydrase (CA) inhibition. The anticonvulsant activity of MSPC enantiomers was evaluated at the rat-maximal electroshock (MES) test, and their CA inhibition evaluated. (R)-MSPC had a 29% higher clearance and consequently, a lower plasma exposure area under the curve (AUC) than (S)-MSPC and racemic-MSPC. Nevertheless, (R)-MSPC had a better brain permeability than its (S)-enantiomer with brain-to-plasma-(AUC)-ratio (BPR) of 2.07 ((R)-enantiomer), 1.85 (racemate), and 0.79 ((S)-enantiomer). As a whole body (in vivo) pharmacodynamic (PD) measure, MSPC-anticonvulsant maximal electroshock seizure (MES) activity was less enantioselective than MSPC-CA inhibition. The lack of significant differences between racemic-MSPC and its individual enantiomers suggest that their anticonvulsant activity might be due to multiple mechanisms of action.


Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Carbamatos/síntese química , Carbamatos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Sistema Nervoso Central/metabolismo , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/química , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
20.
Artigo em Inglês | MEDLINE | ID: mdl-31029222

RESUMO

Topiramate, 2,3:4,5-di-O-isopropylidene-ß-d-fructopyranose sulfamate, is a potent antiepileptic drug with a broad spectrum of activity. It is effective in both partial and generalized seizures. Topiramate was also found to have significant efficacy in migraine prevention with considerable reductions in the frequency of migraine headaches. The most common adverse events, which may accompany the use of topiramate, are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease and taste perversion. The weight loss observed with the use of topiramate in obese, epileptic patients, afforded the approval of this drug as an anti-obesity medication. This action is thought to be based on the selective inhibition of mitochondrial carbonic anhydrase isoforms. This profile is prepared to discuss and explain physical characteristics, proprietary and nonproprietary names of topiramate. It also includes methods of preparation, thermal and spectral behavior and methods of analysis. Pharmacokinetics, metabolism, excretion and pharmacology together with its uses and applications are also discussed.


Assuntos
Anticonvulsivantes/farmacologia , Topiramato/farmacologia , Anticonvulsivantes/química , Epilepsia/tratamento farmacológico , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Topiramato/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA