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The ability of venom-derived peptides to disrupt physiological processes in mammals provides an exciting source for pharmacological development. Our research group has identified a new class of neuroactive peptides from the venom of a Brazilian social wasp, Polybia occidentalis, with the potential pharmacological profile to treat epilepsies. The study was divided into five phases: Phase 1 concerned the extraction, isolation and purification of Occidentalin-1202(n) from the crude venom, followed by the synthesis of an identical analogue peptide, named Occidentalin-1202(s). In Phase 2, we described the effects of both peptides in two acute models of epilepsy-kainic acid and pentylenetetrazole-induced model of seizures-and measured estimated ED50 and therapeutic index values, electroencephalographic studies and C-fos evaluation. Phase 3 was a compilation of advanced tests performed with Occidentalin-1202(s) only, reporting histopathological features and its performance in the pilocarpine-induced status epilepticus. After the determination of the antiepileptic activity of Occidentalin-1202(s), Phase 4 consisted of evaluating its potential adverse effects, after chronic administration, on motor coordination (Rotarod) and cognitive impairment (Morris water maze) tests. Finally, in Phase 5, we proposed a mechanism of action using computational models with kainate receptors. The new peptide was able to cross the blood-brain barrier and showed potent antiseizure effects in acute (kainic acid and pentylenetetrazole) and chronic (temporal lobe epilepsy model induced by pilocarpine) models. Motor and cognitive behaviour were not adversely affected, and a potential neuroprotective effect was observed. Occidentalin-1202 can be a potent blocker of the kainate receptor, as assessed by computational analysis, preventing glutamate and kainic acid from binding to the receptor's active site. Occidentalin-1202 is a peptide with promising applicability to treat epilepsy and can be considered an interesting drug model for the development of new medicines.
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The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.
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Aorta/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , NADPH Oxidase 2/metabolismo , NADPH Oxidases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Topiramato/toxicidade , Doenças Vasculares/patologia , Animais , Anticonvulsivantes/toxicidade , Aorta/efeitos dos fármacos , Aorta/metabolismo , Feminino , Masculino , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Prostaglandina-Endoperóxido Sintases/genética , Ratos , Ratos Wistar , Fatores Sexuais , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/metabolismoRESUMO
Background: Oral-gut inflammation has an impact on overall health, placing subjects at risk to acquire chronic conditions and infections. Due to neuromotor disturbances, and medication intake, cerebral palsy (CP) subjects present intestinal constipation, impacting their quality of life (QOL). We aimed to investigate how oral inflammatory levels predicted gut phenotypes and response to therapy. Methods: A total of 93 subjects aging from 5 to 17 years were included in the study, and assigned into one of the 4 groups: CP with constipation (G1, n = 30), CP without constipation (G2, n = 33), and controls without CP with constipation (G3, n = 07) and without CP and without constipation (G4, n = 23). In addition to characterizing subjects' clinical demographics, medication intake, disease severity levels, salivary cytokine levels [TNF-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10], and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Statistical significance was evaluated by Shapiro-Wilks, Student's T-Test, ANOVA, and ANCOVA analysis. Results: Salivary proinflammatory cytokines were highly correlated with the severe form of gut constipation in G1 (P < 0.001), and out of all cytokines IL-1ß levels demonstrated highest correlation with all gut constipation (P < 0.05). A significant relationship was found between the type of medication, in which subjects taking Gamma-Aminobutyric Acid (GABA) and GABA+ (GABA in association with other medication) were more likely to be constipated than the other groups (P < 0.01). Cleary salivary inflammatory levels and gut constipation were correlated, and impacted QOL of CP subjects. G1 presented a lower QOL mean score of CPCHILD (49.0 ± 13.1) compared to G2 (71.5 ± 16.7), when compared to G3 (88.9 ± 7.5), and G4 (95.5 ± 5.0) (P < 0.01). We accounted for gingival bleeding as a cofounder of oral inflammation, and here were no differences among groups regarding gender (P = 0.332) and age (P = 0.292). Conclusions: Collectively, the results suggest that saliva inflammatory levels were linked to gut constipation, and that the clinical impact of medications that controlled gut was reliably monitored via oral cytokine levels, providing reliable and non-invasive information in precision diagnostics.
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Paralisia Cerebral/complicações , Paralisia Cerebral/epidemiologia , Gastroenterite/complicações , Gastroenterite/epidemiologia , Estomatite/complicações , Estomatite/epidemiologia , Adolescente , Biomarcadores , Paralisia Cerebral/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Citocinas/metabolismo , Feminino , Gastroenterite/diagnóstico , Gastroenterite/metabolismo , Humanos , Mediadores da Inflamação , Masculino , Fenótipo , Vigilância da População , Qualidade de Vida , Saliva/metabolismo , Estomatite/diagnóstico , Estomatite/metabolismo , Avaliação de SintomasRESUMO
OBJECTIVES: To investigate the significance of "subtherapeutic" vs "therapeutic" antiepileptic drug (AED) plasma levels with respect to treatment adherence. MATERIAL AND METHODS: One hundred and seventy patients with refractory temporal lobe epilepsy who underwent video-EEG monitoring in view of a surgical indication had their AEDs (carbamazepine, phenobarbital, phenytoin, and valproate) rapidly withdrawn following a standardized schedule. Plasma levels were measured at admission, and during the 2 days of drug withdrawal. Adherence and nonadherence were identified by the development of plasma levels from day 1 through day 3. Frequencies of an initial level below the reference range in both groups were compared. RESULTS: Adherence was found in 73.2% of cases, and nonadherence in 26.8%. Low levels were seen equally often (about 1/4 of cases) in adherent and nonadherent cases. The vast majority (73.7%) of low levels had another explanation than nonadherence (eg low-dose treatment or enzyme induction). Of 42 nonadherent cases, the vast majority of 76.2% had unsuspicious plasma levels at admission. CONCLUSIONS: "Subtherapeutic" AED plasma levels only rarely are caused by nonadherence whereas levels in the "therapeutic range" by no means prove that the patient is adherent to treatment. For meaningful interpretation, any level needs to be compared with other levels of the same patient. Our findings strongly emphasize the principle of individualized therapeutic AED monitoring as promoted by the Therapeutic Strategies Commission of the ILAE.
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Anticonvulsivantes/administração & dosagem , Monitoramento de Medicamentos/métodos , Epilepsia do Lobo Temporal/tratamento farmacológico , Adesão à Medicação , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Esquema de Medicação , Monitoramento de Medicamentos/normas , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study was to describe sociodemographic, clinical, behavioral, nutritional, and health-related variables from people with epilepsy. A descriptive observational study was carried out in the city of Pelotas, southern Brazil. Sociodemographic, clinical, behavioral, nutritional, and health-related variables were collected. A univariate analysis was performed, calculating the measures of central tendency for continuous variables and proportions for categorical ones. The sample consisted of 101 people, age ranging from 12 to 75years, mostly male (50.5%) and white (59.4%). Only 37.2% from the sample was employed, and the average income was R$ 788.00 Brazilian Reais (US$ 245.90 at the moment of the interview). From all the subjects, 65.6% was in treatment with monotherapy, 62.9% presented more than 15 seizures during the life, 67.3% showed active epilepsy, 64.6% were physically inactive, 52.5% presented normal body mass index, and 50% showed generalized seizures. The most used antiepileptic drug was the carbamazepine. The average score of depression was 12.6±4.1 points and 34.6% showed severe depressive symptoms (equal or higher than 15 points). The mean score of trait and state anxiety was 12.2±3.6 and 15.1±3.4 points, respectively (ranging from 6 to 24 points). The mean score of quality of life and stress was 63.2±18.2 (ranging from 0 to 100 points) and 21.2±7.1 points (ranging from 0 to 40 points), respectively. Considering the medication side effects, the mean score was 42.4±8.9 points, 38.5% showing high rates (higher than 45 points), and only 16% showing good sleep quality. In conclusion, these results are important to improve understanding of these individuals' disease and to subsidize the specific public policies in countries of low and middle income.
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Epilepsia/diagnóstico , Epilepsia/psicologia , Exercício Físico , Qualidade de Vida/psicologia , Convulsões/epidemiologia , Estresse Psicológico , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Ansiedade/epidemiologia , Ansiedade/psicologia , Brasil/epidemiologia , Carbamazepina/uso terapêutico , Criança , Estudos Transversais , Depressão/epidemiologia , Depressão/psicologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Convulsões/psicologia , Fatores SocioeconômicosRESUMO
Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/µl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, γ-aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events.
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Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Levetiracetam/farmacologia , Neostriado/efeitos dos fármacos , Animais , Lesões Encefálicas/tratamento farmacológico , Masculino , Fármacos Neuroprotetores , Ácido Quinolínico/toxicidade , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacosRESUMO
Two lamotriginium salts, namely lamotriginium crotonate [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium but-2-enoate, C9H8Cl2N5+·C4H5O2-, (III)] and lamotriginium salicylate [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium 2-hydroxybenzoate ethanol monosolvate, C9H8Cl2N5+·C7H5O3-·C2H5OH, (IV)] present extremely similar centrosymmetric hydrogen-bonded A...L...L...A packing building blocks (L is lamotriginium and A is the anion). The fact that salicylate salt (IV) is (ethanol) solvated, while crotonate salt (III) is not, has a profound effect on the way these elemental units aggregate to generate the final crystal structure. Possible reasons for this behaviour are analyzed and the hypothesis raised checked against similar structures in the literature.
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RATIONALE: Vigabatrin (VGB) is a drug indicated mostly for the treatment of spasms in childhood and West's syndrome patients. This drug inhibits irreversibly the enzyme GABA-transaminase (GABA-T), increasing GABA concentrations and enhancing GABAergic neurotransmission in the brain, which is known to induce behavioral changes. OBJECTIVES: The aims of this study were to evaluate the effects of VGB in the short-term memory (STM), long-term memory (LTM), motivation, locomotion, and exploratory behavior tests and to detect deleterious or protective effects on DNA in target tissues of the drug. METHODS: Male Wistar rats were treated with a single dose of VGB (100, 250, or 500 mg/kg) or saline solution before the inhibitory avoidance and open-field tasks. DNA damage was evaluated using the alkaline comet assay in peripheral blood, cerebral cortex, and hippocampus after behavioral testing. RESULTS: There was no significant difference in the inhibitory avoidance task between the treated groups and the saline group. In all tested doses, VGB reduced the number of rearings in the open-field task. Besides, VGB 500 mg/kg affected locomotion, though it was not able to induce any DNA damage. CONCLUSIONS: VGB did not affect STM and LTM, but the drug impaired the exploration and locomotion likely associated with its sedative effect. In addition, no DNA damage in cortex and hippocampus was detected after behavioral testing, when brain GABA levels are already increased.
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Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Vigabatrina/farmacologia , Animais , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Humanos , Locomoção/efeitos dos fármacos , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Motivação/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
OBJECTIVE: To evaluate neurologists' knowledge of contraceptive counseling for women receiving antiepileptic drugs (AEDs). METHODS: An interview-based survey was conducted from February 2 to June 30, 2015, among neurologists working in Ribeirão Preto, Brazil. Direct interviews were conducted using a questionnaire that assessed knowledge of the pharmacological interactions between various contraceptive methods and six AEDs (carbamazepine, phenobarbital, topiramate, phenytoin, lamotrigine, and valproate) on the basis of WHO medical eligibility criteria for contraceptive use. RESULTS: Among 42 neurologists who participated, 32 (76%) stated that they treated women with epilepsy and provided them with counseling for family planning. Overall, 34 (81%) recommended the use of a copper intrauterine device irrespective of the AED used, and 26 (60%) stated that they co-prescribed AEDs and hormonal contraceptives. Although 39 (93%) neurologists had knowledge that AEDs might contraindicate the use of some contraceptives, their knowledge regarding the specific drug interactions was lacking. Furthermore, 34 (81%) had no knowledge of WHO medical eligibility criteria for contraceptive use. CONCLUSION: Although most neurologists interviewed had knowledge of interactions between AEDs and hormonal contraceptives, they did not know which specific AEDs interacted with these agents.
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Anticonvulsivantes/efeitos adversos , Anticoncepcionais Orais Hormonais/efeitos adversos , Epilepsia/tratamento farmacológico , Padrões de Prática Médica , Adulto , Anticonvulsivantes/administração & dosagem , Brasil , Anticoncepcionais Orais Hormonais/administração & dosagem , Interações Medicamentosas , Feminino , Humanos , Entrevistas como Assunto , Masculino , NeurologistasRESUMO
INTRODUCTION: Neurocysticercosis (NCC) is a leading causes of secondary epilepsy worldwide. There is increasing evidence on the epileptogenic role of NCC, and the presence of edema, calcified scars, gliosis and hippocampal sclerosis support this phenomenon. AREAS COVERED: We summarized principles of antiepileptic drug (AED) therapy as well as risk factors associated with seizure recurrence after AED withdrawal in patients with NCC. Expert commentary: First-line AED monotherapy is effective as a standard approach to control seizures in most NCC patients. Risks and benefits of AED withdrawal have not been systematically studied, and this decision must be individualized. However, a seizure-free period of at least two years seem prudent before attempting withdrawal. Risk factors for seizure recurrence after AED withdrawal include a history of status epilepticus, poor seizure control during treatment, neuroimaging evidence of perilesional gliosis, hippocampal sclerosis and calcified lesions, as well as persistence of paroxysmal activity in the EEG.