OBJECTIVE: To evaluate the morphometric effect of prenatal exposure to phenytoin, phenobarbital and carbamazepine on the shape of the maxilla the posterior and overall cranial base. MATERIAL AND METHODS: Sample selection: This study is a retrospective analyses of lateral cephalograms of 67 (Phenobarbital =21, Phenytoin=21, Carbamazepine=25) children age 6 to 16 who had been exposed prenatally to one of these drugs and compared to a control group of 44 unexposed children of the same age. Cephalometric films were digitized and anatomical landmarks identified by a single investigator. Landmarks were chosen to outline the maxilla, the posterior and overall cranial base. Morphometric analysis including Procrustes superimposition was used to compare the exposed children to the control group. Principal components analysis (PCA) and MANOVA tests were performed to determine the differences between the two groups. RESULTS: The superimposed average showed a significant difference between the two groups. In the exposed group, the anterior cranial base was vertically shorter. Glabella was more inferior and anterior relative to nasion, and the nasal tip was more superior and posterior. Orbitale was more inferior and posterior, suggesting a more posterior articulation with maxilla. The posterior cranial base was vertically taller and sagittally shorter. Also in the exposed group, the maxilla was vertically shorter. CONCLUSION: These results demonstrate a shorter, retrusive maxilla that articulates more posteriorly with a shorter anterior cranial base, confirming the midface hypoplasia of traditional anticonvulsant facies.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Even though Tulbaghia violacea has been used to treat and manage epilepsy in South Africa by traditional medicine practitioners, no evidence in any literature has shown any scientific scrutiny of the effectiveness of the plant species in therapy. This project was intended, therefore, to investigate the anticonvulsant effect of the leaf methanol extract of Tulbaghia violacea by studying its effect against tonic convulsion induced by either pentylenetetrazole (PTZ), bicuculline, picrotoxin, strychnine or N-methyl-DL-aspartic acid (NMDLA) in mice. Qualitative phytochemical analysis, acute toxicity and HPLC studies were also carried out on the plant species. The doses of 200 (mg/kg, i.p.) and 400 (mg/kg, i.p.) of the leaf methanol extract of T. Violacae significantly delayed the onset of PTZ (100 mg/kg, i.p.)-induced tonic convulsion in a dose dependent manner. Leaf methanol extract of the plant species (200 mg/kg, i.p.) did not affect the incidence of PTZ (100 mg/kg, i.p.)-induced tonic convulsion while 400 mg/kg (i.p.) protected only one mouse against the tonic convulsion. Leaf methanol extract of Tulbaghia violacea (100mg/kg, i.p.) did not significantly affect the onset or incidence of PTZ (100 mg/kg, i.p.)- induce tonic convulsion. Phenobarbitone (12 mg/kg, i.p.), diazepam (0.5 mg/kg, i.p.) and muscimol (2mg/kg, i.p.) significantly delayed the onset of PTZ (100 mg/kg, i.p.)-induced tonic convulsion and also significantly reduced the number of animals convulsing. Muscimol (0.2 mg/kg, i.p.) did not significantly affect the onset or incidence of PTZ (100 mg/kg, i.p.)-induced tonic convulsion. However, combined therapy of sub effective doses of the leaf methanol extract of T. Violacea (100 mg/kg, i.p.) and muscimol (0.2 mg/kg, i.p.) significantly delayed the onset of PTZ (100mg/kg, i.p.)-induced tonic convulsion and but did not significantly reduce the number of animals convulsing. The combined therapy of sub effective doses of the leaf methanol extract of T. violacea (100 mg/kg, i.p.) and muscimol (0.2 mg/kg, i.p.) protected two of the mice against the tonic convulsion. Leaf methanol extract of Tulbaghia violacea (100-400 mg/kg, i.p.) significantly and dose dependently delayed the onset of tonic convulsion produced by bicuculline (30 mg/kg, i.p.), picrotoxin (20 mg/kg, i.p.) or NMDLA (400 mg/kg, i.p.)-induced tonic convulsion but did not affect the incidence of any of the convulsions. Phenobarbitone (12 mg/kg, i.p.), diazepam (0.5 mg/kg, i.p.) or muscimol (2 mg/kg, i.p.) significantly delayed the onset of bicuculline (30 mg/kg, i.p.) or picrotoxin (20 mg/kg, i.p.)-induced tonic convulsion and also significantly reduced the number of animals convulsing. Phenobarbitone (12 mg/kg, i.p.) or diazepam (0.5 mg/kg, i.p.) did affect significantly affect the onset or incidence of NMDLA (400 mg/kg, i.p.)-induced tonic convulsion. LY233053 (5 mg/kg, i.p.) significantly delayed the onset of tonic convulsion produced by NMDLA (400 mg/kg, i.p.) and also significantly reduced the number of animals convulsing. Leaf methanol extract of Tulbaghia violacea (200 and 400 mg/kg, i.p.) significantly delayed the onset of strychnine (2 mg/kg, i.p.)-induced tonic convulsion but did not significantly affect the number of mice convulsing. The dose of 100 mg/kg (i.p.) of leaf methanol extract of T. violacea did not significantly affect the onset or incidence of strychnine (2 mg/kg, i.p.)-induced tonic convulsion. Phenobarbitone (12 mg/kg, i.p.) significantly delayed the onset of strychnine (2 mg/kg, i.p.)-induced tonic convulsion and also significantly reduced the number of animals convulsing. Diazepam (0.5 mg/kg, i.p.) did not significantly delay the onset of strychnine (2 mg/kg, i.p.)-induced tonic convulsion and also did not significantly affect the number of mice convulsing. Phenytoin (30 mg/kg, i.p.) or DMSO (0.25 ml, i.p.) did not significantly affect the onset or incidence of bicuculline (30 mg/kg, i.p.), picrotoxin, strychnine or NMDLA-induced tonic convulsion. The qualitative phytochemical analysis of the plant species showed the presence of alkaloids, saponins, cardiac glycosides, flavonoids, triterpene steroids, quinones and tannins. The LD50 value obtained following oral administration of the leaf methanol extract of Tulbaghia violacea may be greater than 4000 mg/kg. The HPLC fingerprint of the leaf methanol extract of Tulbaghia violacea showed distinct peaks at the following retention times, 2.911, 3.269, 4.010, 7.597, and 15.122 min. The results obtained in this study indicate that the leaf methanol extract of Tulbaghia violacea has anticonvulsant activity. The results obtained also indicate that GABA, glutamic acid and glycine mechanisms may probably be involved in the anticonvulsant activity of the plant extract. The relatively high LD50 obtained for the plant species, given orally, indicate that it is safe in mice.

This thesis describes the synthesis of a series of 5-alkyl-5-(2-thienylmethyl)-barbituric acids.

This thesis describes attempts to synthesize 5-allyl-5-(2-thienyl)-barbituric acid as an improved anticonvulsant.

TOPIC. Advances in the psychopharmacologic treatment of bipolar affective disorders (BPAD). PURPOSE. To increase advanced practice nurses' ability to match prescribing practices with known etiological factors and the neurobiology of this complex set of disorders. SOURCES. Published literature. CONCLUSIONS. A wide array of pharmacological agents exist that can be useful to manage BPAD symptoms. APRNs play a critical role in helping patients and their families to use these drugs effectively.

Carbamazepine (CBZ) is an antiepileptic drug widely detected in drinking water supplies and wastewater effluent. It has been previously found that CBZ is recalcitrant to biological removal processes. Therefore, active CBZ will be exposed to wastewater effluent disinfection processes, which for most treatment plants in the United States involves the addition of free chlorine. However, the chlorination mechanisms of CBZ have not been fully investigated and are currently poorly understood. Our experimental studies were conducted to examine the chlorination of CBZ under controlled conditions. The kinetics, products, and reactivity of CBZ/free chlorine reactions were investigated over the pH range of 5.5-10. Results show that free chlorine reacts with CBZ and the reactivity is pH dependent. Furthermore, the results indicate that temperature affects the reactivity of CBZ with free chlorine. The temperature experiment results were fitted with the Arrhenius equation. The calculated Ea and A values are 48.8 kJ/mol and 1.41x104 s-1, respectively. Four common intermediates were detected based on both UV and mass spectral analysis proposed structures were developed based on m/z from mass spectra. / Master of Science

Cannabinoids, such as the marijuana derivative Δ9-THC, are known to have CBl receptor-mediated anticonvulsant effects in several animal models of seizures and epilepsy, including the rat pilocarpine model of acquired epilepsy. However, the distribution of CBl receptor expression and function in brains of epileptic rats has not been characterized. Therefore, this dissertation was initiated to evaluate the effect of epileptogenesis on the distribution and function of the endogenous CBI receptor system in the rat pilocarpine model, a well-established model of acquired temporal lobe epilepsy. Using immunohistochemistry, we demonstrated that chronically epileptic rats exhibit a unique, long-term, and specific redistribution of hippocampal CBl receptors when compared to controls, with concurrent layer-specific increases and decreases in CBl receptor expression within the hippocampus. In addition, studies in this dissertation demonstrated using [3H] WIN55,212-2 autoradiography and agonist-stimulated [35S]GTPγS autoradiography that this CBl receptor-specific reorganization results in corresponding functional changes manifested by alterations in CBl receptor binding and G-protein activation. These regionally selective changes were dependent on NMDA receptor activation during the initial insult of pilocarpine-induced status epilepticus (SE), and were independent of seizure suppression produced with phenobarbital administration in epileptic rats. Furthermore, time-course studies utilizing these techniques demonstrate that within a week following SE, a widespread loss of CBl receptor expression and function occurs throughout the hippocampus. The subsequent redistribution of CBl receptors that occurs temporally correlates with the emergence of spontaneous recurrent seizures, and is still observed up to 1 year following SE. Overall, the reorganization of cannabinoid receptors in epilepsy implicates the endocannabinoid system in modulating neuroexcitability in the epileptic state. This CBl receptor redistribution represents an essentially permanent neuronal plasticity change associated with epileptogenesis, and could account for the anticonvulsant effect of cannabinoids observed in this model.

As peçonhas de artrópodos são ricas fontes de neurotoxinas, verdadeiras ferramentas moleculares com ação seletiva e específica sobre o Sistema Nervoso Central (SNC) de mamíferos, e de grande relevância clínico-científica. Demonstramos recentemente que a peçonha de P. bistriata, quando injetada por via intracerebroventricular (i.c.v.), desencadeava crises convulsivas em ratos, um indício da existência de neurotoxinas pró-convulsivantes na peçonha dessa aranha. O grupo do Prof. Dr. Joaquim Coutinho-Netto isolou da peçonha dessa aranha várias neurotoxinas, dentre as quais uma denominada PbTx 2.2.1, que possui a capacidade de inibir a captação do neurotransmissor GABA em sinaptosomas corticais de ratos (in vitro), uma ação considerada como potencialmente anticonvulsivante. As frações PbTx 2.2.1 e 1.2.3 protegem retinas de ratos após isquêmia. Mas, não se testou o efeito anticonvulsivante dessa fração em experimentos in vivo. O presente trabalho teve dois objetivos: 1- Propor um método cromatográfico para isolar da peçonha de aranhas, neurotoxinas pró-convulsivantes não protéicas e de baixo peso molecular. Isolar e caracterizar parcialmente estas neurotoxinas da peçonha da aranha P.bistriata; 2- verificar se a fração PbTx 2.2.1 possui efeito anticonvulsivante in vivo. O isolamento da peçonha de P. bistriata, realizado com filtração em gel (Sephadex G-50 e G-25), cromatografia líquida de alta eficiência (CLAE) (colunas de fase reversa e troca catiônica), e CLAE-acoplado a espectrometria de massa (CLAE-MS) produziu uma fração (fração 7) e um subcomponente (fração 7.1) com atividade pró-convulsivante, após injeção i.c.v. Tal fração apresenta características típicas de ácidos nucléicos. Confirmou-se, através de ressonância magnética nuclear (RMN) que o constituinte majoritário desta fração é o nucleosídeo inosina. O método cromatográfico mostrou-se muito lento. Uma outra fração (fração 6) da mesma peçonha inibiu as crises causadas por bicuculina i.c.v., ao passo que a fração 1 apresentou atividade de fosfatase ácida e alcalina. A injeção i.c.v. da fração PbTx 2.2.1, 20 min antes do convulsivante bicuculina também i.c.v., bloqueou as crises convulsivas em 71,4% dos animais, o que caracteriza um efeito anticonvulsivante in vivo desta fração. Conclui-se que: 1- A peçonha de P. bistriata possui, dentre muitas, uma fração (fração 7) com efeito pró-convulsivante quando injetada i.c.v. em ratos. Nesta fração, aparentemente o composto majoritário é o nucleosídeo inosina. A peçonha da mesma aranha possui também uma fração com atividade anticonvulsivante (fração 6) e outra com atividade de fosfatase ácida e alcalina (fração 1). 2- o método cromatográfico proposto pode ser otimizado talvez pelo uso de ultrafiltração; 3- a fração PbTx 2.2.1 apresenta efeito anticonvulsivante in vivo no modelo de indução de crises por injeção i.c.v. de bicuculina. / Arthropod venoms are rich sources of neurotoxins, molecular tools with selective and specific actions over the mamalian central nervous system with great clinical and scientific importance. Previous work of our laboratory showed that the spider venom of Parawixia bistriata, when injected by intracerebroventricular (i.c.v.) route, induced convulsive seizures in rats, a sign of convulsant neurotoxins. The group of Professor Joaquim Coutinho-Netto isolated from this spider venom a neurotoxin called PbTx 2.2.1 which is a GABA transporter inhibitor in the rat cortical synaptosomal preparation (in vitro), a potencially anticonvulsant property. The fractions PbTx 2.2.1 and 1.2.3 protected retinal cells against isquemy. But, it has not been tested if the PbTx 2.2.1 fraction also has an in vivo anticonvulsant action. Present work has two objectives: 1- to propose a chromatographic methodology to isolate non-proteic low molecular weigh convulsant neurotoxins from spider venoms. Isolate and partially characterize these neurotoxins from P. bistriata venom; 2- test if PbTx 2.2.1 has in vivo anticonvulsant effect. Biochemical venom isolation by gel filtration (Sephadex G-50 and G-25), reverse phase and cationic exchange in high pressure liquid cromatography (HPLC) and also HPLC coupled to mass spectrometry (HPLC-MS), has pointed that the P. bistriata spider venom has a fraction (fraction 7) and a subfraction (7.1) with convulsant activity when injected i.c.v. in rats. Fraction 7 has nucleosidic characteristics. Nuclear magnetic ressonance (NMR) has showed that the principal component of this fraction is the nucleoside iosine. An other fraction (fraction 6) isolated from the same venom, inhibited seizures induced by i.c.v. bicuculine and the fraction 1 showed acid and basic phosphatase activity PbTx 2.2.1, when injected i.c.v. 20 min prior to the convulsant bicuculline (i.c.v.), has blocked seizures in 71.4 % of the animals, what was considered an anticonvulsant effect. The conclusions are: 1- the spider venom of P. bistriata has a fraction (fraction 7) with convulsant action when injected i.c.v. in rats. The major component of this fraction is the nucleoside iosine. This spider venom also has another fraction (fraction 6) with anticonvulsant activity and one with acid and alcaline phosphatase (fraction 1); 2- the chomatographic methodology can be improved, perhaps by ultrafiltration methods; 3- the PbTx 2.2.1 fraction has anticonvulsant effect in vivo.

Durante a evolução, alguns animais desenvolveram toxinas que são capazes tanto de paralisar quanto de matar suas presas, através de ação seletiva sobre receptores ou canais iônicos. As acilpoliaminas, por exemplo, são componentes não-proteicos antagonistas dos receptores glutamatérgicos acoplados a canais iönicos, que mostraram-se anticonvulsivantes em diversos modelos animais. Apesar do estudo das alterações comportamentais em animais após a injeção de substâncias químicas (etofarmacologia) ter auxiliado a estudar o mecanismo de ação destas substâncias no SNC, não há relatos sobre os efeitos comportamentais da injeção i.c.v. e i.v. da peçonha da aranha Parawixia bistriata. Descobriu-se recentemente na peçonha bruta da aranha Parawixa bistriata uma ação potencialmente anticonvulsivante in vitro: ela potencia a neurotransmissão gabaérgica e desloca receptores glutamatérgicos de seus sítios específicos em sinaptosomas do cérebro de rato (FONTANA, 1997). O objetivo do presente trabalho é estudar as alterações comportamentais causadas pela injeção central e periférica da peçonha bruta de P. bistriata através de uma metodologia quantificativa (método neuroetológico), e verificar se esta peçonha possui ação anticonvulsivante in vivo em um modelo químico de indução de crises agudas - o pentilenotetrazol (PTZ, 80 mg/kg, i.p.). Os resultados mostram que a injeção i.c.v. da peçonha bruta origina nos ratos dois quadros comportamentais, identificados como crises convulsivas, denominados de crises graves e leves. Nas crises graves, observou-se, entre outros, mioclonias semelhantes às crises convulsivas límbicas descritas por Racine (1972). As crises leves são caracterizadas por tremores generalizados, e sacudidelas de corpo (wet dog shakes). A injeção da peçonha i.v. não origina crises nos animais mas, no entanto, causa um intenso aumento nas interações estatísticas das seqüências comportamentais, que lembram em muito as atividades de deslocamento. Tanto nas crises graves, leves, e na injeção i.v., a neuroetologia permitiu a visualização das interações entre as mioclonias convulsivas límbicas e os outros comportamentos, dados não fornecidos pelas escalas de medição de intensidade das crises límbicas. Buscando indícios da presença de componentes anticonvulsivantes não-proteicos (como acilpoliaminas), injetou-se i.c.v. a peçonha de P. bistriata fervida (numa dose que não causa crises nem alteração motora per se), seguida da injeção i.p. de PTZ. Verificou-se que este tratamento abole as crises clônicas e tônicas induzidas por PTZ. Conclui-se que a peçonha bruta de P. bistriata provavelmente possui componentes pró-convulsivantes com possível ação sobre o sistema límbico. Esta peçonha pode conter, também, componentes anticonvulsivantes não-proteicos, possivelmente acilpoliaminas. / Spider venoms have hight affinity and specificity for neuronal receptors, transporters and ion channels, therefore been important tools to characterize mammal and insect nervous system. However, behavioural alterations in mammals caused by injections of spider venoms have not been studied in detail. In this work we describe the rat behavioural alteration caused by central injection of the crude venom of the spider Parawixia bistriata, using a neuroethological methodology. There were seen two types of seizures, named mild and severe. Neuroethological flowcharts showed that in mild seizures, there was a strong statistical correlation (c2) between tremor followed by laying or by laying left, which indicates that the venom, perhaps, is difficulting central coordination of movements. In severe seizures, this effect is enworsed, with the animal falling.This type of seizure are similar to those described by Racine (1972). Since the crude venom of P. bistriata showed a potencial anticonvulsant activity in vitro, we tested if it would indeed inhibit clonic and tonic convulsions induced by pentilenetetrazole (PTZ; 80 mg/kg, i.p.). Boiled crude venom of P. bistriata was i.c.v. injected, and 20 minutes later, animals (n=10) received PTZ. A control group (n=10) received only PTZ. The results were: central injection of the venom abolished clonic and tonic convulsions induced by PTZ, in 60% of the animals. In conclusion, the crude spider venom of P. bistriata, centrally injected, causes central loss of movement coordination, and elicits limbic seizures similar to those described by Racine (1972), but, when boiled and injected in lower doses, it blocks clonic and tonic convulsions induced by PTZ (80 mg/kg).

Objetivos: Avaliar a farmacocinética e a distribuição tecidual do benzaldeído semicarbazona livre (BS) e incluso em ß-Ciclodextrinas (BS/ß-CD) após administração de diversas doses por diferentes vias de administração. Metodologia: As concentrações plasmáticas de BS foram quantificadas através de método analítico por CLAE-UV desenvolvido e validado, após administração das doses de 10 mg/kg i.v. bolus e 50 e 100 mg/kg p.o. da droga livre e 10 mg/kg i.v. bolus e 50 mg/kg p.o. da droga complexada a ratos Wistar (n = 8 animais/grupo). Os perfis plasmáticos foram avaliados individualmente pelas abordagens não-compartimental e compartimental para determinação dos parâmetros farmacocinéticos. A avaliação compartimental foi realizada utilizando software Scientist 2.0.1 (Micromath®). A ligação do BS a proteínas plasmáticas foi determinada por ultrafiltração na faixa de 1,0 a 60,0 µg/mL. O perfil de penetração tecidual da droga livre e complexada foi investigado em diferentes órgãos utilizando o método de homogeneizado de tecido até 5 h após administração de dose 10 mg/kg i.v. A penetração cerebral também foi avaliada para a droga livre e inclusa em ß-CD após a dose de 50 mg/kg até 4 h após administração (n = 3 animais/tempo coleta). Resultados e Discussão: A fração livre do BS em plasma de ratos foi de 34 ± 5%. O modelo de um compartimento descreveu adequadamente todos os perfis plasmáticos estudados. Após doses intravenosa (10 mg/kg) e oral (50 mg/kg), parâmetros farmacocinéticos como Vd (1,6 ± 0,5 e 2,2 ± 0,8 L/kg, respectivamente) e Cltot (1,4 ± 0,5 and 1,8 ± 0,5 L/h×kg, respectivamente) foram maiores para o BS complexado em relação à droga livre, embora os t1/2 (0,8 ± 0,1 h-1) mantiveram-se similares (p < 0,05). A biodisponibilidade oral do BS/ß-CD (~37%) foi aproximadamente o dobro daquela observada para a droga livre (~20%). O fator de penetração cerebral após doses intravenosa (2,8) e oral (2,5), assim como tempo de residência médio, foram maiores para a droga complexada, independente da via de administração avaliada. Conclusões: A farmacocinética do BS livre e complexado mostra uma rápida distribuição tecidual e uma rápida eliminação. A maior penetração cerebral do complexo em relação à droga livre mostra que a ß-CD é uma estrutura capaz de vetorizar, reter e modificar a liberação do BS nesse órgão, explicando os achados farmacodinâmicos prévios. / Purpose: This study aimed to investigate the pharmacokinetics and tissue distribution of benzaldehyde semicarbazone (BS) free and complexed with ß- cyclodextrin (BS/ß-CD) after administration to rodents at different doses by diverse routes. Methodology: BS plasma concentrations were determinated in Wistar rats after administration of 10 mg/kg i.v bolus and 50 and 100 mg/kg p.o. for the free drug and 10 mg/kg i.v. bolus and 50 mg/kg for the BS/ß-CD (n = 8/group), using a HPLCUV method specifically developed and validated. Individual plasma profiles obtained were evaluated by non-compartmental and compartmental approaches, using the software Scientist 2.0.1 (MicroMath®), analysis to determine the pharmacokinetic parameters. BS protein binding was determined by ultrafiltration at a concentration range of 1.0 a 60.0 µg/mL. BS tissue penetration after free or ß-CD-complexed drug administration was investigated in different tissues homogenates up to 5 h after i.v. bolus dosing of 10 mg/kg dose. Brain penetration of the free and complexed drug was also evaluated up to 4 h after administration of 50 mg/kg p.o. dose (3 animals/time point). Results and Discussion: BS free fraction in plasma was 34 ± 5%. The one-compartmental model described adequately the plasma profiles of all groups investigated. After i.v. (10 mg/kg) and p.o. (50 mg/kg) doses, pharmacokinetic parameters such as Vd (1.6 ± 0.5 e 2.2 ± 0.8 L/kg, respectively) and CLtot (1.4 ± 0.5 and 1.8 ± 0.5 L/h×kg, respectively) were higher for the BS/ß-CD than for the free drug, although the t1/2 (0.8 ± 0.1 h-1) remained the same (p < 0.05). The oral bioavailability of the BS/ß-CD (~ 37%) was approximately 2-fold of that observed for the free BS (~ 20%). The brain penetration factor after i.v. (2.8) and p.o. (2.5) doses, as well as the mean residence time, were higher after BS/ß-CD dosing than after free drug dosing, regardless of the route administrated. Conclusions: BS pharmacokinetics (free and complexed) showed a fast tissue distribution and elimination. The higher brain penetration of the drug after the administration of the complex reveals that the ß-CD may be a potential system to carrier, retain and change the delivery of BS in this organ, explaining the previous pharmacodynamic results.