Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

BACKGROUND: The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique. RESULTS: Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 µM) or gabapentin (1 and 10 µM), but was increased by administration of 100 µM gabapentin. This evoked excitation was increased further in low Mg²+ (0.8 mM) conditions, and this effect of low Mg²+ concentration was antagonized by 30 µM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-D-as-partate (NMDA) receptor blocker. The increased excitation in low Mg²+ conditions was also antagonized by carbamazepine (1,000 µM) and gabapentin (100 µM). CONCLUSION: Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg²+ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg²+ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.

Efficacy, Safety and Tolerability of Trioptal®d: (Oxcarbazepine) in Children and Adolescents with Newly Diagnosed Partial Seizures or Generalized Tonic-Clonic Seizures: Results of a 6 Months, Prospective, Open-Label, Multicentre, Non-Comparative, Observational Post-Marketing Surveillance Study.

Objective: The current study was designed to analyze the extended efficacy and safety of Trioptal® (Oxcarbazepine) in treatment of children and adolescents with newly diagnosed partial seizures or generalized tonicclonic seizures in Indian population. Methods: This was an open-label non-randomized multi-centric observational prospective study (PMS study) across 54 centers in India. Treatment with Trioptal® (Oxcarbazepine) was initiated with a clinically effective dose (8-10 mg/kg/day in children) given in two divided doses as per the prescribing information. The dose was increased depending on the clinical response of the patient. In children, if clinically indicated, the dose was increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose, to a maximum daily dose of 60 mg/kg/day. The efficacy of Trioptal® was assessed primarily by the percentage of seizure-free patients at 24 weeks. Secondary efficacy of the treatment was assessed through: reduction in seizure frequency at 24 weeks and the Global assessment of efficacy by the investigator at 24 weeks. Results: A total of 485 subjects were enrolled in the study. Majority of the subjects (52%) were stabilized at 8-15 mg/kg/day dose of Trioptal® and mean effective dose was 16.1 mg/kg/day (± 7.02). Approximately 70 % of the subjects were seizures free after 24 weeks of Trioptal® treatment and around 88% of the subjects reported the reduction in seizure of more than 50 %. The mean reduction in seizure frequency after 24 weeks of treatment was 82.3%. The overall efficacy with the Trioptal® treatment for 24 weeks was ‘good’ to ‘excellent’ in more than 97% of the subjects as per the assessment by the physician. A total of 59 adverse events were observed in 43 (8.9%) subjects. Headache was the most common adverse event being recorded in 8 subjects, followed by somnolence, nausea, vomiting, skin rash and weight gain. The overall tolerability of Trioptal® as per assessment by the patients was ‘good’ to ‘excellent’ in more than 98% of the subjects. Conclusion: Trioptal® (Oxcarbazepine) treatment is effective, safe and well tolerable in children and adolescents with newly diagnosed partial seizures or generalized tonic-clonic seizures.

Determination of carbamazepine in pharmaceutical formulations / Determinação de carbamazepina em formulações farmacêuticas

The aim of this study was to evaluate the quality of five different solid formulations of carbamazepine. The reference formulation was Tegretol® 200.00 mg (Novartis) and the others were: generic formulation of carbamazepine 200.00 mg (National Industry), similar formulation of carbamazepine 200.00 mg (National Industry), and two formulations of carbamazepine 200.00 mg acquired from two different compounding pharmacies. The latter consisted of capsules obtained in Natal, the capital city of the Brazilian State of Rio Grande do Norte. The quality of samples was evaluated through physical and physical-chemical tests, including: weight, diameter, thickness, content, dissolution, disintegration, hardness, friability and moisture. The results of friability analysis showed that all formulations met Brazilian and United States Pharmacopeia (USP) specifications. In spite of having a higher hardness compared to the reference, the generic formulation had a lower disintegration time. This could be associated to the presence of crospovidone in its formulation. Results of this study showed that all formulations had dissolutions which were in accordance with Brazilian Pharmacopoeia specifications, and quality control tests. An exception was found for the similar formulation, which had a hardness parameter that exceeded the USP standard. However, this difference was not significant given the similar formulation's satisfactory disintegration time.

O objetivo desse trabalho foi avaliar a qualidade de cinco formulações de carbamazepina na dosagem de 200,00 mg: medicamento referência Tegretol® (Novartis), medicamento genérico (indústria nacional), medicamento similar (indústria nacional) e cápsulas do mesmo medicamento obtidas de duas farmácias de manipulação da cidade do Natal, RN. Os ensaios realizados foram: peso médio, diâmetro, espessura, teor, dissolução, desintegração, dureza, friabilidade e umidade. Foi observado que nenhuma das amostras analisadas apresentou friabilidade superior ao limite máximo determinado pela Farmacopéia Americana (1,5 por cento). O medicamento genérico, apesar de apresentar dureza superior em relação ao medicamento de referência, desintegrou em menor tempo, o que pode estar relacionado à crospovidona presente na formulação. As amostras analisadas atenderam às especificações da Farmacopéia Brasileira no que diz respeito à dissolução. Em geral, os resultados das amostras A, B, C, D e E foram considerados satisfatórios uma vez que atenderam as especificações farmacopéicas. Embora a apresentação similar não tenha atendido ao padrão USP no que diz respeito à dureza, esse dado não se mostrou significativo, uma vez que o tempo de desintegração foi satisfatório.

Carbamazepine does not alter the intrinsic cardiac function in rats with epilepsy / Carbamazepina não altera o funcionamento cardíaco intrínseco em ratos com epilepsia

Among the causes for sudden unexpected death (SUDEP) in epilepsy, the effects of antiepileptic drugs on the heart have been poorly explored. Based on this, the aim of our study was to evaluate the heart rate (in vivo and isolated ex vivo) and ventricular pressure (isolated ex vivo) of rats with and without epilepsy treated with carbamazepine. Four groups of adult, male Wistar rats (200-250 g) were studied: [A] control rats (n=8), received neither pilocarpine nor carbamazepine [B] carbamazepine-treated rats (n=8), received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks; [C] rats with epilepsy that received just saline solution (n=8); [D] rats with epilepsy that received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks (n=8). Our results showed significant increase in heart rate in animals with epilepsy (with and without the use of carbamazepine) when compared to the control groups in vivo. In contrast, we did not find differences during isolated ex vivo experiments comparing animals with and without epilepsy and despite the use of carbamazepine. Our results suggest that, in isolation, carbamazepine may not be a potential risk factor for sudden unexpected death in epilepsy.

Entre as causas de morte súbita em epilepsia (SUDEPE), os efeitos das drogas antiepilépticas no coração têm sido pobremente explorados. Desta forma, o objetivo deste estudo foi avaliar a frequência cardíaca (in vivo e de forma isolada ex vivo) e a pressão ventricular (de forma isolada ex vivo) de ratos com e sem epilepsia tratados com carbamazepina. Quatro grupos de ratos Wistar machos adultos (peso 200 a 250 g) foram estudados: [A] ratos controle (n=8), não receberam pilocarpina ou carbamazepina; [B] ratos tratados com carbamazepina (n=8), receberam dose diária de carbamazepina de 120 mg/kg intraperitoneal, durante duas semanas (n=8); [C] ratos com epilepsia que receberam solução salina; [D] ratos com epilepsia que receberam dose diária de carbamazepina de 120 mg/kg intraperitoneal durante duas semanas. Nossos resultados evidenciaram uma diferença estatisticamente significativa na média da freqüência cardíaca in vivo entre os animais com epilepsia (com e sem o uso de carbamazepina) quando comparados aos grupos controles in vivo. Em contraste, não observamos diferenças estatísticas nos experimentos ex vivo quando comparados os animais com ou sem epilepsia, a despeito do uso da carbamazepina. Nossos resultados sugerem que, de forma isolada, a carbamazepina pode não ser um fator de risco potencial para a ocorrência de morte súbita em epilepsia.

Effects of sodium valproate and carbamazepine on food competition aggression in pigeons

Valproate and carbamazepine (CAR) have been proposed as adjunct alternatives for the control of aggression in psychiatric patients, although no definite conclusions have been reached. We examined the effects of these drugs on food competition offensive aggression and other behaviors in high- and low-aggression food-restricted pigeons. These were divided into pairs containing previously ranked high-aggression (N = 10 pairs) and low-aggression females (N = 10 pairs). In Experiment 1, a pigeon in each pair of high- and low-aggression subjects was treated daily with an oral dose of sodium valproate (50 mg kg-1 mL saline-1) for 15 days. The other animal received the vehicle. On days 1, 7, and 15, food competition trials (10 min) were performed 60 min after treatment. In Experiment 2, one pigeon in each pair was treated daily with an oral dose of CAR (20 mg kg-1 mL saline-1) for 15 days. Each pair was submitted to a food competition trial on days 1, 7, and 15 of treatment. Valproate (15 days of treatment) selectively decreased the time spent in offensive aggression (control: 102.7 ± 9.3 vs valproate: 32.7 ± 9.2 s; P < 0.001, ANOVA-2-TAU) of high-aggression pigeons. This was also the case for 7 and 15 days of CAR treatment (control: 131.5 ± 8.9 vs CAR: 60.4 ± 5.3, P < 0.01, and control: 122.7 ± 7.1 vs CAR: 39.1 ± 5.2; P < 0.001, ANOVA-2-TAU, respectively). Thus, the two anticonvulsive drugs have a similar effect on food competition aggression in pigeons.

Erythrocyte phosphoglucomutase activity of bipolar I patients currently using lithium or carbamazepine

Lithium has been used for the last five decades to treat bipolar disorder, but the molecular basis of its therapeutic effect is unknown. Phosphoglucomutase is a key enzyme in the metabolism of glycogen. In yeast, rabbit and human HEK293 cells, it is inhibited by lithium in the therapeutic concentration range. We measured the phosphoglucomutase activity in erythrocytes and the inhibitor constant for lithium in a population of healthy subjects and compared them to those of bipolar patients treated with lithium or carbamazepine. The specific activity of phosphoglucomutase measured in vitro in erythrocytes from control subjects presented a normal distribution, with the difference between the lowest and the highest activity being approximately 2-fold (0.53-1.10 nmol mg Hb-1 min-1). Comparison of phosphoglucomutase activity in untreated bipolar patients and control subjects showed no significant difference, whereas comparison between bipolar patients treated with carbamazepine or lithium revealed significantly lower mean values in patients treated with carbamazepine (747.3 ± 27.6 vs 879.5 ± 35.9 pmol mg Hb-1 min-1, respectively). When we studied the concentration of lithium needed to inhibit phosphoglucomutase activity by 50 percent, a bimodal distribution among the population tested was obtained. The concentration of LiCl needed to inhibit phosphoglucomutase activity by 50 percent was 0.35 to 1.8 mM in one group of subjects and in the other it was 3 to 4 mM. These results suggest that phosphoglucomutase activity may be significant in patients with bipolar disorder treated with lithium and carbamazepine.

Effect of escitalopram and venlafaxine on seizure score and lipid peroxidation in mice receiving carbamazepine antiepileptic therapy

The frequent co-existence of depression in epileptic patients raises the issue of simultaneous use of antidepressants along with anti-epileptic drugs in management of such cases. However, it is necessary to evaluate the safety of these antiepileptic/antidepressant drug combinations. The present study investigates the effect of either antidepressant; escitalopram [selective serotonin reuptake inhibitor, SSRI] or venlafaxine [serotonin/noradrenaline reuptake inhibitor, SNRI], administered alone or in combination, with the conventional antiepileptic drug carbamazepine on chemo-convulsions induced by picrotoxin. In addition, the effect of both antidepressants on lipid peroxidation, as an assumable cause of neuro-degenration in epilepsy, was studied in a model of chronic restraint in mice. The results show enhancement of seizure severity with significant increase in lipid peroxidation upon escitalopram treatment whether alone or in combination with carbamzepine. On the other hand, venlafaxine, administered alone or in combination with carbamazepine, provided significant protection against picrotoxin-induced convulsions as well as lipid peroxidation favoring its application in management of epilepsy-depression co-morbidities

Desenvolvimento pré-embrionário em ratas tratadas com oxcarbazepina nos quatro primeiros dias após a inseminaçäo / Pre-embryo development in rats treated with oxcarbazepine in the first four days after insemination

A oxcarbazepina é uma droga antiepiléptica de alta eficácia e poucos efeitos colaterais, mas pouco estudada quanto a seus efeitos durante a gestaçäo humana e animal. OBJETIVO: Verificar se a administraçäo de oxcarbazepine em ratas, nos quatro primeiros dias após a inseminaçäo, altera a viabilidade ou o desenvolvimento do pré-embriäo. MÉTODOS: Ratas Wistar foram tratadas com 20 ou 200 mg de oxcarbazepina/ Kg de peso corporal, via gástrica, nos dias 1, 2, 3, ou 4 a partir da inseminaçäo ou, consecutivamente, do 1º ao 4º. Os pré-embriões foram coletados no quinto dia, visando verificar a quantidade e o desenvolvimento até a fase de blastocisto expandido. O peso corporal materno e sinais como pelos eriçados e alteraçäo de atividade locomotora foram anotados para verificar indícios de toxicidade materna. Número de corpos lúteos e peso de ovários foram anotados com vistas à capacidade reprodutiva do animal. RESULTADOS: Näo ocorreram perdas de pesos corporais maternos e nenhuma alteraçäo física indicativa de desconforto para as ratas. Peso de ovários e número de corpos lúteos näo diferiram entre tratados e controles. O número médio de pré-embrioes por mäes, o índice de perdas embrionárias, a proporçäo de blastocistos expandidos com relaçäo ao total de pré-embriões e a média de blastocistos expandidos/mäe, näo diferiram entre tratados e controles. CONCLUSÇO: A oxcarbazepina administrada em ratas, seguindo o esquema terapêutico mencionado, näo apresentou efeito tóxico sobre a mäe e näo alterou o desenvolvimento do pré-embriäo

Possible analgesic effect of vigabrin in animal experimental chronic neuropathic pain

Since anticonvulsants have been used for treating neuralgias, an interest has arisen to experimentally test vigabatrin for its gabaergic mechanism of action. For this, 41 Wistar rats were used, and in 25 of them a constractive sciatic neuropathy was induced (Bennet & Xie model). For testing pain symptoms, spontaneous (Scratching) and evoked behaviors to noxious (46 degrees Celsius) and non-noxious (40 degrees Celsius) thermal stimuli were quatified. Moreover, a comparative pharmacological study of vigabatrin with other analgesic anticonvulsant drugs was also performed. The results showed a possible dose-dependent analgesic effect of vigabatrin (gamma-vinyl-GABA) on experimental neuropathic pain, as shown vy the significant (p<0.05) decreasing effect of vigabatrin on scratching and by its significant (p>0.05) increasing effect on the latency of the right hindpaw withdrawal of the animals to noxious thermal stimulus. This was corroborated by similar findings with analgesic anticonvulsants (carbamazepine, phenytoin and valproic acid). This possible and not yet described analgesic effect of vigabatrin seems not to be opioid mediated.

Tratamento farmacológico da neuralgia trigeminal / Pharmacological management of trigeminal

Os autores apresentam revisäo de literatura sobre o tratamento farmacológico da neuralgia trigeminal

Comparative study of carbamazepine by different manufacturs

To investigate the effectiveness of the national carbamazepine as compared to the imported carbamazepine and to explore certain characteristics of epileptic patients in the two groups. Two groups of epileptic patients were selected, one of the them was receiving the national carbamazepine [100 patents] and the other was receiving the imported carbamazepine [100 patients]. The first part of the study was concerned with comparing the two groups of patients regarding their marital status, education, income level, and severity of the convulsive attacks before treatment. The second part was concerned with studding the effectiveness of the national carbamazepine as compared to the imported carbamazepine. The imported group were all asked about their belief of the effectiveness of the imported carbamazepine. The imported carbamazepine groups as compared to the national carbamazepine groups was more likely to be married and highly educated, and they belonged to the high income group. Severity of the epileptic attacks was also related to the type of treatment. All these associations were not significant at the 0.05 [P>0.05]. Eighty three percent of the imported group believed that the imported carbamazepine is more effective than the national carbamazepine. Out of the 29 patients of the imported carbamazepine group who switched from imported carbamazepine to national carbamazepine, only one patient developed convulsive attacks. This case was not followed up to be sure that attack was an epileptic one. The characteristics of the patients and severity of the attacks are not significantly related to the type of treatment. The belief of certain epileptic patients that the important carbamazepine is more effective than national carbamazepine was defected completely. The effectiveness of the two preparations was almost the same. Special emphasis should be given to the education of patients of the effectiveness of our carbamazepine. Research is needed in this field

CSF and plasma amino acid levels in epilepsy and effects of antiepileptics on those levels

The CSF and plasma amino acid profile and the interplay between excitatory and inhibitory amino acids was studied in fifty-four Egyptian epileptic patients before and six months after initiation of drug therapy. Patients were classified into three groups according to the type of seizure [petit mal group n = 22, myoclonic group n = 9 and tonic-clonic group n = 23 patients]. The first two groups of patients were treated with sodium valproate, while the third group received carbamazepine. A significantly low mean gamma amino butyric acid [GABA] level was especially relevant to the petit mal group, while a significantly low mean glycine and taurine levels were especially relevant to the tonic-clonic group. On the other hand, a significantly higher aspartic acid level was especially relevant to the myoclonic group. Following treatment and seizure control, there was a significant increase in the inhibitory amino acid glycine and GABA and decrease in excitatory amino acid glutamic acid in the different epileptic groups whatever the drug used. Taurine was significantly increased in the tonic-clonic group and significantly decreased in the myoclonic group following seizure control. Also, a significant decrease in sulfur containing amino acids, branched chain amino acids together with histidine and arginine mean levels were found following drug therapy in the different groups. There is a disturbed balance between excitatory/inhibitory acid systems in epileptic patients. Different epileptic groups manifest with a special amino acid profile which may be of value in distinguishing between the three studied types of epilepsy. The mechanism of action of antiepileptic drugs aimed at regaining the balance between inhibitory/excitatory amino acids and impose a final common pathway in seizure control. The amino acid taurine is rather considered a neuromodulator than an inhibitory neurotransmitter

Mecanismo de ação das drogas antiepilépticas / Mecanisms of action of the antiepileptic drugs

A Epilepsia é um sintoma ou uma síndrome com diferentes tipos de crises, fisiopatogenia diversificada, múltiplas etiologias e no seu tratamento, contamos com fármacos de comprovada eficácia terapêutica. O propósito do nosso trabalho é uma revisão e atualização sobre os diferentes mecanismos de ação desses compostos antiepilépticos

Aspirin and anticonvulsant interaction.

Aspirin (360 mg/kg, po) per se had anticonvulsant activity in MES model. No effect was observed at lower doses and in other models. Aspirin 216 mg/kg, po (a subanticonvulsant dose) protected animals, receiving subanticonvulsant doses of phenytoin, phenobarbitone and carbamazepine against MES.

La esquizofrenia resistente: ilustración mediante 3 casos clínicos del uso de un algoritmo para la elección de medicamentos / Resistant schizophrenia: 3 clinical cases showing the use of an algorithm for drug selection

En este trabajo se analiza el tratamiento de pacientes con esquizofreniaresistente al uso de neurolépticos clásicos, y se sugiere el uso de un árbol de decisión que, consiste en la identificación de síntomas blanco , que guíen la selección de alternativas terapéuticas, que aumenten o potencien el uso de los neurolépticos. Se revisa la literatura sobre el uso de litio, carbamazepina y clozapina en esquizofrenia y se ilustra el uso de estos medicamentos con un caso clínico

Involvement of adenosine in postictal events in rats given electroshock.

The effect of a selective adenosine antagonist, 8-cyclopentyl 1,3-dimethylxanthine (8-CPT) was used to examine involvement of adenosine in ictal and postictal events in rats subjected to maximal electroshock (MES). MES induces the ictal event of hindlimb tonic extension (HLTE) followed by postictal depression (PID). 8-CPT 10 mg/kg, ip produced maximal significant reduction of PID without affecting HLTE, further confirming involvement of adenosine in PID. Carbamazepine and sodium valproate were studied independently and were coadministered with 8-CPT to determine if their anticonvulsant activity was modulated by adenosine and if they altered PID. 8-CPT did not antagonize the seizure protection afforded by CBZ or SV. CBZ significantly reduced postictal events whereas SV had no significant effect. These observations further confirm a role for adenosine in postictal phenomena.