氯硝西泮抗大鼠听源惊厥耐受性的受体学基础

以听源惊厥大鼠为模型，观察了给予氯硝西泮１ｗｋ及６ｗｋ后，其对听源惊厥大鼠的抗惊作用及抗惊耐受性，同时通过对大鼠脑组织ＧＡＢＡＡ受体的检测，对其抗惊作用耐受性机制进行了研究。结果显示：氯硝西泮对听源惊厥大鼠有明显的抗惊作用，但长期应用可产生耐受性，表现为惊厥等级的升高。模型大鼠的溶剂对照组较正常Ｗｉｓｔａｒ大鼠ＧＡＢＡＡ－受体的Ｂｍａｘ明显降低，给予氯硝西泮可明显增加Ｂｍａｘ；但长期给予则Ｂｍａｘ又降低。提示：氯硝西泮抗大鼠听源惊厥耐受性与ＧＡＢＡＡ－受体下调有关。     

苯妥英与丙戊酸抗癫痫个体化用药的血药浓度监测

我院对１０８例服用苯妥英钠和３３例服用丙戊酸钠的患者进行了血药浓度监测，结果提示癫痫病人对这两种药物的敏感性有很大的个体差异，每位病人的治疗剂量不能只赁经验用药，必须赁血浓数据个体化调用药。     

Fasting and ketogenic diet effects on audiogenic seizures susceptibility of magnesium deficient rats

Because fasting and ketogenic diets decrease seizure susceptibility in epileptics, their anticonvulsant effects were studied using sound-induced seizures in the magnesium-deficient rat. Fasting markedly depressed seizure incidence and severity but did not affect latency (sec to seizure onset). High-fat diet increased incidence of audiogenic seizures and seizure severity, and decreased latency. Gavage of medium chain triglyceride, beta-hydroxybutyrate or glucose did not affect seizure incidence, seizure severity or latency. Nonspecific excitability level was not associated with treatment nor with seizure incidence, severity or latency time.     

Influence of some beta-adrenoceptor antagonists on the anticonvulsant potency of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.     

左乙拉西坦对自发性癫痫大鼠大发作和小发作的作用(英文)

目的　鉴于左乙拉西坦在各种啮齿类动物上的抗癫痫作用不同 ,未见报告其在自发性癫痫大鼠上的作用 ,故研究之。方法　在大脑海马和皮质部位安置电极 ,观察腹腔注射单剂量左乙拉西坦对自发性癫痫大鼠脑电图的影响。结果　给左乙拉西坦(40 ,80和 16 0mg·kg- 1,ip)后 135～ 16 5min ,癫痫小发作的总持续时间分别下降到给药前水平的 (87±15 ) % ,(34± 7) %和 (39± 19) %。大发作的总持续时间下降到 (81± 2 8) % ,(6 5± 11) %和 (5 2± 7) %。大发作的出现频率下降到 (71± 2 9) % ,(5 4± 12 ) %和 (32± 15 ) %。结论　左乙拉西坦具有明显的对抗自发性癫痫大鼠的大发作和小发作的作用     

Influence of carbenoxolone on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice

Carbenoxolone, the succinyl ester of glycyrrhetinic acid, is an inhibitor of 11beta-hydroxy steroid dehydrogenase and gap junctional intercellular communication. It is currently used in clinical treatment of ulcer diseases. Systemic administration of carbenoxolone (1-40 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. Glycyrrhizin, an analogue of carbenoxolone inactive at the gap-junction level, was unable to affect audiogenic seizures at doses up to 30 mg/kg. In combination with conventional antiepileptic drugs, carbenoxolone, 0.5 mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. This effect was not observed after the combination of glycyrrhizin (10 mg/kg, i.p.) with some conventional antiepileptic drugs. The degree of potentiation induced by carbenoxolone was greater for diazepam, felbamate, gabapentin, phenobarbital and valproate, less for lamotrigine, phenytoin and carbamazepine. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with carbenoxolone was more favourable than the combination with glycyrrhizin or saline. Since carbenoxolone did not significantly influence the total and free plasma levels of diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital, valproate and carbamazepine, pharmacokinetic interactions are not likely. However, the possibility that carbenoxolone can modify the brain clearance of the anticonvulsant drugs studied may not be excluded. In addition, carbenoxolone did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, carbenoxolone showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably diazepam, felbamate, gabapentin, phenobarbital, and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Effects of chlordiazepoxide and of valproate on hyponeophagia in rats. Evidence for a mutual antagonism between their anxiolytic properties

The effects of chlordiazepoxide (0,2.5 and 7.5 mg/kg), of valproate (0,100 and 300 mg/kg), and of combinations of these drugs, on hyponeophagia in rats, were studied using a food preference test. Chlordiazepoxide alone reduced the latency for eating, and also enhanced the time of eating and the amount of familiar food eaten at the smaller dose, and of novel food eaten at the larger dose. Valproate alone reduced the latency of eating and enhanced time of eating and the amount of novel food eaten, especially at 300 mg/kg. However, valproate antagonised the effects of chlordiazepoxide on all behavioural measures. These findings are discussed in the context of the GABA hypothesis of the actions of benzodiazepines, with the conclusion that valproate has an atypical pharmacological profile amongst putative GABA agonists, and may have partial agonist activity at the proposed benzodiazepine/GABA receptor complex.     

Comparison of antiepileptic action of valproate and ethosuximide in adult and immature rats

The antiepileptic action of ethosuximide and valproate was studied in immature rats in the pentetrazole (PTZ) model. Valproate antagonized the effect of PTZ in rats of all ages, while ethosuximide was effective only in rats of 25 or more days of age: in 18 day old rats it modified the PTZ seizure pattern and was ineffective in younger animals or only slightly affected the PTZ seizure pattern. Similarly, the ECoG studies have shown that valproate antagonizes PTZ action at all ages, while ethosuximide only in mature rats.     

白芍总甙的抗惊厥作用

采用最大电休克发作（ＭＥＳ）法、士的宁惊厥法和戊血氮最小阈发作（ＭＥＴ）法，观察白芍总甙（ＴＧＰ）对动物惊厥的影响。实验结果表明，ＴＧＰ（２０～８０ｍｇ·ｋｇ－１·ｄ－１，ｉｐ和ｉｇ×３ｄ）呈剂量依赖性对抗小鼠的ＭＥＳ。ＴＧＰ（６０～１００ｍｇ·ｋｇ－１·ｄ－１，ｉｐ）能对抗士的宁引起的小鼠和大鼠的惊厥。ＴＧＰ（４０～８０ｍｓ·ｋｇ－１·ｄ－１，ｉｐ）对小鼠的ＭＥＴ无影响。ＴＧＰ（４０～８０ｍｇ·ｋｇ－１·ｄ－１，ｉｐ）对小鼠ＭＥＳ的作用高峰时间在０．５～１．５ｈ之间。     

Anticonvulsant effects of levetiracetam on audiogenic epileptiform siezures in Krushinsky-Molodkina rats

The new antiepileptic drug levetiracetam (LVT) at doses of 40 and 80 mg/kg exhibits a pronounced anticonvulsant effect, influencing all the parameters of audiogenic epileptiform seizures (AES) in Krushinsky-Molodkina (KM) rats. The latent period of the motor reaction was increased 3-15 times compared to control, and the intensity of single convulsive episodes was significantly decreased. Changes were also detected in the profile of the first stage of motor activity, and the "two-wave" reaction was observed in 50-80% of animals. The mechanism of LVT anticonvulsant action in KM rats is probably associated with an increase in the inhibitory and a decrease in the excitatory processes in the CNS.     

Effect of increments in the concentration of dopamine in the central nervous system on audiogenic seizures in DBA/2J mice

The effect on audiogenic seizures of drug-induced increments in biogenic amines in the brain was determined in DBA/2J mice. One group of mice was treated with L-dihydroxyphenylalanine (L-DOPA) which caused a large rise in levels of norepinephrine and dopamine in the central nervous system, but did not significantly alter the concentration of 5-hydroxytryptamine. This group of animals exhibited a dramatic reduction in the incidence of tonic extensor seizures. A second group of animals that had been pretreated with diethyldithiocarbamate, a dopamine-beta-hydroxylase inhibitor, was also given L-DOPA. In this group of mice, there was a highly significant rise in the concentration of dopamine in brain but no statistically-significant changes in levels of either norepinephrine or 5-hydroxytryptamine. These animals also had a dramatic decrease in the incidence of tonic extensor seizures. A third group of animals that received only diethyldithiocarbamate did not exhibit any statistically-significant changes in the incidence of seizure or in levels of biogenic amines. The drug-induced reduction in the incidence of seizure in the first two groups correlated with a large increase in levels of dopamine in brain. This reduction in seizures did not correlate with changes in levels of norepinephrine or 5-hydroxytryptamine in brain.     

石菖蒲醇提取物的抗惊厥作用

目的：研究石菖蒲醇提取物的抗惊厥作用。方法：采用最大电休克发作（ＭＥＳ）法,士的宁惊厥法和戊四氮最小阈发作（ＭＥＴ）法,观察石菖蒲醇提取物对动物惊厥的影响。结果;石菖蒲醇提取物能明显对抗大鼠,小鼠的最大电休克发作和小鼠的戊四氮最小阈发作及士的宁的惊厥的反应。结论;石菖蒲醇提取物具有明显的抗惊厥作用。     

Acute exposure to caffeine decreases the anticonvulsant action of ethosuximide, but not that of clonazepam, phenobarbital and valproate against pentetrazole-induced seizures in mice

This study examines the effect of acute administration of caffeine sodium benzoate (CAF) on the anticonvulsant action of four conventional antiepileptic drugs (AEDs: clonazepam - CZP, ethosuximide - ETS, phenobarbital - PB and valproate - VPA) against pentetrazole (PTZ)-induced clonic seizures in mice. The results indicate that CAF at a dose of 92.4 mg/kg significantly reduced the threshold for PTZ-induced clonic seizures in mice from 69.5 to 51.7 mg/kg (p<0.05), being ineffective at lower doses of 69.3 and 46.2 mg/kg. Moreover, CAF at doses of and 92.4 mg/kg attenuated the protective action of ETS against PTZ-induced seizures, by increasing its median effective dose (ED50) from 127.7 to 182.3 (p<0.05), and 198.3 mg/kg (p<0.01), respectively. In this case, no pharmacokinetic changes in total brain ETS concentrations after systemic ip administration of CAF (at 92.4 mg/kg) were observed, indicating a pharmacodynamic nature of interaction between ETS and CAF in the PTZ-test in mice. In contrast, CAF (at a dose of 92.4 mg/kg reducing the threshold for PTZ-induced seizures) combined with other AEDs (CZP, PB and VPA) did not affect their anticonvulsant action in the PTZ test in mice. Moreover, CAF (92.4 mg/kg) did not alter significantly total brain concentrations of the remaining AEDs (CZP, PB and VPA). The evaluation of potential acute adverse effects produced by AEDs in combination with CAF revealed that neither CAF (up to 92.4 mg/kg) administered alone nor combined with the studied drugs (at doses corresponding to their ED(50) values in the PTZ-test) affected motor performance of animals in the chimney test. In conclusion, the acute exposure to CAF may diminish the antiseizure protection offered by ETS in epileptic patients. Therefore, patients treated with ETS should avoid CAF.     

The withdrawal of antiepileptic drugs in patients with non-epileptic seizures: safety considerations

The majority of patients with psychogenic non-epileptic seizures (PNES) do not have epilepsy. There are a number of compelling reasons to take these patients off antiepileptic drugs (AEDs), including drug toxicity and teratogenicity, as well as possibly poorer outcome of PNES and increased risk of iatrogenic harm when patients present to emergency rooms on AEDs as emergencies. However, many patients with PNES who do not have epilepsy remain on AEDs postdiagnosis. Some studies do report patients taken off medication as an outcome measure, but with no assessment of the safety of withdrawal, or specification of the criteria for ‘excluding’ epilepsy. One study has assessed the safety of taking patients satisfying some simple criteria for the absence of an underlying epilepsy off AEDs, and has found the procedure to be safe, given appropriate postwithdrawal follow-up. Patients with PNES who do not have evidence of epilepsy should be referred to a centre with appropriate expertise in epilepsy diagnosis so that AEDs can be withdrawn in safe conditions.     

Anticonvulsant effects of 6-methoxy-1,2,3,4-tetrahydro-β-carboline on audiogenic and electroconvulsive seizures in mice

6-Methoxy-1,2,3,4,-tetrahydro-β-carboline (6-MeO-THBC) was tested for anticonvulsant properties against audiogenic seizures in DBA/2J and primed C57BL/6J mice (i.e., mice given a prior auditory exposure) and against electrovulsive seizures in DBA/2J mice. 6-MeO-THBC (100 mg/kg) was found to attenuate both types of behavioral seizures 2 hr after injection as compared to saline controls. In addition, 6-MeO-THBC increased whole brain serotonin and decreased whole brain 5-hydroxyindoleacetic acid 2 hr after injection. These results support previous reports which suggest a serotonergic involvement in behavioral seizures.     

丙戊酸钠对大鼠碳酸锂血清水平的影响

目的探讨丙戊酸钠对碳酸锂血清水平的影响。方法20只大鼠,♀♂各半,随机分成2组,每组各10只。研究组灌喂碳酸锂15 mg.d-15 d后,于d 6开始灌喂丙戊酸钠10 mg.d-1,2种药物共同灌喂3 wk;对照组仅喂碳酸锂15 mg.d-1。分别于d 5、12、19、26抽取尾血2 mL,用于测定碳酸锂血清水平。结果2组4次的碳酸锂血清水平分别是:研究组,(0.198±0.051)(、0.215±0.062)(、0.137±0.042)(、0.177±0.122)mmol.L-1,F=1.949,P=0.139;组内差异无显著性。对照组,(0.172±0.057)(、0.185±0.054)(、0.186±0.059)(、0.180±0.029)mmol.L-1,F=0.166,P=0.919;组内差异无显著性。研究组与对照组血清锂水平比较,仅第3次差异有统计学意义(P<0.05)。结论动物实验表明,丙戊酸钠对碳酸锂的血清水平几乎没有影响,不会引起碳酸锂水平的增高。     

The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures

Modification of the rate of acquisition of the kindled amygdaloid seizure by the convulsants pentylenetetrazol, bicuculline and strychnine was studied. Injections of saline, 25 mg/kg of pentylenetetrazol, 2 mg/kg of bicuculline or 1 mg/kg of strychnine were given 15 min prior to the daily electrical stimulation of the amygdala. The drug doses selected were capable of producing some behavioral and electrical epileptoid activity prior to stimulation without inducing generalized seizures. To determine whether pentylenetetrazol or bicuculline accelerated the rate of development of the kindled amygdaloid seizure or merely augmented the expression of each seizure, a crossover design was implemented. The crossover studies involved switching animals during the acquisition phase (between stimulations 3–6) from prestimulation saline to drug or drug to saline injections. It was found that pentylenetetrazol markedly augmented the expression of seizures during kindling development but the results of the crossover studies showed a less dramatic acceleration in the actual rate of the development of the fully generalized kindled amygdaloid seizure. The bicuculline-treated animals showed little augmentation in the expression of seizures during the kindling acquisition phase and in the actual rate of development of the kindled amygdaloid seizure. The strychnine treated animals showed no augmentation in expression of the seizures nor in the rate of development. The effects of prestimulation injections of bicuculline (1, 2 and 3 mg/kg) and strychnine (0.5, 1 and 2 mg/kg) on fully developed kindled amygdaloid seizures were also evaluated. Pretreatment with bicuculline minimally increased seizure afterdischarge duration at the highest dose. When fully kindled animals were pretreated with strychnine, a paradoxical decrease in afterdischarge length and an increase in severity (tonic hindlimb extension) was seen with the largest dose tested. This study emphasizes the potential importance of crossover studies in evaluating pharmacological manipulations of the rate of acquisition of the kindled seizure.     

Reproductive toxicity of sodium valproate in male rats

Objectives:

To assess the effects of sodium valproate on rat sperm morphology, sperm count, motility, and histopathological changes in testis.

Materials and Methods:

Male Wistar rats (12 week old) were treated with sodium valpraote and sacrificed at the end of 2^nd, 4^th, 5^th, 7^th, 10^th and 15^th week after the last exposure to sodium valproate. Epididymal sperm count, sperm motility, sperm morphology, and histopathology of testes were analyzed.

Results:

Sperm count and sperm motility were decreased significantly by sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. A histopathological study revealed that sodium valproate had caused sloughing of epithelial cells in testes.

Conclusion:

Sodium valproate causes reversible change in sperm motility, sperm count, morphology, and cytoarchitecture of testes.