Effects of some anti-epileptic, neuroleptic and gabaminergic drugs on convulsions induced by D,L-allylglycine.

The antagonism of various seizure and time-related components of the convulsions resulting after IV injection of D,L-allylglycine into male Wistar rats were assessed in a standard test procedure. Trimethadione and ethosuximide did not antagonize the seizure components, whereas clonazepam, phenobarbital, diphenylhydantoin, primidone, valproate sodium, aminoxyacetic acid, etomidate, acetazolamide, flunarizine, pipamperone and baclofen did. The allylglycine test may thus represent a relatively specific method of differentiating between drugs effective against partial or generalized convulsive seizures from those effective against absence seizures. The neuroleptics haloperidol and pimozide were completely inactive in contrast to their reported antagonism of bicuculine seizures. The spectra of the active substances are discussed with respect to Principal Component and Cluster Analysis. Noteworthy are the similarities between baclofen and etomidate; between aminoxyacetic acid, phenobarbital and valproate sodium; and between diphenylhydantoin and flunarizine.     

儿童抗癫痫药物的合理应用

<正> 小儿癫痫发病率高,是导致儿童智力残疾的病因之一。抗癫痫药物是最常应用的药物。由于小儿处于生长发育阶段,各年龄段体内的生理生化过程有所不同,因此,同一药物在小儿体内的吸收、分布、代谢及排泄过程不仅与成人不同,而且在小儿各年龄阶段也有所不同。这是因为儿童由于体格和器官功能等各方面都处于不断发育时期,他们新陈代谢旺盛,循环时间较短,肝肾功能不成熟,药物排泄较快而且药物引起的不良反应也比成人明显增多。如果按照常规方法用药,往往达不到预期的治疗效果,还会引     

新型抗癫药物的治疗安全性

新型抗癫药物对皮肤结缔组织、心血管系统、消化系统、血液系统、神经系统、内分泌和代谢等多系统均可产生药物不良反应,甚至可能影响认知功能,致畸,加重癫症状。本文对新型抗癫药物的不良反应进行综述。     

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.     

盐酸氟桂利嗪注射液人体药动学研究

目的:建立测定人血清中盐酸氟桂利嗪浓度的液相和串联质谱(LC-MS-MS)定量方法,考察健康志愿者单剂量和多剂量静脉滴注盐酸氟桂利嗪的药动学特征。方法:血清样品经正己烷-异丙醇萃取后,以水(0．01 mol·L-1醋酸铵,醋酸调pH值3．5)-甲醇(25:75)为流动相,经C18柱分离,采用离子源为ESI源的LC-MS-MS测定样品。用上述方法研究了32例健康志愿者单剂量以及多剂量静脉滴注盐酸氟桂利嗪的血药浓度-时间过程,并用DAS 2．0软件计算药动学参数。结果:血浆中样品线性关系较好(r=0．999 9),氟桂利嗪的提取回收率均>90％,定量下限为0．5μg·L-1,批内及批间精密度<10％。单剂量静滴盐酸氟桂利嗪2．5,10,15 mg后估算的Tmax分别为(1．16±0．19),(1．22±0．09)和(1．18±0．12)h,t1/2分别为(7．37±3．26),(7．53±4．32)和(6．78±1．23)h,Cmax分别为(19．04±5．13),(95．62±20．27)和(142．08±37．57)μg·L-1,AUC0-t分别为(63．87±14．09),(320．46±77．50)和(518．48±129．13)μg·h·L-1。多剂量静滴盐酸氟桂利嗪10 mg后估算的t1／2为(7．81±1．68)h,Cav为(16．42±4.44)μg·L-1,DF为(5．36±0．98),AUCss,0-t为(418．81±113．16)μg·h·L-1。结论:盐酸氟桂利嗪注射液人体单剂量给药后呈线性药动学特征,多剂量给药后体内无蓄积。     

抗癫痫药物不良反应分析

目的：分析抗癫痫药物所致不良反应,提高对其不良反应的认识。方法：对255例抗癫痫药物所致不良反应报道进行分析,结果：10种抗癫痫药物的不良反应涉及神经、心血管、皮肤、血液、消化等器官,严重者可危及生命。结论：临床在应用抗癫痫药物时,应高度关注其不良反应的严重危害。     

Statistical methods for examining genetic influences of resistance to anti-epileptic drugs

It is generally accepted that genetics may be an important factor in explaining the variation between patients’ responses to certain drugs. However, identification and confirmation of the responsible genetic variants is proving to be a challenge in many cases. A number of difficulties that may be encountered in pursuit of these variants, such as nonreplication of a true effect, population structure and selection bias, can be mitigated or at least reduced by appropriate statistical methodology. Another major statistical challenge facing pharmacogenetic studies is the detection of possible small polygenic effects using large volumes of genetic data, while controlling the number of false-positive signals. Here, we review statistical design and analysis options available for investigations of genetic resistance to anti-epileptic drugs.     

Effect of common anti-epileptic drugs on cognition in schoolchildren with epilepsy

This study was conducted to observe the effect of some commonly used anti-epileptic drugs (AEDs), on cognition, in 118 school going children with epilepsy, in an age range of 9-12 yrs., (Mean 10.4 +/- 1.7 yrs.). For comparison, 28 healthy, age and sex matched schoolchildren served as controls. After a clinical, electrophysiological and radiological evaluation, the cognitive functions were assessed in both groups, using a modified Wechsler's Intelligence Scale. It was observed that cognition was impaired in only 2.5% of children with epilepsy, there being no relationship between cognitive performance and the type of AED used. It is concluded that cognitive functions are impaired in only a limited number of children with epilepsy and effect of phenobarbitone and phenytoin on cognitive functions is comparable to carbamazepine and sodium valproate, particularly when demand of task is not very high.     

Intra-arterial injection of Mesobuthus tamulus venom elicits cardiorespiratory reflexes involving perivascular afferents.

Role of perivascular afferents for the cardiorespiratory alterations produced by Mesobuthus tamulus (BT) envenomation was examined in urethane-anaesthetized male rats. Blood pressure (BP), respiratory rate (RR) and heart rate (HR) were recorded after injecting BT venom/saline in the distal end of femoral artery for 60 min. In addition, paw oedema was also determined. Injection of venom produced an immediate (within 2 s) increase in RR followed by a decrease and finally a sustained increase up to 60 min. BP was increased (within 10 s) by 30-50%, which gradually declined but remained above the initial level up to 60 min. The bradycardiac response was late to occur (after 50 s) and the peak response was seen between 10 and 50 min, which remained at that level. There was oedema in the ipsilateral hind paw (venom injected side) as compared to contralateral side and saline control group. The oedema and cardiorespiratory changes were maximal at 1.0 mg/kg of venom. Pretreatment with indomethacin significantly attenuated the venom-induced responses and also blocked the paw oedema. Present experiments reveal that BT venom in a segment of an artery produces oedema by involving prostaglandins to sensitize the nociceptors present in perivascular tissues to evoke the cardiorespiratory reflexes.     

Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice.

Melatonin (50 mg/kg; 60 min before the test) significantly raised the electroconvulsive threshold in mice. The protective action of melatonin (50 mg/kg) in the electroconvulsive threshold test was reversed by aminophylline, picrotoxin and bicuculline. Melatonin at the subconvulsive dose of 25 mg/kg potentiated the anticonvulsive activity of carbamazepine and phenobarbital (ED50 values were significantly decreased from 12.1 to 8.3 and from 18.9 to 11.8 mg/kg, respectively). No potentiation was observed in the case of valproate and diphenylhydantoin (their ED50s were changed from 253 to 249 and from 10.3 to 9.7 mg/kg, respectively). Melatonin did not influence the plasma or brain levels of anti-epileptics studied, so a pharmacokinetic interaction is not probable. Melatonin (25 mg/kg) alone and its combinations with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, were devoid of significant motor adverse effects, but caused strong long-term memory deficit. Consequently, it does not seem to be a good candidate for the treatment of epilepsy.     

The use of drug level measurements in adult patients receiving theophylline, anti-epileptic drugs and amikacin.

This prospective study was conducted to determine how frequently measurement of drug levels was used in the management of adult patients receiving theophylline, phenytoin, phenobarbitone, carbamazepine or aminoglycosides in a large hospital. Fifty consecutive outpatients with asthma and 40 with epilepsy were interviewed and their records reviewed to determine which drugs had been prescribed and whether a level of the appropriate drug had been measured in the previous six months. Also, the records of 40 in-patients who were currently receiving amikacin were studied to determine whether serum levels had been measured at any stage during therapy with this drug. Serum theophylline levels were measured in only four (eight pc) patients who were taking this drug and were below the target range in two patients. Serum levels had been measured in 21 (52.5 pc) of 40 patients who were receiving 45 anti-epileptic drugs and were within the target in only nine. Serum amikacin levels were measured in 15 (37.5 pc) patients; blood had been taken for both peak and trough levels in 10 patients and found to exceed the target range in two patients. This study revealed that measurement of serum concentrations of theophylline, anti-epileptic drugs and amikacin was underutilised in the management of adult patients receiving these drugs at this hospital.     

Acetylcodeine, an impurity of illicitly manufactured heroin, elicits convulsions, antinociception, and locomotor stimulation in mice.

Acetylcodeine is one of the major impurities present in illicitly manufactured heroin (diacetylmorphine). Data on its pharmacology and toxicology are limited and its ability to alter the toxic effects of diacetylmorphine is not known. The first objective of the present study was to compare the acute pharmacological and toxicological effects of acetylcodeine to those of codeine and diacetylmorphine in mice by assessing nociception in the tail-flick test, locomotor stimulation, and convulsive behavior. The second goal of this study was to determine whether acetylcodeine would alter the convulsant effects of diacetylmorphine. The antinociceptive potencies of acetylcodeine and codeine were similar, as reflected by their ED50 (95% confidence limits) values of 35 (29-44) and 51 (40-65) micromol/kg, respectively. Acetylcodeine was somewhat less potent than codeine in stimulating locomotor behavior, with ED50 values of 28 (22-37) and 12 (6-24) micromol/kg, respectively. Diacetylmorphine was considerably more potent than the other two drugs, producing antinociception and locomotor stimulation at ED50 values of 2.4 (1.4-4.1) and 0.65 (0.36-1.2) micromol/kg, respectively. On the other hand, the convulsant effects of acetylcodeine (ED50=138 (121-157) micromol/kg) and diacetylmorphine (ED50=115 (81-163) micromol/kg) were similar in potency and both were more potent than codeine (ED50=231 (188-283) micromol/kg). Finally, a subthreshold dose of acetylcodeine (72 micromol/kg) decreased the convulsant ED50 dose of diacetylmorphine to 40 (32-49). These findings suggest that the convulsant effects of acetylcodeine are more potent than predicted by its effects on locomotor activity and antinociception. The observation that acetylcodeine potentiated the convulsant effects of diacetylmorphine suggests a mechanism for some of the heroin-related deaths reported in human addicts.