抗癫痫药物血药浓度检测的临床分析

目的通过对临床常用一线抗癫痫药物的血药浓度检测结果进行分析,为临床个体化给药治疗提供参考依据,确保用药安全。方法选择2011年1月至2012年12月新乡医学院第三附属医院药剂科收治的癫痫患者350例,根据患者的自愿原则分为卡马西平组（110例）、苯妥英钠组（90例）、苯巴比妥组（80例）和丙戊酸钠组（70例）。采用高效液相色谱法测定卡马西平、苯妥英钠、苯巴比妥、丙戊酸钠4种抗癫痫药物在各组患者体内的血药浓度,并对结果进行分析评价。结果不同年龄与血药浓度差异有统计学意义（P〈0．01）。结论对抗癫痫药物的血药浓度进行检测,有利于临床医师为患者设计个体化给药方案,保证用药安全,减少药物不良反应的发生。     

638例次抗癫痫药血清浓度监测结果及其与临床疗效关联性分析

目的:为临床抗癫痫药物(AEDs)的合理使用提供科学参考。方法:对采用荧光偏振免疫(FPIA)法对丙戊酸钠、卡马西平、苯妥英钠、苯巴比妥进行血清浓度监测结果进行回顾性统计分析。结果:共监测638例次,359例次(56.27%)血药浓度位于治疗窗内,202例次(31.66%)低于治疗窗,70例次(10.97%)高于治疗窗,7例次(1.10%)未检出血清浓度;各AEDs血清浓度位于治疗窗的比例分别为卡马西平78.65%、苯巴比妥60.00%、丙戊酸钠57.48%、苯妥英钠23.08%,其中卡马西平、丙戊酸钠、苯妥英钠血清浓度位于治疗窗内癫痫治疗有效率分别为72.86%、90.57%、94.44%,明显高于其他浓度范围(χ2卡马西平=6.324,P卡马西平=0.012;χ2丙戊酸钠=122.782,P丙戊酸钠=0.000;χ2苯妥英钠=19.584,P苯妥英钠=0.000),而苯巴比妥在各浓度范围有效率差异无统计学意义(χ2=3.403,P=0.065);53例次联合用药中,12例次血清浓度在治疗窗内,占联合用药例次的22.64%。结论:对癫痫患者进行血清浓度监测,实施个体化给药,对促进抗癫痫药物安全、有效、合理使用具有重要意义。     

对长期服用含西药的中成药的癫痫患者血药浓度监测

目的分析本院癫痫患者因长期服用外院自制中成药导致中枢性神经系统反应的病例。方法用荧光偏振免疫法,测定患者丙戊酸、卡马西平、苯巴比妥、苯妥英钠的血药浓度。结果丙戊酸、卡马西平、苯巴比妥、苯妥英钠血药浓度分别为38.09,0.34,0.18,0.65μg·mL-1。每单一成分均低于最低有效血药浓度;但4种药合并使用,可产生大协同作用。结论尽可能减少合并用药品种,广泛开展治疗药物监测。     

抗癫痫药的“一线主力”

治癫痫,药物是重要手段,抗癫痫药如苯妥英钠、苯巴比妥、卡马西平、丙戊酸钠等"选手"很多,能力也有大有小,临床上它们通常还有"主力"和"替补"之分。今天我们要介绍的,就是"主力"阵容的两大明星——卡马西平和丙戊酸钠。     

托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫的效果观察

目的分析托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫效果。方法选取我院在2014年2月至2016年2月期间收治的150例脑炎继发癫痫患者为本次研究对象,并根据用药的不同分成3组,托吡酯组、卡马西平组以及丙戊酸钠组,每组患者各50例。托吡酯组给予托吡酯药物的口服治疗、卡马西平组给予卡马西平药物的口服治疗、丙戊酸钠组给予丙戊酸钠药物的口服治疗。分析三组患者的治疗效果以及不良反应发生情况,并进行对比。结果托吡酯组的有效率为82%;卡马西平组有效率为78%;戊酸钠组有效率为80%,三组患者的总有效率差异不显著,无统计学意义(P>0.05);托吡酯组、卡马西平组以及丙戊酸钠组患者的不良反应发生率分别为6.0%、20%、12%,卡马西平组不良反应发生率明显高于丙戊酸钠组和托吡酯组,丙戊酸钠组患者的不良反应发生率明显高于托吡酯组,三组差异对比有统计学意义(P<0.05)。结论对于脑炎继发癫痫患者的治疗而言,采用托吡酯、卡马西平以及丙戊酸钠均可达到理想的临床疗效,但卡马西平药物以及丙戊酸钠药物的不良反应发生率较高,托吡酯药物药物不良反应发生率较低,可以有效提升患者的安全性,应用价值较高。     

4种抗癫痫药血药浓度测定及用药体会

癫痫是一种常见神经症状,且反复发作.故为一种长期性疾病,患者需长期服用抗癫痫药物.较常用的抗癫痫药有卡马西平、丙戊酸、苯巴比妥、苯妥英钠.     

丙戊酸钠与苯妥英钠或卡马西平相互作用的血浓度观察

本文报告丙戊酸钠和苯妥英钠或卡马西平合用治疗各型癫痫９０例，丙戊酸钠使苯妥英钠和卡马西平血浓度下降；苯妥英钠和卡马西平是强有力的肝酶诱导剂，使丙戊酸钠血浓度降低，作者认为，抗癫痫药之间的相互作用错综复杂，临床上最好选择单一用药，昼避免联合用药。     

1例症状性癫痫患者使用卡马西平控制癫痫发作不良的分析及体会

目的 探讨1例症状性癫痫患者使用卡马西平和丙戊酸控制癫痫发作不良的治疗策略。方法 查阅国内外文献及药品说明书,分析1例症状性癫痫患者使用卡马西平和丙戊酸控制癫痫发作不良的治疗策略,探究抗癫痫方案的合理性。结果和讨论 卡马西平和丙戊酸联合使用需关注药物暴露情况,进行血药浓度监测,加强随访以提高抗癫痫治疗疗效,降低药物不良反应,提高患者依从性。     

传统抗癫痫药物用于中老年脑卒中后迟发性癫痫的比较研究

目的探讨传统抗癫痫药物在脑卒中后迟发性癫痫中老年患者中的不同特点和疗效。方法对我院2004年1月～2008年12月收治的270例中年（〈65岁）和190例老年（≥65岁）脑卒中后迟发性癫痫患者的药物保留率进行了回顾性分析。结果中年组4种药物保留率依次为卡马西平（87.7%）〉丙戊酸钠（75.8%）〉苯妥英钠（53.7%）〉氯硝西泮（41.2%）;老年组4种药物保留率依次为丙戊酸钠（88.9%）〉苯妥英钠（73.8%）〉卡马西平（59.5%）〉氯硝西泮（43.7%）;中年组卡马西平疗效最好,控制率达66.7%,老年组丙戊酸钠疗效最好,控制率达72.1%。结论临床治疗脑卒中迟发性癫痫时,中、老年患者应分别首选卡巴西平和丙戊酸钠。     

2554例癫痫患者血药质量浓度监测结果回顾性分析

目的了解癫痫患者药物使用情况,促进抗癫痫药物的临床合理使用,提高治疗效果。方法回顾性分析2000-2006年我院门诊或住院患者服用苯妥英钠(PHT)、苯巴比妥(PB)、丙戊酸(VPA)或卡马西平(CBZ)治疗的2554例癫痫患者血药质量浓度监测情况。结果4种抗癫痫药物中血药质量浓度在治疗窗内的百分率分别是卡马西平68.14%,苯巴比妥62.50%,丙戊酸48.91%,苯妥英钠23.01%。其中苯妥英钠血药质量浓度在治疗窗内的比例最低,且波动幅度大。结论抗癫痫药物的血药质量浓度监测对医生调整用药剂量、实现个体化给药有着重要的临床意义。     

Drug therapy reviews: drug therapy of status epilepticus.

Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic status epilepticus one should: (1) maintain vital functions at all times, (2) identify and treat precipitating factors and (3) administer an intravenous loading dose of phenytoin sodium or phenobarbital sodium. Careful use of i.v. diazepam sometimes helps to achieve these objectives. Intravenous phenytoin sodium and phenobarbital sodium provide definitive, long-term control of tonic-clonic seizures but must be administered slowly and require time to reach peak brain concentrations. Intravenous diazepam appears to enter and exit from the brain rapidly and may control seizures while therapeutic brain concentrations of long-acting drugs are being achieved. Phenytoin, phenobarbital and diazepam should not be administered intramuscularly in treating status epilepticus. Treatment of focal motor and complex partial status epilepticus is similar to that of tonic-clonic status epilepticus, but i.v. diazepam is required less frequently and loading doses of phenytoin and phenobarbital sometimes can be given more slowly. Status epilepticus of the absence type is managed with i.v. acetazolamide sodium or diazepam. Paraldehyde, muscle relaxants, general anesthesia and lidocaine may be tried when conventional therapies fail.     

Status epilepticus after massive carbamazepine overdose

We report two patients who experienced status epilepticus after carbamazepine overdose. The first patient was an 18-year-old female with a history of epilepsy. She experienced 4 hour of persistent and prolonged seizures resistant to sodium amytal therapy. The status epilepticus ended with her death. The second patient was an 18-year-old male with a history of bipolar disorder. He experienced 5 hour of persistent and prolonged seizures that appeared to be resistant to diazepam, phenytoin, and phenobarbital. The seizures abated with the infusion of midazolam. This is a report of status epilepticus associated with wide complex tachycardia after carbamazepine overdose, which may be resistant to conventional therapy.     

Therapeutic drug monitoring of anticonvulsants. State of the art

There is considerable interindividual variation in the relationship between control of seizures and the serum anticonvulsant concentration. The minimum effective serum concentration is dependent on the type and severity of the epilepsy, and varies from patient to patient. The therapeutic range should be used as a guide to adjust the dose in order to further improve seizure control or reduce toxicity; the latter is more likely with higher serum concentrations, but can also be present when concentrations are low. A request for the serum concentration of an anticonvulsant should be made only for good clinical reasons, and an interpretation of that concentration can only be made if all the relevant clinical details are available. Indications for the measurement of serum anticonvulsant concentrations include poor seizure control, toxicity, suspected gross noncompliance, status epilepticus and seizure control, toxicity, suspected gross noncompliance, status epilepticus and the elapse of 2 to 4 weeks after the initiation of therapy. Additional drug therapy, pregnancy or illness may alter drug disposition in a well controlled patient and therapeutic drug monitoring may, therefore, help to prevent seizures secondary to these changes. The measurement of anticonvulsants in saliva as opposed to serum may be of benefit in some patients.     

Evaluation of Ames Seralyzer for the therapeutic drug monitoring of phenobarbital and phenytoin

Comparison of a reflective photometry assay (Ames Seralyzer) and a fluorescence polarization immunoassay (Abbott TDx) for measuring phenobarbital and phenytoin serum concentration was performed. Routine phenobarbital and phenytoin plasma levels drawn from patients in the pediatric neurology clinic and pediatric intensive care unit were determined in duplicate by the Abbott TDx and Ames Seralyzer systems. A total of 40 samples were assayed. The interday and intraday variability of the Ames system was determined using calibrators of known concentrations (5-25 micrograms/ml). There was significant correlation between the serum phenobarbital or phenytoin concentrations when determined by the Seralyzer and TDx systems. The intraday variability for the measurement of phenytoin when determined by the Seralyzer had coefficients of variation ranging from 2.2 to 8.9%. The interday variability for phenytoin when measured by both the TDx and the Seralyzer correlated well with known calibrators. The utility of the Ames Seralyzer for acute-care facilities, physician offices, and pharmacy satellites is apparent. Based on statistical analysis, the Seralyzer provides accurate phenobarbital and phenytoin serum measurements for clinical use in therapeutic drug monitoring.     

Refractory generalised convulsive status epilepticus : a guide to treatment

The patient with status epilepticus has continuous or rapidly repeating seizures. Generalised convulsive status epilepticus (GCSE) is the most common form of the disorder and is a life-threatening condition that requires prompt medical management. Status epilepticus that does not respond to first-line benzodiazepines (lorazepam or diazepam) or to second-line antiepileptic drugs (phenytoin/fosphenytoin, phenobarbital or valproate) is usually considered refractory and requires more aggressive treatment.The optimal treatment of refractory GCSE has not been defined, but patients should be treated in an intensive care unit, as artificial ventilation and haemodynamic support are required. Invasive haemodynamic monitoring is often necessary and EEG monitoring is essential.The drug treatment of refractory GCSE involves general anaesthesia with continuous intravenous anaesthetics given in doses that abolish all clinical and electrographic epileptic activity, often requiring sedation to the point of burst suppression on the EEG. Barbiturate anaesthetics, pentobarbital in the US and thiopental sodium in Europe and Australia, are the most frequently used agents and are highly effective for refractory GCSE both in children and adults. Indeed, they remain the only way to stop seizure activity with certainty in severely refractory cases. Other options are midazolam for adults and children and propofol for adults only.Regardless of the drug selected, intravenous fluids and vasopressors are usually required to treat hypotension. Once seizures have been controlled for 12-24 hours, continuous intravenous therapy should be gradually tapered off if the drug being administered is midazolam or propofol. Gradual tapering is probably not necessary with pentobarbital or thiopental sodium. Continuous EEG monitoring is required during high-dose treatment and while therapy is gradually withdrawn. During withdrawal of anaesthetic therapy, intravenous phenytoin/fosphenytoin or valproate should be continued (these agents having been administered during earlier phases of GCSE) to ensure an adequate baseline of antiepileptic medication so as to prevent the recurrence of status epilepticus. If additional medication is needed, the most appropriate antiepileptic drugs are gabapentin for focal seizures and levetiracetam and topiramate for all seizure types, as these drugs can be started at high doses with a low risk of idiosyncratic reactions.Even with current best practice, mortality in patients who experience refractory GCSE is about 50% and only the minority return to their premorbid functional baseline. Therefore, new treatment options are urgently needed. The ideal new drug for refractory GCSE would be one that has the ability to stop seizures more effectively and safely than current drugs, and that has neuroprotective properties to prevent the brain damage and neurological morbidity caused by GCSE.     

Endocannabinoids block status epilepticus in cultured hippocampal neurons

Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg(2+) hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC(50) of 145+/-4.15 nM and 1.68+/-0.19 microM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB(1) receptor since they were blocked by the cannabinoid CB(1) receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus.     

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus

AIMS: Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.     

Evaluation of therapeutic drug level monitoring of phenobarbital, phenytoin and carbamazepine in Iranian epileptic patients

OBJECTIVE: The antiepileptic drugs phenobarbital, phenytoin and carbamazepine are widely used for the treatment of partial and tonic-clonic seizures. Large inter-individual differences in pharmacokinetics of these drugs, and the intermittent nature of epileptic attacks, increase the need for therapeutic drug level monitoring of these drugs. MATERIAL AND METHODS: In this study, data from the therapeutic drug monitoring of phenobarbital, carbamazepine and phenytoin in 328 epileptic patients were evaluated. Serum levels of drugs were determined in a University Department of Pharmacology by high-performance liquid chromatography. RESULTS: In this study, approximately 56% of patients were treated with 1; 30% with 2; and 14% with 3 antiepileptic drugs. In patients receiving 1 antiepileptic drug, the percentages treated with phenobarbital, carbamazepine and phenytoin were 41, 38 and 21%, respectively. In patients who received carbamazepine, serum levels in 40% of the patients were in the range of 4-8 microg/ml and more than in the range 4-12 microg/ml in 74% of the patients. In phenobarbital-treated patients, serum levels in 73% of the patients were in therapeutic range of 10-40 microg/ml, and about 44% of phenytoin-treated patients had serum levels in therapeutic range of 10-20 microg/ml. Approximately 50% of carbamazepine- and phenytoin-treated patients and approximately 70% of phenobarbital-treated patients were completely controlled. The frequency of concentrations within the therapeutic ranges decreased in patients using more than 1 antiepileptic drug. In patients who received both phenobarbital and sodium valproate, serum levels of phenobarbital were significantly (p < 0.05) greater than in patients who were taking this drug in combination with carbamazepine or phenytoin. CONCLUSION: Our results indicate that serum levels of antiepileptic drugs, and the percentage of patients with complete seizure control are comparable with results obtained in other populations in previous studies.     

Modification of the antiepileptic actions of phenobarbital and phenytoin by the taurine transport inhibitor, guanidinoethane sulfonate

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.