苯妥英血药浓度监测130例/次及中毒病例分折

目的:探讨癫痫患者苯妥英(PHT)剂量、血药浓度及疗效间的关系,为临床安全、合理应用PHT提供参考。方法:单用及合用PHT治疗癫痫70例,用荧光偏振免疫法测定PHT血清浓度130例/次。结果:常规剂量PHT治疗的个体差异极其显著,PHT血药浓度超过30μg/ml时极易引起中毒。结论:只有实时监测PHT的血药浓度并个体化给药,才能保证治疗的安全、有效。     

癫痫患者和非癫痫患者苯妥英钠中毒

目的 探讨癫痫和非癫痫患者苯妥英钠(PHT）中毒的临床表现、诊断及治疗异同点,并复习PHT中毒的新进展。方法 回顾性分析我院1988-2008年14例癫痫和非癫痫住院患者PHT中毒的临床表现、中毒的原因、用药情况、PHT血药浓度及预后。 结果 两组患者临床皆表现为小脑性共济失调,部分患者有锥体外系和锥体束表现。癫痫患者用药史明确,诊治及时;而3例非癫痫患者皆因不知情用药所致,3例患者因哮喘服用肺宝,医患忽略其PHT成分,拖延诊断达2年左右;其临床表现为发作性共济失调,发作频率与间隔和哮喘发作相一致。PHT中毒预后良好,停药后症状消失。结论 首次报道PHT复方制剂用于治疗哮喘造成中毒3例。因此,凡遇病因不明小脑综合征患者应高度怀疑PHT中毒的可能。PHT不宜作为一线药物用于非癫痫疾患,并对PHT易中毒的药代动力学和中毒的内因和外因进行文献复习。     

卡马西平血浓度监测及苯妥英钠对其血浓度的影响

46例癫痫患者,30例单用卡马西平(CBZ)治疗,16例CBZ 合用苯妥英钠(PHT)、服药剂量与血药浓度呈正相关。CBZ 的血药浓度与抗癫痫作用之间存在着较大的个体差异,本组资料提示CBZ 血药浓度以6～12μg/ml 为宜。加用PHT0.2±0.1/d,CBZ 的血浓度显著下降。     

抗癫痫药物中毒病例的血药浓度监测及分析

目的：分析分别服用4种抗癫痫药物苯妥英（PHT）、苯巴比妥（PB）、卡马西平（CBZ）、丙戊酸（VPA）中毒病例的血药浓度及其中毒原因，特点，方法：对942例癫痫患者所服抗癫痫药采用荧光偏振免疫法（FPIA）进行血药浓度监测，对高于有效血药浓度范围的106例患者进行分析。结果：中毒病例的血药浓度有较大的个体差异，部分病例在服用常规治疗剂量情况下，血药浓度就已高于有效范围，并出现中毒症状，单一用药时PHT的中毒发生率明显高于其余3种药物（P＜0．01）。联合用药中苯妥英钠与卡马西平联用的中毒比较较高。结论：适时监测血药浓度可避免抗癫痫药物中毒。     

苯妥英钠血药浓度监测与个体差异

目的:通过对苯妥英钠血药浓度监测结果的分析,探讨苯妥英钠剂量与患者血药浓度以及临床疗效间的相互关系.方法:采用化学发光免疫分析法,对98例服用苯妥英钠的癫痫患者的血药浓度监测结果及临床疗效进行分析与评价.结果:苯妥英钠的有效剂量和中毒剂量与分别对应的血药浓度的个体差异均较大.结论:苯妥英钠治疗癫痫患者应重视血药浓度的监测,并应结合临床,着眼于个体化给药.     

难治性癫痫患者的苯妥英钠血药浓度监测及用药分析

本文对38例服用苯妥英钠的难治性癫痫患者进行血药浓度监测和用药分析.结果38例中,中毒人数为21例,用药不足人数7例.提示难治性癫痫患者与苯妥英钠的用药水平有关,临床应用苯妥英钠应个体化,每位患者的治疗剂量不能只凭经验用药,必须进行血药浓度监测.     

癫(癎)与非癫(癎)患者苯妥英钠中毒表现比较

苯妥英钠(phenytoin sodium,PHT)除作为常用的抗癫(癎)药外,还应用于其他疾病.PHT的药代动力学模型呈非线性动力学性质,其有效血药浓度范围窄,极易引起中毒.特别是非癫(癎)患者应用含PHT成分药物,极易被忽略和延误诊治.现将我院1988年1月-2008年12月收入院的14例PHT中毒患者的情况报告如下.     

我院2009年抗癫痫药物血药浓度监测结果分析

目的:促进临床合理应用抗癫痫药物并提高其疗效。方法:回顾性分析我院2009年门诊或住院患者服用丙戊酸(VPA)、卡马西平(CBZ)、苯妥英钠(PHT)的487例癫痫患者的血药浓度监测结果。结果:487例监测中,248例(50.92%)在有效血药浓度范围内;177例(36.34%)低于有效血药浓度;51例(10.47%)高于有效血药浓度;11例(2.26%)未检出血药浓度。其中,在有效血药浓度范围内的3种药物比例分别是VPA(48.18%)、CBZ(74.29%)、PHT(10.87%)。结论:抗癫痫药物的血药浓度监测为临床设计个体化给药方案提供了依据,是保证安全、有效用药的重要措施。     

美罗培南致丙戊酸钠血药浓度降低的3例临床分析

目的:分析美罗培南降低丙戊酸钠(VPA)血药浓度的变化规律。方法:测定患者VPA血药浓度在合用美罗培南前后及停药后的变化,观察患者癫痫发作情况及其浓度是否可剂量依赖性回升。结果:3例患者的VPA血药浓度在合用美罗培南后下降幅度均大于70%。例1有癫痫发作;例2在美罗培南合用24 h即降至低点,停药后7 d回升至单用VPA水平;例3在VPA增量后浓度未回升。结论:美罗培南可明显降低VPA血药浓度并为非剂量调控性,临床上宜尽量避免两者合用。     

苯妥英钠在血药浓度监测下治疗癫痫大发作与部分性发作73例临床观察

目的通过对苯妥英钠血药浓度的监测,观察苯妥英钠治疗73例癫痫患者的临床疗效。方法随机将本院门诊和住院收治的癫痫患者219例分为苯妥英钠（PHT）治疗组（n=73）、苯妥英钠（PHT）对照组（n=73）、苯妥英钠和苯巴比妥（PHT＋PB）双药组（n=73）,并对治疗组的患者进行治疗药物监测（TDM）,双药组与对照组不进行TDM,观察其临床疗效。结果显示首次3组有效率差异无统计学意义（P〉0．05）,经调整DPH血药浓度后,3组疗效比较,治疗组与双药组、对照组有效率比较差异有统计学意义（P〈0．05）,双药组与对照组有效率比较差异无统计学意义（P〉0．05）。结论表明控制癫痫大发作与部分性发作治疗组的个体化给药较双药组、对照组效果佳。     

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。     

一线抗癫癎药物血药浓度监测结果分析

目的:对一线抗癫癎药物血药浓度监测结果进行回顾性分析,指导临床合理用药。方法:对801例服用一线抗癫癎药物病人的血药浓度进行分类汇总,并对结果进行统计学分析。结果:各药在有效血药浓度范围内的病例百分率差异显著(P<0.01),分别为丙戊酸钠(VPA)75.2%、苯巴比妥(PB)67.3%、卡马西平(CBZ)53.1%、苯妥英钠(PHT)20.8%。VPA使用率最高,为60.5%,其血药浓度存在性别差异(P<0.01)。CBZ血药浓度存在年龄差异(P<0.01)。多药联用血药浓度升高的病例增加(P<0.01),以PHT/CBZ方案最为突出。CBZ/VPA、PB/VPA方案在控制率、安全性方面比较好。结论:血药浓度监测对癫癎治疗具有极其重要的临床意义。     

癫痫患者2种治疗药物浓度的监测及其临床意义

目的：监测治疗癫痫患者血清中苯妥英（ＰＨＴ）和卡马西平（ＣＢＺ）的浓度。方法：建立高效液相色谱法,测定住院和门诊７８例癫痫患者血药浓度。结果：其中服用苯妥英２３例,卡马西平５５例,低于治疗有效浓度分别有１４例和１９例,各占６０．８７％和３４．５５％,中毒浓度１例。结论：癫痫患者的治疗与苯妥英和卡马西平的用药水平有关,治疗剂量不能仅凭经验用药,有条件则应进行血药浓度监测,实行个体化给药。     

Phenytoin/clonazepam interaction

An interaction between phenytoin (PHT) and clonazepam (CZP) occurred in an epileptic patient, who had been treated with PHT with partial seizure control. The addition of CZP brought about a significant decrease of PHT plasma levels (from 24.8 to 16 micrograms/ml) in spite of increases in the PHT dose. Gradual reduction of CZP, without modifying the PHT dosage, caused significant increases in PHT plasma levels to 42.4 micrograms/ml with signs of intoxication. A review of the literature shows contradictions: some authors state that there is no interaction between the drugs; other authors state either an increase or decrease in PHT plasma levels. These paradoxical results could be explained by the bidirectional effect of these drugs in hepatic enzyme metabolism. The importance of monitoring plasma levels of antiepileptic drugs is emphasized when several medications are required in the treatment of epilepsy.     

苯妥英钠对丙戊酸钠药动学的影响

目的：研究苯妥英钠（PHT）对丙戊酸钠（VLA）在癫痫治疗中的药动学影响及VAL在唾液中与血液中浓度的相关性。方法：监测病人血清中PHT和VAL浓度,用药动学软件PKBP－N1拟合。结果：与VAL单用相比,PHT可显著降低VAL的血中药物浓度,AUC（P＜0．05）,缩短t1/2。VAL的唾液浓度与其血中浓度相关性不显著（P＞0．05）。结论：在癫痫联合用药治疗中,PHT对VAL的药动学有显著影响,故需监测二者的血药浓度,以达到合理用药。此外,不能用唾液中VAL的浓度作为药物浓度指标。     

Melatonin attenuates phenytoin sodium-induced DNA damage

Abstract

Phenytoin sodium (PHT Na⁺) is a potent antiepileptic drug against epileptic seizures and is used as a prophylactic treatment in traumatic brain injury. PHT Na⁺ leads to the formation of reactive oxygen species (ROS), and DNA is a crucial molecular target of ROS-initiated toxicity. Melatonin and its metabolites possess free-radical-scavenging activity. We therefore designed this study to investigate the potential protective effect of melatonin against PHT Na⁺-induced DNA damage by using the comet assay in a rat model in vivo. Thirty-three 3-month-old male Wistar rats were divided into five groups of control treated with isotonic sodium chloride (a single injection of isotonic sodium chloride and 100?µL in drinking water for 10 days), ethanol treated (in drinking water for 10 days containing 100?µL of ethanol in each 300-mL drinking bottle), melatonin treated (4?mg/kg body weight [b.w.] intraperitoneally [i.p.] at the start, in drinking water for 10 days), PHT Na⁺ treated (a single i.p. injection of 50?mg/kg) and PHT Na⁺ (50?mg/kg b.w., single i.p.) and melatonin (4?mg/kg b.w. i.p. at the start and 4?mg/kg in drinking water for 10 days) cotreated. To determine the protective effects of melatonin, the comet assay was performed using lymphocytes isolated in different time intervals (0, 15, 30, 45 and 60 minutes) from each group of animals. On days 1, 3, 7 and 10, blood samples were taken and the comet assay technique was performed. Our present data suggest that melatonin reversed PHT Na⁺-induced DNA damage.     

关注抗癫癎药的联合用药 警惕药物中毒

癫癎药物治疗原则上要求单一用药。然而,癫癎患者常常因症状控制不佳而联合用药。因抗癫癎药之间相互作用导致药动学的改变,增加了安全隐患,甚至出现药物中毒。本文通过分析癫癎患者联合应用苯妥英钠和丙戊酸钠后,前者影响后者的药动学过程而导致药物过量,提醒应关注抗癫癎药的联合使用,警惕因药物相互作用而引起药物中毒,提高合理用药水平。     

Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.     

Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine

Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients.