Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique

Levetiracetam has recently been approved as an adjunctive medication for partial seizures and frequently will be added to phenytoin. The objective of this study was to determine the presence or absence of a pharmacokinetic drug interaction of levetiracetam with phenytoin. A stable isotope tracer technique using deuterium-labeled (D10) phenytoin and high-performance liquid chromatography with ultraviolet detection (rather than mass spectrometric detection) was employed. Tracer doses of D10-phenytoin were administered i.v. before and 12 weeks after adding levetiracetam to the regimen of 6 subjects on phenytoin monotherapy for epilepsy. Blood was collected for 96 hours after each infusion. The following pharmacokinetic parameters were determined for phenytoin: Cmax, Cmin, Cavo, AUC, CL, t 1/2, VD, and free (nonprotein bound) fraction. The ratio and the 90% confidence interval of the ratio of log-transformed mean values for phenytoin pharmacokinetic parameters before (denominator) and after (numerator) adding levetiracetam all fell within the range of 0.85 to 1.17 (two one-sided test). The authors conclude that the addition of levetiracetam did not bring about clinically important changes in phenytoin pharmacokinetic parameters and that it is not necessary to change the phenytoin dosing rate when levetiracetam is added to phenytoin.     

基因诊断在苯妥英治疗癫痫病中的应用

以近期发表的文献为依据,从分析苯妥英的体内代谢过程和基因诊断的基本理论,以及介绍成功应用基因诊断于苯妥英临床合理应用的实例入手,对利用基因诊断提高苯妥英合理应用水平的理论依据、临床意义、具体方法及适用范围等进行全面的阐述。基因多态是影响苯妥英药效学、药动学和药物不良反应的重要因素。基因诊断可成为提高苯妥英合理应用的有效方法,在苯妥英钠治疗癫痫病中应得到广泛的应用。     

Studies on the crystalline form of phenytoin

Two crystalline forms of phenytoin were isolated and characterized by X-ray diffraction, IR spectroscopy and differential thermal analysis. The dissolution behavior of the two forms was determined in water. The crystals of needle shape (form II) were found to exhibit slower dissolution rate than the other crystal form (form I).     

苯妥英钠与卡马西平在健康志愿者体内药物动力学相互作用

应用高效液相色谱法测定16名健康志愿者单用和联用苯妥英钠和卡马西平的血浓度。动力学过程用一房室模型一级动力学拟合。首次报道中国人体内苯妥英钠和卡马西平相互作用引起的2药最大稳态浓度C_((ss)max),最小稳态浓度C_((ss)min),达峰时间T_(max),消除半衰期T_(1/2),药时曲线下面积AUC等动力学参数变化的资料。结果表明苯妥英钠使卡马西平的T_(1/2)明显缩短,而卡马西平则延长苯妥英钠的T_(1/2)。     

拉莫三嗪对难治性癫痫的治疗作用

目的：评价拉莫三嗪对难治性癫痫的治疗作用和安全性。方法：难治性癫痫病人７６例治疗前３ｍｏ开始填写发作的逐日志，完成后随机分成单盲、安慰剂对照（ｎ＝４４）与双盲、交叉、安慰剂对照（ｎ＝３２）２组，保持原用抗痫药不变，按５０～４００ｍｇ／ｄ（未用丙戊酸者）或２５～２００ｍｇ／ｄ（用丙戊酸者），ｑｏｄ，ｑｎ或ｂｉｄ加用拉莫三嗪，对照组用同等剂量的维生素Ｃ，３ｍｏ为一个疗程。结果：拉莫三嗪有效率为５６％，不良反应较轻。结论：拉莫三嗪治疗难治性癫痫是有效和安全的。     

Lack of pharmacokinetic interaction between lansoprazole and intravenously administered phenytoin

The objective of this randomized, double-blind, two-period crossover study was to investigate whether concomitant steady-state lansoprazole influences the pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin as a model substrate. In addition, the safety of concomitant administration of these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects received 60 mg lansoprazole or placebo once daily for 9 days during each study period. On the morning of day 7, each subject received a single 250 mg intravenous phenytoin dose. There were no statistically significant differences between the two regimens for mean phenytoin Cmax or tmax. There was a minor (< 3%) but statistically significant difference between the two regimens for phenytoin AUC resulting from a very low intrasubject coefficient of variation (2.3%). The treatment and control mean plasma concentration phenytoin profiles were virtually super-imposable. In conclusion, concomitant multidose lansoprazole administration is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin specifically.     

结核分枝杆菌耐乙胺丁醇分子机制的研究

目的　了解结核分枝杆菌耐乙胺丁醇分子机制 ,建立快速分子药敏试验方法。方法　通过聚合酶链反应 (PCR) -单链构象多态性 (SSCP)、PCR-限制性片段长度多态性 (RFL P)和 PCR-直接测序 (DS)技术分析 10 7株结核分枝杆菌临床分离株 emb B基因。结果　以 H3 7Rv标准株为对照 ,10 7株结核分枝杆菌临床分离株的 16 S r DNA SSCP电泳图谱均与结核分枝杆菌标准相同。 38株药物敏感株的 emb B基因、SSCP均泳动正常 ,RFL P和 DS分析与对照株相同。 6 9株耐乙胺丁醇 (EMB)分离株中 ,2 5株 (36 .2 % ) emb B基因 SSCP泳动异常 ;8株 RFL P分析异常 ;DS分析 2 5株均为 30 6位密码子突变 ,其中 1株合并有 2 74位 CGC→ CCC突变 ,其 EMB MICs均≥ 2 0 μg/ml;8株为 30 6位 ATG→ATA或 ATT突变 ,17株为 ATG→GTG或 CTG突变 ,后者 EMB MICs均≥ 30μg/ml。结论　部分结核分枝杆菌耐乙胺丁醇是由于其 emb B基因 (尤其是 30 6位密码子 )突变所致 ,PCR- SSCP技术可能成为测定部分结核分枝杆菌乙胺丁醇耐药基因型的简便、快速的方法     

Plasma concentrations of unbound phenytoin in the management of epilepsy.

In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37 degrees C) and tracer-labelling with [14C]-phenytoin was 6.7%-33.3% with a median of 11.9%. The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P less than 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = -0.83, P less than 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P less than 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.     

Inhibition of phenytoin metabolism by other drugs used in epilepsy.

Phenytoin metabolism is saturable within its normal therapeutic range and, therefore, small changes in the activity of the enzyme can lead to marked changes in serum phenytoin concentrations. The anticonvulsant drugs sulthiame and pheneturide both inhibit the metabolism of phenytoin. The mechanism of this interaction appears to be different for these two drugs. Nortriptyline produces a small increase in serum phenytoin concentrations, but this is unlikely to be of clinical importance. Case reports suggest that both chlorpromazine and chloramphenicol inhibit phenytoin metabolism to a significant degree.     

Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats

The plasma concentration of phenytoin (PHT) is decreased by coadministration of folinate (leucovorin; LV), a folate (FA) analogue. The aim of this study was to examine the effect of LV on the pharmacokinetics of PHT in rats in vivo and to investigate the mechanism of the interaction. LV (50 mg/kg) was administered orally to rats concomitantly given intravenous PHT (50 mg/kg) to evaluate the effect of LV on the pharmacokinetics of PHT. The effect of LV on the plasma protein binding of PHT was investigated by using plasma from rats that had received oral LV. We also examined the effects of LV on the uptake of PHT into isolated rat hepatocytes and on the metabolism of PHT in isolated rat hepatocytes and rat hepatic microsomes. LV significantly increased the systemic clearance (2-fold) and liver-to-blood partition coefficient (1.24-fold) of PHT. However, it did not affect the plasma protein binding or hepatic uptake of PHT. LV increased the metabolism of PHT in isolated rat hepatocytes, with a significant 1.41-fold increase in the maximum rate of metabolism and a decrease in the Michaelis-Menten constant. On the other hand, 5-methyltetrahydrofolate (5-MTHF), a primary metabolite of LV and FA, significantly increased p-hydroxylation of PHT in rat hepatic microsomes, whereas LV and FA themselves had no effect. In conclusion, these results suggest that, in rats, LV, an FA analogue, decreases the plasma concentration of PHT by increasing the hepatic metabolism of PHT, and the increase in the PHT metabolism is, at least in part, attributable to 5-MTHF.     

Lack of pharmacokinetic interaction between nifedipine, sparteine and phenytoin in man.

Nifedipine, sparteine and phenytoin were administered orally to eight healthy subjects separately and as a 'cocktail' on four different occasions to investigate any kinetic interactions. All subjects were extensive metabolizers of sparteine. After drug intake plasma and urine samples were collected up to 32 h and the concentrations of parent drugs and main metabolites were measured. Clearances and formation clearances were not significantly different after single substrate and 'cocktail' administration. Low or non significant correlation coefficients were found between the oxidation of the individual substrates or formation of their metabolites. With this strategy of simultaneous administration of substrates ('cocktail') it appears possible to characterize (and correlate) activities of different cytochrome P-450 isoenzymes, without the disturbing influence of intraindividual variation of drug oxidation with time.     

Serum phenytoin concentration and clinical response in patients with epilepsy.

1 Patients with poorly controlled epilepsy were cautiously transferred from multiple drug therapy to treatment with phenytoin sodium alone. One patient suffered more severe seizures and the initial treatment was restarted. The remainder showed no deterioration. 2 The daily dose of phenytoin was then increased by a small increment at intervals of 2 or more months. The serum phenytoin concentration (total and free) was measured regularly and response was assessed by records of seizure frequency and tests of speech, handwriting, short-term memory and coordination. 3 Patients (n = 11) with partial seizures showed no consistent improvement with increased phenytoin concentration within the range 15 mg/l (60 mumol/l) to the individual threshold for intoxication, greater than or equal to 35 mg/l (140 mumol/l). Patients (n = 4) with generalized seizures however were consistently improved at higher concentrations. 4 Tolerance to phenytoin varied, the threshold for symptomatic intoxication ranging from 35-60 mg/l (140-240 mumol/l) total and 2.7-5.2 mg/l (10.8-20.8 mumol/l) free. Ataxia was the commonest symptom and in some cases this was manifest by worsening of performance on the test of coordination (pursuit rotor). Even at lower phenytoin concentrations the patients performed less well on this test than control subjects. Other tests of performance showed no evidence of impairment at higher phenytoin concentrations. 5 The same daily dose of phenytoin tended to give higher serum drug concentrations after intoxication than before.     

Comparison of four single-point phenytoin dosage prediction techniques using computer-simulated pharmacokinetic values

The predictive abilities of the following four single-point phenytoin dosage adjustment methods were compared using computer-simulated data: the Bayesian feedback method of Vozeh et al. (B), a linearized version of the Bayesian method (LB), the population-clearance method of Graves et al. (G), and the Rambeck nomogram (R). A series of 512 "subjects" with normally distributed values for volume of distribution, weight, and the Michaelis-Menten variables Vmax and Km were simulated. The steady-state serum concentration (SSSC) resulting from the administration of a standard dose of phenytoin sodium (5 mg/kg/day) was calculated, and "subjects" with SSSCs less than or equal to 12 mg/L or greater than or equal to 17 mg/L were entered in the study. If the concentration was greater than 50 mg/L or the standard dosage exceeded Vmax, the dosage was reduced empirically by 25%. Normally distributed random errors were introduced into the SSSC values to simulate actual patient data. The pharmacokinetic values, dosages, and SSSCs were used for predicting the dosage required to attain an SSSC of 14.9 mg/L. In the unstratified population, the mean error and mean-squared error were lowest for methods G and B, followed by methods LB and R. Methods B and LB gave the highest percentages of satisfactory dosage predictions based on the resultant SSSC value. The performance of all methods was superior at initial SSSCs greater than 8 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors affecting the free plasma fraction of phenytoin in patients with epilepsy

The variability and possible factors modifying the free plasma fraction of phenytoin were investigated in 134 patients with epilepsy undergoing long-term treatment. The total and free plasma concentrations of phenytoin were determined using fluorescent polarisation immunoassay. Concentrations of albumin, bilirubin and creatinine were also obtained. The free plasma concentration was separated by ultrafiltration, at 25 degrees C, using Centrifree((R)) filters. Factors related to the free plasma fraction of phenytoin (free plasma concentration/total plasma concentration) were gender, age, dose, therapeutic regimen, total plasma concentration and the biochemical parameters mentioned. The mean of free plasma fraction was 9.1% with a very high variability (between 3.3 and 37%). No significant relationship was found between the free plasma fraction and dose, age, gender, total plasma concentration or the biochemical data. The only variable with a significant effect (p < 0.05) on the free plasma fraction was polytherapy with valproic acid. The variability in the free plasma fraction of phenytoin was high in epileptic patients, and was poorly related to the clinical or analytical variables studied. In the absence of pathologies that modify phenytoin binding (uraemia, hypoalbuminaemia), the only factor predictive of a possible alteration in the binding of phenytoin to plasma proteins was polytherapy with valproic acid.     

Temperature effect on serum protein binding kinetics of phenytoin in monotherapy patients with epilepsy.

The effects of temperature on the binding kinetics of phenytoin (PHT) to serum proteins were determined in patients with epilepsy. Serum samples examined in the study were obtained from 59 patients (31 male, 28 female) with epilepsy on PHT monotherapy. Their age ranged from 3 to 64 years (mean (SD), 23.3 (16.3) years). Protein binding of PHT was evaluated by ultrafiltration under current routine laboratory conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. Significant differences were observed in serum concentrations of unbound PHT between paired data (P < 0.05). The mean association constant (K) of PHT to serum proteins is 0.011 microM-1 at 25 +/- 3 degrees C and 0.006 microM-1 at 37 degrees C, while mean total concentration of binding sites (n(Pt)) is 1002 microM for 25 +/- 3 degrees C and 1112 microM for 37 degrees C. Significant differences were observed in the binding kinetics of PHT to serum proteins for the different temperature conditions of ultrafiltration (P < 0.05). Our study confirms that binding affinity for PHT-serum protein interaction is approximately 45% lower at 37 degrees C than at 25 +/- 3 degrees C and consequently, binding potential (K.n(Pt)) is approximately 39% lower at 37 degrees C than at 25 +/- 3 degrees C.     

难治性癫痫患者致痫灶中CX43的表达

目的探讨由CX43组成的缝隙连接在难治性癫痫患者致痫灶脑组织中的表达,为难治性癫痫的临床研究及治疗提供新的思路。方法以24例行手术治疗的难治性癫痫患者为实验组,6例脑外伤急诊手术患者为对照组,采集其手术切除的致痫灶脑组织,应用免疫组织化学方法,观察CX43的表达并与对照组进行比较。结果免疫组织化学方法检测显示实验组CX43的表达高于对照组(P<0.001)。结论难治性癫痫患者致痫灶脑组织中CX43表达增高,提示CX43所形成的缝隙连接参与癫痫活动,可能在癫痫的发生、发展中发挥重要的作用。     

难治性额叶癫痫的手术治疗

目的探讨手术治疗难治性额叶癫痫的效果和经验。方法对2004-06～2009-06接受手术治疗的25例难治性额叶癫痫患者进行回顾性分析及随访,总结致痫灶的精确定位方法、症状改善及手术治疗情况。结果随访期1～4年,平均2.6年。25例患者中,满意15例,显著改善5例,良好3例,效差2例,无改善0例。手术总有效率为100%,良好率为92%,无手术致死及严重并发症出现。结论手术治疗难治性额叶癫痫是一种有效的方法,术前、术中精确定位致痫灶是手术成功的关键。     

托吡酯与丙戊酸钠缓释片治疗难治性癫痫疗效比较

目的 :比较托吡酯与丙戊酸钠缓释片治疗难治性癫痫的疗效。方法 :托吡酯组 39例 ,丙戊酸钠组 4 1例 ,托吡酯成人及儿童剂量在约 2mo中逐渐增至 2 0 0mg·d- 1及 4mg·kg·d- 1左右 ,po ,bid。丙戊酸钠缓释片成人剂量 0 .5～ 1.0 g·d- 1,儿童剂量逐增至总量 15～ 30mg·kg·d- 1,为每日清晨或早晨、中午 2次服用。治疗 4mo及 6mo后评定疗效。结果 :托吡酯组治疗 6mo的继发性全身发作 ,简单及复杂性部分发作有效例数优于丙戊酸钠组 ,4例在加药期快时出现疲劳、嗜睡、注意力不集中等。丙戊酸钠组 1例发生骨髓造血功能严重低下。结论 :托吡酯治疗难治性癫痫简单及复杂部分性发作伴或不伴继发性全身发作疗效优于丙戊酸钠 ,无骨髓抑制 ,也无肝、肾功能损伤