Aggravation of seizures and/or EEG features in children treated with oxcarbazepine monotherapy

PURPOSE: Exacerbation of epilepsy may occur following initiation of therapy with antiepileptic drugs (AEDs). The aim of this study is to analyze the clinical and EEG characteristics of a group of pediatric patients with worsening of seizures and/or EEG deterioration while on oxcarbazepine (OXC). METHODS: A retrospective analysis of a clinical database was performed to identify patients with epilepsy treated with OXC over the past 3 years. History, neurological examination, and EEG findings were reviewed to identify any who had developed exacerbation of seizures or new abnormalities on EEG. RESULTS: Of 290 patients on OXC, we identified 12 patients with new onset seizures, all with initial normal neurological exam and normal EEG, who developed either worsening of preexisting seizures, new seizure types, and/or EEG deterioration following introduction of OXC monotherapy. EEG changes were primarily characterized by new onset of generalized epileptiform activity not reported on the initial baseline EEG. Following substitution of OXC with a broad spectrum AED, significant improvement of seizure control and improvement in the EEG was observed. CONCLUSIONS: These findings suggest that OXC can aggravate seizures and/or worsen EEG features in children. Following initiation of therapy with OXC, monitoring of patients with follow-up EEGs may be important, especially in patients who do not show adequate response to therapy.     

A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4

PURPOSE: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. METHODS: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. RESULTS: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36-164; p=0.0022) and 181% (CI: 120-260, p<0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139-187, p<0.0001) (OXCZ) and 222% (CI: 192-257, p<0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16-40, p=0.0018) (OXCZ) and 33% (CI: 18-45, p=0.0020) (CBZ). T1/2 decreased by means of 12% (CI: 6-17, p<0.0014) (OXCZ) and 32% (CI: 25-38, p<0.0001) (CBZ). tmax was not changed in either period. CONCLUSION: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance.     

奥卡西平辅助治疗精神分裂症及分裂样精神病兴奋躁动的比较研究

目的评估奥卡西平治疗兴奋躁动精神分裂症、分裂样精神病辅助疗效和安全性。方法将符合中国精神障碍分类与诊断标准第3版中精神分裂症、分裂样精神病诊断标准,并以兴奋躁动为主要表现的80例患者随机分为研究组(n=39)和对照组(n=41),研究组应用抗精神病药物(氯氮平、奥氮平、利培酮、喹硫平、阿立哌唑或齐拉西酮其中之一)联合奥卡西平,对照组单一使用抗精神病药物,观察6周。采用简明精神病量表(BPRS)和阳性和阴性综合征量表(PANSS)兴奋因子,不良反应量表(TESS)在治疗前及治疗后第1,2,4,6周分别评估疗效和安全性。结果治疗6周后,研究组有效28例(71.8%),对照组有效26例(65.0%),2组有效率差异有统计学意义(χ2=6.02,P=0.028)。研究组与对照组患者分别脱落2例和4例。研究组的主要不良反应为镇静(11例)、便秘(10例)、头晕(7例)、心动过速(7例)等,对照组的主要不良反应为便秘(14例)、口干(12例)、心动过速(12例)、锥体外系不良反应(7例)等。结论奥卡西平能有效辅助治疗精神分裂症、分裂样精神病的兴奋状态。     

A validated stability indicating LC method for oxcarbazepine

The present paper describes the development of a stability indicating reversed phase liquid chromatographic (RPLC) method for oxcarbazepine in the presence of its impurities and degradation products generated from forced decomposition studies. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The degradation of oxcarbazepine was observed under base hydrolysis. The drug was found to be stable to other stress conditions attempted. Successful separation of the drug from the synthetic impurities and degradation product formed under stress conditions was achieved on a C18 column using mixture of aqueous 0.02 M potassium dihydrogen phosphate–acetonitrile–methanol (45:35:20, v/v/v) as mobile phase. The developed HPLC method was validated with respect to linearity, accuracy, precision, specificity and robustness. The developed HPLC method to determine the related substances and assay determination of oxcarbazepine can be used to evaluate the quality of regular production samples. It can be also used to test the stability samples of oxcarbazepine.     

Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs

Purpose : Older enzyme‐inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. Methods : Patients 18–50 years of age, on AEDs monotherapy, with no other known cause of hyper‐tHcy were enrolled. Plasma tHcy, folate, vitamin B₁₂, and AEDs levels were determined by standard high‐performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate‐reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. Results : Two hundred fifty‐nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 μm ; physiologic range 5–13 μm ] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm ; normal > 6.8 nm ) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) μm , respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) μm ]. Discussion : Oxcarbazepine and topiramate might cause hyper‐tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper‐tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy.     

The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures

OBJECTIVE: To investigate the effect of oxcarbazepine against standard antiepileptic drug therapy (carbamazepine and valproate) on cognitive function in children and adolescents (aged 6 to <17 years) with newly diagnosed partial seizures. METHODS: A multicentre, open-label, randomised, active-control, three-arm, parallel-group, 6-month study. The primary cognitive variable, the Computerized Visual Searching Task (CVST), assessed mental information processing speed and attention. Secondary variables included additional tests assessing psychomotor speed, alertness, memory and learning, and non-verbal intelligence. RESULTS: Of 112 patients randomised, 99 completed the study. The dropout rate was 11.6%; 13 patients discontinued due to adverse events (n=5) or unsatisfactory therapeutic effect (n=8). Mean CVST time decreased in all groups, indicating an improvement of mental processing speed and no cognitive impairment in any treatment group. No statistically significant difference was observed between oxcarbazepine and combined carbamazepine/valproate. Analysis of secondary variables did not show statistically significant differences between oxcarbazepine, carbamazepine and valproate. Analysis of intelligence test results showed that the number of correct answers increased at end point in all groups. The percentage of patients remaining seizure free throughout treatment was comparable across all groups (oxcarbazepine 58%; carbamazepine 46%; valproate 54%; carbamazepine/valproate 50%). The most common adverse events were fatigue and headache for oxcarbazepine, fatigue and rash for carbamazepine, and headache, increased appetite and alopecia for valproate. CONCLUSION: Oxcarbazepine treatment over 6 months does not display any differential effects on cognitive function and intelligence in children and adolescents with newly diagnosed partial seizures relative to standard antiepileptic drug therapy. No impairment in cognitive function was observed in any treatment group over a 6-month period.     

奥卡西平和卡马西平对致(痫)大鼠认知功能的影响

目的 观察卡马西平、奥卡西平对癫(痫)认知功能的影响.方法 采用随机数字表方法将实验大鼠分为对照组、致(痫)组、奥卡西平组及卡马西平组,每组各20只.对照组用0.9％氯化钠注射液造模;致(痫)组用氯化锂-匹罗卡品造模,不服用药物;奥卡西平组用氯化锂-匹罗卡品造模,并用奥卡西平200 mg/d灌胃;卡马西平组用氯化锂-匹罗卡品造模,并用卡马西平200 mg/d灌胃,通过Morris水迷宫实验测试并记录逃避潜伏期和平台象限游泳时间.实时聚合酶链反应(RT-PCR)法检测ERK-2 mRNA、NCAM-1 mRNA表达,免疫组织化学化法检测细胞外调节蛋白激酶2 (ERK-2)蛋白、神经细胞黏附分子1(NCAM-1)蛋白表达(阳性神经元计数).结果 训练初期,卡马西平组、奥卡西平组、致(痫)组、对照组逃逸潜伏期平均时间、平台象限游泳时间分别为(81±9)和(27±9)s,(72 ±9)s和(32±14)s,(67 ±7)s和(37±13),(36±5)s和(51 ±11)s,卡马西平组、奥卡西平组、致(痫)组和对照组比较,差异均有统计学意义(均P＜0.01).卡马西平组、奥卡西平组、致(痫)组、对照组NCAM/β3-actin和ERK-2 /β3-actin分别为0.60±0.12和0.43 ±0.11、0.66 ±0.03和0.51±0.17、0.95 ±0.21和0.59±0.24、0.48±0.04和0.75 ±0.23,卡马西平组、奥卡西平组的大鼠海马组织NCAM-1 mRNA表达水平明显低于致(痫)组(P＜0.01).致(痫)组中ERK-2的mRNA表达水平明显低于对照组(P＜0.01).卡马西平组、奥卡西平组的大鼠海马组织中ERK-2表达水平明显低于致(痫)组(P＜0.01).结论 ERK-2在癫(痫)发作1个月时在海马的表达水平下降,NCAM-1则相反.二者均参与了癫(痫)认知功能障碍的发病,卡马西平能加重癫(痫)认知功能障碍,奥卡西平对癫(痫)认知功能障碍影响轻微.     

丙戊酸及其与奥卡西平联用治疗儿童癫痫的疗效和安全性比较

目的：考查单用丙戊酸（ VPA）以及VPA与奥卡西平（ OXC）联用治疗儿童癫痫的有效性、安全性和依从性。方法收集2012年10月至2013年10月就诊于中国医科大学附属盛京医院、应用VPA（ VPA组）或VPA联合OXC（ VPA+OXC组）治疗、连续用药2个月以上且随访满1年的癫痫患儿的病历资料进行回顾性分析,记录并比较2组患儿的用药情况[ VPA日剂量、OXC日剂量、VPA标准化血药浓度（ CDR）、用药依从性（以药物保留率评价）]、癫痫控制情况和药物不良反应（ ADR）发生情况。结果共208例患儿纳入研究。VPA组105例,男性62例,女性43例,年龄1~15岁,平均（6.8±3.4）岁;VPA+OXC组103例,男性60例,女性43例,年龄1~15岁,平均（7.4±3.5）岁。VPA 组与 VPA + OXC 组 VPA 日剂量、CDR、药物保留率差异均无统计学意义[（507±207）mg比（498±164）mg,（4.2±2.3）（μg·kg）/（ml·mg）比（4.3±1.6）（μg·kg）/（ml· mg）,81.9%比79.6%,均P>0.05）];随访1年时,VPA+OXC组有效率明显优于VPA组[82.5%（85/103）比61.9%（65/105）,P<0.05）。随访1年期间VPA组与VPA+OXC组ADR症状和肝功能异常发生率差异均无统计学意义[13.3%（14/105）比15.5%（16/103）,4.8%（5/105）比6.8%（7/103）,均P>0.05]。但将患儿按年龄分组比较,则显示1~10岁患儿2组ADR发生率和VPA+OXC组肝功能异常发生率均高于11~15岁患儿（均P<0.05）;按VPA血药浓度分组比较,CDR为5~13（μg·kg）/（ ml·mg）的患儿ADR症状和肝功能异常发生率均高于CDR为1~5（μg·kg）/（ ml·mg）的患儿。结论 OXC与VPA联用治疗儿童癫痫疗效优于单用VAP,同时具有良好的安全性和依从性。患儿年龄和VPA血药浓度可能是发生ADR症状和肝功能异常的危险因素。     

奥卡西平刻痕片仿制药与原研药溶出行为及相关指标的一致性评价研究

目的:评价奥卡西平刻痕片仿制药与原研药溶出行为的一致性,并比较两者的外观、半片制剂的脆碎度及分割质量损失以及不同企业原料药的晶型、晶体形貌。方法:采用高效液相色谱法测定含量;采用桨法(设置转速60 r/min,温度37.0℃)测定仿制药与原研药在4种不同溶出介质[含0.6%十二烷基硫酸钠的盐酸溶液(pH=1.2)、含0.6%十二烷基硫酸钠的醋酸盐缓冲溶液(pH=4.5)、含0.6%十二烷基硫酸钠的磷酸盐缓冲溶液(pH=6.8)、含0.6%十二烷基硫酸钠的水溶液]中的累积溶出度,采用相似因子法评价两者溶出曲线的相似性,并评价半片与整片制剂的批内均一性;采用脆碎度检测仪及电子天平测定半片制剂的脆碎度及分割质量损失;采用X射线衍射仪及扫描电子显微镜观察不同企业原料药的晶型和晶体形貌。结果:奥卡西平检测质量浓度的线性范围为33.42～401.09μg/mL(r=0.999 9);定量限为0.10μg/mL,检测限为0.04μg/mL;精密度、稳定性、重复性、耐用性试验的RSD均小于2%;回收率为99.80%～101.63%(RSD为0.37%～0.91%,n=3)。仿制药A、B和原研药在4种不...     

奥卡西平片的人体相对生物利用度研究

目的:研究国产奥卡西平片的人体相对生物利用度和生物等效性.方法:健康志愿者20名,随机双交叉单剂量口服试验和参比的奥卡西平片,剂量为300 mg,剂间间隔为2周.分别于服药后48 h内多点抽取静脉血.用高效液相色谱法(HPLC)测定血浆中奥卡西平的活性代谢物MHD的浓度.结果:MHD的线性范围为0.10～10.00 mg/L,最低检测浓度为0.10 mg/L,方法的平均回收率为(99.4±4.2)%.20名志愿者随机交叉口服单剂量两种制剂后,MHD的cmax分别为4.61±0.57 mg/L和16.34±5.29 mg/L;tmax分别为4.65±2.74 h和4.20±2.02 h;t1/2(Ke)分别为16.57±4.01 h和16.34±5.29 h;AUC(0-48)分别为100.24±16.62 mg*h/L和97.97±19.01 mg*h/L;AUC(0-inf)分别为118.93±4.61 mg·h/L和115.43±4.64 mg·h/L.试验制剂与参比制剂的相对生物利用度F=(103.4±10.5)%.AUC (0-48),cmax,tmax均无显著性差异.结论: 该方法简便、准确、灵敏度高;两种制剂生物学等效.