苯巴比妥的认知功能评估及其疗效与ABCB1基因多态性的相关性研究
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摘要
癫痫是一种常见的神经系统疾病,全球约有0.4-0.7%的人口患有癫痫。苯巴比妥是世界上应用最广泛的抗癫痫药物之一,对部分性发作和全面性发作均有疗效；其半衰期长、服药方便和价格低廉。但是,长期以来困扰临床医生、患者及家属的,是源于苯巴比妥对认知功能的影响。我们采用多中心、大样本的病例对照研究,通过神经心理学量表对正在接受苯巴比妥治疗的癫痫患者进行检测,评估苯巴比妥治疗癫痫患者的认知功能。
尽管近年来不断有新的AEDs问世,在癫痫治疗上取得了进步,但仍有20%-30%的患者对各种抗癫痫药物不敏感成为耐药性癫痫,苯巴比妥亦不例外。本研究应用分子流行病学方法,探讨ABCB1基因多态性在回、汉族癫痫患者中的分布特点及其与耐药的相关性,以及该多态性与苯巴比妥脑脊液和血药浓度及其比值的关联。
第一部分中国农村地区全身强直.阵挛发作癫痫患者的认知功能评估目的评价中国农村地区未经规范治疗的全身强直-阵挛发作(GTCS)的癫痫患者
的认知功能的状况。
方法采用数字广度测验、言语流畅性测验、听觉词语测验及数字划消测验对144名GTCS的癫痫患者和144名健康对照进行认知功能评定。
结果GTCS的癫痫患者的注意力及计算能力较差,并有瞬间语言记忆、自发的语言运动能力、思维组织能力及干扰抑制能力的下降p<0.001)。
结论未经规范治疗的GTCS的癫痫患者存在广泛的认知功能障碍。抗癫痫药物的不规范使用是认知功能损害的主要影响因素之一。
目的中国农村地区苯巴比妥治疗惊厥性癫痫是有效的,虽然没有正规的认知功能的评估,但很少出现认知功能及行为障碍。这项研究目的是对苯巴比妥治疗中国农村地区癫痫患者的认知功能的评估。
方法对中国农村五省区的144例惊厥性癫痫患者及144名健康者为对照。癫痫组患者采用单药苯巴比妥治疗12个月。在基线、3、6和12个月分别对癫痫患者及健康者进行一组神经心理测试,包括MMSE (Mini Mental State Examination)、HDRS (Hamilton Depression Rating Scale)、DST (digit span test)、 AVLT(auditory verbal learning test)、DCT (digit cancellation test)。在随访结束时评估苯巴比妥的效果。
结果在12个月的随访中,填写认知功能评分及心理测试量表。完成随访的癫痫患者为136(94.4%)例,健康者为137(95.1%)人。两组均显示在数字广度和数字划消测验有改善。然而,在言语流畅性方面,苯巴比妥组显示比对照组有更好的改善,两组比较有显著性差异(P=0.012)。
结论苯巴比妥治疗惊厥性癫痫患者未见认知功能障碍,对认知功能的改善源于其抗癫痫作用,但长期影响有待于进一步研究。
目的研究ABCB1基因的多态性在回、汉族癫痫患者中分布及与苯巴比妥疗效的相关性。
方法收集应用苯巴比妥治疗的回、汉族癫痫患者的临床资料,分为回、汉族癫痫耐药组和回、汉族癫痫控制有效组,并采集患者静脉血。应用SNaPshot SNP分型技术检测ABCB1基因G1199A(rs2229109)、C1236T(rs1128503)、C3435T (rs1045642)和G2677T/A (rs2032582)与MRP2基因C-24T (rs717620)、 G1249A(rs2273697)和C3972T(rs3740066)的基因型。用SHEsis软件对ABCB1基因C1236T(rs1128503)、C3435T(rs1045642)和G2677T/A(rs2032582)进行单体型推断。应用病例对照研究,分析ABCB1基因多态性在回、汉族癫痫患者中的分布特点,通过Logistic回归模型评估各基因型与癫痫耐药发生风险的相关程度,并计算比数比(OR)及95%可信区间(CI)。
结果共入选回、汉族癫痫患者184例,回族62人,汉族122人。其中,回族耐药组32例,汉族耐药组62例；回族控制组30例,汉族控制组60例。1.回、汉族癫痫患者在ABCB1基因G1199A(rs2229109)、C3435T(rs1045642)、 G2677T/A(rs2032582)和C1236T(rsl128503)、MRP2C-24T(rs717620)、G1249A (rs22736397)和C3972T (rs3740066)等7个位点,其各等位基因分布频率及各基因型分布频率未见差异。2.MRP2的多态性与苯巴比妥疗效未见关联。3.在汉族患者中,ABCB1基因C3435T(rs1045642)的CC基因型在耐药组中的分布频率较高,TT基因型在控制组中分布频率较高(p=0.0047)。Logistic回归模型分析提示CC基因型是癫痫耐药的独立危险因素,CC基因型发生癫痫耐药的危险性是TT基因型的9.751倍(OR=9.751,95%CL:2.762-34.420, p=0.000), CT基因型发生癫痫耐药的危险性是TT基因型的5.291倍(OR=5.291,95%CL:0.052-17.770,p=0.007)0回族患者亦有这种趋势(p=0.075),但无统计学差异。回、汉族C等位基因分布频率均在耐药组中较高,T等位基因分布频率均在控制组中较高(P值分别为p=0.033和p=0.003)。4.在汉族患者中,ABCB1基因G2677T/A(rs2032582)的GG基因型在癫痫耐药组的分布频率较高,TT基因型在汉族控制组的分布频率较高(p=0.034)。Logistic回归模型分析提示GG基因型是癫痫耐药的独立危险因素,GG基因型发生癫痫耐药的危险性是TT基因型的10.577倍(OR=10.577,95%CL:2.571-43.518, p=0.001), GA基因型发生癫痫耐药的危险性是TT基因型的4.380倍(OR=4.380,95%CL:1.105-17.355,p=0.036); GT基因型发生耐药的危险性是TT基因型的4.032倍(OR=4.032,95%CL:1.193-13.631, p=0.025)。5. ABCB1基因C3435T(rs1045642)、G2677T/A(rs2032582)和C1236T (rs1128503)所构建的单体型中,汉族癫痫患者CGT单体型在耐药组中的分布频率较高,TTT单体型在控制组中的分布频率较高(p=0.015)。Logistic回归模型分析提示,CGT单体型是癫痫耐药的独立危险因素,CGT发生癫痫耐药的危险性是TTT单体型的3.483倍(OR=3.483,95%CL:1.782-6.808, p=0.000).6. Logistic回归模型分析提示饮酒、发作频率、服用AEDs时间及全面性发作是发生癫痫耐药的独立危险因素。癫痫耐药与性别、年龄、回、汉族、首发年龄、病程、高热惊厥、吸烟和发病距吃药时间等无关联。
结论ABCB1基因的多态性在回、汉族癫痫患者中的分布无差异；ABCB1基因C3435T位点CC基因型、G2677T/A位点的GG基因型和CGT单体型与汉族癫痫耐药显著相关；回族癫痫患者未显示与ABCB1基因的SNPs关联。
目的了解脑脊液、血苯巴比妥浓度及其比值与ABCB1基因的多态性的的关联。
方法采用反相高效液相色谱法(RP-HPLC)检测79例癫痫患者的脑脊液、血苯巴比妥浓度,采用SNaPshot SNP分型技术检测入组癫痫患者ABCB1基因的C1236T、G2677T/A和C3435T的位点的基因型。计算CSF/S P浓度比值,分析该比值与各基因型的相关性。
结果1.在ABCB1基因C1236T位点,CC基因型、CT基因型和TT基因型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。2.在ABCB1基因G2677T/A位点,AA基因型、GA基因型和GG基因型GT基因型、TA基因型和TT基因型中,未发现S PB浓度、CSFPB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。3.在ABCB1基因C3435T位点,CC基因型、CT基因型和TT基因型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。4.在ABCB1基因C3435T、 G2677T/A和C1236T位点所构建的单体型,CA、CGC、CGT和TTT单体型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。
结论脑脊液、血清苯巴比妥浓度及其比值未发现与ABCB1基因的多态性相关,还需扩大样本进一步验证本实验结果。
Epilepsy is one of the most frequent neurologic disorders, affecting approximately0.4-0.7%of the world population. Phenobarbital (PB) on the partial seizures and generalized seizures is the most widely used antiepileptic drug (AED) in the world. PB has long half-life, taking the convenience and low prices. However, long plagued clinicians, patients and their families, is derived from phenobarbital on cognitive function. Therefore, we use multi-center, large sample of case-control study by questionnaire on neuropsychological testing in patients with epilepsy, phenobarbital treatment assessment of cognitive function in patients with epilepsy.
Although in recent years, there have been the advent of new AEDs in the treatment of epilepsy made progress, but still20%-30%of patients on a variety of antiepileptic drugs is not sensitive to a resistant epilepsy. Phenobarbital is no exception, there are also pharmacoresistant problem. The application of molecular epidemiological methods to explore the ABCB1gene polymorphism of distribution in the Hui and Han people with epilepsy and its correlation with drug resistance and the polymorphism of phenobarbital concentration in cerebrospinal fluid,serum and the ratio of the association.
Objective To evaluate the cognitive function in untreated patients with generalized tonic-clonic seizure (GTCS).
Materials and Methods144patients with GTCS and144normal controls were evaluated with a battery of neuropsychologic tests, which comprises Digit Span Test, Verbal Fluency Test, Auditory Verbal Learning Test and Digit Cancellation Test.
Results Patients with GTCS performed worse of general cognitive deficits, such as verbal memory, episodic memory, verbal learning capacity, visual spatial memory, attention, and calculative ability(p<0.001).
Conclusion The cognitive function of untreated patients with GTCS is widely impaired. Unstandardized treatment with anti-epileptic drug is the main impact factor of cognitive function impairment.
Objective A study in rural China confirmed that phenobarbital was effective in controlling convulsive seizures with few cognitive or behavioral adverse effects, although no formal psychometric testing was undertaken. This study was designed to evaluate the effects of phenobarbital treatment on cognition and mood in people with epilepsy in rural China.
Materials and Methods144people with convulsive seizures and144healthy controls were recruited from five sites in rural China. The group of people with epilepsy was treated with phenobarbital monotherapy for12months. At baseline,3,6and12months, cases and controls were evaluated with a battery of neuropsychological tests, comprising the Mini Mental State Examination, the Hamilton Depression Rating Scale, a digit span test, a verbal fluency test, an auditory verbal learning test and a digit cancellation test. Efficacy of phenobarbital was evaluated at the end of follow-up for those with epilepsy.
Results In the12months of follow-up, complete and psychological tests of cognitive function score scale. Complete the follow-up of136patients with epilepsy (94.4%) patients,137healthy (95.1%) people. Both groups were displayed in the DST and the DCT test improved. However, in the AVLT, the phenobarbital group than the control group showed better improvement in both groups had significant difference (p=0.012).
Conclusion Phenobarbital treatment did not impair cognitive function of patients with convulsive seizures, improvement of cognitive function due to its antiepileptic effect, but long-term effects need further study.
Objective To study frequencies of polymorphisms in ABCB1and association of these polymorphisms with phenobarbital response in Hui and Han people with epilepsy.
Materials and Methods We collected clinical data of phenobarbital treatment Hui and Han in epilepsy patients, classified into the Han drug-resistant group, drug responsive group and Hui drug-resistant group, drug responsive group and collected blood of patients. SNaPshot SNP genotyping was employed to genotype of detecting ABCB1gene G1199A (rs2229109), C1236T (rs1128503), C3435T (rs1045642) and G2677T/A (rs2032582) and the MRP2gene C-24T (rs717620), G1249A (rs2273697) and C3972T (rs3740066).Haplotypes were reconstructed to ABCB1gene C1236T (rs1128503), C3435T (rs1045642) and G2677T/A (rs2032582) by SHEsis programs.Application of case-control study, we analyzed ABCB1genetic polymorphism of frequency in the Hui and Han patients with epilepsy.Logistic regression models assessed by the genotype and the risk of epilepsy, the relevance of drug resistance, and calculate the odds ratio (OR) and95%confidence intervals (CI).
Results184people with epilepsy were recruited, including32cases of Hui drug-resistant group, the Han group of62patients with drug resistance; effective control of30patients of Hui and Han control group of60patients effectively.1. The distribution of its allele frequency and the genotype was no different with Hui and Han patients with epilepsy in the ABCB1G1199A (rs2229109), C3435T (rs1045642), G2677T/A (rs2032582) and C1236T (rs1128503) and the MRP2C-24T (rs717620), G1249A (rs22736397) and C3972T (rs3740066).2. MRP2polymorphisms were no association with the efficacy of phenobarbital.3. In Han epilepsy patients, ABCB1C3435T (rs1045642) of the CC genotype of frequency distribution in drug-resistant group was higher than in the control group, and TT genotype of frequency distribution in the control group was higher than in drug-resistant group ((p=0.0047)). Logistic regression analysis showed that the CC genotype was epilepsy pharmacoresistance of an independent risk factor. CC genotype of the risk of epilepsy pharmacoresistance was been9.751times by the TT genotype (OR=9.751,95%CL:2.762-34.420. p=0.000).CT genotype happened the risk of epilepsy pharmacoresistance was been5.291times by the TT genotype (OR=5.291,95%CL:0.052-17.770,p=0.007). Hui epilepsy patients had trend (p=0.075), no significant difference. Hui and Han C allele frequencies were higher in the drug-resistant group, T allele frequency was higher in the control groups.4. In Han epilepsy patients, ABCB1G2677T/A (rs2032582) of the GG genotype of frequency distribution was high in drug-resistant group. TT genotype of the frequency distribution was high in Han control group (p=0.034). Logistic regression analysis showed that GG genotype was independent risk factor for epilepsy pharmacoresistance. GG genotype was happened the risk of epilepsy pharmacoresistance was been10.577times by the TT genotype (OR=10.577,95%CL:2.571-43.518, p=0.001).GA genotypes happened the risk of epilepsy pharmacoresistance was been4.380times by the TT genotype (OR=4.380,95%CL:1.105-17.355, p=0.036).GT genotype happened the risk of epilepsy pharmacoresistance was been4.032times by the TT genotype (OR=4.032,95%CL:1.193-13.631, p=0.025). Hui epilepsy patients had not statistically significant at this site.5. Haplotype were constructed by ABCBlgene C3435T (rs1045642), G2677T/A (rs2032582) and C1236T (rs1128503).In the Han patients with epilepsy, CGT haplotype was the frequency distribution high in the drug-resistant group. TTT haplotype was the frequency distribution high in the control group (p=0.015) Logistic regression analysis revealed that CGT haplotype was an independent risk factor for epilepsy pharmacoresistance. CGT happened risk of epilepsy pharmacoresistance was been3.483times by the TTT haplotype (OR=3.483,95%CL:1.782-6.808,p=0.000). Hui patients with epilepsy had trend (p=0.068), but not significantly.6. Logistic regression analysis revealed that alcohol, seizure frequency, time taking AEDs and generalized seizures was happened epilepsy pharmacoresistance of independent risk factors. Epilepsy pharmacoresistance had no associate with sex, age, nationality, starting age, duration, febrile seizures, smoking, medication and time from the onset.
Conclusions
1. ABCB1gene polymorphism was the frequency distribution no difference in the Hui and Han patients with epilepsy.
2. ABCB1gene C3435T loci CC genotypes, G2677T/A loci GG genotype and CGT haplotype was significantly associated with epilepsy pharmacoresistance in Han epilepsy patients. Hui epilepsy patients did not show associated with SNPs of ABCB1gene.
Objective Understand the ABCB1gene polymorphisms between cerebrospinal fluid (CSF), serum(S) concentrations of phenobarbital and the ratio of the association.
Materials and Methods By reversed-phase high performance liquid chromatography (RP-HPLC) detected of cerebrospinal fluid and serum concentrations of phenobarbital in79patients with epilepsy. SNaPshot SNP genotyping detected ABCB1gene C1236T, G2677T/A and C3435T loci genotypes in patients with epilepsy. We calculated CSF/S PB concentration ratio, to analyze the ratio of the correlation with the genotype.
Results1. CC genotype, CT genotype and TT genotype were not found S PB concentration, CSF PB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene C1236T loci (p>0.05).2. AA genotype, GA genotype and GG genotype GT genotype, TA genotype and TT genotype were not found S PB concentration, CSFPB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene G2677T/A loci (p>0.05).3. CC genotype, CT genotype and TT genotype were not found S PB concentration, CSF PB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene C3435T loci (p>0.05).4. CAC, CGC, CGT and TTT haplotype, not found in S PB concentration, CSF PB concentration and with the CSF/S PB concentration ratio of correlated in ABCB1gene C3435T, G2677T/A and C1236T loci constructing haplotype (p>0.05). Conclusions ABCB1gene polymorphisms in cerebrospinal fluid, serum
concentrations of phenobarbital and the CSF/S PB Ratio was no correlation, need to expand the sample to further verify the experimental results.
尽管近年来不断有新的AEDs问世,在癫痫治疗上取得了进步,但仍有20%-30%的患者对各种抗癫痫药物不敏感成为耐药性癫痫,苯巴比妥亦不例外。本研究应用分子流行病学方法,探讨ABCB1基因多态性在回、汉族癫痫患者中的分布特点及其与耐药的相关性,以及该多态性与苯巴比妥脑脊液和血药浓度及其比值的关联。
第一部分中国农村地区全身强直.阵挛发作癫痫患者的认知功能评估目的评价中国农村地区未经规范治疗的全身强直-阵挛发作(GTCS)的癫痫患者
的认知功能的状况。
方法采用数字广度测验、言语流畅性测验、听觉词语测验及数字划消测验对144名GTCS的癫痫患者和144名健康对照进行认知功能评定。
结果GTCS的癫痫患者的注意力及计算能力较差,并有瞬间语言记忆、自发的语言运动能力、思维组织能力及干扰抑制能力的下降p<0.001)。
结论未经规范治疗的GTCS的癫痫患者存在广泛的认知功能障碍。抗癫痫药物的不规范使用是认知功能损害的主要影响因素之一。
目的中国农村地区苯巴比妥治疗惊厥性癫痫是有效的,虽然没有正规的认知功能的评估,但很少出现认知功能及行为障碍。这项研究目的是对苯巴比妥治疗中国农村地区癫痫患者的认知功能的评估。
方法对中国农村五省区的144例惊厥性癫痫患者及144名健康者为对照。癫痫组患者采用单药苯巴比妥治疗12个月。在基线、3、6和12个月分别对癫痫患者及健康者进行一组神经心理测试,包括MMSE (Mini Mental State Examination)、HDRS (Hamilton Depression Rating Scale)、DST (digit span test)、 AVLT(auditory verbal learning test)、DCT (digit cancellation test)。在随访结束时评估苯巴比妥的效果。
结果在12个月的随访中,填写认知功能评分及心理测试量表。完成随访的癫痫患者为136(94.4%)例,健康者为137(95.1%)人。两组均显示在数字广度和数字划消测验有改善。然而,在言语流畅性方面,苯巴比妥组显示比对照组有更好的改善,两组比较有显著性差异(P=0.012)。
结论苯巴比妥治疗惊厥性癫痫患者未见认知功能障碍,对认知功能的改善源于其抗癫痫作用,但长期影响有待于进一步研究。
目的研究ABCB1基因的多态性在回、汉族癫痫患者中分布及与苯巴比妥疗效的相关性。
方法收集应用苯巴比妥治疗的回、汉族癫痫患者的临床资料,分为回、汉族癫痫耐药组和回、汉族癫痫控制有效组,并采集患者静脉血。应用SNaPshot SNP分型技术检测ABCB1基因G1199A(rs2229109)、C1236T(rs1128503)、C3435T (rs1045642)和G2677T/A (rs2032582)与MRP2基因C-24T (rs717620)、 G1249A(rs2273697)和C3972T(rs3740066)的基因型。用SHEsis软件对ABCB1基因C1236T(rs1128503)、C3435T(rs1045642)和G2677T/A(rs2032582)进行单体型推断。应用病例对照研究,分析ABCB1基因多态性在回、汉族癫痫患者中的分布特点,通过Logistic回归模型评估各基因型与癫痫耐药发生风险的相关程度,并计算比数比(OR)及95%可信区间(CI)。
结果共入选回、汉族癫痫患者184例,回族62人,汉族122人。其中,回族耐药组32例,汉族耐药组62例；回族控制组30例,汉族控制组60例。1.回、汉族癫痫患者在ABCB1基因G1199A(rs2229109)、C3435T(rs1045642)、 G2677T/A(rs2032582)和C1236T(rsl128503)、MRP2C-24T(rs717620)、G1249A (rs22736397)和C3972T (rs3740066)等7个位点,其各等位基因分布频率及各基因型分布频率未见差异。2.MRP2的多态性与苯巴比妥疗效未见关联。3.在汉族患者中,ABCB1基因C3435T(rs1045642)的CC基因型在耐药组中的分布频率较高,TT基因型在控制组中分布频率较高(p=0.0047)。Logistic回归模型分析提示CC基因型是癫痫耐药的独立危险因素,CC基因型发生癫痫耐药的危险性是TT基因型的9.751倍(OR=9.751,95%CL:2.762-34.420, p=0.000), CT基因型发生癫痫耐药的危险性是TT基因型的5.291倍(OR=5.291,95%CL:0.052-17.770,p=0.007)0回族患者亦有这种趋势(p=0.075),但无统计学差异。回、汉族C等位基因分布频率均在耐药组中较高,T等位基因分布频率均在控制组中较高(P值分别为p=0.033和p=0.003)。4.在汉族患者中,ABCB1基因G2677T/A(rs2032582)的GG基因型在癫痫耐药组的分布频率较高,TT基因型在汉族控制组的分布频率较高(p=0.034)。Logistic回归模型分析提示GG基因型是癫痫耐药的独立危险因素,GG基因型发生癫痫耐药的危险性是TT基因型的10.577倍(OR=10.577,95%CL:2.571-43.518, p=0.001), GA基因型发生癫痫耐药的危险性是TT基因型的4.380倍(OR=4.380,95%CL:1.105-17.355,p=0.036); GT基因型发生耐药的危险性是TT基因型的4.032倍(OR=4.032,95%CL:1.193-13.631, p=0.025)。5. ABCB1基因C3435T(rs1045642)、G2677T/A(rs2032582)和C1236T (rs1128503)所构建的单体型中,汉族癫痫患者CGT单体型在耐药组中的分布频率较高,TTT单体型在控制组中的分布频率较高(p=0.015)。Logistic回归模型分析提示,CGT单体型是癫痫耐药的独立危险因素,CGT发生癫痫耐药的危险性是TTT单体型的3.483倍(OR=3.483,95%CL:1.782-6.808, p=0.000).6. Logistic回归模型分析提示饮酒、发作频率、服用AEDs时间及全面性发作是发生癫痫耐药的独立危险因素。癫痫耐药与性别、年龄、回、汉族、首发年龄、病程、高热惊厥、吸烟和发病距吃药时间等无关联。
结论ABCB1基因的多态性在回、汉族癫痫患者中的分布无差异；ABCB1基因C3435T位点CC基因型、G2677T/A位点的GG基因型和CGT单体型与汉族癫痫耐药显著相关；回族癫痫患者未显示与ABCB1基因的SNPs关联。
目的了解脑脊液、血苯巴比妥浓度及其比值与ABCB1基因的多态性的的关联。
方法采用反相高效液相色谱法(RP-HPLC)检测79例癫痫患者的脑脊液、血苯巴比妥浓度,采用SNaPshot SNP分型技术检测入组癫痫患者ABCB1基因的C1236T、G2677T/A和C3435T的位点的基因型。计算CSF/S P浓度比值,分析该比值与各基因型的相关性。
结果1.在ABCB1基因C1236T位点,CC基因型、CT基因型和TT基因型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。2.在ABCB1基因G2677T/A位点,AA基因型、GA基因型和GG基因型GT基因型、TA基因型和TT基因型中,未发现S PB浓度、CSFPB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。3.在ABCB1基因C3435T位点,CC基因型、CT基因型和TT基因型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。4.在ABCB1基因C3435T、 G2677T/A和C1236T位点所构建的单体型,CA、CGC、CGT和TTT单体型中,未发现S PB浓度、CSF PB浓度以及与CSF/S PB浓度比值具有相关性(p>0.05)。
结论脑脊液、血清苯巴比妥浓度及其比值未发现与ABCB1基因的多态性相关,还需扩大样本进一步验证本实验结果。
Epilepsy is one of the most frequent neurologic disorders, affecting approximately0.4-0.7%of the world population. Phenobarbital (PB) on the partial seizures and generalized seizures is the most widely used antiepileptic drug (AED) in the world. PB has long half-life, taking the convenience and low prices. However, long plagued clinicians, patients and their families, is derived from phenobarbital on cognitive function. Therefore, we use multi-center, large sample of case-control study by questionnaire on neuropsychological testing in patients with epilepsy, phenobarbital treatment assessment of cognitive function in patients with epilepsy.
Although in recent years, there have been the advent of new AEDs in the treatment of epilepsy made progress, but still20%-30%of patients on a variety of antiepileptic drugs is not sensitive to a resistant epilepsy. Phenobarbital is no exception, there are also pharmacoresistant problem. The application of molecular epidemiological methods to explore the ABCB1gene polymorphism of distribution in the Hui and Han people with epilepsy and its correlation with drug resistance and the polymorphism of phenobarbital concentration in cerebrospinal fluid,serum and the ratio of the association.
Objective To evaluate the cognitive function in untreated patients with generalized tonic-clonic seizure (GTCS).
Materials and Methods144patients with GTCS and144normal controls were evaluated with a battery of neuropsychologic tests, which comprises Digit Span Test, Verbal Fluency Test, Auditory Verbal Learning Test and Digit Cancellation Test.
Results Patients with GTCS performed worse of general cognitive deficits, such as verbal memory, episodic memory, verbal learning capacity, visual spatial memory, attention, and calculative ability(p<0.001).
Conclusion The cognitive function of untreated patients with GTCS is widely impaired. Unstandardized treatment with anti-epileptic drug is the main impact factor of cognitive function impairment.
Objective A study in rural China confirmed that phenobarbital was effective in controlling convulsive seizures with few cognitive or behavioral adverse effects, although no formal psychometric testing was undertaken. This study was designed to evaluate the effects of phenobarbital treatment on cognition and mood in people with epilepsy in rural China.
Materials and Methods144people with convulsive seizures and144healthy controls were recruited from five sites in rural China. The group of people with epilepsy was treated with phenobarbital monotherapy for12months. At baseline,3,6and12months, cases and controls were evaluated with a battery of neuropsychological tests, comprising the Mini Mental State Examination, the Hamilton Depression Rating Scale, a digit span test, a verbal fluency test, an auditory verbal learning test and a digit cancellation test. Efficacy of phenobarbital was evaluated at the end of follow-up for those with epilepsy.
Results In the12months of follow-up, complete and psychological tests of cognitive function score scale. Complete the follow-up of136patients with epilepsy (94.4%) patients,137healthy (95.1%) people. Both groups were displayed in the DST and the DCT test improved. However, in the AVLT, the phenobarbital group than the control group showed better improvement in both groups had significant difference (p=0.012).
Conclusion Phenobarbital treatment did not impair cognitive function of patients with convulsive seizures, improvement of cognitive function due to its antiepileptic effect, but long-term effects need further study.
Objective To study frequencies of polymorphisms in ABCB1and association of these polymorphisms with phenobarbital response in Hui and Han people with epilepsy.
Materials and Methods We collected clinical data of phenobarbital treatment Hui and Han in epilepsy patients, classified into the Han drug-resistant group, drug responsive group and Hui drug-resistant group, drug responsive group and collected blood of patients. SNaPshot SNP genotyping was employed to genotype of detecting ABCB1gene G1199A (rs2229109), C1236T (rs1128503), C3435T (rs1045642) and G2677T/A (rs2032582) and the MRP2gene C-24T (rs717620), G1249A (rs2273697) and C3972T (rs3740066).Haplotypes were reconstructed to ABCB1gene C1236T (rs1128503), C3435T (rs1045642) and G2677T/A (rs2032582) by SHEsis programs.Application of case-control study, we analyzed ABCB1genetic polymorphism of frequency in the Hui and Han patients with epilepsy.Logistic regression models assessed by the genotype and the risk of epilepsy, the relevance of drug resistance, and calculate the odds ratio (OR) and95%confidence intervals (CI).
Results184people with epilepsy were recruited, including32cases of Hui drug-resistant group, the Han group of62patients with drug resistance; effective control of30patients of Hui and Han control group of60patients effectively.1. The distribution of its allele frequency and the genotype was no different with Hui and Han patients with epilepsy in the ABCB1G1199A (rs2229109), C3435T (rs1045642), G2677T/A (rs2032582) and C1236T (rs1128503) and the MRP2C-24T (rs717620), G1249A (rs22736397) and C3972T (rs3740066).2. MRP2polymorphisms were no association with the efficacy of phenobarbital.3. In Han epilepsy patients, ABCB1C3435T (rs1045642) of the CC genotype of frequency distribution in drug-resistant group was higher than in the control group, and TT genotype of frequency distribution in the control group was higher than in drug-resistant group ((p=0.0047)). Logistic regression analysis showed that the CC genotype was epilepsy pharmacoresistance of an independent risk factor. CC genotype of the risk of epilepsy pharmacoresistance was been9.751times by the TT genotype (OR=9.751,95%CL:2.762-34.420. p=0.000).CT genotype happened the risk of epilepsy pharmacoresistance was been5.291times by the TT genotype (OR=5.291,95%CL:0.052-17.770,p=0.007). Hui epilepsy patients had trend (p=0.075), no significant difference. Hui and Han C allele frequencies were higher in the drug-resistant group, T allele frequency was higher in the control groups.4. In Han epilepsy patients, ABCB1G2677T/A (rs2032582) of the GG genotype of frequency distribution was high in drug-resistant group. TT genotype of the frequency distribution was high in Han control group (p=0.034). Logistic regression analysis showed that GG genotype was independent risk factor for epilepsy pharmacoresistance. GG genotype was happened the risk of epilepsy pharmacoresistance was been10.577times by the TT genotype (OR=10.577,95%CL:2.571-43.518, p=0.001).GA genotypes happened the risk of epilepsy pharmacoresistance was been4.380times by the TT genotype (OR=4.380,95%CL:1.105-17.355, p=0.036).GT genotype happened the risk of epilepsy pharmacoresistance was been4.032times by the TT genotype (OR=4.032,95%CL:1.193-13.631, p=0.025). Hui epilepsy patients had not statistically significant at this site.5. Haplotype were constructed by ABCBlgene C3435T (rs1045642), G2677T/A (rs2032582) and C1236T (rs1128503).In the Han patients with epilepsy, CGT haplotype was the frequency distribution high in the drug-resistant group. TTT haplotype was the frequency distribution high in the control group (p=0.015) Logistic regression analysis revealed that CGT haplotype was an independent risk factor for epilepsy pharmacoresistance. CGT happened risk of epilepsy pharmacoresistance was been3.483times by the TTT haplotype (OR=3.483,95%CL:1.782-6.808,p=0.000). Hui patients with epilepsy had trend (p=0.068), but not significantly.6. Logistic regression analysis revealed that alcohol, seizure frequency, time taking AEDs and generalized seizures was happened epilepsy pharmacoresistance of independent risk factors. Epilepsy pharmacoresistance had no associate with sex, age, nationality, starting age, duration, febrile seizures, smoking, medication and time from the onset.
Conclusions
1. ABCB1gene polymorphism was the frequency distribution no difference in the Hui and Han patients with epilepsy.
2. ABCB1gene C3435T loci CC genotypes, G2677T/A loci GG genotype and CGT haplotype was significantly associated with epilepsy pharmacoresistance in Han epilepsy patients. Hui epilepsy patients did not show associated with SNPs of ABCB1gene.
Objective Understand the ABCB1gene polymorphisms between cerebrospinal fluid (CSF), serum(S) concentrations of phenobarbital and the ratio of the association.
Materials and Methods By reversed-phase high performance liquid chromatography (RP-HPLC) detected of cerebrospinal fluid and serum concentrations of phenobarbital in79patients with epilepsy. SNaPshot SNP genotyping detected ABCB1gene C1236T, G2677T/A and C3435T loci genotypes in patients with epilepsy. We calculated CSF/S PB concentration ratio, to analyze the ratio of the correlation with the genotype.
Results1. CC genotype, CT genotype and TT genotype were not found S PB concentration, CSF PB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene C1236T loci (p>0.05).2. AA genotype, GA genotype and GG genotype GT genotype, TA genotype and TT genotype were not found S PB concentration, CSFPB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene G2677T/A loci (p>0.05).3. CC genotype, CT genotype and TT genotype were not found S PB concentration, CSF PB concentration and with the CSF/S PB concentration Ratio correlated in ABCB1gene C3435T loci (p>0.05).4. CAC, CGC, CGT and TTT haplotype, not found in S PB concentration, CSF PB concentration and with the CSF/S PB concentration ratio of correlated in ABCB1gene C3435T, G2677T/A and C1236T loci constructing haplotype (p>0.05). Conclusions ABCB1gene polymorphisms in cerebrospinal fluid, serum
concentrations of phenobarbital and the CSF/S PB Ratio was no correlation, need to expand the sample to further verify the experimental results.
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