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1.
目的探讨谷胱甘肽S-转移酶π(GST-π)、DNA拓扑异构酶Ⅱ(TopoⅡ)及P-糖蛋白(P-gp)在难治性癫癎(RE)患者脑内的表达及意义。方法32例RE患者手术切除标本,采用免疫组化方法检测GST-π、TopoⅡ及P-gp表达。8例脑血管畸形患者作为对照。结果对照组正常脑组织内星形胶质细胞及血管内皮细胞中有少量GST-π表达(2·2),癫癎组GST-π表达明显增强(10·9,P<0·05)。TopoⅡ在对照组中无表达,癫癎组2例标本有少量表达(0·4,P>0·05)。对照组中P-gp只在脑内血管内皮细胞中少量表达,癫癎组P-gp则在星形胶质细胞及血管内皮细胞中大量表达(12·9,P<0·01)。结论GST-π、P-gp在RE患者脑内表达可能与患者对抗癫癎药耐药有关。  相似文献   

2.
目的 观察难治性颞叶癫痫患者脑组织中多药耐药相关蛋白1( MRPl)及应用MRP1拮抗剂丙磺舒干预后的表达,探讨MRP1与难治性颞叶癫痫多药耐药的关系.方法 应用免疫组化检测难治性颞叶癫痫患者脑组织实验组和对照组MRP1的表达情况,同时应用免疫蛋白印记(Western blot)方法检测实验组、丙磺舒干预组和对照组MRP1的表达.结果 免疫组化结果显示MRP1在难治性颞叶癫痫患者脑组织中表达增强,与对照组比较差异有显著性(P<0.05).Western blot结果显示丙磺舒干预组MRP1蛋白水平较实验组明显较少,差异有显著性(P<0.05).结论 脑内高表达的MRP1参与难治性颞叶癫痫的耐药机制,丙磺舒可以降低脑组织内MRP1的表达.  相似文献   

3.
目的 探讨主穹窿蛋白(major vault protein,MVP)在颞叶癫痫大鼠模型脑组织的表达及其与难治性癫癎耐药是否相关.方法 用氯化锂-匹鲁卡品制作颞叶癫癎模型,并将它分为药物有效组和耐药组;用免疫组化和Western blot法检测MVP表达.结果 MVP主要表达在海马和皮质区的小胶质细胞,血管内皮细胞,血管周围的星形胶质细胞也有表达,神经元中少见表达;耐药组MVP表达较药物有效组和对照组明显增高,具有统计学意义(P<0.05).结论 耐药大鼠模型中MVP过量表达,提示MVP可能与难治性癫癎的耐药性有关.  相似文献   

4.
目的探讨主穹窿蛋白(major vault protein,MVP)在颞叶癫癎大鼠模型脑组织的表达及其与难治性癫癎耐药是否相关。方法用氯化锂-匹鲁卡品制作颞叶癫癎模型,并将它分为药物有效组和耐药组;用免疫组化和Westernblot法检测MVP表达。结果MVP主要表达在海马和皮质区的小胶质细胞,血管内皮细胞,血管周围的星形胶质细胞也有表达,神经元中少见表达;耐药组MVP表达较药物有效组和对照组明显增高,具有统计学意义(P〈0.05)。结论耐药大鼠模型中MVP过量表达,提示MVP可能与难治性癫癎的耐药性有关。  相似文献   

5.
目的 通过对P-糖蛋白、多药耐药相关蛋白和肺耐药相关蛋白在难治性癫痫相关局灶性皮质发育不良脑组织中表达部位的初步研究,以及对其在不同程度病变脑组织中表达量的比较,进一步阐明难治性癫疴的耐药机制,为癫(癎)患者的临床合理用药提供理论依据.方法 选取16例难治性癫(癎)患者手术切除脑组织标本作为患者组(局灶性皮质发育不良Ⅰ型和Ⅱ型患者各8例),5例无癫(癎)发作病史的胶质瘤患者手术切除脑组织标本的非病灶区域作为对照组.应用Envision二步法进行免疫组织化学标记,观察3种耐药蛋白在脑组织中的表达部位和表达强度;应用Western blot法进行SDS-聚丙烯酰胺凝胶电泳,对3种耐药蛋白在脑组织中的表达进行定量分析.结果 P-糖蛋白主要表达于毛细血管内皮细胞,多药耐药相关蛋白主要表达于脑组织内的神经元成分,肺耐药相关蛋白的表达则涌盖了毛细血管内皮细胞、气球细胞及病灶区域部分基质.3种耐药蛋白在局灶性皮质发育不良脑组织中的表达均显著高于对照组脑组织(P-糖蛋白:0.520±0.121,多药耐药蛋白:0.132±0.018,肺耐药相关蛋白:0.092 4-0.018,U=0.000,P<0.01),其中P-糖蛋白和肺耐药相关蛋白在局灶性皮质发育不良Ⅱ型患者的病灶区域(3.809±0.842、0.655±0.303)表达高于病灶周围区域(2.636 4±0.622、0.290±0.096,U=6.000、4.500,P<0.01).结论 P-糖蛋白、多药耐药相关蛋白和肺耐药相关蛋白在不同程度的局灶性皮质发育不良脑组织中具有不同的表达部位和表达量,提示其作用机制和作用强度有所差异.  相似文献   

6.
难治性癫(refractoryepilepsy ,RE)的发病机制一直是近年来研究的难点与热点。以往的研究发现,某些临床特征可能预示RE的发生,包括发病年龄早(1岁以前)、治疗前发作频繁、有高热惊厥史、第一种抗癫药物治疗失败、联合使用两种抗癫药而不能控制发作、有结构性脑损伤以及癫发作类型(如部分性发作)等[1] 。引起RE的原因可能由多因素造成,比如遗传因素、治疗期间抗癫药物耐受问题以及目前所使用的抗癫药作用机制的局限性等[2 ] 。近年来对RE的研究重点集中在多药耐药机制上,与肿瘤患者对多种化疗药物耐药的机制相似,RE的发生可…  相似文献   

7.
目的研究难治性癫患者外周血中多药耐药1(MDR1)基因的表达以及抗癫药物和性发作在难治性癫多药耐药发生中的作用。方法采用逆转录聚合酶链反应(RT-PCR)半定量检测120例研究对象外周血中MDR1基因mRNA的表达。根据析因设计分性发作和抗癫药物两个因素,共分为A组(难治性癫组)、B组(癫治疗有效组)、C组(性发作未用药组)和D组(健康正常对照组),各30例。结果4组的外周血中MDR1基因的表达水平明显不同(F=4.456,P=0.005),其中性发作引起MDR1mRNA的表达明显增高(F=10.005,P=0.002),抗癫药物的作用则不明显(F=0.919,P=0.340),抗癫药物与性发作两者之间没有交互作用(F=2.445,P=0.121)。结论难治性癫患者外周血中MDR1基因mRNA的表达上调是性发作而非使用抗癫药物的结果,外周血中MDR1基因mRNA表达水平的监测可以作为评价癫耐药的一项指标。  相似文献   

8.
目的 观察多药转运蛋白[P-糖蛋白(P-glycoprotein,PGP)和多药耐药相关蛋白(multi-drug resistance associated protein,MRP)]对匹罗卡品慢性癫(癎)大鼠模型海马内拉莫三嗪浓度的影响,探讨PGP和MRP在难治性癫(癎)多药耐药机制中的作用.方法 建立匹罗卡品慢性癫(癎)动物模型,在模型大鼠海马内安置微透析探针,腹腔注射拉莫三嗪(10mg/kg)后于不同时间点收集透析液,并用高效液相色谱检测其中的药物浓度.通过微透析探针局部分别给予PGP拮抗剂维拉帕米和MRP拮抗剂丙磺舒,观察维拉帕米和丙磺舒对模型鼠海马内神经元细胞外液拉莫三嗪浓度的影响.结果 维拉帕米明显升高了癫(癎)大鼠海马细胞外液拉莫三嗪的药物浓度,在给药后60、90、120、150 min(0.65±0.11、0.84±0.09、0.70±0.09和0.58±0.08)与模型组(0.41±0.10、0.50±0.04、0.39±0.09和0.30±0.06)比较差异有统计学意义(F=5.01、8.61、10.23、7.89,P<0.05),丙磺舒也提高了海马内拉莫三嗪的浓度,给药后90、120、150 min(0.75±0.09、0.58±0.10和0.49±0.07)与模型组比较差异有统计学意义(F=6.58、4.56、4.75,P<0.05).结论 PGP和MRP均能够限制拉莫三嗪通过癫(癎)大鼠血脑屏障,从而降低了海马内拉莫三嗪的药物浓度,上述机制可能参与了难治性癫(癎)耐药的发生.  相似文献   

9.
目的 研究杏仁核电刺激点燃的难治性癫痫大鼠脑内多药耐药相关蛋白1(multidrug resistant-associated protein 1 MRP1)表达的情况.方法 建立杏仁核电刺激点燃的难治性癫痫大鼠模型,用免疫组织化学及免疫蛋白印记(western blot)的方法,分析比较MRP1蛋白在癫痫模型组与正常对照组的表达.结果 药物难治性癫痫大鼠组脑内多药耐药相关蛋白的表达显著高于正常对照组(P〈0.01).在癫痫大鼠脑内广泛分布的MRP1免疫阳性细胞主要为毛细血管内皮细胞和星形胶质细胞.结论 癫痫大鼠脑内高表达的MRP1参与了难治性癫痫的耐药机制.  相似文献   

10.
目的探讨杏仁核电点燃及海人酸点燃难治性癫大鼠模型脑组织及外周血P糖蛋白(Pgp)过度表达的可能机制,并比较不同方法致难治性癫大鼠脑组织及外周血中Pgp的表达趋势。方法应用电刺激点燃及海人酸点燃方法对大鼠杏仁核进行点燃,制作难治性癫模型;将其分为A组(杏仁核电点燃,12只),B组(杏仁核海人酸点燃,12只),另设C组(杏仁核埋入电极而不点燃,且给予卡马西平灌胃,8只),D组(杏仁核注射生理盐水,且给予卡马西平灌胃,8只),E组(杏仁核埋入电极而不点燃,且给予生理盐水灌胃,8只),F组(杏仁核注射生理盐水,且给予生理盐水灌胃,8只);采用免疫组化方法分析两种模型大鼠脑组织及外周血Pgp的表达。结果A组、B组大鼠脑组织及外周血Pgp表达明显高于其余4组,差异有统计学意义(均P<0.05);C组、D组大鼠脑组织及外周血Pgp表达高于E组及F组,差异有统计学意义(均P<0.05);A组与B组大鼠脑组织及外周血Pgp的表达差异无统计学意义。结论脑组织及外周血Pgp的过度表达可能是未能控制的癫发作、服用抗癫药(AEDs)等多因素共同作用的结果;难治性癫发生1个月后,脑组织中Pgp高表达的大鼠外周血中Pgp的表达...  相似文献   

11.
Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.  相似文献   

12.
B. J. Wilder 《Epilepsia》1987,28(S2):S1-S7
Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.  相似文献   

13.
Diagnostic Difficulties and Treatment Implications   总被引:1,自引:0,他引:1  
Robert J. Gumnit 《Epilepsia》1987,28(S3):S9-S13
Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.  相似文献   

14.
Cognitive Dysfunction Associated with Antiepileptic Drug Therapy   总被引:7,自引:5,他引:2  
Eileen P.G. Vining 《Epilepsia》1987,28(S2):S18-S22
Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.  相似文献   

15.
Hepatic Considerations in the Use of Antiepileptic Drugs   总被引:5,自引:4,他引:1  
Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.  相似文献   

16.
Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity   总被引:5,自引:1,他引:4  
G. Trube  R. Netzer 《Epilepsia》1994,35(S5):S62-S67
Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.  相似文献   

17.
Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.  相似文献   

18.
Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.  相似文献   

19.
Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.  相似文献   

20.
Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.  相似文献   

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