吡仑帕奈临床应用研究进展

癫痫是一种常见的神经系统慢性疾病,其对患者的认知、心理及社会功能都有着一定的不良影响。迄今为止,抗癫痫发作药物(Anti-seizure medications,ASMs)仍是癫痫的一线治疗选择,而在癫痫患者人群中,仍有许多癫痫患者在多种ASMs联合使用的情况下仍无法有效控制癫痫发作,因此迫切需要一种新型作用靶点及机制的ASMs来为难治性癫痫患者人群带来新的治疗选择与希望。吡仑帕奈作为一种新型第三代ASMs,相比于第二代ASMs主要倾向于通过调节离子通道或增强γ-氨基丁酸(γ-aminobutyric acid, GABA)作用等相关机制来发挥抗癫痫发作作用,吡仑帕奈主要是通过针对兴奋性神经递质-谷氨酸来发挥作用。吡仑帕奈是第一个选择性α-氨基-3-羟基-5-甲基-4-异噁唑(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate,AMPA)受体拮抗剂,也是第一个选择性抑制兴奋性突触后功能的ASMs,由于其独特的作用靶点及机制,已被世界上许多国家批准用于局灶性及全面性癫痫患者的辅助添加治疗与单药治疗。另外,随着对吡仑帕奈神经保护、抗氧化、神经...     

儿童癫痫患者中吡仑帕奈使用的专家建议

<正>吡仑帕奈是一种新型抗癫痫发作药物,属于非竞争性选择性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(a-amino-3hydroxyl-5-methyl-4-isoxazolepropionateacid,AMPA)受体拮抗剂,它通过靶向突触后膜谷氨酸活动,抑制兴奋性神经传递,从而发挥抗癫痫发作作用^[1]。2021年7月,吡仑帕奈在中国获批用于成人和4岁以上儿童局灶性癫痫(伴或不伴继发全面性发作)的单药及添加治疗^[2]。美国和日本此前已经批准该适应证,     

吡仑帕奈作为添加治疗及单药治疗疗效评价及真实世界研究现状

癫痫是世界上最常见的慢性神经系统疾病之一。迄今为止,在所有的抗癫痫治疗方法中,药物治疗仍然是治疗癫痫患者的基石。目前,已有20多种抗癫痫药可供临床医师选择,但只有约70%的癫痫患者可以通过抗癫痫药治疗,使癫痫发作得到充分控制。吡仑帕奈(PER)作为第三代新型抗癫痫药带来了新的作用机制和更优的药代动力学,且已在多个国家上市并投入临床使用。目前PER多用于癫痫患者的添加治疗,并取得了良好的疗效。而PER在单药治疗中的应用前景同样值得我们关注。该文对PER的药物特点、临床疗效及不良反应等进行阐述,并着重对吡仑帕奈作为添加治疗和单药治疗的临床试验疗效评价及近期真实世界应用现状进行汇总,为实际临床应用提供理论依据。[国际神经病学神经外科学杂志, 2022, 49(6):70-76]     

吡仑帕奈治疗儿童难治性癫痫的研究进展

吡仑帕奈是第三代新型抗癫痫药,自其上市,已经在许多国家广泛用于治疗各种儿童癫痫,并取得较好疗效。本文综述了吡仑帕奈在儿童难治性癫痫治疗方面的临床疗效、不良反应、认知功能影响等,有助于临床医生更全面地了解吡仑帕奈在儿童癫痫治疗方面的临床特点,尽可能大地在控制发作和降低不良反应间取得平衡,以更好地治疗癫痫患儿。     

Ⅲ期临床试验非盲延期阶段联合使用吡仑帕奈的局灶性癫痫患者的四年药物安全性、耐受性及发作结局：307号研究

评估307号研究(临床试验验证码:NCT00735397)Ⅲ期非盲延期阶段(OLEx)联合使用吡仑帕奈的局灶性癫痫患者的药物安全性、耐受性及痫性发作结局。患者在完成任一III期双盲试验后均可进入非盲延期阶段(Open-labelextension,OLEx)。对所有OLEx队列中有同样最小吡伦帕奈暴露剂量的局灶性癫痫和继发全面性癫痫(Secondarily generalized seizures,SGS)的患者进行药物安全性及耐受性和痫性发作结局(每28 d中位痫性发作减少率、反应率和无发作率)的分析。另外,针对OLEx的早期失访进行了额外的敏感性分析。从1 480例双盲试验中随机分组的患者共纳入1 218例。大部分患者(65.4%～80.9%)仅用吡仑帕奈12 mg,每日一次,进行治疗,并在相同剂量下完成长期的检测,或是相对基线联合使用少量抗癫痫药物(AEDs)。长期的药物安全性及耐受性结果与双盲研究一致。导致超过1%的患者研究中断治疗的紧急不良反应事件(Treatment-emergent adverse events,TEAEs)包括眩晕、易激、疲劳。有临床意义的TEAEs稳定期为4年。所有队列中患者的痫性发作结局随时间持续改善。对于接受3年(n=436)、4年(n=78)药物治疗的患者28 d中位痫性发作减少率分别为62%、70.6%,相应的50%反应率为59.6%、67.9%。最大28 d中位痫性发作减少率发生于基线水平的SGS患者,接受3年(n=190)、4年(n=28)药物治疗分别为88.0%和100.0%。在这些队列中分别有40.0%和53.6%的患者达到了无SGS。排除早期失访后的28 d中位痫性发作减少率结果类似。长期吡仑帕奈联合用药(≤4年)不会导致新的药物安全性及耐受性问题,并且可以很大程度地减少痫性发作,特别是基线水平的SGS患者。     

吡仑帕奈治疗儿童难治性癫痫的疗效和安全性研究

目的评估吡仑帕奈在儿童难治性癫痫患者中的有效性、安全性与耐受性。方法回顾性分析2020年1月—2021年1月在苏州大学附属儿童医院就诊的34例难治性癫痫患儿的病历资料,通过对比患儿的基线情况与吡仑帕奈添加治疗后第4、8、12、24、36、48周的癫痫发作情况,来评估吡仑帕奈的疗效与不良反应。结果患儿添加吡仑帕奈治疗时的平均年龄为(8.1±4.1)岁,男女性别比为1∶1。吡仑帕奈添加治疗后,第4、8、12、24、36、48周的有效率分别为37.5%、46.7%、50.0%、47.4%、53.8%、42.9%,不良反应发生率为32.4%,药物保留率为88.2%。结论吡仑帕奈治疗难治性癫痫具有良好的有效性、安全性与耐受性。个性化治疗和较好的基线发作控制水平或许可以提高吡仑帕奈治疗的有效性和药物保留率。     

新型抗癫痫药物的研究进展

癫痫常需多种药物联合治疗。目前,拉科酰胺,依佐加滨,吡仑帕奈和醋酸艾司利卡西平等新型抗癫痫药物不断被应用到临床试验中。本文对近年应用于临床新药的作用机制、临床评价、安全性、药代动力学、药效学、注意事项及药物相互作用方面的研究进展进行综述。     

第三代新型抗癫痫药吡仑帕奈在癫痫治疗中的研究进展

吡仑帕奈是第三代新型抗癫痫药物(AEDs),也是首个治疗癫痫的高度选择性非竞争性α-氨基-3-羟基-5-甲基-4-异喃恶唑丙酸(a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid,AMPA)型谷氨酸受体拮抗剂.现已在许多国家广泛用于治疗各种癫痫,并取得较好疗效.文章...     

吡仑帕奈单药治疗儿童局灶性癫痫的临床疗效研究

目的 探讨吡仑帕奈(Perampanel,PER)单药治疗在儿童局灶性癫痫的疗效及安全性。方法 选取2021年1月—2022年6月在无锡市儿童医院神经内科就诊新发、既往未使用过抗癫痫发作药物的局灶性癫痫患儿46例,其中男24例、女22例,平均年龄(7.2±2.4)岁,PER单药治疗组为PER组(23例),左乙拉西坦(Levetiracetam,LEV)单药治疗组为LEV组(23例),对比两组的临床疗效及不良反应发生情况。结果 3个月PER组总有效率为87.0%(20/23),LEV组总有效率为73.9%(17/23),P<0.05,差异有统计学意义;6个月PER组总有效率为78.3%(18/23),LEV组总有效率为60.9%(14/23), P<0.05,差异有统计学意义。PER组有2例患儿出现不良反应,其中嗜睡1例、头晕1例,通过暂时减少药物剂量、减慢加药速度,不良反应均消失。LEV组有3例患儿出现不良反应,均为不同程度的暴躁易怒,通过减慢加药速度,3～6个月期间2例患儿症状消失,1例患儿症状减轻。结论 新型抗癫痫发作药物PER对于局灶性癫痫具有较好的抗癫痫效果,优于L...     

疑似奥卡西平加重局灶性癫痫患者临床表现与EEG变化1例报告

正奥卡西平(OXC)是一种新型的抗癫痫药物(AED),是用于局灶性癫痫的一线治疗药物。OXC虽被认为治疗局灶性癫痫有效,但可加重某些患者局灶性癫痫发作,如伴中央颞区棘波的良性儿童癫痫(BECT)。现报道1例局灶性癫痫患者口服OXC期间症状和EEG恶化,疑与OXC有关。1病例患者,男,18岁,因"发作性意识丧失4年"于2016年3月就诊我科。患者4年前出现发作性意识丧失,均发生     

Neuroimaging in epilepsy in tropics

Epilepsy is a major public health problem in many tropical countries. Also, some of the tropical diseases are major contributors to the higher prevalence of epilepsy in these countries. The etiologic factors responsible for epilepsy in these countries are quite different from those in the developed world. This article discusses the etiologic factors and neuroimaging of epilepsy in light of the conditions in these tropical countries.     

癫痫与抑郁关系的研究进展

抑郁是癫痫患者中常见的精神障碍,严重地影响了患者的生活质量。传统的观点认为癫痫患者因为存在着诸多社会学问题易出现抑郁倾向,癫痫和抑郁是单向的联系,但大量的研究已经证明癫痫和抑郁之间存在双向的联系,一种异常状态的存在可能易转化为另一种异常状态的发展。癫痫和抑郁存在着共同的发病机制。本文主要就癫痫和抑郁的双向联系以及抗抑郁药物在癫痫患者中的应用进行阐述。     

Sudanophilic lipid accumulation in astrocytes in periventricular leukomalacia in monkeys

Summary Sudanophilic lipid accumulation is a characteristic feature of periventricular leukomalacia (PVL) of infants. At least two types of lipid-containing cells have been identified, one being the macrophage, the other the pre-myelin glial cell. A third type of lipid-containing cell has been seen in two monkeys with spontaneous PVL. Electron microscopically this cell appears to be an astrocyte. This probably represents a reaction of the astrocyte to hypoxia and may be the equivalent of the hypertrophic astrocytes found in human infants.Supported in part by NIH grant HDO 8633 and the Regional Primate Research Center Grant RR-00166     

Increase in cathepsin D activity in rat brain in aging

Cathepsin D-like activity in homogenates of five brain areas of 3-month-old and 24-month-old Fischer 344 rats was measured. With hemoglobin as substrate at pH 3.2, more than 90% of the activity was inhibited by pepstatin. In each area studied, activity was more than twice as high in the old rat brain: 140-160% higher in the cortex, cerebellum, pons-medulla, and striatum and 90-100% higher in the hippocampus and spinal cord. The greatly increased metabolic capacity in the absence of an increase in protein turnover may have a role in age-related pathological degeneration in the brain.     

Characteristics of nociceptors in the periodontium--an in vitro study in rats

Recent studies have indicated that nociceptors can be classified into various types according to their physiological properties. These studies have clarified that the frequency distribution of various nociceptor types is different among body sites and animal species. In the present study, we investigated the physiological properties of rat's periodontal nociceptors in an in vitro jaw-nerve preparation. Responses were recorded from functional single filaments in the inferior alveolar nerve. To determine the nociceptor type, calibrated von Frey filaments, heat, and bradykinin (BK) stimuli were used. We found five subtypes of nociceptors in the periodontal ligaments of the lower incisor: Adelta-high threshold mechanonociceptors (Adelta-HTM, n=28), Adelta-mechanoheat nociceptors (Adelta-MH, n=6), Adelta-polymodal nociceptors (Adelta-POLY, n=26), C-high threshold mechanonociceptors (C-HTM, n=3) and C-polymodal nociceptors (C-POLY, n=4). Most nociceptors were Adelta-innervated, while only a small number of C-innervated nociceptors were found. The present results suggest that periodontal nociceptors transmit mainly fast pain, and may thus play a role in rapid detection of injure-related stimuli during mastication.     

Gender in Voice Perception in Autism

Deficits in the perception of social stimuli may contribute to the characteristic impairments in social interaction in high functioning autism (HFA). Although the cortical processing of voice is abnormal in HFA, it is unclear whether this gives rise to impairments in the perception of voice gender. About 20 children with HFA and 20 matched controls were presented with voice fragments that were parametrically morphed in gender. No differences were found in the perception of gender between the two groups of participants, but response times differed significantly. The results suggest that the perception of voice gender is not impaired in HFA, which is consistent with behavioral findings of an unimpaired voice-based identification of age and identity by individuals with autism. The differences in response times suggest that individuals with HFA use different perceptual approaches from those used by typically developing individuals.     

Defects in Bioenergetic Coupling in Schizophrenia

Synaptic neurotransmission relies on maintenance of the synapse and meeting the energy demands of neurons. Defects in excitatory and inhibitory synapses have been implicated in schizophrenia, likely contributing to positive and negative symptoms as well as impaired cognition. Recently, accumulating evidence has suggested that bioenergetic systems, important in both synaptic function and cognition, are abnormal in psychiatric illnesses such as schizophrenia. Animal models of synaptic dysfunction demonstrated endophenotypes of schizophrenia as well as bioenergetic abnormalities. We report findings on the bioenergetic interplay of astrocytes and neurons and discuss how dysregulation of these pathways may contribute to the pathogenesis of schizophrenia, highlighting metabolic systems as important therapeutic targets.     

Ethnic disparities in problem behaviour in adolescence contribute to ethnic disparities in social class in adulthood

BACKGROUND: It is important for prevention of social class disparities to know how ethnic disparities in social class arise among migrant children. We contribute to this understanding by examining the role of problem behaviour in adolescence. METHODS: Prospective observational study with 753 Dutch native and 217 Turkish migrant adolescents (11-18 year) followed for 10 years. Internalising and externalising problems were assessed in adolescence and employment status and occupational level were assessed in adulthood. The difference in odds ratios (OR) before and after adjustment for internalising and externalising problems was an indication of the predictive value of disparities in internalising and externalising problems for the development of social class disparities. RESULTS: A total of 135 (62%) of the Turkish and 602 (80%) of the Dutch adults were employed. Internalising and externalising problems were not associated with employment status. Of the employed, 65 (48%) Turkish and 179 (30%) Dutch adults worked in low-level occupations (p < 0.0001). Internalising and externalising problems were associated with both ethnicity and occupation. The OR for low-level occupation for Turkish adults was 1.78 (1.19-2.65), indicating ethnic disparities. Adjustment for internalising problems lowered the OR with 36% to 1.50 (0.97-2.31), and adjustment for externalising problems lowered it with 8% to 1.72 (1.15-2.57). Findings were similar for men and women and did not vary by age. CONCLUSIONS: Ethnic disparities in occupational level in adulthood could partly be attributed to disparities in mental health between Turkish migrants and Dutch natives in adolescence. Prevention of ethnic disparities in mental health at young age may therefore also contribute to the prevention of occupational differences in adulthood.     

Progress in neuroprotection in Parkinson's disease

Slowing or aborting the progress of neurodegeneration in Parkinson's disease (PD) remains the most important unmet need of this disorder. There are several recent developments in trial design and also in drugs under investigation for possible neuroprotective effect. Emphasis has been placed on clinical as opposed to imaging end-points and these include change in a clinical rating scale, e.g. United Parkinson's disease Rating Scale (UPDRS), or time to additional therapy. The introduction of the delayed-start, or wash-in, trial design adds an additional dimension to drug evaluation for neuroprotection. Compounds that have been recently tested in clinical trial include the monoamine oxidase-B inhibitor rasagiline, the anti-apoptotic agents TCH346 and CEP1347, and the promitochondrial agent creatine. The dopamine agonists have been evaluated for a neuroprotective effect using imaging end-points. Perhaps the most important and simplest concept for neuroprotection has been the theory that early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients.     

Changes in parasympathetic system in medulla oblongata in male pigs in the course of tachycardia-induced cardiomyopathy

Background

Autonomic imbalance constituting a fundamental feature of heart failure (HF) has been assessed mainly at the periphery. Changes in the functioning of autonomic centers in the brain remain unclear. We investigated the molecular elements of parasympathetic system, i.e. α7 nicotinic acetylcholine receptor (α7nAChR) and enzymes metabolizing acetylcholine (acetylcholinesterase, AChE, choline acetyltransferase, ChAT) in medulla oblongata (MO) of male pigs with chronic tachycardia-induced cardiomyopathy.

Methods

The mRNA levels of AChE, ChAT, α7nAChR and X-box binding protein 1 (spliced form, XBP1s) in MO were analyzed using qPCR, AChE and ChAT activities using spectrophotometry, proteasome activity using fluorometry, and the protein level of α7nAChR using Western blotting.

Results

The development of systolic HF was accompanied by an increase in circulating catecholamines, a decrease in the AChE and α7nAChR mRNA in MO, an increase in AChE activity (all p < 0.05), and no change in either the mRNA or activity of ChAT. Both circulating catecholamine levels and AChE activity were inversely related to systolic function of left myocardial ventricle (p < 0.05). The level of α7nAChR protein in MO and its cytoplasmatic fraction were higher in pigs with moderate and severe HF as compared to the other animals (p < 0.01). There was no difference in proteasome activity in MO between diseased and healthy animals, whereas the XBP1s mRNA decreased during HF progression (p < 0.05).

Conclusions

Molecular elements of parasympathetic system are changed within the medulla oblongata during the progression of systolic non-ischemic heart failure in male pigs, indicating a functional link between MO and heart in HF.