胆碱酯酶抑制剂治疗阿尔茨海默病(老年性痴呆)的研究进展

<正>阿尔茨海默病（Alzheimer’s disease,AD）是最常见的与年龄有关的神经衰退症。随着世界老年人口的急速增长,AD发病率日趋增高,仅我国的AD患者已超过500万。AD已成为继心脑血管疾病和恶性肿瘤之后,威胁人类健康的“第三大杀手”[1]。目前,胆碱酯酶抑制剂（ChEIs）是唯一对AD有效的药物,本文综述这类药物的研究进展。1　ChEIs冶疗AD的概况 AD的病因至今仍不十分明确。神经精神病学研究显示,AD是一种复杂的神经衰退症,突触功能异常或丧失是发生痴呆的决定性因素。神经化学研究显示,在大脑皮层和海马中的突触含有乙酰胆碱（ACh）、谷氨酸、5-羟色胺（5-HT）等对AD有重要影响的递质。一系列证据提示;AD的主要临床症状是因类胆碱能的神经递质减少引起,它们包括:大脑皮层和海马中乙酰胆碱酶的减少,前脑基底前端中胆碱能递质数量的减少,这些都与AD患者认知力的欠缺有关系;前脑基底神经原的损害和乙酞胆碱中毒章碱感受器的阻滞都会影响人类与实验动物的记忆力和注意力,提示胆碱能路径对AD患者的认知力有重要作用[2]。在AD患者中,胆碱能的缺陷主要是在脑部疾病的末期发生。一项对脑部损伤不严重的AD患者的调查数据显示,在AD早期,胆碱能的耗损几乎不能甚至无法测出。而事实上,对于轻、中度AD患者,ChEIs的疗效     

M1胆碱受体激动剂治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer disease，AD)是一种以胆碱能神经元进行性退变、老年斑和神经元缠结为病理特征的神经退行性疾病。尽管AD发病机制尚未阐明，但β淀粉样肽沉积和tau蛋白磷酸化与胆碱能神经退变的恶性循环(vicious cycle)无疑是造成AD的重要病理机制之一。大量研究表明胆碱能神经突触后膜的M1受体的数目在整个病程中变化不大，M1受体选择性激动剂不但可以直接补偿胆碱能的功能，而且可以调节β淀粉样前体蛋白代谢和降低tau蛋白的过度磷酸化，有助于打破这一恶性循环，改善AD的学习记忆功能并延缓病情的发展。因此M1胆碱受体激动剂被认为是最有前途的治疗AD药物之一。目前Xanomeline、Sabcomeline等具有相对选择性M1受体激动剂业已进入新药临床试验阶段。     

阿尔茨海默病的药物治疗进展

该文从阿尔茨海默病(AD)的流行病学及病因学着手，重点介绍了改善脑血液循环和脑细胞代谢药物、改善胆碱能神经传递药物、钙离子拮抗药、激素类药物、非甾体抗炎药、自由基消除药和抗氧化药、毒蕈碱受体激动药、中药、疫苗等近年来在治疗AD病方面的研究进展。     

支气管扩张剂及祛痰药的应用评价

目的:评价抗胆碱能类药物和茶碱制剂以及祛痰药的临床应用情况。方法:收集国内外近期相关文献进行分析评价。结果及结论:抗胆碱能药物、茶碱药物和祛痰药都是临床应用较多的药物,抗胆碱能药物多用于治疗COPD和哮喘,剂量小,持续时间长,不良反应少。茶碱类药物治疗剂量和中毒剂量较接近,临床应用受到一定限制,但其药理作用广泛仍有潜在的研究前景。     

黄芩素对抗阿尔采末病及改善学习记忆能力的研究进展

阿尔采末病(Alzheimer's disease,AD)是一种以进行性认知障碍和记忆能力损害为主的中枢神经系统退行性疾病。随着人口老龄化的加剧,AD给患者及其家庭和社会带来了巨大的压力,对人类生活质量的影响乃至生存的威胁日趋明显[1,2]。对于AD这类多因素疾病,目前的治疗药物主要包括胆碱能药物、非胆碱能药物、脑细胞代谢增强剂、雌激素、抗氧化剂等。但该类药物存在问题较多,诸如作用持续时间短、毒副作用大、难于透过血脑屏障、来源困难、实际应用受限等。因此,研发理想的治疗AD的新药成为目前关注的热点。近年来,多数研究者都把目光转向天然产物,对中药、植物药逐步开展了筛选、评价及研发工作,希望从中找到治疗AD的候选药物。黄芩素作为传统中药黄芩的提取物,其表现出的抗氧化、抗炎性、抗凋亡以及改善学习记忆能力的卓越功效,使其有望成为治疗AD的潜在理想药物。     

阿尔采末病胆碱能学说研究进展

中枢胆碱能系统参与调节哺乳动物的神经元兴奋性、皮质可塑性以及学习记忆过程 ,与脑认知功能密切相关。阿尔采末病 (Alzheimersdisease ,AD)是老年性痴呆的最常见原因 ,主要表现为进行性的认知功能下降。基底前脑胆碱能损伤导致的中枢胆碱能系统功能低下是AD患者认知功能障碍的基础。在AD病程中存在一个恶性循环 ,即脑内的胆碱能神经传递早期受损 ,导致神经退行性病变的易损区内Aβ的大量产生以及tau蛋白过度磷酸化 ,而Aβ又进一步削弱胆碱能神经传递的效应 ,中枢胆碱能功能障碍可能是AD患者认知功能障碍的根源     

肝素类药物防治阿尔采末病的研究进展

本文分析了阿尔采末病(AD)的病理机制,对肝素类药物神经保护机制的进展进行了综述。阐明了肝素类药物可通过调节IP3受体介导的细胞内钙释放,影响淀粉样蛋白(Aβ)沉积及其毒性、调节tau蛋白的磷酸化状态,保护胆碱能神经元等发挥神经保护作用,从而延缓AD的发生与发展。     

57家医院阿尔茨海默病患者用药情况

目的了解北京、上海、广州(简称北上广)3个城市阿尔茨海默病(AD)患者用药情况,为临床合理用药提供参考。方法收集汇总北上广3个城市57家医院2016—2018年AD患者用药情况,对患者基本资料、处方情况、使用频度、用药方案等进行统计分析。结果在药物选择上,北上广3个城市57家医院AD患者3年间用药处方数排名前10位的药物主要为一线抗AD药物、神经营养类药物、精神症状治疗药物;一线抗AD药物主要有多奈哌齐和美金刚,均占总处方数的30%以上。具体用药方案中,胆碱酯酶抑制剂(ChEI)类药物和N-甲基-D-天冬氨酸(NMDA)受体拮抗剂类药物联用方案的占比年复合增长率增长最快(22.2%),精神症状治疗药物在AD患者中使用广泛,镇静催眠药的选择仍以苯二氮?(BZD)类药物为主。结论北上广3个城市57家医院医生在遴选AD患者用药时基本能依据指南规范,首选一线治疗药物,实现多靶点治疗,用药情况基本合理,但在精神症状治疗药物的选择上还存在一些问题,如镇静催眠药的选择仍需斟酌。     

阿尔茨海默氏病临床药物治疗进展

<正> 近年来,阿尔茨海默氏病(Alzheimer’s disease,AD)的分子基础和病理生理的研究已经取得巨大进步,但是由于AD发病机制错综复杂,尚未获得治疗该病的有效方法。因而临床工作者应该按照循证医学的观点,选择应用相对“成熟”的药物。1 胆碱酯酶抑制剂能量代谢、血流量变化和病理研究表明,AD患者大脑皮质、海马结构、边缘系统等区域的胆碱能神经     

抗阿尔茨海默症海藻天然产物及其药理机制研究进展

阿尔茨海默症(AD)是老年人群发病率最高的神经退性疾病,主要以语言、学习、记忆等认知功能受损及人格改变为特征,目前还没有治疗AD的特效药物,给社会带来的经济和健康问题日益突出。AD的发病机制十分复杂,普遍认为有β淀粉样蛋白沉积假说、tau蛋白假说、神经炎性损伤假说、胆碱能缺失假说和氧化应激假说等多种机制。海洋蕴藏着大量的藻类生物,研究表明来源于海藻的天然产物具有神经保护作用,具有开发成为治疗AD药物的潜力。我国自主研发的昆布来源的甘露寡糖二酸GV971已进入抗AD临床III期实验,为AD患者带来了新希望。本文从AD不同发病机制假说角度综述具有抗AD潜力海藻来源的天然产物及其作用机理,为抗AD海藻药物开发提供参考。     

Therapeutic frontiers in Alzheimer's disease.

Alzheimer's disease (AD), the most common type of primary degenerative dementia, is the leading cause of cognitive impairment in the geriatric population. It is a devastating illness, both to the patients and the families involved. Although much research continues to be conducted, the etiology and effective treatment for the disease remain to be found. One of the primary hypotheses of the disease is that the cognitive decline of AD involves the loss of related cholinergic neurons. Although the cholinergic theory is still valid, efforts aimed at increasing levels of acetylcholine have yielded disappointing results. Currently, in the United States, several drugs are in various stages of development for the treatment of AD. The mechanisms of these agents include cerebral protectants, enhancers of neuronal signal amplification, tonic stimulation, and nerve growth factors. Other avenues being investigated include the development of novel drug delivery systems to enhance CNS concentrations of therapeutic agents.     

Current concepts on selected plant secondary metabolites with promising inhibitory effects against enzymes linked to Alzheimer's disease

Alzheimer's disease (AD) has become one of the deadliest diseases for human beings with special incidence in elderly population. It is a progressive neurodegenerative disease and the most prevalent cause of dementia. The neuropathology of AD has not been fully elucidated yet, however, cholinergic hypothesis is the most accepted theory nowadays, resulting from the cholinergic deficit emerging in the brains of AD patients. Shortage of the neurotransmitters, acetylcholine and butyrylcholine has been demonstrated, and therefore, inhibition of the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that break down acetylcholine and butyrylcholine has become a standard approach for AD treatment. However, cholinesterase inhibitors are only effective in symptomatic treatment and have no ability to impede the disease. The pathogenesis of AD is highly complex and another hypothesis is the formation of amyloid plaques containing beta-amyloid peptide, which causes neurolesions in the brains of AD patients. Beta-amyloid peptide is generated after the sequential cleavage of amyloid precursor protein, especially by the beta- and gamma-secretase in the amyloidogenic pathway. The secretases involved in the processing of amyloid precursor protein are of particular interest and, consequently, the inhibition of secretase enzyme family of protease type has become another desired treatment strategy for AD. On the other hand, medicinal plants are attractive sources for drug research and development as they produce chemically-varying molecules with preferred biological activities. The aim of this article is to review the available data on selected inhibitors from plant secondary metabolites with emphasis on cholinesterase, prolyl endopeptidase, and secretase enzyme families as being the current treatments of AD.     

Development of new Alzheimer's disease drug candidates using donepezil as a key model

Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by β-amyloid precipitation, β-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aβ aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.     

Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents

Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning and brain deposits of amyloid beta peptide (A beta) and neurofibrillary tangles (NFT). A small fraction of early onset familial AD (FAD) is caused by mutations in genes, such as the beta-amyloid precursor protein (APP) and presenilins that increase the load of A beta in the brain. These studies together with findings that A beta is neurotoxic in vitro, provide evidence that some aggregates of this peptide are the key to the pathogenesis of AD. The yield of A beta and the processing and turnover of APP are regulated by a number of pathways including apolipoprotein E, cholesterol and cholinergic agonists. Early studies showed that muscarinic agonists increased APP processing within the A beta sequence (sAPP alpha). More recently, we have presented evidence showing that some, but not all, anticholinesterases reduce secretion of sAPP alpha as well as A beta into the media suggesting that cholinergic agonists modulate A beta levels by multiple mechanisms. Herein we review the recent advances in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. We propose and support the position that the influence of cholinergic stimulation on amyloid formation is critical in light of the early targeting of the cholinergic basal forebrain in AD and the possibility that maintenance of this cholinergic tone might slow amyloid deposition. In this context, the dual action of certain cholinesterase inhibitors on their ability to increase acetylcholine levels and decrease amyloid burden assumes significance as it may identify a single drug to both arrest the progression of the disease as well as treat its symptoms. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. We critically discuss recent trends in AD research, from molecular and genetic to clinical areas, as it relates to the effects of cholinergic agents and their secondary effects on A beta. Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development.     

The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer’s disease

The ‘second-generation’ cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer’s disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug–drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.     

Pharmacological treatment of Alzheimer disease: from psychotropic drugs and cholinesterase inhibitors to pharmacogenomics

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more "molecular approach" based on new data on the pathogenic events underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into main categories: primary events (genetic factors, neuronal apoptosis), secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction). All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis. This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment. Stem-cell activation, genetically manipulated cell transplantation, gene therapy and antisense oligonucleotide technology constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration. The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.     

Factors associated with complex visual hallucinations during antidepressant treatment

Published case reports on complex visual hallucinations (CVH) occurring during antidepressant (AD) treatment were reviewed. Thirteen cases of CVH associated with SSRI treatment, 16 cases during tricyclic drug treatment and seven cases with other AD drug treatments were found. Nine patients were taking concomitant drugs while on therapy with SSRIs and four had a neurological disease in addition to depression. The cholinergic impoverishment occurring in dementia states or during concomitant therapy with anticholinergic drugs could increase the sensitivity to serotonergic agonists, triggering the manifestation of CVH. During tricyclic drug treatment, half of the reports were of hypnopompic or hypnagogic hallucinations and this can be associated with the effects of tricyclics (TCA) on sleep architecture. It is likely that the potent anticholinergic effect of amitriptyline was potentiated in a situation of a rapidly changing state of consciousness. In general, the review supports the view that an imbalance between serotonin and acetylcholine systems is at the root of AD-induced CVH, with a profile defined by a cholinergic hypoactivity and a serotonergic hyperactivity. Caution is needed when administering a combination of serotonergic and anticholinergic AD in the treatment of the demented population and in other already compromised patients because there is a risk of precipitating CVH.     

Possibility of a new anti-alzheimer's disease pharmaceutical composition combining memantine and vitamin D

Alzheimer's disease (AD) is the leading cause of dementia. In addition to a decrease in brain cholinergic activity, AD is also marked by glutamatergic excitotoxicity that results in neuronal death, characterized clinically by a loss of learning and memory abilities. The currently available drugs for symptomatic treatment of AD (i.e. memantine and acetylcholinesterase inhibitors) only temporarily slow down the natural history of the disease process. Among them, memantine is the only one that acts as a non-competitive low-affinity modulator of N-methyl-D-aspartate (NMDA) receptors. Memantine's modulation of NMDA receptors has been reported to prevent the neuronal necrosis induced by glutamatergic calcium neurotoxicity, but not the neuronal apoptosis resulting from oxidative stress. This observation calls for new drug regimen strategies based on memantine combined with molecules having antioxidant effects, in order to create a multi-target therapy to increase neuronal protection and prevent AD progression. We wish to highlight that vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. The combination of memantine plus vitamin D may provide, in one treatment, enhanced protection against several degenerative processes linked to AD. Based on the present rationale, a clinical trial testing this hypothesis is currently in recruitment (AD-IDEA trial; ClinicalTrials.gov identifier: NCT01409694). This new pharmaceutical composition may provide an effective solution to the problem of neuronal death and cognitive decline in AD.     

神经生长因子治疗阿尔采末病的胆碱能神经机制

神经生长因子 (nervegrowthfactor,NGF)是中枢胆碱能神经元存活和功能维持最重要的神经营养因子之一 ,对阿尔采末病 (Alzheimersdisease,AD)的治疗潜力已引起人们极大兴趣。投射于大脑皮质和海马的基底前脑胆碱能神经元退变是AD早期病变 ,也是导致患者认知功能降低的主要原因。NGF可通过兴奋残存神经元上高亲和性TrkA受体 ,促进中枢胆碱能神经元的存活和正常功能的发挥 ,同时神经元激活也使其自身免受AD的有害作用 ,即所谓“useitorloseit”现象。然而 ,NGF不能透过血脑屏障 ,如何使外源性NGF到达脑内靶区是亟待解决的难题 ,一旦获得理论和技术上的突破 ,NGF防治AD的临床应用才更具价值     

Development of cholinergic drugs for the treatment of Alzheimer's disease

Alzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long-term habituation of locomotor activity and retention of a one-trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long-term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.