阿尔茨海默病防治药物研究进展

阿尔茨海默病（Alzheimer’s disease,AD）是一种中枢神经系统变性疾病,早期是隐匿性认知功能减退,在510年内发展成严重的记忆丧失、行为和人格改变、语言障碍、丧失独立生活能力,最终近似植物人状态,常因褥疮、肺炎等继发性感染死亡。AD发病率与年龄高度相关,60岁左右人群的发病率为1%,之后约每56年翻一番[1]。随着世界人口老龄化,AD成为社会广泛关注的问题。AD患者具有神经炎性斑、神经纤维缠结、神经纤维的串珠样变性和弥漫性斑等标志性病理学特征[2]。这些特征在疾病进程中的作用仍存在争议,但最终会导致内嗅区皮层、海马区、     

中医药防治老年痴呆的研究进展

随着世界人口的老龄化，老年痴呆的发病率也大大增加，据统计65岁以后每隔5年的发病率呈指数增长。北京协和医院最新流行病学调查结果表明，我国是世界上痴呆患者最多的国家，65岁以上老人老年痴呆患病率高达10．1％，约有500万老人患痴呆。其中310万老人患阿尔茨海默病(Alzheimersdisease,AD)，占6．6％：140万     

阿尔茨海默病的治疗现状

阿尔茨海默病(Alzheimer disease，AD)是一种神经变性疾病，临床特征表现为进行性记忆和认知功能丧失。世界范围约1500万人受累。65岁人群的发病率为每年0．5%，85岁以后为8%。因为患病后仍能存活10多年，患病率在65岁为3％，至85岁为47%。遗传性AD多于60岁以前发病，证实是淀粉样前身蛋白基因的突变和早老素(presenilin)1和2的基因突变所致；而散发性AD和某些家族性AD发现有四种载脂蛋白E(apollipoprotein E,apoE)的变异型。     

特应性皮炎治疗新药——地索奈德泡沫剂

<正>特应性皮炎(Atopic dermatitis,AD)的临床特征是持续瘙痒性的红色皮疹,好发于幼年期,大约80%的患者在5岁前发病,11岁以前儿童AD的累积发病率为10%～20%[1]。流行病学调查显示,近半个世纪以来,AD的发病率有逐渐升高的趋     

阿尔茨海默病的治疗进展

阿尔茨海默病(AD)是一种进行性以高级认知功能障碍和记忆功能丧失为特征的疾病。其发病率随年龄增加而增高,65岁的发病率约为0.5%,至85岁以上可达8%,目前全世界有1700～2500万AD患者[1],AD给患者及家属带来了深重的负担和痛苦。至今为止,AD的病因与发病机制尚未完全明确,更没有     

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     

利斯的明的临床研究与安全性评价

阿尔茨海默病(Alzheimerdisease,AD)也称老年性痴呆或早老性痴呆,是一种可引起脑功能逐渐衰退的神经退行性疾病,主要表现为认知功能障碍、日常生活能力丧失及精神行为异常。在美国引起死亡的疾病当中,AD仅次于心血管病、癌症和脑卒中,被列为第四位。近年来我国AD流行病学调查结果显示,老年人患病率与西方国家相近,北方地区65岁以上居民AD发病率为4.2%;目前我国60岁以上老年人口约1.3亿,占总人口10%,预计至下世纪中叶可达4亿人左右,将成为世界上老龄人口最多的国家。因此,AD病的治疗研究已成为人们关注的热点,2000年6月,国家药品食品监…     

γ-分泌酶、淀粉样前体蛋白和早老蛋白1在阿尔采末病中相关性的研究进展

阿尔采末病近年来发病率逐渐升高,对其发病机制的研究逐步深入。APP、PS1为已被明确的痴呆基因,γ-分泌酶是生成Aβ的限速酶,三者都是目前AD领域研究的热点,但是三者在AD间的具体相互作用机制及过程迄今还尚未明确,这些都可能是发现AD治疗新途径的潜在位点。     

阿尔茨海默病中β-淀粉样蛋白毒性作用的研究现状

阿尔茨海默病(alzheimer's disease,AD)是老年期痴呆症中最常见的一种进行性神经变性疾病,在65岁以上老年人中的发病率为7%-10%,80岁以上老年人中发病率大约为40%[1].     

全球首个非激素类特应性皮炎软膏进入我国

目前,我国特应性皮炎(简称AD)发病率正逐年上升,治疗时通常使用激素类外用药物,疗效肯定但众多副作用成为健康隐患。世界上非激素治疗AD的第一种外用免疫调节剂——他克莫司软膏(商品名:普特彼),已被批准进入我国市场。     

F-18 stilbenes as PET imaging agents for detecting beta-amyloid plaques in the brain

Imaging agents targeting beta-amyloid (Abeta) may be useful for diagnosis and treatment of patients with Alzheimer's disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Abeta plaques in AD brain homogenates (Ki = 15 +/- 6 and 5.0 +/- 1.2 nM, respectively). In vivo biodistributions of [18F]3e and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75% dose/g at 2 min), and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Abeta plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Abeta plaque imaging agents for studying patients with AD.     

Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and thus, the in vivo imaging of plaques and tangles would be beneficial for the early diagnosis of AD. It has been suggested that 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (curcumin) may be responsible for low age-adjusted prevalence of AD in India. In the present study, eight novel derivatives of curcumin and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (dehydrozingerone) were synthesized and their binding affinities for beta-amyloid (Abeta) aggregates were measured. Of these ligands, fluoropropyl-substituted curcumin (8) showed the highest binding affinity (Ki=0.07 nM), and therefore, 8 was radiolabeled and evaluated as a potential probe for Abeta plaque imaging. Partition coefficient measurement and biodistribution in normal mice demonstrated that [18F]8 has a suitable lipophilicity and reasonable initial brain uptake. Metabolism studies also indicated that [18F]8 is metabolically stable in the brain. These results suggest that [18F]8 is a suitable radioligand for Abeta plaque imaging.     

Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents

The synthesis and evaluation of a series of neutral analogues of thioflavin-T (termed BTA's) with high affinities for aggregated amyloid and a wide range of lipophilicities are reported. Radiolabeling with high specific activity [(11)C]methyl iodide provided derivatives for in vivo evaluation. Brain entry in control mice and baboons was high for nearly all of the analogues at early times after injection, but the clearance rate of radioactivity from brain tissue varied by more than 1 order of magnitude. Upon the basis of its rapid clearance from normal mouse and baboon brain tissues, [N-methyl-(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]6-OH-BTA-1) was selected as the lead compound for further evaluation. The radiolabeled metabolites of [(11)C]6-OH-BTA-1 were polar and did not enter brain. The binding affinities of [N-methyl-(3)H]6-OH-BTA-1 for homogenates of postmortem AD frontal cortex and synthetic Abeta(1-40) fibrils were similar (K(d) = 1.4 nM and 4.7 nM, respectively), but the ligand-to-Abeta peptide binding stoichiometry was approximately 400-fold higher for AD brain than Abeta(1-40) fibrils. Staining of AD frontal cortex tissue sections with 6-OH-BTA-1 indicated the selective binding of the compound to amyloid plaques and cerebrovascular amyloid. The encouraging in vitro and in vivo properties of [(11)C]6-OH-BTA-1 support the choice of this derivative for further evaluation in human subject studies of brain Abeta deposition.     

Quick assembly of 1,4-diphenyltriazoles as probes targeting beta-amyloid aggregates in Alzheimer's disease

Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to Abeta aggregates (Ki = 4-30 nM), were conveniently assembled by "click chemistry." Two radioiodinated probes, [125I]10a and [125I]10b, and two radiofluorinated probes, [18F]17a and [18F]17b, exhibited moderate lipophilicities and showed excellent initial brain penetrations and fast washouts from the normal mouse brain. In vitro autoradiography of postmortem AD brain sections and homogenates showed that these triazoles were binding to Abeta plaques. Preliminary results strongly suggest that use of click chemistry, which led to a 1,4-diphenyltriazole-based core, is a highly convenient and flexible approach for assembling novel imaging agents for targeting Abeta aggregates in senile plaques in the living human brain.     

Synthesis and evaluation of 11C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as PET tracers for imaging β-amyloid plaques in Alzheimer's disease

We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.     

Radioligand development for PET imaging of beta-amyloid (Abeta)--current status

Two of the main pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques and neurofibrillary tangles. Significant evidence supports a critical and probable causative role of beta amyloid (Abeta) plaque formation. Since neuroprotective treatments are typically most effective at early stages of injury, the detection and measurement of Abeta load in living brain should be performed at early and perhaps even presymptomatic stages of AD. Two primary targets of molecular imaging research with positron emission tomography (PET) are to develop surrogate markers (radioligands) for assessing disease progression and for monitoring the efficacy of developmental therapeutics. Here, we review the current status of radioligand development for PET imaging of Abeta aggregates. General structure-activity relationships have emerged, including the identification of at least three different ligand binding sites in various Abeta aggregates and recognition of the general structural requirements for ligand binding at each site. Also a few radioligands applicable to imaging Abeta plaques in living human brain with positron emission tomography (PET) have emerged, including [(11)C]PIB, [(11)C]SB-13 and [(18)F]FDDNP.     

Isomerization of (Z,Z) to (E,E)1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene in strong base: probes for amyloid plaques in the brain.

In developing probes for detecting beta-amyloid (Abeta) plaques in the brain of Alzheimer's disease (AD), we have synthesized 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (5, BSB). Due to the presence of two double bonds, formation of four different isomers is possible. Four isomers, E,E-5, E,Z-5, Z,E-5, and Z,Z-5, were prepared. Surprisingly, all showed strong fluorescent labeling of Abeta plaques in the brain of postmortem brain sections of patients with confirmed AD. In vitro binding assay also showed that all four isomers of BSB (E,E-5, E,Z-5, Z,E-5, and Z,Z-5) displayed a similar high binding affinity inhibiting the binding of [(125)I]E,E-6, 1-iodo-2,5-bis-(3-hydroxycarbonyl-4-methoxy)styrylbenzene (IMSB) to Abeta(1-40) aggregates. The inhibition constants (K(i)) of E,E-5, E,Z-5, Z,E-5, and Z,Z-5 were 0.11 +/- 0.01, 0.19 +/- 0.03, 0.27 +/- 0.06, and 0.13 +/- 0.02 nM, respectively. Due to the fact that geometric stability of these styrylbenzenes is unknown, and the conversion of Z,Z-5 to E,E-5 may occur automatically in the binding or labeling assaying conditions, we have investigated the kinetics of conversion of Z,Z-5 to E,E-5 by NMR in D(2)O/NaOD at elevated temperatures (70, 95, and 115 degrees C). The activation energy was determined to be 14.15 kcal/mol. The results strongly suggest that the isomeric conversion at room temperature in aqueous buffer solution is unlikely. All of the styrylbenzene isomers clearly showed potential as useful tools for studying Abeta aggregates in the brain. The data suggest that, despite the rigidity of this series of styrylbenzenes, the binding sites on Abeta aggregates may have certain flexibility and the binding pockets could be adaptable for binding to other smaller ligands. Such information could be exploited to develop new ligands for detecting amyloid plaques in AD.     

Synthesis and structure-affinity relationships of new 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine derivatives as ligands for human beta-amyloid plaques

A new and extensive set of 4-(6-iodo-H-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine (IMPY) derivatives was synthesized and assayed for affinity toward human Abeta plaques. 6-Ethylthio- (12h), 6-cyano- (12e), 6-nitro- (12f), and 6-p-methoxybenzylthio- (15d) analogues were discovered to have high affinity (KI < 10 nM). However, introduction of a hydrophilic thioether group in the 6-position (15a-c, 15e-g) reduced or abolished affinity. In secondary N-methyl analogues, a bromo substituent in the adjacent ring position (14a) imparted high affinity (KI = 7.4 nM) whereas a methyl substituent did not (14c). The tolerance for nonhydrophilic thioether substituents in the 6-position opens up the possibility of developing new sensitive positron emission tomography radioligands for imaging human Abeta plaques in Alzheimer's disease, especially in view of the amenability of thioethers to be labeled with carbon-11 or fluorine-18 through S-alkylation reactions. The structure-activity relationships revealed in this study extends insight into the topography of the binding site for IMPY-like ligands in human Abeta plaques.     

Synthesis of 6-[2-(Benzoxazol-2-ylmethylamino)ethoxy]-1-Alkyl-1H-lndole-2-Carboxylic acid and inhibitory activity on β-Amyloid aggregation

6-[2-(benzoxazol-2-ylmethylamino)ethoxy]-1-alkyl-1H-indole-2-carboxylic acids were designed and synthesized as beta-amyloid (Abeta) fibril assembly inhibitors. Their inhibitory activity on Abeta, aggregation was evaluated by thioflavin T assay although their activities were insignificant.     

Novel benzofuran derivatives for PET imaging of beta-amyloid plaques in Alzheimer's disease brains

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.