石杉碱甲药剂学相关研究进展

石杉碱甲为高效、高选择性、可逆的乙酰胆碱酯酶抑制剂,由于其在治疗阿尔茨海默病方面的显著疗效,引起世界各国药学工作者广泛关注和研究.石山碱甲虽为难溶性生物碱,但其口服吸收迅速而完全,现有的剂型研究主要集中在亲水凝胶骨架片、缓释包衣小丸、透皮缓释贴剂、鼻用凝胶脑靶向制剂以及注射用缓释微球等缓控释给药系统,且多数经体内外评价证实具有显著的缓控释特征.文中综述了石杉碱甲药剂学相关的研究进展,包括其基本理化性质、体内外吸收和代谢动力学以及新型给药系统(尤其是缓控释制剂)等,以期为进一步开发高效、低毒、稳定、方便的新产品提供剂型选择依据和处方研究参考.     

石杉碱甲缓释微球的安全性药理研究

石杉碱甲为胆碱酯酶抑制剂,对乙酰胆碱酯酶具有选择性抑制作用,易通过血脑屏障,具有促进记忆再现和增强记忆保持的作用。石杉碱甲缓释微球是以石杉碱甲为主要成分制成的长效缓释制剂,用于“良性记忆障碍以及痴呆、脑器质性病变引起的记忆障碍”,给药途径为肌肉注射,使用剂量为1.5mg/(人.14d);大鼠给药后72h药效最强。按化学药品新药审批的有关技术要求,观察了石杉碱甲缓释微球对动物精神神经系统、心血管系统和呼吸系统的影响。结果显示股四头肌肌肉注射石杉碱甲缓释微球300,600和1200μg/kg72h对小鼠的自主活动、一般行为、协调运动无明显…     

石杉碱甲鼻用原位凝胶喷雾剂的制备及稳定性研究

目的：开发石杉碱甲经鼻脑靶向给药系统。方法：制备了石杉碱甲溶液、环糊精包合物、微乳、嵌断共聚物纳米粒和原位凝胶5种剂型，通过考察各剂型的纤毛毒性和体外透牛嗅黏膜扩散特性，选择原位凝胶为最佳剂型。以每喷主药含量、黏度、渗透压、粒径和体外释药特性等为考察指标筛选出原位凝胶喷雾剂的优化处方，并对其进行了稳定性研究。结果：以优化处方制备的喷雾剂，加速试验和长期留样试验6个月，内容物性状、pH值、黏度、粒径、渗透压、有关物质、含量和每喷含量无明显变化。结论：石杉碱甲鼻用原位凝胶喷雾剂制备工艺简便，制剂稳定，纤毛毒性低，药物透牛嗅黏膜扩散快而完全，适宜开发为经鼻脑靶向给药系统。     

“重大创新药物——石杉碱甲”专题征稿启事

<正>为展示近年来石杉碱甲相关研究成果,进一步开发、利用石杉科植物资源,本刊将出版1期"重大创新药物——石杉碱甲"专题。关注与石杉碱甲有关的研究、开发与应用。专题注重内容包括石杉科植物的资源、栽培、采收加工及与石杉碱甲相关的化学、质量分析、药理、毒理、制剂、药动、临床、上市等     

“重大创新药物——石杉碱甲”专题征稿启事

<正>为展示近年来石杉碱甲相关研究成果,进一步开发、利用石杉科植物资源,本刊将出版1期"重大创新药物——石杉碱甲"专题。关注与石杉碱甲有关的研究、开发与应用。专题注重内容包括石杉科植物的资源、栽培、采收加工及与石杉碱甲相关的化学、质量分析、药理、毒理、制剂、药动、临床、上市等     

“重大创新药物——石杉碱甲”专题征稿启事

<正>为展示近年来石杉碱甲相关研究成果,进一步开发、利用石杉科植物资源,本刊将出版1期"重大创新药物——石杉碱甲"专题。关注与石杉碱甲有关的研究、开发与应用。专题注重内容包括石杉科植物的资源、栽培、采收加工及与石杉碱甲相关的化学、质量分析、药理、毒理、制剂、药动、临床、上市等     

“重大创新药物——石杉碱甲”专题征稿启事

<正>为展示近年来石杉碱甲相关研究成果,进一步开发、利用石杉科植物资源,本刊将出版1期"重大创新药物——石杉碱甲"专题。关注与石杉碱甲有关的研究、开发与应用。专题注重内容包括石杉科植物的资源、栽培、采收加工及与石杉碱甲相关的化学、质量分析、药理、毒理、制剂、药动、临床、上市等     

Anticholinesterase effects of huperzine A,E2020,and tacrine in rats

目的：比较石杉碱甲、Ｅ２０２０和他克林对大鼠胆碱酯酶的抑制作用．方法：比色法测定大鼠各脑区的ＡＣｈＥ及血清中ＢｕＣｈＥ活力．结果：三药灌胃后对大鼠脑中ＡＣｈＥ均产生剂量依赖性抑制．以石杉碱甲作用最强．他克林对ＢｕＣｈＥ的抑制显著强于Ｅ２０２０和石杉碱甲，其副反应最为明显．单次经口给药后，石杉碱甲对脑内ＡＣｈＥ的抑制作用长于Ｅ２０２０和他克林．多次给药后，对胆碱酯酶的抑制作用三药均未有耐受性产生．结论：石杉碱甲是一种高选择性ＡＣｈＥ抑制剂，具有口服活性高，作用时程长，副反应小的优点，适于临床应用．     

石杉碱甲磷脂原位凝胶的制备及其在大鼠体内的药动学研究

目的 制备石杉碱甲磷脂原位凝胶(PSE-H)并研究其在大鼠体内的药动学.方法 采用直接载药法制备PSE-H,建立石杉碱甲(Hup A)血浆样品的分析方法,研究不同剂量制剂及制剂中Hup A油酸复合物的形成对PSE-H药动学特征的影响.结果 PSE-H在体内持续释放Hup A达15 d.将Hup A制备成油酸复合物可降低制剂中药物的突释作用;随着制剂重量的增加,缓释作用增强,突释作用降低.结论 通过直接载药法制备PSE-H,方法简便可行,Hup A在体内持续释放达15 d,有望成为可生产的缓控释新剂型.     

本刊“重大创新药物——石杉碱甲”专题征稿启事

<正>为展示近年来石杉碱甲相关研究成果,进一步开发、利用石杉科植物资源,本刊将出版1期"重大创新药物——石杉碱甲"专题。关注与石杉碱甲有关的研究、开发与应用。专题注重内容包括石杉科植物的资源、栽培、采收加工及与石杉碱甲相关的化学、质量分析、药理、毒理、制剂、药动、临床、     

The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques

Nootropic agents or cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible cognitive enhancers, huperzine A and IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty. Huperzine A is a reversible acetylcholinesterase (AChE) inhibitor, its administration results in regionally specific increases in acetylcholine levels in the brain. In human clinical trials, Huperzine A resulted in cognitive improvement in patients with mild to moderate form of Alzheimer's disease (AD) showing its potential as a palliative agent in the treatment of AD. IDRA 21 is a positive allosteric modulator of glutamate AMPA receptors. It increases excitatory synaptic strength by attenuating rapid desensitization of AMPA receptors and may thus have beneficial therapeutic effects to ameliorate memory deficits in patients with cognitive impairments, including AD. The present study evaluated the effects of the two drugs in normal, intact, young adult monkeys to determine whether they can result in cognitive enhancement in a system that is presumably functioning optimally. Six young pigtail macaques (Macaca nemestrina) were trained on delayed non-matching-to-sample task, a measure of visual recognition memory, up to criterion of 90% correct responses on each of the four delays (10s, 30s, 60s, and 90s). They were then tested on two versions of the task: Task 1 included the four delays intermixed within a session and the monkeys performed it with the accuracy of 90%. Task 2 included, in each of 24 trials, a list of six objects presented in succession. Two objects from the list were then presented for choice paired with novel objects and following two of the four delays intermixed within a session. This task with a higher mnemonic demand yielded an average performance of 64% correct. Oral administration of huperzine A did not significantly affect the monkeys' performance on either task. However, a significant negative correlation was found between the baseline performance on each delay and the change in performance under huperzine A, suggesting that under conditions in which the subjects were performing poorly (55-69%), the drug resulted in improved performance, whereas no improvement was obtained when the baseline was close to 90%. In fact, when the subjects were performing very well, huperzine A tended to reduce the performance accuracy, indicating that in a system that functions optimally, the increased availability of acetylcholine does not improve performance or memory, especially when the animals are close to the maximum performance. In contrast, oral administration of IDRA 21 significantly improved performance on Task 2, especially on the longest delay. This finding supports the potential use of this drug in treatment of cognitive and memory disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

石杉碱甲国内临床应用回顾

近年来已有多个胆碱酯酶抑制剂被批准用于治疗阿尔采末病。从民间草药蛇足石杉分离到的新型生物碱石杉碱甲,是一种高效、高选择性的中枢乙酰胆碱酯酶抑制剂。临床前试验证实石杉碱甲对一系列认知障碍模型动物的学习和记忆均有改善作用,1994年批准在国内临床用于治疗阿尔采末病和良性记忆障碍。随着临床应用的扩大,发现石杉碱甲对血管性痴呆及不同病因引起的认知功能障碍也表现出较好的疗效,具有广阔的临床应用前景。     

石杉碱甲改善老年大鼠水迷宫操作记忆障碍(英文)

目的:测试石杉碱甲对自然衰老及东莨菪碱导致的空间记忆缺损的作用。方法:采用大鼠的水迷宫操作,检测石杉碱甲对获得及记忆的作用。结果:连续7天获得试验期间,皮下注射石杉碱甲0.1-0.2mg/kg能明显缩短老年大鼠找到平台的潜伏期。在第8天撤去平台的记忆测试,石杉碱甲0.1,0.2与0.4 mg/kg明显延长老年大鼠在该平台区的游泳时间。单次腹腔注射东莨菪碱0.1mg/kg明显损害已训练达标老年大鼠的空间记忆。皮下注射石杉碱甲0.4 mg/kg明显翻转东莨菪碱产生的记忆损害作用。结论:石杉碱甲能改善老年大鼠自然衰老或东莨菪碱产生的记忆障碍。     

Huperzine A ameliorates the impaired memory of aged rat in the Morris water maze performance

AIM: To determine the memory-improving properties of huperzine A in aged rats with memory impairments naturally occurring or induced by scopolamine. METHODS: Morris water maze was used to investigate the effects of huperzine A on the acquisition and memory impairments. RESULTS: During 7-day acquisition trials, aged rats took longer latency to find the platform. Huperzine A (0.1-0.2 mg/kg, s.c.) could significantly reduce the latency. In the probe trials on the eighth day, huperzine A (0.1, 0.2 and 0.4 mg/kg, s.c.) significantly increased the time in the quadrant where plateform had disappeared in aged rats. In the acute experiment, scopolamine (0.1 mg/kg, i.p.) significantly impaired spatial memory in the trained aged rats. Huperzine A (0.4 mg/kg, s.c.) significantly reversed the memory deficits induced by scopolamine. CONCLUSION: Huperzine A ameliorates the impaired memory naturally occurring or induced by scopolamine in aged rats.     

Huperzine A

Huperzine A, an alkaloid isolated from Huperzia serrata, is a putative nootropic agent developed by the Chinese Academy of Sciences. Huperzine A is currently in phase III trials in China for the treatment of patients with Alzheimer's disease. The mechanism of action of huperzine A is suggested to be facilitated through the slow reversible inhibition of acetylcholinesterase. Marco Hi-Tech Joint Venture has exclusive worldwide marketing and distribution rights to huperzine A. Marco Hi-Tech Joint Venture is a corporation principally owned by Hi-Tech Pharmacal and Marco International, a global trading and finance firm formed to import huperzine A from China. Marco Hi-Tech Joint Venture also has rights to synthetic analogues of huperzine A. In July 2003, Savient Pharmaceuticals acquired the exclusive rights from Marco Hi-Tech to market huperzine A in Europe and the US. Clinical trials of huperzine A in elderly patients with age-associated memory loss are underway in the US, and a phase II study funded by an NCI grant is being planned.     

Prolonged effects of poly(lactic-co-glycolic acid) microsphere-containing huperzine A on mouse memory dysfunction induced by scopolamine

Huperzine A is an anticholinesterase and cognitive enhancer, which is able to alleviate the symptoms of memory dysfunction in the mouse. The fast metabolization rate and narrow therapeutic spectrum makes it unfit for clinical use. Poly(lactic-co-glycolic acid) microsphere as delivery system effectively maintains the blood concentration of huperzine A by a slow-release effect over a long time. In the present article, we investigated the prolonged protective effect of microsphere-containing huperzine A on memory dysfunction induced by scopolamine. Spectrophotometric assay was used to determine the activity of acetylcholinesterase (AChE) and passive avoidance tests to evaluate memory performance. The results show that a bolus dose of microsphere-containing huperzine A (at a dose of 300 microg/kg or 600 microg/kg) administered intramuscularly can effectively maintain drug activity and significantly decrease the activity of AChE from day 3 to 14, the strongest effect seen on day 3 and 7. Accompanying the reduction of the activity of AChE, microsphere-containing huperzine A (300 microg/kg or 600 microg/kg) remarkably increased transfer latency time and no transfer response on the second trial through mitigating the memory impairments induced by scopolamine as compared to the scopolamine model group. Microsphere-containing huperzine A showed cognitive enhancing properties and anticholinesterase activity and may thus be a candidate for treatment of memory impairment.     

Systemic administration of the potential countermeasure huperzine reversibly inhibits central and peripheral acetylcholinesterase activity without adverse cognitive-behavioral effects

Huperzine A is potentially superior to pyridostigmine bromide as a pretreatment for nerve agent intoxication because it inhibits acetylcholinesterase both peripherally and centrally, unlike pyridostigmine, which acts only peripherally. Using rhesus monkeys, we evaluated the time course of acetylcholinesterase and butyrylcholinesterase inhibition following four different doses of -(-)huperzine A: 5, 10, 20, and 40 μg/kg. Acetylcholinesterase inhibition peaked 30 min after intramuscular injection and varied dose dependently, ranging from about 30% to 75%. Subsequently, cognitive-behavioral functioning was also evaluated at each dose of huperzine A using a six-item serial-probe recognition task that assessed attention, motivation, and working memory. Huperzine did not impair performance, but physostigmine did. The results demonstrate that huperzine A can selectively and reversibly inhibit acetylcholinesterase without cognitive-behavioral side effects, thus warranting further study.     

石杉碱甲的含量测定与药动学研究进展

石杉碱甲作为治疗阿尔采末病的一种有效药物,在临床上的应用取得了较大的进展。随着检测技术的发展,关于石杉碱甲含量测定及药动学的研究也越来越多。本文就目前石杉碱甲含量测定及药动学研究进行综述,以期为石杉碱甲的研究提供参考。     

石杉碱甲对血管性痴呆小鼠海马NMDA受体及mRNA表达的影响

目的:观测石杉碱甲对血管性痴呆小鼠海马神经元N-甲基D-天门冬氨酸(NMDA)受体免疫组化和原位杂交变化的影响,探讨石杉碱甲干预作用的机制.方法:双侧颈总动脉线结,反复缺血-再灌注法制备模型,药物组用石杉碱甲溶液灌胃,跳台试验和水迷宫试验观测其行为学改变,采用免疫组化和原位杂交技术观测小鼠海马神经元NMDA受体及其mRNA的表达变化.结果:在跳台试验中,模型组小鼠学习阶段的反应时间延长、错误次数增加,记忆阶段的潜伏时间缩短、错误次数增加;水迷宫试验中,其学习阶段的游全程时间延长和错误次数增加,记忆阶段的游全程时间延长和错误次数增加(与假手术组相比,P＜0.01).石杉碱甲明显改善了模型小鼠上述学习、记忆成绩(P＜0.01).同时,药物组海马的NMDA受体及其mRNA表达也较模型组的表达明显增高(P＜0.01),且海马两者的表达在药物组与假手术组间差异无显著性.结论:石杉碱甲改善血管性痴呆小鼠学习、记忆成绩与其恢复海马低水平的NMDA受体及其mRNA有关.