盐酸美金刚联合维生素D对阿尔茨海默病患者认知功能的影响

<正>阿尔茨海默病(AD)患者是痴呆最常见的形式,不仅脑内胆碱能活性降低,同时存在谷氨酸兴奋性毒性,导致突触可塑性丧失和神经元死亡,表现为学习和记忆能力下降~[1]。临床上常用乙酰胆碱酯酶抑制剂治疗AD,可以提高脑胆碱能活动,在突触中保持较高水平乙酰胆碱,但这些药物不改变AD发病机制~[2]。相比较,盐酸美金刚治疗AD,可以改善可塑性和抑制谷氨酸兴奋性毒性~[2]。临床上盐酸美金刚治疗中、重度     

美金刚口服液治疗阿尔采末病的多中心、随机、双盲、平行对照试验

目的 评价美金刚口服液治疗中、重度阿尔采末病(AD)的有效性及安全性.方法 将237例中、重度AD患者随机分为2组,试验组服用美金刚口服溶液20 mL·d-1,对照组服用美金刚片20 mg·d-1,治疗16 wk,在wk 4、8、12和16末进行AD认知评定量表(ADAS-Cog)、日常生活能力量表(ADL)和临床疗效...     

盐酸美金刚治疗轻中度阿尔茨海默病的临床研究

目的 探讨盐酸美金刚治疗轻中度阿尔茨海默病的有效性和安全性.方法 使用简易智能状态量表（MMSE）筛选出轻、中度AD患者（评分在10～23分之间）,并对其进行12周盐酸美金刚治疗.分别于治疗前、治疗后4、12周对AD患者进行MMSE、Alzheimer病评估量表（ADAS-cog）、日常生活自理量表（ADL）评定,同时评定药物的不良反应.结果 50例轻中度AD患者盐酸美金刚治疗4周时,AD患者的MMSE、ADAS-cog和ADL指标已有所改善（P＜0.05）,治疗12周末较治疗前有显著改善（P＜0.01）.50例AD患者盐酸美金刚治疗后12w共有4例（8%）患者出现不良反应.1例出现头疼和头晕,1例出现贫血,1例出现轻度幻觉,1例表现为疲劳.不良反应经对症治疗后均好转,无死亡病例.结论 盐酸美金例不但能明显改善轻中度AD患者的认知功能和日常生活自理能力,而且具有较高的临床安全性.     

美金刚对阿尔茨海默病伴精神障碍患者治疗的研究

目的研究美金刚治疗阿尔茨海默病(AD)伴精神障碍患者的认知改善和精神症状减轻的疗效。方法采用开放性对照研究,诊断入组标准采用美国国立神经病、语言交流障碍和卒中研究所-老年性痴呆及相关疾病学会(NINCDS-ADRDA)制定的"很可能AD"诊断标准。共纳入60例AD患者,按就诊或住院顺序分为美金刚组及传统治疗组(服用吡拉西坦),连续服药12周。应用简易智力状态检查(MMSE)和神经精神症状问卷(NPI)和护理者苦恼分级评分评价疗效。结果 58例患者完成实验。美金刚组治疗后12周患者认知功能显著改善,MMSE评分显著增高,NPI评分显著降低,护理者苦恼分级评分显著降低。与传统治疗组比较,美金刚组MMSE评分变化、NPI评分变化以及护理者苦恼分级评分变化显著改善,差异均有统计学意义(P<0.05)。结论盐酸美金刚可改善中、重度AD患者的认知功能,尤其明显改善患者精神症状,并减轻照料者负担。     

国家食品药品监督管理总局批准国产盐酸美金刚原料药和制剂新药上市

国家食品药品监督管理总局于2013年8月7日发布通告，已于近期批准国产盐酸美金刚溶液和盐酸美金刚片用于中重度至重度阿尔茨海默病（AD）的治疗。     

美金刚与多奈哌齐随机对照治疗阿尔茨海默病的Meta分析

目的:系统评价美金刚治疗阿尔茨海默病(AD)的有效性和安全性。方法:按照系统评价的要求全面检索Medline、中国数字医院图书馆和中国生物医学文献光盘数据库,对符合纳入标准的文献进行分析。结果:共纳入42项研究,419例患者。美金刚(治疗组)与盐酸多奈哌齐(对照组)治疗AD的简易精神状态量表(MMSE)评分变化比较,合并比值比(OR)为0.09,经Z检验,P=0.85,治疗组与对照组的MMSE评分变化比较,差异无统计学意义;美金刚与盐酸多奈哌齐治疗AD的日常生活活动能力量表(ADL)评分变化比较,合并OR=-0.16,经Z检验,P=0.83,治疗组与对照组的ADL评分变化比较,差异无统计学意义;美金刚与盐酸多奈哌齐治疗AD的安全性比较,合并OR=0.28,经Z检验,P=0.009,治疗组与对照组在治疗AD的安全性方面比较,差异有统计学意义,美金刚较盐酸多奈哌齐不良反应发生率低。结论:美金刚治疗AD疗效确切、使用安全。     

盐酸美金刚片治疗中、重度阿尔茨海默病的临床研究

目的评估盐酸关金刚片治疗中、重度阿尔茨海默病（Alzheimer disease,AD）的有效性和安全性。方法将100例中、重度AD患者随机分为2组,对照组给予盐酸多奈哌齐10mg·d,试验组给予盐酸美金刚片20mg·d,疗程16周,每4周随访1次,评估简易精神状态量表（MMSE）、阿尔茨海默病评价量表-认知分量表（ADAS-cog）、日常生活能力量表（ADL）、临床疗效总评量表（CGI）。结果盐酸多奈哌齐组MMSE、ADAS-cog、ADL评分治疗前后比较有统计学意义（P〈0．05）,盐酸美金刚片组ADL、ADAS-cog和MMSE评分治疗前后比较有统计学意义（P〈0．05）。治疗前2组各量表评分比较（P〉0．05）与治疗16周后2组评分比较（P〉0．05）,无统计学差异。试验组不良反应率为6．25％。结论盐酸美金刚片可以改善中、重度AD患者的症状,且具有良好的安全性和耐受性。     

NMDA对老年性痴呆大鼠βAPP及BACE1表达的影响

目的 探讨N-甲基-D-天冬氨酸(NMDA)受体抑制剂(盐酸美金刚)对老年性痴呆(AD)大鼠β-淀粉样前体蛋白(APP)及β分泌酶(BACE1)表达的影响。方法 30只SD大鼠随机分为假手术组,模型组,治疗组(盐酸美金刚组);除假手术组外,其余两组大鼠海马注射10 μg β淀粉样蛋白(Aβ)1-40构建AD大鼠模型,治疗组大鼠腹腔注射10 mg/(kg.d)盐酸美金刚,其余两组给予等量生理盐水,连续给药14 d,处死大鼠取血及海马组织。ELSIA法检测血清及海马组织中Aβ含量,western blot及RT-PCR法检测海马组织中APP和BACE1蛋白及mRNA表达量。结果 与假手术组比较,模型组中Aβ含量显著提高,APP及BACE1蛋白及mRNA含量显著提高;与模型组比较,治疗组中Aβ含量显著降低,APP及BACE1蛋白及mRNA含量显著下降。结论 盐酸美金刚能通过阻断APP裂解,从而抑制AD大鼠海马组织中Aβ沉积。     

中重度至重度AD使用美金刚省钱

英国和法国的研究人员报告，美金刚(menantine)(Ⅰ)治疗的价效比好，在中重度至重度阿尔茨海默病(AD)患者中使用(Ⅰ)比不用药物治疗省钱。他们利用英国和丹麦的流行病学研究资料，以及一项记录(Ⅰ)疗效及安全性的关键性随机对照试验建立了Markov模型。该模型比较了中重度至重度AD患者两年期间使用(Ⅰ)及不用药物治疗后的费用及结果。     

美金刚的临床应用现状及进展

盐酸美金刚临床主要用于治疗中、重度阿尔茨海默病和血管性痴呆,可改善临床症状,延缓疾病进展,提高病人的生活质量。随着更多深入的临床试验研究,目前有很多美金刚应用于其他方面治疗的报道。无论长期还是短期应用,美金刚都是安全和相对经济的一种选择。     

Memantine: a review of its use in Alzheimer's disease

Memantine (Ebixa, Axura, Namenda, Akatinol) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer's type. In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer's disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer's disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer's disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer's disease.     

Alzheimer's disease and the glutamate NMDA receptor

Current treatment of Alzheimer's disease (AD) has focused on the use of cholinesterase inhibitors. This review emphasizes emerging therapies for the treatment and/or prevention of AD with a focus on glutamatergic excitotoxicity in dementia and the therapeutic promise of the uncompetitive, low to moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, memantine. Preclinical studies and clinical trials in AD, as well as the extensive clinical use of memantine for neurodegenerative conditions in Europe since 1982 support the safety, tolerability, and efficacy of this agent. Memantine was recently approved in Europe for the treatment of moderately severe to severe AD and is an investigational drug in the United States.     

Memantine hydrochloride: pharmacological and clinical profile

Memantine (Axura, Merz Pharmaceuticals GmbH; Ebixa, H. Lundbeck A/S, Namenda, Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC50 of 1-3 microM. In animal models, memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.     

Memantine

Memantine, an uncompetitive antagonist with moderate affinity for NMDA receptors, demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Memantine 20 mg/day significantly slowed the rate of deterioration in outpatients with moderate to severe Alzheimer's disease in a 28-week US randomised, double-blind, placebo-controlled, multicentre study. Memantine 10 mg/day improved measures of dementia in care-dependent inpatients with Alzheimer's disease or vascular dementia in a 12-week randomised, double-blind study. Significantly more memantine than placebo recipients were responders according to Clinical Global Impression of Change scores and the Behavioural Rating Scale for Geriatric Patients Care Dependence subscale. Memantine 20 mg/day significantly improved cognition-related outcomes (cognitive subscale of the Alzheimer's Disease Assessment Scale) in patients with vascular dementia in two 28-week randomised, double-blind, placebo-controlled, multicentre trials. No statistically significant between-group difference was seen in other primary endpoints. Adverse events (incidence in memantine recipients greater than in placebo recipients) occurring in patients with moderately severe to severe dementia included diarrhoea, insomnia, dizziness, headache and hallucination.     

Memantine for the treatment of Alzheimer's disease: tolerability and safety data from clinical trials.

BACKGROUND: Memantine, a moderate-affinity, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, is the first non-cholinergic agent approved for the treatment of Alzheimer's disease (AD), and the first medication approved in the US and Europe for the treatment of moderate to severe stages of the disease. The objective of this study was to analyse safety and tolerability data from phase III memantine trials and from the open-label extensions of those trials. METHOD: We conducted an analysis of the pooled data for tolerability and safety from six double-blind, placebo-controlled, memantine trials with a minimum duration of 24 weeks (three trials in mild to moderate AD and three in moderate to severe AD; 20 mg/day; 2311 patients) and four open-label extensions of those trials (two in mild to moderate AD and two in moderate to severe AD; 20 mg/day, 1405 patients), for a total treatment period of up to 2 years. RESULTS: The analysis revealed that adverse events occurring during both short- and long-term memantine treatment were minimal, and similar in type and frequency to those reported for placebo-treated patients. The most frequently reported adverse events in placebo-controlled trials included agitation (7.5% memantine vs 12.0% placebo), falls (6.8% vs 7.1%), dizziness (6.3% vs 5.7%), accidental injury (6.0% vs 7.2%), influenza-like symptoms (6.0% vs 5.8%), headache (5.2% vs 3.7%) and diarrhoea (5.0% vs 5.6%). Discontinuations due to adverse events were similar in memantine- and placebo-treated groups (8.9% vs 9.8%, respectively). CONCLUSION: Consistent with the favourable tolerability profile of memantine observed in clinical use, this analysis of pooled safety data indicates that both short- and long-term memantine treatment of patients with AD is safe and well tolerated, with an adverse event profile similar to that of placebo.     

Memantine in dementia: a review of the current evidence

Introduction: As the world's population ages, the incidence of Alzheimer's disease (AD) is projected to double every 20 years. Understanding the pathogenesis of AD and developing effective treatments is a public health imperative. Memantine is a low- to moderate-affinity, non-competitive NMDA receptor antagonist that is currently approved for the treatment of moderate to severe AD.

Areas covered: We discuss the current evidence, emphasizing more recent studies examining the effects of memantine in AD. We also look at the gaps in the current knowledge; the studies that will be required to fill these gaps are also discussed. The present paper reviews: the pharmacology of memantine; evidence for its use in moderate to severe AD, as well as in mild to moderate AD; adverse events related to memantine use; its effects specifically on behaviours including aggression and agitation; the pharmacoeconomics of memantine; and the use of memantine in other dementias. Memantine has shown modest benefits in cognition, function, global and behavioural measures, and has shown little potential for drug-drug interactions.

Expert opinion: For the treatment of moderate to severe AD, memantine should be offered as a therapeutic option, either on its own, or in combination with a cholinesterase inhibitor.     

Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.     

Memantine: new preparation. Poor evaluation and uncertain benefit in Alzheimer's disease

(1) The standard treatment for mild to moderately severe Alzheimer's disease is donepezil, an anticholinesterase with some beneficial effects (progression is slowed in about 10% of patients, by six months on average) and mainly gastrointestinal adverse effects. (2) Memantine, a drug first developed several decades ago, belongs to the family of NMDA glutamate receptor inhibitors. Marketing authorisation was recently granted for memantine in moderately severe and severe Alzheimer's disease. (3) The clinical evaluation dossier on memantine is poor. Marketing approval was obtained thanks to only one placebo-controlled trial. It included only 252 patients treated for 28 weeks. Patients with moderately severe Alzheimer's disease were not analyzed separately from those with severe forms, even though the response criteria are different for the two categories of patients. (4) According to the chosen endpoint, 5% to 19% of patients were clinically improved by memantine. It is not known whether this benefit persists beyond six months. (5) The report of a trial comparing memantine + donepezil with placebo + donepezil does not analyse the response rate. Use of this combination is not currently justified. (6) In clinical trials the main adverse effects of memantine were neurological (dizziness and headache). Fairly lengthy pharmacovigilance data from Germany are relatively reassuring. (7) In practice, donepezil remains the reference option for moderately severe Alzheimer's disease. Memantine is a second-line option, as its adverse effects differ from those of anticholinesterases. There is still no drug offering a clear benefit for patients with severe forms of the disease.     

Combination therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive, degenerative brain disease. The mainstay of current management of patients with AD involves drugs that provide symptomatic therapy. Two classes of medications have been approved by the US FDA for the treatment of AD: the cholinesterase inhibitors (ChEIs), which include galantamine and rivastigmine (both approved for use in mild to moderate AD) and donepezil (approved for use in mild to severe AD); and the non-competitive NMDA receptor antagonist memantine (approved for use in moderate to severe AD). The European and Asian regulatory bodies have also approved ChEIs as monotherapy in mild to moderate AD. Future research directions are mostly focusing on disease modification and prevention. This review covers key studies of the efficacy, safety and tolerability of combination therapy in AD, defined as a combination of the NMDA receptor antagonist memantine with any of the ChEIs (donepezil, galantamine or rivastigmine) for the treatment of AD. Relevant studies were identified via a PubMed search. This review shows that combination therapy for AD seems to be safe, well tolerated and may represent the current gold standard for treatment of moderate to severe AD and possibly mild to moderate AD as well.