Koch Horst J, Szecsey Alexander, Haen Ekkehard
Psychiatrische Universitätsklinik, Universitätsstrasse 84, D-93053 Regensburg, Germany.
Curr Pharm Des. 2004;10(3):253-9. doi: 10.2174/1381612043386392.
Memantine, a non-competitive NMDA antagonist, has been clinically used in the treatment of dementia in Germany for over ten years. The rationale for this indication is strongly related to the physiological and to the pathological role of glutamate in neurotransmission. Physiologically, NMDA receptors mediate synaptic plasticity by acting as a coincidence detector. Only those synapses that show temporally and spatially discrete activation of NMDA receptors undergo plastic changes secondary to Ca++ influx after rapid unblocking of Mg++, thus crucially contributing to memory and learning processes. The voltage-dependency of Mg++ is so pronounced that under pathological conditions it leaves the NMDA channel upon moderate depolarisation, thus interrupting memory and learning. Its pharmacological properties allow memantine to rapidly leave the NMDA channel upon transient physiological activation by synaptic glutamate (restoring significant signal transmission), but to block the sustained activation of low glutamate concentration under pathological conditions, i.e. to protect against excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes as it ameliorates cognitive and memory deficits. Memantine has shown to be effective and safe in the treatment of dementia, particularly Alzheimer's disease, in controlled clinical trials. Provided that the dose is slowly increased it is generally well tolerated and safe up to 20 and 30 mg per day, with intake preferably in the morning. The compound is completely absorbed after oral intake with Cmax values after 6 hours, undergoes little metabolism and has a terminal elimination half life between 60 and 100 hours. Due to its low potential of interaction, memantine can be combined with acetylcholinesterase inhibitors, the mainstay of current symptomatic treatment of Alzheimer's disease and it is suited in elderly patients receiving multiple drug therapy.
美金刚是一种非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂，在德国临床上用于治疗痴呆症已有十多年。这一适应症的理论依据与谷氨酸在神经传递中的生理和病理作用密切相关。生理上，NMDA受体作为一种巧合探测器介导突触可塑性。只有那些在Mg++快速解除阻断后显示NMDA受体在时间和空间上离散激活的突触，在Ca++内流后才会发生继发的可塑性变化，从而对记忆和学习过程起到关键作用。Mg++的电压依赖性非常明显，以至于在病理条件下，它会在适度去极化时离开NMDA通道，从而中断记忆和学习。其药理特性使美金刚在突触谷氨酸短暂生理性激活时能迅速离开NMDA通道（恢复显著的信号传递），但在病理条件下能阻断低谷氨酸浓度的持续激活，即防止兴奋性毒性作为神经退行性疾病的发病机制。在基于神经退行性和血管过程的各种动物模型中，美金刚作为神经保护剂可改善认知和记忆缺陷。在对照临床试验中，美金刚已证明在治疗痴呆症，尤其是阿尔茨海默病方面有效且安全。只要缓慢增加剂量，通常耐受性良好，每天服用20毫克和30毫克时是安全的，最好在早晨服用。该化合物口服后完全吸收，6小时后达到Cmax值，代谢很少，终末消除半衰期在60至100小时之间。由于其相互作用的可能性低，美金刚可与乙酰胆碱酯酶抑制剂联合使用，乙酰胆碱酯酶抑制剂是目前阿尔茨海默病对症治疗的主要药物，它适用于接受多种药物治疗的老年患者。
