Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease.
Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease.
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DOI：
10.1111/j.1527-3458.2002.tb00221.x
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发表时间：
2006-06
期刊：
影响因子：
--
通讯作者：
S. Lilienfeld
中科院分区：
文献类型：
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作者：
S. Lilienfeld
加兰他敏氢溴酸盐是一种三级生物碱药物，已在包括美国和欧洲几个国家在内的许多国家开发并批准用于治疗轻度至中度阿尔茨海默病（AD）。加兰他敏具有独特的双重作用模式。它是一种可逆的竞争性乙酰胆碱酯酶（AChE）抑制剂，是唯一一种积极上市的治疗AD的药物，经证实具有作为烟碱乙酰胆碱受体（nAChR）变构调节剂的活性。后一种活性被认为是特别重要的，因为nAChR的表达和活性的降低对AD患者中枢胆碱能神经传递的减少有很大贡献。加兰他敏表现出良好的药代动力学特征，包括在推荐维持剂量（16和24 mg/天）下可预测的线性消除动力学、相对较短的半衰期（约7 h）和高生物利用度。它在多种途径中广泛代谢，主要通过细胞色素P450酶CYP 2D 6和CYP 3A 4在肝脏中代谢，发生具有临床意义的药物间相互作用的可能性较低。在长达6个月的四项大型随机、双盲、安慰剂对照试验中，加兰他敏16和24 mg/天显著有益于认知和整体功能，进行日常生活活动（ADL）和行为的能力，相对于安慰剂和基线，长达6个月。看护者负担（看护者监督患者或帮助他们进行ADL所花费的时间）和看护者痛苦（与患者的行为症状相关）也有所减少。在一项长期美国研究中，接受加兰他敏24 mg/天治疗12个月的患者的认知和功能能力保持在基线或接近基线水平至少12个月。这些益处通过早期和持续的加兰他敏治疗而最大化，并且再次与照顾者负担的显著减少相关。加兰他敏治疗与脑血管疾病有关的痴呆症的疗效试验也取得了积极的结果。没有与加兰他敏使用相关的安全性问题。不良事件的发生率，特别是影响胃肠道系统的胆碱能介导的事件，通常较低，并且可以使用推荐的缓慢剂量递增方案最小化。因此，加兰他敏可能有助于减轻照顾痴呆症患者的总体负担和成本。考虑到所有证据，加兰他敏有可能成为痴呆症的一线治疗药物。
Galantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild-to-moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half-life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug-drug interactions. During four large randomized, double-blind, placebo-controlled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who received galantamine 24 mg/day for 12 months in a long-term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose-escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first-line therapy for dementia.