Giacobini E
Department of Geriatrics, University Hospitals of Geneva, University of Geneva, Medical School, Switzerland.
Jpn J Pharmacol. 1997 Jul;74(3):225-41. doi: 10.1254/jjp.74.225.
Clinical trials in the USA, Japan and Europe have confirmed the hypothesis that a steady state increase of acetylcholine resulting from cholinesterase inhibition in the brain results in an improvement of cognitive function in mild to moderate Alzheimer disease (AD) patients. During the last decade, a systematic effort to develop a pharmacological treatment for AD has resulted in two drugs being registered for the first time in the USA and Europe for this specific indication. Both are cholinesterase inhibitors (ChEI). Based on these first positive results, several second generation ChEI are being developed. An additional effect of certain ChEI is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. It is possible that the drug effect is one of slowing down cognitive deterioration. Comparison of clinical effects of 5 ChEI demonstrates a rather similar magnitude of improvement. For some drugs, this may represent a limit, while for others it may be possible to increase the benefit further. To maximize and prolong positive drug effects, it is important to start early and adjust the dosage during the treatment. Other strategies may involve combinations with other cholinergic drugs such as muscarinic or nicotinic agonists. A second important class of drugs which is being developed is that of muscarinic m1 agonists. However, their clinical use is still limited by side effects. The increased knowledge and recognition of the beta-amyloid molecule as a central focus of AD pathology has strongly stimulated research with the hope of finding ways of influencing its processing and deposition. At this point, no product in this line of development has reached clinical trial level. Other pharmacological approaches are related to preventive and neuroprotective interventions (estrogens, anti-oxidants and anti-inflammatories). In conclusion, given the relatively short time of research in this field, results are encouraging.
美国、日本和欧洲的临床试验证实了这样一种假说：大脑中胆碱酯酶抑制导致乙酰胆碱稳态增加，可改善轻度至中度阿尔茨海默病（AD）患者的认知功能。在过去十年中，为开发AD的药物治疗方法而进行的系统努力，已使两种药物首次在美国和欧洲获批用于这一特定适应症。这两种药物均为胆碱酯酶抑制剂（ChEI）。基于这些初步的积极结果，几种第二代ChEI正在研发中。与安慰剂相比，某些ChEI的另一个作用是在6个月至1年的治疗期内将认知功能维持在恒定水平。药物作用可能是减缓认知衰退。5种ChEI临床效果的比较显示改善程度相当相似。对某些药物来说，这可能是一个局限，而对另一些药物来说，可能有进一步增加获益的可能。为了最大化并延长药物的积极作用，尽早开始治疗并在治疗期间调整剂量很重要。其他策略可能包括与其他胆碱能药物联合使用，如毒蕈碱或烟碱激动剂。正在研发的另一类重要药物是毒蕈碱m1激动剂。然而，它们的临床应用仍受副作用限制。对β-淀粉样蛋白分子作为AD病理核心焦点的认识和重视不断增加，有力地推动了相关研究，以期找到影响其加工和沉积的方法。目前，这一研发领域尚无产品进入临床试验阶段。其他药理学方法与预防和神经保护干预措施（雌激素、抗氧化剂和抗炎药）有关。总之，鉴于该领域的研究时间相对较短，结果令人鼓舞。
