痴呆药物治疗的全球研究进展

Global Drug Development in Dementia

发展更加有效的痴呆治疗方法，特别是对阿尔采默氏病的治疗是当前亟需国际协力合作的一项重大的全球性任务。阿尔采默氏病的生物学治疗包括几方面：对症治疗。阿尔采默氏病认知障碍的生物学基础无疑是多方面的。研究的焦点集中在乙酰胆碱。阿尔采默氏病“胆碱能假说”的提出就是基于许多实验。全球为开发促胆碱药物（ｃｈｏｌｉｎｏｍｉｍｅｔｉｃｄｒｕｇｓ）进行了多方尝试，包括胆碱前体物，胆碱酶抑制剂，选择性ＭＮ型胆碱受体激动剂。早期应用胆碱前体的尝试未能成功。最成功的方法是胆碱酶抑制剂的开发，这类药物抑制乙酰胆碱的分解，使其在突触间隙中贮存的时间更长。毒扁豆硷（ｐｈｙｓｏｓｔｉｇｍｉｎｅ）是早期用的实验药物，但其半衰期短，限制了临床应用。第一种在美国获准的药物是Ｔａｃｒｉｎｅ。Ｄｏｎｅｐｅｚｉｌ是美国和欧洲批准的第二个乙酰胆碱酯酶抑制剂。此药物具备良好性能，应用更加容易：胆碱酶抑制剂如ｒｉｖａｓｔｉｇｍｉｎｅ，Ｍｅｔｒｉｆｏｎａｔｅ和缓释口服毒扁豆硷也正在申请报批，ｒｉｖａｓｔｉｇｍｉｎｅ刚刚在英国获得批准。值得关注的天然植物提取物ｇａｌａｎｔａｍｉｎｅ和ｈｕｐｅｒｚｉｎｅ分别是从番红花球茎和一种中草药中提炼出夹的。Ｎ型受体激动剂为?

Abstract The development of more effective treatments for dementia, particularly Alzheimer′s Disease is a major global challenge requiring international collaboration and cooperation Basic neuroscience discoveries, novel approaches to development of medications and a spirit of innovation in long term care will serve us well as we approach the next millennium The world is continuing to age at a rapid rate In countries that are industrialized, prevalence rates of individuals over the age of 65 are now approaching 20%.In the future more older people will live in the less industrialized parts of the world and the rate of aging in some of those countries is even greater than those in western Europe and North America China, for example, has implemented a successful birth control program that will lead to a larger number of individuals surviving into their later years However the combination of more older people with fewer younger people to develop and maintain the economy will lead to potentially tremendous econoinic difficulties that will be shared by the countries around the world at different times during their development Unfortunately, older individuals are more at risk for cognitive impairment due to dementia The most common dementia in the world for older individuals is probably Alzheimer′s Disease, although in some countries vascular dementia rivals that claim Alzheizer′s Disease is a progressive neuropsychiatric condition in which death of nerve cells are associated with patholngical hallmarks, namely senile plaques and neurofibrillary tangles (Whitehouse et al, 1982 [12] ) The death of nerve cells occurs in selective populations, including cholinergic basal forebrain, bioaminergic locus coeruleus and raphe nuclei, hippocampus amygdala and various regions of the neocortex This cell loss is associated with loss of neurotransmitter markers including acetyl choline, noradrenaline, serotonin, corticotrophin releasing factor and somatostatin (Price et al, 1986, [11] ) In the early stages of disease it may be difficult to differentiate Alzheimer′s Disease from normal age related cognitive decline In the mild stages, loss of memory and attention is sometimes associated with changes in personality In the moderate stages the cognitive problems progress to involve language and perception and the patient becomes partially dependent on others for their activities of daily living, In the final stages, the patient′s cognitive impairment progresses to the point where they may not be able to recognize family or even speak and they may become completely dependent on their caregivers The course with vascular diseases is somewhat different, as the etiology appears most commonly to be multiple small strokes, although other pathogenic mechanisms might be at work Thus, the clinical course is frequently stuttering and the pattern of neuropsychological disabilities variable depending on where the strokes appear The diagnostic criteria for vascular dementia are a little less clear than Alzheimer′s Disease, thus the rates of multi infarct dementia diagnosed in different countries varies (McKhann et al 1984; NINCDS AIREN, [19] ) A combination of vascular dementia and Alzheimer′s Disease is also a common cause of dementia In this paper we will review the biological treatments of Alzhemier′s Disease,focusing on current efforts to produce drugs to improve symptoms as well as to alter the natural course of the illness Finally, we will make some comments about non biological therapies and the importance of integrating them with drug treatment We will conclude by discussing some of the future opportunities and challenges that lie ahead