老年痴呆症大流行:扑热息痛是罪魁祸首吗?

Günther Robert Norman Jones
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引用次数: 0

摘要

历史背景:临床上认识到一种与阿尔茨海默病极为相似的痴呆症可追溯到 1800 年左右。从煤焦油中提取的镇痛剂在这一流行病的传播中所起的作用可追溯到 1887 年苯乙哌啶(PN)的问世;其肾毒性;费舍尔和阿尔茨海默氏症患者观察到的这一疾病的特征性病变;以及苯乙哌啶的主要代谢产物扑热息痛(PA)的发现;发现扑热息痛(PA)是苯乙哌啶的主要代谢产物;肾损伤和痴呆症与大量使用苯乙哌啶有关;以及用扑热息痛替代苯乙哌啶未能阻止和逆转阿尔茨海默型痴呆症发病率的指数式增长。费舍尔在阿尔茨海默病之前就观察到了他的第一个病例;有人建议将该综合征重新命名为费舍尔-阿尔茨海默病(F-AD)。疾病发展:PA 代谢酶位于额叶皮层和海马的突触区,F-AD 病变就发生在这些区域。肝中毒的起始化学损伤包括 PA 代谢的高活性产物与蛋白质的共价结合;类似的事件据信也会发生在大脑中,大脑蛋白质抗原特征的改变会激活小胶质细胞。β-淀粉样蛋白形成后,与 PA 本身一样,会诱导一氧化氮合酶。过氧化亚硝酸盐通过硝化酪氨酸残基修饰脑蛋白,进一步挑战小胶质细胞并加剧淀粉样蛋白级联。自发性神经再支配、N-乙酰半胱氨酸给药和酪氨酸补充可减轻 F-AD 的早期发展:结论:F-AD 主要是一种人为疾病,其主要风险因素是 PA。
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The Alzheimer pandemic: is paracetamol to blame?

Historical background: The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD). Disease development: PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.

Conclusion: F-AD is primarily a man-made condition with PA as its principal risk factor.

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