心臟血管藥物治療阿滋海默病之研究

Acetylcholinesterase Inhibition by the Cardiovascular drugs for Alzheimer's disease

邱世英(Shyh-Ying Chiou)

指導教授 ： 林隆堯

中山醫學大學/醫學院/醫學研究所/博士(2006年)

https://doi.org/10.6834/CSMU.2006.00066

摘要

阿滋海默病是很常見的老人疾病，尤其是65歲以上的老人更容易罹病，在已開發國家65歲以上之老人約為6%罹病率，而在美國至少有二百萬至四百萬人得此病，而一年之花費粗估約花費1千億美元，因此老人痴呆症之治療及預防則為很重要之課題，臨床上都是利用乙醯膽鹼酯酵素抑制劑來治療。
本研究之目的係決定乙醯膽鹼酯酵素和丁醯膽鹼酯酵素被五種心臟血管藥物lovastatin, simvastatin, amlodipine besylate, nifedipine、hydralazine hydrochloride和兩種benzodiazepines：diazepam和Chlordiazepoxide hydrochloride的抑制作用之動力學及機轉，這些藥物都是乙醯膽鹼酯酵素和丁醯膽鹼酯酵素的可逆性、混合型之抑制劑，實驗結果顯示，五種心血管藥物對於乙醯膽鹼酯酵素及丁醯膽鹼酯酵素抑制之pKi值和藥物之分子量呈直線之關係，斜率分別為0.005及0.0021因此丁醯膽鹼酯酵素，與心血管藥物間之凡德瓦作用（van der Waals’ ）比乙醯膽鹼酯酵素與心血管藥物間者弱，這可能原因是丁醯膽鹼酯酵素之活性區域比乙醯膽鹼酯酵素之活性區域更寬廣，但丁醯膽鹼酯酵素之周邊陰離子區域不及乙醯膽鹼酯酵素之周邊陰離子區域者明顯重要，由於五種心血管藥物對於乙醯膽鹼酯酵素和丁醯膽鹼酯酵素抑制之pKi值存在著線性關係表示此種抑制作用係經過共同之反應機理。
正如治療阿滋海默病之用藥donepezil，心血管藥amlodipine besylate也是非常好的乙醯膽鹼酯酵素及丁醯膽鹼酯酵素抑制劑，因此在治療阿滋海默病方面，心血管藥物應有其功效。

關鍵字

阿滋海默病 ； 乙醯膽鹼酯酵素 ； 丁醯膽鹼酯酵素 ； 酵素抑制 ； 心臟血管藥物 ； 安息香重氮類安眠藥

並列摘要

Alzheimer's disease is the most common dementia.
The prevalence for Alzheimer’s disease in developed countries appears to be about 6% among those 65 years or older. From 2 to 4 million Americans have Alzheimer's disease and the cost of caring for these patients is enormous with a total cost approaching $100 billion per year. Any treatment that prevents or delays the onset, slow the progression, or improves the symptoms will have a dramatic personal, financial, and societal impact. In clinical. acetylcholinesterase inhibitors reduce the breakdown of synaptic acetylcholine, have been modestly effective in improving the cognitive deficits of Alzheimer’s disease.
The goal of this work is to determine enzyme kinetics and mechanisms of acetylcholinesterase and butyrlcholinesterase inhibition by five cardiovascular drugs, lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride, and two benzodiazepines, diazepam and chlordiazepoxide hydrochloride. All drugs in this study are reversible mixed-type inhibitors of acetylcholinesterase and butyrylcholinesterase. The pKi values for acetylcholinesterase and butyrylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with the molecular weights of the drugs with the slopes of 0.005 and 0.0021, respectively. Therefore, van der Waals’ interactions between acetylcholinesterase and the cardiovascular drugs are stronger than those between butyrylcholinesterase and the drugs. This is probably due to a smaller active site gorge and a more significant peripheral anionic substrate binding site of acetylcholinesterase than those of butyrylcholinesterase. The fact that the pKi values for both butyrylcholinesterase and acetylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with each other suggests that both enzyme inhibition reactions proceed via a common mechanism. Furthermore, amlodipine besylate may be useful in Alzheimer’s disease treatment like donepezil.

並列關鍵字

acetylcholinesterase ； butyrylcholinesterase ； enzyme inhibition ； cardiovascular drug ； benzodiazepines

參考文獻

1. National Institutes on Aging. Progress report on Alzheimer’s disease: taking the next steps. Silver Springs, MD: Alzheimer’s disease Education and Referral Center, 2001.

2. Ernst RL, Hay JW. The US economic and social costs of Alzheimer’s disease revisited. Am J Public Health 1994; 84: 1261-1264.

5. Monthly Vital Statistics Report. Hyattsville, MD: National Center for Health Statistics 1997; 46(1,Suppl. 2): 1-6.

6. Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 2001; 15: 169-173.

7. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939-944.