博士 / 中山醫學大學 / 醫學研究所 / 94 / 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.
| Identifer | oai:union.ndltd.org:TW/094CSMU5534028 |
| Creators | Shyh-Ying, 邱世英 |
| Contributors | Long- Yau Lin, 林隆堯 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 76 |
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