Global Pharmaceutical Research and Development, Neuroscience, Abbott Laboratories, 100 Abbott Park Rd, Dept R48B, Bldg AP4, Abbott Park, IL 60064, USA.
Psychopharmacology (Berl). 2012 Mar;220(1):97-107. doi: 10.1007/s00213-011-2456-4. Epub 2011 Sep 8.
Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process.
Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration.
METHODS/RESULTS: In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory.
These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.
药物开发是一项高风险和高失败率的企业，提供新药化合物早期药效学活动的研究可以节省时间和金钱，提高药物开发过程的效率。
设计了临床前和临床试验，以检验东莨菪碱诱导的认知障碍模型在预测潜在认知化合物药效学信号方面的效用，以东莨菪碱乙酰胆碱酯酶抑制剂多奈哌齐为例。
方法/结果：在正常健康大鼠中，东莨菪碱（0.3mg/kg）显著损害了其在双平台水迷宫和 T 迷宫上的表现。多奈哌齐在 0.5 和 1.0mg/kg 时可逆转水迷宫表现的缺陷。1.0mg/kg 多奈哌齐对 T 迷宫中与东莨菪碱相关的表现缺陷有逆转趋势。在正常健康人群中，东莨菪碱（0.3 和 0.5mg）可靠地以剂量和时间依赖的方式损害认知药物研究测试组合评分（注意力功率、注意力连续性、工作记忆质量、情景性次要记忆质量和记忆速度）。多奈哌齐（10mg）显著减轻了东莨菪碱诱导的注意力功率、注意力连续性、工作记忆质量和记忆速度损伤。
这些发现表明，逆转东莨菪碱诱导的认知障碍是预测动物和人类认知化合物药效学信号的可行模型。讨论并举例说明了东莨菪碱诱导的认知障碍模型在药物开发的各个决策点的应用，重点是 Go/No Go 决策。
