Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI)
Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI)
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DOI：
10.1177/0269881107066855
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发表时间：
2007-03-01
影响因子：
4.1
通讯作者：
Wamsley, James
中科院分区：
文献类型：
--
作者：
Dunbar, Geoffrey C.;Inglis, Fraser;Wamsley, James
正常老年人的认知能力下降与神经元烟碱型乙酰胆碱受体(NAChRs)的选择性丢失有关。尼古丁通过吸入或经皮给药有助于认知，但不可接受的副作用限制了其用途。本研究评价了一种高选择性的α-4-β-2nAChR部分激动剂异普尼克林在老年老年记忆障碍患者(n=76)中的安全性、耐受性和对认知功能的影响。这项双盲交叉对照研究探索了口服剂量在50-150毫克范围内的递增异丙肾上腺素，作为晨间单次给药，为期3周。评估药物动力学(PK)，并通过认知药物研究(CDR)计算机化测试组测量认知功能。Ispronichne具有良好的安全性，在150毫克以下的剂量下耐受性良好。在生化、血液学、尿液分析、生命体征、心电图或动态监测方面未见有临床意义的影响。最常见的药物不良反应是头晕(头晕)。在整个剂量范围内，人们都看到了对认知的有益影响。在衡量注意力和情景记忆的因素中，这一分数最高为50毫克。PK分析表明，血浆Cmax范围为5-25/35 ng/ml异丙肾上腺素与最有益的效果有关。这些早期结果表明，异普利克林耐受性良好，没有表现出尼古丁的典型副作用。异丙肾上腺素对AAML受试者的认知也有有益的影响，这一点在临床前动物研究预测的Cmax范围内表现得最为明显。
Cognitive decline seen in the normal elderly is associated with selective toss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronichne, a highly selective partial agonist at the alpha 4 beta 2 nAChR, in elderly subjects (n=76) with age associated memory impairment (AAMI). This double-blind, ptacelho-controtted cross-over study explored ascending oral doses of ispronicline in the range 50-150mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronichne had a favourabte safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispromichne was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispromictine also had a beneficial effect on cognition in subjects with AAML This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.