ADHD Treatment & Amphetamine Neurotoxicity

描述(由申请人提供)：注意力缺陷多动障碍(ADHD)是一种常见的致残神经精神障碍，困扰着3%-7%的儿童和1%-5%的成年人。兴奋剂是治疗ADHD的主要药物。在用于治疗ADHD的各种兴奋剂中，苯丙胺是最常给儿童和成年人开的处方之一。大量数据表明，苯丙胺有可能破坏动物的脑多巴胺(DA)轴突和轴突终末。接受安非他明治疗ADHD的人类可能会引起类似的安非他明诱导的DA神经毒性，这一可能性尚未得到调查，主要是因为在动物中产生DA神经毒性效应的剂量比治疗ADHD所用的剂量高。然而，我们实验室最近的初步研究结果表明，与通常用于治疗ADHD的口服安非他明相似的剂量方案治疗的狒狒在纹状体中出现DA神经毒性变化。试点数据还表明，与狒狒脑DA神经毒性有关的苯丙胺血浆水平与已报道的接受苯丙胺治疗ADHD的人的水平相当。拟议研究的目的是：1)证实我们在更多成年狒狒身上的初步观察结果，并看看它们是否可以推广到青少年动物；2)确定是否可以将在狒狒身上的发现推广到另一个已知以与人类相似的方式代谢苯丙胺的非人类灵长类物种(松鼠猴子、成年和青少年)；以及3)测量苯丙胺在非人类灵长类动物中的血浆浓度，以便比较与苯丙胺有关的苯丙胺在2个非人类灵长类物种中的水平和药代动力学特征，以及以前在人类中记录的那些。总之，拟议的研究结果将有助于确定是否有理由担心苯丙胺对接受苯丙胺治疗ADHD的人可能产生的DA神经毒性，以及是否对安非他明可能导致的ADHD队列的DA神经毒性进行对照研究。

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a common and disabling neutopsychiatric disorder that afflicts 3-7% of children and 1-5% of adults. Stimulant drugs are the mainstay of treatment for ADHD. Of the various stimulant drugs used to treat ADHD, amphetamine is among the most often prescribed, both to children and adults. A significant body of data indicates that amphetamine has the potential to destroy brain dopamine (DA) axons and axon terminals in animals. The possibility that humans receiving amphetamine for the treatment of ADHD might incur similar amphetamine-induced DA ncurotoxicity has not been investigated, largely because the doses that produce DA neurotoxic effects in animals are higher, on a ing/kg basis, than the doses used in the treatment of ADHD. However, recent preliminary findings in our laboratory indicate that baboons treated with an oral dosing regimen of amphetamine similar to that used commonly to treat ADHD sustain DA neurotoxic changes in the striatum. Pilot data also indicate that plasma levels of .amphetamine associated with brain DA ncurotoxicity in baboons are on the order of those reported in humans treated with amphetamine for ADHD. The aims of the proposed studies are: 1) To confirm our preliminary observations in a larger number of adult baboons, and to see if they can be extended to adolescent animals; 2) To determine if findings in baboons can be extended to another non-human primate species (squirrel monkeys, adult and adolescent) known to metabolize amphetamine in a manner similar to humans ; and 3) To measure plasma concentrations of amphetamine engendered by dosing regimens of amphetamine in non-human primates, in order to compare the levels and pharmacokinctic profiles of amphetamine associated with DA ncurotoxicity in 2 non-human primate species with those previously documented in humans. Together, results of the proposed studies will help determine whether concern over possible amphetamineinduced DA neurotoxicity in humans receiving amphetamine for the treatment of ADHD is warranted, and if controlled studies of possible amphetamine-induced DA neurotoxicity in human ADHD cohorts are indicated.