ADHD Treatment & Amphetamine Neurotoxicity

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种常见的致残性神经精神障碍，困扰着3-7%的儿童和1-5%的成人。兴奋剂药物是治疗多动症的主要方法。在各种用于治疗多动症的兴奋剂药物中，安非他明是儿童和成人最常用的处方药之一。大量数据表明，安非他明有可能破坏动物脑多巴胺（DA）轴突和轴突终末。人类接受安非他明治疗ADHD的可能性可能会产生类似的安非他明诱导的DA神经毒性，这尚未得到调查，主要是因为在动物中产生DA神经毒性作用的剂量（以毫克/千克为基础）高于用于治疗ADHD的剂量。然而，我们实验室最近的初步发现表明，口服安非他明治疗狒狒与通常用于治疗多动症的安非他明治疗方案相似，纹状体中DA神经毒性变化持续存在。试验数据还显示血浆水平。在狒狒中，安非他命与脑DA核毒性的关系与用安非他命治疗多动症的人的毒性相同。拟建研究的目的是：1)在大量成年狒狒中证实我们的初步观察结果，并看看它们是否可以推广到青春期动物；2)确定狒狒的发现是否可以推广到另一种已知以与人类相似的方式代谢安非他命的非人类灵长类物种（松鼠猴，成年和青少年）；3)测量安非他明给药方案在非人类灵长类动物中产生的安非他明血浆浓度，以比较安非他明在2种非人类灵长类动物中与DA毒性相关的水平和药代动力学特征与先前在人类中记录的安非他明水平和药代动力学特征。总之，拟议研究的结果将有助于确定是否有理由担心接受安非他明治疗ADHD的人可能存在安非他明诱导的DA神经毒性，以及是否有必要对人类ADHD队列中可能存在的安非他明诱导的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.