Smith L, De Salvia M, Jenner P, Marsden C D
Neurodegenerative Diseases Research Centre, King's College, London, England, UK.
Mov Disord. 1996 Mar;11(2):125-35. doi: 10.1002/mds.870110203.
The D2 dopamine agonist piribedil is not widely used in the treatment of Parkinson's disease because it was thought to be effective mainly on parkinsonian tremor and to produce a high incidence of peripheral side effects, particular nausea. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates to reevaluate the antiparkinsonian ability of piribedil after its oral administration in the presence or absence of domperidone pretreatment. Adult common marmosets (Callithrix jacchus) were treated with the nigral toxin MPTP to induce a parkinsonian syndrome characterised primarily by bradykinesia and other motor deficits. Oral administration of a solution of piribedil [1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine] produced a dose-related reversal of all MPTP locomotor and behavioural deficits. However, this effect was short lived and associated with unwanted effects, particular nausea and retching, which clearly hindered locomotion. In contrast, after pretreatment with the peripheral dopamine antagonist domperidone, administration of piribedil did not induce nausea or retching in MPTP-treated marmosets. In these animals, piribedil caused a more marked and longer lasting enhancement of locomotor activity and a further reduction in behavioural deficits than that observed after administration of piribedil alone. In addition, piribedil induced increased vigilance and awareness. These data show that piribedil can reverse akinesia and rigidity in MPTP-treated primates. In addition, they show the drug to be effective without peripheral side effects when used in conjunction with domperidone. These data indicate that piribedil should be an effective monotherapy for Parkinson's disease.
D2多巴胺激动剂吡贝地尔在帕金森病治疗中未得到广泛应用，因为它被认为主要对帕金森震颤有效，且会产生较高发生率的外周副作用，尤其是恶心。在本研究中，我们使用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的灵长类动物，在有或没有多潘立酮预处理的情况下，重新评估吡贝地尔口服后的抗帕金森病能力。成年普通狨猴（Callithrix jacchus）用黑质毒素MPTP处理，以诱发主要以运动迟缓及其他运动功能缺陷为特征的帕金森综合征。口服吡贝地尔[1-(3,4-亚甲二氧基苄基)-4-(2-嘧啶基)哌嗪]溶液可使所有MPTP诱导的运动和行为缺陷出现剂量相关的逆转。然而，这种作用持续时间较短，且伴有不良影响，尤其是恶心和干呕，这明显阻碍了运动。相比之下，在用外周多巴胺拮抗剂多潘立酮预处理后，给MPTP处理的狨猴服用吡贝地尔不会诱发恶心或干呕。在这些动物中，与单独服用吡贝地尔相比，吡贝地尔引起的运动活动增强更为显著且持续时间更长，行为缺陷进一步减少。此外，吡贝地尔可提高警觉性和意识。这些数据表明，吡贝地尔可逆转MPTP处理的灵长类动物的运动不能和强直。此外，这些数据表明，该药物与多潘立酮联合使用时无外周副作用且有效。这些数据表明，吡贝地尔应该是一种有效的帕金森病单一疗法。
