Sub-chronic administration of the dopamine D1 antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys:: stable therapeutic effects and wearing-off dyskinesia
Sub-chronic administration of the dopamine D1 antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys:: stable therapeutic effects and wearing-off dyskinesia
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DOI：
10.1007/s002130051124
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发表时间：
1999-10-01
影响因子：
3.4
通讯作者：
Cools, AR
中科院分区：
文献类型：
--
作者：
Andringa, G;Stoof, JC;Cools, AR
理由：SKF 83959在体外作为D-1拮抗剂，但据称在mptp治疗的狨猴急性给药后可诱导抗帕金森效应。目的：本研究的目的是评估亚慢性给药SKF 83959对双侧mptp治疗的恒河猴的治疗效果和不良反应，并将这些效果与左旋多巴和多巴胺激动剂SKF 82958的效果进行比较。方法：左颈动脉给予MPTP (2.5 mg)， 6周后给予右颈动脉（1.25 mg）。这些猴子（n=4）先前长期服用左旋多巴（22天，10 mg/kg）和SKF 82958（22天，1 mg/kg）。在最后一次给药SKF 82958 3个月后，SKF 83959在第1天至第15天以0.5 mg/kg的剂量给药，在第16天至第18天以1.0 mg/kg的剂量给药。结果：SKF 83959增加了所有动物的目标定向肢体运动，包括那些对左旋多巴无反应的动物。这种治疗效果在治疗期间没有减弱。在身体位移和不良反应方面，对SKF 83959的反应有很大的变化：身体位移的大量增加与口面部运动障碍同时发生（n=2），而身体位移的少量增加与肌张力障碍同时发生（n=2）。与左旋多巴的不良影响相反，SKF 83959的运动障碍效应主要局限于治疗第一天。与左旋多巴和SKF 82958不同，SKF 83959不诱导类癫痫行为。结论：亚慢性给药SKF 83959既可诱导明确且随时间稳定的治疗效果，也可诱导有限数量的运动障碍效应在治疗过程中逐渐消失。多巴胺D-1拮抗剂SKF 83959可能被认为是帕金森病的一种替代治疗方法，特别是对于那些对左旋多巴无反应的患者。
Rationale: SKF 83959 acts as a D-1 antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. Objective: The aim of the present study was to evaluate the therapeutic and undesired effects of subchronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of L-dopa and the dopamine agonist SKF 82958. Methods: MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n=4) had previously been treated chronically with L-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg: from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18, Results:SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to L-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n=2), whereas a small increase in body displacement co-occurred with dystonia (n=2). In contrast to the undesired effects of L-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike L-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. Conclusion: Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D-1 antagonist SKF 83959 may be considered as an alternative treatment in Parkinson's disease, especially in those patients who do not respond to L-dopa.