Michel Anne, Nicolas Jean-Marie, Rose Sarah, Jackson Michael, Colman Peter, Briône Willy, Sciberras David, Muglia Pierandrea, Scheller Dieter K, Citron Martin, Downey Patrick
UCB BioPharma, Braine L'Alleud, Belgium.
King's College, Institute of Pharmaceutical Science, London, United Kingdom.
PLoS One. 2017 Aug 30;12(8):e0182887. doi: 10.1371/journal.pone.0182887. eCollection 2017.
Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD).
In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications.
Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD.
When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects.
We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.
在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的帕金森病（PD）狨猴模型中研究两种经临床测试的药物——NR2B拮抗剂拉地普地尔和A2A拮抗剂托扎adenant的联合使用情况。
在帕金森病中，仍需要开发非多巴胺能药物来有效治疗运动症状，而不诱发左旋多巴诱导的运动并发症。
在不添加左旋多巴的情况下，单独及联合给予临床相关剂量的拉地普地尔和托扎adenant，并在帕金森病灵长类动物模型中评估治疗的抗帕金森病疗效。
与单独测试的药物相比，联合用药使MPTP处理的狨猴的运动活性显著增加，运动功能障碍得到改善。此外，联合用药带来的运动恢复几乎完全没有运动障碍。有趣的是，接受治疗的灵长类动物并未受到过度刺激，而是在探索新物体的驱动下能够正常移动。
我们在灵长类动物模型中证明，“拉地普地尔/托扎adenant”组合显著改善运动活性，扩展了先前在单侧损伤的6-羟基多巴胺（6-OHDA）大鼠中获得的结果。迄今为止积累的临床前数据的强度表明，使用这种A2A和NR2B拮抗剂组合可为帕金森病患者带来显著的运动改善，而不会诱发左旋多巴治疗引起的运动并发症。尽管这些临床前数据令人鼓舞，但仍需要在临床中得到证实。
