Institute of Biomedical Technology, Technological Park of Sardinia Sardegna Ricerche, Cagliari, Italy.
Eur Psychiatry. 2010 Mar;25(2):92-100. doi: 10.1016/j.eurpsy.2009.05.008. Epub 2009 Jul 28.
It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.
有人提出，要想在精神分裂症患者中达到治疗效果，抗精神病药物在纹状体中对多巴胺 D2 受体的占有率必须超过 60-65%。然而，在高 D2 受体占有率水平下，发生锥体外系症状（EPS）的风险会增加。口服抗精神病药物后，血浆药物浓度的峰值和谷值可能与 D2 受体占有率的波动相吻合。帕利哌酮是一种新型抗精神病药，有口服缓释片（帕利哌酮缓释片）和口服液两种剂型，是利培酮的主要活性代谢产物，与传统的口服抗精神病药制剂相比，具有较少的峰谷波动和稳定的 D2 受体占有率。本研究使用与临床实践中相似的制剂，从时间上持续的抗精神病疗效和锥体外系症状的易感性方面，对帕利哌酮缓释片和利培酮普通片的药理学特性进行了临床前评价。反复皮下（SC）给予利培酮会导致 d-苯丙胺诱导的过度活动抑制出现显著波动，而持续 SC 给予帕利哌酮则表现出稳定的抑制作用。同样，反复 SC 给予利培酮会导致在棒上的潜伏期出现显著波动，而持续 SC 给予帕利哌酮则显著降低在棒上的潜伏期。这些在动物模型中的结果表明，尽管利培酮和帕利哌酮具有相似的药理作用，但帕利哌酮的持续给药可实现更稳定的抗精神病疗效，同时减少运动障碍，类似于在临床研究中观察到的帕利哌酮缓释片的作用。
