Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy.
Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy.
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DOI：
10.1517/14740338.4.1.69
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Borges, Nuno
中科院分区：
文献类型：
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作者：
Borges, Nuno
接受左旋多巴和芳香族 L-氨基酸脱羧酶抑制剂联合治疗的帕金森病患者通常会在几年后出现运动并发症。为了尽量减少这个问题，开发了选择性儿茶酚-O-甲基转移酶 (COMT) 抑制剂，以改善左旋多巴较差的药代动力学特征。托卡朋和恩他卡朋是此类中的两种上市药物，两者都能延长左旋多巴的半衰期并改善临床参数，例如增加“开启”持续时间和减少“关闭”时间。托卡朋上市后不久，由于与三名帕金森病患者死亡有关，在欧盟被暂停使用。这些患者的死因是暴发性肝炎。托卡朋引起肝损伤的机制已被研究。结果表明，该药物诱导线粒体氧化磷酸化解偶联，从而显着降低细胞产生 ATP 的能力。这种毒性作用在体外和体内的多个模型中均得到证实，但诱导其所需的浓度明显高于抑制 COMT 所需的浓度。托卡朋代谢能力的个体差异可能会产生较高的血浆水平，并可能解释其在小样本患者中的毒性作用。最近，根据新的临床数据和对其在其他国家使用情况的持续监测，托卡朋的暂停被取消。欧洲药品评估机构的结论是，在某些情况下，托卡朋的临床疗效优于恩他卡朋，并且通过适当的肝功能监测和其他措施可以实现足够的安全性水平。结论是，托卡朋可以安全地用于对没有反应或由于其他原因不能与其他 COMT 抑制剂一起使用的帕金森病患者。
Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.