帕金森病病例分享.ppt

谢谢 左旋多巴---金标准, 帕金森病最有效的对症治疗药物;疾病进展(蜜月期过后),左旋多巴治疗疗效衰退,逐渐出现一系列并发症.左旋多巴长期治疗引起的问题 5年后50% 病人出现诸如症状波动(“开-关”现象)，异动症，疗效逐步减退等运动并发症。 * * 表现为每次用药有效时间缩短，症状随左旋多巴血药浓度发生规律性的波动。 推测有许多因素参与导致左旋多巴反应的波动。胃酸增加，服用影响胃排空药物（如抗胆碱能类药）及饮食摄入改变等均可导致周围性左旋多巴药代动力学变化。黑质神经元储备多巴胺能神经元减少，故不能有效缓冲左旋多巴波谷，导致中枢性左旋多巴药代动力学变化。纹状体受体敏感性变化，高亲和性／低亲和性多巴胺受体间平衡改变，导致中枢性左旋多巴药效的变化。脉冲样刺激-间断给药模式-左旋多巴半衰期短所致疾病的进展加重，黑质神经元减少。 多巴胺受体非生理性脉冲样刺激，致突出可塑性改变、基因和蛋白表达失调，基底核输出神经元放电模式改变，过去关注剂峰，近年关注谷底。 * * * * * Researchers now believe that wearing-off is caused by a combination of factors. Even from the beginning of treatment, the short duration of levodopa availability (half-life) results in rapid changes in the levels of the drug in the blood (peaks and troughs). In early Parkinson’s, the capacity of the brain to store levodopa and dopamine permits smoother release of dopamine in the brain, and a more constant clinical effect. However, as Parkinson’s disease progresses the number of dopamine cells in the brain continues to decrease and the brain has fewer cells that can take up levodopa and store it as dopamine for release when levels are low – in these circumstances the brain is said to have lost its ‘buffering’ capacity. With the loss of this buffering capacity, variations in levodopa drug blood levels are often associated with variability in symptom control (e.g. wearing-off) and side effects (e.g. dyskinesia). The long-term benefits of levodopa therapy may be improved by maintaining more stable levodopa levels in the blood stream and consequently reducing the variations of levodopa and dopamine in the brain to provide what is called ‘more continuous dopaminergic stimulation’. * * * * * 柯丹对纹状体产生持续性的DA能刺激，为A级证据；曲线下面积增加了35-40%； Catechol-O-methyltransferase (COMT) inhibitors delay the breakdown of levodopa, which leads to an increase in levodopa bioavailability and more stable concentrations of plasma levodopa. The addition of a COMT inhibitor therefore combines the rapid onset of levodopa with prolonged efficacy, and theoretica