Combining entacapone with levodopa/DDCI improves clinical status and quality of life in Parkinson’s Disease (PD) patients experiencing wearing-off,regardless of the dosing frequency: results of a large multicentre open-label study

Summary. The efficacy of entacapone and its impact on patient quality of life (QOL) was investigated in an open-label study of 899 patients with idiopathic Parkinsons Disease (PD) experiencing wearing-off fluctuations. Patients were divided into 3 groups (3, 4 or 5 doses daily) based on their current levodopa dosage frequency. Patients received 200mg entacapone with each levodopa/dopa-decarboxylase inhibitor (DDCI) dose, while continuing their same levodopa/DDCI dosage regimen for 4 weeks. Primary efficacy measure was the Investigators Clinical Global Impression of Change (CGIC). Patient QoL was assessed using the validated 8-item Parkinsons Disease Questionnaire (PDQ-8). Investigators CGIC revealed that 76.5% of entacapone treated patients experienced an improvement in global status after 4 weeks. Treatment with entacapone was also associated with improvement in patient QoL, with a mean reduction (improvement) in PDQ-8 score of 1.8 from baseline. This study confirms and extends the results of earlier studies demonstrating that, independent of dosing frequency, completing levodopa/DDCI therapy with entacapone provides clinically relevant improvements in global status and QoL in PD patients experiencing wearing-off on their current levodopa dosing frequency.     

左旋多巴治疗帕金森病发生剂末现象的相关因素

目的 探讨左旋多巴治疗帕金森病发生剂末现象的相关因素。方法 收集帕金森病患者临床资料,通过统计学分析对比分析剂末现象发生的相关因素。结果 剂末现象的发生与性别、年龄、教育年限、体重、毒药物接触史、吸烟史、饮酒史、高蛋白饮食、脑血管病史无关（P>0.05）。发生剂末现象的患者发病年龄早,病程长,左旋多巴起始、终点剂量高,左旋多巴用药时间长,疾病进展阶段（H&Y分期）高,统一帕金森病评分量表第三部分（UPDRSⅢ）评分高,汉密尔顿焦虑评分（HAMA）评分高（P<0.05）。其中发病年龄、左旋多巴起始剂量、H&Y分期、焦虑是发生剂末现象的独立影响因素（P<0.05）;独立预测因素分别为H&Y分期、HAMA评分、发病年龄、左旋多巴起始剂量（P<0.05）。H&Y分期具有较好的敏感度和特异度（80.9%）。随治疗时间的增长,中晚期患者剂末现象发生风险高（P<0.05）。结论 多种因素影响左旋多巴临床治疗中发生剂末现象。     

Optimizing levodopa therapy for Parkinson's disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

After 40 years of clinical experience, levodopa remains the gold standard treatment for Parkinson's disease (PD) despite the recent emergence of a host of new therapies. Some physicians are cautious when prescribing levodopa because of its association with motor complications. Evidence now suggests that levodopa-associated complications are a result of deep troughs in delivery of levodopa to the brain caused by the short plasma half-life of conventional levodopa formulations (levodopa and a dopa decarboxylase inhibitor [DDCI]). Dosing strategies, such as dose increases and dose fractionation, may be effective in the short term. For the longer-term, levodopa/carbidopa/entacapone provides pharmacokinetically optimized levodopa therapy that significantly increases the plasma half-life and bioavailability of levodopa, providing more consistent plasma levodopa levels without deep troughs. Evidence from clinical trials in PD patients experiencing re-emergence of symptoms due to wearing-off has consistently shown that levodopa/DDCI and entacapone significantly increases ON-time and affords greater functionality, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) with conventional levodopa. These trials have also shown that levodopa/DDCI and entacapone is generally well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re-emergence of symptoms due to wearing-off may benefit from optimized levodopa therapy with levodopa/carbidopa/entacapone.     

Chronic levodopa therapy enhances dopa absorption: Contribution to wearing-off

Summary Effects of the chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon are re-evaluated. The concentration of plasma levodopa and clinical symptoms were determined 4 hours after oral levodopa (levodopa 100 mg+benserazide 25 mg) administration on 55 parkinsonian patients. Long-term levodopa therapy markedly increased the peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC); whereas, it decreased time to the peak concentration (Tmax) and the elimination half-life (T1/2). These results suggest that longterm levodopa therapy accelerates the absorption of levodopa. The wearingoff group (n=23), however, had a markedly higher Cmax and AUC, and a shorter Tmax and T1/2 than the stable group (n=32). We speculate that the clinical expression of stable or wearing-off depends on the absorption of levodopa as well as the presynaptic terminal and post synaptic receptors.     

Apomorphine in the treatment of Parkinson's disease

Motor fluctuations, refractory to conventional medical management, are one of the most troubling aspects of Parkinson's disease. Apomorphine is a dopaminergic agent that has been known to the medical community for more than a century, but has only recently been developed to treat such motor fluctuations. In this article, the authors review the historical background, structure, mechanism of action, pharmacologic properties, clinical trials, indications and side effects, as well as avenues of further research, of apomorphine.     

End-of-dose deterioration in non ergolinic dopamine agonist monotherapy of Parkinson’s disease

The study was designed to investigate the possible occurrence of “wearing-off” (WO) during dopamine agonist (DA) monotherapy. Sixty patients with “de novo” idiopathic PD were randomised into one of two DA monotherapy branches to receive oral ropinirole at 15 mg per day, or pramipexole at 2.1 mg per day. DA doses could be increased in the following two years but levodopa could not be added until the study ended. WO was assessed by self-evaluation charts confirmed by a blinded observation of a 30% or greater deterioration in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. Proc Mixed and Kaplan-Meier curves evaluated treatment variables as a function of time. T-tests were used to compare post-hoc variables reclassified according to WO occurrence. Thirty patients received ropinirole, and 30 pramipexole monotherapy. Eighteen patients (30%) experienced “wearing-off” 15–21 months after beginning monotherapy. No differences were observed between treatments. WO phenomena was observed 3.4 ± 0.3 hours after intake of the morning or afternoon dose and consisted of UPDRS score worsening by 11.1 ± 2.1 points (69–111% more than “on” score). Statistical evaluation gave evidence of differences between patients who experienced WO and those who did not: UPDRS motor scores obtained at admission to the study were higher (by 3.4 ± 0.2 points, p = 0.01 t-test) and DA doses at 6–12 months were higher in fluctuating patients. UPDRS motor scores deteriorated, however. similarly and there were no differences, in UPDRS scores recorded in ON conditions, between fluctuating and non-fluctuating patients at the end of the study. Our findings provide evidence of WO phenomena in patients with early PD receiving non-ergolinic DA monotherapy. Received in revised form: 5 June 2006     

Development of a Patient Questionnaire to facilitate recognition of motor and non-motor wearing-off in Parkinson’s disease

Summary. We previously reported that the use of a specifically designed Wearing-Off Questionnaire (WOQ) identified symptoms of wearing-off more frequently than standard assessments conducted by movement disorder specialists during a routine office visit. In the previous study we used a WOQ of 32 symptoms; however this tool was not designed for daily use. In this paper we describe the retrospective development of a simpler, 19-symptom WOQ more suitable for routine clinical use.