Pramipexole in the treatment of advanced Parkinson's disease

Pramipexole is a novel nonergoline dopamine agonist with a preference for the dopamine D₃ receptor subtype. Its efficacy and safety in the treatment of advanced Parkinson's disease has been investigated in several clinical studies. This review provides a summary of the data currently available, particularly in reference to the recent results of the European clinical phase III study and the potential tremorlytic activity of pramipexole. Interim analysis of the open-label European clinical phase III study has provided evidence of long-term efficacy and safety of pramipexole. In another study pramipexole has been shown to be significantly superior to placebo with an improvement in tremor score by 48% (vs. 13% in the placebo group). In addition to its likely usefulness in the treatment of rest tremor in Parkinson's disease, data suggest that pramipexole is of interest due to its reported low frequency of cardiovascular and gastrointestinal side-effects. However, studies comparing pramipexole with other antiparkinsonian agents would be useful to further define its benefits in the treatment of tremor-dominant Parkinson's disease and to further document its favourable adverse event profile.     

Pramipexole for the treatment of early Parkinson's disease

Pramipexole is a nonergolinic dopamine agonist, with high affinity for the D2 subfamily of dopamine receptors. Pramipexole is efficacious for the symptomatic treatment of early Parkinson's Disease (PD) and its early use, before that of levodopa can delay the emergence of levodopa-related motor complication. Dosage should be increased gradually from a starting dose of 0.375 mg/day up to a maximum of 4.5 mg/day in equally divided doses taken three times per day with pramipexole immediate-release or equivalent daily dosages once-daily with pramipexole extended-release. Pramipexole can also improve depressive symptoms and possibly health-related quality of life in PD. Nonetheless, its use is not devoid of tolerability problems. While peripheral adverse drug reactions, such as nausea, vomiting or orthostatic hypotension, can be effectively treated and usually pose few problems to most patients, neuropsychiatric events can seriously limit the use of pramipexole in some cases. Indeed, excessive daytime somnolence, impulse-control disorders, hallucinations or delusions can severely affect patients, causing important personal or social handicap. Patients should be informed about the risk of such neuropsychiatric complications and their presence should be actively detected at each consultation. More effort will have to be put into further studying the risk-benefit ratio of pramipexole and other dopamine agonists in the treatment of early PD.     

Pramipexole in the treatment of Parkinson's disease: new developments

The nonergot dopamine agonist pramipexole is an efficient and safe drug for the treatment of Parkinson's disease. Clinicians may favor pramipexole over other dopamine agonists because of its suggested higher tolerability with respect to peripheral dopaminergic side effects. Importantly, nonergot dopamine agonists such as pramipexole may not cause restrictive valvular heart disease and may therefore represent the first choice in patients with valvular lesions under treatment with ergot dopamine agonists. However, particular caution has to be exercised in younger Parkinson's disease patients with a shorter disease duration regarding the occurrence of sudden onset of sleep. In light of cost-effectiveness and quality-of-life issues, its final significance for the initial treatment of patients with early Parkinson's disease remains to be determined.     

Pramipexole in treatment-resistant depression: an extended follow-up

We evaluated the long-term antidepressant safety and response of adjunctive pramipexole, a D2-D3 dopamine agonist, in the course of drug-resistant depression. Twenty-three patients with treatment-resistant major depressive episode (MDE) were followed up after a 16-week pramipexole add-on trial. Pramipexole was added to current treatment with TCA or SSRI, at increasing doses from 0.375-1.500 mg/day. The LIFE scale was administered at baseline of the acute trial, at Weeks 16, 32, and 48. Patients were analyzed for sustained remission (score= <2 at LIFE for at least 8 weeks) and recurrence (after remission score > =3 at LIFE for at least 2 weeks) of depression. Of 23 patients, 12 had major depression and 11 had bipolar depression (16 women; mean age=52.8 years). Mean age of onset and median duration of current MDE were 35.1 years and 6 months, respectively; all subjects had at least two prior MDEs. Mean pramipexole dose was 0.990 mg/day. Median duration of follow-up was 28 weeks. Mean baseline MADRS and CGI-S scores were 33.7+/-8.4 (sd) and 4.6+/-0.8, respectively. Median time to sustained remission from baseline was 10 weeks and overall 60.9% (14/23) of subjects recovered within Week 22. Recurrence of depression occurred in 35.7% (5/14) of remitters after Week 24 and within Week 28 from remission. Although there were no sleep attacks, two cases of hypomania and one case of psychotic mania occurred at Weeks 22, 24, and 30, respectively. Pramipexole augmentation of antidepressant treatment was relatively safe and presumably effective in the long-term course of treatment resistant depression.     

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Pramipexole in Parkinson's disease. A short-term study using the combined levodopa-dopamine agonist test

The aim of our study was to investigate the efficacy of pramipexole in advanced parkinsonian patients by means of an acute stimulation test. We studied the motor effects of pramipexole in fluctuating parkinsonian patients by comparing the response to acute levodopa with the response to levodopa + pramipexole. The adjunct of pramipexole to levodopa increased the time spent on from 136 +/- 22.3 to 186 +/- 20.6 minutes (p<0.01), while it did not change the latency to on, the magnitude of the motor improvement, or the duration and severity of dyskinesias. The main effect of pramipexole in fluctuating parkinsonian patients is an increased duration of the on phase.     

Randomized trial of IPX066, carbidopa/levodopa extended release,in early Parkinson's disease

ObjectiveIPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients.MethodsThis was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39).ResultsAll IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P ≤ 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported.ConclusionIPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety.     

Pramipexole reverses Parkinson's disease‐related motivational deficits in rats

Recent evidence suggests that Parkinson's disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal‐directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion‐based model, with stereotaxic infusion of 6‐hydroxydopamine (6‐OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6‐OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD‐associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD. © 2014 International Parkinson and Movement Disorder Society     

Randomized,double‐blind,multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was ?5.1 (1.3) in the placebo group, ?8.1 (1.1) in the pramipexole ER group (P = 0.0282), and ?8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was ?2.7 (1.3) in the placebo group, ?7.4 (1.1) in the pramipexole ER group (P = 0.0010), and ?7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID. © 2010 Movement Disorder Society     

Long-term,open-label,safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease

Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects’ preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (≥ 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen.     

Endogenous dopamine release after pharmacological challenges in Parkinson's disease

Using (11)C-raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in (11)C-raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by (18)F-dopa uptake. Localization of significant changes in (11)C-raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease.     

普拉克索在帕金森病治疗中的临床应用

帕金森病为一中老年人常见的慢性进展性中枢神经系统变性疾病，主要由于黑质致密区多巴胺能神经元变性导致黑质一纹状体通路多巴胺神经递质明显减少而发病。左旋多巴替代疗法虽然在帕金森病初期能有效地改善临床症状，但长期应用后疗效衰退并引起症状波动、运动障碍和精神症状等并发症。多巴胺受体激动药具有克服上述左旋多巴的不足，延缓左旋多巴治疗的开始时间并加强其治疗效果。根据多巴胺受体激动药的化学性质可将其分为麦角碱类和非麦角碱类，前临床常用药物有溴隐亭、培高利特、卡麦角林、麦角乙脲等，后包括阿朴吗啡、吡贝地尔、罗匹尼罗和普拉克索等。[第一段]     

Case-Control study of the extended tau gene haplotype in Parkinson's disease.

We investigated the association of Parkinson's disease with tau gene haplotypes. In a sample of 319 unrelated Parkinson's disease patients and 196 control subjects, we observed an increased risk of Parkinson's disease for persons with the H1/H1 genotype (odds ratio = 1.5; 95% confidence interval: 0.98-2.23); however, the finding was not statistically significant. The results remained similar after adjusting for the possible misclassification of progressive supranuclear palsy patients as Parkinson's disease, but became statistically significant after restricting the analysis to nondemented subjects.     

多巴胺受体激动剂普拉克索治疗帕金森病非运动症状的疗效观察

目的 研究多巴胺受体激动剂普拉克索治疗帕金森病(PD)非运动症状的临床疗效.方法 给予29例PD患者普拉克索0.5 mg每天3次(经过3周加量期)治疗,持续12个月;在治疗前和治疗12个月后进行汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)和简易精神状态检查(MMSE)量表评分,观察治疗前后感觉异常、便秘、排尿障碍、性功能障碍和肢体水肿的变化,以及不良反应.结果 PD患者治疗后HAMA、HAMD评分比治疗前显著降低(均P<0.01),而MMSE量表评分与治疗前的差异无统计学意义.治疗后感觉异常的患者(6例,20.7%)比治疗前(11例,37.9%)显著减少(P<0.05),治疗前后排尿障碍、便秘、性功能障碍及肢体水肿患者比例的差异无统计学意义.患者未出现明显不良反应.结论 普拉克索能够减轻PD患者的焦虑、抑郁状态,改善其感觉异常的症状.     

普拉克索添加治疗帕金森病临床随机对照研究

目的 评价新型多巴胺受体激动剂普拉克索联合美多巴与单用美多巴治疗帕金森病(PD)患者的疗效及安全性. 方法 采用随机对照开放式研究,将70例PD患者按照随机数字表法分为普拉克索+美多巴组和美多巴组,每组各35例.治疗12周后判断其疗效及安全性.疗效判定的主要指标为统一PD评定量表第Ⅲ部分(UPDRSⅢ)的运动检查总评分相对患者基线的变化和第Ⅱ部分(UPDRS Ⅱ)的日常生活活动能力总评分相对患者基线的变化;次要指标为第Ⅰ部分(UPDRS Ⅰ)的精神、行为和情感总评分相对患者基线的变化和第Ⅳ部分(UPDRS Ⅳ)的治疗并发症总评分相对患者基线的变化和美多巴药物每日剂量相对基线的变化.安全性指标依据药物的不良反应来判定. 结果 普拉克索+美多巴组患者UPDRS Ⅲ总评分均值与基线相比下降了11.40分,高于美多巴组(9.26分),比较差异有统计学意义(P<0.05);UPDRS Ⅱ总评分均值与基线相比下降了4.57分,高于美多巴组(4.50分),比较差异无统计学意义(P<0.05);UPDRS Ⅰ总评分均值与基线相比下降了0.66分,低于美多巴组(1.14分),差异无统计学意义(P0.05);UPDRS Ⅳ总评分均值与基线相比下降了0.22分,美多巴组则升高了0.06分,差异有统计学意义(P<0.05).与基线相比,治疗后12周普拉克索+美多巴组美多巴的日用量下降了163.57 mg/d,美多巴组升高了8.57 mg/d,差异有统计学意义(P<0.05).普拉克索+美多巴组在治疗后12周发生疗效减退、症状波动、异动症的例数均低于美多巴组,差异有统计学意义(P<0.05).美多巴组出现了明显的疗效减退、症状波动、异动症,而普拉克索+美多巴组无明显的上述症状,但有2例出现突然入睡发作、1例嗜睡、1例直立性低血压. 结论 普拉克索+美多巴组在改善PD运动功能方面优于美多巴组,在日常活动,精神、行为和情绪方面疗效相似.同时服用普拉克索可以明显减少美多巴的用量及其治疗后所引起的并发症(疗效减退、症状波动及异动症)的发生率.普拉克索可引起突然入睡发作、嗜睡、直立性低血压等副作用.     

Pramipexole, a nonergot dopamine agonist, is effective against rest tremor in intermediate to advanced Parkinson's disease.

We evaluated the efficacy of the nonergot dopamine receptor agonist pramipexole in 16 patients with advanced Parkinson's disease and marked rest tremor during an "on" period. The patients were drawn from a larger placebo-controlled, double-blind, randomized trial, which was not originally designed to investigate the effect of pramipexole on tremor. Eleven patients received pramipexole. The first effects were seen with a pramipexole dose of 0.75 mg/d with a reduction of the tremor item A of Unified Parkinson's Disease Rating Scale (UPDRS III, "on" state) by 25% and of rigidity and akinesia by 22%. Under the highest dose, 4.5 mg/d, the tremor score was improved by 61% over baseline (p < 0.0056, Wilcoxon signed rank) and the sum of rigidity and akinesia items by 66% (p < 0.0038, Wilcoxon signed rank). Five patients received placebo and did not improve. Based on this sample of patients, the nonergot dopamine receptor agonist pramipexole appears to have a potent anti-rest tremor action while being effective against akinesia and rigidity.