Association of the DRD2 and DRD3 polymorphisms with response to pramipexole in Parkinson’s disease patients

Objective  To evaluate the impact of the DRD2 TaqIA and DRD3 Ser9Gly polymorphisms on the efficacy of pramipexole in treating patients with Parkinson’s disease (PD). Methods  Thirty patients with PD prospectively received pramipexole 0.25 mg three times daily for 2 months. Unified Parkinson Disease Rating Scale (UPDRS) assessments were conducted at baseline and 2 months after treatment initiation. Improvement by 20% or more in the total score on the UPDRS was considered to indicate responsiveness. The PCR–restriction fragment length polymorphism analysis was used to analyze the DRD2 Taq1A and DRD3 Ser9Gly genotype. Results  The DRD2 Taq1A allele frequencies were A141.7 (A1) and 58.3% (A2), and the DRD3 Ser9Gly allele frequencies were 68.3 (Ser) and 31.7% (Gly). When the subjects were grouped by the DRD3 Ser9Gly polymorphism, the response rates for pramipexole treatment were significantly higher in the Ser/Ser group (60%) than in the group containing the Gly allele (13%). There was a significant association between the DRD3 Ser9Gly polymorphism and response rate to pramipexole in PD patients (P = 0.024). When the subjects were grouped by the DRD2 Taq1A polymorphism, there were no significant differences among the three Taq1A genotypes. Conclusions  DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. A large-scale and multi-dose group study in patients with PD is necessary for evaluating the impact of the genetic polymorphisms of the dopamine receptor on the therapeutic effects of pramipexole.     

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

Rationale Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. Objectives These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. Materials and methods The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-selective and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 and sumanirole-induced hypothermia. Results D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A, and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride’s profile of action was more similar to the D2 antagonists than to the D3 antagonists. Conclusions D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors.     

Continuous subcutaneous infusion of pramipexole protects against lipopolysaccharide-induced dopaminergic cell death without affecting the inflammatory response

The D2/D3 dopamine receptor agonist pramipexole, protects against toxin-induced dopaminergic neuronal destruction but its mechanism of action is unknown. Inflammation following glial cell activation contributes to cell death in Parkinson's disease and we now report on the effects of acute or chronic administration of pramipexole on lipopolysaccharide (LPS) induced inflammation and nigral dopaminergic cell death in the rat. At 48 h and 30 days following supranigral administration of LPS, approximately 70% of tyrosine hydroxylase (TH) immunoreactive (-ir) cells in substantia nigra had degenerated with a corresponding loss of TH-ir terminals in the striatum. In rats acutely treated with pramipexole (2 × 1 mg/kg; s.c.) 48 h following LPS application, there was no difference in the number of TH-ir cells or terminals compared to LPS-treated rats receiving vehicle. However, the continuous subcutaneous infusion of pramipexole for 7 days prior to LPS and 21 days subsequently, produced a marked preservation of both TH-ir cells and terminals. At 48 h or 30 days, LPS induced an up-regulation of ubiquitin-ir within the nigral TH-ir neurones, which was reduced by pramipexole treatment. Thirty days following supranigral LPS administration (9 days after the end of infusion), (+)-amphetamine (5 mg/kg, i.p.) caused robust ipsiversive rotation. In rats treated with LPS but receiving continuous subcutaneous administration of pramipexole, (+)-amphetamine-induced rotation was markedly reduced. LPS-induced increase in the levels of inflammatory markers, were not affected by either acute administration or continuous infusion of pramipexole. Continuous infusion of pramipexole protected dopaminergic neurones against inflammation induced degeneration but without modification of the inflammatory response.     

Choosing the Right Dopamine Agonist for Patients with Parkinson's Disease

Summary

Dopamine receptor agonists (DA) are assuming an increasing importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, choosing the right DA for patients with PD unfortunately remains more a pragmatic medical art than a science. The aim of this review is to provide a realistic point of view on the strengths and weaknesses of five DAs: bromocriptine, ropinirole, pergolide, pramipexole and piribedil.

This has been done by analysing their respective: (1) flexibility in PD, i.e. in monotherapy, in early and in late combination with levodopa; (2) safety profile and (3) titration schedule. These five DAs are not evenly matched regarding these three criteria. The differences observed highlight the therapeutic value of piribedil, which has a flexible indication, adapted to all stages of PD, a safer profile and the most simple initiation schedule.     

Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole

Abstract

Background:

The death of dopaminergic neurons in Parkinson's disease (PD) appears to have various causes, including oxidative stress, excitotoxicity, mitochondrial dysfunction (and associated apoptosis), ubiquitin/proteasomal dysfunction, and inflammation, any of which could in principle be the therapeutic target of a neuroprotective drug. The biology of dopaminergic neurons offers further potential targets, involving neurotrophic factors, dopamine-neuron genes, and even neurogenesis.     

Efficacy and safety of pramipexole in chinese patients with restless legs syndrome: results from a multi-center, randomized, double-blind, placebo-controlled trial

Background

We performed a six-week study of pramipexole vs. a placebo in Chinese restless legs syndrome patients.

Methods

Overall, 305 enrolled patients were assigned randomly in a 2:1 ratio to the pramipexole group (N = 202) and the placebo group (N = 103).

Results

Of 287 patients in the full analysis set, the pramipexole group showed significant improvement compared with the placebo group in the change of their International Restless Legs Syndrome Study Group Rating Scale of Severity (IRLS) total score from baseline to week 6 after adjustment of centers and baseline characters (−15.87 ± 0.66 vs. −11.35 ± 0.92, p < 0.0001) and in the proportion of patients who were “much improved” and “very much improved” when measured by Clinical Global Impressions-Improvement (81.9% vs. 54.3%, p < 0.0001). At week 6, the IRLS responder rate was 73.8% (pramipexole) and 48.9% (placebo) (p < 0.0001) and the patient global impression responder rate was 68.6% (pramipexole) and 43.5% (placebo) (p < 0.0001). The proportion of adverse events was 62.9% in the pramipexole group and 43.7% in the placebo group, respectively. No deaths occurred.

Conclusion

Pramipexole was effective and well-tolerated in Chinese patients with restless legs syndrome.     

普拉克索片联合美多芭治疗帕金森病的疗效分析

目的探讨普拉克索片联合多巴丝肼片(商品名:美多芭)治疗帕金森病的疗效。方法88例帕金森病患者,随机分为研究组和对照组,每组44例。研究组患者给予普拉克索片联合美多芭治疗,对照组患者给予美多芭单药治疗。比较两组患者治疗前后统一帕金森病评定量表(UPDRS)评分、简易精神状态评价量表(MMSE)评分和临床疗效、不良反应发生情况。结果治疗后,研究组患者UPDRS评分(35.22±6.35)分明显低于对照组的(38.05±6.49)分,MMSE评分(26.38±4.69)分明显高于对照组的(23.29±3.19)分,差异具有统计学意义(P<0.05)。研究组患者总有效率为86.4%,明显高于对照组的68.2%,差异具有统计学意义(P<0.05)。两组患者不良反应发生率比较差异无统计学意义(P>0.05)。结论普拉克索片联合美多芭治疗帕金森病可明显改善患者的运动症状与认知功能。     

普拉克索联合高压氧舱治疗帕金森病伴睡眠障碍患者的疗效观察

目的 探讨普拉克索联合高压氧舱治疗帕金森病合并睡眠障碍的临床疗效.方法 选取80例合并睡眠障碍的帕金森病患者,根据治疗方法的不同分为3组.普拉克索组25例,给予口服盐酸普拉克索治疗;高压氧组25例,给予高压氧舱吸氧治疗;联合组30例,给予口服盐酸普拉克索联合高压氧舱吸氧治疗.3组患者均接受为期2个月的治疗,观察并记录患者治疗前后睡眠质量水平及焦虑抑郁程度的差异.结果 治疗后,联合组患者PQSI评分、ESS评分分别为(4.36±1.22)、(2.19±3.52),均明显低于普拉克索组[(6.88±1.83)、(5.62±4.33)]和高压氧组[(6.54±1.66)、(5.16±3.96)],组间比较差异有统计学意义(P＜0.05);联合组患者UPDRS-Ⅲ评分、H-Y分级评分低于普拉克索组和高压氧组,但组间比较差异无统计学意义(P＞0.05);联合组卧床时间、总睡眠时间、睡眠效率明显高于普拉克索组和高压氧舱组(P＜0.05),睡眠潜伏期和睡眠觉醒次数明显低于普拉克索组和高压氧舱组(P＜ 0.05).3组患者临床不良反应发生率比较差异无统计学意义(P＞0.05).结论 普拉克索联合高压氧舱治疗帕金森病伴睡眠障碍患者临床疗效显著,能够有效提高睡眠效率,改善睡眠质量,值得临床推广.     

普拉克索联合多巴丝肼片治疗帕金森病的效果及其对患者生活质量的影响

目的 探究在普拉克索与多巴丝肼片联合治疗帕金森病(PD)患者的临床效果及对患者生活质量的影响.方法 48例帕金森病患者,通过双盲法分为常规组与联合组,每组24例.常规组采用多巴丝肼片治疗,联合组在常规组基础上加入普拉克索治疗.比较两组患者治疗效果以及治疗前后生活质量.结果 联合组治疗总有效率91.67％高于常规组的54...     

普拉克索在治疗帕金森病中对心脏瓣膜不良反应的荟萃分析评价

目的:系统评价普拉克索在治疗帕金森病中对患者心脏瓣膜不良反应的情况。方法:通过检索Pubmed、Embase、CochraneDatabase及中国生物医学文献数据库,检索国内外2008年8月前已发表的普拉克索在治疗帕金森病中对心脏瓣膜不良反应的诊断试验,对所纳入的研究进行质量评价及荟萃分析。结果:共纳入5项研究(492例),荟萃分析结果显示:普拉克索组与未服用多巴胺受体激动剂的对照组左房室瓣反流发生率差异无统计学意义[加权均数差值(WMD)=1.33,95%可信区间(CI):0.53～3.36],右房室瓣反流发生率差异无统计学意义(WMD=1.95,95%CI:0.60～6.35),主动脉瓣反流发生率差异无统计学意义(WMD=1.04,95%CI:0.42～2.62)。结论:普拉克索对帕金森病患者心脏瓣膜的不良反应较小,但还需更多高质量研究予以进一步证实。