盐酸普拉克索降解杂质BI-IO460BS的合成

报道了盐酸普拉克索降解杂质BI-IO460BS的合成方法.焦谷氨醇经对甲苯磺酰氯取代、氰化钾氰化、碘丙烷N-丙基化、氰解并甲酯化、氧硫交换、氨腈取代、水解得BI-IO460BS.反应总收率为5.9％,并经MS和1H NMR等进行了结构确证.     

Parkinson's disease treatment may cause impulse–control disorder via dopamine D3 receptors

In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine, or bromocriptine, it has been observed that a significant number of patients develop impulse–control disorders, such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high‐affinity states of these receptors, namely D2High and D3High, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of impulse–control disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, impulse–control disorders. While the number of studies are limited, the proportion of patients with impulse–control disorder in Parkinson patients treated with an add‐on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behavior associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti‐Parkinson action. Synapse, 69:183–189, 2015 . © 2015 Wiley Periodicals, Inc.     

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson’s disease: an open-label study

Objective: Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson’s disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted).

Methods: PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment.

Results: 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson’s Disease Rating Scale II and III, Parkinson’s Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in ‘off’ time, awakenings and nocturias were observed.

Conclusions: Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.     

盐酸普拉克索B晶型的制备和表征

目的 制备盐酸普拉克索的B晶型并优化制备工艺,同时进行结构表征和稳定性研究。方法 制备盐酸普拉克索的B晶型,采用热重法(TGA)、差示扫描量热法(DSC)、X射线粉末衍射(PXRD)、X射线单晶衍射(SXRD)等分析手段,对盐酸普拉克索B晶型进行表征研究。结果 制备得到了盐酸普拉克索B晶型,其晶型属正交晶系,空间群P2₁2₁2₁,结构中不含溶剂(包括水)。盐酸普拉克索B晶型热处理后晶型不发生转变。结论 盐酸普拉克索B晶型为无水晶型,热稳定性优于一水合物晶型,具有高温稳定性。     

Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients

We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson''s disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F=0.63; p=0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group''s pattern was similar to that reported in healthy individuals (treatment × time × block interaction, p<0.05). Analyses of choice strategy using the expectancy valence model revealed that after 8 weeks on pramipexole, BPD patients attended more readily to feedback related to gains than to losses, which could explain the impaired learning. There were no significant changes in mood symptoms over the 8 weeks, and no increased propensity toward manic-like behaviors were reported. Our results suggest that the enhancement of dopaminergic activity influences risk-associated decision-making performance in euthymic BPD. The clinical implications remain unknown.     

艾司西酞普兰添加治疗对帕金森病患者非运动症状的临床疗效

目的：考察普拉克索添加艾司西酞普兰治疗对帕金森病患者非运动症状的临床疗效。方法：将60例帕金森病患者按收治顺序单双号分为观察组和对照组,每组30例。对照组采用口服盐酸普拉克索治疗,观察组则在口服盐酸普拉克索基础上添加艾司西酞普兰治疗,连续治疗8周后,分别以帕金森病综合评分量表（UPDRS）、汉密尔顿抑郁量表（HAMD）、汉密尔顿焦虑量表（HAMA）、匹兹堡睡眠质量指数（PQSI）和生活质量综合评定量表（GQOLI-74）的评分为指标,对比考察2组患者的综合症状、抑郁和焦虑症状、睡眠和生活质量等的变化。结果 ：与治疗前相比,2组患者治疗后,UPDRS总分、运动检查以及精神、行为和情感评分均显著降低（P〈0.05）,治疗并发症和日常生活评分无显著差异（P〉0.05）,其中观察组患者的UPDRS总分以及精神、行为和情感评分较对照组显著降低（P〈0.05）,而2组患者的治疗并发症、日常生活和运动检查评分无显著差异（P〉0.05）;且2组患者治疗后,HAMD、HAMA和PQSI评分均显著降低（P〈0.05）,其中观察组患者的HAMD、HAMA和PQSI评分较对照组显著降低（P〈0.05）,而2组患者的GQOLI-74评分均显著升高（P〈0.05）,其中观察组患者GQOLI-74评分显著高于对照组（P〈0.05）。结论 ：普拉克索添加艾司西酞普兰治疗可有效改善帕金森病患者抑郁、焦虑、睡眠障碍等非运动症状,从而提高患者生活质量,具有重要的临床意义。     

普拉克索联合持续正压通气对阻塞性睡眠呼吸暂停低通气综合征合并不宁腿综合征患者睡眠障碍的影响

目的观察普拉克索联合持续正压通气(CPAP)对阻塞性睡眠呼吸暂停低通气综合征(OSAHS)合并不宁腿综合征(RLS)患者睡眠障碍的影响。方法将40例OSAHS合并RLS患者随机分为对照组和观察组,每组20例。对照组在CPAP治疗基础上加用安慰剂,每晚1次;观察组在CPAP治疗基础上加用普拉克索0.125 mg,每晚1次。疗程6 mo。比较2组治疗前后睡眠呼吸紊乱指数(AHI)、周期性腿动指数(PLMI)、腿动指数(LMI)、国际不宁腿量表(IRLS)评分和Epworth嗜睡量表(ESS)评分。结果 2组治疗后各指标均较治疗前有显著下降(P<0.05,P<0.01),治疗后AHI、PLMI、LMI在组间有非常显著差异(均P<0.01)。对照组和观察组IRLS评分(12.00±3.13 vs.7.00±2.13)和ESS评分(3.51±1.28 vs.6.39±1.35)组间比较均有非常显著差异(P<0.01)。结论普拉克索联合CPAP治疗OSAHS合并RLS患者睡眠障碍安全、有效。     

长效与标准非麦角类多巴胺受体激动剂治疗帕金森病的Meta分析

目的运用Meta分析的方法,系统评价长效非麦角类多巴胺受体激动剂（NEDA）与标准NEDA在帕金森病（PD）中的有效性、耐受性和安全性。 方法制定检索策略后,检索PubMed,EMBASE,Cochrane图书馆和Web of Knowledge等数据库,同时进行参考文献的追溯和手工检索（截至2019年8月15日）。按照纳入标准和排除标准进行文献筛选,然后进行文献质量评价和数据提取。采用权重均数差（WMD）、相对危险度（RR）以及95%CI作为统计量,运用Cochrane协作网提供的RevMan 5.3软件和Stata 12.0对数据进行分析。 结果（1）共纳入11个随机对照研究,共3280例患者。（2）Meta分析结果如下。有效性方面：长效NEDA与标准NEDA间在减少UPDRS Ⅱ部分评分（WMD=-0.15,95%CI：-0.63~0.33）,Ⅲ部分评分（WMD=0.04,95%CI：-0.24~0.33）和UPDRS Ⅱ＋Ⅲ部分总和评分（WMD=0.12,95%CI：-1.25~1.49）上差异均无统计学意义（P>0.05）。耐受性方面：两种制剂在总的退出人数（RR=1.11,95%CI：0.95~1.31）、因为不良事件退出的人数（RR=1.14,95%CI：0.90~1.45）上,差异无统计学意义（P>0.05）。安全性方面：两种制剂在总的不良事件的发生风险（RR=1.02,95%CI：0.97~1.07）和严重不良事件（RR=0.96,95%CI：0.73~1.26）的发生风险上,差异均无统计学意义（P>0.05）。 结论对PD患者,长效NEDA与标准NEDA在有效性、耐受性和安全性上相似。     

Dopamine agonist‐induced antecollis in Parkinson's disease

Few cases of dopamine agonist‐induced antecollis in Parkinson's disease (PD) have been reported. Literature review of 16 PD patients including our 3 cases with dopamine agonist‐induced antecollis showed predominance of (1) Japanese, (2) women, and (3) Hoehn‐Yahr stage of ≥3. We experienced three Japanese PD patients who subacutely exhibited antecollis following increased dopamine agonist dose that improved just after withdrawal of the agonist. One patient developed antecollis during increasing pramipexole dose in combination with cabergoline. Antecollis in another patient appeared during increasing pramipexole dose; it worsened after substituting pergolide for pramipexole, but improved after withdrawal of pergolide. Our cases indicate that there is no specific dopamine agonist causing antecollis, and it is possibly caused by a number of single dopamine agonists or a combination of them. Dopamine agonist‐induced antecollis should be considered when encountering antecollis in PD patients being treated with dopamine agonists and withdrawal of the agonist can improve symptoms. © 2009 Movement Disorder Society     

Anhedonia in Japanese patients with Parkinson's disease

Aim: Anhedonia has been proposed as a specific mood disorder related to the dopaminergic nerve dysfunction seen in Parkinson's disease (PD). This study examined hedonic tone in patients with PD using the Snaith–Hamilton Pleasure Scale (SHAPS) and investigated the associations with depressive mood by the Self‐Rating Questionnaire for Depression (SRQ‐D). Methods: This study examined 100 patients with PD and 111 age‐matched controls (C2) recruited from 300 healthy subjects (C1) to compare the frequency of anhedonia and to clarify whether anhedonia in PD is associated with depression and anti‐Parkinson medication. Results: Forty‐six percent of PD patients revealed possible/probable depression and 10 patients (10%) with PD showed anhedonia as compared to 3.3% in C1 and 2.7% in C2. The reduction in hedonic tone was related to depression in PD. Among 10 PD patients with anhedonia, seven were in anhedonia with depression and three were in anhedonia without depression. There was no sex difference in anhedonia and depression. No patients treated with pramipexole showed anhedonia but also the highest proportion of normal hedonic tone was found in patients treated with pramipexole among PD patients. In analysis of each SHAPS item, no significant difference was seen on social interaction scores in contrast to the significant reduction of interest/pastimes and sensory experience and food/drink scores between PD patients and C1/C2. Conclusion: Anhedonia may overlap depressive syndrome but some PD patients without depression presented anhedonia. Pramipexole could maintain hedonic tone. The PD patients could enjoy attracting attention and wish to do things helpful for others. Geriatr Gerontol Int 2011; 11: 275–281.