盐酸普拉克索的合成工艺研究

目的对盐酸普拉克索的合成工艺进行研究并优化。方法以关键中间体(S)-2,6-二氨基-4,5,6,7-四氢苯并噻唑为原料,经CH3CH2CHO/NaBH4还原胺化得到普拉克索,在丙酮中成盐,用乙醇-水混合溶剂重结晶得到抗帕金森氏病药物盐酸普拉克索。另外,考察了原料的投料量、反应时间、反应温度、反应溶剂对产物纯度和收率的影响。结果与结论目标化合物的结构经1H-NMR、13C-NMR、MS谱确证,总收率达57.3%(以(S)-2,6-二氨基-4,5,6,7-四氢苯并噻唑计)。与原文献工艺路线相比,该合成工艺简化了操作,提高了收率,更适合于工业化生产。     

Box-Behnken效应面法优化盐酸普拉克索缓释片处方及体外释放机制

通过单因素试验筛选盐酸普拉克索缓释片处方,采用Box-Behnken效应面法优化处方并制备盐酸普拉克索缓释片。单因素试验考察羟丙基甲基纤维素(HPMC)不同型号、不同用量及与不溶性缓释材料组合使用对盐酸普拉克索缓释片体外释放度的影响。确定以HPMC K100M、Eudragit RSPO、Eudragit L100为主要考察因素,以不同时间的累积释放度为评价指标。Box-Behnken效应面法优化处方得出三者的最优范围,以其中优选处方HPMC K100M 101.5 mg、Eudragit RSPO 98 mg和Eudragit L100 13.7 mg和其他辅料制备盐酸普拉克索缓释片并考察释放度。通过相似因子计算,优选处方的体外累积释放度预测值和实测值相似度均大于80。对体外释药数据进行方程拟合,探讨其释药机制,Eudragit RSPO促进盐酸普拉克索的释放,Eudragit L100阻滞盐酸普拉克索的释放,二者互为拮抗作用。结果表明,该处方制备的普拉克索缓释片pH依赖性小,体外释放行为稳定,实现了该缓释片的处方优化。     

普拉克索治疗帕金森病运动并发症的临床疗效观察

目的 评估普拉克索治疗帕金森病运动并发症的临床疗效及安全性.方法 收集92例晚期帕金森病患者并随机分为治疗组和对照组,每组46例.对照组给予多巴丝肼治疗,治疗组在对照组的基础上给予普拉克索,疗程均为12周.两组患者于治疗前后分时间点进行统一帕金森病评定量表修正(UPDRSⅣ-)的评分、不良反应的记录,疗程结束后评估疗效.结果 治疗后对照组和治疗组UPDRSⅣ-评分与基线比较均有下降,治疗组下降更显著,两组比较差异有统计学意义(P＜0.01).治疗组第12周剂末现象(93.75％vs 70.59％)、开关现象(91.67％ vs 63.64％)以及异动症(84.62％ vs48.00％)的总有效率优于对照组,差异均有统计学意义(P＜0.05).两组不良反应发生率差异无统计学意义(P＞0.05).结论 普拉克索治疗帕金森病运动并发症有效,安全性好.     

Randomized,controlled trial of rasagiline as an add‐on to dopamine agonists in Parkinson's disease

Dopamine agonists (DA) are often used as first‐line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase‐B (MAO‐B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18‐week, randomized, double‐blind, placebo‐controlled trial of rasagiline 1 mg/d as an add‐on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent‐to‐treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, ?2.4 ± 0.95; 95% confidence interval [CI], ?4.3, ?0.5; P = 0.012). Mean improvement (LS mean ± SE) was ?3.6 ± 0.68 in the rasagiline group and ?1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society     

Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome.

Although dopamine agonists are becoming first-line therapy for restless legs syndrome (RLS), few reports describe treatment periods exceeding 12 weeks. Here, 150 RLS patients who had responded to pramipexole during a 6-month run-in period (mean dose, 0.50 mg) were randomly assigned to receive placebo or continue receiving pramipexole at an individually optimized dose of 0.125 to 0.75 mg/day for a further 3 months. Patients switched to placebo reached the primary endpoint (a predefined worsening on both the Clinical Global Impressions-Global Improvement scale and the International RLS Study Group Rating Scale) significantly more often than patients who continued to receive pramipexole (85.5% vs. 20.5%; P < 0.0001). They also reached the primary endpoint faster, in 5 versus 42 days to a Kaplan-Meier survival estimate of 0.85 and 7 versus > 84 days to an estimate of 0.5. Over the total 9 months, clinician and patient ratings of symptoms, sleep, and quality of life identified no decline in pramipexole's benefit or tolerability. The great majority of adverse events (AEs) were mild or moderate, and of expected types. Augmentation was considered an AE, but in this population of responders it did not occur.     

Restless legs syndrome

Restless legs syndrome (RLS), first described in 1672 and given its name in 1945, is one of the most common sleep and movement disorders. Modern population-based studies demonstrate a prevalence between 5% and 15% in adult white populations. According to the diagnostic criteria, RLS is defined as an irresistable desire to move limbs, usually associated with paresthesias/dysesthesias and motor restlessness. The symptoms start or worsen at rest and improve with activity. Additionally, the symptoms worsen in the evenings and/or nights, which often results in disturbance of sleep with daytime tiredness. There is often a family history of RLS. Initially, the disease course is usually fluctuating and later may become continuous or chronic-progressive. The diagnosis is based on the patient history and is supported by a normal neurological examination. RLS is confirmed by the finding of periodic limb movements (PLM) in polysomnographic investigations and by a response to dopaminergic medication. A large number of studies have confirmed the effect of levodopa (L-dopa) in the treatment of RLS. A majority of the patients treated over a longer period of time with L-dopa, however, develop problems with an effect called augmentation, where the RLS symptoms begin appearing earlier during the day and involve new parts of the body with increasing severity. A large number of studies have now confirmed that dopamine agonists can also be effective in RLS therapy, and that this treatment seems to involve less risk for augmentation. This paper provides a general review of RLS with a focus on current treatment options.     

消旋-7-氧代普拉克索的合成

1,3-环己二酮(2)经溴代、与硫脲环合、酮的α-溴代及叠氮取代制得2-氨基-6-叠氮-7-氧代-4,5,6,7-四氢苯并噻唑(6),6依次经硼氢化钠和锌粉还原后经正丙醛/三乙酰氧基硼氢化钠还原氨化,最后由氯铬酸吡啶鎓盐(PCC)氧化得到盐酸普拉克索质量研究的杂质对照物消旋-7-氧代普拉克索,总收率为11.7％.     

Pramipexole extended-release (once-daily formulation) for the treatment of Parkinson's disease

Importance of the field: Immediate-release pramipexole (P-IR) is indicated three times daily for the symptomatic treatment of early and advanced Parkinson's disease (PD). An extended-release formulation of pramipexole (P-ER) has been developed to allow a once-daily formulation and to provide more stable dopaminergic stimulation.

Areas covered in this review: This review summarizes clinical pharmacology and pharmacokinetics of P-ER for the treatment of early and advanced PD. The advantages and disadvantages of the strategies available at present for achieving continuous dopaminergic stimulation in the treatment of PD are discussed first. The pharmacological properties are then summarized. Finally, the clinical pharmacology and pharmacokinetics of P-ER are described.

What the reader will gain: The reader will gain knowledge of the development of P-ER, its current place in the pharmacotherapy of PD, and future directions.

Take home message: P-ER has been shown to be efficacious in early and advanced PD and it has the same clinical profile when administered once daily as P-IR administered three times daily. An overnight switching of P-IR to dose-equivalent P-ER is successful in 80% of patients with early PD.