Cost-Effective Isolation of a Process Impurity of Pregabalin

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.     

普瑞巴林对术后疼痛预防效果的系统评价

目的 系统评价普瑞巴林术后镇痛的有效性及安全性,以期为术后镇痛药物的选择提供证据. 方法 计算机检索PubMed、EMbase、Cochrane Library(CENTRAL,2015年第5期)、万方数据库、中国生物医学文献数据库(China BiologyMedicine Disc,CBM)、中国知网(China National Knowledge Infrastructure,CNKI)数据库,查找有关普瑞巴林对患者术后镇痛效果评价的随机对照试验(randomized controlled trails,RCT).检索时限均为从建库至2015年5月.由2名研究者严格按照纳入与排除标准独立筛选文献,并相互交叉核对结果.数据提取完毕后采用RevMan 5.3软件进行Meta分析. 结果 最终纳入24项研究,共计1 718例患者.Meta分析结果显示:普瑞巴林具有良好的术后镇痛效果.主要表现在静止状态下/活动状态下术后24 h疼痛评分的降低[标准化均数差(standard mean difference,SMD)=-0.50,95％置信区间(confidence interval,CI)(-0.67,-0.33),P＜0.01],术后24 h阿片类药物使用量的减少[SMD=-1.08,95％CI(-1.62,-0.55),P＜0.01]. 结论 普瑞巴林具有良好的术后镇痛效果,但受纳入研究数量和质量限制,本研究尚需更多大样本高质量研究加以验证.     

普瑞巴林治疗带状疱疹后遗神经痛的临床观察

目的探讨普瑞巴林对带状疱疹后遗神经痛的有效性与安全性。方法选择带状疱疹后遗神经痛患者72例并随机分为两组各36例。观察组采用普瑞巴林治疗,对照组采用加巴喷丁治疗,观察比较两组的疗效及不良反应。结果治疗4周后,观察组总有效率为83.33%,显著高于对照组(P<0.05);两组的VAS评分均比治疗前降低,但观察组降低更显著(P<0.01);两组均无严重不良反应发生。结论普瑞巴林治疗带状疱疹后遗神经痛安全有效,能显著改善患者的VAS评分,无严重不良反应。     

普瑞巴林剂量对腹腔镜子宫全切术患者术后疼痛的影响

目的探讨不同剂量(75、150和300 mg)普瑞巴林预先给药在腹腔镜子宫切除术患者中的术后镇痛效果。方法该研究为前瞻性、随机、安慰剂对照和双盲研究。共纳入82例美国麻醉医师协会(ASA)分级为Ⅰ～Ⅱ级并择期行腹腔镜子宫切除术的患者。患者随机分成4组,其中第1、2和3组(每组20例)术前1晚、术前30 min和术后6 h分别口服浓度为75、150和300 mg的普瑞巴林,而对照组(n=22)按照相同方案接受安慰剂治疗。主要临床结局是术后24 h静息和运动时的疼痛视觉模拟评分(VAS)。药物相关副作用评估作为次要观察指标。嗜睡采用Ramsay镇静评分评估,而恶心和呕吐用数值评分评估。结果不同浓度预先普瑞巴林给药的镇痛效果优于安慰剂。事后检验显示,4组间AVS评分差异有统计学意义,表明浓度下降,疼痛评分作为时间自变量而下降。普瑞巴林浓度达到最高(300 mg)时,镇静评分高于其他组。结论预先服用75、150和300 mg普瑞巴林对减轻腹腔镜子宫切除术后疼痛具有重要作用。比较不同浓度与副作用表明,口服150 mg普瑞巴林是减轻腹腔镜子宫切除术后疼痛的安全有效方法。     

Postmortem analysis of quetiapine and pregabalin in human bone

In this study quetiapine and pregabalin were analyzed in human bones. A method previously developed for the determination of antidepressants in human bone was tested for the analysis of these two substances. Bones were pulverized and subjected to the extraction protocol, and after undergoing solid-phase extraction, samples were analyzed using gas chromatography–mass spectrometry. The assay was validated in the range 0.3–500 ng/mg, mean analytical recovery was 76.9% for quetiapine and 90.9% for pregabalin, matrix effect was 83% for quetiapine and 91% for pregabalin and process efficiency was 63.8% for quetiapine and 82.7% for pregabalin. The intra- and inter-day precision was below 3% in all cases and the intra- and inter-assay accuracy values were in almost all cases better than 12%. The validated method was then applied to bone samples from forensic cases. Drugs were detected in bone in 2 of the 3 blood positive cases. The approximate concentrations in bone were 40 ng/mg for pregabalin and 7 ng/mg for quetiapine. To our knowledge, this is the first time these substances were detected in bones. With this study the number of substances with a validated protocol to be used in human bones in case of necessity is expanded.     

普瑞巴林联合重组人干扰素α-2b对带状疱疹后遗神经痛的影响

目的研究普瑞巴林联合重组人干扰素α-2b治疗带状疱疹后遗神经痛(postherpetic neuralgia,PHN)的临床疗效。方法选取2016年1月至2018年12月咸宁市中心医院收治的92例PHN患者作为研究对象,并按照随机数表法将其随机分为试验组(46例)和对照组(46例),其中对照组患者予以口服普瑞巴林治疗,试验组患者在口服普瑞巴林的基础上肌肉注射重组人干扰素α-2b,对比观察两组患者的临床疗效及血清白细胞介素-6(IL-6)、白细胞介素-10(IL-10)水平的变化情况,并采用视觉模拟评分法(visual analogue score,VAS)评估患者治疗前后的疼痛程度。结果治疗后,两组患者疼痛程度均逐渐减轻(F=113.518、45.298,P=0.000、0.000),且治疗第3、5、10、30天试验组患者VAS评分均显著低于对照组(t=2.525、7.172、6.237、6.000,P=0.013、0.000、0.000、0.000);治疗第30天,试验组患者治疗总有效率为86.96%,明显高于对照组患者的治疗总有效率69.57%(Mann-Whitney U=759.500,Z=-2.462,P=0.014);治疗第30天,两组患者血清IL-6水平均降低,且试验组显著低于对照组(t=27.773,P=0.000),血清IL-10水平均升高,且试验组显著高于对照组(t=13.607,P=0.000)。结论普瑞巴林联合重组人干扰素α-2b治疗带状疱疹后遗神经痛,可有效减轻患者疼痛,疗效显著,值得临床推广应用。     

Efficacy and Safety of Pregabalin for Muscle Cramps in Liver Cirrhosis: A Double-Blind Randomized Controlled Trial

BackgroundMuscle cramp is possibly related to peripheral nerve hyperexcitability (PNH), and one of the most debilitating symptoms frequently encountered in patients with liver cirrhosis. We investigated whether pregabalin, a gamma-aminobutyric acid analogue, can suppress neuronal excitability and reduce muscle cramps in cirrhotic patients.MethodsWe conducted a randomized, double-blind, placebo-controlled trial in which study participants with cirrhosis from a single tertiary center were enrolled. Primary endpoint was the relative change in cramp frequency from the run-in to standard dose treatment phase (4 weeks per each). Secondary endpoints included the responder rate, and the changes in cramp frequency during sleep, pain intensity, health-related quality of life (Liver Disease Quality of Life Instrument, Short Form-36) and electrophysiological measures of PNH.ResultsThis study was terminated early because of insufficient accrual. 80% (n = 56) of the target number of participants (n = 70) were randomized to pregabalin (n = 29) or placebo (n = 27). Median baseline frequency of muscle cramps (interquartile range) was 5.8 (3.5–10) per week in the pregabalin group and 6.5 (4.0–10) in the placebo group (P = 0.970). The primary analysis showed a significant reduction in cramp frequency with pregabalin compared to placebo (−36% vs. 4.5% for the percentage change, P = 0.010). Secondary outcomes did not differ significantly between the two groups. Adverse effects with pregabalin were mainly dizziness and lethargy.ConclusionWith multiple problems emerging from premature termination in mind, the results suggested an acceptable safety profile and favorable effect of pregabalin in reducing muscle cramps compared to placebo in cirrhotic patients.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01271660","term_id":"NCT01271660"}}NCT01271660     

Pregabalin and gabapentin for the treatment of sciatica

Whilst pregabalin (PGB) and gabapentin (GBP) are both used to treat neuropathic pain, their relative role in sciatica is unclear. Our aim was to extensively review the roles of PGB and GBP in treating sciatica. The efficacy, side effects (SE) profile and cost of PGB and GBP in neuropathic pain states were reviewed with special reference to sciatica. Eleven articles matched the criteria: seven systematic reviews, one retrospective cross-sectional study, one placebo-controlled-crossover study, one randomized placebo-controlled double-blind study and one case report. GBP and PGB appeared to demonstrate comparable efficacy and SE. However, the amount and quality of evidence was low, and only indirect comparisons were available. Importantly, no direct “head-to-head” study existed. Globally, costs varied widely (by up to 31 times) and unpredictably (PGB cheaper than GBP, or vice versa). Formulary regulator rulings were globally disparate; however, many exclusively favoured the more expensive drug (whether GBP or PGB). No studies assessed PGB-GBP interchange. Weak evidence suggests that efficacy and SE with GBP and PGB are probably similar; however, firm conclusions are precluded. Despite weak data, and having cited minor titration, but definite cost, advantages, UK National Institute for Health and Clinical Excellence favoured PGB over GBP. Given that no evidence supports unhindered PGB-GBP interchange, neither drug should probably be favoured. Prospective “head-to-head” studies are urgently required to provide robust evidence-based knowledge for choice of GBP or PGB in sciatica.     

Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat

PURPOSE: To determine whether a pharmacologic treatment could delay or prevent the epileptogenesis induced by status epilepticus (SE) through the protection of some brain areas, we studied the effects of the long-term exposure to pregabalin (PGB) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. METHODS: SE was induced in adult and 21-day-old (P21) rats. At 20 min after pilocarpine, rats received 50 mg/kg PGB (pilo-preg) or saline (pilo-saline). PGB treatment was given daily at the dose of 50 mg/kg for 7 days after SE and at 10 mg/kg from day 8 until killing. Neuronal damage was assessed in hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from adult and P21 animals killed 6 days after SE. The number of glial fibrillary acidic protein (GFAP)-reactive astrocytes was tested by immunohistochemistry in sections adjacent to those used for cell counting. The latency to spontaneous seizures was controlled by visual observation and EEG recording. RESULTS: PGB induced neuroprotection in layer II of piriform cortex and layers III-IV of ventral entorhinal cortex of adult rats, whereas no hippocampal region was protected. In P21 rats, damage was limited to the hilus and similar in pilo-preg and pilo-saline animals. The number of GFAP-positive astrocytes was higher in pilocarpine- than in saline-treated rats. It was decreased in pilo-preg compared with pilo-saline rats in layer II of the piriform cortex. Adult pilo-preg rats became epileptic after a longer latency (39 days) than did pilo-saline rats (22 days). CONCLUSIONS: These data underline the antiepileptogenic consequences of long-term PGB treatment, possibly mediated by the protection of piriform and entorhinal cortices in the lithium-pilocarpine model of epilepsy.