罗替戈汀透皮贴剂不良反应的meta分析

发布时间：2018-03-30 00:11

本文选题：罗替戈汀透皮贴剂　切入点：不良反应　出处：《山东大学》2017年硕士论文

【摘要】：背景帕金森病(Parkinson' s disease,PD)是一种慢性进行性黑质多巴胺能神经元明显死亡伴基底神经节内缺乏多巴胺的变性病,在中老年人中常见,近年来有年轻化的趋势。据统计,我国有超过250万PD患者。PD的非运动症状常常出现在运动症状十余年前,如嗅觉减退、便秘、睡眠障碍等,随后运动症状表现为运动迟缓、震颤、肌强直和姿势平衡障碍。不宁腿综合征(restless leg syndrome,RLS)也称为Ekbom综合征,是一种在中老年人群中不少见的运动障碍性和睡眠障碍性疾病。流行病学数据显示,RLS患病率为2.5%-15%,男女比例约1:2,患病率随着年龄的增长逐年升高。其典型的临床特征为下肢极度的不适感和活动患肢的欲望。尽管上述两种疾病临床表现有显著不同,目前普遍认为,二者均与中枢神经系统多巴胺能神经元损害相关,并且左旋多巴(L-dopa)制剂和多巴胺受体激动剂(Dopamine agonist,DA)等多巴胺能药物对其二者有明确疗效。最早的DA是溴隐亭(Bromocriptine),由于其不良反应较大,目前已较少使用。近年来,非麦角类DA为治疗的首选药物,普拉克索(Pramipexole)是新型选择性D3受体DA,罗匹尼罗(Ropinirole)和卡麦角林(Cabergoline)是D2受体DA。这类长半衰期的药物能保持相对较稳定的血药浓度,以此避免纹状体突触后膜受到DAs对多巴胺受体产生的波动样刺激,延缓疾病的进展。罗替戈汀(Rotigotine)于20世纪80年代被报道,2007年作为首个透皮给药剂型DA上市,2008年曾因制造问题被召回,2012年再次于美国上市。罗替戈汀作用于D,、D2、D3受体,每日1次,作用可持续24小时,因为其使用方便简单、没有药物首过效应(通过皮肤吸收入血)、血药浓度波动较小、易于患者长期使用等特点,很快在临床上得到广泛应用。然而,罗替戈汀的不良反应大大影响了患者的依从性,主要有恶心、呕吐、皮肤红斑、皮疹、局部皮肤瘙痒等。目的通过对大量随机对照试验进行荟萃分析,综合评价与罗替戈汀透皮贴剂(rotigotine transdermal patch,R-TDP)治疗相关的不良反应事件(adverse events,AEs)。方法使用Pubmed,Embase,Cochrane在线图书馆和Clinicaltrial.gov检索所有研究罗替戈汀的治疗效果和不良反应的随机对照试验(randomized controlled trial,RCT),不论其已经被发表还是没有被发表。根据设定的纳入排除标准筛选研究,将符合标准的研究用Cochrane推荐的"偏倚风险评估"工具进行评估。提取试验的基本信息、试验类型、方法学特征、试验对象特征、干预措施和结局指标、meta分析的效应指标和样本含量等信息。选用RR值作为效应量,用I2进行异质性检验,然后使用M-H法,随机效应模型对罗替戈汀的相关的严重不良反应事件(serious adverse events,SAEs)、退出试验总数(overall withdrawals,OWs)、不良反应相关的退出试验(adverseeffectrelated withdrawals,AERWs)、伴随治疗出现的不良反应事件(treatment-emergent adverse events,TEAEs)和各种不良反应症状的发生率使用Review Manager 5.3软件进行Meta分析。最后,使用Stata 14.0软件应用Egger法和Harbord法对发表偏倚进行分析。结果一共有31项RCT,总共7169例患者纳入研究,其中4753例患者被随机分为罗替戈汀治疗组,2416例患者被随机分为安慰剂对照组。SAEs,OWs与罗替戈汀透皮贴剂治疗并不显著相关。AERWs与罗替戈汀治疗相关,差别有统计学意义。亚洲人进行罗替戈汀治疗不增加AERWs,而欧美人增加AERWs。剂量为lmg/24h、3mg/24h和6.75mg/24h时,罗替戈汀治疗增加AERWs。头痛、头晕、嗜睡、恶心、呕吐、失眠、用药局部反应、幻觉、运动障碍、厌食和消化不良在罗替戈汀治疗组发生率高于安慰剂组,差别有统计学意义。然而直立性低血压和窦炎在罗替戈汀治疗组较安慰剂治疗组发生率低,差别有统计学意义。结论Meta分析结果显示,和安慰剂相比,罗替戈汀很少引起严重的不良反应,但随着剂量的增加不良反应出现的风险增加。亚洲人对罗替戈汀耐受性比欧美人更好。罗替戈汀主要引起患者头痛、头晕、嗜睡、恶心、呕吐、失眠、用药局部反应、幻觉、运动障碍、厌食和消化不良11个不良反。罗替戈汀对直立性低血压和窦炎可能有潜在的保护作用。
[Abstract]:The background of Parkinson's disease (Parkinson's, disease, PD) is a chronic progressive death of dopaminergic neurons in the substantia nigra dopamine deficiency with obvious degeneration of basal ganglia, common in older people and younger trend in recent years. According to statistics, China has more than 2 million 500 thousand non motor symptoms in PD patients with.PD often appear motor symptoms in more than ten years ago, such as hyposmia, constipation, sleep disorder, then movement symptoms of tremor, bradykinesia, rigidity and postural. Restless legs syndrome (restless leg, syndrome, RLS) also known as Ekbom syndrome, is a rare among elderly people in movement disorders and sleep disorders. The epidemiological data show that the prevalence rate of RLS was 2.5%-15%, the ratio of male to female is about 1:2, the prevalence increased with age increased year by year. The typical clinical features of lower extremity for extreme discomfort and live Move the limb desires. Although the clinical manifestations of the two diseases are significantly different, it is generally believed that both of the two and central nervous system damage to dopaminergic neurons, and levodopa (L-dopa) and preparation of dopamine receptor agonist (Dopamine agonist, DA) and other dopaminergic drugs have specific effect on the earliest. The DA is bromocriptine (Bromocriptine), because of its side effects, has been rarely used. In recent years, non ergot DA drug of choice for the treatment of pramipexole (Pramipexole) is a new type of selective D3 receptor DA, ropinirole (Ropinirole) and cabergoline (Cabergoline) is a drug D2 receptor DA. such a long half-life can maintain the blood drug concentration is relatively stable, in order to avoid the striatal postsynaptic membrane by wave like DAs on the production of dopamine receptor stimulation, delay the progression of the disease. Rotigotine (Rotigotine) in the 20 world Ji reported in 80s, 2007 as the first transdermal medicament DA market, 2008 has been recalled due to manufacturing problems, again in 2012 in the United States listed. Rotigotine in D, D2, D3, receptor, 1 times a day, sustainable 24 hours, because its use is simple and convenient, there is no first pass drug (the effect of absorption through the skin into blood), blood concentration fluctuation is small, easy to patients with long-term use, will soon be widely used in clinic. However, as for the adverse reaction of the Luo greatly affect the compliance of patients, including nausea, vomiting, skin erythema, rash, skin itching and other local. Through a meta-analysis of large randomized controlled trials, comprehensive evaluation and rotigotine transdermal patch (rotigotine transdermal, patch, R-TDP) treatment related adverse events (adverse events, AEs). Methods using Pubmed, Embase, Cochrane and online library All of the Clinicaltrial.gov retrieval rotigotine treatment effect and adverse reaction of randomized controlled trials (randomized controlled, trial, RCT), whether it has been published or unpublished. According to the set included in the screening of exclusion criteria, will meet the standard of Cochrane recommended by "bias risk assessment tools for assessment. The information extraction test types, methodological characteristics, test object characteristics, interventions and outcomes, meta analysis of the effect of index and sample content. Choose the RR value as the effect size, heterogeneity test was carried out with I2, and then use the M-H method, the random effects model of rotigotine related serious adverse events (serious adverse events SAEs (overall), the total number of exit test withdrawals, OWs), exit test related adverse events (adverseeffectrelated withdrawals, AERWs ), with the treatment emergent adverse events (treatment-emergent adverse, events, TEAEs) and the incidence of adverse reaction symptoms using Review Manager 5.3 software for Meta analysis. Finally, the analysis of publication bias in the use of Stata 14 software using Egger method and Harbord method. Results a total of 31 RCT, a total of 7169 cases were included in the study among the patients, 4753 patients were randomly divided into rotigotine treatment group, 2416 patients were randomly divided into placebo control group.SAEs, OWs and rotigotine transdermal patch treatment was not significantly related to.AERWs and Luo Tige Ting treatment, the difference was statistically significant. The Asians of rotigotine treatment does not increase AERWs, and Europe the beauty of increasing doses of AERWs. for lmg/24h, 3mg/24h and 6.75mg/24h, rotigotine treatment increased AERWs. headache, dizziness, drowsiness, nausea, vomiting, insomnia, Administration Bureau of the Ministry of reaction, illusion, avoidance movement Okay, anorexia and dyspepsia in the rotigotine treatment group was higher than that in the placebo group, the difference was statistically significant. However, orthostatic hypotension and sinusitis in the rotigotine treatment group than in the placebo group occurrence rate is low, the difference was statistically significant. Conclusion the results of Meta analysis showed that compared with placebo, rotigotine rarely cause adverse the reaction is serious, but as the dose increases the risk of adverse reactions. The increase of rotigotine tolerance of Asians as Americans better. Rotigotine is mainly caused by headache, dizziness, drowsiness, nausea, vomiting, insomnia, local drug reaction, hallucinations, movement disorders, anorexia and dyspepsia 11 Luo adverse reaction. Rotigotine in orthostatic hypotension and sinusitis may have potential protective effects.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R742.5

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