本文選題：羅替戈汀透皮貼劑　切入點(diǎn)：不良反應(yīng)　出處：《山東大學(xué)》2017年碩士論文

【摘要】：背景帕金森病(Parkinson' s disease,PD)是一種慢性進(jìn)行性黑質(zhì)多巴胺能神經(jīng)元明顯死亡伴基底神經(jīng)節(jié)內(nèi)缺乏多巴胺的變性病,在中老年人中常見,近年來(lái)有年輕化的趨勢(shì)。據(jù)統(tǒng)計(jì),我國(guó)有超過(guò)250萬(wàn)PD患者。PD的非運(yùn)動(dòng)癥狀常常出現(xiàn)在運(yùn)動(dòng)癥狀十余年前,如嗅覺(jué)減退、便秘、睡眠障礙等,隨后運(yùn)動(dòng)癥狀表現(xiàn)為運(yùn)動(dòng)遲緩、震顫、肌強(qiáng)直和姿勢(shì)平衡障礙。不寧腿綜合征(restless leg syndrome,RLS)也稱為Ekbom綜合征,是一種在中老年人群中不少見的運(yùn)動(dòng)障礙性和睡眠障礙性疾病。流行病學(xué)數(shù)據(jù)顯示,RLS患病率為2.5%-15%,男女比例約1:2,患病率隨著年齡的增長(zhǎng)逐年升高。其典型的臨床特征為下肢極度的不適感和活動(dòng)患肢的欲望。盡管上述兩種疾病臨床表現(xiàn)有顯著不同,目前普遍認(rèn)為,二者均與中樞神經(jīng)系統(tǒng)多巴胺能神經(jīng)元損害相關(guān),并且左旋多巴(L-dopa)制劑和多巴胺受體激動(dòng)劑(Dopamine agonist,DA)等多巴胺能藥物對(duì)其二者有明確療效。最早的DA是溴隱亭(Bromocriptine),由于其不良反應(yīng)較大,目前已較少使用。近年來(lái),非麥角類DA為治療的首選藥物,普拉克索(Pramipexole)是新型選擇性D3受體DA,羅匹尼羅(Ropinirole)和卡麥角林(Cabergoline)是D2受體DA。這類長(zhǎng)半衰期的藥物能保持相對(duì)較穩(wěn)定的血藥濃度,以此避免紋狀體突觸后膜受到DAs對(duì)多巴胺受體產(chǎn)生的波動(dòng)樣刺激,延緩疾病的進(jìn)展。羅替戈汀(Rotigotine)于20世紀(jì)80年代被報(bào)道,2007年作為首個(gè)透皮給藥劑型DA上市,2008年曾因制造問(wèn)題被召回,2012年再次于美國(guó)上市。羅替戈汀作用于D,、D2、D3受體,每日1次,作用可持續(xù)24小時(shí),因?yàn)槠涫褂梅奖愫?jiǎn)單、沒(méi)有藥物首過(guò)效應(yīng)(通過(guò)皮膚吸收入血)、血藥濃度波動(dòng)較小、易于患者長(zhǎng)期使用等特點(diǎn),很快在臨床上得到廣泛應(yīng)用。然而,羅替戈汀的不良反應(yīng)大大影響了患者的依從性,主要有惡心、嘔吐、皮膚紅斑、皮疹、局部皮膚瘙癢等。目的通過(guò)對(duì)大量隨機(jī)對(duì)照試驗(yàn)進(jìn)行薈萃分析,綜合評(píng)價(jià)與羅替戈汀透皮貼劑(rotigotine transdermal patch,R-TDP)治療相關(guān)的不良反應(yīng)事件(adverse events,AEs)。方法使用Pubmed,Embase,Cochrane在線圖書館和Clinicaltrial.gov檢索所有研究羅替戈汀的治療效果和不良反應(yīng)的隨機(jī)對(duì)照試驗(yàn)(randomized controlled trial,RCT),不論其已經(jīng)被發(fā)表還是沒(méi)有被發(fā)表。根據(jù)設(shè)定的納入排除標(biāo)準(zhǔn)篩選研究,將符合標(biāo)準(zhǔn)的研究用Cochrane推薦的"偏倚風(fēng)險(xiǎn)評(píng)估"工具進(jìn)行評(píng)估。提取試驗(yàn)的基本信息、試驗(yàn)類型、方法學(xué)特征、試驗(yàn)對(duì)象特征、干預(yù)措施和結(jié)局指標(biāo)、meta分析的效應(yīng)指標(biāo)和樣本含量等信息。選用RR值作為效應(yīng)量,用I2進(jìn)行異質(zhì)性檢驗(yàn),然后使用M-H法,隨機(jī)效應(yīng)模型對(duì)羅替戈汀的相關(guān)的嚴(yán)重不良反應(yīng)事件(serious adverse events,SAEs)、退出試驗(yàn)總數(shù)(overall withdrawals,OWs)、不良反應(yīng)相關(guān)的退出試驗(yàn)(adverseeffectrelated withdrawals,AERWs)、伴隨治療出現(xiàn)的不良反應(yīng)事件(treatment-emergent adverse events,TEAEs)和各種不良反應(yīng)癥狀的發(fā)生率使用Review Manager 5.3軟件進(jìn)行Meta分析。最后,使用Stata 14.0軟件應(yīng)用Egger法和Harbord法對(duì)發(fā)表偏倚進(jìn)行分析。結(jié)果一共有31項(xiàng)RCT,總共7169例患者納入研究,其中4753例患者被隨機(jī)分為羅替戈汀治療組,2416例患者被隨機(jī)分為安慰劑對(duì)照組。SAEs,OWs與羅替戈汀透皮貼劑治療并不顯著相關(guān)。AERWs與羅替戈汀治療相關(guān),差別有統(tǒng)計(jì)學(xué)意義。亞洲人進(jìn)行羅替戈汀治療不增加AERWs,而歐美人增加AERWs。劑量為lmg/24h、3mg/24h和6.75mg/24h時(shí),羅替戈汀治療增加AERWs。頭痛、頭暈、嗜睡、惡心、嘔吐、失眠、用藥局部反應(yīng)、幻覺(jué)、運(yùn)動(dòng)障礙、厭食和消化不良在羅替戈汀治療組發(fā)生率高于安慰劑組,差別有統(tǒng)計(jì)學(xué)意義。然而直立性低血壓和竇炎在羅替戈汀治療組較安慰劑治療組發(fā)生率低,差別有統(tǒng)計(jì)學(xué)意義。結(jié)論Meta分析結(jié)果顯示,和安慰劑相比,羅替戈汀很少引起嚴(yán)重的不良反應(yīng),但隨著劑量的增加不良反應(yīng)出現(xiàn)的風(fēng)險(xiǎn)增加。亞洲人對(duì)羅替戈汀耐受性比歐美人更好。羅替戈汀主要引起患者頭痛、頭暈、嗜睡、惡心、嘔吐、失眠、用藥局部反應(yīng)、幻覺(jué)、運(yùn)動(dòng)障礙、厭食和消化不良11個(gè)不良反。羅替戈汀對(duì)直立性低血壓和竇炎可能有潛在的保護(hù)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.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R742.5

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