左旋多巴诱导的异动症的最新治疗药物研究进展
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摘要
左旋多巴诱导的异动症(levodopa-induced dyskinesia,LID)是帕金森病多巴胺治疗的常见副作用,严重影响患者的生活质量。其发生机制尚不清楚,但是帕金森病异动症动物模型提供了关于左旋多巴诱导的异动症机制的重要知识。目前除了调整治疗方案之外只有少数几种能减轻LID症状的药物,并且这些药物不能延缓病程,所以现在急需研究新的药物来干预其进展。本综述从机体多巴胺能、谷氨酸能、5-羟色胺能、阿片、GABA能、腺苷、肾上腺神经递质等系统出发,阐述致病机理的同时综述相关的最新治疗药物,其中还包括一些尚未进入临床、只进行了动物试验的药物。除了治疗异动症的经典药物金刚烷胺、吗啡之外,本综述还加入了马福利特、咖啡因等新近正在研究的药物,在常用剂型之外还加入了新的剂型,以快速缓解症状或减轻多巴胺的波动性刺激。本综述旨在为异动症的治疗提供更多的备选方案以期早日达到控制疾病进展的目的。
Levodopa-induced dyskinesias( LID) is the most common side effect in Parkinson's disease( PD) treatment with dopaminergic and it seriously affect the patients' living quality. The underlying mechanism and pathological substrate of LID are not fully understood but animal models of parkinsonism with LID have provided important knowledge about the mechanisms underlying LID. Now in addition to adjust the treatment plan there is only a few drugs can relieve symptoms of LID and these drugs can not delay the course of the disease. So there is an urgent need for research on new drugs to make an intervention on its progress. Here we review the most relevant advances in relation to the dopaminergic system,the glutamatergic system,the serotonergic system,the opioid system,the GABAergic system,the adenosine system,the adrenergic neurotransmission and the related newly studied medicines to treat LID. Some of these drugs are not used clinically and only studied on animal models. Except for the classic medicines for LID treatment amantadine and morphine,there are also newly studied medicines such as mavoglurant and caffeine. For the classic druges there are newly studied dosage form for the sake of control the LID symptom rapidly or remission the pulsatile stimulation of DA receptors. The ultimate aim of this review is provide more choices for LID treatment and control the process of LID as soon as possible.
Levodopa-induced dyskinesias( LID) is the most common side effect in Parkinson's disease( PD) treatment with dopaminergic and it seriously affect the patients' living quality. The underlying mechanism and pathological substrate of LID are not fully understood but animal models of parkinsonism with LID have provided important knowledge about the mechanisms underlying LID. Now in addition to adjust the treatment plan there is only a few drugs can relieve symptoms of LID and these drugs can not delay the course of the disease. So there is an urgent need for research on new drugs to make an intervention on its progress. Here we review the most relevant advances in relation to the dopaminergic system,the glutamatergic system,the serotonergic system,the opioid system,the GABAergic system,the adenosine system,the adrenergic neurotransmission and the related newly studied medicines to treat LID. Some of these drugs are not used clinically and only studied on animal models. Except for the classic medicines for LID treatment amantadine and morphine,there are also newly studied medicines such as mavoglurant and caffeine. For the classic druges there are newly studied dosage form for the sake of control the LID symptom rapidly or remission the pulsatile stimulation of DA receptors. The ultimate aim of this review is provide more choices for LID treatment and control the process of LID as soon as possible.
引文
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[7]Paquette MA,Martinez AA,Macheda T,et al.Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease:role of NMDA vs.5-HT1A receptors[J].Eur Neurosci,2012,36(9):3224-3234.
[8]张锦萍,刘鹏,张尊胜,等.美金刚治疗帕金森病疗效荟萃分析[J].徐州医学院学报,2016,36(5):301-306.
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[10]Rascol O,Fox S,Gasparini F,et al.Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias[J].Parkinsonism Relat Disord,2014,20(9):947-956.
[11]Morin N,Morissette M,Grégoire L,et al.Chronic treatment with MPEP,an m Glu5 receptor antagonist,normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys[J].Neuropharmacology,2013,73:216-231.
[12]Rascol Olivier,Fox Susan,Gasparini Fabrizio,et al.Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa induced dyskinesias[J].Parkinsonism&Related Disorders,2014,20(9):947-956.
[13]Andrew C Mc Creary,Mark A Varney,Adrian Newman-Tancredi.The novel 5-HT1A receptor agonist,NLX-112 reduces L-DOPA-induced abnormal involuntary movements in rat:A chronic administration study with microdialysis measurements[J].Neuropharmacology,2016,105:651-660.
[14]Bezard E,Munoz A,Tronci E,et al.Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia[J].Neurosci Res,2013,77(4):242-246.
[15]Bishop C,George JA,Buchta W,et al.Serotonin transporter inhibition attenuates levodopa-induced dyskinesia without compromising levodopa efficacy in hemi-parkinsonian rats[J].Eur J Neurosci,2012,36(6):2839-2848.
[16]Potts Lisa F,Park Eun S,Woo Jong-Min,et al.Dual-agonist/antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease[J].Annals of Neurology,2015,77(6):930-941.
[17]Daniele Antonio,Panza Francesco,Greco Antonio,et al.Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease?The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease[J].Parkinsons Disease,2016,25(3):1812-1826.
[18]Perez-Lloret S,Merello M.Two new adenosine receptor antagonists for the treatment of Parkinson’s disease:istradefylline versus tozadenant[J].Expert Opin Pharmacother,2014,15(8):1097-1107.
[19]Wills AM,Eberly S,Tennis M,et al.Caffeine consumption and risk of dyskinesia in CALM-PD[J].Mov Disord,2013,28(3):380-383.
[20]Dungo R,Deeks ED.Istradefylline:first global approval[J].Drugs,2013,73(8):875-882.
[21]Lewitt PA,Hauser RA,Lu M,et al.Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease(FJORD study)[J].Neurology,2012,79(2):163-169.
[22]Barnum Christopher J,Bhide Nirmal,Lindenbach David,et al.Effects of noradrenergic denervation on L-DOPA induced dyskinesia and its treatment by alpha-and beta-adrenergic receptor antagonists in hemiparkinsonian rats[J].Pharmacology Biochemistry and Behavior,2012,100(3):607-615.
[23]Gerlach M,Halley P,Riederer P,et al.The effect of piribedil on levodopa-induced dyskinesias in a rat model of Parkinson’s disease:differential role of a2 adrenergic mechanisms[J].Neural Transm,2013,120(1):31-36.
[24]Dezsi L,Vecsei L.Safinamide for the treatment of Parkinson’s disease[J].Expert Opin Invest Drugs,2014,23(5):729-742.
[25]Gregoire L,Jourdain VA,Townsend M,et al.Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys[J].Parkinsonism Relat Disord,2013,19(5):508-514.
[26]丁喜晴,朱忠方,崔桂云,等.钙调激酶Ⅱ参与帕金森病运动并发症发病机制的实验研究[J].徐州医学院学报,2015,35(7):427-431.
[27]Decressac M,Bj9rklund A.m TOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats[J].Parkinsons Dis,2013,3(1):13-17.
[28]缪茂军,陈小武,曹学兵,等.m TOR信号通路在左旋多巴诱发异动症中的作用及机制研究[J].卒中与神经疾病,2016,23(3):182-190.
[29]中华医学会神经病学分会帕金森病及运动障碍学组.中国帕金森病治疗指南(第三版)[J].中华神经科杂志,2014,47(6):428-433.
[2]Grosset KA,Malek N,Morgan F,et al.Inhaled dry powder apomorphine(VR040)for‘off’periods in Parkinson’s disease:an in-clinic double-blind dose ranging study[J].Acta Neurol Scand,2013,128(3):166-171.
[3]Hauser RA,Dubow J,Dzyngel B,et al.Efficacy of sublingual apomorphine(APL-130277)for the treatment of“off”episodes in patients with Parkinson’s disease[J].Mov Disord,2015,30(Suppl 1):233.
[4]Ory-Magne F,Corvol JC,Azulay JP,et al.Withdrawing amantadine in dyskinetic patients with Parkinson disease:the AMANDYSK trial[J].Neurology,2014,82(4):300-307.
[5]Pahwa R,Tanner CM,Hauser RA,et al.Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease(EASED Study)[J].Mov Disord,2015,30(6):788-795.
[6]Gardoni F,Sgobio C,Pendolino V,et al.Targeting NR2A-containing NMDA receptors reduces Levodopa-induced dyskinesias[J].Neurobiol of Aging,2012,33(9):2138-2144.
[7]Paquette MA,Martinez AA,Macheda T,et al.Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease:role of NMDA vs.5-HT1A receptors[J].Eur Neurosci,2012,36(9):3224-3234.
[8]张锦萍,刘鹏,张尊胜,等.美金刚治疗帕金森病疗效荟萃分析[J].徐州医学院学报,2016,36(5):301-306.
[9]Stocchi F,Rascol O,Destee A,et al.AFQ056 in Parkinson patients with levodopa-induced dyskinesia:13-week,randomized,dose-finding study[J].Mov Disord,2013,28(13):1838-1846.
[10]Rascol O,Fox S,Gasparini F,et al.Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias[J].Parkinsonism Relat Disord,2014,20(9):947-956.
[11]Morin N,Morissette M,Grégoire L,et al.Chronic treatment with MPEP,an m Glu5 receptor antagonist,normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys[J].Neuropharmacology,2013,73:216-231.
[12]Rascol Olivier,Fox Susan,Gasparini Fabrizio,et al.Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa induced dyskinesias[J].Parkinsonism&Related Disorders,2014,20(9):947-956.
[13]Andrew C Mc Creary,Mark A Varney,Adrian Newman-Tancredi.The novel 5-HT1A receptor agonist,NLX-112 reduces L-DOPA-induced abnormal involuntary movements in rat:A chronic administration study with microdialysis measurements[J].Neuropharmacology,2016,105:651-660.
[14]Bezard E,Munoz A,Tronci E,et al.Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia[J].Neurosci Res,2013,77(4):242-246.
[15]Bishop C,George JA,Buchta W,et al.Serotonin transporter inhibition attenuates levodopa-induced dyskinesia without compromising levodopa efficacy in hemi-parkinsonian rats[J].Eur J Neurosci,2012,36(6):2839-2848.
[16]Potts Lisa F,Park Eun S,Woo Jong-Min,et al.Dual-agonist/antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease[J].Annals of Neurology,2015,77(6):930-941.
[17]Daniele Antonio,Panza Francesco,Greco Antonio,et al.Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease?The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease[J].Parkinsons Disease,2016,25(3):1812-1826.
[18]Perez-Lloret S,Merello M.Two new adenosine receptor antagonists for the treatment of Parkinson’s disease:istradefylline versus tozadenant[J].Expert Opin Pharmacother,2014,15(8):1097-1107.
[19]Wills AM,Eberly S,Tennis M,et al.Caffeine consumption and risk of dyskinesia in CALM-PD[J].Mov Disord,2013,28(3):380-383.
[20]Dungo R,Deeks ED.Istradefylline:first global approval[J].Drugs,2013,73(8):875-882.
[21]Lewitt PA,Hauser RA,Lu M,et al.Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease(FJORD study)[J].Neurology,2012,79(2):163-169.
[22]Barnum Christopher J,Bhide Nirmal,Lindenbach David,et al.Effects of noradrenergic denervation on L-DOPA induced dyskinesia and its treatment by alpha-and beta-adrenergic receptor antagonists in hemiparkinsonian rats[J].Pharmacology Biochemistry and Behavior,2012,100(3):607-615.
[23]Gerlach M,Halley P,Riederer P,et al.The effect of piribedil on levodopa-induced dyskinesias in a rat model of Parkinson’s disease:differential role of a2 adrenergic mechanisms[J].Neural Transm,2013,120(1):31-36.
[24]Dezsi L,Vecsei L.Safinamide for the treatment of Parkinson’s disease[J].Expert Opin Invest Drugs,2014,23(5):729-742.
[25]Gregoire L,Jourdain VA,Townsend M,et al.Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys[J].Parkinsonism Relat Disord,2013,19(5):508-514.
[26]丁喜晴,朱忠方,崔桂云,等.钙调激酶Ⅱ参与帕金森病运动并发症发病机制的实验研究[J].徐州医学院学报,2015,35(7):427-431.
[27]Decressac M,Bj9rklund A.m TOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats[J].Parkinsons Dis,2013,3(1):13-17.
[28]缪茂军,陈小武,曹学兵,等.m TOR信号通路在左旋多巴诱发异动症中的作用及机制研究[J].卒中与神经疾病,2016,23(3):182-190.
[29]中华医学会神经病学分会帕金森病及运动障碍学组.中国帕金森病治疗指南(第三版)[J].中华神经科杂志,2014,47(6):428-433.