新型多巴胺受体激动剂普拉克索治疗帕金森病的临床研究
摘要
目的:观察新型多巴胺受体激动剂普拉克索在各期帕金森病患者中的疗效,并对其安全性及不良反应进行总结。
方法:根据病情分级,早期患者给予普拉克索单药治疗,中晚期患者联合复方左旋多巴等抗帕金森病药物治疗。治疗前后分别用改良Webster量表及UPDRS-Ⅲ量表进行测试,评价其治疗意义及应用价值。
结果:普拉克索单药应用于早期PD患者,绝大部分患者改良的Webster量表及UPDRS-Ⅲ量表评分减少或明显减少,总有效率达85.7%。联合用药组患者用药后改良的Webster及UPDRS-Ⅲ总体评分均明显降低,总体有效率达93.7%。其中1例存在“开-关”现象的患者,普拉克索明显缩短了“关”期时间,“开”期改良的Webster评分和UPDRS-Ⅲ评分也分别较前减少48.7%和39.6%。患者合并的焦虑/抑郁、便秘、多汗、睡眠障碍、不安腿综合征、疼痛等均较前明显改善。普拉克索最常见不良反应为嗜睡,发生率约27.3%,其次为胃肠道不适,发生率约17.4%,均在继续服药过程中逐渐减轻或消失。
结论:(1).普拉克索单药应用于早期的帕金森病患者,疗效确切;(2).联合复方左旋多巴应用于中晚期帕金森病患者,能有效改善患者的运动症状,提高生活质量;(3).对于帕金森病患者的非运动症状有较好的疗效;(4).用于中国人群的帕金森病患者治疗,平均用药剂量远低于国外,安全性较好;(5).相对较高的治疗费用可能使其临床应用受到一定限制。
Parkinson’s Disease (PD) is one kind of CNS degeneration diseases popular in the old, which is characterized by static tremor, rigidity, bradykinesia et al. Now the most popular and effective antiparkinsonian medication is levodopa. With dopaminergic therapy and the pathogenic condition progressing, curative effect decreases in most patients, the complications such as "open-off" phenomenon and end of the dose deterioration appear unavoidably, which seriously influent the life quality of Parkinsonian. Recent researches show that dopamine agonists (DA) can reduce symptoms in early PD, maybe can delay the usage of dopamine and the appearance of motor complications (fluctuations and dyskinesias); in the treatment of advanced PD as an adjunct to levodopa, DA can reduce symptoms and daily levodopa dosage. Primapexole, a new non-Ergot-DA, which is free of the severe side effects (fibrosis and valve disease) linked with ergotic DA, has less harmful effect and potential neuroprotection. Pramipexole went on sale since 2007 March in China, we firstly used it in the treament of PD,gained good effect. A group of 23 patients treated with pramipexole were designed to evaluate its efficacy and safety. According to Hoehn-Yahr scale, 23 patients are divided into 2 groups, Group A(monotherapy group),Group B(associated with levodopa).Group A were given a beginning dosage of 0.125mg three times daily(t.i.d),adding 0.375mg every week until the symptoms become stable (the max tolerated dose is 4.5mg/d).Group B were given pramipexole at the basis of the medication being taken, similar to Group A. Modified Webster Scale (MWS) and Unified Parkinson's Disease Rating ScaleⅢ(UPDRS-Ⅲ) were measured before and 4 weeks after symptoms becoming stable.The results demonstrate that: In group A, MWS and UPDRS-Ⅲdecreased in most patients,the total effective power was 85.7%. In group B, MWS and UPDRS-Ⅲdecreased significantly,total effective power was 93.7%.In the patient with“on-off”phenomenon,“off”time decreased, MWS and UPDRS-Ⅲdecrasesd significantly in“open”time.The non-motor symptoms such as anxiety/depression, constipation, hyperhidrosis improved significantly. The first side effect was somnolence,the incidence was 27.3%, the second was indisposition of gastrointestinal tract with a incidence of 17.4%.They both disappeared or lessened in the following treament. Pramipexole can be used to treat the symptoms of Parkinson's disease safely and effectively both as monotherapy in the early stages and in the advanced phases in association with levodopa.
方法:根据病情分级,早期患者给予普拉克索单药治疗,中晚期患者联合复方左旋多巴等抗帕金森病药物治疗。治疗前后分别用改良Webster量表及UPDRS-Ⅲ量表进行测试,评价其治疗意义及应用价值。
结果:普拉克索单药应用于早期PD患者,绝大部分患者改良的Webster量表及UPDRS-Ⅲ量表评分减少或明显减少,总有效率达85.7%。联合用药组患者用药后改良的Webster及UPDRS-Ⅲ总体评分均明显降低,总体有效率达93.7%。其中1例存在“开-关”现象的患者,普拉克索明显缩短了“关”期时间,“开”期改良的Webster评分和UPDRS-Ⅲ评分也分别较前减少48.7%和39.6%。患者合并的焦虑/抑郁、便秘、多汗、睡眠障碍、不安腿综合征、疼痛等均较前明显改善。普拉克索最常见不良反应为嗜睡,发生率约27.3%,其次为胃肠道不适,发生率约17.4%,均在继续服药过程中逐渐减轻或消失。
结论:(1).普拉克索单药应用于早期的帕金森病患者,疗效确切;(2).联合复方左旋多巴应用于中晚期帕金森病患者,能有效改善患者的运动症状,提高生活质量;(3).对于帕金森病患者的非运动症状有较好的疗效;(4).用于中国人群的帕金森病患者治疗,平均用药剂量远低于国外,安全性较好;(5).相对较高的治疗费用可能使其临床应用受到一定限制。
Parkinson’s Disease (PD) is one kind of CNS degeneration diseases popular in the old, which is characterized by static tremor, rigidity, bradykinesia et al. Now the most popular and effective antiparkinsonian medication is levodopa. With dopaminergic therapy and the pathogenic condition progressing, curative effect decreases in most patients, the complications such as "open-off" phenomenon and end of the dose deterioration appear unavoidably, which seriously influent the life quality of Parkinsonian. Recent researches show that dopamine agonists (DA) can reduce symptoms in early PD, maybe can delay the usage of dopamine and the appearance of motor complications (fluctuations and dyskinesias); in the treatment of advanced PD as an adjunct to levodopa, DA can reduce symptoms and daily levodopa dosage. Primapexole, a new non-Ergot-DA, which is free of the severe side effects (fibrosis and valve disease) linked with ergotic DA, has less harmful effect and potential neuroprotection. Pramipexole went on sale since 2007 March in China, we firstly used it in the treament of PD,gained good effect. A group of 23 patients treated with pramipexole were designed to evaluate its efficacy and safety. According to Hoehn-Yahr scale, 23 patients are divided into 2 groups, Group A(monotherapy group),Group B(associated with levodopa).Group A were given a beginning dosage of 0.125mg three times daily(t.i.d),adding 0.375mg every week until the symptoms become stable (the max tolerated dose is 4.5mg/d).Group B were given pramipexole at the basis of the medication being taken, similar to Group A. Modified Webster Scale (MWS) and Unified Parkinson's Disease Rating ScaleⅢ(UPDRS-Ⅲ) were measured before and 4 weeks after symptoms becoming stable.The results demonstrate that: In group A, MWS and UPDRS-Ⅲdecreased in most patients,the total effective power was 85.7%. In group B, MWS and UPDRS-Ⅲdecreased significantly,total effective power was 93.7%.In the patient with“on-off”phenomenon,“off”time decreased, MWS and UPDRS-Ⅲdecrasesd significantly in“open”time.The non-motor symptoms such as anxiety/depression, constipation, hyperhidrosis improved significantly. The first side effect was somnolence,the incidence was 27.3%, the second was indisposition of gastrointestinal tract with a incidence of 17.4%.They both disappeared or lessened in the following treament. Pramipexole can be used to treat the symptoms of Parkinson's disease safely and effectively both as monotherapy in the early stages and in the advanced phases in association with levodopa.
引文
1. 吴江.神经病学.北京:人民卫生出版社,2005
2. Block G, Liss C, et al. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson’s Disease. A multi-center 5-year study. The CR First Study Group. Eur Neurol, 1997,37(1):23-27
3. Zenettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s Disease. N Engl J Med,2007, 356(1):39-46
3. Kenangil G, Ozekmekci S, Koldas L, et al. Assessment of valvulopathy in Parkinson’s Disease patients on pergolide and/or cabergoline. Clin Neurol Neurosurg.2007,109(4):350-353
4. 中华医学会神经病学分会运动障碍及帕金森病学组.帕金森病治疗指南.中华神经科杂志,2006,39(6):409-412
5. Block G, Liss C, Reines S, et al. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson’s Disease. A multi-center 5-year study. The CR First Study Group. Eur Neurol, 1997,37(1):23-27
6. Micrau J, Schingnitz G. Biochemical and Pharmacological studies on Pramipexole, a potent and selective D2 receptor agonist. Eur J Pharmacol, 1992,215:161-170
7. Gu M, Iravani MM, Cooper JM, et al. Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem, 2004, 91:1075-1081
8. Asanuma M, Miyazaki I, Diaz-Corrales FJ, et al. Pramipexolehas ameliorating effects on levodopa-induced abnormal dopamine turnover in parkinsonian striatum and quenching effects on dopamine-semiquinone generated in vitro. Neurol Res, 2005,27:533-539
9. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease: A randomied dose-ranging study. JAMA. 1997 Jul,9;278(2):125-30
10. Shannon KM,Bennett JP Jr,et al. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. Neurology. 1997 Sep;49(3):724-8. Erratum in: Neurology 1998 Mar;50(3):838
11. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group.JAMA.2000,284(15):1931-1938
12.Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004 Jul;61(7):1044-53. Erratum in: Arch Neurol. 2005 Mar;62(3):430
13. Lieberman A, Ranhosky A, et al. Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology, 1997 ,Jul;49(1):162-168
14.Guttman M, et al. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. international Pramipexole Bromocriptine Study Group. Neurology. 1997 Oct;49(4):1060-1065
15.Wen Hongbo, et al. Efficacy of pramipexole in the treatment of Parkinson’s Disease: a multi-center,randomized,double-blind, bromocriptine-control trial. Chin J Neurol, 2006,39(9):604-606
1. 吴江.神经病学.北京:人民卫生出版社,2005
2. 中华医学会神经病学分会运动障碍及帕金森病学组.帕金森病治疗指南[J]中华神经科杂志 2006,39(6):409-412
3. Kozlov AP, Druzin MY, Kurzina NP, et al. The role of D1-dependent dopaminergic mechanisms of the frontal cortex in delayed responding in rats[J]. Neurosci Behav Physiol, 2001,31(4):405-411
4. El-Ghunidi M, Fletcher PJ, Drago J. Spatial learning deficit in dopamine D(1) receptor knockout mice [J]. Eur J Pharmacol. 1999,383(2):95-106
5. Baldwin AE, Sadeghian K, Kelley AE. Appetitive instrumental learning requires coincident of NMDA and dopamine D1 receptors within the medial prefrontal cortex [J]. NeuroscI, 2002, 22(3):1063-1071
6. Umegaki H, Minoz J, Meyer RC, et al. Involvement of dopamine D(2) receptors in complex maze learning and acetyl-choline release in ventral hippocampus of rats [J]. Neuroscience, 2001, 103(1):27-33
7. Greba Q, Gifkins A, Kokkinidis L. Inhibition of amygdaloid dopamine D2 receptors impairs emotional learnIng measured with fear-potentiated startle [J]. Brain Res, 2001, 899(1-2):218-226
8. Smith JW, Fetsko LA, Xu R, et al. dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and in avoidance learning [J]. Neuroscience, 2002,113(4):755-765
9. Wooten GF. Agonists vs levodopa in PD: The thrilla of whitha. Neurology, 2003,60(3):360-362
10. Rascol O, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa [J]. New Engl Med, 2000, 342:1484-1491
11. The Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson’s disease: A 4-year randomized controlled trial [J]. Arch Neurol, 2004, 61:1044-1053
12. Cristina S, Zangalia R, Mancini F, et al. High-dose ropinirole in advanced Parkinson’s disease with severe dyskinesias [J]. ClinNeurophamacol, 2003,26(3):146-150
13. Caroline M. Dopamine agonist in early therapy for Parkinson’s disease promise and problems [J]. JAMA, 2000, 284(15):1971-1973
14. Hauser RA, Gauger L, Anderson WM, et al. Pramipexole induced somnolence and episodes of daytime sleep [J]. Mov Disord, 2000,15(4):658-663
15. Olanow CW, et al. Levodopa in the treatment of Parkinson’s disease: Current controversies [J]. Mov Disord, 2004,19:997-1005
16. Barone P, et al. Pramipexole versus Sertraline in treatment of depression in Parkinson’s disease: A national multicenter parallel-group randomized study [J]. J Neurol 2006, 253(5):601-607
17. The Parkinson-Control study: A 1-year randomized, double-blind trail comparing piribedil (150 mg/day) with bromocriptine (25 mg/day) in early combination with levodopa in Parkinson’s disease [J]. Mov Disord, 2006,21(4):500-509
18. Schapira AH. Dopamine agonists and neuroprotection in Parkinson’s disease[J]. Eur Neurol. 2002,9(3):7-14
19. Jenner PG, Brin MF. Levodopa neurotoxicity: experimental studies versus clinical relevance [J]. Neurology, 1998, 50(6Suppl6):S39-S43
20. Ogawa N, Tanaka K, Asanuma M, et al. Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro. Brain Res, 1994, 657:207-213
21. Zou L, Jankovic J, Rowe D , et al. Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity [J]. Life Sci, 1999, 64:1275-1285
22. Ling ZD, Robie HG, Tong CW, et al. Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures [J]. Pharmacol Exp Ther, 1999, 289(1):202-210
23. Takashima H, Tsujihata M, Kishikawa M, et al. Bromocriptine protects dopaminergic neurons from levodopa-induced toxicity by stimulating D2 receptors [J]. Exp Neurol, 1999, 159(1):98-104
24. Rajput AH, Fenton M, Birdi S, t al. Is levodopa toxic to human substantia nigra? Mov Disord, 1997, 12(5):634-638
25. Iida M, Miyazaki I, Tanaka K, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine against [J]. Brain Res, 1999, 838(1-2):51-59
26. Le WD, Jankovic J, Xie W, et al. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection[J]. Neural Transm, 2000, 107(10):1165-1173
27. Hara H, Ohta M, Ohta K, et al. Apomorphine attenuates 6-hydroxy- dopamine-induced apoptotic cell death in SH-SY5Y cells [J]. Redox Rep, 2003,8(4):193-197
28. Cassarino DS, Fall CP, Smith TS, et al. Pramipexole reductive oxygen species production in vitro. And inhibits the mitochondrial permeability transition produced by the Parkinsonian neurotoxin methylpyridinium ion[J]. Neurochem, 1998,71(1):295-301
29. Abramova NA, Cassarino DS, Khan SM, et al. Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma [J]. Neurosci Res, 2002, 67(4):494-500
30. Guo H, Tang Z, Yu Y, et al. Apomorphine induces trophic factors that support fetal rat mencencephalic dopaminergic neurons in cultures [J]. Eur Neurosci, 2002, 16(10):1861-1870
2. Block G, Liss C, et al. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson’s Disease. A multi-center 5-year study. The CR First Study Group. Eur Neurol, 1997,37(1):23-27
3. Zenettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s Disease. N Engl J Med,2007, 356(1):39-46
3. Kenangil G, Ozekmekci S, Koldas L, et al. Assessment of valvulopathy in Parkinson’s Disease patients on pergolide and/or cabergoline. Clin Neurol Neurosurg.2007,109(4):350-353
4. 中华医学会神经病学分会运动障碍及帕金森病学组.帕金森病治疗指南.中华神经科杂志,2006,39(6):409-412
5. Block G, Liss C, Reines S, et al. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson’s Disease. A multi-center 5-year study. The CR First Study Group. Eur Neurol, 1997,37(1):23-27
6. Micrau J, Schingnitz G. Biochemical and Pharmacological studies on Pramipexole, a potent and selective D2 receptor agonist. Eur J Pharmacol, 1992,215:161-170
7. Gu M, Iravani MM, Cooper JM, et al. Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem, 2004, 91:1075-1081
8. Asanuma M, Miyazaki I, Diaz-Corrales FJ, et al. Pramipexolehas ameliorating effects on levodopa-induced abnormal dopamine turnover in parkinsonian striatum and quenching effects on dopamine-semiquinone generated in vitro. Neurol Res, 2005,27:533-539
9. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease: A randomied dose-ranging study. JAMA. 1997 Jul,9;278(2):125-30
10. Shannon KM,Bennett JP Jr,et al. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. Neurology. 1997 Sep;49(3):724-8. Erratum in: Neurology 1998 Mar;50(3):838
11. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group.JAMA.2000,284(15):1931-1938
12.Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004 Jul;61(7):1044-53. Erratum in: Arch Neurol. 2005 Mar;62(3):430
13. Lieberman A, Ranhosky A, et al. Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology, 1997 ,Jul;49(1):162-168
14.Guttman M, et al. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. international Pramipexole Bromocriptine Study Group. Neurology. 1997 Oct;49(4):1060-1065
15.Wen Hongbo, et al. Efficacy of pramipexole in the treatment of Parkinson’s Disease: a multi-center,randomized,double-blind, bromocriptine-control trial. Chin J Neurol, 2006,39(9):604-606
1. 吴江.神经病学.北京:人民卫生出版社,2005
2. 中华医学会神经病学分会运动障碍及帕金森病学组.帕金森病治疗指南[J]中华神经科杂志 2006,39(6):409-412
3. Kozlov AP, Druzin MY, Kurzina NP, et al. The role of D1-dependent dopaminergic mechanisms of the frontal cortex in delayed responding in rats[J]. Neurosci Behav Physiol, 2001,31(4):405-411
4. El-Ghunidi M, Fletcher PJ, Drago J. Spatial learning deficit in dopamine D(1) receptor knockout mice [J]. Eur J Pharmacol. 1999,383(2):95-106
5. Baldwin AE, Sadeghian K, Kelley AE. Appetitive instrumental learning requires coincident of NMDA and dopamine D1 receptors within the medial prefrontal cortex [J]. NeuroscI, 2002, 22(3):1063-1071
6. Umegaki H, Minoz J, Meyer RC, et al. Involvement of dopamine D(2) receptors in complex maze learning and acetyl-choline release in ventral hippocampus of rats [J]. Neuroscience, 2001, 103(1):27-33
7. Greba Q, Gifkins A, Kokkinidis L. Inhibition of amygdaloid dopamine D2 receptors impairs emotional learnIng measured with fear-potentiated startle [J]. Brain Res, 2001, 899(1-2):218-226
8. Smith JW, Fetsko LA, Xu R, et al. dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and in avoidance learning [J]. Neuroscience, 2002,113(4):755-765
9. Wooten GF. Agonists vs levodopa in PD: The thrilla of whitha. Neurology, 2003,60(3):360-362
10. Rascol O, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa [J]. New Engl Med, 2000, 342:1484-1491
11. The Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson’s disease: A 4-year randomized controlled trial [J]. Arch Neurol, 2004, 61:1044-1053
12. Cristina S, Zangalia R, Mancini F, et al. High-dose ropinirole in advanced Parkinson’s disease with severe dyskinesias [J]. ClinNeurophamacol, 2003,26(3):146-150
13. Caroline M. Dopamine agonist in early therapy for Parkinson’s disease promise and problems [J]. JAMA, 2000, 284(15):1971-1973
14. Hauser RA, Gauger L, Anderson WM, et al. Pramipexole induced somnolence and episodes of daytime sleep [J]. Mov Disord, 2000,15(4):658-663
15. Olanow CW, et al. Levodopa in the treatment of Parkinson’s disease: Current controversies [J]. Mov Disord, 2004,19:997-1005
16. Barone P, et al. Pramipexole versus Sertraline in treatment of depression in Parkinson’s disease: A national multicenter parallel-group randomized study [J]. J Neurol 2006, 253(5):601-607
17. The Parkinson-Control study: A 1-year randomized, double-blind trail comparing piribedil (150 mg/day) with bromocriptine (25 mg/day) in early combination with levodopa in Parkinson’s disease [J]. Mov Disord, 2006,21(4):500-509
18. Schapira AH. Dopamine agonists and neuroprotection in Parkinson’s disease[J]. Eur Neurol. 2002,9(3):7-14
19. Jenner PG, Brin MF. Levodopa neurotoxicity: experimental studies versus clinical relevance [J]. Neurology, 1998, 50(6Suppl6):S39-S43
20. Ogawa N, Tanaka K, Asanuma M, et al. Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro. Brain Res, 1994, 657:207-213
21. Zou L, Jankovic J, Rowe D , et al. Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity [J]. Life Sci, 1999, 64:1275-1285
22. Ling ZD, Robie HG, Tong CW, et al. Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures [J]. Pharmacol Exp Ther, 1999, 289(1):202-210
23. Takashima H, Tsujihata M, Kishikawa M, et al. Bromocriptine protects dopaminergic neurons from levodopa-induced toxicity by stimulating D2 receptors [J]. Exp Neurol, 1999, 159(1):98-104
24. Rajput AH, Fenton M, Birdi S, t al. Is levodopa toxic to human substantia nigra? Mov Disord, 1997, 12(5):634-638
25. Iida M, Miyazaki I, Tanaka K, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine against [J]. Brain Res, 1999, 838(1-2):51-59
26. Le WD, Jankovic J, Xie W, et al. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection[J]. Neural Transm, 2000, 107(10):1165-1173
27. Hara H, Ohta M, Ohta K, et al. Apomorphine attenuates 6-hydroxy- dopamine-induced apoptotic cell death in SH-SY5Y cells [J]. Redox Rep, 2003,8(4):193-197
28. Cassarino DS, Fall CP, Smith TS, et al. Pramipexole reductive oxygen species production in vitro. And inhibits the mitochondrial permeability transition produced by the Parkinsonian neurotoxin methylpyridinium ion[J]. Neurochem, 1998,71(1):295-301
29. Abramova NA, Cassarino DS, Khan SM, et al. Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma [J]. Neurosci Res, 2002, 67(4):494-500
30. Guo H, Tang Z, Yu Y, et al. Apomorphine induces trophic factors that support fetal rat mencencephalic dopaminergic neurons in cultures [J]. Eur Neurosci, 2002, 16(10):1861-1870