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1 Parkinson Parkinson * ** Key Words : Parkinson s disease, Treatment, History of treatment in Japan, Levodopa, Dopamine agonist I Parkinson PD Ayurveda Ayurveda ,000 ayur life veda science mucuna pruriens atamagupta kampva ta Mucuna pruriens l dopa 5000 PD PD L dopa PD 1817 James Parkin son 1 PD Jean Martin Char cot Leopold Ordenstein PD scopolamine trihexyphenidyl trihexyphenidyl PD 28 Table PD trihexyphenidyl trihexyphenidyl 4 6mg trihexyphenidyl 6 1 L 1 trihexyphenidyl L PD Trihexyphenidyl 9 levodopa trihexyphenidyl 78.7 levodopa 83.6 Amantadine trihexyphenidyl 80.0 amantadine levodopa trihexyphenidyl levodopa 4g trihexyphenidyl 10mg 67 cross over 8 levodopa trihexy phenidyl levodopa 32 trihexyphenidyl 21 6 levodopa A History on the Treatment of Parkinson s Disease in Japan and a Perspective for the Future. Yoshikuni MIZUNO : Professor Emeritus, Juntendo University 35

2 Table 1 The year and the month of anti Parkinson drugs which was introduced into the market of Japan and the listing of pharmaceutical pricing Introduction into the market Pharmaceutical pricing Trihexyphenidyl 1953 Showa 28 August 1954, January Levodopa 1972 Showa 47 January 1972, February Amantadine 1975 Showa 50 December 1975, September Bromocriptine 1979 Showa 54 April 1979, April Levodopa DCI 1980 Showa 55 February 1980, February L threodops 1989 Heisei1 May 1989, May Pergolide 1994 Heisei 6 August 1994, August Talipexole 1996 Heisei 8 June 1996, August Cabergoline 1999 Heisei 11 June 1999, June Pramipexole 2004 Heisei 16 January 2003, December Ropinirole 2006 Heisei 18 December 2006, December Entacapone 2007 Heisei 19 April 2007, March Selegiline 2007 Heisei 19 July 2007, July Zonisamide 2009 Heisei 21 March 2009, March Pramipexole LA 2011 Heisei 23 July 2011, July Apomorphine 2012 Heisei 24 July 2012, May Ropinirole CR 2012 Heisei 25 August 2012, August Rotigotine 2013 Heisei 25 February 2013, February Istradefylline 2013 Heisei 25 May 2013, May levodopa 57.4 trihexyphenidyl 37.7 levodopa levodopa 69.8 trihexyphenidyl 45.3 levodo pa levodopa trihexyphenidyl PD amantadine HCl Schwab 11 PD PD PD 10 trihexyphenidyl cross over amantadine 300mg tri hexyphenidyl 9mg amantadine trihexyphenidyl decarboxylase in hibitor DCI carbidopa benserazide carbidopa levodopa cross over levodopa carbidopa 588mg levodopa 2,827mg levodopa benserazide mg levodopa 2,776mg cross over levodopa levodopa Levodopa Yahr 14 levodopa 8g Yahr 36

3 Barbeau levodopa benserazide 4.5g 650mg levodopa II bromocriptine 16, mg 22.5mg 1 100mg 18 slow and low 19 Levodopa levodopa 20 levodopa pergolide 21 cabergoline , talipexole 26 pramipex ole 27 PD 3.17mg clinical global improvement ratio pramipexole trihexypheni dyl 9, 10 ropinirole 28 rotigotine 29, 30 pramipexole ropinirole , 32 Rotigotine Pisa D2 D levodopa PD III L Dops PD PD L threodops PD L threodops 40 PD IV MAOB COMT Monoamine oxidase B MAOB MAOB MAOA B 41 MAO MAOB MAOB selegiline DATAOP study 42 PD selegiline levodopa 43 Hoehn and Yahr 3.59 / / 0.98 P levodopa Entacapone O COMT O methylation levodopa 37

4 30 44 Entacapone levodo pa levodopa entacapone 45 entacapone entacapone V Zonisamide Zonisamide PD zonisamide PD PD 46 2 PD VI GABA PD GABA GABA GABA 47 UPDRS 48 VII PD PD PD PD PD complex I Fig PD 52 RNA PD Huntington Machado Joseph superoxide dismutase RNA short interacting RNA PD 53 COI 1 Parkinson J : An Essay on the Shaking Palsy, Sherwood, Neely, and Jones, London, 1817, p

5 日本における PD 治療の歴史と将来への提言 Fig. 1 Pathogenesis of Parkinson s disease A part of α-synuclein was reported to enter the mitochondria and inhibited complex I inducing mitochondrial damage and contributing to neuronal death. Oligomers of α-synuclein induce damage to membrane structures such as autophagosome, proteasome and synaptic vesicles inducing oxidative stress. Aggregates of α-synuclein may damage the axonal flow. 2 Ordenstein L : Sur la paralysie agitante et la sclérose en plaques généralisée. Delahaye, Cited from Lehmann HC, Hartung HP, BC Kieseier BC. Leopold Ordenstein : on paralysis agitans and multiple sclerosis. Multiple Sclerosis 13 : , Roussy MG : Les injections sous-cunanées de Scopolamine dans la Maladie de Parkinson. Rev Neurol 13 : , Ryan GMS, Wood JS : Benadryl in the treatment of Parkinsonism. Results in forty cases. Lancet 1 : , Doshay LJ, Constable K : Artane therapy for Parkinsonism. JAMA 140 : , Corbin KB : Trihexyphenidyl, evaluation of the new agent in the treatment of Parkisonism. JAMA 141 : , Schwab RS, Tillmann WR : Artane in the treatment of Parkinson s disease ; a report of its effectiveness alone and in combination with benadryl and parpanit. N Engl J Med 241 : , 秋元波留夫 式場 聡 長尾朋典ほか パーキンソン症候群に 対する Trihexyphenyl HCl の治療経験 CLINICAL STUDY OF TRIHEXYPHENYL HCL TO PAKINSON SYNDROME. 脳神経 13 : , 平山惠造 宇尾野公義 中西孝雄ほか Parkinson 症候群に対 する L-DOPA ならびに Trihexyphenidyl の治療効果 二重盲検 神経治療 法による検討 神経進歩 15 : , 塩沢瞭一 平山惠造 石島武一ほか パーキンソン症候群に対す る Amantadine HCl Symmetrel ならびに Trihexyphenidyl の治療効果 二重盲検法による検討 神経進歩 5 : , Schwab RS, England AC Jr, Poskanzer DC et al : Amantadine in the treatment of Parkinson s disease. JAMA 208 : , 加瀬正夫 安藤一也 伊藤 清ほか 特発性パーキンソニズム に対する Carbidopa L-Dopa 併用療法と L-Dopa 単独療法の 二重盲検法による比較検討 医のあゆみ 101 : , 水野美邦 宇尾野公義 中西孝雄ほか パーキンソン病に対す る L- ドーパおよび Benserazide R の併用効果 二 重盲検法による L- ドーパ単独療法と併用療法の比較 神経進 歩 21 : , Yahr MD, Duvoisin RC, Sehear MJ et al : Treatment of Parkinsonism with levodopa. Arch Neurol 21 : , Barbeau A, Mars H, Botez MI et al : Levodopa combined with peripheral decarboxylase inhibition in Parkinson s disease. CMAJ 106 : , 豊倉康夫 岩田 誠 加瀬正夫ほか パーキンソン症候群に対 するブロモクリプチンの臨床的有用性 多施設二重盲検法によ る塩酸アマンタジンとの比較試験 臨評価 12 : , 1984 Vol. 32 No

6 17 12 : , Cotzias GC, Van Woert MH, Schiffer LM : Aromatic amino ac ids and modification of parkinsonism. N Engl J Med 276 : , Teychenne PF, Bergsrud D, Racy A et al : Bromocriptine : low dose therapy in Parkinson disease. Neurology 32 : , : , pregolide mesilate LY Bromocriptine mesilate 27 : , CG 101 L DOPA III 12 : , Pritchett AM, Morrison JF, Edwards WD et al : Valvular heart disease in patients taking pergolide. Mayo Clin Proc 77 : , Serratrice J, Disdier P, Habib G et al : Fibrotic valvular heart disease subsequent to bromocriptine treatment. Cardiology Rev 10 : , p B HT920 III 21 : , Mizuno Y, Yanagisawa N, Kuno S et al : Randomized, double blind study of pramipexole with placebo and bromocriptine in advanced Parkinson s disease. Mov Disord 18 : , Mizuno Y, Abe T, Hasegawa K et al : Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkin son s disease : STRONG Study. Mov Disord 22 : , Mizuno Y, Nomoto M, Kondo T et al : Transdermal rotigotine in early stage Parkinson s disease : A randomized, double blind, placebo controlled trial. Mov Disord 28 : , Nomoto M, Mizuno Y, Kondo T et al : Transdermal rotigotine in advanced Parkinson s disease : a randomized, double blind, placebo controlled trial. J Neurol 261 : , Mizuno Y, Yamamoto M, Kuno S et al : Efficacy and safety of extended versus immediate release pramipexole in Japanese patients with advanced and L dopa undertreated Parkin son disease : a double blind, randomized trial. Clin Neuro pharmacol 35 : , Hattori N, Nishioka H, Hasegawa K et al : Comparison of rop inirole controlled and immediate release in Japanese pa tients with advanced Parkinson s disease. Neurology Clin Neurosci 2015 in press, doi: /ncn Uzawa A, Mori M, Kojima S et al : Dopamine agonist induced antecollis in Parkinson s disease. Mov Disord 24 : , Ponfick M, Gdynia HJ, Ludolph AC et al : Camptocormia in Parkinson s disease : a review of the literature. Neurodegener Dis 8 : , Galati S, Möller JC, Städler C : Ropinirole induced Pisa syn drome in Parkinson disease. Clin Neuropharmacol 37 : 58 59, Millan MJ, Maiofiss L, Cussac D et al : Differential actions of antiparkinson agents at multiple classes of monoaminergic re ceptor. I. A Multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Neurol 303 : , Pondal M, Marras C, Miyasaki J et al : Clinical features of dop amine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry 84 : , Garcia Ruiz PJ, Martinez Castrillo JC, Alonso Canovas A et al : Impulse control disorder in patients with Parkinson s dis ease under dopamine agonist therapy : a multicentre study. J Neurol Neurosurg Psychiatry 85 : , L DOPS 15 : , Shy Drager L threo 3,4 dihydroxyphenylserine L DOPS 141 : , Levitt P, Pintar J, Breakfield X : Immunocytochemical demon stration of monoamine oxidase B in brain astrocytes and sero tonergic neurons. Proc Natl Acad Sci USA 79 : , The Parkinson Study Group : Effect of deprenyl on the progres sion of disability in early Parkinson s disease. N Engl J Med 321 : , FPF : , Mizuno Y, Kanazawa I, Kuno S et al : Placebo controlled, dou ble blind dose finding study ofentacapone in fluctuating Par kinsonian patients. Mov Disord 22 : 75 80, Stocchi F, Rascol O, Kieburtz K et al : Initiating levodopa/carbi dopa therapy with and without entacapone in early Parkinson disease : the STRIDE PD study. Ann Neurol 68 : 18 27, Murata M, Hasegawa K, Kanazawa I et al : Zonisamide im proves motor function in Parkinson disease : a randomized, double blind study. Neurology 68 : 45 50, Mori A, Shindou T, Ichimura M et al : The role of adenosine A2A receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons. J Neurosci 16 : , Mizuno Y, Hasegawa K, Kondo T et al : Clinical efficacy of is tradefylline KW 6002 in Parkinson s disease : a random ized, controlled study. Mov Disord 25 : ,

7 49 Sato K, Hatano T, Yamashiro K et al : Prognosis of Parkinson s disease : Time to Stage III, IV, V, and to motor fluctuations. Mov Disord 21 : , Masliah E, Rockenstein E, Adame A et al : Effects of alpha sy nuclein immunization in a mouse model of Parkinson s dis ease. Neuron 46 : , Devi L, Raghavendran V, Prabhu BM et al : Mitochondrial im port and accumulation of alpha synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson dis ease brain. J Biol Chem 283 : , Kokhan VS, Afanasyeva MA, Van kin GI : Synuclein knock out mice have cognitive impairments. Behav Brain Res 231 : , Kumar P, Wu H, McBride JL et al : Transvascular delivery of small interfering RNA to the central nervous system. Nature 448 : 39 43, 2007 A History on the Treatment of Parkinson s Disease in Japan and a Perspective for the Future Yoshikuni MIZUNO Professor Emeritus, Juntendo University A history of the treatment of Parkinson s disease PD in Japan was reviewed. Treatment of PD was started by in troduction of trihexyphenidyl into the market of Japan in August of Trihexyphenidyl is an anti cholinergic drug, which has been effective in tremor, rigidity, bradyki nesia, and difficulty of gait in PD. According to one study, the improvement ratio of mild or more than mild was seen in 78.7% of the patients, whereas that of levodopa was seen in 83.6% of the patients. Levodopa was introduced in 1972 and levodopa combined with a dopa decarboxylase in This caused a real improvement in many symptoms of PD. But soon after, it has been realized that many patients with PD will develop wearing off, dyskinesia, and freezing of gait. Because of this, combined use of a dopamine agonist and levodopa has been introduced ; however, dopamine ago nists have many side effects and ergot dopamine agonists were found to cause cardiac valve insufficiency after a long term use in some patients. Therefore, in advanced PD patients with more than 10 years of disease duration, it is most important to find a wise use of levodopa adapting to the daily fluctuation of symptoms. After dopamine agonists, many drugs such as a monoamine oxidase B inhibitor, a COMT inhibitor, zonisamide, istradefylline, have been in troduced to overcome wearing off phenomena. But none of them has completely alleviated motor fluctuations in PD. Still levodopa is the most reliable symptomatic drug in PD. Many disease modifying treatments have been investigat ed in the world. But none of them is yet successful. In this respect, reducing the synthesis of synuclein appears to be important, as PD is not only a dopamine loss but also in volving many other neurotransmitters as shown by many non motor symptoms and wide spread synuclein aggre gation in advanced PD patients. 41

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