Parkinson Parkinson * ** Key Words : Parkinson s disease, Treatment, History of treatment in Japan, Levodopa, Dopamine agonist 32 35 41 2015 I Parkinson PD Ayurveda Ayurveda 5000 10,000 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 2 1868 2007 PD scopolamine 3 4 1949 trihexyphenidyl 5 7 1961 8 trihexyphenidyl PD 28 Table 1 1965 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 81.8 10 levodopa 1972 9 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
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 8 12 100 levodopa carbidopa 588mg levodopa 2,827mg 44.1 23.6 48.1 28.8 levodopa benserazide 13 90 679 mg levodopa 2,776mg cross over 53 20 27 levodopa levodopa Levodopa Yahr 14 levodopa 8g 1 54 37 Yahr 36
Barbeau 15 60 levodopa benserazide 4.5g 650mg 50 43 levodopa II bromocriptine 16, 17 54 1 30mg 22.5mg 1 100mg 18 slow and low 19 Levodopa levodopa 20 levodopa 70 60 65 pergolide 21 cabergoline 22 2002 23, 24 25 talipexole 26 pramipex ole 27 PD 3.17mg clinical global improvement ratio pramipexole 61.2 28.0 47.1 trihexypheni dyl 9, 10 ropinirole 28 rotigotine 29, 30 pramipexole ropinirole 1 1 31, 32 Rotigotine Pisa 33 35 D2 D3 36 37 38 levodopa 40 50 PD III L Dops PD PD L threodops PD 39 31 14 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 / 0.88 3.07 / 0.98 P 0.002 levodopa Entacapone O COMT O methylation levodopa 37
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 90 100 49 PD 20 25 10 50 PD 2 2008 PD complex I Fig. 1 51 6 7 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, p1 66 38
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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 : 1384 1395, 2006 50 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 : 857 868, 2005 51 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 : 9089 9100, 2008 52 Kokhan VS, Afanasyeva MA, Van kin GI : Synuclein knock out mice have cognitive impairments. Behav Brain Res 231 : 226 230, 2012 53 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 1958. 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 1980. 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