パーキンソニズムに対するL-Dopaと末梢性脱炭酸酵素抑制剤（MK 486）の併用療法—臨床効果とカテコールアミン代謝

L-DOPA THERAPY COMBINED WITH DECARBOXYLASE INHIBITOIZ (MK 486) IN PARKINSONISM:CLINICAL EFFECTS AND CATECHOLAMINE METABOLISM

I．はじめに

　パーキンソニズムに対するL-Dopaの効果が確立されてより，本症候群は"Striatal dopamine deficiency　syndrome"^8）とさえ呼ばれるに至つている。しかし，L-Dopa療法には無効例ないし効果不十分の例もかなりみられ，しかも大量投与に伴なう副作用が高率に出現することから^1,4,20），従来の抗コリン剤，アマンタジンなどのほか，諸種の酵素抑制剤なども併用の試みがなされてきた。L-Dopa投与の目的は勿論線状体におけるDopa—mine （以下DA）を高めることにあり，従つてL-Dopaの効果を高め，副作用を少なくする目的で，Monoamine　oxidase抑制剤^1），Catechol-O-methyl transferase抑制剤^6,9），Dopamine-β-hydroxylase抑制剤^13）なども試みられたが，著るしい効果をうることはできなかつた。それは摂取したL-Dopaの大部分が腸管，肝，腎，肺など脳以外の部に多量存在する脱炭酸酵素により脱炭酸され^17），DAあるいはさらに進んだ代謝産物へと代謝されてしまうためである（第1図参照）。そして末梢におけるDAは，脳血液関門を通過しえないため，脳内DAを高めることはできず，単に末梢における作用（副作用）を示すのみという臨床上不都合な結果をもたらしている。そこで末梢におけるDopaの脱炭酸を抑制するのが最も脳内DAを高めうることが見出され，多くの脱炭酸酵素抑制剤の検討から，臨床応用可能で強力な末梢性脱炭酸酵素抑制剤としてL-α-hydrazinomethyldopa（以下MK 486と略す。第2図）が浮かび上がつてきた。

　MK 486はそれのみの投与では何らの明らかな作用はみられないが，アミン前駆物質とくにL-Dopaの作用に強く影響を与え，末梢におけるDopa脱炭酸酵素抑制の結果，脳内アミンを著るしく高めることから，パーキンソニズムにおけるL-Dopa療法において，その効果を著るしく高めるものとして臨床応用が試みられるに至つた^3,11,20）。

Fourteen patients with Parkinsonism were treated with a combination of L-Dopa and peripheral de-carboxylase inhibitor, L-α-hydrazinomethyldopa (MK 486). Modification of L-Dopa effect by MK 486 was also studied in Parkinsonaim patients aswell as in cats.

1) Concentrations of dopa and dopamine in plasma and brain were measured in cats following the intraperitoneal injection of L-Dopa alone (100 mg/ kg) or combined with MK 486 (10 mg/kg).

Dopa levels in plasma and brain in the combi-nation with MK 486 were three times as high as in L-Dopa alone.

Dopamine levels in caudate nucleus were increased up to maximum six times in the combination.

2) Plasma dopa and dopamine levels were meas-ured in Parkinsonian patients. Clinical pharma-cological studies disclosed that a 1:10 ratio of MK 486 to L-Dopa in dosage was preferable.

3) Maximum plasma dopa levels in the combi-nation were reached four times as high as in L-Dopa alone.

Plasma dopa was measured at high level over the period of five hours.

MK 486 markedly reduced plasma levels of dopamine.

4) There was no significant change in Dopa and dopamine levels in cerebrospinal fluid between L-Dopa alone and combination of MK 486. Dopamine levels in CSF were still high at 4 hours in the combination of MK 486.

5) In the clinical studies of fourteen patients with Parkinsonism, the effectiveness of the combi-nation therapy (mean dosage of L-Dopa: 770 mg/ day) was observed in all cases.

Marked improvement was noted in 7 cases out of 12 (58%) with akinesia, in 9 cases out of 13 (69%) with rigidity and in 4 cases out of 11 (36%) with tremor.

Maximum plasma dopa levels were higher in cases with marked improvement than the other, and were the highest in patients with dyskinesias of a side effect.

6) An addition of Vitamin Bs did not show adverse effects.

7) Nausea and vomiting of the side effect, which were less severe than those experienced with L-Dopa alone, were noted in 9 cases (65%). Dyskinesias in extremities, face, mouth and tongue were ob-served in 5 cases (36%). These dyskinesias were seen in a high percentage of cases with marked improvement and were never observed in the ex-tremities contralateral to the side of thalamotomy.