末梢性脱炭酸酵素抑制剤とL-dopaの併用療法におけるpyridoxine同時投与の効果—実験的，臨床的検討

INFLUENCE OF PYRIDOXINE ON L-DOPA METABOLISM AFTER COMBINED ADMINISTRATION OF L-DOPA WITH PERIPHERAL DECARBOXYLASE INHIBITOR: EXPERIMENTAL AND CLINICAL STUDIES

I．はじめに

　パーキンソニズムのL-dopa療法に関しては，すでに膨大な基礎的および臨床的研究がなされており，本疾患におけるL-dopa投与の効果については現在疑う余地はない。しかし，L-dopa療法にはなお種々の副作用があり，また全症例の5〜10％においてL-dopa無効例もみられることから^6,8,23），本疾患に対するL-dopa療法にはなお種々の問題点を残している。ことにL-dopa投与で十分な臨床効果を得るためには少なくとも3g／日程度の大量投与を必要とするため，胃腸症状が投与例の50〜60％にもみられ^2,6,18,28），そのためL-dopaを有効量まで十分増量しえない例も多く，本治療法における重要な課題となつている。そこで最近ではL-dopaにMK-486（L-α-methyldopa hydrazine），Ro4-4602（1-（DL-seryl）-2-（2,3,4-trihydroxybenzyl） hydrazine hydrochroride）などの末梢性脱炭酸酵素抑制剤（Peripheral decarbox—ylase inhibitor：DCIと略す）^{2,8,13,20,24,25,26）}あるいはFusaric acid（5-butyl picolinic acid：-Dopamine-β-hydroxylase inhibitor）^21）を併用し，少量のL-dopa投与で効果的に脳内dopamine（DA）を上昇させようとする試みが行なわれ，すでに一部では臨床的に使用されはじめている。さらに線状体におけるDA受容体の刺激剤（DA receptor stimulant）であるET495（Piribedil）の臨床応用も試みられ，L-dopa無効例における効果が注目されはじめている^4,27）。

　一方，L-dopa単独療法あるいはDCIと併用したL-dopa療法において，脳内dopaあるいはDA濃度が上昇した場合，dopa脱炭酸酵素（dopa decarboxylase，　DCと略す）活性の低下をきたすことが指摘されているが^10,17），このような脳におけるDC活性の低下は脳内でのDAの合成を規制する1つの要素となる。そこですでに．1971年Yahrら^29）やCotziasら^5,7）はDCIをL-dopaと併用することにより，末梢でのDC活性を抑制しておけば，さらにpyridoxineの同時投与によつてDCの補酵素であるpyridoxal phosphateの濃度が上昇し，ひいては脳内でのDC活性が上昇するので，より効率よくdopaをDAに代謝しうるであろうと述べている。

Influence of pyridoxine on dopa metabolism after administration of L-dopa combined with peripheral decarboxylase inhibitor (MK-486: L-a-methyldopa hydrazine) was investigated experimentally, and clinically as well.

1) Tremor monkeys which had constant tremor and hypokinesias of contralateral upper limbs to the sides of stereotaxically placed ventro-medial teg-mental lesions were used to investigate the influ-ence of L-dopa, MK-486 and pyridoxine on their tremor and hypokinesias. Administration of L-dopa combined with MK-486 brought a cease of tremor at first and the alleviation of tremor con-tinued a few hours, then chreoathetoid involuntary.

movement appeared on the same side. In the case of concomitant administration of pyridoxine, both time durations of discontinuance of tremor and of continuance of choreoathetoid involuntary movement were elongated by 30-50% compared with in the case in which pyridoxine was not administered.

2) Dopamine (DA) concentrations of rats brains were about 30% higher with administration of than without pyridoxine (L-dopa combined with MK-486 only).

3) Pyridoxine was administered to 5 patients who had been receiving L-dopa combined with MK-486. Adminsitrations of pyridoxine showed good clinical effects in two of them, in whom L-dopa effects were enhanced and sustained longer with pyridoxine than without pyridoxine (L-dopa combined with MK-486 only). Moreover pyridoxine did not show any adverse effect on L-dopa therapy of these pa-tients in whom L-dopa had been given in combina-tion with MK-486.

4) Pyridoxine does increase the DA level in the brain, and does not show any adverse effect on the L-dopa therapy of parkinsonism when L-dopa was given with peripheral decarboxylase inhibitor. And it was considered that administration of pyridoxine should be tried in the case in which combined ad-ministration of L-dopa with peripheral decarboxylase inhibitor shows unsatisfactory effect in the therapy of parkinsonism.