犬髄腔内ACNUの動態解析—HPLCとautoradiographyによる検討

Intrathecal Distribution of ACNU by Various Modes of its Administration Analyzed by HPLC and Autoradiography

　悪性脳腫瘍の髄膜播種症が近年増加傾向にある。その治療の1つとしてACNUの髄腔内投与が考えられる。雑種成犬腰部1回5mg投与では脊髄腔に豊富な薬剤がみられるが，大槽内ではHPLC法でも検出域値以下であった。大槽1回注入では腰部への移行はin vitroでのグリオーマ細胞90％成長抑制条件（10μg／ml；30min以上）を満足する濃度に達したが，注入初期で大槽部に高濃度の薬剤が検出され副作用が問題となる。さらに脳室へはほとんど移行がみられなかった。脳室1回注入では腰部に充分な薬剤が認められず，治療としては満足できないと考えられた。脳室—腰部灌流法では大槽でも腰部でも上記in vitroの有効薬剤濃度が達成され，脳表には有効な薬剤濃度がみられないものの，試みた範囲では最良の治療法と考えられた。臨床応用する場合，脳室—腰部ACNU灌流法が現時点で有用な治療法と考えられるが，有効な治療効果を得るには髄液内ACNUの計測が必要と考えられる。

Various modes of administration of ACNU (nimustine hydrochloride) were tried to make clear which mode is the best method to obtain intrathecal diffuse distribution of ACNU to match the condition of killing of glioma cells (10μg/ml ; > 30min.). Tried modes of administration included 1) bolus injection into ventricular cavity, 2) bolus injection into cisterna magna, 3) bolus injection into lumbar subarachnoid space, 4) ventriculo-lumbar perfusion, 5) chiasmatic cistern-lumbar perfusion. Used dose of ACNU was 5mg/body for all modes of adminis-tration. ACNU level in CSF was measured by HPLC method specially developed by authors. To make clear intrathecal distribution of ACNU, autoradio-graphy using 14C-ethylene-ACNU was studied after administration of 10μCi/Kg of radioactive ACNU. The images were studied by image analyzer system (BAS-2,000 system developed by Fuji Film Co. Ltd). Among the modes of administration tried, ventriculo-lumbar perfusion method gave the best results in terms of lumbar, ventricular, cisterna magna, and basal cistern distribution of ACNU to match the cell kill condition experimentally ascer-tained. Although, bolus injection of ACNU into cisterna magna gave sufficient amount of ACNU in lumbar region, the initial level of ACNU was too high in cisterna magna, and administration of ACNU onece a week for three times in a canine cisterna magna resulted in considerable deteriora-tion of brain stem and basal structure. In addition to it, the level of ACNU in ventricular cavity was not detectable. Lumbar bolus injection resulted in also too much ACNU accumulation at the injected lum-bar area, and at the cisterna magna region, ACNU was not detectable.

Chiasmatic-lumbar perfusion method resulted in poor distribution of the drug at the cisterna magna and lumbar region. Autoradiographic pictures of lumbar bolus injection, cisterna magna bolus injec-tion, ventriculo-lumbar perfusion, and chiasmatic cistern-lumbar perfusion gave sufficient imforma-tion of drug distribution for clinical application.