Cephalosporin系抗生物質の痙攣誘発作用について 第1報 Cephalosporin系抗生物質の脳室内投与による痙攣誘発作用とその構造ー活性相関

Newton and Abraham(1))により見い出されたcephalosporin Cが,現在のcephalosporin系抗生物質のprototypeである.この薬物は, penicillinやchloramphenicolに比較するとその抗菌力は必ずしも強くないが,広域な抗菌スペクトルを有し,penicillinaseに比較的抵抗し得る事が特長であった.その化学構造は,penicillin Gに類似したβ-lactam環を有する7-amino-cephalosporanic acidを基本骨格としている事が明らかとなり,この骨格に種々な側鎖を結合する事により,抗菌力,安定性のより優れた半合成の類似化合物が多数作られた.これらの半合成cephalosporin系抗生物質は,グラム陽性球菌,グラム陰性球菌,グラム陽性桿菌及び一部のグラム陰性桿菌に対し殺菌的に作用し,しかも抗菌作用も強く,またpenicillinに対し耐性を獲得した梅毒トレポネーマやブドウ球菌に対しても有効(2))であるため,広く臨床で使用されている.口腔外科領域においても,これらのcephalosporin系抗生物質の静脈内投与や点滴静注が繁用されており,しかも投与量は時に数gの大量に達する.一方,penicillin Gの静脈内投与後に痙攣が誘発されたという報告(3,4))があり,また,penicillin Gの大脳皮質内適用後誘発される痙攣は,抗痙攣薬の薬効評価に用いられている程周知である(5,6)).penicillin Gによる痙攣誘発作用は,その構造内のβ-lactam環が関与すると考えられている(7,8)).もし,この説が正しければ,その構造式にβ-lactam環をもっているcephalosporin系抗生物質も当然penicillinと同様な痙攣誘発作用をもつ可能性がある.この仮説の当否を調べ,且つ種々な化学構造をもつcephalosporin系抗生物質の痙攣誘発効果の強弱が,それらの化学構造とどのような相関を示すのかを検討する目的で本実験を行なった.

Stainless-steel electrodes were implanted stereotaxically into the hippocampus and amygdala and screw electrodes were fixed in the frontal and accipital skull of male Wistar rats. A cannula guide was also implanted in the right lateral ventricle. Ten days after operation, unanesthetized rats were placed in an observation box and electroencephalograms were recorded before and after intraventricular injection of the test drugs. Behavioral changes were observed simultaneously. When the epileptogenic properties of 10 cephalosporins and penicillin G as the refefence drugs were compared, cefazolin was definitely more potent than penicillin. At doses higher than 32 μg/head, cefazolin provoked tremendous epileptiform activity; "spike and wave complex" appeared in close session in all tracings for more than 30 min and svere convusion were observed with this repeatedly. Cefotiam was a little bit stronger than penicillin; both ceftezole and cephaloridine were almost equipotent and their activities were slightly weaker than penicillin. No epileptogenic signs or behavious was observed in the EEGs after 1000 μg/head of cephalexin and cephradine. Cephapirin, cefmetazole, cephalothin and ceftizoxime caused some epileptogenic symptoms but less markedly, diminishing the activity in this order both in EEGs and the behavioral signs between active and inert drugs. The compounds with two different heterocyclic rings substituted at position 7 of the beta-lactam ring and at position 3 of the dihydrothiazine ring (R2) of 7-aminocephalosporanic acid were potent in producing epileptogenic signs both in EEGs and behaviors. While the compounds with a heterocyclic ring substituted at either position of 7-amino-cephalosporanic acid were less potent. The compounds such as cefizoxime, cephalexin and cephradine which had a small group substituted at R2 produced almost no epileptogenic activity.