Prolongation of anesthetic effects of levobupivacaine with maltosyl-β -cyclodextrin

天然环糊精及其衍生物已在鞘内施用，以提高溶解度，降低全身毒性，或提高药物特性的生物利用度。为了评估它们的神经毒性，我们分别以50、125和250 mM的浓度给药磺基丁醚- β -环糊精、羟丙基- β -环糊精和麦芽糖基- β -环糊精，或5%和10%的甘露醇，或生理盐水给药大鼠鞘内间隙，之后观察到神经系统症状（死亡、抽搐或刺激）、摇尾潜伏期和脊髓组织学病变。结果显示，生理盐水、磺基丁醚- β -环糊精（50 mM）和麦芽糖基- β -环糊精（50 mM和125 mM）给药的大鼠无神经症状或组织学异常，尽管一些环糊精衍生物和甘露醇在不同剂量下会产生神经损伤和形态损伤。麦芽糖基- β -环糊精是本研究中三种环糊精衍生物中最安全的。我们使用0.5%或1%左布比卡因与麦芽糖基- β -环糊精络合在100 mM处用于大鼠鞘内和坐骨神经阻滞。左旋布比卡因对鞘内神经阻滞和坐骨神经阻滞的麻醉效果均延长1.4 ~ 2倍，无神经损伤。

Natural cyclodextrins and their derivatives have been administered intrathecally to improve solubility, to reduce systemic toxicity, or to enhance the bioavailability of drug properties. To evaluate their neurotoxicities, we administered sulfobutylether-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and maltosyl-beta-cyclodextrin at the concentration of 50, 125, and 250 mM, respectively, or 5 and 10% mannitols, or saline solution to the intrathecal space in rats, after that, observed neurological symptoms (death, convulsion, or irritation), tail flick latency, and histological lesion of the spinal cord. The results showed no neurological symptoms or histological abnormalities in rats that received with saline, sulfobutylether-beta-cyclodextrin at 50 mM, and maltosyl-beta-cyclodextrin at 50 and 125 mM, although some cyclodextrin derivatives and mannitols at various dosages produced neurological impairments and morphologic damage. Maltosyl-beta-cyclodextrin is the safest among three cyclodextrin derivatives administered intrathecally in this study.We used 0.5 or 1% levobupivacaine complexed with maltosyl-beta-cyclodextrin at 100 mM for intrathecal and sciatic nerve blocks in rats. The anesthetic effects of levobupivcaine were prolonged 1.4〜2 times in both intrathecal and sciatic nerve blocks with no neurological impairments.