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

天然环糊精及其衍生物已被鞘内给药，以改善溶解度，降低全身毒性，或提高药物性质的生物利用度。为了评价它们的神经毒性，我们将浓度分别为50、125和250 mM的磺丁基-β-环糊精、羟丙基-β-环糊精和麦芽糖基-β-环糊精，或5和10%甘露醇或生理盐水溶液给予大鼠鞘内，然后观察神经症状（死亡、惊厥或刺激）、甩尾潜伏期和脊髓的组织学损伤。结果显示，接受生理盐水、50 mM磺丁基醚-β-环糊精和50和125 mM麦芽糖基-β-环糊精的大鼠没有神经症状或组织学异常，尽管不同剂量的一些环糊精衍生物和甘露醇产生神经损伤和形态学损伤。麦芽糖基-β-环糊精是鞘内给药的三种环糊精衍生物中最安全的一种，我们使用0.5%或1%的左旋布比卡因与100 mM麦芽糖基-β-环糊精复合物用于大鼠鞘内和坐骨神经阻滞。左旋布比卡因在鞘内和坐骨神经阻滞中的麻醉作用均延长1.4 ~ 2倍，且无神经功能损害。

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.