[消旋布比卡因（S50-R50）和布比卡因对映体混合物（S75-R25）的药物递送系统：环糊精络合对小鼠坐骨神经阻滞的影响]
[Drug-delivery systems for racemic bupivacaine (S50-R50) and bupivacaine enantiomeric mixture (S75-R25): cyclodextrins complexation effects on sciatic nerve blockade in mice].
作者信息
Araújo Daniele Ribeiro de, Fraceto Leonardo Fernandes, Braga Angélica de Fátima de Assunção, Paula Eneida de
机构信息
UNICAMP, Brazil.
出版信息
Rev Bras Anestesiol. 2005 Jun;55(3):316-28. doi: 10.1590/s0034-70942005000300008.
BACKGROUND AND OBJECTIVES
Bupivacaine-induced side effects have led to the search for new local anesthetics (LA) with similar potency and lower toxicity, such as bupivacaine enantiomeric mixture (S75-R25). Drug-delivery systems for LA in carriers, such as cyclodextrins (CD), have been developed to improve anesthetic potency and therapeutic index of those drugs. This study aimed at preparing, characterizing and evaluating the anesthetic efficacy of inclusion complexes of bupivacaine enantiomeric mixture (S75-R25) and racemic bupivacaine (S50-R50) with hydroxypropylb- cyclodextrin (HPb-CD) comparing them to clinically available preparations.
METHODS
Inclusion complexes were obtained by mixing appropriate volumes of HPb-CD and S50-R50 or S75-R25 to final 1:1 or 1:2 molar ratios and were characterized by phase solubility experiments. Affinity constants (K) were determined between HPb-CD and each LA. Motor and sensory blocks induced by plain or complexed LA formulations were evaluated in mice by sciatic nerve block. Three LA concentrations were used during the experiment: 0.125, 0.25 and 0.5%.
RESULTS
Solubility experiments results were indicative of S50-R50:HPb-CD and S75-R25:HPb-CD complexation, with similar affinity constant (K) values: 14.7 M-1 and 14,3 M-1, respectively. In vivo experiments have shown that complexation has enhanced differential nerve blockade induced by LA: i) motor blockade duration induced by S75-R25 was similar, to the induced by but less intense S50-R50 ( p < 0.001). S50-R50HPb-CD and S75-R25HPb-CD complexes have decreased onset (p < 0.01 and p < 0.05, respectively), without changing motor block intensity (Emax) as compared to plain drugs; ii) sensory block evaluation has revealed higher analgesic intensity with S50-R50HPb-CD (2-fold, p < 0.001) and S75-R25HPb-CD (1.5-1.8-fold, p < 0.01 and p < 0.001, respectively) with both molar ratios (1:1 and 1:2, LA:CD), in addition to prolonging analgesic effect as compared to S50-R50 and S75-R25.
CONCLUSIONS
More pronounced analgesic effects obtained by complexation with HPb-CD have shown that both formulations, S50-R50HPb-CD and S75-R25HPb-CD, are very useful for postoperative pain relief, requiring lower LA concentrations. Nevertheless, it is worth noticing that S75-R25 - being less toxic than racemic bupivacaine - is an interesting alternative for the development of more effective and safe drug-delivery systems as compared to racemic bupivacaine (S50-R50).
背景与目的
布比卡因引起的副作用促使人们寻找效力相似但毒性更低的新型局部麻醉药（LA），如布比卡因对映体混合物（S75-R25）。已开发出用于将LA载于环糊精（CD）等载体中的药物递送系统，以提高这些药物的麻醉效力和治疗指数。本研究旨在制备、表征并评估布比卡因对映体混合物（S75-R25）和消旋布比卡因（S50-R50）与羟丙基-β-环糊精（HPb-CD）形成的包合物的麻醉效果，并将其与临床可用制剂进行比较。
方法
通过混合适当体积的HPb-CD与S50-R50或S75-R25，使其最终摩尔比达到1:1或1:2，从而获得包合物，并通过相溶解度实验对其进行表征。测定HPb-CD与每种LA之间的亲和常数（K）。通过坐骨神经阻滞在小鼠中评估普通或复合LA制剂诱导的运动和感觉阻滞。实验中使用了三种LA浓度：0.125%、0.25%和0.5%。
结果
溶解度实验结果表明形成了S50-R50:HPb-CD和S75-R25:HPb-CD包合物，其亲和常数（K）值相似，分别为14.7 M-1和14.3 M-1。体内实验表明，包合作用增强了LA诱导的差异性神经阻滞：i）S75-R25诱导的运动阻滞持续时间与S50-R50诱导的相似，但强度较弱（p < 0.001）。与普通药物相比，S50-R50HPb-CD和S75-R25HPb-CD包合物的起效时间缩短（分别为p < 0.01和p < 0.05），而运动阻滞强度（Emax）不变；ii）感觉阻滞评估显示，两种摩尔比（1:1和1:2，LA:CD）的S50-R50HPb-CD（镇痛强度提高2倍，p < 0.001）和S75-R25HPb-CD（镇痛强度提高1.5 - 1.8倍，分别为p < 0.01和p < 0.001）的镇痛强度更高，且与S50-R50和S75-R25相比，镇痛效果延长。
结论
与HPb-CD形成包合物后获得的更显著镇痛效果表明，S50-R50HPb-CD和S75-R25HPb-CD这两种制剂对于术后疼痛缓解非常有用，所需LA浓度较低。然而，值得注意的是，与消旋布比卡因（S50-R50）相比，S75-R25毒性更低，是开发更有效、更安全药物递送系统的一个有吸引力的选择。
Zotero 插件