Department of Biochemistry, Institute of Biology, State University of Campinas, (Unicamp) Campinas, SP, Brazil.
J Drug Target. 2012 Jan;20(1):85-96. doi: 10.3109/1061186X.2011.622400. Epub 2011 Nov 2.
Local anesthetics (LA) are among the most important pharmacological compounds used to attenuate or eliminate pain. However, systemic toxicity is still a limitation for LA application, especially for ester-type drugs, such as tetracaine (TTC) that presents poor chemical stability (due to hydrolysis by plasma esterases). Several approaches have been used to improve LA pharmaceutical properties, including the employment of drug-delivery systems. Here we used beta-cyclodextrin (β-CD) or hydroxypropyl-beta-cyclodextrin (HP-β-CD) to develop two new TTC formulations (TTC:β-CD and TTC:HP-β-CD). The inclusion complexes formation, in a 1:1 stoichiometry, was confirmed by differential scanning calorimetry, X-ray diffraction, UV-VIS absorption and fluorescence. Nuclear magnetic resonance (DOSY experiments) revealed that TTC association with HP-β-CD is stronger (Ka=1200 mol/L(-1)) than with β-CD (Ka=845 mol/L(-1)). Moreover, nuclear Overhauser effect (NOE) experiments provided information on the topology of the complexes, where TTC aromatic ring is buried inside the CD hydrophobic cavity. In vitro tests with 3T3 fibroblast cells culture revealed that complexation decreased TTC cytotoxicity. In addition, the total analgesic effect of TTC, tested in rats through the infraorbital nerve test, was improved in 36% with TTC:β-CD and TTC:HP-β-CD. In conclusion, these formulations presented potential for future clinical use, by reducing the toxicity and increasing the antinociceptive effect of tetracaine.
局部麻醉剂（LA）是用于减轻或消除疼痛的最重要的药理学化合物之一。然而，全身毒性仍然是 LA 应用的限制，特别是对于酯类药物，如四卡因（TTC），其化学稳定性差（由于血浆酯酶水解）。已经采用了几种方法来改善 LA 的药物特性，包括使用药物传递系统。在这里，我们使用β-环糊精（β-CD）或羟丙基-β-环糊精（HP-β-CD）来开发两种新的 TTC 配方（TTC：β-CD 和 TTC：HP-β-CD）。通过差示扫描量热法、X 射线衍射、紫外-可见吸收和荧光证实了 1:1 化学计量比的包合复合物形成。核磁共振（DOSY 实验）表明，TTC 与 HP-β-CD 的缔合强度更强（Ka=1200 mol/L(-1)），而与β-CD 的缔合强度较弱（Ka=845 mol/L(-1)）。此外，核 Overhauser 效应（NOE）实验提供了关于复合物拓扑结构的信息，其中 TTC 芳环被埋藏在 CD 疏水性腔内。用 3T3 成纤维细胞培养进行的体外试验表明，络合降低了 TTC 的细胞毒性。此外，通过眶下神经试验在大鼠中测试 TTC 的总镇痛作用时，TTC：β-CD 和 TTC：HP-β-CD 使 TTC 的镇痛作用提高了 36%。总之，这些配方具有降低毒性和提高四卡因的镇痛作用的潜力，有未来临床应用的潜力。
