From the São Francisco University, UNIFAG, Bragança Paulista, São Paulo, Brazil.
Laboratory of Inflammation, São Leopoldo Mandic Institute and Research Center, Campinas, São Paulo, Brazil.
Anesth Analg. 2019 Aug;129(2):387-396. doi: 10.1213/ANE.0000000000003837.
Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations.
The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer.
Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system.
All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.
我们的研究小组最近开发了具有离子梯度的脂质体，并以包含罗哌卡因（RVC；2%或 0.75%）的供体和受体囊泡的组合方式。为了寻找这些新型制剂在术后疼痛控制中的应用，我们评估了这些新 RVC 制剂的麻醉持续时间、药代动力学和组织反应。
本研究使用的制剂为含有醋酸钠缓冲液（pH5.5）的大多室囊泡（LMVV）或与 LMVV 以组合方式作为供体，与外部 pH 为 7.4 的大单室囊泡（LUV）作为受体囊泡。Wistar 大鼠分为 6 组（n=6），并接受坐骨神经阻滞（0.4mL），使用 6 种 RVC 制剂（LMVVRVC0.75%、LMVV/LUVRVC0.75%、LMVVRVC2%、LMVV/LUVRVC2%、RVC0.75%和 RVC2%）。为了验证麻醉效果，对动物进行疼痛压力测试，同时监测运动阻滞。坐骨神经区域周围组织的组织病理学也在治疗后 2 天和 7 天进行评估。大鼠（n=6）接受后爪切口，在注射 6 种 RVC 制剂之一后，通过 von Frey 细丝的撤回反应测量机械性痛觉过敏。最后，新西兰白兔（n=6）接受 6 种 RVC 制剂之一的坐骨神经阻滞（3mL）。在注射前（0 分钟）和注射后 15、30、45、60、90、120、180、240、300、360、420、480 和 540 分钟收集血样。使用三级四极杆质谱仪测定 RVC 血浆水平。
与 RVC 溶液相比，所有脂质体制剂的感觉阻滞持续时间和强度更长（P<0.05）。与所有制剂相比，阳性对照（利多卡因 10%）的组织病理学评估显示出更高的毒性（P<0.05）。在后爪切口后，所有动物均出现切口后痛觉过敏，脂质体制剂表现出更长的镇痛作用（P<0.05）。LMVVRVC0.75%与 RVC 0.75%相比，达到最大浓度的时间和平均停留时间更长（P<0.05），因此 LMVV 能够通过这种脂质体系统的缓慢释放来降低 RVC 的全身暴露。
所有含有 0.75%RVC 的新型脂质体制剂均能改变药代动力学并延长麻醉持续时间，这是由于 RVC 从脂质体中的缓慢释放，而不会对局部组织产生显著的毒性作用。
Zotero 插件