From the Division of Dermatopathology, Department of Pathology, Children's Hospital, Boston, Massachusetts; Covidien Surgical Solutions, Bedford, Massachusetts; Pain Research Center, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; EKG Life Science Solutions, St. Louis, Missouri; and Mallinckrodt Pharmaceuticals, St. Louis, Missouri.
Anesth Analg. 2015 Jan;120(1):36-44. doi: 10.1213/ANE.0000000000000507.
Prolonged local anesthesia, particularly desirable to minimize acute and chronic postoperative pain, has been provided by microspheres that slowly release bupivacaine (MS-Bup). In this study, we report on the systemic drug concentrations and the local dermatopathology that occur after subcutaneous injection of MS-Bup.
Rats (approximately 300 g) were injected under the dorsolumbar skin with MS-Bup containing 40 mg of bupivacaine (base) or with 0.4 mL of 0.5% bupivacaine-HCl (BupHCl; 1.78 mg bupivacaine). Blood was drawn, under sevoflurane anesthesia, at 10 minutes to 144 hours, and the serum analyzed for total bupivacaine by liquid chromatography-tandem mass spectrometry. In different animals, skin punch biopsies (4 mm) were taken at 1, 3, 7, 14, and 30 days after the same drug injections, sectioned at 5 μm, and stained with hematoxylin-eosin. Samples from skin injected with BupHCl, with MS-Bup suspended in carboxymethyl cellulose (MS-Bup.CMC), or in methyl cellulose (MS-Bup.MC) were compared with their respective drug-free controls (placebos).
Serum bupivacaine reached a maximal average value (n = 8) of 194.9 ng/mL at 8 hours after injection of MS-Bup (95% upper prediction limit = 230.2 ng/mL), compared with the maximal average (n = 6) serum level of 374.9 ng/mL (95% prediction limit = 470.6 ng/mL) at 30 minutes after injection of BupHCl. Serum bupivacaine decreased to undetectable levels (<3.23 ng/mL) at 8 hours after BupHCl and was detectable at approximately 20% of the maximal value at 144 hours after MS-Bup injection. BupHCl injection resulted in moderate lymphocytic infiltration of skeletal muscle at 1 and 3 days. MS-Bup.CMC and placebo-CMC caused extensive infiltration of macrophages, lymphocytes, and some neutrophils at 1 to 7 days, whereas MS-Bup.MC and placebo-MC caused only mild inflammation.
Subcutaneous administration of microspheres releasing bupivacaine results in lower blood levels lasting for much longer times than those from bupivacaine solution.
微球可缓慢释放布比卡因（MS-Bup），从而提供长时间的局部麻醉，这尤其有利于减轻急性和慢性术后疼痛。在这项研究中，我们报告了皮下注射 MS-Bup 后出现的全身药物浓度和局部皮肤病理变化。
在背部皮肤下，给大约 300g 的大鼠注射含有 40mg 布比卡因（碱）的 MS-Bup 或 0.5%布比卡因盐酸盐（BupHCl；1.78mg 布比卡因）0.4ml。在七氟醚麻醉下，于 10 分钟至 144 小时时抽取血清，采用液相色谱-串联质谱法分析总布比卡因。在不同的动物中，于药物注射后 1、3、7、14 和 30 天，用 4mm 的皮肤活检穿孔器取出皮肤活检，切成 5μm 的切片，并用苏木精-伊红染色。将注射 BupHCl、悬浮在羧甲基纤维素（MS-Bup.CMC）或甲基纤维素（MS-Bup.MC）中的 MS-Bup 以及其各自的无药物对照（安慰剂）的皮肤样本进行比较。
与注射 BupHCl 后 30 分钟时的最大平均血清布比卡因浓度（n=6）374.9ng/ml（95%预测上限=470.6ng/ml）相比，MS-Bup 注射后 8 小时时达到最大平均血清布比卡因浓度（n=8）194.9ng/ml（95%预测上限=230.2ng/ml）。BupHCl 注射后 8 小时血清布比卡因降至无法检测水平（<3.23ng/ml），MS-Bup 注射后 144 小时时约为最大浓度的 20%可检测到。BupHCl 注射后 1 天和 3 天导致骨骼肌中度淋巴细胞浸润。MS-Bup.CMC 和安慰剂-CMC 在 1 天至 7 天引起广泛的巨噬细胞、淋巴细胞和一些中性粒细胞浸润，而 MS-Bup.MC 和安慰剂-MC 仅引起轻度炎症。
皮下给予布比卡因微球可释放布比卡因，其导致的血液水平低于布比卡因溶液，持续时间也长于布比卡因溶液。
