The cellular infiltrate was mainly composed of macrophages, lymphocytes, fibroblasts/fibrocytes, and occasional giant cells. In a similar study in rats, formulations containing 2%, 4%, 8%, 16%, 32%, or 64% of a mixture of bupivacaine

and lidocaine base 4:1 in medium-chain triglyceride were evaluated, together with 0.5%, 1.0%, and 2.0% bupivacaine HCl solutions, bupivacaine 4.2% or 7.0% in medium-chain triglyceride, and 20% lidocaine base in a polar lipid vehicle [30]. Inhibitors,research,lifescience,medical Histopathologic examination of sciatic nerves by light microscopy revealed slight to moderate signs of neurotoxicity only after administration of the 64% formulation, Inhibitors,research,lifescience,medical a week after dosing. With regard to pathological effects of EXPAREL on peripheral nerves, no remarkable findings were observed using the sellekchem standard hematoxylin- and eosin-staining method. The brachial plexus sites analyzed for histopathological changes were normal on Day 3 and Day 15. There was no evidence of adverse local reactions even at the highest concentration, 25mg/mL (30mg/kg dose). With the exception of granulomatous inflammation, there were no observations of abnormal gross pathology findings at the site of drug administration or elsewhere, and no

significant changes in blood chemistry or animal behavior beyond Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical those observed with Bupivacaine solution or saline. It is postulated that macrophages currently phagocytosed liposome material, as they would any other foreign material in tissues. The increased presence of these cells was therefore not

unexpected; the transient local inflammatory Inhibitors,research,lifescience,medical response to EXPAREL is a normal foreign body reaction appearing in parallel with liposome deposition. In Boogaerst’s study in rabbits, the systemic bupivacaine concentration were lower during the first 10 minutes (P < 0.05) and higher after 24 hours (P < 0.05) after brachial plexus injection of 2.5mg bupivacaine in 1mL of 0.25% multilamellar liposomal bupivacaine made of Drug_discovery PC and cholesterol (ratio 4:3) compared to bupivacaine solution, while the Cmax was not very different between the two formulations (~0.2μg/mL) [31]. In our studies, the PK profile displays an initial rise (reflective of unencapsulated drug present in the aqueous phase of EXPAREL) (i.e., outside of the particles) followed by a curve typical of a slow release delivery system (as afforded by the DepoFoam delivery system). In both rabbits and dogs, the peak plasma concentrations of bupivacaine with EXPAREL were significantly attenuated, that is, up to approximately fourfold (9mg/kg; 106 versus 433 and 402 versus 1490ng/mL, resp.) compared with equivalent doses of bupivacaine solution (9mg/kg, P < 0.05).