Abstract
We previously reported the development of a novel formulation of an ultra-long-acting local anesthetic based on bupivacaine encapsulated in large multivesicular liposomes (Bupisomes) embedded in hydrogel. This formulation (Bupigel) prolonged bupivacaine release from the formulation in dissolution-like studies in vitro and analgesia in vivo in mouse, rat, and pig models. In this study we assessed Bupigel neurotoxicity on rabbit sciatic nerve using histopathology and electrophysiologic testing. Sciatic nerves of both hind limbs were injected dropwise with different formulations. Nerve conduction studies and needle electromyography two weeks after perineural administration showed signs of neural damage after injection of free lidocaine and bupivacaine, while there was no sign of neural damage after injection with saline, demonstrating the validity of the method. This test also did not show evidence of motor or sensory nerve damage after injection with liposomal bupivacaine at a dose 10-times higher than free bupivacaine. Histologically, signs of neural damage could be observed with lidocaine. Nerves injected with Bupigel showed mild signs of inflammation and small residues of hydrogel in granulomas, indicating a long residence time of the hydrogel at the site of injection, but no histopathological signs of nerve damage. This demonstrated that early signs of neural damage were detected electrophysiologically, showing the usefulness and sensitivity of electrodiagnostic testing in detection of neural damage from new formulations.
Highlights
Laboratory of Membrane and Liposome Research, Department of Biochemistry, IMRIC, Institute of Neurology, Schneider Children’s Medical Center of Israel, Tel-Aviv University, Pediatric Neuromuscular Laboratory, Felsenstein Medical Research Center, Tel-Aviv University, Petach Tikva 4920235, Israel
The occurrence of life-threatening adverse events related to local anesthetic systemic toxicity has been increasing in recent years [1], highlighting the critical need for long-acting local anesthetics that extend the anesthetic effect while limiting the dose administered to patients, and risks associated with their use as well as the need for additional opioids
1) show that all the containing compared to formulations free bupivacaine, either Bupiin solution or somes exhibit prolonged compared to freeformulations bupivacaine,released either inonly solution or in hydrogel
Summary
Nerves injected with Bupigel showed mild signs of inflammation and small residues of hydrogel in granulomas, indicating a long residence time of the hydrogel at the site of injection, but no histopathological signs of nerve damage This demonstrated that early signs of neural damage were detected electrophysiologically, showing the usefulness and sensitivity of electrodiagnostic testing in detection of neural damage from new formulations. The duration of action of LA is limited, lasting only a few hours, and patients may experience breakthrough pain before they are able to take or tolerate oral analgesics, necessitating the use of strong parenteral analgesics (frequently opioids) in the immediate postsurgical period Another limitation of the clinical application of LAs is their systemic toxicity, including cardiac and neurological toxicity. The cardiotoxic and neurotoxic effects of LAs have been known for some time [2,3] and are dose dependent, but the severity of the published maps and institutional affiliations
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