A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower C
max versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.
EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.
ABSTRACr Lung innervation has been studied in the past by methylene blue staining and silver impregnation and more recently by histochemical methods. These techniques give only a partial picture of the total innervation. We have delineated the innervation of the lung in man and three other mammalian species by immunostaining with antibodies to two new markers of nervous tissue. These markers are neurone-specific enolase (NSE), an enzyme present in nerve cells in both the central and the peripheral nervous systems, and S-100, a protein found in glial cells. Throughout the respiratory tract NSE was localised in ganglion cells and nerve fibres in all species examined, while S-100 was found in the supporting glial cells of ganglia and in the Schwann cells of peripheral nerves. The distribution of NSE immunoreactivity in serial sections was compared with that of acetylcholinesterase-containing, noradrenergic, and peptide-containing nerves. In all areas NSE was found to be a specific marker for all three types of nerves. Thus these two antibodies provide an effective histological means of examining both the neuronal and the nonneuronal components of the lung innervation and should be of value in investigating this system in lung disease.The lung has a rich nerve supply, consisting of both sensory and motor divisions. The methods used to demonstrate this innervation by light microscopy in earlier studies included methylene blue and silver staining."3 More recently, histochemical techniques have been applied, for example, to localise acetylcholinesterase, which is thought to be a marker for cholinergic nerves,46 and to demonstrate formaldehyde-induced fluorescence in aminergic nerves.78 All these methods have their limitations and give only a partial view of the total innervation.Recently two highly acidic soluble proteins have been isolated from brain extracts and characterised.9The first, neurone-specific enolase (NSE), is an isoenzyme of the glycolytic enzyme enolase.'0 Antibodies raised against this enzyme and used as immunochemical reagents show that it is specifically localised in neurones" in both the central and the Address for reprint requests:
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.