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1.  Opposing Roles of Membrane and Soluble Forms of the Receptor for Advanced Glycation End Products in Primary Respiratory Syncytial Virus Infection 
The Journal of Infectious Diseases  2012;205(8):1311-1320.
Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager−/−) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager−/− mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager−/− mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.
doi:10.1093/infdis/jir826
PMCID: PMC3308901  PMID: 22262795
2.  The Safety of EXPAREL ® (Bupivacaine Liposome Injectable Suspension) Administered by Peripheral Nerve Block in Rabbits and Dogs 
Journal of Drug Delivery  2012;2012:962101.
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 Cmax 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.
doi:10.1155/2012/962101
PMCID: PMC3270427  PMID: 22363842
3.  Safety Evaluation of EXPAREL (DepoFoam Bupivacaine) Administered by Repeated Subcutaneous Injection in Rabbits and Dogs: Species Comparison 
Journal of Drug Delivery  2011;2011:467429.
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.
doi:10.1155/2011/467429
PMCID: PMC3189577  PMID: 22013534

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