title: The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs.
abstract: OBJECTIVE
  DepoFoam bupivacaine (DB) is in development for prolonged postoperative analgesia. Studies were conducted to evaluate the potential local and systemic toxicity and any effect on wound healing after wound infiltration.
  
  
  METHODS
  The model simulates an inguinal hernia (skin incision ∼2.5 and 5.5 cm). Animals (four/sex/group of each species) received DB 9, 18 or either 25 or 30 mg/kg, bupivacaine solution (B(sol); 7.5 mg/ml, 9 mg/kg) or saline. DB was given at 0.6, 1.2 and 1.0 or 1.2 ml/kg, respectively, and B(sol) or saline at 1.2 ml/kg. Each dose was infiltrated in small fractions on Day 1. End points included histology on Days 3 and 15. Wound healing was recorded on Day 2 through Day 15.
  
  
  RESULTS
  There was no adverse effect in either species. Notably, granulomatous inflammation was noted in surgical sites from 8 of 24 rabbits in the DB groups only. Based on the minimal to mild severity on Day 15, this was considered a normal reaction against the liposomes. Except for granulomatous inflammation, there were no differences in overall incidence or severity of histologic changes in the sites dosed to DB, saline or B(sol).
  
  
  CONCLUSIONS
  The data reported here are the first demonstration of the safety of DB in toxicology species.
authors.affiliation: Clinical Research & Drug Safety Assessment, Pacira Pharmaceuticals, Inc., San Diego, CA 92121, USA. brigitter@pacira.com
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Richard
authors.forename: Laura R
authors.initials: LR
authors.lastname: Ott
authors.forename: Dean
authors.initials: D
authors.lastname: Haan
authors.forename: Abram N
authors.initials: AN
authors.lastname: Brubaker
authors.forename: Phaedra I
authors.initials: PI
authors.lastname: Cole
authors.forename: Keith G
authors.initials: KG
authors.lastname: Nelson
authors.forename: Paul E
authors.initials: PE
authors.lastname: Ross
authors.forename: Marlon C
authors.initials: MC
authors.lastname: Rebelatto
authors.forename: Paul E
authors.initials: PE
authors.lastname: Newton
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006552:Hernia, Inguinal / Q000601:surgery; D007267:Injections; D008081:Liposomes; D008297:Male; D010149:Postoperative Pain / Q000188:drug therapy*; D011817:Rabbits; D011897:Random Allocation; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D008081:Liposomes; D002045:Bupivacaine