title: Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits.
abstract: BACKGROUND
  Sunitinib (Sutent) is a Food and Drug Administration-approved receptor tyrosine kinase inhibitor found to reduce postoperative adhesion formation in animal models. The objective of the present study was to evaluate anastomotic healing and potential drug-related toxicities after short-term sunitinib administration in New Zealand White rabbits.
  
  
  METHODS
  Under an approved study protocol, 40 rabbits underwent a laparotomy followed by colonic transection and anastomosis. Animals were randomly assigned to treatment with oral sunitinib (10 mg/kg/d) or placebo, received one preoperative dose followed by 10 postoperative doses, and were divided into two groups following the procedure: group I animals were euthanized on completion of drug treatment and group II animals were euthanized 30 d after completion of treatment. Prior to study completion, animals underwent an echocardiogram and laboratory test results were obtained. At necropsy, intestinal bursting strength (in mmHg) was evaluated.
  
  
  RESULTS
  All animals survived until designated euthanasia. There was no evidence of intra-abdominal sepsis or intestinal obstruction. Sunitinib-treated animals were found to have lower intestinal anastomotic strength compared with placebo-treated animals, as measured by bursting pressure at euthanasia, and a greater percentage of bursting at the anastomosis. On echocardiography, all ejection and shortening fractions were within established normal reference values. There were no significant differences in liver enzymes between animals. There were no wound infections, dehiscence, or delayed wound healing in any animal.
  
  
  CONCLUSIONS
  These results caution against the administration of sunitinib in cases involving intestinal anastomoses because of the elevated risk of anastomotic leak. No evidence of cardiotoxicity, hepatotoxicity, or detrimental effect on wound healing was found in any animal.
authors.affiliation: Department of Surgery and The Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Fallon
authors.affiliation: Department of Surgery and The Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Deepika
authors.initials: D
authors.lastname: Nehra
authors.affiliation: Department of Surgery and The Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Carlson
authors.affiliation: Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David W
authors.initials: DW
authors.lastname: Brown
authors.affiliation: Animal Resources Children's Hospital, Boston, Massachusetts.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Nedder
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Department of Surgery and The Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: mark.puder@tch.harvard.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Puder
mesh_terms: D000284:Administration, Oral; D000714:Anastomosis, Surgical; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000601:surgery*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D010919:Placebos; D011183:Postoperative Complications / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology / Q000633:toxicity*; D011817:Rabbits; D011897:Random Allocation; D013314:Stress, Mechanical; D000077210:Sunitinib; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D010919:Placebos; D011758:Pyrroles; D000077210:Sunitinib
keywords: Adhesions; Anastomosis; Bursting strength; Cardiotoxicity; Echocardiogram; Hepatotoxicity; Rabbit; Safety; Sunitinib; Sutent