Combined intraoperative administration of a histone deacetylase inhibitor and a neurokinin-1 receptor antagonist synergistically reduces intra-abdominal adhesion formation in a rat model.
BACKGROUND
Intra-abdominal adhesions are the most frequent postoperative complication after abdominopelvic surgery. Our laboratory has previously shown that an intraoperative peritoneal lavage containing either the histone deacetylase inhibitor valproic acid (VPA) or a neurokinin-1 receptor antagonist (NK-1RA) reduced adhesions by approximately 50% in a rat model. The objective of this study was to determine whether the combination of these 2 drugs was more effective in reducing adhesions than either alone.


METHODS
Rats underwent laparotomy with creation of peritoneal ischemic buttons to induce adhesions. A single dose of VPA (25 mg/kg), NK-1RA (50 mg/kg), a combination of both, or 0.9% saline was lavaged intraperitoneally just before wound closure. On postoperative day 7, adhesions were quantified. To investigate early mechanisms of adhesiogenesis, adhesions were created as described and adhesive button tissue was harvested at 30 minutes and 3 hours postoperatively and fibrinogen and vascular endothelial growth factor (VEGF) protein levels, both indices of peritoneal extravasations, were determined by Western blot analysis. Peritoneal fluid was collected in similar experiments at 30 minutes, and 3 and 6 hours to measure fibrinolytic activity, an index of the ability of the peritoneum to degrade fibrinous adhesions.


RESULTS
The coadministration of VPA plus NK-1RA reduces adhesions by 72.6% relative to saline (P < .001); this reduction was greater than either compound alone (P < .001). Peritoneal fibrinolytic activity was significantly increased at 3 and 6 hours postoperatively in animals administered the combination therapy versus saline (P = .01). VPA plus NK-1RA significantly decreased fibrinogen and VEGF protein levels at 3 and 6 hours compared with saline controls.


CONCLUSIONS
These results suggest that a combined pharmacologic approach targeting multiple adhesiogenic pathways provides optimal adhesion prevention.
Department of Surgery, Boston University School of Medicine, Boston, MA.
Michael R
MR
Cassidy
Department of Surgery, Boston University School of Medicine, Boston, MA.
Alan C
AC
Sherburne
Department of Surgery, Boston University School of Medicine, Boston, MA.
Stanley J
SJ
Heydrick
Department of Surgery, Boston University School of Medicine, Boston, MA. Electronic address: afstucchi@gmail.com.
Arthur F
AF
Stucchi
D000005:Abdomen; D000818:Animals; D004195:Disease Models, Animal; D004357:Drug Synergism; D005340:Fibrinogen / Q000032:analysis; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D007430:Intraoperative Care; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D000267:Tissue Adhesions / Q000517:prevention & control*; D014635:Valproic Acid / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D014945:Wound Healing / Q000187:drug effects
D056572:Histone Deacetylase Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D042461:Vascular Endothelial Growth Factor A; D014635:Valproic Acid; D005340:Fibrinogen