Reduction of adhesion formation in rabbits by intraperitoneal administration of lazaroid formulations

Adhesion formation is a major source of postoperative morbidity andmortality. In this study, the ability of a variety of lazaroid formulations[the antioxidant 21-aminosteroid PNU74006F (tirilazad) and thenon-steroidal 2-methylaminochroman derivative PNU83,836E] to reduce i.p.adhesion formation in three rabbit models was examined. In initial studies,PNU83836E was administered via Alzet miniosmotic pump to the site ofinjury. In the sidewall and double uterine horn models, PNU83,836E wasadministered via Alzet miniosmotic pump for the entire postoperativeinterval. In the sidewall model, there was a dose- dependent reduction inthe area of the sidewall injury that was involved in adhesions. In thedouble uterine horn model, PNU83,836E was administered via Alzetminiosmotic pump to the area of injury for 1, 2, 3 or 7 days.Administration for as little as 24 h after surgery significantly reducedthe extent of adhesion formation and the reduction was increased if it wasadministered for longer. Further studies were conducted in which variouslazaroid formulations were administered as a bolus at the end of surgery.In both the sidewall and double uterine horn models, administration ofeither PNU83,386E (in citrate buffer) or PNU74006F (in cyclodextrin orlipid emulsion vehicles) at the end of surgery reduced adhesion formation.Administration of a bolus of PNU74006F 10 min prior to initiation ofsurgery with or without additional treatment at the end of surgery furtherincreased its efficacy in the reduction of adhesion formation.Administration of a minimum of 1.5 mg before and after surgery (3 mg total)was required for maximal efficacy. These studies demonstrate that pre- andpostoperative administration of either a steroidal (PNU74006F) ornon-steroidal (PNU83,836E) lazaroid intraperitoneally reduced the formationand reformation of postoperative adhesions in three animal models.