Evaluation of Models, Methodologies, Devices and New Surgical Concepts: Time-Dependent Effect of Tolmetin Sodium in a Rabbit Uterine Adhesion Model

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Abstract
Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) that reduces adhesion formation in several animal models after a single intraperitoneal (i.p.) dose delivered at the time of surgery. We set out to determine the period during which tolmetin could prevent adhesions. Adhesions were induced in New Zealand White rabbits (2-3 kg) by abrading the uterine horns and removing their mesouterine vasculature. Tolmetin sodium (1 mg/5 ml saline) was given at various times relative to the start of surgery as a single dose i.p. One week later adhesions were assessed using a standard scoring system (0 = no adhesions; 1 = light adhesions involving both uterine horns: 2 = more tenacious adhesions to bowel or bladder; 3 = tenacious adhesions to bowel and bladder partly immobilizing the uterus; 4 = completely fixed horns adherent to bowel and bladder). Scores were arranged in ascending rank order. Mean rank positions were calculated for each group and compared against controls (Dunnett's multiple comparison). Tolmetin sodium was most effective when administered within I hour of surgery. Mild effects could still be observed after 4 hours and the effect diminished after 24 hours. When these effects are compared to the temporal biochemical and cellular effects of tolmetin obtained in related studies, the data support the hypothesis that tolmetin reduces adhesions at least in part by modulating fibrinolytic activity of resident macrophages and macrophages present in the early postsurgical period.