The combination of two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), has shown excellent postsurgical antiadhesive properties. However, the high molecular, positively charged PL is toxic in high doses, proposed as lysis of red blood cells. This study aims to elucidate the in vivo toxicity and biodistribution of PL and complex bound PLPG comparing intravenous and intraperitoneal administration. Fifty-six Sprague-Dawley rats were used in a model with repeated blood samples within 30 min examining blood gases and blood smears. Similarly, FITC labelled PL were used to track bio distribution and clearance of PL, given as single dose and complex bound to PG after intravenous and intraperitoneal administration. Tissue for histology and immunohistochemistry was collected. Blood gases and blood smears as well as histology points to a toxic effect of high dose PL given intravenously but not after intraperitoneal administration. The toxic effect is exerted through endothelial disruption and subsequent bleeding in the lungs, provoking sanguineous lung edema. FITC-labelled PL experiments reveal a rapid clearance with differences between routes and complex binding. This study advocates a new theory of the toxic effects in vivo of high molecular PL. PLPG complex is safe to use as antiadhesive prevention based on this toxicity study given that PL is always intraperitoneally administered in combination with PG and that the dose is adequate.

Objective: Postoperative pleural adhesions lead to major problems in repeated thoracic surgery. To date, no antiadhesive product has been proven clinically effective. Previous studies of differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG) have shown promising results reducing postoperative abdominal adhesions in experimental settings. This pilot study examined the possible pleural adhesion prevention by using the PL+PG concept after pleural surgery and its possible effect on key parameters; plasmin activator inhibitor-1 (PAI-1) and tissue growth factor beta 1 (TGFb) in the fibrinolytic process.Methods: A total of 22 male rats were used in the study, one control group (n=10) and one experimental group (n=12). All animals underwent primary pleural surgery, the controls receiving saline in the pleural cavity and the experimental group the PL+PG solution administered by spray. The animals were evaluated on day 7. Macroscopic appearance of adhesions was evaluated by a scoring system. Histology slides of the adhesions and pleural biopsies for evaluation of PAI-1 and TGFb1 were taken on day 7.Results: A significant reduction of adhesions in the PL+PG group (p<0.05) was noted at day 7 both regarding the length and severity of adhesions. There were no significant differences in the concentration of PAI-1 and TGFb1 when comparing the two groups.Conclusions: PL+PG may be used to prevent pleural adhesions. The process of fibrinolysis, and fibrosis was though not affected after PLPG administration.

Background: Abdominal adhesions develop on damaged peritoneal surfaces and constitute a significant health related problem. Previous animal studies have shown promising anti-adhesive effects when administering the polycation <i>α</i>-poly-L-lysine (<i>α</i>PL) and the polyanion poly-L-glutamate (PG) together. The objective of the study was to examine the effect of these differently charged polypeptides when administered by spraying and to evaluate any possible effect on fibrinolysis, fibrosis and inflammation. Methods: Rabbits were treated with PLPG after cecal abrasive surgery and analysis from peritoneal biopsies of active tPa/PAI-1 complex and from peritoneal fluid of IL-6 and active TGFb1 at day 0, 1, 4 and 10 were measured after surgery. Histological specimens were analyzed on day 10 regarding inflammation and fibrosis. Peritoneal adhesions were evaluated by adhesion score. All values were compared to the control group (NaCl). Results: PLPG-treated rabbits had a significant diminished adhesion score on day 10 as compared to the control group (p < 0.005). Significantly reduced collagen depositions on the peritoneum were seen in the PLPG group when evaluating the histological specimens (p < 0.05). No significant differences between the experimental and control groups were seen in peritoneal fluid when analyzing for active protein levels. Conclusion: This is the first study to investigate the effect on key parameters in adhesion formation as well as the preventive effect of the PLPG complex on abdominal adhesions in rabbits and also the first study where administration by spraying the polypeptides was used. PLPG was non-toxic in this setting and without significant differences in adhesion formation parameters and a significant reduction in adhesions was observed. This was verified both macroscopically and histologically

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