Small bowel obstruction and toxicity of a new model of adhesion prevention

Abstract Background: Small bowel obstruction (SBO) is a common surgical diagnosis. If no signs of strangulation are evident, the majority of the patients can be conservatively managed. Approximately one third of the patients need surgical treatment and there is a need for early parameters that can predict operative intervention. The etiology of SBO in most cases is postoperative abdominal adhesions. Laparoscopic surgery generates less surgical trauma and thereby possibly less adhesion formation and subsequent decreased risk of SBO. The burden of postoperative adhesions is substantial and there is a need for an adhesion preventive agent that can be used in different clinical situations and reduce the clinical complications caused by adhesions, ie SBO, infertility and chronic abdominal pain. Previous experimental studies have reported promising anti adhesive effect of intraabdominally installed differently charged polypeptides in different clinical settings. However, there was observed toxicity of the cationic polypeptide when administered alone. Aims/methods: The aims of the retrospective clinical studies were to identify early parameters predicting surgical intervention in patients with SBO (I) and to determine whether there is a difference in the incidence of SBO after open versus laparoscopic surgery for suspected appendicitis (II). In the experimental studies the aims were to establish the lowest anti adhesive dose of α-polylysine (PL) in combination with polyglutamate (PG) and determine the toxic dose of α-PL (III), to investigate the possible anti adhesive effect of another four cationic polypeptides in combination with PG (IV). Furthermore, explore the mechanism of toxicity as well as the biodistribution of α-PL, alone or in combination with PG, after intravenous and intraperitoneal administration (V). Results/conclusions: 109 patients were included, 65 were conservatively managed and 44 were surgically treated. We identified five parameters, possible to retrieve within 4 hours from hospital admission, that were more frequent in the patients that were surgically treated for SBO. These parameters can possibly be used to advance the selection of patients for operation (I). The incidence of SBO after open and laparoscopic surgery for suspected appendicitis was low in both groups, 1% (24/2333) and 0,4% (10/2372) respectively. The difference was minor but significant, favoring the laparoscopic approach (II). We could show that the anti adhesive effect of α-PL/PG was dose dependent and the lowest effective dose for α-PL was established. The toxic dose of α-PL was determined and the gap between the lowest effective dose and the toxic dose is probably too narrow (III). All four alternative cationic polypeptides (polyarginine, lactoferrin, lysozyme,ε-PL) investigated in the fourth study showed anti adhesive effect. ε-PL, another isoform of PL, was superior to the other three and showed less toxicity than α-PL (IV). High doses of intravenous α-PL caused a damage to endothelial cells with subsequent edema and extravasation of blood in lung and liver. The biodistribution and accumulation of α-PL and α-PL/PG in blood and organs is lower and slower after intraperitoneal than intravenous administration (V)

Circulating insulin-like growth factor I in relation to melanoma risk in the European Prospective Investigation into Cancer and Nutrition

Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma

Toxicity and Dose Response of Intra-Abdominally Administered Poly-L-alpha-Lysine and Poly-L-Glutamate for Postoperative Adhesion Protection.

Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents

Small bowel obstruction: early parameters predicting the need for surgical intervention

To study and identify early clinical and radiological findings that could help to predict operative intervention for small bowel obstruction. One hundred and nine consecutive patients with small bowel obstruction who underwent small bowel follow-through examination with Gastrografin(A (R)) during 2005-2006. The patients were divided into an operative group and a non-operative group, n = 44 and 65, respectively. Findings primarily noted were those which were possible to register within 1-4 h from hospital arrival. In univariate analyses, factors found to be significantly associated with surgical intervention were no prior abdominal surgery, the presence of radiological differential air fluid levels, and absence of flatulence 24 h prior to admission, CRP > 10 mg/L and dehydration at admission. In multivariate analyses, the presence of dehydration and radiological differentiated air fluid levels were independent predictive factors of significance. Absence of all factors significantly favored non-operative treatment, while operative treatment was significantly favored when two or more factors were present. The presence of two or more early predictive factors as defined above, available at admission, significantly correlates with a likelihood of complete obstruction and the need of surgical intervention

Prevention of Abdominal Adhesions - Present State and What's beyond the Horizon?

Intra-abdominal adhesions are normally found after most surgical procedures. Many of the adhesions are asymptomatic, but in about 5% they will lead to readmission due to adhesion-related disorders, such as small bowel obstruction, pelvic pain and infertility. This review discusses possible ways to prevent abdominal adhesions and provides an update as comes to where we stand today in research regarding experimental and clinical use of various antiadhesive agents

Cationic polypeptides in a concept of oppositely charged polypeptides as prevention of postsurgical intraabdominal adhesions

Two differently charged polypeptides, α-poly-L-lysine and poly-L-glutamate, have previ- ously been shown to effectively reduce postoperative intraabdominal adhesions. Though α-poly-L-lysine showed toxicity in doses too close to the lowest the-rapeutic dose, the aim in the present study was to investigate the possible antiadhesive effect of another four cationic polypeptides

Prevention of pleural adhesions by bioactive polypeptides - a pilot study.

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

Prevention of Adhesions by PL/PG after Adhesiolysis

Background: Previous studies of differently charged polypeptides, Poly-L-lysine (PL) and Poly-L-Glutamate (PG) have shown promising results, reducing postoperative adhesions. This study aimed to investigate the possible anti adhesion effect of those combined polypeptides, after adhesiolys. The concentration of tPA, PAI-1 and active TGFb1 in biopsies from adhesions, unharmed peritoneum before and after adhesiolysis, was also investigated. Materials and methods: A total of 24 male rats were divided in three groups A (N=8), B (N=8) and C (N=8). All rats underwent primary adhesion creating surgery at day 0, and adhesiolysis at day 7. Adhesions were evaluated at day 7 and 14, where group B received PL/PG after surgery at day 0 and after adhesiolysis at day 7, and group C received PL/PG after adhesiolysis at day 7. Tissue plasminogen activator (tPA), Plasminogen activator inhibitor 1(PAI-1) and active transforming growth factor beta 1(TGF-β1) were collected from biopsies of adhesions and normal peritoneum at day 0, 7 and 14. Results: Significant reduction of adhesions p<0.05 was seen in group B at day 7 after primary surgery, and at day 14 after adhesiolysis. Significantly p<0.05 reduction of adhesions was seen at day 14 after adhesiolysis in group C. Some variations were seen in tPA, PAI-1 and active TGFb1. Conclusions: PL/PG may be used to prevent adhesion formation after adhesiolysis. The process of fibrinolysis and fibrosis was not affected, after PL/PG prophylaxis and adhesiolysis