sirolimus and Peritoneal-Diseases

Peritoneal adhesion formation is a challenging postoperative complication. We aim to evaluate the effect of orally administered sirolimus, prednisolone, and their combination to prevent this entity.. Eighty female albino underwent intraperitoneal injection of 3 mL of 10% sterile talc solution to induce peritoneal adhesion, and were subsequently and randomly divided into four groups (each n = 20); including a control group; 1 mg/kg oral prednisolone daily in the morning; 0.1 mg/kg oral sirolimus daily; and a combination group which received both drugs, with the same dosage. On the 29th day, abdominal cavities were explored, and classification was done based on Nair classification.. All rats were healthy on the 29th day, in which exploration was performed. The rats in the control group had extensive intra-abdominal adhesions, while 17 (85%) rats in the control group had substantial adhesion; however, the prednisolone, sirolimus, and combination group had lesser adhesion formation. Also, 14 (70%) rats of prednisolone group, 13 (65%) of sirolimus group, and 16 (80%) of combination group had insubstantial adhesion. The decrease in the grade of peritoneal adhesion bands was highly significant in the combination group (P > 0.001).. The combination of sirolimus and prednisolone was effective for preventing peritoneal adhesions in rats.

Topics: Abdominal Cavity; Animals; Disease Models, Animal; Female; Peritoneal Diseases; Postoperative Complications; Prednisolone; Rats; Sirolimus; Tissue Adhesions

The most serious complication of peritoneal dialysis is encapsulating peritoneal sclerosis (EPS). The prolonged inflammatory stimuli, fibrogenic cytokine overexpression, and angiogenesis that underlie EPS ultimately result in increased production of fibrous tissue, encapsulating the bowel loops. In recent years, inhibitors of mammalian target of rapamycin (mTOR) as an alternative agent for calcineurin inhibitor toxicity have been widely used in organ transplantation. These agents have also been used since the 1990s in endovascular medicine for drug-eluting stents because of antiproliferative effects on vascular smooth muscle cells and potent anti-inflammatory properties by direct action on human immune cells. Because of the shared characteristics of EPS and other fibrotic processes, we hypothesized that everolimus, an mTOR inhibitor can reverse the process responsible for the eventual development of EPS. We allocated 32 non-uremic albino Wistar rats to 4 groups: control group, 2 mL isotonic saline injected intraperitoneally (IP) daily for 3 weeks; CG group, 2 mL/200 g (0.1%) chlorhexidine gluconate (CG) injected IP daily and ethanol (15%) dissolved in saline, for 3 weeks; resting group, CG (weeks 0 - 3), plus peritoneal rest (weeks 3 - 6); and Evo-R, CG (weeks 0 - 3), plus 0.3 mg/L everolimus in drinking water (weeks 3 - 6). At the end of the study, we performed a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution, and examined the dialysate-to-plasma ratio of urea (D/P urea), dialysate white blood cell count, ultrafiltration (UF) volume, and morphologic change in the parietal peritoneum. Exposure to CG for 3 weeks resulted in alterations in peritoneal transport (increased D/P urea, decreased UF volume, p < 0.05) and morphology (increased inflammation, neovascularization, fibrosis, and peritoneal thickness, p < 0.05). Peritoneal rest has some beneficial effect only on UF failure and dialysate cell count (p < 0.05). However; everolimus was more effective than peritoneal rest with regard to vascularity and peritoneal thickness (p < 0.05). Everolimus has beneficial effects on UF failure, inflammation, and fibrosis. Everolimus may have therapeutic value in the management of EPS.

Topics: Animals; Cell Proliferation; Everolimus; Female; Immunosuppressive Agents; Injections, Intraperitoneal; Peritoneal Dialysis; Peritoneal Diseases; Peritoneum; Protein Kinases; Rats; Rats, Wistar; Sclerosis; Sirolimus; TOR Serine-Threonine Kinases