Effects of Late Administration of Pentoxifylline in Experimental Severe Acute Pancreatitis
Tiago a. Kunitake, José Jukemura*, Ana Maria M. Coelho, Marcel C. Machado, José Eduardo M. Cunha
Gastroenterology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Acute pancreatitis (AP) is a typical cause of systemic inflammatory response (SIRS), which can lead to multiple organ dysfunction syndrome (MODS), whose the first sign is often the adult respiratory distress syndrome. The systemic effects of AP have many similarities to those of other conditions such as septicaemia, severe burns and trauma. Cytokines play a critical role in the pathogenesis of AP and more so of the subsquent inflammatory response. Levels of these cytokines appear to be correlated with the severity of pancreatic inflammation. Tumor necrosis factor alpha (TNF-α) has a central role in the inflammatory cascade of AP and its related systemic complications. Pentoxifylline is a drug with rheologic and anti-inflammatory properties and inhibits the production of TNF-α. Some authors have shown amelioration of experimental AP using pentoxifylline; however, drug administration started on the time of the induction of pancreatitis, that is not possible in clinical practice. Our aim is determine the effects of pentoxifylline in experimental severe AP, starting drug administration one hour after the induction of disease (after the inflammatory cascade activation).
Methods: severe AP was induced by injection of 0,5mL of 2,5% sodium taurochoate into the pancreatic duct. Sixty male Wistar rats were utilized and divided into two groups: Control (AP plus saline) and Pentoxifylline (AP plus 25mg/kg pentoxifylline, starting administration one hour after induction). Systemic inflammatory response was analyzed measuring inflammatory cytokines levels in blood (IL-6 and IL-10) and peritoneal fluid samples (TNF-α). Lung samples were collected to evaluate sequestration of neutrophils within this organ by assessment of tissue myeloperoxidase enzyme activity (MPO). Twenty rats of each group were kept alive for study of mortality rate in 72 hours.
Results: the Pentoxifylline group had a statiscally significant reduction of plasma IL-6 levels (278.9 ± 87.2 vs. 63.9 ± 20.4, p<0.05), plasma IL-10 levels (37.6 ± 5.3 vs. 17.1 ± 7.3, p<0.05) and peritoneal levels of TNF-α (87.6 ± 14.8 vs. 49.6 ± 9.4, p=0.05). Pentoxifylline also reduced 72-hour mortality rate (30% vs. 10%), but the difference was not significant (p=0.10). There was no difference in MPO activity between two groups (0.175 ± 0.030 vs. 0.128 ± 0.016).
Conclusion: late administration of pentoxifylline decreased the systemic inflammatory response, but it did not improve mortality rate. The drug failure to ameliorate pulmonary damage by neutrophilic infiltration. Supported by FAPESP 2007/1758-3