Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis
ABSTRACT Drotrecogin alfa (activated), the pharmacologic form of activated protein C and the first Food and Drug Administration-approved drug for treatment of severe sepsis, is beneficial in experimental acute pancreatitis (AP).
Male Sprague-Dawley rats.
Mild (intravenous cerulein) or severe (intravenous cerulein plus intraductal glycodeoxycholic acid) AP was induced in 72 rats, and coagulation evaluated. Rats with severe AP were randomized to treatment with drotrecogin alfa (activated), 100 microg/kg per hour, or isotonic sodium chloride.
Histologic scoring of pancreatic necrosis, inflammation of the pancreas and lung (measured by myeloperoxidase concentration), coagulation measures, and 24-hour survival.
Severe consumptive coagulopathy, hemoconcentration, and leukocytosis were observed 6 hours after induction of severe AP, but not in mild AP. Treatment of AP with drotrecogin did not worsen coagulation measures. Although the degree of pancreatic necrosis was comparable in treated and untreated animals with severe AP, drotrecogin significantly reduced myeloperoxidase levels in the pancreas (P = .009) and lungs (P = .03). The 24-hour survival in severe AP was markedly improved in animals treated with drotrecogin (86% vs 38%; P = .05).
Animals with severe AP have severe consumptive coagulopathy, but administration of drotrecogin alfa (activated), 100 microg/kg per hour, does not worsen coagulation abnormalities. Drotrecogin treatment reduces inflammation in the pancreas and lungs and significantly improves survival. These results encourage clinical investigation of drotrecogin in the treatment of severe AP.
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ABSTRACT: Sepsis is the tenth leading cause of death in the U.S. and creates a $16.7 billion burden on the healthcare system every year. Sepsis is characterized by a severe uncontrolled inflammatory response to the infection. Various cells and mediators are activated, and the result is a complex interaction between the inflammation and coagulation cascades leading to capillary leakage and end-organ ischemia. Current therapeutic strategies, such as recombinant human activated protein C, focus on this interplay. However, this drug's precise mechanism of action is not well understood. The aim of this study was to assess cytokine production, tissue damage, and apoptosis in a rat model of sepsis in response to various doses of this drug. Sprague-Dawley rats were divided into eight groups, including negative control, sham, sepsis only, and five treatment groups. The sepsis and treatment groups were given Escherichia coli. Each of the treatment groups received a different dose of recombinant activated protein C to complete 30-min or 270-min infusion times from the onset of sepsis. Serum and tissue samples were collected. Interleukin (IL)-6 concentrations were measured, and serum malondialdehyde (MDA) concentrations were determined to assess generalized tissue damage. Apoptosis in the lung was evaluated using a semi-quantitative ligation-mediated polymerase chain reaction assay. The physiologic effects of recombinant activated protein C are dose dependent and determined by the duration of infusion. Higher doses of the drug were associated with less inflammation, apoptosis, and generalized tissue damage. Sepsis increased the mean concentration of MDA (2.1 vs. 10.9 pmol/mg of protein) and IL-6 (0 vs. 10,763 pg/mL) compared with sham-treated animals, as well as the magnitude of apoptosis in lung (2,037 vs. 8,709 pixels) (all p < 0.05). Infusion of recombinant activated protein C attenuated these responses in a dose-response manner. Interleukin-6 and MDA concentrations were increased by lower-dose therapy, but attenuated significantly by the higher-dose infusion at 5 mg/kg/h. Apoptosis was attenuated by both the lower and the higher dose, but more so with the higher dose. These data can assist in establishing an optimal dose and infusion time of this drug for extrapolation to therapy of human beings. The goal now is to elucidate these findings further so that the maximum benefit of the drug may be achieved with the least possible harmful effects.Surgical Infections 07/2007; 8(3):377-86. DOI:10.1089/sur.2006.082 · 1.72 Impact Factor
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ABSTRACT: Our aim was to investigate the changes of mitogen-activated protein kinases (MAPKs) by activated protein C (APC) treatment in rats with severe acute pancreatitis (SAP), and relate them to changes in SAP severity, thus providing evidence for developing clinical therapies. Sprague-Dawley rats were given an intravenous injection of saline (SAP group), APC (50 microg/kg or 10 microg/kg), or CNI1493 just before SAP induction. One group of rats underwent a sham operation (control group). Experimental samples were harvested 16 h after SAP induction. The gene expression of pancreatic MAPKs was evaluated by cDNA microarrays. The mRNA and protein/phosphorylated protein levels of p38 MAPK, extracellular signal-regulated protein kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) and the protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were determined in pancreatic tissue. The severity of disease was evaluated by pancreatic histology, the pancreatic wet/dry weight ratio, and the serum amylase level. In rats treated with APC (50 microg/kg) or CNI1493, the severity of pancreatitis and expression of pancreatic TNF-alpha and IL-1beta proteins were attenuated by the decreased expression and activity of p38 MAPK and JNK (vs. the SAP group, P < 0.01). The expression and activity of ERK1/2 were increased in APC-treated rats, especially in the group treated with APC 50 microg/kg (vs. the SAP or CNI1493-treated group, P < 0.01, respectively). Inhibition of expression of pancreatic p38 MAPK and JNK and upregulation of ERK1/2 expression by APC treatment may protect against pancreatic injury, thus ameliorating severity of the disease.Journal of Gastroenterology 11/2007; 42(11):887-96. DOI:10.1007/s00535-007-2104-2 · 4.02 Impact Factor
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ABSTRACT: Sepsis is a systemic illness caused by invasion of tissues by pathogens. It is highly lethal, causing circulatory failure and death. There has been extensive research trying to identify possible therapies for sepsis. Apart from source control, and antibiotic and supportive therapy, glucocorticoids, anticoagulant agents, and immunoglobulins have been tried in both the experimental setting and in septic patients. Newer strategies include novel anticoagulant agents like ethyl pyruvate, statins, insulin receptor modulators and Toll-like receptor modulators. This review article summarizes both the current therapies and endeavors for future treatment in sepsis. Özet: Sepsis, dokuların patojen organizmalar tarafından işgal edilmesi sonucu ortaya çıkan sistemik bir hastalıktır. Dolaşım bozukluğu ve ölümle sonuçlanabilir. Sepsis tedavisi alanında birçok araştırma yapılmıştır. Kaynak kontrolü, antibiyotik ve destek tedavisi dışında glukokortikoidler, immunoglobulinler, antikoagülan ajanlar da hem deneysel hem de klinikte kullanılan tedavi yöntemleridir. Yeni tedavi stratejileri etil pirüvat gibi antikoagülanları, statinleri, insülin ve toll-like reseptör modülatörlerini içermektedir. Bu makalede sepsisin hem güncel tedavisi hem de gelecekte uygulanabilecek olası tedavi yaklaşımları tartışılmıştır.