ABSTRACT
OBJECTIVE: To characterize effects of IV administration of pirfenidone on clinical, biochemical, and hematologic variables and circulating tumor necrosis factor (TNF)-alpha concentrations in horses after infusion of a low dose of endotoxin. ANIMALS: 18 healthy adult horses. PROCEDURES: Horses were randomly assigned to 3 groups (n = 6 horses/group) and administered an IV infusion of 30 ng of endotoxin/kg or saline (0.9% NaCl) solution during a 30-minute period. Lipopolysaccharide-pirfenidone horses received endotoxin followed by pirfenidone (loading dose of 11.6 mg/kg and then constant rate infusion [CRI] at 9.9 mg/kg/h for 3 hours). Lipopolysaccharide-saline horses received endotoxin followed by infusion (loading dose and CRI for 3 hours) of saline solution. Saline-pirfenidone horses received saline solution followed by pirfenidone (loading dose and then CRI for 3 hours). Physical examination variables were recorded and blood samples collected at predetermined intervals throughout the 24-hour study period. Blood samples were used for CBCs, biochemical analyses, and determinations of TNF-alpha concentrations. RESULTS: IV infusion of pirfenidone after administration of a low dose of endotoxin failed to attenuate the clinical, clinicopathologic, or cytokine alterations that developed secondary to endotoxin exposure. Intravenous infusion of pirfenidone after administration of saline solution induced mild transient clinical signs, but associated clinicopathologic changes were not detected. CONCLUSIONS AND CLINICAL RELEVANCE: IV administration of pirfenidone was tolerated with only mild transient clinical adverse effects during infusion. However, administration of pirfenidone did not protect horses from the systemic effects of experimentally induced endotoxemia. Further studies of related, but more potent, drugs may be warranted.
Subject(s)
Endotoxemia/veterinary , Horse Diseases/drug therapy , Pyridones/therapeutic use , Analysis of Variance , Animals , Endotoxemia/drug therapy , Horses , Injections, Intravenous/veterinary , Lipopolysaccharides , Male , Pyridones/administration & dosage , Tumor Necrosis Factor-alpha/bloodABSTRACT
Septic shock results from a systemic host response to infection, in particular, and is associated with multiorgan dysfunction (MOD). Effective preventive measures against organ failure are essential as it is the cumulative burden of MOD that invariably leads to death. The aim of this study was to determine if a novel compound, 5-ethyl-1-phenyl-2-(1H) pyridone (5-EPP), could decrease the increased serum levels of various biomarkers of MOD in LPS/D-Galactosamine (LPS/D-GalN) and cecal ligation and puncture (CLP) models of septic shock in mice. Treatment with 5-EPP minimized the liver dysfunction as assessed by its ability to decrease the increased serum levels of aminotransferases. It also reduced proinflammatory cytokines such as TNF-alpha, IL-6 and IL-12, and offered complete protection against mortality in LPS/D-GalN model. 5-EPP treatment also offered a significant protection against LPS alone- induced mortality. Pretreatment with 5-EPP minimized the kidney, heart and muscle damage as assessed by its ability to decrease the CLP-induced increases in the serum levels of blood urea nitrogen, creatine kinase, glucose and mortality. Several possible mechanisms for the beneficial effects of 5-EPP in the LPS/D-GalN, LPS alone, and CLP models of septic shock have been discussed. It was concluded from the findings of this study that 5-EPP, a novel pyridone, is a promising candidate for the management of septic shock by offering protection against MOD and mortality clinically seen in septic patients.
Subject(s)
Biomarkers/blood , Multiple Organ Failure/blood , Pyridones/therapeutic use , Shock, Septic/drug therapy , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Blood Urea Nitrogen , Cells, Cultured , Cytokines/blood , Disease Models, Animal , Galactosamine/toxicity , Humans , Lipopolysaccharides/toxicity , Male , Mice , Pyridones/pharmacology , Shock, Septic/blood , Shock, Septic/mortalityABSTRACT
Septic shock results from a systemic host response to infection, in particular, and is associated with multiorgan dysfunction (MOD). Effective preventive measures against organ failure are essential as it is the cumulative burden of MOD that invariably leads to death. The aim of this study was to determine if a novel compound, 5-ethyl-1-phenyl-2-(1H) pyridone (5-EPP), could decrease the increased serum levels of various biomarkers of MOD in LPS/D-Galactosamine (LPS/D-GalN) and cecal ligation and puncture (CLP) models of septic shock in mice. Treatment with 5-EPP minimized the liver dysfunction as assessed by its ability to decrease the increased serum levels of aminotransferases. It also reduced proinflammatory cytokines such as TNF-alpha, IL-6 and IL-12, and offered complete protection against mortality in LPS/D-GalN model. 5-EPP treatment also offered a significant protection against LPS alone- induced mortality. Pretreatment with 5-EPP minimized the kidney, heart and muscle damage as assessed by its ability to decrease the CLP-induced increases in the serum levels of blood urea nitrogen, creatine kinase, glucose and mortality. Several possible mechanisms for the beneficial effects of 5-EPP in the LPS/D-GalN, LPS alone, and CLP models of septic shock have been discussed. It was concluded from the findings of this study that 5-EPP, a novel pyridone, is a promising candidate for the management of septic shock by offering protection against MOD and mortality clinically seen in septic patients.
