Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentoxifylline (PTXF) is a methylxanthine that modifies leukocyte function and inhibits cytokine release. To evaluate its effects on the cardiovascular manifestations of sepsis secondary to group B streptococci, 14 anesthetized, mechanically ventilated piglets were studied over a 240-min period. Animals were randomly assigned to a treatment group that received a PTXF bolus (20 mg/kg) followed by a continuous infusion of 5 mg/kg/h before and during group B streptococci (1 x 10(8) colony forming units/kg/min) administration and a control group that received saline as a placebo. Comparison of the hemodynamic measurements and arterial blood gases during the first 90 min of PTXF treatment with those of the control group resulted in the following 90 min values: systemic arterial blood pressure was significantly higher in the PTXF group (89 +/- 10 versus 56 +/- 30 mm Hg; p less than 0.005) as was cardiac output (0.18 +/- 0.04 versus 0.10 +/- 0.07 L/kg/min; p less than 0.005). Pulmonary vascular resistance remained lower in the PTXF-treated animals (135 +/- 117 versus 248 +/- 119 mm Hg/L/min/kg; p less than 0.001), and these animals were less acidotic as measured by pH (7.07 +/- 0.2 versus 7.31 +/- 0.1; p less than 0.05) and base deficit (-15 +/- 9 versus -5 +/- 2 mmol/L; p less than 0.05). Median survival time was significantly longer in the PTXF group (210 versus 90 min; p less than 0.002). These data demonstrate that PTXF can ameliorate some of the deleterious hemodynamic manifestations of group B streptococci sepsis and result in improved survival in a young animal model.
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PMID:Effects of pentoxifylline on the cardiovascular manifestations of group B streptococcal sepsis in the piglet. 163 22

Pentoxifylline (PTX), a methylxanthine, can suppress polymorphonuclear leukocyte (PMN) activation and attenuate sepsis-induced acute lung injury. We investigated whether PTX prevents non-PMN-dependent lung injury. First we studied four groups of granulocyte-depleted guinea pigs (control, PTX, Escherichia coli, and E. coli + PTX). Lung injury was assessed by wet-to-dry lung weight (W/D) ratio and lung tissue-to-plasma 125I-albumin ratio (albumin index, AI). The E. coli group showed a significant increase in the lung W/D ratio and AI compared with the control and PTX groups. However, PTX did not prevent the E. coli-induced increase in the lung W/D ratio and AI. Next we investigated the effects of PTX on endothelial cell monolayer permeability and adenosine 3',5'-cyclic monophosphate (cAMP) levels. Whereas E. coli lipopolysaccharide (LPS) alone increased the endothelial permeability, PMNs added to the endothelial monolayers and exposed to LPS enhanced the increase. PTX attenuated the permeability increase mediated by LPS-exposed PMNs. PTX did not prevent the LPS-induced increase in permeability when PMNs were not present, although PTX increased endothelial cell cAMP levels. These data demonstrate that 1) PTX does not prevent lung injury in granulocyte-depleted guinea pigs; 2) PTX does not prevent LPS-induced increases in endothelial cell permeability, despite increased cAMP levels; and 3) PTX attenuates PMN-dependent increases in endothelial cell permeability.
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PMID:Pentoxifylline does not attenuate acute lung injury in the absence of granulocytes. 165 91

Neutrophils and neutrophil-derived oxidants have been implicated in the development of acute lung injury such as that seen in the adult respiratory distress syndrome (ARDS), in bronchopulmonary dysplasia (BPD), and in animal models of lung injury, including the isolated perfused lung. Both neutrophil-derived oxidant production and retention of neutrophils in the lung are required for injury in this model. Pentoxifylline can reduce lung injury from sepsis in the guinea pig and endotoxin-induced neutrophil sequestration and lung injury in the dog. It is also known to increase neutrophil deformability, which may affect retention in the pulmonary microvasculature. We evaluated neutrophil oxidant production, retention in isolated lungs, and neutrophil-mediated acute lung injury after phorbol myristate acetate (PMA) in the presence of pentoxifylline. Pentoxifylline (2 mM) significantly reduced superoxide anion and hydrogen peroxide production in vitro from PMA-stimulated neutrophils when pentoxifylline was directly added to the incubation mixtures, but not when neutrophils were preincubated with the agent. Pentoxifylline did not reduce retention of neutrophils in isolated lungs as determined by infusion of 111In-labeled neutrophils and gamma counting. Pentoxifylline prevented increases in total lung weight, lung-to-body-weight ratio, and perfusate thromboxane concentrations when it was present in perfusate buffer, whether or not neutrophils were preincubated in pentoxifylline prior to infusion into the lung. Pentoxifylline did not reduce injury to lungs perfused with glucose and glucose oxidase. We conclude that pentoxifylline reduces neutrophil oxidant production and neutrophil-dependent lung injury.
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PMID:Pentoxifylline reduces injury to isolated lungs perfused with human neutrophils. 166 Feb 29

Endotoxin induces alterations in the neonatal red cell membrane that result in decreased deformability and an increase in whole blood viscosity. These rheologic alterations are detrimental to flow in the microcirculation. Pentoxifylline (PTX), a methyl xanthine derivation, increases red cell deformability presumably through its effect on intracellular adenosine 5-triphosphate. The purpose of this study was to evaluate the effect of PTX on endotoxin-induced alterations in the neonatal red blood cell. Anticoagulated whole blood specimens obtained from the cord of 12 neonates at birth were used to study the effects of Escherichia coli endotoxin (LPS) with and without PTX (50 micrograms/mL) on red cell deformability and whole blood viscosity. LPS resulted in a significant (P less than .001) decrease in deformability compared with controls. PTX reversed these endotoxin-induced alterations (P less than .01), normalizing deformability to control values (P = NS). LPS resulted in a significant increase (P less than .005) in blood viscosity that was reversed by PTX (P = NS). Pentoxifylline reverses the detrimental rheologic effect of endotoxin in the neonate. This activity may be helpful in sustaining normal microcirculation in neonatal sepsis.
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PMID:The role of pentoxifylline in endotoxin-induced alterations of red cell deformability and whole blood viscosity in the neonate. 206 13

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents that attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.
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PMID:Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence. 217 54

We have investigated the effects of recombinant human tumor necrosis factor-alpha (rhTNF alpha) on polymorphonuclear leukocytes (PMNs), concentrating on the mechanisms involved in the alterations of PMN-directed migration and adherence by this cytokine. RhTNF alpha profoundly suppressed PMN chemotaxis toward FMLP by 80%. At similar concentrations, it enhanced adhesion to gelatin-coated plastic dishes by more than tenfold and increased the expression of the CD11b antigen to 182% of the control. The monoclonal antibody 60.1, which is directed against the alpha chain of the CD11b/CD18 complex, completely blocked rhTNF alpha, induced inhibition of the chemotactic response to FMLP, and rhTNF alpha induced hyperadherence, suggesting that these effects were related to rhTNF alpha's effects on CD11b antigen expression. The fluid state of the PMN membrane was also decreased by rhTNF alpha. N-butanol, a known membrane fluidizer, partially inhibited the effect of rhTNF alpha on membrane fluidity and chemotaxis and completely reversed its effects on adherence and the expression of the CD11b antigen. Pentoxifylline, an agent that has previously been studied for its ability to prevent some effects of rhTNF alpha on PMNs, completely prevented the effect of rhTNF alpha on chemotaxis, the expression of the CD11b antigen, and membrane fluidity. Pentoxifylline partially prevented changes in adherence caused by this cytokine. Increased CD11b antigen expression caused by rhTNF alpha may result in enhanced PMN adhesion and suppression of migration. These events may, in turn, lead to the accumulation of PMNs on the vascular endothelium, resulting in the extensive vascular and tissue damage that is seen in gram-negative sepsis.
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PMID:Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration. 218 25

Tumor necrosis factor, a mononuclear phagocyte-derived peptide produced in response to lipopolysaccharide, has been shown to mediate certain aspects of septic shock and multiple organ failure resulting from gram-negative septicemia. In the present investigation, pretreatment of animals with pentoxifylline inhibited lipopolysaccharide-induced serum tumor necrosis factor in a dose-dependent fashion. Pentoxifylline prevented the sequestration of neutrophils seen in animals given intravenous lipopolysaccharide. Furthermore, pentoxifylline protected animals from the lethal effects of an intravenous challenge with lipopolysaccharide. These data indicate that pentoxifylline inhibits lipopolysaccharide-induced tumor necrosis factor and may be an effective agent in mitigating the lethal consequences of sepsis and other disease processes mediated by this cytokine.
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PMID:Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality. 223 23

Pentoxifylline (Trental) is a well-known vasoactive drug with proven clinical efficacy in various circulatory disorders. It improves the microcirculation due to its rheologic effects on red blood cells, platelets, and plasmatic components, resulting in a decrease of whole blood viscosity. Surprisingly, it has been found that pentoxifylline will also be of great benefit in different models of animal sepsis, including both gram positive and gram negative bacteria. In these experiments, survival rates are significantly increased in the pentoxifylline group when compared with the controls, which is paralleled by a decrease in germ counts. By different experimental approaches it could be shown that this drug interferes with pathologic granulocyte-endothelium interactions which are closely related to septic symptoms, both downregulating intravasal granulocyte hyperreactivity as well as stimulating antiaggregatory activity of the vessel endothelium. Through this way, beneficial effects of pentoxifylline may be expected in various diseases related to infection, sepsis, and shock which, however, have still to be proven in detailed clinical studies.
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PMID:The effect of pentoxifylline in septic shock--new pharmacologic aspects of an established drug. 265 50

This study examines the changes in pulmonary leucostasis and capillary ultrastructure in 18 rabbits divided into three groups. Those in the first group were sham operated, and those in the second and third groups underwent peritonitis induction; those in the latter group were treated with pentoxifylline (PTF). White blood cells (WBC) were counted, and tissue area, total capillary area, and capillary patency were measured from electron micrographs of lung tissue. Pulmonary WBCs were 1.2 per unit field in the sham group, 9.7 in the test group (P less than 0.001 compared with sham), and 2.5 in the PTF group (P less than 0.001 compared with sham). Capillary patency was 53 +/- 5% in the sham group, 12 +/- 4% (P less than 0.001 compared with sham) in the test group, and 24 +/- 2% (P less than 0.001 compared with sham) in the PTF group. Pentoxifylline treatment attenuates pulmonary leucostasis, pulmonary capillary occlusion, and endothelial and epithelial damage associated with peritonitis in rabbits. This study shows that PTF warrants investigation into its potential protective effects on the lungs in clinical sepsis.
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PMID:Pentoxifylline reduces pulmonary leucostasis and improves capillary patency in a rabbit peritonitis model. 273 27

The effect of pretreatment with pentoxifylline on normothermic liver ischemia was studied in rats. This drug, a dimethylxanthine and fosfodiesterase inhibitor, improves microcirculation, decreases neutrophil activity in experimental sepsis and hemorrhagic shock, and inhibits "in vitro" cytokine production by isolated Kupffer cells. Partial liver ischemia was induced by occlusion of afferent vessels to the median and left lateral lobes for 60', followed by resection of nonischemic lobes just before reperfusion. The rats were divided in 4 groups: I (n = 6) sham operation, II (n = 6) resection of right and caudate lobes, III (n = 42) normal saline pretreatment and 60' ischemia, IV (n = 42) pentoxyfilline pretreatment (50mg/K/i.p. 2 h before clamping) and 60' ischemia. 12 animals were sacrificed 1 h and 6 h after reperfusion respectively (gr III and IV), and 20 rats were observed for a maximum of 24 h after reperfusion. Serum transaminases, LDH, CK (isoenzymes), bilirubin, and total bile acids were determined in each animal. A sample of the left lobe was taken for histological examination. Extent of necrosis 24 h after reperfusion was assessed. Bile output was measured before ischemia and during the first hour of reperfusion. Pentoxifylline pretreatment was associated with a lower rise in serum transaminases and LDH after reperfusion, but it did not modify the changes in either serum CK activity (mainly CKBB), or total bile acid concentration. A reduction of bile output was not avoided by pentoxifylline pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Liver damage due to normothermic ischemia and reperfusion in the rat. The effects of pentoxifylline pretreatment]. 766 19


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