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 (PTX), a xanthine derivative used in the treatment of circulatory insufficiency, has been found to have protective effects in different models of sepsis. We hypothesized that this drug might improve the cellular oxygen availability following endotoxin challenge by increasing oxygen delivery (DO2) and/or tissue oxygen extraction. The oxygen extraction capabilities were studied during a reduction in blood flow induced by cardiac tamponade. Fourteen anesthetized, ventilated, and paralyzed dogs, received intravenous 2 mg/kg of Escherichia coli endotoxin followed by a continuous infusion of 20 ml/kg.h of saline. 30 min later tamponade was induced by repeated bolus injections of warm saline into the pericardial space. Seven dogs were pretreated with PTX as an intravenous bolus of 20 mg/kg, followed by a continuous infusion at 20 mg/kg.h, and the other seven dogs served as a control group. PTX largely attenuated the systemic and pulmonary vasoconstriction observed in the control group and resulted in significant increases in cardiac index, DO2 and oxygen consumption (VO2). PTX also improved ventilation/perfusion matching in the lungs as indicated by a higher PaO2 and PvO2 and a lower venous admixture than in the untreated group during cardiac tamponade (both p < .05). In addition, the critical DO2 (DO2 crit) was lower and the critical oxygen extraction ratio was higher in the PTX treated than in the control group (9.1 +/- 1.8 vs. 11.6 +/- 2.4 ml/kg.min, and 70.6 +/- 14.0 vs. 49.3 +/- 14.6%, both p < .05). The VO2/DO2 dependency slope was also steeper in the PTX-treated than in the control group (.80 +/- .28 vs. .43 +/- .19, p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pentoxifylline improves the tissue oxygen extraction capabilities during endotoxic shock. 772 87

Tumor necrosis factor-alpha (TNF alpha) is recognized as a principal mediator of a variety of inflammatory conditions. In animal models, pentoxifylline attenuates the morbidity and mortality of bacterial sepsis, an effect which has been attributed to its ability to suppress the induction of TNF alpha. To determine whether pentoxifylline also directly inhibits the effects of TNF alpha, the ability to inhibit cytotoxicity on the TNF alpha-sensitive murine fibrosarcoma cell line, L929, was examined. Cell viability was assessed by crystal violet staining and cell proliferation was assessed by [3H]-thymidine uptake assay. TNF alpha induced dose-dependent cytotoxicity. At concentrations of TNF alpha of 1000 U/ml, viability at 3 days was approximately 35% of control. When L929 cells were co-incubated with TNF alpha (1000 U/ml) and pentoxifylline (1 mM), cell viability increased to approximately 75% of control (P = 0.001). At concentrations of TNF alpha of 10,000 U/ml, cell viability which was 11% of control with TNF alpha alone increased to 53% in the presence of pentoxifylline (P = 0.002). TNF alpha at 1000 and 10,000 U/ml concentrations decreased [3H]-thymidine uptake to approximately 5% of control values. Co-incubation with pentoxifylline significantly increased uptake to 13% of control at both TNF alpha concentrations (P = 0.002). Pentoxifylline did not affect the level of type I TNF alpha receptor--ligand cross-link product. However, in TNF alpha receptor binding assays, incubation with pentoxifylline 1 mM for 4 h was associated with an increase in the receptor affinity (control: KD = 0.42 nM vs pentoxifylline-treated: KD = 0.21 nM, P = 0.006), without significant change in number of type I TNF alpha receptors, suggesting that pentoxifylline affects post-receptor signalling events. We have observed that pentoxifylline prevents the TNF alpha-mediated activation of sn-2 arachidonic acid-specific cytosolic phospholipase A2, an important component of the signal transduction pathway of TNF alpha cytotoxicity. Because pentoxifylline does not inhibit all activities mediated by the type I TNF alpha receptor, its selective inhibition of post-receptor signalling may facilitate further study into the mechanisms underlying the diverse effects of TNF alpha.
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PMID:Pentoxifylline inhibits tumor necrosis factor-alpha-mediated cytotoxicity and cytostasis in L929 murine fibrosarcoma cells. 780 30

The potential role of tumor necrosis factor alpha (TNF alpha) and eicosanoids in the pathogenesis of experimental neonatal sepsis models was investigated. Lethality was induced in neonatal rats by administration of heat killed group B streptococci (GBS, 7 mg kg-1 intracardially) or Salmonella enteritidis endotoxin (0.35 mg kg-1 intracardially). The relative efficacy of six compounds with putative TNF alpha and eicosanoid inhibitory actions were tested. These were: ibuprofen (3 and 20 mg kg-1), a cyclo-oxygenase inhibitor; CGS85515 (30 mg kg-1), a lipoxygenase inhibitor; LY203647 (30 mg kg-1), a leukotriene D4 receptor antagonist; pentoxifylline (10, 50 and 100 mg kg-1), a TNF inhibitor; cloricromene (2 and 10 mg kg-1), a thromboxane A2 synthetase inhibitor with TNF alpha inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg-1), a dual cyclo-oxygenase/lipoxygenase inhibitor with TNF alpha inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNF alpha at 2.5 h post-injection with killed GBS (P < 0.05). On the contrary, pretreatment with ibuprofen, CGS85515 or LY203647 did not significantly affect TNF alpha levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNF alpha and eicosanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.
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PMID:Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis. 792 Apr 63

Pentoxifylline (Trental, 5 mg/kg/h for 6 h) was administered to 17 premature infants with sepsis, on 3 successive days. A statistically significant decrease in mortality rate (P < 0.04) was observed in comparison to a retrospectively analysed group of 13 septic infants, who were treated in a comparative way but without the use of a pentoxifylline infusion. The suggestion that pentoxifylline may be an effective drug in the treatment of Gram-negative sepsis in premature infants should be tested in a double-blind, randomized study.
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PMID:Pentoxifylline treatment of sepsis of premature infants: preliminary clinical observations. 795 28

Certain phosphatidic/plasmanic/plasmenic acid (PA) species function as lipid intermediates in cell activation and may function directly as intracellular signaling molecules. PA can also be dephosphorylated to 1,2-diradyl-sn-glycerol by phosphatidate phosphohydrolase. Treatment of various cell types, including murine P388 monocytic leukemia cells, with bacterial lipopolysaccharide rapidly stimulates large increases in PA and PA-derived diradylglycerol. Pentoxifylline, 1-(5-oxohexyl)-3,7-dimethylxanthine, inhibits lipopolysaccharide-stimulated formation of PA in P388 cells at high concentrations (IC50 = 500 microM). Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] is a unique metabolite of pentoxifylline in humans and is > 800-fold more active as an inhibitor of PA formation than pentoxifylline (IC50 = 0.6 microM). Lisofylline does not inhibit lipopolysaccharide-induced activation of phosphatidylinositol-specific phospholipase C and generation of phosphatidylinositol-derived diradylglycerol. Lisofylline but not pentoxifylline protects BALB/c mice from endotoxin lethality when administered 4 hr after lipopolysaccharide. This protective effect is independent of either agent's effect on suppression of plasma tumor necrosis factor alpha. These data suggest that inhibitors of PA formation may have significant clinical potential in the treatment of sepsis and septic shock.
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PMID:Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid. 817 Oct 2

Sepsis induces metabolic disorders that include loss of body weight, muscle wasting, and acute-phase protein synthesis in liver. Cytokines are generally recognized as active mediators of these disorders, and the implication of tumor necrosis factor (TNF) has been frequently discussed in the recent past. However, the identity of the active agent in alterations of protein metabolism is still controversial. To improve our understanding of the role of cytokines in mediating muscle wasting observed in sepsis, we investigated muscle and liver protein metabolism in the following three groups of rats: infected control rats (INF-C); infected rats pretreated with pentoxifylline (PTX-INF), which is a potent inhibitor of TNF secretion; and pair-fed rats for the PTX-INF group pretreated with pentoxifylline. Pentoxifylline nearly completely suppressed TNF secretion but did not influence the transient fall in rectal temperature, the decreased hematocrit, and the increased liver protein mass and synthesis observed in INF-C rats. Pentoxifylline decreased the anorexia, the loss of body weight and muscle protein observed in INF-C animals, and partially prevented the decrease in muscle protein synthesis induced by infection. The overall data indicate that pentoxifylline is an effective agent in mitigating the characteristic muscle protein wasting induced by sepsis and confirm the limited role of TNF in the mediation of the acute-phase protein synthesis. Our results suggest a probable implication of TNF in the regulation of protein balance in muscle but do not allow discarding possible implication of other mediators that would be inhibited by pentoxifylline.
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PMID:Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis. 823 42

The resting membrane potential (RMP) of skeletal muscle cells was investigated in a hyperdynamic animal model of sepsis. Reduced membrane potential is known to parallel the clinical course of sepsis and hemorrhagic shock in animal models. Pentoxifylline (PTF), a dimethyl xanthine derivative of the theophylline family, may improve the metabolic effects of sepsis. A cecal ligation and puncture (CL&P) sepsis model in Wistar rats was used in which RMP was measured with differing administration regimes of PTF. The RMP decreased less rapidly in our study when PTF was administered after CL&P and this effect was most noticeable after 18 hours. Administration of PTF before CL&P had little effect on membrane potential fall-off. These results suggest a potential role for PTF in the management of sepsis.
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PMID:Pentoxifylline improves resting membrane potential in sepsis. 830 80

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.
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PMID:Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees. 834 9

Pentoxifylline inhibited the TNF production of purified human white blood cells and whole blood cultures stimulated either by LPS or by Staphylococcus aureus. PTX did not influence the CD14 expression. The in vitro TNF and IL-6-producing capacities of septic patients were higher than in the control group. Administration of PTX to septic patients resulted in the normalization of TNF synthesis and in a moderate decrease in IL-6 production. It also subsequently led to an improvement in the clinical status. A further improvement in APACHE II score could be achieved by administration of PentaglobinO (Biotest). The prevention of in vitro TNF production by PentaglobinO could be demonstrated involving the use of whole blood rather than purified lymphocytes. The level of soluble ICAM-1 in the serum of septic patients was significantly higher than in normal individuals, but it decreased following PTX and PentaglobinO therapy. It is presumed that PTX and PentaglobinO can antagonize cytokine production at different levels, resulting in synergistic action that is beneficial in the treatment of sepsis.
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PMID:Effects of pentoxifyllin and PentaglobinO on TNF and IL-6 production in septic patients. 854 3

The influence of pentoxifylline on human polymorphonuclear granulocyte (PMN) respiratory burst activity (RBA) was studied in 23 patients fulfilling the established criteria of sepsis and in 10 healthy donors. Pentoxifylline (PTX) was administered (5 mg/kg) by intravenous infusion in 13 septic patients over a period of 180 min. The control group consisted of 10 patients with septic syndrome who received an infusion of physiological saline. For determination of RBA, 10 mL of blood was drawn at respective time intervals before, during, and after treatment with PTX or a placebo. RBA measurements were performed using a chemiluminescence assay after stimulation of PMN with formyl-methionyl-leucyl-phenylalanine (FMLP), phorbol-myristate-acetate, and opsonized zymosan, respectively. RBA measurements of each patient were performed in replicate samples. CL was measured for 1 h at respective time intervals (1, 3, 5, 8, 10, 15 min etc). RBA of PMN of septic patients was compared with RBA of PMN of healthy donors and patients receiving PTX were compared with controls. Our results demonstrate that PMN of patients with sepsis had an increased oxidative response compared with healthy donors. We found that PTX administered intravenously was able to reduce this reactivity. RBA was significantly decreased during PTX infusion when PMN were stimulated with FMLP and phorbol-myristate-acetate, compared with the control group. No significant decrease was observed when PMN were stimulated with opsonized zymosan. These data suggest that PTX may be a valuable drug in septic state.
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PMID:In vivo modulation of human neutrophil function by pentoxifylline in patients with septic syndrome. 857 49


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