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

Polymyxin B, a relatively toxic antibiotic, has potent endotoxin-neutralizing properties that may be beneficial as adjunctive therapy in gram-negative sepsis. Polymyxin B nonapeptide (deacylated polymyxin B) is devoid of antibiotic activity but retains the capacity to disorganize the outer membrane of gram-negative bacteria. To evaluate the potential therapeutic usefulness of this derivative, we produced purified polymyxin B nonapeptide, tested its in vivo toxicity in animals, and evaluated its in vitro antiendotoxin activity. Effectiveness as an antiendotoxin agent was assessed by examining the ability of polymyxin B nonapeptide to block the enhanced release of toxic oxygen radicals induced by lipopolysaccharide in human neutrophils (priming). In vivo, at doses of 1.5 and 3.0 mg/kg, polymyxin B nonapeptide did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were observed with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concentration-dependent manner, but the parent compound, polymyxin B, was 63 times more effective on a weight basis. The inhibitory activity of both compounds, however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. We conclude that polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compound. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. The findings suggest that these compounds block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.
 ...
PMID:Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide. 255 95

Polymyxin B (PMB), an antibiotic, and sodium deoxycholate (NaD), a bile salt, are surface-active agents. Each protected mice against an otherwise lethal challenge with purified endotoxin (P less than .001). To determine if either of these agents was effective in treating established, overwhelming gram-negative septicemia, we infected rabbits by intraperitoneal injection of Escherichia coli K1. Animals were treated with moxalactam 1 hr after infection, then randomly assigned to groups receiving either saline, PMB, or NaD. Serial samples of blood were assayed for bacterial concentration, levels of plasma endotoxin, arterial blood gases, and complete blood cell counts. Physiologic functions were monitored continuously. Although levels of bacteremia and endotoxemia were similar in all three groups, rabbits receiving PMB had significantly higher mean arterial blood pressure, blood pH, and bicarbonate concentrations than did control rabbits (P less than .05). Rabbits receiving NaD fared no better than controls. In this model, PMB moderates some of the deleterious effects of established, overwhelming gram-negative bacterial sepsis.
 ...
PMID:Polymyxin B moderates acidosis and hypotension in established, experimental gram-negative septicemia. 282 Nov 23

The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production in whole blood ex vivo after exposure of log-phase Escherichia coli to antibiotics belonging to different classes, in a final concentration of 0.5, 5, or 50 times the MIC. After 4 h of incubation at 50 times the MIC, ceftazidime and ciprofloxacin treatment resulted in levels of endotoxin, TNF-alpha, and interleukin-6 significantly higher than those of imipenem and gentamicin (P < 0.001). Similar differences in cytokine induction were measured after 8 h of incubation. At 0.5 times the MIC, the differences between the antibiotics in measured endotoxin and cytokine levels were small, with levels comparable to the levels in untreated cultures. Polymyxin B and, to a lesser degree, recombinant bactericidal/permeability-increasing protein 21 (rBPI-21) were found to be potent inhibitors of TNF-alpha release, supporting the concept that the differences between the antibiotics in cytokine production were indeed due to differences in amounts of biologically active endotoxin. The presence of serum from patients suffering from untreated sepsis decreased TNF-alpha production significantly, in a concentration-dependent manner.
 ...
PMID:Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum. 776 3

The authors evaluated the efficacy of treatment by extracorporeal perfusion on experimental canine septic shock. Canine septic shock was produced by intravenous infusion of Escherichia coli endotoxin and treated by three techniques: no treatment (Sham), hemoperfusion over Polymyxin B immobilized fiber (PMX), and plasma perfusion over anion exchange resin (Resin). The 24 hr survival rates of the Sham, PMX, and Resin groups were 0%, 80%, and 40%, respectively. In the PMX group, blood pressure was significantly better over 6 hr than that recorded in the Sham group. In the PMX group, phagocytic function evaluated by neutrophil function, opsonic index, and complement were better than that of the Sham group. In addition, blood endotoxin levels in the PMX group were significantly lower, resulting in a significant suppression of TNF release. In the Resin group, some parameters were significantly better than those of the Sham group, but the efficacy of this treatment was less than that of the PMX treatment. Hemoperfusion over Polymyxin B immobilized fibers can detoxify circulatory endotoxin, resulting in improvement of systemic and organic disorders caused by sepsis.
 ...
PMID:Experimental study of extracorporeal perfusion for septic shock. 826 46

The lipopolysaccharide endotoxin is the most powerful immune stimulant known and a causative agent in the clinical syndrome known as sepsis. Sepsis is responsible for more than 100,000 deaths annually, in large part due to the lack of a rapid, reliable, and sensitive diagnostic technique. This study describes the detection of LPS from E. coli at concentrations as low as 10 ng/mL, in 30 s using an evanescent wave fiber-optic biosensor. Polymyxin B, covalently immobilized onto the surface of the fiber-optic probe, selectively bound fluorescently labeled LPS. Unlabeled LPS was detected in a competitive assay format using labeled LPS for signal generation. The competitive assay format worked in both buffer and plasma with similar sensitivities. This method can be used with other LPS capture molecules such as antibodies, lectins, or antibiotics, to simultaneously detect LPS and to determine the LPS serotype. The LPS assay using the fiber-optic biosensor is applicable to both clinical and environmental testing.
 ...
PMID:Detection of endotoxin using an evanescent wave fiber-optic biosensor. 893 15

Polymyxin B (PMB) is a cyclic decapeptide antibiotic which also binds and neutralizes endotoxin. Unfortunately, PMB can be considerably nephrotoxic at clinically utilized doses, thereby limiting its utility as a therapeutic antiendotoxin reagent. We sought to change the pharmacokinetics and toxicity profile of PMB by covalently linking it to a human immunoglobulin G (IgG) carrier. Conjugates of PMB with IgG were prepared by EDAC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide]-mediated amide formation. Analysis by dot enzyme-linked immunosorbent assay with an anti-PMB monoclonal antibody showed that the purified conjugate contained bound PMB. The IgG-PMB conjugate reacted with lipid A and J5 lipopolysaccharide in Western blot assays in a manner comparable to that of whole antiserum with anti-lipid A reactivity; unconjugated IgG had no reactivity. The PMB bound in the conjugate retained its endotoxin-neutralizing activity compared to that of unbound PMB as evidenced by its dose-dependent inhibition of tumor necrosis factor release by endotoxin-stimulated human monocytes in vitro; unconjugated IgG had no activity. By this assay, the PMB-IgG conjugate was determined to have approximately 3.0 microg of bound functional PMB per 100 microg of total protein of conjugate (five molecules of PMB per IgG molecule). The PMB-IgG conjugate was also bactericidal against clinical strains of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae relative to unconjugated IgG with MBCs of <4 microg of conjugate per ml for each of the tested strains. The conjugate appeared to be nontoxic at the highest doses deliverable and provided statistically significant protection from death to galactosamine-sensitized, lipopolysaccharide-challenged mice in a dose-dependent fashion when administered prophylactically 2 h before challenge. However, neither free PMB nor the PMB-IgG conjugate could protect mice challenged with endotoxin 2 h after administration. This suggests that these reagents can play a role in prophylaxis but not in therapy of sepsis. These experiments demonstrated that the PMB-IgG conjugate retains bound yet functional PMB as evidenced by its endotoxin-neutralizing activity both in vitro and in vivo. Further work is required to define the role that this or related conjugate compounds may play in the prophylaxis of endotoxin-mediated disease.
 ...
PMID:Covalent polymyxin B conjugate with human immunoglobulin G as an antiendotoxin reagent. 951 36

Sepsis, septic shock, and multiple organ dysfunction are heterogeneous and sophisticated clinical syndromes which result from the interplay of mediators of cellular function and inflammation. Secondary mediators such as lipids (prostaglandin, thromboxane, platelet-activating factor), peptides (bradykinin, vasoactive intestinal peptide), amines (histamine, serotonin) and complements are key mediators which lead to the state of shock in human sepsis. Endotoxin may also cause multiple organ dysfunction syndrome (MODS). New antiendotoxin treatment and the strategy for sepsis including endotoxemia are reviewed. Monoclonal antibodies directed at core epitopes and lipid A (E5, HA1-A) could not reproduce the beneficial effects. Bactericidal/permeability increasing protein (BPI)). Endotoxin neutralizing protein (ENP)) and E5531 may have potential in the treatment of sepsis. Another treatment using extracorporeal endotoxin removal is reported. Polymyxin B immobilized fiber (PMX), commercialized as Toraymyxin, is now widely used in Japan for severe sepsis and septic MODS. PMX treatment improves the symptoms related to the septic state, a hemodynamic disorders, and cytokine levels including tumor mecrosis factor, interleukin (IL)-6, and IL-10, with a decrease in endotoxin levels. Phase II, III, and IV clinical trials with extracorporeal endotoxin removal by PMX revealed that endotoxin removal is helpful in the treatment of septic patients.
 ...
PMID:[Sepsis and organ failure--its pathogenesis and treatment]. 978 88

Polymyxin B (PMB), a cyclic cationic peptide antibiotic, despite its severe side effects continues to occupy a premiere position for treating endotoxicosis. Its mode of neutralization of endotoxin has remained elusive for the last three decades. Several synthetic peptide mimics of PMB, capable of binding endotoxin, have been made. However, the binding ability alone appears to be a deceptive indicator of endotoxin neutralizing activity as molecules with similar binding propensities could either sequester or opsonize the toxin. Hence identification of additional physical parameters which describe adequately the outcome of PMB-endotoxin interaction become imperative. Surface plasmon resonance (SPR) studies reported here show that several mimics of PMB despite exhibiting lipopolysaccharide binding affinities comparable with it but, unlike it, do not sequester the endotoxin. These studies thus provide a striking illustration of the difference in the behavior of PMB, vis a vis its mimics toward the endotoxin lamellae, and define further, in chemical terms, mechanism of the action of PMB and allow us to posit that the design of molecules as effective antidotes for sepsis should incorporate the ability to sequester endotoxin specifically.
 ...
PMID:Surface plasmon resonance studies resolve the enigmatic endotoxin neutralizing activity of polymyxin B. 1051 30

Lipopolysaccharides (LPS) are proinflammatory bacterial products implicated in the pathogenesis of gram-negative sepsis and septic shock. Polymyxin B (PMB), a cyclic, cationic peptide antibiotic, inhibits biological activities of LPS through high-affinity binding to the lipid A moiety. Small synthetic peptides have been designed to mimic the primary and secondary structures of PMB to determine structural requirements for binding and detoxification of lipid A and to assess possible therapeutic potential. The purpose of this study was to compare and contrast the endotoxin-neutralizing activities of two synthetic antiendotoxin peptides (SAEP-2 and SAEP-4), PMB, and an LPS core-specific monoclonal antibody (MAb), WN1 222-5, based on their abilities to inhibit CD14-mediated target cell uptake of fluorescein isothiocyanate (FITC)-conjugated LPS, detected by flow cytometry and confocal microscopy, and LPS-induced production of the proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), as measured by bioassays. PMB and SAEP-4 produced dose-dependent inhibition of FITC-LPS uptake by CD14-transfected Chinese hamster ovary fibroblasts (CHO-CD14 cells) and by human peripheral blood mononuclear cells. The anti-LPS MAb, WN1 222-5, also blocked LPS uptake by these cells and synergized with PMB and SAEP-4. LPS-induced IL-6 release was inhibited by PMB, SAEP-4, and MAb WN1 222-5, and these inhibitory activities were additive or synergistic. LPS-induced TNF-alpha release by PBMC was also inhibited by PMB and SAEP-4 alone and in combination with anti-LPS MAb. SAEP-2, in contrast, produced comparatively minor decrements in cellular uptake of LPS and LPS-induced cytokine responses, and did so only in the absence of serum, while a nonsense peptide exerted no discernible inhibitory effect on LPS uptake or LPS-induced cytokine expression in the presence or absence of serum. Thus, PMB and SAEP-4, like the LPS-reactive MAb, WN1 222-5, block proinflammatory activities of LPS in part by preventing LPS recognition by membrane-bound CD14-expressing target cells. Differences in peptide structure, however, like those exemplified by SAEP-2 and SAEP-4, may differentially affect the endotoxin-neutralizing potency of these peptides despite similar binding activity against lipid A, reflecting possible differences in peptide solubility or peptide regulation of intracellular signal transduction.
 ...
PMID:Influence of synthetic antiendotoxin peptides on lipopolysaccharide (LPS) recognition and LPS-induced proinflammatory cytokine responses by cells expressing membrane-bound CD14. 1067 85

Lipid A is the causative agent of Gram-negative sepsis, a leading cause of mortality among hospitalized patients. Compounds that bind lipid A can limit its detrimental effects. Polymyxin B, a cationic peptide antibiotic, is one of the simplest molecules capable of selectively binding lipid A and may serve as a model for further development of lipid A binding agents. However, association of polymyxin B with lipid A is not fully understood, primarily due to the low solubility of lipid A in water and inhomogeneity of lipid A preparations. To better understand lipid A-polymyxin B interaction, pure lipid A derivatives were prepared with incrementally varied lipid chain lengths. These compounds proved to be more soluble in water than lipid A, with higher aggregation concentrations. Isothermal titration calorimetric studies of these lipid A derivatives with polymyxin B and polymyxin B nonapeptide indicate that binding stoichiometries (peptide to lipid A derivative) are less than 1 and that affinities of these binding partners correlate with the aggregation states of the lipid A derivatives. These studies also suggest that cooperative ionic interactions dominate association of polymyxin B and polymyxin B nonapeptide with lipid A.
 ...
PMID:Synthesis of lipid A derivatives and their interactions with polymyxin B and polymyxin B nonapeptide. 1260 30


1 2 3 4 Next >>