Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long periods in space may expose astronauts to the potentially harmful effects of ionizing radiation. We have used a primate model to evaluate any role of lipopolysaccharide (LPS, endotoxin) in radiation sickness. Vervet monkeys, which had been whole-body 60Co irradiated with an LD100 exposure, had periodic blood samples taken for the determination of LPS, anti-LPS IgG antibodies and bacteriological studies. On day 2 post-irradiation, primates were treated i.m. with either sterile 0.9% saline, or equine anti-LPS hyperimmune plasma (Anti-LPS), or orally with tripotassium-dicitrato-bismuthate ("Denol"). Gram positive bacteria were evident in blood samples of all animals as early as 2 d post-irradiation. Gram negative bacteria were found in the blood of saline- and Denol-treated primates by days 5 and 8, respectively, but first appeared on day 13 in the anti-LPS-treated animals. The saline controls and Denol-treated animals showed insignificant rises in plasma LPS on day 3, which increased further thereafter achieving significance on day 8 (p less than 0.01). These elevated levels persisted until death. However, in anti-LPS-treated monkeys, LPS concentrations remained below baseline until day 9, after which they rose significantly until death, but, were significantly less than the concentrations in both other groups (p less than 0.001). The anti-LPS-treated animals survived significantly longer than both the other groups (p less than 0.005). Since LPS may cause nausea, vomiting, diarrhea, anorexia and headaches, Anti-LPS administration may be of value in reducing plasma LPS concentration in humans and improving their performance and survivability.
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PMID:Anti-LPS antibodies reduce endotoxemia in whole body 60Co irradiated primates: a preliminary report. 224 44

Endotoxins (lipopolysaccharides, LPS) are potent bacterial poisons always present within the intestines in considerable amounts. Several pathophysiological conditions such as hypovolaemia, hypoxia, intestinal ischaemia, burns and radiation lead to a breakdown in the barrier and depending upon the extent of the injury, endotoxins enter the systemic circulation in increasing amounts. Antibiotics do not inactivate the endotoxins which continue to exert their toxic effects leading to nausea, vomiting, diarrhoea, fever, disseminated intravascular coagulation, vascular collapse and organ failure. When nonabsorbable antibiotics are given prior to the insult, systemic endotoxaemia is prevented. Immunotherapy, using anti-lipopolysaccharide IgG, inactivates plasma endotoxins, destroys gram-negative bacteria and opsonises them and may become a major form of therapy. An outline of endotoxin and anti-lipopolysaccharide and its importance to the anaesthetist and intensive care specialist is presented.
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PMID:Endotoxins and anti-endotoxins (their relevance to the anaesthetist and the intensive care specialist). 265 93

Endotoxemia occurs when intestinal ischemia allows bacterial lipopolysaccharide to translocate from colonic flora into the bloodstream, which triggers release of cytokines that can cause hypotension, rigors, fever, shock, and even death. Recently, blood endotoxin levels were shown to be higher in athletes needing medical attention (330 pg.ml-1) than in their competitors with similar performances (81 pg.ml-1). Though there were no data showing that these athletes had elevated core temperatures or severe illness, speculation followed that endotoxin may play a causal role in heat stroke. We examined the relationship between endotoxemia and mild post-exertional illness in 39 cyclists after a 100-mile ride. Thirteen cyclists had at least one of the following: orthostatic hypotension, rigors, nausea, vomiting, diarrhea, or syncope. Only 2/26 case-controls had any of these symptoms. Data were collected on vital signs, hemoglobin, sodium, creatine kinase, creatinine, and uric acid. Endotoxin titer was determined by chromogenic assay; tumor necrosis factor alpha (TNF-alpha) titer was determined by ELISA. One ill cyclist had an endotoxin level of 330 pg.ml-1, one control had an endotoxin level of 150 pg.ml-1, but endotoxin level was < or = 64 pg.ml-1 in all others. Comparison of pre- and post-ride data showed that controls increased creatine kinase activity (154 +/- 34 vs 561 +/- 191 IU.dl, P < 0.05), creatinine concentration (1.5 +/- 0.0 vs 1.6 +/- 0.0 mg.dl-1, P < 0.05), and uric acid concentration (5.4 +/- 0.3 vs 6.3 +/- 0.3 mg.dl-1, P < 0.05). Ill cyclists had lower serum sodium than post-ride controls (138 +/- 2 vs 142 +/- 0.6 mEq.l-1, P < 0.05), but there were no differences between groups in CK, creatinine, or uric acid. These findings suggest that endotoxemia may complicate, but does not cause mild post-exertional illness in cyclists.
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PMID:Exercise-associated collapse in cyclists is unrelated to endotoxemia. 853 21

Natural killer (NK) cells may be expanded in vivo with a prolonged course of daily subcutaneous interleukin-2 (IL-2). However, cellular activation requires higher concentrations of IL-2 than are achieved with low-dose therapy. The objective of the current trial was to determine the toxicity and immunological effects of periodic subcutaneous intermediate-dose IL-2 pulses in patients receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL-2 at 1.25 x 10(6) International Units (1.25 MIU) m(-2) day(-1). After 4-6 weeks, patients received escalating 3-day intermediate-dose IL-2 pulses administered as single daily subcutaneous injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m(-2) day(-1), with transient hypotension, fatigue, and nausea/vomiting dose-limiting. Subcutaneous IL-2 resulted in in vivo expansion of CD56+ NK cells (796+/-210%) and CD56bright natural killer (NK) cells (3247+/-1382%). Expanded NK cells coexpressed CD16, and showed lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrations above 100 pM. Cellular activation was suggested by rapid margination of NK cells following pulsing, coincident with peak IL-2 levels, with return to baseline by 24 h. In.addition, interferon gamma production in response to lipopolysaccharide was augmented. Subcutaneous daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outpatient regimen that results in in vivo expansion and potential activation of NK cells, with possible application in the treatment of malignancy and immunodeficiency.
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PMID:Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing. 975 16

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.
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PMID:Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. 1069 May 16

Our previous studies suggested that the cytokine tumor necrosis factor-alpha (TNF-alpha) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function, such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF-alpha is capable of affecting gastric function via the DVC circuitry has been impeded by the lack of an antagonist for TNF-alpha. The present studies used localized central nervous system applications of the TNF-adsorbant construct (TNFR:Fc; TNF-receptor linked to the Fc portion of the human immunoglobulin IgG1) to attempt to neutralize the suppressive effects of endogenously produced TNF-alpha. Gastric motility of thiobutabarbital-anesthetized rats was monitored after systemic administration of lipopolysaccharide (LPS) to induce TNF-alpha production. Continuous perfusion of the floor of the fourth ventricle with TNFR:Fc reversed the potent gastroinhibition induced by LPS, i.e., central thyrotropin-releasing hormone-induced increases in motility were not inhibited. This disinhibition of gastric stasis was not seen after intravenous administration of similar doses of TNFR:Fc nor ventricular application of the Fc fragment of human immunoglobulin. These results validate our previous studies that suggest that circulating TNF-alpha may act directly within the DVC to affect gastric function in a variety of pathophysiological states.
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PMID:LPS-induced suppression of gastric motility relieved by TNFR:Fc construct in dorsal vagal complex. 1218 Nov 77

CD10, also known as neutral endopeptidase or CALLA, is a major metalloproteinase that regulates levels of biologically active peptides that initiate inflammatory, cardiovascular, and neurogenic responses. Relative tissue expression levels of CD10, its peptide substrates, and their receptors constitute the basic regulatory mechanism. Neutrophils contain abundant CD10 and are rapid responders to an inflammatory septic challenge. Expression of neutrophil surface antigens in response to inflammation was studied in the primate model of Escherichia coli-mediated sepsis and in human volunteers injected with lipopolysaccharide (LPS). There was a rapid and profound (up to 95%) reduced baboon neutrophil CD10 expression in response to E. coli injections of 5.71 x 106 CFU/kg to 2.45 x 109 CFU/kg that gradually resolved to preinjection levels. The reduction was both dose and time dependent. Reduced CD10 antigen on mature baboon neutrophils and bands was observed by immunohistochemistry. Human volunteers challenged with 4ng/kg LPS experienced transient chills, nausea, fever, and myalgia. Up to approximately 20% of their neutrophils had reduced CD10 expression, peaking at 2 to 8 h after injection. By 24 h, neutrophil CD10 expression resolved to preinjection levels. In contrast, in both the baboon and human studies, other neutrophil surface antigens were only slightly decreased (CD11a) or increased (CD11b, CD18, CD35, CD66b, and CD63). These data present the novel observation that neutrophil CD10 expression decreases significantly in response to in vivo inflammatory challenge. This decrease appears to be unique to CD10 and may contribute to a reduced regulation of bioactive peptides released in response to inflammatory challenge.
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PMID:Reduced neutrophil CD10 expression in nonhuman primates and humans after in vivo challenge with E. coli or lipopolysaccharide. 1286 56

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.
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PMID:The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. 1678 Aug 33

The effects of systemic treatment with lipopolysaccharide (LPS) on conditioned gaping in a rodent model of anticipatory nausea were examined. Stimulation of the immune system has been found to enhance, impair, or have no effect on various learning and memory tasks. The development of anticipatory nausea is formed through a classically conditioned response to a context that has been paired previously with toxin-induced nausea and/or vomiting. Rats display a distinctive conditioned gaping response when injected with a nausea-inducing drug such as LiCl. In the present study, male Long-Evans rats were injected intraperitoneally with LPS (200microg/kg) or saline (NaCl) followed 90min later by an injection of the toxin LiCl or saline before being placed in a distinctive context on four conditioning days (72h apart). On the condition test day, rats (n=6/group) were placed in the distinctive context in a drug-free state and behavioral responses were videotaped. Rats given LPS followed by LiCl were found to have significantly fewer gaping responses when compared to rats given NaCl followed by LiCl. All groups were also found to have similar levels of spontaneous ingestive behaviors suggesting that the decrease in gaping was not due to motor impairment. The present results suggest that activation of the immune system with LPS administration significantly impairs the acquisition of anticipatory nausea.
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PMID:Lipopolysaccharide (LPS) blocks the acquisition of LiCl-induced gaping in a rodent model of anticipatory nausea. 1905 65

Clinical utility of phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory agents has, to date, been limited by adverse effects including nausea and emesis, making accurate assessment of emetic versus anti-inflammatory potencies critical to the development of inhibitors with improved therapeutic indices. In the present study we determined the in vitro and in vivo anti-inflammatory potencies of the first-generation PDE4 inhibitor, rolipram, the second-generation inhibitors, roflumilast and cilomilast, and a novel third generation inhibitor, 1-ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1). The rank-order potency against lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha production by human peripheral blood mononuclear cells was roflumilast (IC(50) = 5 nM) > EPPA-1 (38) > rolipram (269) > cilomilast (389), and against LPS-induced pulmonary neutrophilia in the rat was EPPA-1 (D(50) = 0.042 mg/kg) > roflumilast (0.24) > rolipram (3.34) > cilomilast (4.54). Pica, the consumption of non-nutritive substances in response to gastrointestinal stress, was used as a surrogate measure for emesis, giving a rank-order potency of rolipram (D(50) = 0.495 mg/kg) > roflumilast (1.6) > cilomilast (6.4) > EPPA-1 (24.3). The low and high emetogenic activities of EPPA-1 and rolipram, respectively, detected in the pica model were confirmed in a second surrogate model of emesis, reversal of alpha(2)-adrenoceptor-mediated anesthesia in the mouse. The rank order of therapeutic indices derived in the rat [(pica D(50))/(neutrophilia D(50))] was EPPA-1 (578) > roflumilast (6.4) > cilomilast (1.4) > rolipram (0.15), consistent with the rank order derived in the ferret [(emesis D(50))/(neutrophilia D(50))]. These data validate rat pica feeding as a surrogate for PDE4 inhibitor-induced emesis in higher species, and identify EPPA-1 as a novel PDE4 inhibitor with an improved therapeutic index.
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PMID:The identification of a novel phosphodiesterase 4 inhibitor, 1-ethyl-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1), with improved therapeutic index using pica feeding in rats as a measure of emetogenicity. 1949 3


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