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PubMed1983

Effect of naloxone treatment on the cardiopulmonary response to endotoxin in sheep.

The administration of small dosages of endotoxin to sheep results in cardiopulmonary changes characterized by an elevation in pulmonary lymph flow, vascular resistance, and hemoconcentration, and a reduction in cardiac output. These changes are not as great when the narcotic antagonist, naloxone (2 mg/kg/h for 5 h), is infused prior to and during the endotoxin response. The present study evaluates the ovine response to endotoxin when naloxone is administered 1 h after the endotoxin infusion. Sheep were prepared by implanting cardiopulmonary and lung lymphatic catheters. One week following the last surgical procedure, the sheep, in the awake state, were given 0.75 micrograms/kg of endotoxin and the variables were measured. Three days later, a second dose of endotoxin was administered and variables were again measured. An infusion of naloxone was given with one of the dosages of lipopolysaccharide. Two dosages of the narcotic antagonist were used. One group received 2 mg/kg bolus + 2 mg/kg/h for 5 h; another group was given twice this amount. Both dosages were started 1 h after endotoxin. The response to endotoxin was essentially the same whether or not the sheep were treated with naloxone. If naloxone pretreatment is effective and posttreatment is not, then it is possible that an opiatelike substance might be released by endotoxin which in turn results in the ultimate release of the lesion-producing substance.

Animals↗
PubMed1982

Thromboxane, prostaglandin I2 (epoprostenol), and the hemodynamic changes in equine endotoxin shock.

This study had 2 objectives: (i) to correlate plasma thromboxane and prostaglandin I2 (epoprostenol) concentrations with hemodynamic changes occurring in equine endotoxin shock, and (ii) to determine the effects of flunixin meglumine on plasma concentrations of these prostaglandins relative to hemodynamic changes. Shock was induced in 2 groups, each of 4 anesthetized ponies, and in a 3rd group of 2 ponies. Group A ponies were given endotoxin only (and were not treated), and group B ponies were given endotoxin and then treated with flunixin meglumine. Group C ponies were treated with flunixin meglumine 5 minutes before they were fiven endotoxin. Arterial, pulmonary arterial, and central venous pressures were measured and blood samples were collected at 0, 0.1, 0.25, 0.5, 1, 1, 3, and 4 hours after ponies were given the endotoxin. The plasma thromboxane and prostaglandin I2 concentrations were increased in equine endotoxic shock. Increased thromboxane concentration was associated with the high pulmonary arterial and central venous pressures and low arterial blood pressure in the minutes immediately after the ponies were given endotoxin. The increased prostaglandin I2 concentration was associated with systemic hypotension at 1 to 2 hours after endotoxin. Treatment of ponies with flunixin meglumine after endotoxin was given (group B) prevented the prostaglandin I2 rise and the associated hypotension. Treatment with fluixin meglumine before endotoxin was given prevented the increase of the plasma thromboxane and prostaglandin I2 values, along with the associated hemodynamic changes.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Immunochemical localization of inducible nitric oxide synthase in endotoxin-treated rats.

BACKGROUND: Administration of endotoxin to rodents produces widespread tissue induction of nitric oxide synthase (NOS). To understand the mechanisms of the resulting endotoxin shock, it is important to know the cellular distribution of the inducible NOS (iNOS). EXPERIMENTAL DESIGN: We have investigated the localization and time course of expression of iNOS in rats at time 0 (control) and 3, 6, 9, and 24 hours after administration of endotoxin and also in endotoxin- and cytokine-stimulated RAW 264 murine macrophage and A7r5 aortic smooth muscle cells. We have used a rabbit antiserum to a synthetic peptide selected from the deduced sequence of the cloned macrophage enzyme (residues 47-71) and immunochemical techniques. RESULTS: The antiserum reacted with an approximately 130-kilodalton protein (the molecular weight of iNOS) in Western blots of total cytoplasmic proteins from livers of endotoxin-treated rats, RAW 264 murine macrophages stimulated with endotoxin and combinations of cytokines, and purified liver iNOS, but not in control, untreated tissues. Strong cytoplasmic immunostaining was seen in RAW 264 murine macrophages and A7r5 rat aortic smooth muscle cells after stimulation, but not in nonstimulated cells. Three hours after endotoxin treatment in rats, iNOS immunoreactivity was detectable in many tissues and was at its strongest at 6 and 9 hours after stimulation. Staining was detected predominantly in macrophages distributed abundantly in heart, lung, liver, and kidney. It was also present in Kupffer cells and hepatocytes, biliary epithelium, mesangial cells, airway epithelium, and nerves supplying mesenteric blood vessels but was not detected in any vasculature. By 24 hours there was a reduction in the number of cells stained compared with that seen at 6 and 9 hours. In addition, at 24 hours after endotoxin treatment, granulomatous lesions showing iNOS staining were evident, particularly in the liver. CONCLUSIONS: Antiserum raised to macrophage NOS recognizes an inducible enzyme in a wide variety of cells. Macrophages are the major site of iNOS expression in endotoxin-treated rats and show greatest staining between 6 and 9 hours after treatment. Although staining was not seen in vascular cells in vivo, levels of the enzyme that are below the immunocytochemistry detection limit cannot be excluded.

Amino Acid Oxidoreductases↗
PubMed1988

Induction of hypermetabolism in guinea pigs by endotoxin infused through the portal vein.

Endotoxin has been suspected of inducing hypermetabolism in animals. To delineate its mechanism more precisely, three experiments were performed using male Hartley guinea pigs that involved intermittent or continuous administration of endotoxin intraperitoneally for seven days and continuous infusion of low-dose endotoxin through the portal vein for five days. The doses of endotoxin were 0.3 mg, 0.36 mg, and 0.014 mg per 100 g of body weight per day, respectively. Hypermetabolic response was induced only in the experiment involving the infusion of endotoxin through the portal vein; the hypermetabolic response was correlated significantly with endotoxin levels in the plasma. These results indicate that endotoxin translocated from the gut into the mesenteric vein will induce hypermetabolism more readily than endotoxin translocated into the peritoneal cavity.

Animals↗
PubMed1996

Neutrophils are required for endotoxin-induced myocardial cross-tolerance to ischemia-reperfusion injury.

BACKGROUND: Although polymorphonuclear neutrophilic leukocytes (PMNs) contribute to oxidative stress after endotoxemia, it is unknown whether preischemic PMN induction is required for endotoxin-mediated myocardial resistance to ischemia-reperfusion (I/R). OBJECTIVE: To determine whether neutrophils mediate endotoxin-induced myocardial cross-tolerance to I/R. DESIGN AND INTERVENTIONS: Rats received sublethal endotoxin (0.5 mg/kg intraperitoneally) with and without rabbit anti-rat PMN antibody (anti-PMN antibody, 0.15 mL intravenously, to achieve an absolute neutrophil count of < 200/microL) or antibody alone, 24 hours prior to global myocardial I/R (20-40 minutes, Langendorff mode). SETTING: The University of Colorado Surgical Research Laboratories, Denver. MAIN OUTCOME MEASURES: Myocardial developed pressure, coronary flow, end diastolic pressure, and time to ischemic contracture were recorded with a pressure amplifier-digitizer (MacLab, AD Instruments Inc, Milford, Mass). Myocyte damage was assessed by determining creatine kinase leakage in the coronary flow effluent by creatine kinase assay. RESULTS: Sublethal endotoxin induced cross-tolerance to I/R, as demonstrated by improved recovered developed pressure and coronary flow, and decreased time to ischemic contracture, end diastolic pressure, and creatine kinase leak (P < .05, analysis of variance and Bonferroni-Dunn). Anti-PMN antibody administered prior to sublethal endotoxin abolished these protective effects (P < .05). Polymorphonuclear neutrophil leukocyte depletion alone failed to abrogate the deleterious effects of I/R. CONCLUSIONS: (1) Sublethal endotoxin induces myocardial cross-tolerance to I/R; (2) PMN induction is required for endotoxin-mediated myocardial resistance to I/R; and (3) while myocardial I/R injury is equally severe after antibody-mediated PMN depletion, endotoxin-induced tolerance to I/R does not occur in the neutropenic host.

Animals↗
PubMed1996

Early signaling events by endotoxin in PC12 cells: involvement of tyrosine kinase, constitutive nitric oxide synthase, cGMP-dependent protein kinase, and Ca2+ channels.

We studied the effects of endotoxin from Escherichia coli (E. coli) on Ca2+ channel activity in PC12 cells using the cell-attached patch clamp technique. Endotoxin (1-100 ng/ml) decreased channel availability (n x Po) to about one third of control values, an effect that required 3.5 +/- 1 min (mean +/- SD; n = 13) to reach steady state. The biophysical properties of the channel, including slope conductance (22 pS; 40 mM Ba2+), voltage dependence of n x Po, and open times (tau 1 = 0.78 ms, tau 2 = 8.9 ms) for the two open states at 0 mV, were not altered. The effect of endotoxin was blocked by polymyxin-B, indicating involvement of the lipid-A moiety of lipopolysaccharide, and by the tyrosine kinase (tk) inhibitor, tyrphostin. The effect of endotoxin was mimicked by 8-bromo-cGMP (100 microM), and was blocked by the inhibitor of cGMP-dependent protein kinase (PKG), H-8, suggesting involvement of the cGMP/PKG pathway. The effect of endotoxin also was blocked by the nitric oxide (NO) synthase inhibitor, NG-monomethyl-L-arginine monoacetate, suggesting involvement of nitric oxide synthase (NOS). The rapidity of the effect of endotoxin on Ca2+ channel activity suggested that constitutive NOS (cNOS) was involved, in accordance with our finding that endotoxin-induced transcriptional induction of NOS, as measured by nitrite production, required > 6 hr. We conclude that early signaling events by endotoxin in PC12 cells involve tk, cNOS, cGMP/PKG, and Ca2+ channels.

Animals↗
PubMed1981

Effect of endotoxin on arachidonic acid release and thromboxane B2 production by human platelets.

Plasma thromboxane A2, which is elevated during endotoxemia, has previously been shown to be a major factor contributing to the mortality and morbidity that occurs in endotoxin shock in the experimental animal. Using a minimal dose of Escherichia coli endotoxin (1 microgram/ml), we have demonstrated that the preincubation of human platelets with endotoxin induces changes in platelet arachidonic acid release and the subsequent conversion of the released arachidonic acid to thromboxane B2, and stable end product of thromboxane A2. In paired experiments, in the presence of endotoxin, the addition of the aggregating agent thrombin (0.5 U/ml) caused human platelets to release 29.1 +/- 3.4% of 14C-arachidonic acid from prelabeled platelet phospholipids. This value was significantly elevated (p less than 0.02) when compared with the release of 14C-arachidonic acid from platelets in the absence of endotoxin (21.9 +/- 3.6%). Similarly, comparison of the results of the conversion of the released arachidonic acid to platelet thromboxane B2 (TxB2) revealed that TxB2 production was significantly increased (P less than 0.01) when human platelets were preincubated with endotoxin prior to the addition of thrombin (6.1 +/- 0.6%) when compared with TxB2 formation observed in the absence of endotoxin (3.4 +/- 0.5%). The absolute amount of released arachidonic acid that was converted to TxB2 in the presence of endotoxin (1.8 +/- 0.3%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%) was also significantly higher (P less than 0.01) than the value observed in its absence (0.8 +/- 0.2%). This study suggests that one of the tissue sources of the proaggregatory vasoconstrictor thromboxane A2 during endotoxemia is the platelet.

Arachidonic Acids↗
PubMed1990

Presence of endotoxins in different agricultural environments.

Gram-negative bacterial endotoxins are contaminants of dusts from agricultural products. They represent a potential health hazard for farmers working in many different processes. However, the occurrence of endotoxins has not been well characterized in the various farming operations. Therefore, two farming activities with potential for generating airborne endotoxins were studied: 1) chopping of baled corn stalks or straw for bedding in New York State, and 2) oat bin unloading in Alabama. Actual airborne endotoxin levels in dusts obtained during bedding chopper operations far exceeded [90 endotoxin units (EU)/m3] the level at which acute pulmonary function decrements occur in cotton dust-exposed individuals. Endotoxin contamination of laboratory-generated dust from an oat sample likewise exceeded these levels. This study documents the presence of potentially hazardous exposures to endotoxins in two common farm processes, which expands the knowledge of airborne endotoxin exposures on the farm.

Agriculture↗
PubMed1989

Effect of repetitive low-dose endotoxin on liver parenchymal and Kupffer cell fibronectin release.

Repetitive low-dose endotoxin, at a dose which will result in endotoxin tolerance, produces a marked but transient 2- to 3-day increase in plasma fibronectin. This elevation of fibronectin appears to contribute to increased hepatic Kupffer cell phagocytic function observed with repetitive low-dose endotoxin administration. Although numerous cell types synthesize fibronectin, hepatocytes are believed to be the major cell source of fibronectin in the plasma. Since Kupffer cells also synthesize fibronectin, we sought to determine the relative contribution of hepatic Kupffer cells, as compared to parenchymal cells, to the elevation of plasma fibronectin following repetitive low-dose endotoxin administration. Kupffer cells isolated from rats previously treated for 3 consecutive days with 100 micrograms Salmonella enteritidis endotoxin released greater (p less than 0.01) amounts of fibronectin over time in culture (3, 6, 12 and 24 hr) as compared to Kupffer cells isolated from normal rats. Experiments in which fibronectin was normalized to DNA content of the cells in culture also showed similar results for fibronectin release by Kupffer cells (normal: 2.9 +/- 0.5 ng per microgram DNA per 24 hr; endotoxin-treated: 53.3 +/- 1.3 ng per microgram DNA per 24 hr). Hepatocytes from endotoxin-treated rats released less (p less than 0.01) fibronectin over time than hepatocytes isolated from normal animals. As with Kupffer cells, results for fibronectin release by hepatocytes were similar when normalized to the DNA content (normal: 190.0 +/- 9.4 ng per microgram DNA per 24 hr; endotoxin-treated: 83.3 +/- 4.2 ng per microgram DNA per 24 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Endotoxin contamination in wound dressings made of natural biomaterials.

Contamination by endotoxin of nine kinds of wound dressings made of natural biomaterials (calcium alginate, collagen, chitin, and poly-L-leucine) was examined with the use of water extracts. By applying the Limulus amoebocyte lysate (LAL) test, high concentrations of endotoxin were detected in extracts from three kinds of products made of calcium alginate. These extracts evoked fever in rabbits and induced the release of a proinflammatory (pyrogenic) cytokine, interleukin-6 (IL-6), from human monocytic cells (MM6-CA8). The effects disappeared when the extracts were treated with endotoxin-removing gel column chromatography or with an endotoxin antagonist, B464, confirming that the contaminating pyrogen was endotoxin. A noteworthy finding was that one of the endotoxin-containing extracts showed very weak IL-6-inducibility in human monocytic cells in contrast to its high pyrogenicity to rabbits. The discrepancy could be explained based on differences between humans and rabbits in sensitivity to the endotoxin, because the extract showed higher proinflammatory-cytokine (TNF-alpha)-inducibility in rabbit whole-blood cells (WBCs) than human WBCs. The results suggest that the LAL test is a useful method of detecting endotoxin contamination in wound dressings and the MM6-CA8 assay is a good supplement to the LAL test for evaluating pyrogenicity in humans accurately.

Animals↗
PubMed1997

The involvement of an LPS inducible I kappa B kinase in endotoxin tolerance.

When human ovarian carcinoma cells are challenged with endotoxin, an I kappa B kinase is transiently induced within 3 to 5 min. This enzyme activity causes the hyperphosphorylation and subsequent degradation of I kappa B which allows NF-kappa B to translocate to the nucleus where it activates transcription. When endotoxin treated cells are rechallenged with a second dose of LPS, I kappa B kinase is not detected and I kappa B remains in the cytoplasm where it sequesters NF-kappa B. We report here the absence of endotoxin inducible I kappa B kinase activity in endotoxin tolerant cells suggesting that I kappa B kinase may play an important role in endotoxin tolerance. When cells tolerant to endotoxin are treated with TNF, I kappa B kinase activity is induced. Thus cells that are endotoxin tolerant are not cross tolerant to TNF. Dexamethasone, a known inhibitor of NF-kappa B activation does not inhibit endotoxin dependent induction of I kappa B kinase suggesting that the mechanism of action of dexamethasone is different from the tolerance mechanism reported here.

Base Sequence↗
PubMed1997

Blocking both E-selectin and P-selectin inhibits endotoxin-induced leukocyte infiltration into the eye.

The initial contact between leukocytes and the vascular endothelium at sites of inflammation is mediated by selectins. The purpose of this study was to investigate the role of the two selectins expressed on the vascular endothelium, E-selectin and P-selectin, in the pathogenesis of endotoxin-induced uveitis. Endotoxin-induced uveitis was produced in female C3H/HeN mice using Salmonella typhimurium endotoxin injected into one hind footpad. At the time of endotoxin injection mice were treated with an intraperitoneal injection of a monoclonal antibody against E-selectin or P-selectin, a combination of both anti-selectin antibodies, or isotype-matched control antibodies. In a second set of experiments, antibody treatment was administered 6 hr after endotoxin injection, when inflammatory cells are already entering the eye. Ocular inflammation was graded histologically by a masked observer. When administered at the time of endotoxin injection, anti-P-selectin antibody decreased ocular inflammation by 37% compared to control animals (P = 0.05). There was no statistical decrease in ocular inflammation in animals treated with anti-E-selectin antibody. The combination of anti-P-selectin and anti-E-selectin antibodies decreased infiltrating inflammatory cells by 61% (P < 0.01). When treatment was delayed until 6 hr after endotoxin injection, the combination of anti-P-selectin and anti-E-selectin antibodies again decreased ocular inflammation by 60% (P < 0.01). Immunohistochemical staining showed decreased ICAM-1 expression in the eyes of animals treated with the combination of anti-P-and anti-E-selectin antibodies. Blocking both P-selectin and E-selectin resulted in a significant decrease in endotoxin-induced intraocular inflammation.

Animals↗
PubMed2002

Cold storage sensitizes rat femoral artery to an endotoxin-induced decrease in endothelium-dependent relaxation.

Cold-stored arteries, tissues or organs are transferred in vascular, reconstructive and transplantation surgery. The function of transferred vessels and tissues diminishes when infection complicates transplantation, thereby contributing to morbidity. To evaluate the mechanisms involved, the effects of cold storage on basal vascular reactivity and the sensitivity to the vascular effects of endotoxin were tested in isolated rat femoral artery segments. A crossover design was followed, so that prior to cold storage 4 vessels were incubated for 2 h at 37 degrees C with endotoxin (Escherichia coli 0127:B8, 50 microg mL(-1)) in Krebs solution and 4 with Krebs solution only, while, after cold storage, segments from the former vessels were incubated with Krebs solution only and segments from the latter with endotoxin in Krebs solution. Vascular reactivity was tested in a wire myograph by the addition of depolarizing 125 mM KCl or norepinephrine (NE) as well as the endothelium-dependent vasodilator acetylcholine (ACh) and endothelium-independent vasodilator sodium nitroprusside (SNP). Cold storage did not affect vascular reactivity in the absence of endotoxin. Endotoxin decreased maximum response to NE prior to storage and sensitivity to SNP prior to and after cold storage. After cold storage, endotoxin decreased relaxation to ACh and increased vasoconstriction in response to KCl and NE (P < 0.05). We conclude that cold storage does not alter endothelial and smooth muscle function but sensitizes rat femoral artery to an endotoxin-induced decrease in endothelium-dependent relaxation and thereby to an increase in vasoconstrictor responses, whereas endotoxin alone only decreases receptor-dependent vasoconstrictor responses and sensitivity to NO donors. This may explain in part the detrimental effect of infection on function of cold-stored arterial grafts and tissue/organ transfers.

Acetylcholine↗
PubMed1984

Role of histamine in the antitumour activity of endotoxin.

The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H1 receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H2 receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H1 receptor antagonists diphenhydramine and promethazine but not by the H2 receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H1 antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine. Data indicate that intact H1 receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H2 blockade may facilitate this by stimulating H1 receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.

Animals↗
PubMed1988

The effect of nifedipine alone or combined with low dose acetylsalicyclic acid on endotoxin-induced pulmonary hypertension in the piglet.

Cardiovascular responses to the calcium antagonist nifedipine, alone and combined with low dose acetylsalicyclic acid (ASA), were evaluated in a piglet model of endotoxin-induced pulmonary hypertension. All animals were anesthetized, paralyzed and mechanically ventilated. Cardiac output (CO), pulmonary artery pressure (PAP), aortic blood pressure (SAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAPM) and arterial blood gases were measured before and after induction of pulmonary hypertension by E. coli endotoxin and after treatment. Results of treated groups were compared to a control group of piglets subjected to the same dose (0.15 micrograms/kg i.v.) of endotoxin. Control animals responded to a bolus injection of endotoxin within 15 min with an increase in mean PAP by 110%. Pulmonary vascular resistance (PVR) increased by 144%. Mean arterial pressure did not change significantly from baseline values. In animals treated with a single dose of 1 mg/kg ASA prior to endotoxin, the initial pulmonary response was not quantitatively different from control values, whereas ASA 20 mg/kg abolished the pulmonary vascular reaction. The increase of systemic vascular resistance (SVR) produced by endotoxin was aggravated by high dose ASA. In piglets treated with nifedipine (4 micrograms/kg/min) over 30 min after the application of endotoxin with and without additional infusion of nifedipine 60 min prior to endotoxin the PVR could be attenuated. The combination of nifedipine and low dose ASA showed synergistic effects compared to control. The increase of mean PAP was significantly reduced, the PVR remained in baseline range due to a marked elevation of cardiac output.

Animals↗
PubMed1991

Significance of urinary endotoxin concentration in patients with urinary tract infection.

Endotoxin is a component of the outer membrane of gram-negative rods (GNR). Since GNR are responsible for the majority of urinary tract infection (UTI), we measured the concentration of endotoxin in urine using chromogenic endotoxin-specific assay and examined its diagnostic utility in patients with suspected UTI. In all 18 urine samples with an endotoxin concentration exceeding 350 pg/ml and 2 samples with 10-350 pg/ml of endotoxin concentration, GNR were detected at a count of 10(4) cfu/ml. Negative for endotoxin were 3 samples of culture positive for gram-positive cocci (GPC), 2 samples containing various bacterial contaminants and all 37 samples with no growth on culture. Two urine samples collected 5 h after antibiotic dosage showed negative culture for GNR but a significant concentration of endotoxin. In an in vitro experiment, a residual concentration of antibiotic in urine inhibited bacterial growth, leading to a false-negative culture. These results suggest that chromogenic endotoxin assay is a reliable method for diagnosing UTI caused by GNR and detecting false-negative culture of GNR.

Adult↗
PubMed1981

Effects of endotoxin on the pharmacology of antineoplastic agents.

Patients with cancer often develop serious gram-negative bacterial infections. Since bacterial endotoxins have been shown to affect the in vitro hepatic metabolism of antineoplastic agents, significant infection may adversely affect drug pharmacokinetics and metabolism in these patients. To evaluate the clinical significance of these effects, bacterial endotoxin (0.5 mg/kg, IV) was administered to male beagle dogs 1 or 24 h prior to the administration of radiolabeled 5-fluorouracil (5-FU), methotrexate (MTX), arabinosylcytosine (Ara-C), or vinblastine (VLB) as an IV bolus. Drug levels in plasma and urine were measured at various times after administration and standard pharmacokinetic parameters were calculated. The pharmacokinetics of all four agents were found to be significantly altered by the administration of bacterial endotoxin. However, there were no detectable patterns to these changes so that no predictions could be made. In studies on rats, chronic, nonlethal endotoxin administration (0.8 mg . kg-1 . day-1 for 10 days) resulted in a dramatic decrease in the distribution of [14C]methylglyoxal bis(guanylhydrazone) (MGBG) in liver, kidney, intestine, heart and lung tissue. This suggests that bacterial endotoxin may also effect drug pharmacokinetics by altering drug penetration into various organs. In studies on hepatic microsomes isolated from rats, bacterial endotoxin incubation affected aniline hydroxylase activity only at concentrations greater than 0.4 mg/ml, at least tenfold higher than the LD 50 of endotoxin in rats. It therefore seems likely that the endotoxin may require in vivo metabolism to affect changes in drug metabolism and disposition.

Animals↗
PubMed1995

Dose-response relationship for the antipyretic effect of meloxicam in an endotoxin model in cats.

The antipyretic efficacy of meloxicam was evaluated in a feline endotoxin model using a replicated change-over design. Twelve adult cats of both sexes were allocated at random to three experimental groups. At 30 min prior to the intravenous (i.v.) endotoxin challenge (0.5 microgram/kg body weight(b.w.)), 2 animals in each group received an i.v. injection of 0.1, 0.3 or 0.5 mg meloxicam/kg b.w. and the two remaining animals in each group received physiological saline. In a second phase, 21 days later, the meloxicam/placebo treatment was exchanged within each group. The rectal temperature and scores for general demeanour were determined at 30-min intervals from before dosing to 300 min after the endotoxin challenge. Haematological parameters were analysed before and 60 min after administration of endotoxin. The results indicated a significant dose-dependent antipyretic response to meloxicam after endotoxin challenge. The antipyretic response in the medium- and high-dose meloxicam groups did not differ significantly, but both were significantly different from the low-dosage group. The individual effects of endotoxin on general demeanour were rather variable but meloxicam tended to have a beneficial effect. Endotoxin induced a reduction in the white blood cell count but this was not influenced by meloxicam. It was concluded that the pyretic endotoxin model is very suitable for studying new NSAIDs in cats and that the optimum single dose of meloxicam in this model was 0.3 mg/kg b.w.

Animals↗