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PubMedDate not supplied

[The characteristics of the structural development of the thymus and spleen in the progeny of white rats exposed to pyrogenal action during pregnancy].

Thymus and spleen structural changes of progeny of experimental animals after single exposure to 100-150 mg/l kg of bacterial pyrogenal lipopolysaccharide on 11th, 14 and 18th days of pregnancy were studied in the experiment performed on 60 female outbred albino rats and 205 rats--pups aged 20- and 45 days. Relative thymus and spleen masses were defined, their morphofunctional state was assessed morphometrically. To reveal the pecularities of the immune system reaction to foreign antigens in progeny, one part of control and experimental rats were subjected to immunization with ram erythrocytes (T-dependent antigen) and another one--with pyrogenal (T-independent antigen). Prenatal pyrogenal effect retarded thymus and spleen formation. Normalization of their structure and compensation of the effect were incomplete and occurred by 45th day of postnatal development. Most expressed changes were observed in the progeny of the rats treated with pyrogenal on 14th day of pregnancy: sharp decrease of the population density of lymphoid cells occurred in the thymus while lymphoid nodules disappeared in the spleen in response to immune challenge.

Animals↗
PubMed1995

Pyrogen reactions to human serum albumin during plasma exchange.

Reactions to human serum albumin (HSA) in therapeutic plasma exchange (TPE) are rare. Nevertheless, older literature describes possible adverse effects, including specific immune responses to albumin or other proteins, and reactions due to contaminating organisms or pyrogen. During an eight day period three patients in our unit had unusual reactions after infusion of 1.5-2 L of HSA. Patient 1 had trembling that persisted for 20 min. Patient 2 had shaking for 40 min despite calcium gluconate infusion, and fever to 100.8 degrees F. Patient 3 had severe rigors that subsided after 90 min when meperidine was finally given, and fever to 103.5 degrees F. Record reviews revealed that all three patients had received HSA from the same lot, and that only one other TPE patient had received HSA from that lot. Neither our pharmacy nor the manufacturer was aware of other reactions associated with that lot. Material from a bottle only partially infused to patient 3 was negative in culture and was negative for pyrogen when retested by the manufacturer. Nevertheless, because patients 1 and 2 had each had multiple previous uneventful TPEs and because all three patients tolerated subsequent TPEs without incident when another brand of HSA was used, we conclude that these patients had pyrogen reactions to the implicated HSA lot. This experience illustrates the value of cluster recognition in arousing suspicion of unusual reactions to HSA and the value of recorded lot numbers in pursuing such suspicions. Apheresis personnel should be aware of the potential for pyrogen reactions with HSA and should record lot numbers of all fluids infused during TPE.

Adult↗
PubMed1985

Dose-dependent reduction of lipopolysaccharide pyrogenicity by polymyxin B.

Lipopolysaccharides (LPS) from Gram-negative bacteria are potent pyrogens in mammals. Polymyxin B (PB), a cationic polypeptide antibiotic, binds lipid A, the active moiety of LPS, with high affinity and abrogates several biological responses to LPS. We studied the effect of PB on pyrogenicity of purified LPS from E. coli 0111:B4 in rabbits. PB reduced the pyrogenic response to LPS in a dose-dependent manner at mass ratios (PB:LPS) from 5:1 to 100:1. Previous reports have suggested that PB is effective only at much higher doses. In our hands, PB itself is pyrogenic, unless previously gamma-irradiated. Our results confirm in vivo the anti-endotoxic action of PB.

Animals↗
PubMed1984

Effects of leukocytic pyrogen and sodium salicylate on hypothalamic thermosensitive neurons in vitro.

The effects of leukocytic pyrogen and sodium salicylate (Sal) were studied on the single-unit activities of neurons in the preoptic and anterior hypothalamus (PO/AH) recorded in tissue slices in vitro. The pyrogen applied to the immediate vicinity of the recorded neurons decreased the firing rate of the majority of warm-sensitive neurons, but had no effect on the activities of thermally insensitive neurons. The pyrogen-induced inhibition of warm-sensitive neurons was reversibly blocked by local application of Sal. The results support the view that the pyretic and antipyretic effects of intrahypothalamic pyrogen and Sal are caused by their offsetting actions on the PO/AH thermosensitive neurons.

Animals↗
PubMed2004

Monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs: test design and data analysis.

An optimised test designed for an in vitro monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs is described, together with ways to address the inherent variability of such assays in which cells are cultured using 96-well plates. The test preparation is cultured with peripheral blood mononuclear cells (PBMNC) and the contaminants in the test article stimulate the release from the cells of the endogenous pyrogenic cytokine interleukin-6 (IL-6). The test system is in use within the pharmaceutical industry and at a national control authority for detecting pro-inflammatory and pyrogenic contaminants, including 'rabbit-negative' and 'LAL-negative' non-endotoxin pyrogens. Products tested include small molecules, biologicals and vaccines. The PBMNC/IL-6 monocyte activation test has been approved by the US FDA as an 'end-product release test' and also is being used for in-process testing.

Cell Culture Techniques↗
PubMed1988

Effects of leukocytic pyrogen (interleukin-1) on local cerebral glucose utilization in rats with and without premedication with indomethacin or dexamethasone.

Changes in body temperature were recorded in freely moving rats given phosphate-buffered saline or leukocytic pyrogen (interleukin-1) while the animals were in an infant incubator maintained at 25.5 +/- 0.5 degrees C. The leukocytic pyrogen increased body temperature by at least 1 degree C within 1 h. This rise in temperature was prevented by premedication with indomethacin (10 mg/kg) but not dexamethasone (0.5 mg/kg) given 15 min before the leukocytic pyrogen. Local rates of glucose utilization were measured in 47 regions of the central nervous system. In none of the regions previously reported to have an increased rate of glucose utilization associated with an ambient temperature of 32.5 degrees C (McCulloch et al., 1982b) was an increase found in the present experiments. It was concluded that the intensity of the changes in local cerebral glucose utilization in response to the fever caused by the leukocytic pyrogen was insufficient to be measured. Neither indomethacin nor dexamethasone caused remarkable changes in rates of local glucose utilization.

Animals↗
PubMedDate not supplied

Pyrogen reactions associated with the infusion of normal serum albumin (human).

In November, 1974, eight patients in three hospitals had pyrogen reactions associated with the infusion of 25% Normal Serum Albumin from the same lot. The reactions were recognized because the same physician or nurse observed several patients having recurrent reactions or because a single patient receiving several vials had consecutive reactions. The remaining albumin in three vials associated with reactions had apparent endotoxin concentrations of 4, 16, and 32 ng/ml and that 22 vials from recalled supplies had a median concentration of 4 ng/ml (range: 2 to 64) as determined by the Limulus amebocyte lysate test, but the lot again passed the rabbit pyrogen test. In a prospective study to determine the efficacy of the Limulus test in quality control, patients had their temperatures taken hourly during albumin infusions and the remaining fluid was tested by the Limulus assay. The albumin in 443 of the 662 vials infused (65%) gave a positive test and 311 of these vials (45%) had apparent endotoxin concentrations of 4 to 64 ng/ml, but no patient had a reaction. Because of the limitations of both the rabbit pyrogen and Limulus test, the detection of some pyrogenic lots continues to depend on hospital surveillance and reporting os suspect reactions.

Adult↗
PubMed2001

The antioxidant system beta-D(+) glucose-glucose oxidase-catalase: tests for pyrogenicity and antigenicity.

PURPOSE: beta-D(+) glucose-glucose oxidase (E.C.# 1.1.3.4)-catalase (E.C.# 1.11.1.6) (GO-CAT) is being investigated as a new antioxidant system for use in pharmaceutical solutions. This study reports the results of tests for pyrogenicity and antigenicity of GO-CAT derived from Aspergillus niger when used parenterally in autoclaved preparations. METHODS: The Limulus amebocyte lysate (LAL) method was used to test the pyrogenicity of native GO-CAT. Pyrogenicity/antigenicity was evaluated in vivo by injecting autoclaved GO-CAT into New Zealand white rabbits. Antigenicity was also evaluated by Ouchterlony and Western blotting. RESULTS: None of the native GO-CAT concentrations tested (up to 30.83 u/ml) produced a positive gel clot in the LAL test, thereby suggesting its non-pyrogenicity. The rabbits, which received seven injections of autoclaved GO-CAT over a period of eleven weeks, remained healthy during and after the GO-CAT injections. All Ouchterlony and Western blot assays using sera from rabbits injected with autoclaved GO-CAT were negative. Furthermore, autoclaved GO-CAT could not be detected in Ouchterlony assays using a mouse monoclonal antibody (GO40 mAb) to native A. niger glucose oxidase. Control samples containing native GO-CAT produced an antigen-antibody complex reaction in Ouchterlony assays against the GO40 mAb. Antigen-antibody complexes could be detected by non-denaturing PAGE in samples containing native GO-CAT/GO40 and boiled GO-CAT/GO40, but not in samples containing autoclaved GO-CAT/GO40. These results indicate autoclaved GO-CAT is neither pyrogenic nor antigenic. CONCLUSIONS: Based on these results, there is potential for the use of beta-D(+) glucose-glucose oxidase-catalase as an antioxidant system in pharmaceutical solutions, particularly in terminally autoclaved aqueous formulations for parenteral use.

Animals↗
PubMed1958

Studies on the pathogenesis of fever. V. The relation of circulating endogenous pyrogen to the fever of acute bacterial infections.

An endogenous pyrogen, which is indistinguishable from leucocytic pyrogen, has been demonstrated in the blood streams of rabbits with fevers caused by experimental pneumococcal and streptococcal infections. Like the endogenous pyrogen previously detected in the serum of animals with fever produced by the intravenous injection of typhoid vaccine, the newly discovered circulating factor acts directly upon the thermoregulatory centers of the brain. Its origin from polymorphonuclear leucocytes at the site of infection appears to have been established. The possible relationship of this circulating endogenous pyrogen to the pathogenesis of other forms of fever is discussed.

Animals↗
PubMed1999

Detection of pyrogenic toxins of Staphylococcus aureus in sudden infant death syndrome.

It has been suggested that pyrogenic toxins of Staphylococcus aureus are involved in the series of events leading to some cases of sudden infant death syndrome (SIDS). The objectives of the study were to screen tissues from SIDS infants for pyrogenic toxins and to compare incidence of identification of these toxins among these infants from different countries. An enzyme-linked immunosorbent assay (ELISA) and a flow cytometry method were used to screen body fluids and frozen or formalin-fixed tissues for pyrogenic toxins of S. aureus, toxic shock syndrome toxin 1 (TSST), staphylococcal enterotoxins A (SEA), B (SEB), and C1 (SEC). Toxins were identified in tissues of 33/62 (53%) SIDS infants from three different countries: Scotland (10/ 19, 56%); France (7/13, 55%); Australia (16/30, 53%). In the Australian series, toxins were identified in only 3/19 (16%) non-SIDS deaths (chi2 = 5.42, P < 0.02). The flow cytometry method was useful for toxin detection in both frozen and fixed tissues, but ELISA was suitable only for frozen tissues or those fixed for less than 12 months. Identification of pyrogenic toxins in > 50% of SIDS infants from three different countries indicated further investigation into the role the toxins play in cot deaths might result in development of additional measures to reduce further the incidence of these infant deaths.

Bacterial Toxins↗
PubMed1964

Relation of pyrogenic and emetic properties of enterobacteriaceal endotoxin and of staphylococcal enterotoxin.

Martin, William J. (College of Medicine, University of Utah, Salt Lake City), and Stanley Marcus. Relation of pyrogenic and emetic properties of enterobacteriaceal endotoxin and of staphylococcal enterotoxin. J. Bacteriol. 87:1019-1026. 1964.-The pyrogenic, endotoxic fraction of enterobacteriaceal organisms, isolated in a relatively impure or purified state, is both pyrogenic in rabbits and cats as well as emeticogenic in cats in microgram amounts. Employing classical methods for preparation of enterobacteriaceal endotoxin from known enterotoxic strains of Staphylococcus aureus yielded preparations with less than one-hundredth the activity of the enterobacteriaceal material. However, a purified enterotoxin material from an S. aureus strain, with protein-like rather than polysaccharidelike properties, was found to be both pyrogenic and emeticogenic in microgram amounts. These results suggest the probability that the enterobacteriaceal pyrogenemetic substance(s) is a significant part of the whole cell, whereas the staphylococcal enterotoxin is elaborated as a metabolic product which apparently does not accumulate in the whole cell.

Animals↗
PubMed1968

Pyrogenic responses to staphylococcal enterotoxins A and B in cats.

Pyrogenic responses, ranging up to 4.8 F, were induced in cats by oral administration of highly purified staphylococcal enterotoxin B in doses from 10 to 100 mug/kg. Fever was a more sensitive indicator of intoxication than was emesis. Highly purified preparations of enterotoxin A, whether administered intravenously (0.01 to 1.0 mug/kg), orally (10 to 25 mug/kg), or into the cerebral ventricles (0.005 to 0.020 mug in 0.20 ml), were also pyrogenic in cats. Tolerance to the pyrogenic activity was produced by repeated intravenous injection of a given dose of enterotoxin A but not by repeated intracerebroventricular injection. Enterotoxin A was more potent than enterotoxin B after intravenous injection in causing both fever and emesis. Cross-tolerance could not be demonstrated between enterotoxin A and enterotoxin B or Salmonella typhosa endotoxin. This lack of cross-tolerance plus the inability of large oral doses (100 to 4,700 mug/kg) of endotoxin to cause fever or emesis indicate that the reported responses were attributable to the specific toxins administered and not to contamination by other pyrogens.

Animals↗
PubMed1990

Outbreak of gram-negative bacteremia and pyrogenic reactions in a hemodialysis center.

During the period from April 4, 1988, to April 20, 1988, nine pyrogenic reactions and five gram-negative bacteremias occurred in 11 patients undergoing dialysis. All pyrogenic reactions and gram-negative bacteremias occurred among patients in whom a reprocessed dialyzer was used. The rate of pyrogenic reactions or bacteremias per 100 sessions using a reprocessed dialyzer was higher than in sessions during which a new dialyzer was used (4.5 vs. 0; p = 0.03). Dialyzers were manually reprocessed with 2.5% Renalin germicide. The Renalin concentrations varied widely in 12 dialyzers stored after manual reprocessing during the epidemic period (0.9-4.2%); the median endotoxin concentrations varied from 0 to 246 ng/ml and were higher in dialyzers with Renalin concentrations less than or equal to 1.0% than in dialyzers with higher concentrations (p = 0.01). Experiments using a dilution technique described by a technician resulted in Renalin concentrations ranging from 1.4% at the surface to 3.5% at the bottom of the preparation container. These findings suggest that failure to adequately admix Renalin during dilution may be associated with low levels of disinfectant, high levels of bacteria and endotoxins in dialyzers, and outbreaks of pyrogenic reactions and gram-negative bacteremias in dialysis patients.

Acetic Acid↗
PubMed1991

Selective depletion of macrophages prevents pituitary-adrenal activation in response to subpyrogenic, but not to pyrogenic, doses of bacterial endotoxin in rats.

The mechanisms by which bacterial endotoxin [lipopolysaccharide (LPS)] stimulates the hypothalamo-pituitary-adrenal axis (HPAA) have not been elucidated. The present study was designed to investigate the involvement of macrophages in plasma ACTH and corticosterone responses to LPS administration in rats using selective in vivo macrophage depletion. Intraperitoneal administration of subpyrogenic doses of LPS to normal rats resulted in elevated plasma ACTH and corticosterone concentrations, measured 2 h later. The response showed a remarkable steep dose relationship, with minimal effective doses between 0.5-1.5 micrograms (ACTH) and 0.5 micrograms or less (corticosterone)/kg BW. Plasma PRL, LH, and catecholamine (norepinephrine, epinephrine) levels were not significantly changed under the conditions used. Only at 6 h after LPS administration was a small elevation of norepinephrine noted. To deplete macrophages, rats were injected with liposomes encapsulated with dichloromethylene diphosphonate (Cl2MDP). Histochemical (acid phosphatase) and immunocytochemical techniques (monoclonal antibodies to rat macrophages coded ED1 and ED3) were applied to examine the efficiency of macrophage elimination by the Cl2MDP liposomes in cytospins of peritoneal exudates and in sections of the liver and spleen. Since cells of the macrophage lineage are considered to be the main source of IL-1 in the circulation, we also measured circulating levels of immunoreactive interleukin-1 beta (IL-1) concentrations in control and Cl2MDP liposome-treated rats by the use of a newly developed RIA. Reduced numbers of macrophages were seen in peritoneal lavages of Cl2MDP liposome-treated animals, whereas the morphological appearance and numbers of mast cells, granulocytes, and T-cells were unaffected. Similarly, macrophages were effectively eliminated in the spleen, mesenteric lymph nodes, and liver, as inferred from the reduction of macrophage staining in these organs. Plasma IL-1 concentrations could only be detected in response to a pyrogenic (2.5 mg/kg, iv) and not to a subpyrogenic (0.025 mg/kg, ip) dose of LPS. The increase in plasma IL-1 concentrations in response to the pyrogenic dose of LPS, reaching levels of 20-40 ng/ml in control rats, was blunted in animals treated with the Cl2MDP liposomes. Macrophage depletion by Cl2MDP liposomes did not affect either resting plasma corticosterone levels or the corticosterone response to ether exposure. At subpyrogenic doses of LPS, plasma ACTH and corticosterone responses were completely prevented by macrophage depletion. In contrast, at pyrogenic doses of LPS, plasma ACTH and corticosterone responses were not significantly affected by depleting macrophages. These data demonstrate that activation of the HPAA by a subpyrogenic dose of LPS is macrophage dependent. However, macrophage-independent mechanisms mediate activation of the HPAA in response to a pyrogenic dose of LPS.

Adrenal Glands↗
PubMed1993

Modulation of the prostaglandin responses of conscious rabbits to the pyrogen polyinosinic:polycytidylic acid by corticotrophin-releasing factor-41.

The pyrogenic interferon inducer polyinosinic:polycytidylic acid (Poly I:C) was shown to stimulate rises in both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in conscious rabbits in vivo. Poly I:C (2.5 micrograms/kg) stimulated a fivefold rise in circulating immunoreactive (ir) PGE2, with a lag phase of 60 min, which was sustained during the subsequent 4-h period of observation. Poly I:C also stimulated a 2.5-fold rise in circulating irPGF2 alpha with a lag phase of 90 min, which was followed by a return to basal levels after 5 h. The rises in circulating irPGE2 and irPGF2 alpha stimulated by Poly I:C were prevented by pretreatment with the non-steroidal anti-inflammatory drug ketoprofen. Both the irPGE2 and irPGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.) were antagonized by the corticotrophin-releasing factor-41 (CRF-41) receptor antagonist (alpha-helical CRF (9-41), 25 micrograms/kg, i.v.) administered 5 min prior to the pyrogen. Peripheral immunoneutralization using an anti-CRF-41 monoclonal antibody (KCHMB001, 2.5 mg/kg, i.v.) administered 5 min prior to the pyrogen, also inhibited both the PGE2 and PGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.). However, control mouse IgG also inhibited the PGE2 response. In conclusion, these results suggest a modulatory role for endogenous peripheral CRF-41 in the circulating prostaglandin responses to the pyrogen Poly I:C and this effect may be responsible for the antipyretic actions of peripherally administered CRF-41 antagonists and antibodies.

Animals↗
PubMed1995

[Detection of Pyrogens using human whole blood]

The use of human whole blood as an in vitro model for detection of compounds with the potential to induce fever is described. As a readout, mediators (endogenous pyrogens) released from leukocytes such as tumor necrosis factor (TNF), interleukin I (IL-I), interleukin 6 (IL-6) and prostaglandin E2 (PGE2) are quantitated. In fact, minute concentrations of pyrogens induced the release of mediators in amounts that were easily detectable. Endotoxins as well as other bacterial components induce this reaction. We used the antipyrogenic drug aspirin to show that in blood of volunteers the ex vivo stimulated PGE2 release was inhibited for several hours. This model seems superior to the rabbit pyrogen test or the Limulus assay for endotoxin. We propose to evaluate this system as an alternative in vitro method for pyrogen testing.

Journal Article↗
PubMed2001

The cAMP-mediated protein kinase signal transduction pathway is involved in the pyrogenic effect of CRH in rats.

OBJECTIVE: To determine whether the cyclic adenosine monophosphate (cAMP) mediated protein kinase signal transduction pathway is involved in the pyrogenic action of corticotropin releasing hormone (CRH) in rats. METHODS: Corticotropin releasing hormone, 2',3'-dideoxyadenosine (DDA) and adenosine-3',5'-(cyclic) monophosphorothionate, Rp-Isomer (Rp-cAMPS), were administered intracerebroventricularly (i.c.v.). The colonic temperature was measured using a thermistor, and the content of cAMP in the hypothalamus was determined by radioimmunoassay. Hypothalamic incubation was used to assess the effects of CRH on the content of cAMP in the hypothalamus in vitro. RESULTS: Microinjection (i.c.v.) of CRH (2.5 micrograms, 5.0 micrograms and 10 micrograms) caused increases in colonic temperature and the hypothalamus cAMP level in conscious rats. CRH increased hypothalamus cAMP level in vitro. The pyrogenic effects of CRH were abolished or markedly inhibited by prior injection (i.c.v.) of an adenylate cyclase inhibitor, DDA (30 micrograms), or an inhibitor of cAMP-dependent protein kinase, Rp-cAMPS (15 micrograms). CONCLUSION: cAMP mediates the pyrogenic action of centrally administered of CRH in rats, and protein kinase A may play an important role in the central CRH-induced fever. The cAMP-dependent protein kinase signal transduction pathway may be involved in the central mechanisms of the pyrogenic action of CRH in rats.

Animals↗
PubMed1986

[Effect of bacterial lipopolysaccharide pyrogenal on the development of the Syrian hamster embryo].

Pyrogenal is injected to female hamsters (Mesocricetus auratus) at various time of pregnancy twice, with a 24 hour's interval: at first 100 or 50, and then--50 or 25 minimal pyrogenic doses. The embryos are examined on the 15th day of the intrauterine development by means of main teratologic methods. Pyrogenal injected on the 9th--10th day of the embryonal development produces hydrocephaly, micrognathia, retardation in development, hemorrhagic syndrome. Pyrogenal injected during some other time of pregnancy produces hemolysis of erythrocytes. This is proved by presence of hemosiderin in the foetal liver.

Abnormalities, Drug-Induced↗