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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↗

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↗

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↗

PubMed1983

A highly sensitive pyrogen test for antibiotics I: detection of trace amounts of endotoxin in injectable sodium ampicillin preparations.

The rabbit pyrogen test (specified in the pharmacopeia) and the Limulus amebocyte lysate (LAL) test are influenced by high concentrations of certain antibiotics. Therefore, it has not been possible to detect trace amounts of endotoxin which may contaminate these antibiotics. To detect trace amounts of endotoxin in injectable sodium ampicillin, an ultrafiltration technique was utilized which removed the antibiotic and left a solution which contained predominantly the endotoxin. After ultrafiltration, a trace amount of pyrogen (which otherwise could not be detected) was found using both the rabbit pyrogen and the LAL tests. The endotoxin was also determined quantitatively using a chromogenic endotoxin reagent which is made by combining the Limulus amebocyte lysate and a synthetic substrate with a suitable chromophore.

Ampicillin↗

PubMed1990

Fever response induced by intravenous and intracerebroventricular injection of pyrogen in thyroidectomised and protein-calorie malnourished rabbits.

The development of a fever in response to intravenous (IV, 1.5 micrograms/kg body mass) and intracerebroventricular (ICV, 1.5 micrograms/animal) injections of Escherichia coli lipopolysaccharide (LPS) was studied in control, thyroidectomised and protein-calorie malnourished rabbits (New Zealand Whites, n = 55). ICV injection of LPS in control rabbits produced a fever response, the characteristics of which differed from those obtained after IV pyrogen injection. Thyroid deficiency caused an attenuated fever response, irrespective of whether LPS had been administered by IV or ICV injection. Protein-calorie malnourished rabbits showed a smaller fever response after IV or ICV pyrogen injections. Malnourished rabbits, refed over a period of 15 days, showed a typical biphasic fever response, but with lower magnitude than controls. The results of these experiments suggest that ICV injection of LPS is not an appropriate model for the study of fever mechanisms in disease states, and that the attenuated fever response observed in protein-calorie malnourished rabbits may be related, at least in part, to a decreased ability to produce the endogenous pyrogen interleukin-1.

Animals↗

PubMed1985

Naloxone does not influence a pyrogen fever in rabbits.

Rabbits were made febrile by an intravenous injection of homologous endogenous pyrogen (Interleukin 1). When naloxone (0.1 mg/kg i.v.) followed by 0.06 mg (kg X hr)-1 infusion) was given at the same time as the pyrogen, the resulting fever was indistinguishable from that following pyrogen alone. It appears unlikely that opioid receptors which are blocked by naloxone play an important part in the fever process.

Animals↗

PubMed1993

Endogenous pyrogen formation by human blood monocytes stimulated by polyriboinosinic acid:polyribocytidylic acid.

The pyrogenic response to supernatants from human blood monocytes stimulated with polyriboinosinic acid:polyribocytidylic acid (poly I:C) was characteristic of a response to endogenous pyrogen in that it was brief and monophasic, and was destroyed by heating the supernatants at 70 degrees C for 30 min. Pyrogen production was unimpaired when the incubations were carried out in the presence of cycloheximide (50 micrograms/ml; an inhibitor of protein synthesis) or indomethacin (50 micrograms/ml; an inhibitor of prostaglandin synthesis). Also, neither interferon, interleukins, tumor necrosis factor nor prostaglandin E2 were detectable in the supernatants from the poly I:C-stimulated human monocytes.

Animals↗

PubMed1977

Effect of prostaglandin, pyrogen and noradrenaline, injected into the hypothalamus, on thermoregulation in newborn lambs.

Thirteen newborn lambs were implanted stereotaxically with an array of 4 guide tubes positioned bilaterally so that their tips lay above various hypothalamic loci. At postnatal ages 50-70 h, rectal temperature was monitored, and bilateral 1 microliter injections were made into the hypothalamus. Prostaglandin E1 (0.2 microgram) and prostaglandin E2 (0.2-2.0 microgram) did not cause fever on any occasion though injections were made into 44 sites throughout the hypothalamus. Nevertheless, lambs that did not develop fever following central injection were often, if sensitized by bacterial pyrogen given earlier able to develop fever after intravenous injection of bacterial pyrogen. Infusion of a bacterial pyrogen (S. abortus equi, 0.2 microgram) into these same sites caused fever only when injections were made into the anterior hypothalamic/preoptic area (AH/POA). Eight lambs were placed in a 10 degrees C environment and noradrenaline was injected. Rectal temperature fell by 0.5-1.4 degrees C after 7 bilateral injections into the AH/POA, but 9 injections into other hypothalamic areas caused little temperature change. When 6 lambs were placed at a temperature of 30 degrees C and noradrenaline was injected, no consistent temperature changes were observed after microinjection into the AH/POA or other parts of the hypothalamus.

Animals↗

PubMed1983

Reduced hypothalamic thermosensitivity following intraventricular injection of pyrogen in conscious rabbits.

Hypothalamic temperature thresholds for vasodilatory and respiratory reactions were determined before and after i.c.v. injection of pyrogen in rabbits. During the rising phase of fever the increases in the hypothalamic thresholds for vasodilatory and respiratory reactions differed from those found in the pre-pyrogen preoptic anterior hypothalamic area (POAH) heating by 2.1 +/- 0.2 degrees C and 1.89 +/- 0.31 degrees C, respectively. During the plateau phase of fever the threshold for vasodilatory reaction was further increased (by 0.7 +/- 0.23 degrees C), whereas that for panting remained at the same level. It is concluded that pyrogen exerts a depressive action on POAH thermosensitivity.

Animals↗

PubMed1992

Electrical stimulation of the paraventricular nucleus attenuates pyrogen fever in the rabbit.

Arginine vasopressin (AVP) perfused within the ventral septal area (VSA) suppresses fever normally evoked by pyrogenic substances, including Salmonella abortus equi (SAE). Neurons containing AVP and located within the paraventricular nucleus (PVN) or the nearby bed nucleus of the stria terminalis (BnST) are believed to have projections to this septal region. A series of experiments was undertaken to determine whether electrical stimulation of these areas, which might be expected to cause the release of AVP within the VSA, would affect similarly the pathogenesis of fever. A stainless steel cannula was implanted surgically in each of 22 male New Zealand White rabbits and a monopolar electrode was lowered through this guide cannula to the PVN or BnST areas. Electrical stimulation (20 Hz, 10 s on, 10 s off, 2.6-3.2 V) was initiated 30 min prior to and was continued until 90 min after the intravenous (i.v.) administration of 0.1-1.0 micrograms of SAE (1.0 ml carrier vehicle). While afebrile body temperature remained unchanged, electrical stimulation of sites located in the rostral extension of the PVN effectively attenuated the pyrogen-induced fever. Stimulation of sites outside these areas did not affect either the absolute magnitude or the duration of the fever. Although the reduction in fever was most pronounced during the period of electrical stimulation, in some cases the fever remained suppressed beyond the application of the current. These experiments provide the first evidence that electrical stimulation of paraventricular areas with AVP-containing cell bodies is effective in suppressing a fever evoked by systemic administration of a pyrogen. Although untested, it is possible that a stimulus-induced release of AVP within the VSA is responsible for the attenuation of the fever.

Animals↗

PubMed1982

The detection of endotoxin by in vitro production of endogenous pyrogen: comparison with limulus amebocyte lysate gelation.

The sensitivities of leukocyte endogenous pyrogen (EP) production and limulus amebocyte lysate (LAL) gelation to endotoxin from E. coli (minimum i.v. pyrogenic dose 4 ng/kg in rabbits) were determined. Concentrations of 0.5-1.0 ng/ml could be detected by LAL. The minimum endotoxin concentrations which generated detectable EP from 2 X 10(6) monocytes was 10-fold lower (0.05-0.1 ng/ml). At an endotoxin concentration of 0.4 ng/ml the minimum number of monocytes required for detectable EP production was 5 X 10(5). It is concluded that the LAL gelation test cannot safely be used to exclude significant endotoxin contamination in a cellular system where EP production is being measured. The same conclusion applies even more forcibly to the in vitro production of lymphocyte activating factor (LAF, interleukin-1), since it appears that LAF and EP are identical and sub-pyrogenic amounts of EP are easily detectable in the LAF assay.

Animals↗

PubMed1980

Synthesis and pyrogenic effect of 3 alpha, 7 alpha-dihydroxy-5 beta-androstan-17-one and 3 alpha-hydroxy-5 beta-androstane-7, 17-dione.

The first chemical synthesis of 3 alpha, 7 alpha-dihydroxy-5 beta-androstan-17-one and 3 alpha-hydroxy-5 beta-androstane-7, 17-dione is reported. In this method, the 17 beta-side chain of commercial chenodesoxycholic acid was degraded in 6 steps after selective protection of the hydroxyl groups: 3 alpha-OH by a tert-butyldimethylsilyl group and 7 alpha-OH by an acetoxy group. The capacity of 3 alpha, 7 alpha-dihydroxy-5 beta-androstan-17-one and 3 alpha-hydroxy-5 beta-androstane-7, 17-dione to release a pyrogen by human leukocytes was investigated by two independent methods: supernatants from leukocytes incubated with a steroid are injected to rabbits whose fever is measured, or tested by the Limulus Test (a pyrogen detection technique). The 7-keto substituted etiocholanolone still possessed pyrogenic activity, while the 7 alpha-hydroxyl substituted one did not.

Animals↗

PubMed1991

A novel process for preparing an acellular pertussis vaccine composed of non-pyrogenic toxoids of pertussis toxin and filamentous hemagglutinin.

A novel process for preparing non-pyrogenic toxoids of pertussis toxin (PT) and filamentous hemagglutinin (FHA) is described. The process consists of chromatographies on perlite then on hydroxylapatite. Purification yields for PT and FHA are 62 and 68%, respectively. The purification process takes advantage of the novel use of perlite (a filter aid) for the simultaneous purification of PT and FHA. The hydroxylapatite, in addition to removing the remaining contaminants, also concentrates the antigens. The resulting PT and FHA are approximately 95% pure, and are non-pyrogenic as judged by the rabbit pyrogen test. The purification process is simple, inexpensive, and does not use blood components or toxic substances. The mild conditions in which the PT and FHA are purified ensure the recovery of native protein. The purified PT and FHA are detoxified in the presence of glycerol using glutaraldehyde and formaldehyde, respectively, to produce antigenic components of an acellular pertussis vaccine. The final PT and FHA toxoids are immunogenic in guinea-pigs and have been shown to be protective in the mouse intracerebral challenge test.

Bordetella pertussis↗