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At least 19 recordsLinked to original sources
PubMed1978

Group A streptococcal pyrogenic exotoxin: pyrogenicity, alteration of blood-brain barrier, and separation of sites for pyrogenicity and enhancement of lethal endotoxin shock.

Group A streptococcal pyrogenic exotoxin type C (SPE C) was shown to produce fever by crossing the blood-brain barrier. The toxin directly stimulated the hypothalamic fever response control center, thus bypassing a requirement for endogenous pyrogen release. SPE C was detected in the cerebrospinal fluids of toxin-treated rabbits by pyrogen tests and a hemagglutination inhibition assay. The toxin altered the permeability of the blood-brain barrier to endotoxin, Streptococcus pneumoniae, and Haemophilus influenzae as well as to itself. SPE C did not alter the in vivo differential and total counts of peripheral blood leukocytes and did not elicit endogenous pyrogen release from leukocytes in vitro. In vivo, peripheral blood platelet counts remained unchanged after SPE treatment. Cycloheximide pretreatment of rabbits did not inhibit fever production by SP C. In contrast to the hypothermia observed in mice treated with endotoxin intravenously susceptibility to lethal endotoxin shock. The abilities of SPE C to produce fever and enhance lethal shock were shown to be separate functions of the molecule; fever results from stimulation of the hypothalamus, and enhancement appears not to involve the central nervous system.

Bacterial Toxins↗
PubMed1991

[The effects and properties of sodium nucleinate as a pyrogen working-standard. 9. Pyrogen detection with epinephrine-skin-, dactinomycin- and LAL-tests. The suitability of sodium nucleinate as a pyrogen standard].

Sodium nucleinate (NN) as well as bacterial lipopolysaccharide (LPS) can be detected by epinephrine-skin, dactinomycin and LAL tests. In the quantitative determination of two pyrogen standards for rabbit tests, consisting of NN, a smaller value was found by LAL test for the standard of greatest pyrogenic effect than for that less pyrogenically effective in rabbits. A standard consisting of NN can be used for the pyrogen test in rabbits. But in the future, if necessary a standard consisting of endotoxin will be used, due to its better comparability of results obtained by LAL and rabbit tests.

Animals↗
PubMed1990

[The effects and properties of sodium nucleinate used as a pyrogen working standard. 7. Pyrogen removal by filtration and pyrogen destruction by steam sterilization].

Solutions containing bacterial lipopolysaccharides (P) and sodium nucleinate (NN) solutions filtered through cellulose asbestos filters became pyrogen free. But the filters, with respect to the pyrogenicity of these solutions, became earlier exhausted in case of NN than in case of P. A 12-min heating to 121 degrees C in the autoclave led to a significant lowering of pyrogenicity both in P- and in NN-solutions. After a 2-h heating in same conditions both P- and NN-solutions in the chosen ranges of concentration became pyrogen free.

Animals↗
PubMed2002

Evaluation of the in vitro pyrogen test system based on proinflammatory cytokine release from human monocytes: comparison with a human whole blood culture test system and with the rabbit pyrogen test.

The reliability of an in vitro pyrogen test system based on proinflammatory cytokine release from human monocytic cells was assessed by comparison with a test system based on a human whole blood culture as well as with the conventional rabbit pyrogen test. The human cells used as the pyrogen indicator cells were newly selected by subcloning of a human monocytic cell line, Mono-Mac-6. The selected cells, named MM6-CA8, responded to various pyrogens, including endotoxin, peptidoglycan (PG), Staphylococcus aureus Cowan 1 (SAC), and poly(I x C), with a high sensitivity and produced proinflammatory cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor alpha. Among these cytokines, IL-6 was produced most sensitively in response to traces of the pyrogens and detected in the largest quantities in the culture medium. The cytokine-producing responses of MM6-CA8 cells correlated significantly with the responses of cultured human whole blood, which represents an ex vivo culture test system reproducing pyrogen-induced cytokine production in the human body. In terms of cytokine inducibility, the pyrogens were ranked in the order endotoxin > PG > poly (I. C) > SAC in both culture systems, a ranking which almost agreed with the ranking of their pyrogenicity as assessed by the rabbit pyrogen test. These results suggest that the in vitro responsiveness of MM6-CA8 cells to various pyrogens is highly relevant for human pyrogenic reactions. Therefore, the in vitro test system is useful and reliable for detecting the presence of materials that are pyrogenic for humans.

Animals↗
PubMed1984

Human leukocytic pyrogen test for detection of pyrogenic material in growth hormone produced by recombinant Escherichia coli.

Human growth hormone is biosynthetically produced in recombinant strains of Escherichia coli as methionyl human growth hormone (met-hGH). When purified from the bacterial culture, met-hGH is biologically active in established assays for growth hormone. Therefore, a phase I trial of met-hGH was carried out in healthy human adults; during the first trial, however, signs, symptoms, and clinical laboratory tests characteristic of an acute-phase response to pyrogenic agents was observed. Prior testing of the met-hGH preparation used in the phase I trial did not reveal evidence of toxicity, and the U.S. Pharmacopeial Convention rabbit pyrogen test, as well as the Limulus amoebocyte lysate (LAL) test, had not detected significant levels of exogenous pyrogens or endotoxin. In addition, standard inhibition studies with added endotoxin showed no inhibition by the LAL test. When this preparation of met-hGH was incubated with human blood mononuclear cells, leukocytic pyrogen (LP) was released into the supernatant medium, suggesting that the preparation contained pyrogenic material. Various lots of met-hGH based on different purification and formulating methods were tested by the human LP assay for contaminating pyrogens. The results of these tests aided in the identification of procedures for met-hGH preparations which did not induce LP in vitro. Thus, subsequent lots of met-hGH which had passed the LP test were used in repeat clinical studies, and no inflammatory or pyrogenic reactions were observed. When the LP test was used, experiments revealed that the original lot of met-hGH was contaminated with endotoxin which had not been detected in the LAL or rabbit pyrogen tests. Lyophilization in glycine-phosphate buffer had resulted in a 10- to 20-fold reduction of endotoxin reactivity in the LAL test and the U.S. Pharmacopeial Convention rabbit pyrogen test. These data provide a probable explanation for the negative result from the LAL and rabbit pyrogen test in the initial lot of met-hGH which induced acute-phase reactions. In addition, these studies demonstrate that the release of LP from human cells is a reliable indicator of the presence of materials that are pyrogenic for humans.

DNA, Recombinant↗
PubMed1970

Studies on steroid fever. II. Pyrogenic and anti-pyrogenic activity in vitro of some endogenous steroids of man.

The pyrogenic properties of some C-19 and C-21 steroids were examined by in vitro incubation of human blood leukocytes with serum-buffer solutions of the steroids and injection of the 18-hr supernatants into rabbits. In previous studies this method demonstrated release of leukocyte endogenous pyrogen by etiocholanolone. With two exceptions, steroids known to cause fever in man, such as 11beta-OH etiocholanolone and 3alpha-hydroxy-5beta-pregnane-20-one were also pyrogenic in vitro. All steroids tested which are nonpyrogenic in man, such as androsterone, 3beta-OH etiocholanolone, and 3alpha, 17alpha-dihydroxy-5beta-pregnan-20-one were also nonpyrogenic in vitro. Solubility in aqueous solution did not correlate with pyrogenic capacity. Inhibition of pyrogen release from human leukocytes in vitro by hydrocortisone and estradiol was demonstrated. Hydrocortisone-treated leukocytes released less pyrogen than did normal leukocytes when stimulated either by etiocholanolone or by phagocytosis of heat-killed staphylococci. On the other hand, estradiol-treated blood leukocytes and mononuclear cells showed significant suppression of pyrogen release when phagocytosis, but not etiocholanolone, was used as the stimulus. When blood cells were incubated with progesterone, greater than normal amounts of pyrogen were released following phagocytosis, and the inhibiting effect of estradiol could be partially reversed. Neither estradiol nor hydrocortisone appeared to act on rabbit leukocytes. These studies indicate that a variety of naturally-occurring steroids may alter pyrogen release from leukocytes. Alterations in steroid balance in man may influence normal temperature regulation and contribute to clinical fevers.

Androsterone↗
PubMed1988

[The effects and properties of sodium nucleinate as a pyrogen working standard. 5. Interactions between pyrogens and corticotropin].

In rabbits, the simultaneous i.v. injection of corticotrophin (ACTH) and bacterial lipopolysaccharide or sodium nucleinate (NN), as well as ATCH application before and after administration of one of the two pyrogens, induces changes in the course of body temperature as compared with other animals injected only one of the pyrogens. Principal differences between the effect of a bacterial lipopolysaccharide and that of sodium nucleinate cannot be observed. At simultaneous pyrogen application, the administration of ACTH leads to a delayed occurrence of temperature increases. Prophylactic ACTH injection induces, if performed only 30 min before pyrogen application, a still greater delay of pyrogen-induced temperature increase, while pyrogens applied 2 h after administration of ACTH induce temperature increases almost immediately. If ACTH is administered after pyrogen application this will at first lead to a temperature reduction, to be followed by repeated increase of temperature so that as a rule temperature curves with two peaks develop. This is true irrespective of whether ACTH application is performed 30, 60, or 90 min after pyrogen administration. Orientation tests have shown that only a part of ACTH present in the test solution can be detected if the biological assay of ACTH is made using the method based on the determination of the ascorbic acid content in the suprarenal glands of prednisolone-treated rats and if one of the two pyrogens simultaneously is applied.

Adrenocorticotropic Hormone↗
PubMed1963

MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS. I. SPECIFICITY OF PYROGENIC TOLERANCE AND THE ROLE OF HYPERSENSITIVITY IN PYROGENICITY, LETHALITY, AND SKIN REACTIVITY.

Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD(50). The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.

Animals↗
PubMed1964

STUDIES ON BACTERIAL PYROGENICITY. 3. SPECIFICITY OF THE UNITED STATES PHARMACOPEIA RABBIT PYROGEN TEST.

The specificity of the first or "presumptive" portion of the USP rabbit pyrogen test was investigated by use of a new absolute standard of reference. The reference standard was a 0.9% sodium chloride solution prepared to be pyrogen-free. Details of the preparation were described. The hypothesis was explored that the temperature response of rabbits after intravenous injection of the standard solution was independent of exogenous pyrogen. Reactions observed among the rabbits in our colony allowed a classification of these animals ranging from "consistently reliable" to "consistently unreliable." Details of the experimental results and implications for pyrogen testing are discussed. The recommendation was made that all rabbit test animals be "screened" in sham and actual tests before being used for pyrogen testing.

Animals↗
PubMed1976

Studies with the International Pyrogen Standard on the sensitivity and reproducibility of pharmacopoeial pyrogen testing.

Rabbits, 27 or 36 in each experiment, were injected with the International Pyrogen Standard (I.P.St.) in different seasons. The maximum temperature rises were registered, randomized and interpreted according to the requirements of the B.P. (1973), U.S.P. (1970), P. Hung. (1970) and P. Nord. (1962). Although the dose of 3.5 ng kg(-1) I.P.St. proved to be non-pyrogenic as tested in summer, when tested in winter the same dose was qualified pyrogenic (to be rejected) by up to one third of the combinations by the criteria of the four Pharmacopoeias. In the spring experiment "to be rejected" qualifications predominated as based on the response of large groups of rabbits. Exclusion of the rabbits showing low sensitivity (before randomization) barely influenced the results with 3.5 ng kg(-1) I.P.St. in the experiment in which the mean temperature rise was 0.49 degrees. If, however, the mean temperature rise was higher (0.57 or 0.69 degrees), such a selection practically resulted in the disappearance of "passable" qualifications in the triplet groups and a great predominance of "to be rejected" qualifications in the larger groups. The dose 7.0 ng kg(-1) consistently proved to be pyrogenic in large groups of rabbits.

Animals↗
PubMed1974

Studies on the mechanism of endogenous pyrogen production. II. Role of cell products in the regulation of pyrogen release from blood leukocytes.

Some characteristics of the process by which endogenous pyrogen (EP), the mediator of fever, is released from cells were examined by using human blood leukocytes incubated in vitro. Studies were designed to examine a possible role for leukocyte products, including EP, in the induction, augmentation, or suppression of pyrogen release by blood leukocytes. Products of stimulated leukocytes, including a partially purified preparation of EP, did not induce significant activation of nonstimulated cells. Also, no evidence was obtained that stimulated cell products either augment or inhibit pyrogen production by other stimulated cells. A feedback control of EP production was thus not observed. A crude preparation of EP, containing other products of activated cells, maintained its pyrogenicity when incubated at pH 7.4 but not at pH 5.0. These studies thus provide no support for hypothesized control mechanisms regulating production of EP by blood leukocytes. By contrast, local inactivation of EP at inflammatory sites may modify the amount of EP entering the blood, and hence fever.

Animals↗
PubMed1982

Interactions between bacterial pyrogen and proteolipid extracted from the cerebrum. (III). Variation in affinity of proteolipid proteins derived from rabbit, rat and chicken cerebrums to bacterial pyrogen.

We undertook comparative studies on the binding of cerebral proteolipids to LPS using rabbits, rats and chickens in order to clarify the differences in inactivating effects of proteolipids from these three sources on the pyrogenicity of LPS. The Sephadex LH-20 column elution profiles of lipid phosphorus and cerebrosides were not significantly different for the three sources of proteolipid, but a larger amount of proteolipid-protein possessing LPS pyrogenicity inactivating potency was eluted with chloroform (C)/methanol(M) (4:1) in rats and chickens than in rabbits. A complex of proteolipid-protein with LPS was obtained in C effluent from incubation mixtures of rat and chicken proteolipids with LPS, corresponding to our previous observation with rabbit proteolipid. The increasing order of binding capacity of the proteolipids derived from the three species was as follows: chicken, rat and rabbit, which was in parallel with pyrogenic inactivating potency. From these data, we suggest that the difference in pyrogenic inactivating potency among the proteolipids of some species depends on the difference in binding capacity of the proteolipids to LPS or probably lipid A.

Animals↗
PubMed1994

Pyrogenic activity of human native and human recombinant interleukins-1 beta: stabilization with albumin enhances the pyrogenic action of recombinant IL-1 beta delivered into the rabbit brain.

The pyrogenic potential of natural and recombinant human IL-1 beta in rabbits was found to be very similar when the substances were given intravenously. Under these conditions, stabilization of rIL-1 beta with human serum albumin (HSA) failed to affect the pyrogenic activity of recombinant IL-1 beta. When the two preparations were administered directly into the PO/AH area of the brain, recombinant IL-1 beta was less pyrogenic than its natural counterpart. This lower pyrogenicity of recombinant IL-1 beta was corrected if the injected material contained HSA, which is known to stabilize in vitro the biological activities of IL-1 beta against slow degradation. The possibility is now considered that the central and peripheral systems for IL-1 inactivation are different. The existence of an intrabrain IL-1 pool is suggested and its significance for neuroimmunomodulation is stressed.

Animals↗
PubMed1990

[The effects and properties of sodium nucleinate as a pyrogen working standard. 8. Pyrogen adsorption to charcoal and plastic].

Not only solutions containing bacterial lipopolysaccharide (P) but also sodium nucleinate (NN) solutions can be made free from pyrogens by treatment with charcoal adsorbing the two pyrogens. When shaking P- and NN-containing solutions with polyethylene granulate, P and NN are also partly adsorbed to this granulate. NN adsorption is smaller than that of P, relative to the determined pyrogenicity of the solutions tested. It could be discussed if this difference could also be interpreted in a way that NN itself and not only a contamination of this substance with lipopolysaccharide is the reason for the pyrogenic effect.

Adsorption↗