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PubMed1977

Factors affecting pyrogen testing in rabbits.

A response of rabbits to toxins causing fever and originating from microorganisms may be related to different factors. In this respect the race and the age of the animals were examined as variables. Three rabbit strains of local origin were used: New Zealand White, White of Dendermonde and Holland race. As pyrogen preparations sterile surface water and preparations of E. coli strains were used. A bacterial count, as for ordinary drinking water examination, was carried out in order to evaluate the presence of bacteria to pyrogenicity. An attempt was made to remove the pyrogens by absorption on charcoal and by filtration through asbestos filters. A decrease of pyrogenicity was obtained but the fever toxins did not completely disappear with the simple procedure. The stability of the toxins found in surface waters was examined over a short range of preservation. Only a slow decrease in pyrogenic activity was seen. Pyrogens of E. coli were prepared in vitro, but used unpurified. A slight difference in the strains was observed, but all E. coli's were pyrogenic.

Age Factors↗

PubMed1978

Heterogeneity of group A streptococcal pyrogenic exotoxin type B.

Streptococcal pyrogenic exotoxin type B purified from culture filtrates of either the NY-5 or T-19 strain of group A streptococcus was found to be heterogeneous in charge. Three protein fractions with isoelectric points of 8.0, 8.4, and 9.0 were isolated by differential solubility in ethanol and acetate-buffered saline followed by isoelectric focusing and shown to be antigenically identical to streptococcal pyrogenic exotoxin type B. The molecular weights of all three fractions were approximately 17,500, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with aggregates forming in the presence of hyaluronic acid. Only the pI 8.4 fraction showed the characteristic activities of streptococcal pyrogenic exotoxin in rabbits: pyrogenicity and ability to enhance susceptibility to lethal endotoxin shock. The pI 8.0 and pI 9.0 fractions were not pyrogenic, but could be used to immunize against pyrogenicity. These two fractions failed either to enhance lethal endotoxin shock or to immunize against enhancement activity. When the isolated fractions were electrofocused again they appeared heterogeneous, suggesting an instability of the B toxin molecular forms.

Amino Acids↗

PubMed1975

Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic neurons in the cat.

Leukocytic pyrogen and sodium acetylsalicyclate (NaASA) were microinjected into the preoptic/anterior hypothalamic (PO/AH) area of cats to examine the direct effects of these agents on identified thermoregulatory neurons. The pyrogen and NaASA were administered under thermoneutral conditions to preparations that displayed peripheral or peripheral and central thermoreceptor input. The majority of neurons studied with proximate injection of pyrogen responded in a manner consistent with the set-point hypothesis; i.e., units responding to heating with increased activity were depressed and those showing a decreased discharge with the heat test were excited by the pyretic agent. Injection of NaASA without pyrogen pretreatment caused no significant modification of thermoregulatory neuron discharge in most cases. However, when NaASA was administered after pyrogen, it uniformly antagonized the pyretic effect causing a return of the discharge to the control rate. It may be concluded that pyrogen and NaASA act directly in the PO/AH area to produce fever and antipyresis, respectively, by appropriately offsetting the activity of thermoregulatory neurons.

Animals↗

PubMed1979

Effects of pyrogen on the medullary temperature-responsive neurone of rabbits.

Effects of intravenously injected endogenous pyrogen on the unit activity of temperature-responsive neurones (TR neurones) of medulla oblongata were investigated in urethanized rabbits with an intact or lesioned preoptic/anterior hypothalamic area (PO/AH). TR neurones of the medulla responded to pyrogen in the same manner as did those of the PO/AH; the firing rate in the warm-responsive neurones were depressed and the cold-responsive neurones augmented. However, one-fourth of the medullary TR neurones did not respond to pyrogen in the PO/AH intact group (the control group). Following lesion of the PO/AH, the relative frequencies of TR neurones affected by pyrogen decreased as compared with those in control, and such was suggested to be more apparent in TR neurones discharging at rates of 10 imp./sec or more. Effects of the PO/AH-lesion were also seen in that the magnitude of the facilitatory or inhibitory effect of pyrogen was reduced in the PO/AH-lesioned group as compared with the control group. In some TR neurones an antipyretic agent (Sulpyrine, 48--151 mg/kg) was found to abolish responses to pyrogen.

Action Potentials↗

PubMed1975

[Pyrogen testing in vitro using the Limulus test].

The applicability of the Limulus test for the pyrogen test was checked in comparison to the pyrogen test in rabbits. In 6 out of 24 lots of raw materials and drugs pyrogens could be detected by means of the pyrogen test in rabbits. 2 of these 6 lots showed positive reaction in the Limulus test, there were no false positive results. Testing 7 bacterial strains in modified quantity of germs the Limulus test turned out to be more sensitive than the pyrogen test in rabbits. The application of this in vitro test as a complement to the pyrogen test in rabbits for a certain kind of problems is discussed.

Animals↗

PubMed1977

Pyrogen tests of infusions, blood anticoagulant solutions, plastic materials and rubber products.

The methods of the pyrogen test in rabbit as adopted by the authors are presented. The test includes positive and negative controls. The conditions of using the same rabbits on two consecutive days are discussed. Methods of sampling of sterile infusions and the preparation for pyrogen test of anticoagulant solutions containing citrate, phosphate and/or edetate ions are presented. The necessity of pyrogen control of distilled water is stressed. Attention is called on the importance of testing for pyrogenicity of the plastic materials and the rubber-wares to be applied during the production of anticoagulant solutions and infusions. A pyrogen test highly sensitive for detecting traces of detergent is applied for washed glassware. It is emphasized that sensitive pyrogen tests are indispensable not only when new derivatives are being introduced, but also during routine control, because occasional changes in the manufacturer's technology may sometimes be demonstrable in this way.

Animals↗

PubMed1990

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit.

Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic tolerance between brain and peripheral tissues, however, has not been ascertained.

Animals↗

PubMed1991

Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1976

Colchicine stimulation of pyrogen production by human blood leukocytes.

The effect of colchicine, an anti-inflammatory agent, on endogenous pyrogen (EP) production by human blood leukocytes in vitro was examined. Colchicine not only failed to suppress EP production by human leukocytes stimulated by phagocytosis, but, in the absence of other stimuli, micromolar concentrations of the drug induced pyrogen production and release by both polymorphonuclear (PMN) and mononuclear leukocytes. The response was dose related, occurring at concentrations above 0.1 muM. Colcemid and vinblastine, other agents which bind to microtubular protein, also induced pyrogen release from human leukocytes, whereas lumicolchicine, a light-alerted derivative of colchicine without affinity for microtubules, was ineffective. Colchicine did not induce EP production by rabbit leukocytes, even at 100 muM concentration. Studies of the mechanism of PMN leukocyte activation by Colcemid indicated that although the time required for contact between drug and leukocyte was brief, pyrogen production and release did not begin for 6 or more hours. If added during this time, puromycin prevented subsequent production and release of pyrogen. These results indicated that agents which interfere with the assembly of microtubules induce EP production and secretion by human leukocytes in vitro.

Animals↗

PubMed1978

The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues.

The pyrogenic efect of the synthetic adjuvant N-acetylmuramyl-L-alanine-D-isoglutamine, also known as muramyl dipeptide (MDP), was studied in rabbits. MDP induced biphasic fevers in rabbits, but two structural analogues, N-acetylmuramyl-L-alanine-D-glutamic acid (MDPA) and the dimethylester of MDPA, were 10 times less pyrogenic. This finding was supported by studies in which MDP and its analogues released leukocytic pyrogen (LP) from rabbit phagocytic cells in vitro. In addition, MDP released LP from human phagocytes. Human phagocytes, however, required a 10-fold greater concentration of MDP than did rabbit cells. The structural analogues were similarly less effective than the parent molecule in releasing LP from human cells. All preparations of MDP were negative in the limulus amebocyte lysate test and failed to show pyrogenic cross-tolerance with bacterial endotoxin. Thus MDP, which is a pyrogenic molecule, is also able to release LP from rabbit phagocytes and to a lesser degree from human phagocytes, but does not cause gelation of limulus amebocyte lysate.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1977

The production of antibody against human leukocytic pyrogen.

Human peripheral blood leukocytes were stimulated with killed staphylococci in vitro to release leukocytic pyrogen (LP). Supernates from these stimulated leukocytes were concentrated, emulsified in Freund's complete adjuvant, and injected intradermally into rabbits. After seven monthly booster injections, rabbit antiserum destroyed the pyrogenic activity of human LP, and the titer of this neutralizing ability increased in the subsequent 7 mo. The pyrogen-neutralizing capacity of the rabbit antiserum was recovered in the globulin fraction, the IgG and IgM peaks of Sephadex G-200, and the acid-eluted fraction of a goat anti-rabbit IgG immunoadsorbant. The neutralizing antibody was specific for human LP inasmuch as it had no effect on rabbit, guinea pig, or monkey LP. When coupled to Sepharose, this antibody bound human LP; after acid elution from this immunoadsorbant, LP was recovered without loss of biologic or chemical characteristics. The antiserum was also absorbed with stimulated leukocyte supernates which did not contain LP, and this had no effect on the titer of anti-LP. Crude human LP, eluted from immunoadsorbant columns prepared from absorbed antiserum, contained significantly reduced contaminating protein when evaluated by polyacrylamide gel electrophoresis. These studies have established that specific antibody to human leukocytic pyrogen can be produced. This antibody is useful in the further study and purification of leukocytic pyrogen and its role in the pathogenesis of human fever.

Animals↗

PubMed1976

Pyrogen from mouse macrophages causes fever in mice.

Mouse peritoneal macrophages, after phagocytosis, release an endogenous (leucocyte) pyrogen. Intravenous injection of stimulated cell culture supernatant produces a prompt, monophasic fever in mice maintained in a 35 degree environment. The pyrogen is distinct from endotoxin, and resembles cell pyrogens of other species in heat-lability and pronase sensitivity. Human leucocyte pyrogen produces identical responses in mice. Measurement of fever in mice appears to provide a sensitive biological assay for endogenous pyrogens.

Animals↗

PubMed1976

[Effect of cytostatic drugs on fever development following administration of bacterial pyrogen].

A study was made of the development of pyretic reaction to the administration of a bacterial lipopolysaccharide (pyrogenal) after preliminary treatment of rabbits with actinomycin D and cortisone. Such treatment failed to change the reactivity of thermoregulating centres to the endogenous pyrogen. Intravenous injection of bacterial pyrogen was followed by marked shortening of pyretic reaction; the reaction was markedly inhibited in response to its intracysternal administration. An important role played by polymorphonuclear leukocytes in the formation of endogenous pyrogens in the mechanism of pyrexia induced by bacterial pyrogens was shown in this work.

Animals↗

PubMed1975

[The effect of leukocyte pyrogen on thermosensitive neurons of the anterior hypothalamus].

Impulse activity of neurons of the medial preoptic and septal brain areas of rabbits caused by variations in the local temperature and systemic injections of the leukocytic and bacterial pyrogens was studied. The firing rate of the warmsensitive neurons decreased and that of the cold thermodetectors was activated as a result of pyrogen action. As compared with the bacterial pyrogen, leukocytic pyrogen caused a more rapid decrease of the warmthermodetector activity. Thermoneutral neurons failed to react considerably either to the leukocytic or to the bacterial pyrogen.

Animals↗

PubMed1992

[The place of pyrogen therapy in the modern treatment of schizophrenia patients].

The author analyses experience gained with the use of the pyrogenic drugs sulfazin and pyrogenal in the treatment of schizophrenic patients. Pyrogenal and sulfazin were administered to 26 patients with different forms of schizophrenia to overcome psychopharmacotherapeutic resistance and to 11 patients to enhance the sensitivity to insulin during insulin coma therapy. Based on the clinical analysis the author demonstrates the efficacy of the use of the pyrogenic drugs, particularly pyrogenal, in schizophrenic patients in order to overcome the resistance to pharmacotherapy and insulin.

Convulsive Therapy↗

PubMed1978

Further studies on the antipyretic action of polymyxin B in pyrogen-induced fever.

A study of the antipyretic effect of polymyxin B was undertaken to determine how this agent reduces fever in rabbits. It involved the effects of the drug: (1) on fever induced by exogenous pyrogenes (E. coli lipopolysaccharide, synthetic double-stranded ribonucleic acid, sodium nucleinate from yeast) and leucocytic pyrogen, (2) on the release of endogenous pyrogen in vivo and in vitro, and (3) on leucocytic and exogenous pyrogens in vitro. The results indicate that polymyxin B produces an antipyretic effect in endotoxin-induced fever primarily by an interaction of this cationic macromolecule with the anionic endotoxin molecule. Further it is likely that polymyxin B inhibits endogenous pyrogen synthesis and/or release from polymorphonuclear leucocytes.

Animals↗

PubMed1978

[Body temperature and the reaction to pyrogenal in germ-free and ordinary animals].

Body temperature, as well as pyrexia in response to pyrogenal in germfree and conventional mice and miniature piglets were studied. A decrease of the mean body temperature in the intact germ-free mice and miniature piglets in comparison with conventional animals of the corresponding species was revealed. The absence of marked pyretic response to pyrogenal after intraperitoneal injections of 10 minimal pyrogenic doses to mice and after intramuscular injections of 500 minimal pyrogen doses of pyrogenal to miniature piglets was observed in germfree animals. The data obtained indicated an important role of autoflora in the development of the organism capacity to temperature reaction and pyrexia.

Animals↗

PubMed1979

Production of endogenous pyrogen.

The production and release of endogenous pyrogen by the host is the first step in the pathogenesis of fever. Endogenous pyrogen is a low-molecular-weight protein released from phagocytic leukocytes in response to several substances of diverse nature. Some of these agents stimulate production of endogenous pyrogen because they are toxic; others act as antigens and interact with either antibody or sensitized lymphocytes in order to induce its production. Some tumors of macrophage origin produce the molecule spontaneously. Whatever the mechanism involved, endogenous pyrogen is synthesized following transcription of new DNA and translation of mRNA into new protein. Once synthesis is completed, the molecule is released without significant intracellular storage. Recent evidence suggests that following release, molecular aggregates form which are biologically active. In its monomer form, endogenous pyrogen is a potent fever-producing substance and mediates fever by its action on the thermoregulatory center.

Animals↗