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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↗
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↗
PubMed1977

Comparison of endotoxin and leukocytic pyrogen pyrogenicity in newborn guinea pigs.

Guinea pigs under 8 days of age generally are unable to develop fever (viz., deltaTre greater than 0.5 degrees C) in response to a standardized dose of endotoxin (2 mug/kg iv of Salmonella enteritidis [SE]). This study was undertaken to determine whether this lack of responsiveness might be due to an incapacity of leukocytes from young neonates to produce sufficient leukocytic pyrogen (LP). Three series of experiments were performed at Ta = 27 degrees C: guinea pigs aged 0-2, 4, and 8 days were injected iv with: a) 2, 4, 8, or 16 mug/kg of SE, b) 0.1, 0.5, or 1.0 ml of LP generated by 8 mug of SE/25 X 10(6) leukocytes from adult guinea pigs (LPa), or c) 0.1 or 1.0 ml of LP generated by 8 mug of SE/25 X 10(6) leukocytes from 0-5-, 6-12-, and 13-16-day-old guinea pigs (LPn). Adult guinea pigs received iv 1.0 ml of LPa or LPn. The results revealed that fever could be induced in these animals from birth, but the required doses of SE, LPa and LPn were greater the younger the guinea pigs. Under these conditions, LPn, regardless of the donors' ages, produced fever in all the recipients. It is concluded that the pyrogenic unresponsiveness of newborn guinea pigs to endotoxin may be related not to an inability of leukocytes from these neonates to elaborate LP, but rather to an insensitivity of, presumably, their hypothalamic febrogenic mechanisms to low levels of LP.

Age Factors↗
PubMed1992

[The action of pyrogenal and endogenous pyrogen on visceral afferent systems].

Pyrogenal in the dose 5 mcg increased the adrenaline release in dogs. Interleukin-1 increased the noradrenaline release. Neither capsaicin, nor M- and N-cholinoreceptor blockade, nor pre-decentralization of the inferior mesenteric ganglion, abolished the effects. Mechanical and chemical stimuli during continuous perfusion of the colon with subliminal doses of pyrogenal increased the adrenaline release, too. A possible direct effect of endotoxins on peripheral adrenergic neurons, is discussed.

Afferent Pathways↗
PubMed1976

[Role of the adenyl cyclase system in achieving the immunogenesis-stimulating action of bacterial lipopolysaccharides--pyrogenal and endogenous serum pyrogen].

Experiments were conducted on rabbits immunized intraperitoneally with corpuscular typhoid vaccine; the number of antibody-forming cells in the spleen proved to increase after tha administration of bacterial lipopolysaccharide (LPS)--pyropeneal, and endogenous serum pyrogen (EPS) together with theopylline. The data obtained indicated that the adenylcyclase system played a certain role in the mechanism of the stimulating action of LPS and EPS.

Adenylyl Cyclases↗
PubMed1977

Human leukocytic pyrogen: purification and development of a radioimmunoassay.

Leukocytic pyrogen is a small endogenous protein that mediates fever. Because of the limitations of bioassays, circulating leukocytic pyrogen has not been demonstrated during fever in humans. The pyrogen was produced in vitro after phagocytosis of staphylococci by blood monocytes. Antibody against the pyrogen was obtained from rabbits immunized with leukocytic pyrogen and the antiserum was purified by solid-phase immunoadsorbants. Purified antibody to the pyrogen was attached to activated Sepharose 4B and used in conjunction with gel filtration to purify the pyrogen. The pyrogen was labeled with 125I and further purified by gel filtration and ion-exchange chromatography. The final preparation of 125I-labeled pyrogen demonstrated a homogeneous band during isoelectric focusing and other separation procedures. With antibody to pyrogen attached to Sepharose, less than 0.1 of a rabbit pyrogenic dose of human leukocytic pyrogen inhibited the binding of 125I-labeled pyrogen to this immunoadsorbant, and this inhibition was not affected by the presence of human serum. Thus, a radioimmunoassay for human leukocytic pyrogen has been developed that may be used to detect circulating pyrogen during fever in humans.

Antibodies↗
PubMed1979

Hypothalamic sensitivity to leukocytic pyrogen of adult and new-born guinea-pigs.

1. Experiments were conducted to localize the hypothalamic site of action of microinjected leucocytic pyrogen and to compare the pyrogenic sensitivity of this locus in adult and new-born guinea-pigs.2. To identify the site reactive to leucocytic pyrogen, bilateral (0.8-1.0 mm from the mid line) injections of 1 microliter were made into conscious adult guinea-pigs via cannulas stereotaxically palced at 0.5 mm intervals and varying depths from the olfactory tegmentum to the mammillary bodies. Injections into the preoptic area produced sharp monophasic fevers with short latencies, whereas injections into circumjacent sites evoked smaller fevers with longer latencies. 3. To assess the ontogeny of the pyrogenic sensitivity of this locus, the febrile response to 1.00, 0.50, and 0.25 microliter leucocytic pyrogen injected bilaterally was compared to 0 to 5-, 6 to 12-, and 13 to 16-day old and in adult guinea-pigs. The minimum pyrogenic dose in both new-born and adult guinea-pigs was 0.25 microliter, but the 0 to 5-day old animals which responded with a fever to this dose were few in number and large in weight; 'small-for age' neonates became hypothermic. 4. The number of febrile animals increased with age; it also could be increased by increasing the dose of leucocytic pyrogen at any age. 5. These results suggest that febrile responsiveness may depend on the stage of development of, presumably, the pyrogen-receptive mechanism. They further imply that the preoptic sites where leucocytic pyrogen acts and thermoafferents are integrated may not be the same, since thermoregulatory capability is fully competent from birth.

Aging↗
PubMed1978

Spontaneous pyrogen production by mouse histiocytic and myelomonocytic tumor cell lines in vitro.

Tumor-associated fever occurs commonly in acute leukemias and lymphomas. We investigated the capacity for in vitro production of pyrogen by three mouse histiocytic lymphoma cell lines (J-774, PU5-1.8, p 388 D1), one myelomonoyctic line (WEHI-3), and tow lymphoma-derived lines, RAW-8 and R-8. Pyrogen was released spontaneously into the culture medium during growth by all cell lines with macrophage or myeloid characteristics including lysozyme production; R-8 cells, of presumed B-lymphocyte origin, did not produce pyrogen. When injected into mice, the pyrogens gave fever curves typical of endogenous pyrogen, were inactived by heating to 56 degrees C and by pronase digestion, and appeared to be secreted continuously by viable cells. Two pyrogenic molecular species produced by H-774 cells were identified by Sephadex filtration, one of mol wt approximately equal to 30,000, and the other greater than or equal to 60,000. By contrast, three carcinoma cell lines of human origin and SV-40 3T3 mouse fibroblasts did not produce pyrogen in vitro. These results suggest that some malignant cells derived from phagocytic cells of bone marrow origin retain their capacity for pyrogen production, and may spontaneously secrete pyrogen during growth.

Adenocarcinoma↗
PubMed1977

Tests alternative to the rabbit bioassay for pyrogens.

The rabbit bioassay is currently the only legally acceptable method to test for pyrogenic contamination of parenteral preparations and medical devices designed to enter the parenterum. However, research efforts have recently made available alternative procedures to test for pyrogens which may have significant value in quality control. Part of the reluctance to accept tests other than the rabbit test may be due to the low visibility of emerging understanding of a significant theory of testing in which it is contended that the parameters of sensitivity and specificity are inversely related and that accuracy is an ideal. The rabbit pyrogen assay will detect 1 to 10 ng of enterobacteriaceal endotoxin (ET). The limulus test will detect 0.01 to 0.1 ng/ml of ET; some of the other tests approach the rabbit assay in sensitivity. Since it is current dogma that pyrogen is equivalent to ET, the basis for the use of ET to standardize pyrogen tests is rationalized. The source of ET in practice is bacterial contamination; therefore, numbers of bacteria that contaminate parenteral preparations can be directly related to potential pyrogenicity. Further, viable counts of bacteria in parenteral preparations, prior to sterilization, is a reliable test for pyrogens. Other tests such as nitroblue tetrazolium reduction and actinomycin-D enhancement of lethality of pyrogen for mice deserve consideration in quality control procedures. The limulus test, the most practical of currently available alternative tests for detection of ET and therefore, of pyrogen has application where the rabbit test cannot be used. Therefore, control personnel must learn of the availability, performance and interpretation of the limulus test. Practical considerations must govern the choice of an alternative test when the use of a test other than the rabbit bioassay is indicated.

Animals↗
PubMed1979

[Experimental protective action of kanamycin, ampicillin and their combination with methyluracil and pyrogenal].

Efficacy of kanamycin, ampicillin and their combinations with methyluracyl and pyrogenal in experimental Coli infections was studied. The antibiotics were administered an hour after the infection. Methyluracyl and pyrogenal were used according to 2 schemes. Scheme No. I: the drug is used daily for 7 days in increasing doses, the last dose is administered 24 hours before the infection. Scheme No. 2: the drug is used once at the moment of the infection. The methyluracyl doses were: 0.5, 1.0, 2.5 mg and 5 mg and 5 mg per a mouse during the following 4 days. The pyrrogenal doses were: 5, 10, 15, 25, 30 and 35 minimum pyrogenic doses. 5 mg of methyluracyl and 35 minimum pyrogenic doses of pyrogenal were used according to scheme No. 2. The most pronounced increase in the efficacy of kanamycin, ampicillin and their combination was observed in the animals treated simultaneously with methyluracyl and pyrogenal according to scheme No. 1. The efficacy of kanamycin and ampicillin increased 3 and 2.68 times respectively. ED50 of kanamycin and ampicillin used in combination in the animals treated with methyluracyl and pyrogenal was lowered 4 and 2.9 times respectively as compared to that in the animal groups treated only with the antibiotic combination and 21 and 15.2 times respectively when the antibiotics were used alone. Sanation of the animal organs was also rather successful. A single administration of methyluracyl and pyrogenal simultaneously with the infection (scheme No. 2) had a lower effect on the efficacy.

Ampicillin↗
PubMed1978

The febrile responses in rabbits and rats to leucocyte pyrogens of different species.

1. We have investigated the effects on body temperature of rats and rabbits of leucocyte pyrogen derived from the blood of rat, rabbit, ox, pig and baboon. 2. In the rabbit intravenous injections (3.5 ml.) of solutions containing leucocyte pyrogen derived from ox, pig and rabbit blood produced fevers with short latencies; no fevers resulted from injections of similar solutions derived from rat or baboon blood. 3. In the rat intraperitoneal injections (2.0 ml.) of solutions containing leucocyte pyrogen derived from ox blood caused a fever, while pig leucocyte pyrogen produced a marked hypothermia. Neither rabbit, baboon, nor rat leucocyte pyrogen had any significant effect on rectal temperature of the rats. 4. Our results show that there is a variability of response in the rat and the rabbit to injection of leucocyte pyrogen of different species; leucocyte pyrogen may be species specific.

Animals↗
PubMed1979

Influence of sex and age on febrile responses to peripheral and central administration of pyrogens in the rabbit.

1. Intravenous injections of leucocytic pyrogen in doses of 15, 30 and 60 mul./kg caused febrile reactions in male rabbits that were related to age of the animal: rabbits under 2 yr of age developed fevers that were related to dose of pyrogen, while rabbits 2-3 yr old showed large febrile responses which were not dose-related.2. Female rabbits of comparable ages generally showed smaller febrile reactions to I.V. leucocytic pyrogen, and still older females (3-5 yr) developed fever only after the largest dose.3. Dose-related febrile responses to 2.5, 5 and 10 mul. leucocytic pyrogen given intracerebroventricularly (I.C.V.) were greater in male rabbits 1-3 yr old than in females of comparable age. Female rabbits 3-5 yr old showed dose-related fevers that were smaller than those of younger animals of both sexes.4. There were no major differences in response to 125, 250 and 500 ng PGE(2), given I.C.V., between male and female rabbits under 2 yr of age. Females 2-3 yr of age had greater responses to PGE(2) than males of comparable age whilst the oldest females showed smaller responses.5. It is concluded that the febrile response of the rabbit to peripheral and central leucocytic pyrogen varies with both age and sex. Differences in sensitivity of central fever controls to endogenous pyrogen in animals of different ages and sexes may account for the different responses to peripheral pyrogen.

Aging↗
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↗