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British Medical Journal Mar 1957
Topics: Fever; Humans; Pyrogens
PubMed: 13396301
DOI: No ID Found -
The Journal of Experimental Medicine Dec 1957The "endogenous serum pyrogen" that appears in the circulating blood after a single intravenous injection of endotoxin does not produce leukopenia in normal animals,...
The "endogenous serum pyrogen" that appears in the circulating blood after a single intravenous injection of endotoxin does not produce leukopenia in normal animals, fails to provoke the local Shwartzman reaction, and elicits no "tolerance" when injected daily. Suppression of the febrile response to endotoxin by prednisone does not prevent the appearance of pyrogen in the blood. Animals given large amounts of endotoxin daily continue to respond with high fevers despite failure of endogenous serum pyrogen to appear in detectable amounts after the first two or three injections. Analysis of the response to daily injections shows clearly that the fever during the first 2 hours after administration of endotoxin is unrelated to levels of endogenous serum pyrogen; in contrast, the magnitude of the fever after the 2nd hour correlates well with endogenous pyrogen in some instances. The leukopenic response to endotoxin could not be correlated with the appearance of endogenous serum pyrogen. The differences between endotoxin and endogenous pyrogen and the similarities between leukocyte extracts (sterile exudates) and endogenous pyrogen are summarized and discussed. Dissociation of the febrile response to bacterial endotoxin and levels of endogenous serum pyrogen are discussed and it is concluded that a mechanism involving both direct and indirect action of endotoxins offers the best explanation for the pyrogenic action of these bacterial products.
Topics: Animals; Endotoxins; Fever; Injections; Injections, Intravenous; Interleukin-1; Leukocytes; Pyrogens
PubMed: 13481245
DOI: 10.1084/jem.106.6.787 -
The Journal of Experimental Medicine Oct 1969Polymorphonuclear neutrophilic leukocytes of the dog, cat, and goat release leukocytic pyrogen under the same conditions as the heterophile polymorphonuclear leukocytes...
Polymorphonuclear neutrophilic leukocytes of the dog, cat, and goat release leukocytic pyrogen under the same conditions as the heterophile polymorphonuclear leukocytes of the rabbit. The characteristics of the febrile response to an intravenous injection of homologous leukocytic pyrogen in all four species are very similar: a brisk monophasic fever reaching a peak between 30 and 50 min with smooth defervescence to the baseline by 3 hr. Shivering, which is not obvious in the rabbit, is noted in the dog, cat, and goat during the first 30 min. Quantitative differences in response reveal the cat to be the most sensitive of of these species to homologous leukocytic pyrogen, followed by the rabbit, dog, and goat. The response to heterologous pyrogen is in most cases markedly diminished compared to that after equal doses of homologous protein, suggesting the operation of species specificity, although canine and feline pyrogen behaved very similarly in all tests. Species specificity of leukocytic pyrogen is probably related to amino acid substitutions in different species of a common mammalian protein effector molecule.
Topics: Animals; Cats; Dogs; Fever; Glycogen; Goats; Leukocytes; Neutrophils; Peritonitis; Pyrogens; Rabbits; Species Specificity
PubMed: 5343431
DOI: 10.1084/jem.130.4.707 -
Infection and Immunity Feb 1975Endotoxic lipopolysachharide (LPS) was obtained from phenol-water extraction of cell walls prepared from mass-cultivated Fusobacterium necrophorum. The LPS was...
Endotoxic lipopolysachharide (LPS) was obtained from phenol-water extraction of cell walls prepared from mass-cultivated Fusobacterium necrophorum. The LPS was relatively free of nucleic acids and low in protein, and constituted about 4% of the cell walls. Upon acid hydrolysis, some of the components detected were hexosamines (7.0%), neutral and reducing sugars (50.5%), heptose (6.4%), 2-keto-3-deoxyoctonate (0.8%), lipid A (21.0%), and phosphorus (1.7%). Under electron microscopy the LPS appeared mainly as ribbon-like trilaminar structures, and upon chemical treatment it displayed a behavior resembling that reported in certain enterobacterial LPS. The LPS was lethal to mice, 11-day-old chicken embryos, and rabbits. Endotoxicity in mice was enhanced at least 1,380-fold by the addition of 12.5 mug of actinomycin D. Induced tolerance to lethal effect of the endotoxin and rapidly acquired resistance to infection by F. necrophrum viable cells were also demonstrated in mice. The endotoxin produced both localized and generalized Shwartzman reactions as well as biphasic pyrogenic responses in rabbits. These results firmly establish the presence of a classical endotoxin in F. necrophorum, thus providing strong support to our recent suggestion that cell wall-associated components may contribute significantly to the pathogenicity of F. necrophorum.
Topics: Animals; Bacterial Proteins; Cell Wall; Chick Embryo; Dactinomycin; Endotoxins; Female; Fusobacterium; Heptoses; Hexosamines; Immune Tolerance; Immunity; Immunization; Lethal Dose 50; Lipopolysaccharides; Mice; Microscopy, Electron; Phenols; Phosphorus; Polysaccharides, Bacterial; Pyrogens; Rabbits; Shwartzman Phenomenon
PubMed: 1112618
DOI: 10.1128/iai.11.2.371-379.1975 -
Zeitschrift Fur Naturforschung. C,... 2002The probable antipyretic, antiinflammatory, analgesic and antioxidant properties of Kageneckia oblonga, Rosaceae, were investigated and the major compounds of its active...
The probable antipyretic, antiinflammatory, analgesic and antioxidant properties of Kageneckia oblonga, Rosaceae, were investigated and the major compounds of its active extracts were isolated. The study comprised the acute toxicity of the extracts of global methanol, hexane, dichloromethane and methanol. The cytotoxicity of global methanol extract was studied in three tumoral cell lines. All the extracts exhibited the pharmacological activities under study. Methanol and dichloromethane were the most toxic extracts. From the global methanol extract, isolations were performed of prunasin, 23,24- dihydro-cucurbitacin F, and a new cucurbitacin, 3beta-(beta-D-glucosyloxy)-16alpha,23alpha-epoxycucurbita-5,24-diene-11-one. The cytotoxicity of both cucurbitacins on human neutrophils at the assayed concentrations was not statistically significant. In-vitro assays showed that both cucurbitacins can be partly responsible for the analgesic, antipyretic, and anti-inflammatory activities. Evaluation was done of the cytotoxicity of global methanol extract, 23, 24-dihydrocucurbitacin F, aqueous extracts and prunasin against P-388 murine leukaemia, A-549 human lung carcinoma and HT-29 colon carcinoma. Since global methanol extract presented a strong cytotoxicity against P-388 murine leukaemia, A-549 human lung carcinoma, and HT-29 cell lines, it is highly probable that this extract contain one or more cytotoxic compounds that could be investigated for their potential use as an agent against cancer.
Topics: Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Survival; Colonic Neoplasms; Female; Fever; Guinea Pigs; Hexanes; Humans; Lung Neoplasms; Male; Methane; Methanol; Methylene Chloride; Mice; Phytotherapy; Plant Extracts; Plants, Medicinal; Pyrogens; Rabbits; Rosaceae; Structure-Activity Relationship; Triterpenes; Tumor Cells, Cultured; Water
PubMed: 11926521
DOI: 10.1515/znc-2002-1-218 -
BMC Pharmacology & Toxicology Sep 2014Pyrogen detection is of utmost importance in pharmaceutical industry, laboratories and health care institutions. As an alternative to the animal-consuming rabbit pyrogen... (Comparative Study)
Comparative Study
BACKGROUND
Pyrogen detection is of utmost importance in pharmaceutical industry, laboratories and health care institutions. As an alternative to the animal-consuming rabbit pyrogen test or Limulus amoebocyte lysate test, the monocyte activation test was introduced as a gold standard method in the European Pharmacopoeia. However, the monocyte activation test has not gained wide acceptance in practice.
METHODS
We stimulated bovine whole blood with different endotoxin preparations (lipopolysaccharide E.coli 0127:B8 and 0113:H10), as well as the non-endotoxin pyrogens peptidoglycan and lipoteichoic acid. Prostaglandin E₂ (PGE₂) served as read out.
RESULTS
Employing PGE₂ as read out enabled detection limits of 0.04 EU/ml for lipopolysaccharide 0127:B8, 0.25 EU/ml for lipopolysaccharide 0113:H10 and 10 μg/ml of lipoteichoic acid as well as peptidoglycan. To evaluate the bWBA test system as a possible alternative to the MAT we performed a peer-to-peer comparison of the two methods and confirmed similar sensitivities.
CONCLUSIONS
In conclusion, the bovine whole blood assay (bWBA) reproducibly enabled sensitive detection of endotoxin and non-endotoxin pyrogens and may thus become a viable alternative for pyrogen testing.
Topics: Animals; Cattle; Monocytes; Pyrogens
PubMed: 25209100
DOI: 10.1186/2050-6511-15-50 -
The Journal of Physiology Oct 19731. Samples of cisternal cerebrospinal fluid (c.s.f.) were collected from unanaesthetized cats while rectal temperature was continuously recorded. From the same cat,...
1. Samples of cisternal cerebrospinal fluid (c.s.f.) were collected from unanaesthetized cats while rectal temperature was continuously recorded. From the same cat, samples were collected during normal body temperature, during pyrogen fever and when the fever was brought down by an I.P. injection of an antipyretic. Fever was produced by injection of the bacterial pyrogen of Shigella dysenteriae either into the third ventricle, cisterna magna or I.V. The samples of c.s.f. were assayed for PGE(1)-like activity on the rat stomach fundus strip preparation rendered insensitive to 5-HT.2. In samples of c.s.f. collected during normal body temperature, usually either no PGE(1)-like activity was detected, or its activity was low. Higher values were obtained in only a few cats.3. In each experiment the PGE(1)-like activity increased, often many-fold, in samples collected during the pyrogen fever, irrespective, of the route of administration of the pyrogen. However, on I.V. injection, about 1000 times larger doses of the pyrogen were required than on injection into the liquor space to produce fever and the increase in PGE(1)-like activity of cisternal c.s.f.4. The antipyretic drugs indomethacin, paracetamol and aspirin, injected I.P. during the pyrogen fever, brought down temperature, and the PGE(1)-like activity of the cisternal c.s.f. again became low.5. When samples of cisternal c.s.f. were subjected to thin layer chromatography the prostaglandin-like activity was solely or mainly found in the zone corresponding to the prostaglandins of the E series.6. These findings support the theory that pyrogens produce fever by increasing synthesis and release of prostaglandin in the preoptic anterior hypothalamic area, and that antipyretics of the aspirin type bring down this fever because they inhibit this synthesis.7. It is concluded that pyrogen increases prostaglandin synthesis not only in the preoptic anterior hypothalamic area. When injected into the liquor space increased synthesis of prostaglandin probably occurs in many regions near the surface of the brain stem, and when injected I.V. may occur in other parts of the C.N.S. as well. But to produce fever the prostaglandin has to act on the preoptic anterior hypothalamic area.
Topics: Acetaminophen; Animals; Aspirin; Body Temperature; Cats; Cerebral Ventricles; Chromatography, Thin Layer; Cisterna Magna; Fever; Indomethacin; Injections, Intraperitoneal; Injections, Intravenous; Injections, Spinal; Prostaglandins; Pyrogens; Shigella dysenteriae
PubMed: 4588122
DOI: 10.1113/jphysiol.1973.sp010346 -
The Journal of Physiology Apr 19771. The role of 5-hydroxytryptamine (5-HT) in temperature regulation and in fever in the rabbit has been investigated. 2. Intrahypothalamic microinjections of 5-HT in the...
1. The role of 5-hydroxytryptamine (5-HT) in temperature regulation and in fever in the rabbit has been investigated. 2. Intrahypothalamic microinjections of 5-HT in the conscious rabbit alters body temperature in a dose-dependent manner. 3. Low doses (5-5nmol) of 5-Ht and control saline injections produced a small, non-significant increase in temperature, with a long latency. 4. Doses of 14 nmol 5-HT produce a hyperthermia with a 45 min delay; while microinjections of 28 nmol result in a biphasic response; an initial short hypothermia is followed later by a hyperthermia. 5. Depleting the rabbit's brain of 5-HT by pretreatment with p-chlorophenylalanine (PCPA) fails to affect its body temperature at thermoneutral temperatures but significantly impairs the ability to thermoregulate against a cold stress. 6. PCPA pretreatment did not, however, impair the febrile response to bacterial pyrogen and prostaglandin E1. 7. These results reveal a dissociation between the effects of 5-HT depletion on temperature regulation, and on fever. The site of action of 5-HT in temperature regulation must be proximal to the fever input, but distal to the convengence of peripheral and hypothalamic temperature inputs.
Topics: Animals; Body Temperature Regulation; Female; Fenclonine; Fever; Hypothalamus; Male; Prostaglandins E; Pyrogens; Rabbits; Serotonin; Skin Temperature
PubMed: 140237
DOI: 10.1113/jphysiol.1977.sp011775 -
The Yale Journal of Biology and Medicine 1985Certain febrile diseases are unaccompanied by infection or apparent hypersensitivity. In myocardial infarction or pulmonary embolism, for example, fever has been...
Certain febrile diseases are unaccompanied by infection or apparent hypersensitivity. In myocardial infarction or pulmonary embolism, for example, fever has been attributed to inflammation and/or tissue necrosis. Exogenous (microbial) pyrogens stimulate both human and animal monocytes/macrophages to produce endogenous pyrogen (EP) in vitro. To determine if plasma and cellular endogeneous mediators (EMs) of inflammation induced EP production, human mononuclear cells (M/L) were incubated for 18 hours with varying amounts of EM and the supernates assayed for EP in rabbits. Neutrophils (PMNs), which do not generate EP and yet are a feature of acute inflammation, were tested. Neither viable, phorbol myristic acetate-stimulated PMNs nor sonicated PMNs, red blood cells, or M/L stimulated human monocytes to produce EP. Human C3b and C5a, which mediate phagocytosis and chemotaxis, respectively, were also inactive. Despite its chemoattractant properties, the synthetic peptide FMLP failed to induce EP release. Since Poly I:Poly C (PIC: a synthetic, double-stranded RNA) is a potent pyrogen in rabbits, we investigated PIC, as well as a native, single-stranded RNA (from E. coli) and DNA (from calf thymus). None was active in vitro, and only PIC caused fever when given to rabbits intravenously. In summary, we have been unable to find an endogenous activator of EP from human monocytes to explain fevers associated with inflammation alone.
Topics: Humans; In Vitro Techniques; Interleukin-1; Monocytes; Neutrophils; Proteins; Pyrogens
PubMed: 3875936
DOI: No ID Found -
Innate Immunity Oct 2015The monocyte activation test (MAT) is a promising replacement of the currently used rabbit pyrogen test to detect the presence of pyrogens in injectable drugs. In the...
The monocyte activation test (MAT) is a promising replacement of the currently used rabbit pyrogen test to detect the presence of pyrogens in injectable drugs. In the MAT, drugs are incubated with a source of human monocytes and production of pyrogenic cytokines used as readout. The best results are obtained with human mononuclear cells (MNC). However, donor variation requires testing on four different donors, and for most laboratories access to fresh MNCs is a problem. The current study shows how to overcome these problems using frozen pooled MNCs. The MAT is performed by thawing pooled MNC and co-culture overnight with a test substance, LPS or non-endotoxin pyrogens, with IL-6 production as the readout. The study demonstrates that fresh and frozen pooled MNC have comparable sensitivity. The reproducibility of the MAT performed with different batches of frozen pooled MNC was excellent. Different non-endotoxin pyrogens induce IL-6, confirming the ability of the MAT to detect a variety of pyrogens. In conclusion, the MAT using frozen pooled MNC is a highly sensitive, specific and reproducible pyrogen test, able to detect and quantify endotoxin and non-endotoxin pyrogenic contaminations in parenteral pharmaceuticals.
Topics: Animals; Cells, Cultured; Cryopreservation; Drug Evaluation; Humans; Infusions, Parenteral; Interleukin-6; Monocytes; Pharmaceutical Preparations; Pyrogens; Rabbits; Reproducibility of Results; Sensitivity and Specificity
PubMed: 25907070
DOI: 10.1177/1753425915583365