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The Yale Journal of Biology and Medicine 1974The mechanism of fever in patients with Hodgkin's disease was investigated by examining endogenous pyrogen production by blood, spleen, and lymph node cells incubated in... (Review)
Review
The mechanism of fever in patients with Hodgkin's disease was investigated by examining endogenous pyrogen production by blood, spleen, and lymph node cells incubated in vitro. Blood leucocytes from febrile or afebrile patients with Hodgkin's disease did not produce pyrogen spontaneously. Spleen cells, however, frequently released pyrogen during initial incubations, unlike spleen cells from patients with non-malignant diseases. Pyrogen production occurred from spleens without observed pathologic infiltrates of Hodgkin's disease. Lymph nodes involved with Hodgkin's disease produced pyrogen more frequently than did nodes involved with other diseases. Pyrogen production by tissue cells was prolonged, required protein synthesis, and in some cases was due to mononuclear cells; it did not correlate with fever in the patient. These studies demonstrate spontaneous production of endogenous pyrogen in vitro by lymphoid tissue cells from patients with Hodgkin's disease.
Topics: Animals; Cycloheximide; Fever; Hodgkin Disease; Humans; Leukocytes; Lymph Nodes; Lymphoma; Protein Biosynthesis; Pyrogens; Rabbits; Spleen; Time Factors
PubMed: 4611062
DOI: No ID Found -
Journal. Palestine Arab Medical... Jul 1947
Topics: Pyrogens
PubMed: 20259834
DOI: No ID Found -
Clinical Infectious Diseases : An... Oct 2000Fever is thought to be caused by endogenous pyrogenic cytokines, which are elaborated and released into the circulation by systemic mononuclear phagocytes that are... (Review)
Review
Fever is thought to be caused by endogenous pyrogenic cytokines, which are elaborated and released into the circulation by systemic mononuclear phagocytes that are activated by exogenous inflammatory agents and transported to the preoptic-anterior hypothalamic area (POA) of the brain, where they act. Prostaglandin (PG) E2 is thought to be an essential, proximal mediator in the POA, and induced by these cytokines. It seems unlikely, however, that these factors could directly account for early production of PGE2 following the intravenous administration of bacterial endotoxic lipopolysaccharides (LPS), because PGE2 is generated before the cytokines that induce it are detectable in the blood and the before cyclooxygenase-2, the synthase that they stimulate, is expressed. Hence other, more quickly evoked mediators are presumed to be involved in initiating the febrile response; moreover, their message may be conveyed to the brain by a neural rather than a humoral pathway. This article reviews current conceptions of pyrogen signalling from the periphery to the brain and presents new, developing hypotheses about the mechanism by which LPS initiates fever.
Topics: Brain; Complement System Proteins; Cyclooxygenase 2; Cytokines; Dinoprostone; Fever; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrogens; Signal Transduction; Synaptic Transmission
PubMed: 11113020
DOI: 10.1086/317522 -
Alternatives To Laboratory Animals :... Jul 2016In the quality assurance of medical products, tests for sterility are essential. For parenteral pharmaceuticals, avoiding the presence of pyrogens is crucial. These... (Review)
Review
In the quality assurance of medical products, tests for sterility are essential. For parenteral pharmaceuticals, avoiding the presence of pyrogens is crucial. These fever-inducing substances (endotoxins and non-endotoxins) are not eliminated by standard sterilisation processes, and are biologically active once in the bloodstream, causing risks to human health, ranging from mild reactions (e.g. fever) to septic shock and death. Therefore, for injectable formulations, pyrogen testing is mandatory. Over the years, various pyrogen testing methods have been introduced, namely: in the 1940s, the rabbit pyrogen test, which is an in vivo test that measures the fever reaction as an endpoint; in the 1970s, the Limulus Amoebocyte Lysate (LAL) test, which is an in vitro test (with the haemolymph of the horseshoe crab) that specifically detects endotoxin; and in 2010, the Monocyte-Activation Test (MAT), which is a non-animal based in vitro pyrogen test that represents a full replacement of the rabbit test. Due to the ubiquity and biological significance of pyrogens, we are currently further developing the MAT so that it can be used for other applications. More specifically, our focus is on the detection of pyrogenic contamination on medical devices, as well as on the measurement of air quality. In addition, further improvements to permit the use of cryopreserved blood in the MAT, to overcome the limitations in the availability of freshly-drawn blood from human donors, are ongoing.
Topics: Animal Testing Alternatives; Animals; Cytokines; Gene Expression Regulation; History, 20th Century; History, 21st Century; Horseshoe Crabs; Humans; Limulus Test; Monocytes; Pyrogens; Rabbits
PubMed: 27494624
DOI: 10.1177/026119291604400305 -
Toxicology in Vitro : An International... Aug 2021The Bacterial Endotoxin Test (BET) is a method for exclusion of endotoxin-related pyrogen contamination in pharmaceutical products, as an alternative to the Rabbit... (Review)
Review
The Bacterial Endotoxin Test (BET) is a method for exclusion of endotoxin-related pyrogen contamination in pharmaceutical products, as an alternative to the Rabbit Pyrogen Test (RPT). However, BET does not detect a broad range of biologically relevant pyrogens, and interferences can limit its practical use for different medical products. This work aimed to scope the evidence in the scientific literature for case-by-case validity assessments of BET in different uses for medical products. A search strategy was conducted in PubMed, Scopus, and Web of Science in April 2020, according to the PRISMA-ScR statement. Twenty-two references were included, evaluating medical products for endotoxin contamination through both BET and RPT according to standardized protocols. A critical appraisal was performed through ToxRTool, followed by data extraction and qualitative synthesis of outcomes and methodological issues. Four classes of products assessed by BET were identified, including nanoparticles, drugs, blood and biological products. A considerable variation was observed on the BET methods used. Collectively, the evidence indicates different factors influencing the outcome of BET, including the chemical nature of samples that may cause interference depending on the selected method. While some applications to medical products appear adequate, others, such as nanoparticles, may require the use of different in vitro pyrogen testing methods, reinforcing the need for case-by-case validation for each BET method and type of medical product.
Topics: Animal Testing Alternatives; Animals; Biological Assay; Endotoxins; Pyrogens; Rabbits
PubMed: 33831473
DOI: 10.1016/j.tiv.2021.105160 -
Trends in Biotechnology Aug 2001
Review
Topics: Animals; Arthropod Proteins; Blood Coagulation; Endotoxins; Enzyme Precursors; Genetic Engineering; Horseshoe Crabs; Pyrogens; Recombinant Proteins; Serine Endopeptidases
PubMed: 11451451
DOI: 10.1016/s0167-7799(01)01694-8 -
Lancet (London, England) Jul 1979
Topics: Body Temperature; Fever; Humans; Immunity, Innate; Infections; Pyrogens
PubMed: 89286
DOI: No ID Found -
Japanese Journal of Infectious Diseases Mar 2020Fever is a systemic inflammatory response of the body to pyrogens. Nuclear factor κB (NF-κB) is a central signaling molecule that causes the excessive secretion of...
Fever is a systemic inflammatory response of the body to pyrogens. Nuclear factor κB (NF-κB) is a central signaling molecule that causes the excessive secretion of various pyrogen-induced pro-inflammatory factors. This study explored the feasibility of a novel reporter gene assay (RGA) for pyrogen detection using RAW264.7 cells stably transfected with the NF-κB reporter gene as a pyrogenic marker. The RGA could detect different types of pyrogens, including the lipopolysaccharide of gram-negative bacteria, the lipoteichoic acid of gram-positive bacteria, and the zymosan of fungi, and a good dose-effect relationship was observed in terms of NF-κB activity. The limits of detection of the RGA to those pyrogens were 0.03 EU/ml, 0.001 μg/ml, and 1 μg/ml, respectively. The method had good precision and accuracy and could be applied to many molecules (e.g., nivolumab, rituximab, bevacizumab, etanercept, basiliximab, Haemophilus influenzae type b conjugate vaccine, 23-valent pneumococcal polysaccharide vaccine, group A and group C meningococcal conjugate vaccine, diphtheria, tetanus, pertussis [acellular, component], poliomyelitis [inactivated] vaccine, and imject alum adjuvant). The results of this study suggest that the novel RGA has a wide pyrogen detection spectrum and is sufficiently sensitive, stable, and accurate for various applications.
Topics: Animals; Biological Assay; Fever; Genes, Reporter; Limit of Detection; Mice; NF-kappa B; Pyrogens; RAW 264.7 Cells; Sensitivity and Specificity
PubMed: 31666494
DOI: 10.7883/yoken.JJID.2019.163 -
ALTEX 2023The use of pyrogen tests to assess the risk of endotoxin in biological products has increased recently due to concerns of some regulatory authorities about products...
The use of pyrogen tests to assess the risk of endotoxin in biological products has increased recently due to concerns of some regulatory authorities about products exhibiting low endotoxin recovery (LER). Manufacturers increasingly seek to reduce the use of animals unless essential to assure patient safety. The current study compares the ability of the monocyte activation test (MAT) and the bacterial endotoxin test (BET) to the rabbit pyrogen test (RPT) to detect endotoxin spikes in samples of products shown to exhibit LER. Product samples or water were spiked with endotoxin and held for three days or tested immediately in the BET, the RPT, and two variations of the MAT at the same time. Results show high sensitivity to endotoxin of both the BET and MAT, and much lower sensitivity of the RPT, indicating that much higher levels of reference standard endotoxin are required to induce pyrogenicity in the RPT than the 5 endotoxin units (EU) per kg common threshold. The results of the BET and MAT correlated well for the detection of endotoxin spike in water. We also show that LER (masking of endotoxin) found in the BET is also seen in the MAT and RPT, suggesting that the products themselves elicit a biological inactivation of spiked endotoxin over time, thereby rendering it less or non-pyrogenic. We conclude that the non-animal MAT option is a suitable replacement for the RPT to measure spiked endotoxin in biopharmaceuticals.
Topics: Animals; Rabbits; Endotoxins; Pyrogens; Animal Testing Alternatives; Monocytes; Biological Assay
PubMed: 35796330
DOI: 10.14573/altex.2202021 -
Federation Proceedings Jan 1979The 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...
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.
Topics: Animals; Humans; Leukocytes; Phagocytes; Protein Biosynthesis; Pyrogens; Radioimmunoassay; Species Specificity; Structure-Activity Relationship; Transcription, Genetic
PubMed: 759239
DOI: No ID Found