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Toxins Aug 2018A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical... (Comparative Study)
Comparative Study Review
A pyrogen is a substance that causes fever after intravenous administration or inhalation. Gram negative endotoxins are the most important pyrogens to pharmaceutical laboratories. In the International, United States, Japanese and European Pharmacopoeias, there are two official methods to evaluate pyrogenicitythat is, the bacterial endotoxin test, and the pyrogen test. The main objective of this review is to compare the monographs of each test among the different Pharmacopeias, to detect similarities and differences. The former can be considered fully harmonized, and only non-significant differences were detected. The latter, which is the only available assay for some products and formulations to demonstrate apyrogenicity, shows large differences, which should be considered.
Topics: Animals; Biological Assay; Endotoxins; Humans; Pharmacopoeias as Topic; Pyrogens
PubMed: 30115887
DOI: 10.3390/toxins10080331 -
Deutsches Arzteblatt International Mar 2018Persistent fever of unknown cause is only rarely of cardiac origin, but heart disease must be considered in the differential diagnosis. Aside from endocarditis,... (Review)
Review
BACKGROUND
Persistent fever of unknown cause is only rarely of cardiac origin, but heart disease must be considered in the differential diagnosis. Aside from endocarditis, pericarditis and various other conditions may be responsible.
METHODS
This review is based on pertinent articles retrieved by a selective search in PubMed and Google Scholar employing the term "fever" in combination with "myocardial infarction," "pericarditis," "endocarditis," and "postcardiac injury," with additional consideration of current cardiological guidelines.
RESULTS
Endocarditis is associated with fever in 90% of cases, but 25-50% of patients also develop high body temperatures after acute myocardial infarction. In pericarditis, a temperature above 38°C indicates a poorer prognosis; if accompanied by other warning signs, it is an indication for hospitalization and pericardiocentesis. Fever can arise after cardiac surgical procedures as a manifestation of post - cardiotomy syndrome, a special type of perimyocarditis. There may be a latency period of up to 3 months.
CONCLUSION
Fever can have both infectious and non-infectious cardiac causes. Its interpretation depends on the clinical context. The evidence base for treatment is sparse, and controlled trials are needed.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Cardiac Surgical Procedures; Cytokines; Endocarditis; Endocarditis, Bacterial; Fever; Humans; Inflammation Mediators; Myocardial Infarction; Pericarditis; Pyrogens; Time Factors
PubMed: 29642989
DOI: 10.3238/arztebl.2018.0193 -
Toxins Mar 2019Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by are potent activators of the immune system. These protein toxins bind to major... (Review)
Review
Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation of both monocytes/macrophages and T lymphocytes. The bridging of TCRs with MHC class II molecules by superantigens triggers an early "cytokine storm" and massive polyclonal T-cell proliferation. Proinflammatory cytokines, tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 elicit fever, inflammation, multiple organ injury, hypotension, and lethal shock. Upon MHC/TCR ligation, superantigens induce signaling pathways, including mitogen-activated protein kinase cascades and cytokine receptor signaling, which results in NFκB activation and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. In addition, gene profiling studies have revealed the essential roles of innate antimicrobial defense genes in the pathogenesis of SEB. The genes expressed in a murine model of SEB-induced shock include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, endoplasmic reticulum/mitochondrial stress responses, immunoproteasome components, and IFN-stimulated genes. This review focuses on the signaling pathways induced by superantigens that lead to the activation of inflammation and damage response genes. The induction of these damage response genes provides evidence that SEB induces danger signals in host cells, resulting in multiorgan injury and toxic shock. Therapeutics targeting both host inflammatory and cell death pathways can potentially mitigate the toxic effects of staphylococcal superantigens.
Topics: Animals; Bacterial Toxins; Cell Death; Cytokines; Humans; Oxidative Stress; Pyrogens; Receptors, Antigen, T-Cell; Shock, Septic; Signal Transduction; Staphylococcus; Superantigens
PubMed: 30909619
DOI: 10.3390/toxins11030178 -
ALTEX 2021Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this...
Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration's Center for Devices and Radiologic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH's Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and follow-up activities are discussed.
Topics: Animal Testing Alternatives; Animals; Endotoxins; Equipment and Supplies; Monocytes; Pyrogens; Rabbits; Toxicity Tests
PubMed: 33452530
DOI: 10.14573/altex.2012021 -
BioTechniques May 2021Testing of parenteral pharmaceuticals and medical devices for pyrogens (fever-inducing substances) is critical to patient safety. The original rabbit pyrogen test has...
Testing of parenteral pharmaceuticals and medical devices for pyrogens (fever-inducing substances) is critical to patient safety. The original rabbit pyrogen test has largely been replaced by different bacterial endotoxin tests based on amebocyte lysate (LAL), sourced from the blood equivalent of horseshoe crabs after comparative studies to the rabbit pyrogen test. Since 2004 a bacterial endotoxin test based on recombinant factor C (rFC), the endotoxin sensor protein inside of LAL, has been used as an animal-free alternative to LAL. Likewise, numerous studies compared LAL and rFC. Here we describe the history of pyrogen and bacterial endotoxin testing and summarize the evidence presented by those studies. We demonstrate that rFC and LAL are equivalent and comparable.
Topics: Animal Testing Alternatives; Animals; Endotoxins; Horseshoe Crabs; Pyrogens; Rabbits
PubMed: 33956506
DOI: 10.2144/btn-2020-0165 -
Scientific Reports Aug 2023Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory...
Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory agencies require rabbit pyrogen testing (RPT) for demonstration of vaccine reactogenicity. Recently, the monocyte activation test (MAT) gained popularity as in vitro alternative, yet this assay was primarily designed to test pyrogen-free products. The aim was to adjust the MAT to enable testing of pyrogen containing vaccines in an early stage of development where no reference batch is yet available. The MAT and RPT were compared for assessing unknown safety profiles of pertussis outer membrane vesicle (OMV) vaccine candidates to those of Bexsero as surrogate reference vaccine. Pertussis OMVs with wild-type LPS predominantly activated TLR2 and TLR4 and were more reactogenic than Bexsero. However, this reactogenicity profile for pertussis OMVs could be equalized or drastically reduced compared to Bexsero or a whole-cell pertussis vaccine, respectively by dose changing, modifying the LPS, intranasal administration, or a combination of these. Importantly, except for LPS modified products, reactogenicity profiles obtained with the RPT and MAT were comparable. Overall, we demonstrated that this pertussis OMV vaccine candidate has an acceptable safety profile. Furthermore, the MAT proved its applicability to assess reactogenicity levels of pyrogen containing vaccines at multiple stages of vaccine development and could eventually replace rabbit pyrogen testing.
Topics: Animals; Rabbits; Lipopolysaccharides; Whooping Cough; Pyrogens; Monocytes; Biological Assay
PubMed: 37542099
DOI: 10.1038/s41598-023-39908-7 -
European Journal of Microbiology &... Sep 2018The fever-inducing effect of lipopolysaccharides (LPS) is well known, and human blood is extremely responsive to this pyrogen. Recently, the safety of LPS-containing... (Review)
Review
The fever-inducing effect of lipopolysaccharides (LPS) is well known, and human blood is extremely responsive to this pyrogen. Recently, the safety of LPS-containing food supplements and probiotic drugs as immune-stimulants has been questioned, although these products are orally taken and do not reach the bloodstream undigested. The concerns are understandable, as endotoxaemia is a pathological condition, but the oral uptake of probiotic products containing LPS or Gram-negative bacteria does not pose a health risk, based on the available scientific evidence, as is reviewed here. The available methods developed to detect LPS and other pyrogens are mostly used for quality control of parentally applied therapeuticals. Their outcome varies considerably when applied to food supplements, as demonstrated in a simple comparative experiment. Products containing different strains can result in vastly different results on their LPS content, depending on the method of testing. This is an inherent complication to pyrogen testing, which hampers the communication that the LPS content of food supplements is not a safety concern.
PubMed: 30345085
DOI: 10.1556/1886.2018.00017 -
ALTEX 2021The whole blood pyrogen test invented 25 years ago, and its variant based on cryo-preserved blood one year later, brought momentum into the field of pyrogen testing,...
The whole blood pyrogen test invented 25 years ago, and its variant based on cryo-preserved blood one year later, brought momentum into the field of pyrogen testing, which, despite the broad application of the Limulus amebocyte lysate (LAL) assay, aka bacterial endotoxin test (BET), consumed several hundred thousand rabbits per year world-wide. The resulting international validation and lengthy acceptance and implementation process of what are called now monocyte activation tests (MATs) finally is impacting on animal numbers - at least in Europe - reducing them by more than 70% and counting. The author sees no reason for continuing any regulatory rabbit testing for pyrogens except the lack of acceptance of MATs in some regions of the world. The availability of MATs has opened also the discussion about the shortcomings of LAL/BET, namely its restriction to Gram-negative pyrogens, non-reflection of the potency of these in humans, interference and masking by many products, and animal welfare concerns for horseshoe crabs. The obvious advantages of MATs in all these respects should lead to a shift from LAL/BET to MATs. We are starting to see this for vac-cines and medical devices, but other areas like safety testing of blood transfusions, cell therapies and nanomaterials, and the assessment of air-borne pyrogens still need to grasp the opportunity provided by MATs. While the different MATs can jointly serve these needs, the whole blood MAT has some advantages as discussed here.
Topics: Animal Testing Alternatives; Animals; Biological Assay; Cryopreservation; Endotoxins; Horseshoe Crabs; Monocytes; Pyrogens; Rabbits
PubMed: 33452528
DOI: 10.14573/altex.2101051 -
Physiological Reviews Jan 1991The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was... (Review)
Review
The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was equivalent to IL-1 (both alpha and beta) and subsequently to IL-1 alpha, IL-1 beta, and TNF. However, as more data have been obtained, it has become clearer that many cytokines and hormones are capable of participating in the febrile response. It is also becoming apparent that EPs and ECs might influence body temperature during nonpathological states, perhaps contributing to the elevation in temperature during or after exercise, the circadian variation in temperature, and others. Medical textbooks have begun to list IL-1 as the EP. As I attempted to make clear in this review, evidence that IL-1 alpha is a circulating EP is poor. The evidence is considerably stronger that IL-1 beta is an EP, at least during LPS-induced fever in rodents. The point I have tried to emphasize is that before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one. As summarized in Tables 4 and 5, there are many candidates for EPs and ECs, but much more experimental evidence is essential before we gain a clear understanding of the relationship between contact with an exogenous pyrogen, the release of EPs and ECs, and the development of fever.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Fever; Humans; Pyrogens
PubMed: 1986393
DOI: 10.1152/physrev.1991.71.1.93 -
American Journal of Obstetrics and... Jan 2014The purpose of this study was to evaluate the quality of compounded 17-hydroxyprogesterone caproate (17-OHPC).
OBJECTIVE
The purpose of this study was to evaluate the quality of compounded 17-hydroxyprogesterone caproate (17-OHPC).
STUDY DESIGN
Compounded 17-OHPC that was obtained from 15 compounding pharmacies throughout the United States was analyzed for potency, impurities, sterility, and pyrogen status.
RESULTS
Eighteen samples were supplied by 15 compounding pharmacies. The concentration of 17-OHPC in all samples was within the specification limits, and all tested samples passed sterility and pyrogen testing. Only 1 of 18 samples was out of specification limits for impurities.
CONCLUSION
Compounded 17-OHPC that was obtained from 15 pharmacies throughout the United States did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities.
Topics: 17 alpha-Hydroxyprogesterone Caproate; Drug Compounding; Humans; Hydroxyprogesterones; Pyrogens; Quality Assurance, Health Care; Quality Control; United States
PubMed: 24200163
DOI: 10.1016/j.ajog.2013.09.039