Apport des tests in vitro dans deux cas de drug-induced aseptic meningitis (DIAM) par hypersensibilité retardée allergique à l’amoxicilline

SummaryLupus anticoagulants (LAs) are immunoglobulins (IgG, IgM, or both) which interfere with in vitro phospholipid (PL) dependent tests of coagulation (e.g. APTT, dilute PT, dilute Russell Viper Venom Time). These antibodies may be identified in a wide variety of clinical settings. With the exception of heparinized patient samples, the presence of LAs is often the most common cause of an unexplained APTT in a routine clinical laboratory. The diagnosis of LAs is difficult due to variable screening reagent sensitivity and intrinsic heterogeneity of LAs. Recently, Rauch and colleagues have shown human monoclonal hybridoma LAs were inhibited by hexagonal (II) phase PLs. In contrast, lamellar phase PLs had no effect. We have evaluated a new assay system, Staclot LA®, which utilizes a hexagonal (II) phase PL (egg phosphatidylethanolamine [EPE]) as a confirmatory test for LAs. Plasma samples from the following patient populations were studied: LA positive, heparinized, oral anticoagulated, hemophilia A and B, and specific factor inhibitors (factors V, VIII, IX). Unlike previous studies, the LA positive patients were a mixed population including: autoimmune diseases, drug-induced, and post-infection. Our findings confirm the specificity of hexagonal (II) phase PL neutralization of LAs.

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Recent Progress in Prediction Systems for Drug-induced Liver Injury Using in vitro Cell Culture

Drug Metabolism Letters ◽

10.2174/1872312814666201202112610 ◽

2020 ◽

Vol 14 ◽

Author(s):

Shogo Ozawa ◽

Toshitaka Miura ◽

Jun Terashima ◽

Wataru Habano ◽

Seiichi Ishida

Keyword(s):

Cell Culture ◽

Recent Progress ◽

Inflammatory Cells ◽

Protein Adducts ◽

In Vitro Assays ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Culture Systems ◽

Cell Culture Systems

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. Objective: In this study, the recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as for the limitations of in vitro cell culture systems for DILI research. Methods: Information related to DILI was collected through a literature search of the PubMed database. Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4+ helper T lymphocytes and recognition by CD8+ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells, or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILIinducing drugs with approximately 50% sensitivity and 90% specificity. Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.

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Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

Journal of Bone and Mineral Research ◽

10.1002/jbmr.1839 ◽

2013 ◽

Vol 28 (5) ◽

pp. 1101-1116 ◽

Cited By ~ 38

Author(s):

Zhican Wang ◽

Yvonne S Lin ◽

Leslie J Dickmann ◽

Emma-Jane Poulton ◽

David L Eaton ◽

...

Keyword(s):

Drug Induced ◽

Cyp3a4 Induction

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Ibuprofen-Induced Aseptic Meningitis in a Male Adolescent with Intracranial Hypertension and Visual Impairment: A Case Report

Case Reports in Neurology ◽

10.1159/000514091 ◽

2021 ◽

Vol 13 (1) ◽

pp. 233-238

Author(s):

Seyed Mohammad Mousavi Mirzaei ◽

Zahra Ahmadi

Keyword(s):

Visual Impairment ◽

Intracranial Hypertension ◽

Aseptic Meningitis ◽

Rare Complication ◽

Clinical Signs ◽

Male Adolescent ◽

Drug Induced ◽

Blurred Vision ◽

Inflammatory Drugs

Drug-induced aseptic meningitis (DIAM) is a rare complication of certain drugs, most commonly reported with ibuprofen use. The present study reports on a male adolescent with intracranial hypertension and visual impairment accompanied by DIAM. We present a 16-year-old male patient who after ibuprofen consumption displayed headache, fever, photophobia, and blurred vision following heavy exercises. Examination of cerebrospinal fluid showed a mononuclear pleocytosis and an increase in protein concentration. Other examinations had normal results. The development of common clinical signs following ibuprofen use reflected DIAM. The patient’s vision was found to improve with supportive care and stopping of the drug during follow-up. Given the widespread use of nonsteroidal anti-inflammatory drugs and the fact that these drugs are the most common cause of DIAM, the probability of occurrence of this event should be always kept in mind, and screening for autoimmune diseases in these patients is of great importance.

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Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury

Toxicological Sciences ◽

10.1093/toxsci/kfaa182 ◽

2021 ◽

Author(s):

Yanshan Cao ◽

Ahsan Bairam ◽

Alison Jee ◽

Ming Liu ◽

Jack Uetrecht

Keyword(s):

Liver Injury ◽

Skin Rash ◽

Covalent Binding ◽

Reactive Metabolites ◽

Important Data ◽

Drug Induced ◽

Interindividual Differences ◽

Immune Mediated ◽

Sulfate Conjugate

Abstract Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, one possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be one factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.

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Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

Archives of Toxicology ◽

10.1007/s00204-021-03075-3 ◽

2021 ◽

Author(s):

Lawrence Howell ◽

Rosalind E. Jenkins ◽

Stephen Lynch ◽

Carrie Duckworth ◽

B. Kevin Park ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Rna Polymerase Ii ◽

Liver Tissue ◽

Drug Disposition ◽

Multiple Drug ◽

Proteomic Profiling ◽

Cytochrome P450 3A ◽

Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

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Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

Toxicology Research ◽

10.1093/toxres/tfab035 ◽

2021 ◽

Author(s):

Jiapan Gao ◽

Delu Che ◽

Xueshan Du ◽

Yi Zheng ◽

Huiling Jing ◽

...

Keyword(s):

Contact Dermatitis ◽

Mast Cells ◽

Pharmaceutical Products ◽

Drug Induced ◽

Inflammatory Infiltration ◽

Local Inflammatory Response ◽

Allergic Contact ◽

G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

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A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry

Nature Communications ◽

10.1038/s41467-021-24156-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yanwen Chen ◽

Travis B. Lear ◽

John W. Evankovich ◽

Mads B. Larsen ◽

Bo Lin ◽

...

Keyword(s):

Rational Design ◽

Surface Expression ◽

In Vitro Models ◽

Lung Epithelial Cells ◽

Cell Surface Receptor ◽

Pharmacokinetic Data ◽

Drug Induced ◽

Global Pandemic ◽

Surface Receptor

AbstractSARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection.

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In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1091 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1091-1097 ◽

Cited By ~ 7

Author(s):

Hideki Kita ◽

Hirotami Matsuo ◽

Hitomi Takanaga ◽

Junichi Kawakami ◽

Koujirou Yamamoto ◽

...

Keyword(s):

Brain Tissue ◽

Threshold Concentration ◽

Current Response ◽

Drug Induced ◽

Inhibition Ratio ◽

New Quinolones ◽

The Central Nervous System ◽

Anti Inflammatory

ABSTRACT We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

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