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  1. Article ; Online: Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study.

    In 't Veld, Aliede E / Grievink, Hendrika W / van der Plas, Johan L / Eveleens Maarse, Boukje C / van Kraaij, Sebastiaan J W / Woutman, Tess D / Schoonakker, Mascha / Klarenbeek, Naomi B / de Kam, Marieke L / Kamerling, Ingrid M C / Jansen, Manon A A / Moerland, Matthijs

    Immunologic research

    2023  Volume 71, Issue 4, Page(s) 617–627

    Abstract: Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To ...

    Abstract Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC
    MeSH term(s) Humans ; Hydroxychloroquine/pharmacology ; Hydroxychloroquine/therapeutic use ; Pharmacology, Clinical ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Immunosuppression Therapy ; Cytokines
    Chemical Substances Hydroxychloroquine (4QWG6N8QKH) ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Cytokines
    Language English
    Publishing date 2023-02-22
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ZDB-ID 632857-x
    ISSN 1559-0755 ; 0257-277X
    ISSN (online) 1559-0755
    ISSN 0257-277X
    DOI 10.1007/s12026-023-09367-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1755: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Monitoring of Ex Vivo Cyclosporin a Activity in Healthy Volunteers Using T Cell Function Assays in Relation to Whole Blood and Cellular Pharmacokinetics.

    In 't Veld, Aliede E / Jansen, Manon A A / Huisman, Bertine W / Schoonakker, Mascha / de Kam, Marieke L / Moes, Dirk Jan A R / van Poelgeest, Mariëtte I E / Burggraaf, Jacobus / Moerland, Matthijs

    Pharmaceutics

    2022  Volume 14, Issue 9

    Abstract: Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who ... ...

    Abstract Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose-effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment.
    Language English
    Publishing date 2022-09-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics14091958
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells.

    Grievink, Hendrika W / Jirka, Silvana M G / Woutman, Tess D / Schoonakker, Mascha / Rissmann, Robert / Malone, Karen E / Feiss, Gary / Moerland, Matthijs

    Clinical and translational science

    2020  Volume 13, Issue 5, Page(s) 891–895

    Abstract: LL-37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL-37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll-like ... ...

    Abstract LL-37 is a cationic antimicrobial peptide and the sole human member of cathelicidins. Besides its bactericidal properties, LL-37 is known to have direct immunomodulatory effects, among which enhancement of antiviral responses via endosomal toll-like receptors (TLRs). Omiganan pentahydrochloride is a synthetic cationic peptide in clinical development. Previously, omiganan was primarily known for its direct bactericidal and antifungal properties. We investigated whether omiganan enhances endosomal TLR responses, similar to LL-37. Human peripheral blood mononuclear cells were treated with endosomal TLR3, -7, -8, and -9 ligands in the presence of omiganan. Omiganan enhanced TLR-mediated interferon-α release. Subsequent experiments with TLR9 ligands showed that plasmacytoid dendritic cells were main contributors to omiganan-enhanced IFN production. Based on this type I interferon-enhancing effect, omiganan may qualify as potential treatment modality for virus-driven diseases. The molecular mechanism by which omiganan enhances endosomal TLR responses remains to be elucidated.
    MeSH term(s) Anti-Infective Agents/pharmacology ; Antimicrobial Cationic Peptides/pharmacology ; Cells, Cultured ; Dendritic Cells ; Drug Evaluation, Preclinical ; Endosomes/drug effects ; Endosomes/immunology ; Endosomes/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Healthy Volunteers ; Humans ; Interferon-alpha/analysis ; Interferon-alpha/metabolism ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Ligands ; Male ; Primary Cell Culture ; Signal Transduction/drug effects ; Signal Transduction/immunology ; Toll-Like Receptors/metabolism
    Chemical Substances Anti-Infective Agents ; Antimicrobial Cationic Peptides ; Interferon-alpha ; Ligands ; Toll-Like Receptors ; omiganan pentahydrochloride (LX2P9RD54V)
    Language English
    Publishing date 2020-04-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.12789
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Low dose ionizing radiation strongly stimulates insertional mutagenesis in a γH2AX dependent manner.

    Zelensky, Alex N / Schoonakker, Mascha / Brandsma, Inger / Tijsterman, Marcel / van Gent, Dik C / Essers, Jeroen / Kanaar, Roland

    PLoS genetics

    2020  Volume 16, Issue 1, Page(s) e1008550

    Abstract: Extrachromosomal DNA can integrate into the genome with no sequence specificity producing an insertional mutation. This process, which is referred to as random integration (RI), requires a double stranded break (DSB) in the genome. Inducing DSBs by ... ...

    Abstract Extrachromosomal DNA can integrate into the genome with no sequence specificity producing an insertional mutation. This process, which is referred to as random integration (RI), requires a double stranded break (DSB) in the genome. Inducing DSBs by various means, including ionizing radiation, increases the frequency of integration. Here we report that non-lethal physiologically relevant doses of ionizing radiation (10-100 mGy), within the range produced by medical imaging equipment, stimulate RI of transfected and viral episomal DNA in human and mouse cells with an extremely high efficiency. Genetic analysis of the stimulated RI (S-RI) revealed that it is distinct from the background RI, requires histone H2AX S139 phosphorylation (γH2AX) and is not reduced by DNA polymerase θ (Polq) inactivation. S-RI efficiency was unaffected by the main DSB repair pathway (homologous recombination and non-homologous end joining) disruptions, but double deficiency in MDC1 and 53BP1 phenocopies γH2AX inactivation. The robust responsiveness of S-RI to physiological amounts of DSBs can be exploited for extremely sensitive, macroscopic and direct detection of DSB-induced mutations, and warrants further exploration in vivo to determine if the phenomenon has implications for radiation risk assessment.
    MeSH term(s) Animals ; Cell Line ; Cells, Cultured ; DNA Breaks, Double-Stranded ; DNA-Directed DNA Polymerase/metabolism ; Histones/metabolism ; Humans ; Mice ; Mutagenesis, Insertional/radiation effects ; Radiation, Ionizing ; Recombinational DNA Repair ; DNA Polymerase theta
    Chemical Substances Histones ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2020-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1008550
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers.

    Buters, Thomas P / Hameeteman, Pieter W / Jansen, Iris M E / van Hindevoort, Floris C / Ten Voorde, Wouter / Grievink, Hendrika W / Schoonakker, Mascha / de Kam, Marieke L / Gilroy, Derek W / Feiss, Gary / Rissmann, Robert / Jansen, Manon A A / Burggraaf, Jacobus / Moerland, Matthijs

    Clinical pharmacology and therapeutics

    2022  Volume 111, Issue 4, Page(s) 964–971

    Abstract: The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS ... ...

    Abstract The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty-four healthy male volunteers received a two-and-a-half-day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two-and-a-half-day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti-inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti-inflammatory effects of such compounds in a minimally invasive manner.
    MeSH term(s) Adrenal Cortex Hormones ; Anti-Inflammatory Agents/therapeutic use ; Blister/drug therapy ; Clobetasol/pharmacology ; Clobetasol/therapeutic use ; Cytokines ; Drugs, Investigational ; Erythema/drug therapy ; Glucocorticoids/pharmacology ; Healthy Volunteers ; Humans ; Lipopolysaccharides ; Male ; Prednisolone/pharmacology
    Chemical Substances Adrenal Cortex Hormones ; Anti-Inflammatory Agents ; Cytokines ; Drugs, Investigational ; Glucocorticoids ; Lipopolysaccharides ; Prednisolone (9PHQ9Y1OLM) ; Clobetasol (ADN79D536H)
    Language English
    Publishing date 2022-01-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2516
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 20: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

    Buters, Thomas P / Hameeteman, Pieter W / Jansen, Iris M E / van Hindevoort, Floris C / Ten Voorde, Wouter / Florencia, Edwin / Osse, Michelle / de Kam, Marieke L / Grievink, Hendrika W / Schoonakker, Mascha / Patel, Amit A / Yona, Simon / Gilroy, Derek W / Lubberts, Erik / Damman, Jeffrey / Feiss, Gary / Rissmann, Robert / Jansen, Manon A A / Burggraaf, Jacobus /
    Moerland, Matthijs

    British journal of clinical pharmacology

    2021  Volume 88, Issue 2, Page(s) 680–690

    Abstract: Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the ... ...

    Abstract Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.
    Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.
    Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1β, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.
    Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.
    MeSH term(s) Cytokines/metabolism ; Healthy Volunteers ; Humans ; Inflammation/chemically induced ; Interleukin-6/metabolism ; Lipopolysaccharides ; Male ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Cytokines ; Interleukin-6 ; Lipopolysaccharides ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2021-08-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1111/bcp.14999
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1118: Show issues Location:
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