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  1. Article ; Online: Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.

    Liu, Xu / Wang, Yashuo / Gutierrez, Jennifer S / Damsker, Jesse M / Nagaraju, Kanneboyina / Hoffman, Eric P / Ortlund, Eric A

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 39, Page(s) 24285–24293

    Abstract: Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of ...

    Abstract Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.
    MeSH term(s) Humans ; Hydrogen Bonding ; Ligands ; Muscular Dystrophy, Duchenne/drug therapy ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/metabolism ; Pregnadienediols/administration & dosage ; Pregnadienediols/chemistry ; Protein Binding ; Receptors, Glucocorticoid/chemistry ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism
    Chemical Substances Ligands ; Pregnadienediols ; Receptors, Glucocorticoid ; VBP15 compound
    Keywords covid19
    Language English
    Publishing date 2020-09-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2006890117
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    Zs.A 1148: Show issues Location:
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  2. Article ; Online: A novel dissociative steroid VBP15 reduces MUC5AC gene expression in airway epithelial cells but lacks the GRE mediated transcriptional properties of dexamethasone.

    Garvin, Lindsay M / Chen, Yajun / Damsker, Jesse M / Rose, Mary C

    Pulmonary pharmacology & therapeutics

    2016  Volume 38, Page(s) 17–26

    Abstract: Overproduction of secretory mucins contributes to morbidity/mortality in inflammatory lung diseases. Inflammatory mediators directly increase expression of mucin genes, but few drugs have been shown to directly repress mucin gene expression. IL-1β ... ...

    Abstract Overproduction of secretory mucins contributes to morbidity/mortality in inflammatory lung diseases. Inflammatory mediators directly increase expression of mucin genes, but few drugs have been shown to directly repress mucin gene expression. IL-1β upregulates the MUC5AC mucin gene in part via the transcription factors NFκB while the glucocorticoid Dexamethasone (Dex) transcriptionally represses MUC5AC expression by Dex-activated GR binding to two GRE cis-sites in the MUC5AC promoter in lung epithelial cells. VBP compounds (ReveraGen BioPharma) maintain anti-inflammatory activity through inhibition of NFκB but exhibit reduced GRE-mediated transcriptional properties associated with adverse side-effects and thus have potential to minimize harmful side effects of long-term steroid therapy in inflammatory lung diseases. We investigated VBP15 efficacy as an anti-mucin agent in two types of airway epithelial cells and analyzed the transcription factor activity and promoter binding associated with VBP15-induced MUC5AC repression. VBP15 reduced MUC5AC mRNA abundance in a dose- and time-dependent manner similar to Dex in the presence or absence of IL-1β in A549 and differentiated human bronchial epithelial cells. Repression was abrogated in the presence of RU486, demonstrating a requirement for GR in the VBP15-induced repression of MUC5AC. Inhibition of NFκB activity resulted in reduced baseline expression of MUC5AC indicating that constitutive activity maintains MUC5AC production. Chromatin immunoprecipitation analysis demonstrated lack of GR and of p65 (NFκB) binding to composite GRE domains in the MUC5AC promoter following VBP15 exposure of cells, in contrast to Dex. These data demonstrate that VBP15 is a novel anti-mucin agent that mediates the reduction of MUC5AC gene expression differently than the classical glucocorticoid, Dex.
    MeSH term(s) A549 Cells ; Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/pharmacology ; Bronchi/cytology ; Bronchi/drug effects ; Cell Line ; Dexamethasone/administration & dosage ; Dexamethasone/pharmacology ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Gene Expression Regulation/drug effects ; Glucocorticoids/administration & dosage ; Glucocorticoids/pharmacology ; Humans ; Inflammation Mediators/metabolism ; Interleukin-1beta/metabolism ; Mucin 5AC/genetics ; Mucins/antagonists & inhibitors ; Mucins/metabolism ; Pregnadienediols/administration & dosage ; Pregnadienediols/pharmacology ; RNA, Messenger/metabolism ; Time Factors
    Chemical Substances Anti-Inflammatory Agents ; Glucocorticoids ; Inflammation Mediators ; Interleukin-1beta ; MUC5AC protein, human ; Mucin 5AC ; Mucins ; Pregnadienediols ; RNA, Messenger ; VBP15 compound ; Dexamethasone (7S5I7G3JQL)
    Language English
    Publishing date 2016-06
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 1399707-5
    ISSN 1522-9629 ; 1094-5539
    ISSN (online) 1522-9629
    ISSN 1094-5539
    DOI 10.1016/j.pupt.2016.04.004
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    Zs.A 2389: Show issues Location:
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  3. Article ; Online: Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

    Dang, Utkarsh J / Damsker, Jesse M / Guglieri, Michela / Clemens, Paula R / Perlman, Seth J / Smith, Edward C / Horrocks, Iain / Finkel, Richard S / Mah, Jean K / Deconinck, Nicolas / Goemans, Nathalie M / Haberlová, Jana / Straub, Volker / Mengle-Gaw, Laurel / Schwartz, Benjamin D / Harper, Amy / Shieh, Perry B / De Waele, Liesbeth / Castro, Diana /
    Yang, Michele L / Ryan, Monique M / McDonald, Craig M / Tulinius, Mar / Webster, Richard I / Mcmillan, Hugh J / Kuntz, Nancy / Rao, Vamshi K / Baranello, Giovanni / Spinty, Stefan / Childs, Anne-Marie / Sbrocchi, Annie M / Selby, Kathryn A / Monduy, Migvis / Nevo, Yoram / Vilchez, Juan J / Nascimento-Osorio, Andres / Niks, Erik H / De Groot, Imelda J M / Katsalouli, Marina / Van Den Anker, John N / Ward, Leanne M / Leinonen, Mika / D'Alessandro, Andrea L / Hoffman, Eric P

    Neurology

    2024  Volume 102, Issue 5, Page(s) e208112

    Abstract: Background and objectives: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to ... ...

    Abstract Background and objectives: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
    Methods: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
    Results: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78,
    Discussion: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
    Trial registration information: ClinicalTrials.gov Identifier: NCT03439670.
    Classification of evidence: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
    MeSH term(s) Humans ; Male ; Biomarkers ; Muscular Dystrophy, Duchenne/drug therapy ; Prednisone/adverse effects ; Pregnadienediols/adverse effects ; Child, Preschool ; Child
    Chemical Substances Biomarkers ; Prednisone (VB0R961HZT) ; Pregnadienediols ; VBP15 compound
    Language English
    Publishing date 2024-02-09
    Publishing country United States
    Document type Randomized Controlled Trial ; Journal Article
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000208112
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  4. Article ; Online: Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone.

    Fiorillo, Alyson A / Tully, Christopher B / Damsker, Jesse M / Nagaraju, Kanneboyina / Hoffman, Eric P / Heier, Christopher R

    Physiological genomics

    2018  Volume 50, Issue 9, Page(s) 735–745

    Abstract: Corticosteroids are highly prescribed and effective anti-inflammatory drugs but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use ...

    Abstract Corticosteroids are highly prescribed and effective anti-inflammatory drugs but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use is an important goal for treatment of chronic inflammatory diseases such as Duchenne muscular dystrophy (DMD). We have developed vamorolone (VBP15), a first-in-class dissociative glucocorticoid receptor (GR) ligand that shows the anti-inflammatory efficacy of corticosteroids without key steroid side effects in animal models. miRNAs are increasingly recognized as key regulators of inflammatory responses. To define effects of prednisolone and vamorolone on the muscle miRNAome, we performed a preclinical discovery study in the mdx mouse model of DMD. miRNAs associated with inflammation were highly elevated in mdx muscle. Both vamorolone and prednisolone returned these toward wild-type levels (miR-142-5p, miR-142-3p, miR-146a, miR-301a, miR-324-3p, miR-455-5p, miR-455-3p, miR-497, miR-652). Effects of vamorolone were largely limited to reduction of proinflammatory miRNAs. In contrast, prednisolone activated a separate group of miRNAs associated with steroid side effects and a noncoding RNA cluster homologous to human chromosome 14q32. Effects were validated for inflammatory miRNAs in a second, independent preclinical study. For the anti-inflammatory miRNA signature, bioinformatic analyses showed all of these miRNAs are directly regulated by, or in turn activate, the inflammatory transcription factor NF-κB. Moving forward miR-146a and miR-142 are of particular interest as biomarkers or novel drug targets. These data validate NF-κB signaling as a target of dissociative GR-ligand efficacy in vivo and provide new insight into miRNA signaling in chronic inflammation.
    MeSH term(s) Animals ; Base Sequence ; Chronic Disease ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Inflammation/genetics ; Mice, Inbred C57BL ; Mice, Inbred mdx ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Models, Biological ; Muscles/drug effects ; Muscles/metabolism ; Muscles/pathology ; Muscular Dystrophy, Duchenne/genetics ; NF-kappa B/metabolism ; Prednisone/pharmacology ; Pregnadienediols/pharmacology ; Promoter Regions, Genetic/genetics ; Receptors, Glucocorticoid/metabolism ; Reproducibility of Results ; Signal Transduction
    Chemical Substances MicroRNAs ; NF-kappa B ; Pregnadienediols ; Receptors, Glucocorticoid ; VBP15 compound ; Prednisone (VB0R961HZT)
    Language English
    Publishing date 2018-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2038823-8
    ISSN 1531-2267 ; 1094-8341
    ISSN (online) 1531-2267
    ISSN 1094-8341
    DOI 10.1152/physiolgenomics.00134.2017
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    Zs.A 5697: Show issues Location:
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  5. Article: Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment

    Liu, Xu / Wang, Yashuo / Gutierrez, Jennifer S / Damsker, Jesse M / Nagaraju, Kanneboyina / Hoffman, Eric P / Ortlund, Eric A

    Proc. Natl. Acad. Sci. U. S. A

    Abstract: Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of ...

    Abstract Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #32917814
    Database COVID19

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  6. Article ; Online: Th1 and Th17 cells: adversaries and collaborators.

    Damsker, Jesse M / Hansen, Anna M / Caspi, Rachel R

    Annals of the New York Academy of Sciences

    2010  Volume 1183, Page(s) 211–221

    Abstract: Autoreactive effector CD4+ T cells have been associated with the pathogenesis of autoimmune disorders. Early studies implicated the interferon (IFN)-gamma-producing T helper (Th)1 subset of CD4+ cells as the causal agents in the pathogenesis of ... ...

    Abstract Autoreactive effector CD4+ T cells have been associated with the pathogenesis of autoimmune disorders. Early studies implicated the interferon (IFN)-gamma-producing T helper (Th)1 subset of CD4+ cells as the causal agents in the pathogenesis of autoimmunity. However, further studies have suggested a more complex story. In models thought to be driven by Th1 cells, mice lacking the hallmark Th1 cytokine IFN-gamma were not protected but tended to have enhanced susceptibility to disease. Identification of the IL-17-producing CD4+ effector cell lineage (Th17) has helped shed light on this issue. Th17 effector cells are induced in parallel to Th1, and, like Th1, polarized Th17 cells have the capacity to cause inflammation and autoimmune disease. This, together with the finding that deficiency of the Th17-related cytokine IL-23 but not the Th1-related cytokine IL-12 causes resistance, led to the notion that Th17 cells are the chief contributors to autoimmune tissue inflammation. Nevertheless, mice lacking IL-17 are not protected from disease and display elevated numbers of IFN-gamma-producing CD4+ T cells, and, in some cases, lack of IFN-gamma does confer resistance. Recent studies report overlapping as well as differential roles of these cells in tissue inflammation, which suggests the existence of a more complex relationship between these two effector T-cell subsets than has hitherto been suspected. This review will attempt to bring together current information regarding interaction, balance, and collaborative potential between the Th1 and Th17 effector lineages.
    MeSH term(s) Animals ; Autoimmunity/immunology ; Cell Lineage/immunology ; Humans ; Lymphocyte Activation/physiology ; Mice ; Models, Biological ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/physiology ; Th1 Cells/immunology ; Th1 Cells/physiology
    Language English
    Publishing date 2010-02-12
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 211003-9
    ISSN 1749-6632 ; 0077-8923
    ISSN (online) 1749-6632
    ISSN 0077-8923
    DOI 10.1111/j.1749-6632.2009.05133.x
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    Se 110: Show issues Location:
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  7. Article ; Online: Vamorolone, a dissociative steroidal compound, reduces collagen antibody-induced joint damage and inflammation when administered after disease onset.

    Damsker, Jesse M / Cornish, Michaelyn R / Kanneboyina, Priya / Kanneboyina, Ila / Yu, Qing / Lipson, Rachel / Phadke, Aditi / Knoblach, Susan M / Panchapakesan, Karuna / Morales, Melissa / Fiorillo, Alyson A / Partridge, Terence / Nagaraju, Kanneboyina

    Inflammation research : official journal of the European Histamine Research Society ... [et al.

    2019  Volume 68, Issue 11, Page(s) 969–980

    Abstract: Objective and design: The objective of this study was to assess the effect of vamorolone, a first-in-class dissociative steroidal compound, to inhibit inflammation when administered after disease onset in the murine collagen antibody-induced arthritis ... ...

    Abstract Objective and design: The objective of this study was to assess the effect of vamorolone, a first-in-class dissociative steroidal compound, to inhibit inflammation when administered after disease onset in the murine collagen antibody-induced arthritis model of arthritis.
    Animals: 84 DBA1/J mice were used in this study (n = 12 per treatment group).
    Treatment: Vamorolone or prednisolone was administered orally after disease onset for a duration of 7 days.
    Methods: Disease score and bone erosion were assessed using previously described scoring systems. Cytokines were measured in joints via immunoassay, and joint cathepsin B activity (marker of inflammation) was assessed using optical imaging of joints on live mice.
    Results: We found that vamorolone treatment led to a reduction of several disease parameters including disease score, joint inflammation, and the presence of pro-inflammatory mediators to a degree similar of that observed with prednisolone treatment. More importantly, histopathological analysis of affected joints showed that vamorolone treatment significantly reduced the degree of bone erosion while this bone-sparing property was not observed with prednisolone treatment at any of the tested doses.
    Conclusions: While many intervention regimens in other studies are administered prior to disease onset in animal models, the current study involves delivery of the potential therapeutic after disease onset. Based on the findings, vamorolone may offer an efficacious, yet safer alternative to conventional steroidal compounds in the treatment of rheumatoid arthritis and other inflammatory diseases.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal/immunology ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/immunology ; Arthritis, Experimental/pathology ; Collagen Type II/immunology ; Cytokines/immunology ; Joints/drug effects ; Joints/immunology ; Joints/pathology ; Lipopolysaccharides ; Male ; Mice, Inbred DBA ; Pregnadienediols/therapeutic use
    Chemical Substances Anti-Inflammatory Agents ; Antibodies, Monoclonal ; Collagen Type II ; Cytokines ; Lipopolysaccharides ; Pregnadienediols ; VBP15 compound
    Language English
    Publishing date 2019-08-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1221794-3
    ISSN 1420-908X ; 1023-3830
    ISSN (online) 1420-908X
    ISSN 1023-3830
    DOI 10.1007/s00011-019-01279-z
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  8. Article ; Online: Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy.

    Mavroudis, Panteleimon D / van den Anker, John / Conklin, Laurie S / Damsker, Jesse M / Hoffman, Eric P / Nagaraju, Kanneboyina / Clemens, Paula R / Jusko, William J

    Journal of clinical pharmacology

    2019  Volume 59, Issue 7, Page(s) 979–988

    Abstract: Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative ... ...

    Abstract Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined. Population PK modeling of all data together indicated that the PK of vamorolone can be well described by a 1-compartment model with zero-order absorption. Both men and boys showed a dose-linearity of PK parameters for the doses examined, with no accumulation of the drug during daily dosing. Ingestion with food resulted in markedly enhanced absorption of the drug, as tested in healthy men. There were similar PK of vamorolone in healthy men and DMD boys with apparent clearance averaging 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.
    MeSH term(s) Adult ; Anti-Inflammatory Agents/pharmacokinetics ; Anti-Inflammatory Agents/therapeutic use ; Area Under Curve ; Humans ; Male ; Middle Aged ; Muscular Dystrophy, Duchenne/drug therapy ; Pregnadienediols/pharmacokinetics ; Pregnadienediols/therapeutic use ; Young Adult
    Chemical Substances Anti-Inflammatory Agents ; Pregnadienediols ; VBP15 compound
    Language English
    Publishing date 2019-02-11
    Publishing country England
    Document type Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 188980-1
    ISSN 1552-4604 ; 0091-2700 ; 0021-9754
    ISSN (online) 1552-4604
    ISSN 0091-2700 ; 0021-9754
    DOI 10.1002/jcph.1388
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  9. Article ; Online: Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy.

    Heier, Christopher R / Yu, Qing / Fiorillo, Alyson A / Tully, Christopher B / Tucker, Asya / Mazala, Davi A / Uaesoontrachoon, Kitipong / Srinivassane, Sadish / Damsker, Jesse M / Hoffman, Eric P / Nagaraju, Kanneboyina / Spurney, Christopher F

    Life science alliance

    2019  Volume 2, Issue 1

    Abstract: Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle ... ...

    Abstract Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.
    MeSH term(s) Aldosterone/chemistry ; Aldosterone/pharmacology ; Aldosterone/therapeutic use ; Animals ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; CRISPR-Associated Protein 9/genetics ; Cardiomyopathies/drug therapy ; Computer Simulation ; Disease Models, Animal ; Eplerenone/chemistry ; Eplerenone/pharmacology ; Eplerenone/therapeutic use ; Gene Knockout Techniques ; Hydrogen Bonding ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mineralocorticoid Receptor Antagonists/chemistry ; Mineralocorticoid Receptor Antagonists/pharmacology ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Muscular Dystrophy, Duchenne/drug therapy ; Myocarditis/drug therapy ; Myocarditis/metabolism ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Prednisolone/chemistry ; Prednisolone/pharmacology ; Prednisolone/therapeutic use ; Pregnadienediols/chemistry ; Pregnadienediols/pharmacology ; Pregnadienediols/therapeutic use ; RAW 264.7 Cells ; Receptors, Glucocorticoid/chemistry ; Receptors, Glucocorticoid/drug effects ; Receptors, Glucocorticoid/genetics ; Receptors, Mineralocorticoid/agonists ; Receptors, Mineralocorticoid/chemistry ; Receptors, Mineralocorticoid/drug effects
    Chemical Substances Anti-Inflammatory Agents ; Mineralocorticoid Receptor Antagonists ; Pregnadienediols ; Receptors, Glucocorticoid ; Receptors, Mineralocorticoid ; VBP15 compound ; Aldosterone (4964P6T9RB) ; Eplerenone (6995V82D0B) ; Prednisolone (9PHQ9Y1OLM) ; CRISPR-Associated Protein 9 (EC 3.1.-)
    Language English
    Publishing date 2019-02-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.201800186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis.

    Damsker, Jesse M / Conklin, Laurie S / Sadri, Soheil / Dillingham, Blythe C / Panchapakesan, Karuna / Heier, Christopher R / McCall, John M / Sandler, Anthony D

    Inflammation research : official journal of the European Histamine Research Society ... [et al.

    2016  Volume 65, Issue 9, Page(s) 737–743

    Abstract: Objective and design: The goal of this study was to assess the capacity of VBP15, a dissociative steroidal compound, to reduce pro-inflammatory cytokine expression in vitro, to reduce symptoms of colitis in the trinitrobenzene sulfonic acid-induced ... ...

    Abstract Objective and design: The goal of this study was to assess the capacity of VBP15, a dissociative steroidal compound, to reduce pro-inflammatory cytokine expression in vitro, to reduce symptoms of colitis in the trinitrobenzene sulfonic acid-induced murine model, and to assess the effect of VBP15 on growth stunting in juvenile mice.
    Materials: In vitro studies were performed in primary human intestinal epithelial cells. Colitis was induced in mice by administering trinitrobenzene sulfonic acid. Growth stunting studies were performed in wild type outbred mice.
    Treatment: Cells were treated with VBP15 or prednisolone (10 μM) for 24 h. Mice were subjected to 3 days of VBP15 (30 mg/kg) or prednisolone (30 mg/kg) in the colitis study. In the growth stunting study, mice were subjected to VBP15 (10, 30, 45 mg/kg) or prednisolone (10 mg/kg) for 5 weeks.
    Methods: Cytokines were measured by PCR and via Luminex. Colitis symptoms were evaluated by assessing weight loss, intestinal blood, and stool consistency. Growth stunting was assessed using an electronic caliper.
    Results: VBP15 significantly reduced the in vitro production of CCL5 (p < 0.001) IL-6 (p < 0.001), IL-8 (p < 0.05) and reduced colitis symptoms (p < 0.05). VBP15 caused less growth stunting than prednisolone (p < 0.001) in juvenile mice.
    Conclusion: VBP15 may reduce symptoms of IBD, while decreasing or avoiding detrimental side effects.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Body Size/drug effects ; Cells, Cultured ; Colitis/chemically induced ; Colitis/drug therapy ; Colitis/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Female ; Humans ; Male ; Mice, Inbred BALB C ; NF-kappa B/metabolism ; Pregnadienediols/pharmacology ; Pregnadienediols/therapeutic use ; Trinitrobenzenesulfonic Acid
    Chemical Substances Anti-Inflammatory Agents ; Cytokines ; NF-kappa B ; Pregnadienediols ; VBP15 compound ; Trinitrobenzenesulfonic Acid (8T3HQG2ZC4)
    Language English
    Publishing date 2016-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1221794-3
    ISSN 1420-908X ; 1023-3830
    ISSN (online) 1420-908X
    ISSN 1023-3830
    DOI 10.1007/s00011-016-0956-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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