Browsing by Subject "Pyrazoles"

Now showing 1 - 7 of 7
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    Caffeine Consumption and Heart Rate and Blood Pressure Response to Regadenoson
    (Public Library of Science, 2015) Bitar, Abbas; Mastouri, Ronald; Kreutz, Rolf P.; Department of Medicine, IU School of Medicine
    BACKGROUND: Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing. METHODS: 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected. RESULTS: Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2±17.1 vs. 7.2±10.2 mmHg, p = 0.001), heart rate change (32.2±14 vs. 27.3±9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5±15.6 vs. 60.7±8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12-24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13±15.8 vs. 7±10.2, p = 0.007), and heart rate change (32.1±15.3 vs. 27.3±9.6, p = 0.017) as compared to those who drank coffee 12-24 hours prior to testing (group 2). CONCLUSIONS: Caffeine exposure 12-24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing.
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    Elexacaftor/Tezacaftor/Ivacaftor Improved Clinical Outcomes in a Patient with N1303K-CFTR Based on In Vitro Experimental Evidence
    (American Thoracic Society, 2021) Huang, Yunjie; Paul, Grace; Lee, Jesun; Yarlagadda, Sunitha; McCoy, Karen; Naren, Anjaparavanda P.; Pediatrics, School of Medicine
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    The HIF-PHI BAY 85–3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model
    (Wiley, 2021-06) Noonan, Megan L.; Ni, Pu; Agoro, Rafiou; Sacks, Spencer A.; Swallow, Elizabeth A.; Wheeler, Jonathan A.; Clinkenbeard, Erica L.; Capitano, Maegan L.; Prideaux, Matthew; Atkins, Gerald J.; Thompson, William R.; Allen, Matthew R.; Broxmeyer, Hal E.; White, Kenneth E.; Medical and Molecular Genetics, School of Medicine
    Fibroblast growth factor-23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23-related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine-containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient-equivalent dose of BAY 85-3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle-treated CKD mice (120-fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY-treated CKD mice. The BAY-treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY-treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp-6 and hepcidin expression were downregulated in all BAY-treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte-like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo-transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF-PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).
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    Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism
    (Elsevier, 2020-03-01) Kline, Jeffrey A.; Puskarich, Michael A.; Pike, Jonathan; Zagorski, John; Alves, Nathan J.; Emergency Medicine, School of Medicine
    Background: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). Methods: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. Results: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. Conclusions: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.
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    Management of hypertension in advanced kidney disease
    (Wolters Kluwer, 2022) Georgianos, Panagiotis I.; Agarwal, Rajiv; Medicine, School of Medicine
    Purpose of review: The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD). Recent findings: In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension. Summary: Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.
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    Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715
    (American Association for Cancer Research, 2014-02) Slee, Roger B.; Grimes, Brenda R.; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L.; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray; Department of Medical and Molecular Genetics, IU School of Medicine
    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.
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    Transcriptomic Analysis of Healthy and Atopic Dermatitis Samples Reveals the Role of IL-37 in Human Skin
    (American Association of Immunologists, 2021-10-26) Zhou, Jiajun; Gemperline, David C.; Turner, Matthew J.; Oldach, Jonathan; Molignano, Jennifer; Sims, Jonathan T.; Stayrook, Keith R.; Dermatology, School of Medicine
    Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to one in five children and millions of adults in developed countries. Clinically, AD skin lesions manifest as subacute and/or chronic lichenified eczematous plaques, which are often intensely pruritic and prone to secondary bacterial and viral infections. Despite the emergence of novel therapeutic agents, treatment options and outcomes for AD remain suboptimal. An improved understanding of AD pathogenesis may help improve patient outcomes. Dysregulated Th2-polarized skin inflammation and impaired skin barrier function interact to drive AD pathogenesis; however, much remains to be understood about the molecular mechanisms underlying this interplay. The current study used published clinical trial datasets to define a skin-related AD gene signature. This meta-analysis revealed significant reductions in IL1F7 transcripts (encodes IL-37) in AD patient samples. Reduced IL1F7 correlated with lower transcripts for key skin barrier function genes in the epidermal differentiation complex. Immunohistochemical analysis of normal (healthy) human skin specimens and an in vitro three-dimensional human skin model localized IL-37 protein to the epidermis. In comparison with normal human skin, IL-37 levels were decreased in AD patient skin. Addition of Th2 cytokines to the aforementioned in vitro three-dimensional skin model recapitulates key aspects of AD skin and was sufficient to reduce epidermal IL-37 levels. Image analysis also indicated close relationship between epidermal IL-37 and skin epidermal differentiation complex proteins. These findings suggest IL-37 is intimately linked to normal keratinocyte differentiation and barrier function and implicates IL-37 as a potential biomarker and therapeutic target for AD.