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  1. Artikel ; Online: Breakthrough: a first-in-class virtual simulator for dose optimization of ACE inhibitors in translational cardiovascular medicine.

    Schneider, Benjamin K / Ward, Jessica / Sotillo, Samantha / Garelli-Paar, Catherine / Guillot, Emilie / Prikazsky, Marc / Mochel, Jonathan P

    Scientific reports

    2023  Band 13, Heft 1, Seite(n) 3300

    Abstract: The renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies ...

    Abstract The renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.
    Mesh-Begriff(e) Humans ; Animals ; Dogs ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Prospective Studies ; Aldosterone/metabolism ; Renin-Angiotensin System ; Heart Failure/drug therapy ; Cardiovascular Agents/pharmacology ; Biomarkers/metabolism
    Chemische Substanzen Angiotensin-Converting Enzyme Inhibitors ; Aldosterone (4964P6T9RB) ; Cardiovascular Agents ; Biomarkers
    Sprache Englisch
    Erscheinungsdatum 2023-02-26
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-30453-x
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Dose-response of benazepril on biomarkers of the classical and alternative pathways of the renin-angiotensin-aldosterone system in dogs.

    Sotillo, Samantha / Ward, Jessica L / Guillot, Emilie / Domenig, Oliver / Yuan, Lingnan / Smith, Joseph S / Gabriel, Vojtech / Iennarella-Servantez, Chelsea A / Mochel, Jonathan P

    Scientific reports

    2023  Band 13, Heft 1, Seite(n) 2684

    Abstract: Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin-angiotensin-aldosterone system (RAAS); however, the dose-dependent effects of benazepril on ... ...

    Abstract Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin-angiotensin-aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet. Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 h post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (- 38%, P = 0.004), Ang1-5 (- 53%, P = 0.001), ACE-S (surrogate for ACE activity; - 59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; - 22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; + 58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans.
    Mesh-Begriff(e) Animals ; Dogs ; Aldosterone/pharmacology ; Angiotensin II/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Biomarkers ; Renin-Angiotensin System
    Chemische Substanzen Aldosterone (4964P6T9RB) ; Angiotensin II (11128-99-7) ; Angiotensin-Converting Enzyme Inhibitors ; benazepril (UDM7Q7QWP8) ; Biomarkers
    Sprache Englisch
    Erscheinungsdatum 2023-02-15
    Erscheinungsland England
    Dokumenttyp Journal Article ; Randomized Controlled Trial, Veterinary ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-29771-x
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

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