Journal article
Preclinical study of the long-range safety and anti-inflammatory effects of high-dose oral meglumine
Journal of cellular biochemistry, v 120(7), pp 12051-12062
27 Feb 2019
PMID: 30809852
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Meglumine is a methylamino derivative of sorbitol that is an approved drug excipient. Recent preclinical studies suggest that administration of high-dose oral meglumine can exert beneficial medicinal effects to treat diabetes, obesity, and fatty liver disease (NAFLD/nonalcoholic steatohepatitis [NASH]). Here we address gaps in knowledge about the pharmacology and toxicology of this substance administered at high concentrations to explore its medicinal potential. We observed that high-dose meglumine limited secretion of proinflammatory cytokines and cell adhesion molecules from activated human THP-1 or murine RAW264.7 monocytes. Preclinical pharmacokinetic analysis in Swiss mice confirmed that meglumine was orally available. Informed by this data, oral doses of 18 to 75 mM meglumine were administered ad libitum in the drinking water of Sprague-Dawley rats and two cohorts of C57BL/6 mice housed in different vivariums. In a 32-week study, urinary isoprostane levels trended lower in subjects consistent with the possibility of anti-inflammatory effects. In full lifespan studies, there was no detrimental effect on longevity. Heart function evaluated in C57BL/6 mice using an established noninvasive cardiac imaging system showed no detrimental effects on ejection fraction, fractional shortening, left ventricle function or volume, and cardiac output in mice up to 15-month old, with a potential positive trend in heart function noted in elderly mice consistent with earlier reported benefits on muscle stamina. Finally, in a transgenic model of inflammation-associated skin carcinogenesis, the incidence, number, and growth of skin tumors trended lower in subjects receiving meglumine. Overall, the evidence obtained illustrating the long-range safety of high-dose oral meglumine support the rationale for its evaluation as a low-cost modality to limit diabetes, hypertriglyceridemia, and NAFLD/NASH.
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Details
- Title
- Preclinical study of the long-range safety and anti-inflammatory effects of high-dose oral meglumine
- Creators
- Kaylend Manley - Lankenau Institute for Medical ResearchArturo Bravo-Nuevo - Lankenau Institute for Medical ResearchAllyson R Minton - Lankenau Institute for Medical ResearchSummer Sedano - Lankenau Institute for Medical ResearchAlice Marcy - Dynamis PharmaceuticalsMelvin Reichman - Lankenau Institute for Medical ResearchAnnette Tobia - Dynamis PharmaceuticalsCarol M Artlett - Drexel UniversitySusan K Gilmour - Lankenau Institute for Medical ResearchLisa D Laury-Kleintop - Lankenau Institute for Medical ResearchGeorge C Prendergast - Lankenau Institute for Medical Research
- Publication Details
- Journal of cellular biochemistry, v 120(7), pp 12051-12062
- Publisher
- Wiley
- Grant note
- Lankenau Medical Center Foundation and Main Line Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000471300600118
- Scopus ID
- 2-s2.0-85062359556
- Other Identifier
- 991019168907904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology