Preclinical study of the long-range safety and anti-inflammatory effects of high-dose oral meglumine.

Autor: Manley K; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Bravo-Nuevo A; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Minton AR; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Sedano S; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Marcy A; Dynamis Pharmaceuticals Inc, Jenkintown, Pennsylvania., Reichman M; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Tobia A; Dynamis Pharmaceuticals Inc, Jenkintown, Pennsylvania., Artlett CM; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania., Gilmour SK; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Laury-Kleintop LD; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania., Prendergast GC; Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
Jazyk: angličtina
Zdroj: Journal of cellular biochemistry [J Cell Biochem] 2019 Jul; Vol. 120 (7), pp. 12051-12062. Date of Electronic Publication: 2019 Feb 27.
DOI: 10.1002/jcb.28492
Abstrakt: 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.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
Externí odkaz: