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

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 antiinflammatory 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. K E Y W O R D Sdrug discovery, preclinical pharmacology, preclinical toxicology

Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus

“…median lethal dose (LD 50 ) of meglumine in mice is 1.7 g/kg, and full life-span studies with high-dose meglumine in rodents reported no detrimental effects. 39 | Solubility of topiramate in vs When TPM solubility in meglumine was compared with its published solubility in SBE-β-CD (Captisol), the advantage of meglumine became rapidly apparent (Figure 2). For dissolving TPM over the chosen concentration range of 10-50 mg/mL, meglumine concentrations of 0.5%-3.5% were sufficient, whereas >10fold higher concentrations of SBE-β-CD were needed.…”

Electrochemical oxidation of meglumine in a pharmaceutical formulation using a nanocomposite anode

“…Meglumine is a sugar alcohol derived from glucose that contains an amino group modification. It can be applied either as a counterion to form a salt with active pharmaceutical ingredients (APIs) or as a functional excipient in the pharmaceutical industry and in clinical analysis, since it has low toxicity alongside high biocompatibility and biodegradability [1,2]. Moreover, it can act as catalyst in multicomponent reactions [3,4].…”

“…Once used in clinical studies, GBCAs are excreted mostly unmetabolized, thereby s a counterion [1,2] clinical analysis [1,2]. Moreover, it can act , since or as a functional excipient , since can be applied either as a counterion to form a salt with or as a functional excipient can be applied either as a counterion to form a salt with being discharged into water bodies.…”

One-Step Biocatalytic Synthesis of Sustainable Surfactants Using Selective Amide Bond Formation

“…These results led us to examine the scope of other amino alcohols for CAR-A catalyzed amide formation using octanoic, decanoic and dodecanoic acid as acyl donors. Using 5 mM acid loadings, it was found that D-glucamine (6) was well accepted as amine donor forming secondary amides 10, 14 and 18 (Figure 2B). Next, we were interested to see if the amine moiety has to be located at the terminal position of the linear sugar for the amidation to occur.…”

“…1 is an inexpensive and non-toxic compound that has been an approved drug excipient for decades. [6] This substrate is then coupled to a fatty acid via chemical amide bond formation, typically using sodium methoxide which requires careful handling under completely dry conditions. [4] In attempts to develop a less toxic and greener approach to the synthesis of MEGAs, enzymatic methods have gained some interest over the years.…”