In Silico Studies on Pharmacokinetics and Neuroprotective Potential of ²⁵Mg²⁺: Releasing Nanocationites - Background and Perspectives

Abstract

Sharp blood circulation disorders are known for their capability to promote such abundant and hardly treatable pathologies as myocardium infarction and the ischemic brain stroke (“insult”). Noteworthy, the stroke — related brain tissue metabolic damages involve an essential ATP deplete clash along with a suppression of brain specific nucleotide — associated kinases and ATP synthase, both Mg2+ — dependent complex enzyme “machineries”. This itself makes the latter’s a legitimate target for some advanced pharmaceuticals as long as the drug — induced overstimulation of corresponding enzymatic activity is the case. Thus, magnetic isotope effects (MIE) of the nuclear spin possessing paramagnetic 25Mg2+ ions might modulate the brain creatine kinase, alfa-glycerophosphate kinase and pyruvate kinase catalytic activities in a way of a remarkable ATP hyperproduction required to compensate the hypoxia caused acute metabolic breakdown. To realize the Magnesium-25 pharmacological potential, a low-toxic amphiphilic cationite nanoparticles were introduced lately. Particularly, the Magnesium — releasing porphyrin-fullerene nanoadduct (cyclohexyl-C60-porphyrin, PMC16) has been proposed to meet expectations dealing with a targeted delivery of 25Mg2+ towards the brain ischemia surrounding areas. In order to optimize a multi-step [25Mg2+]4PMC16 preclinical trial scenario, the In Silico algorithms are to be developed and analyzed. In this study, these algorithms are in a focus with a special emphasize on a novel combination of slightly modified Gompertzian equation systems and a non-Markov population dynamics concept. This In Silico approach takes into account some literature-available patterns of brain hypoxia pathogenesis, the resulted simulation model could be considered as a promising tool for further research on experimental nanopharmacology of the ischemic stroke.

In Silico Track to Reveal a Translational Potential of Porphyrin-c60 Nanoparticles in the Ischemic Stroke Related Preclinical Studies

“…The pharmacokinetics of porphyrin-fullerene nanoagents for preclinical research optimization is solvable in silico on a computational experiment basis [32]. However, for comprehensive optimization of research algorithms, pharmacokinetics (PK) (i.e.…”

An Advanced in Silico Model to Optimize the Pharmacokinetic Studies ON25 Mg2+ – Releasing Porphyrin – Fullerene Nanoparticles in Brain Ischemic Disorders

“…First of all, this concerns an increase in the compartmentalization of the model to take into account both additional methods of drug administration and the ways of its elimination. It is also of interest to supplement the capabilities of the model with pharmacodynamic and others modules, primarily due to the ability to describe the features of more subtle and complex intracellular Mg-dependent processes in relation to the therapeutic features of nanopreparations of the PMC16 line and taking into account the pathophysiology of ischemic stroke as we described in [32].…”