Pharmacometric studies of new potential antihypoxant on the basis of gluconatogermanate complex of zinc

Abstract

Pharmacological researches on pre-clinical stage of studying of potential medical drugs are one of the
key tasks, which will furthermore determine effectiveness and safety of pharmacotherapy. Currently, it’s
possible to affirm, that in experimental pharmacotherapy the most optimal from the scientific-methodic
viewpoint is mathematical modeling, which allows to eliminate various errors as much as possible during
this kind of researches. Earlier we have established, that synthesized compound of germanium (IV) and
zinc on the basis of gluconic acid (BIOGERM-Zn) is a leading compound by antihypoxic activity under
confined space hypoxia (CSH) conditions and is safe for animals.
The аim of the study – to conduct pharmacometric research of pharmacotherapeutic effect of the
leading compound by building a mathematical model and on it’s basis conduct a calculation of optimal
regimen of BIOGERM-Zn dosage in CSH conditions.
Experiments were conducted on 104 male mice weighting 19–22 g. Pathological process, which
develops in animals in CSH conditions, was the experimental model.
During the development of dosage regimen leader compound was administered to the animals in form
of 0.11–0.66% water solution, in interval of doses between 11 mg/kg to 66 mg/kg intraperitoneally, once,
40 min before starting of CSH modeling.
Criteria of efficiency of compound, which is being studied, was the lifespan of mice inside hermetic
containment.
Optimization of dosage regimen of BIOGERM-Zn was conducted by model method, which allows to
establish it’s efficiency and optimal dose, which was calculated by the search of maximal function of corresponding mathematical model in analyzed dose range of compound, which is being studied in current experiment conditions. It was conducted analysis of "dose – effect" curves and averaged criterias of
effectiveness and safety. Dependence between effect and dose was described by exponential and polynomial mathematic
models. Calculated maximums of these models determine the range of optimal dose values. Comparative analysis of data obtained showed, that maximum of 2-nd grade polynom corresponds with the maximum
of bis(exponential) model. By the results of calculations on the basis of classic bis(exponential) model, it
was established, that lifespan of animals inside hermetic containment is 41 min under optimal dose
40 mg/kg of complex BIOGERM-Zn.
On the basis of analysis of graphic "dose – effect" in logarithmic coordinates a D50 dose was established, which is 50 mg/kg and corresponds with the result by polynom of 5th grade (51 mg/kg).