Litvinenko D. Finding a Potential AntihypoxantAmong New Germanium Coordination Compounds and Studying Pharmacokynetics Thereof

This thesis paper addresses a topical problem of experimental pharmacology, namely finding and studying compounds having antihypoxic properties in order to create a new highly effective and safe medicinal product for prevention and elimination of effects of a confined space hypoxia (CSH). In this light, Germanium coordination compounds with such bioactive ligands as microelements and organic acids which stand out for their diversity of pharmacodynamic effects, acceptable pharmacokinetic profile and relative harmlessness, seem to be promising. Screening studies employed 6 original heterometallic complexes of Germanium (IV) and 3D-metals (zinc,copper, manganese) based on citric and tartaric acids The studies were conducted on 492 white sexually mature non-pedigree rats of both sexes, 160–200 g. According to the findings obtained in the trial with further extrapolation thereof onto a human in order to identify a number of toxicopathic parameters of acute toxicity and unsafety using a probit analysis, all GCCs studied with single intra-abdominal injection are of low toxicity and moderate toxicity for mammals and humans. Two compounds had the highest value LD50: OKAGERM-1 (LD50 582.53 mg/kg), OKAGERM-4 (LD50 551.81 mg/kg); however OKAGERM-4 is the safest in terms of slope of dose-probit curves. OKAGERM-4 has been also established to belong to the IV toxicity grade (low-toxicity substances) and not to have any potential or real risk of causing fatal poisoning if administered parenterally to warm-blooded animals, suggesting harmlessness and safety of the potential antihypoxant. Mangan(II) tartratogermanate(IV) – OKAGERM-4 was experimentally proven to be the most effective compound; its pharmacological and preventive effectiveness, in the setting of CSH, displays through probable increase in T value by 51.9% compared to the control (hypoxia w/o any drug) and by 36.9% compared to Armadin. If a lead-compound is used, the P value is increased by 52.9% compared to the control, and by 11.7% compared to the reference drug. The Rp for OKAGERM-4 makes up 1.53 (Armadin – 1.12).If OKAGERM-4 is used, a favourable clinical course of CSH is observed. Pharmacometric studies using mathematic modeling in software environment through interpolation of experimental findings onto Lagrange polynomials and Newtonian polynomials with further calculation of maximum test function, established optimal dosing regimen for OKAGERM-4 if administered intraperitoneally: 40 minutes before the hypoxia effect – 96.8 mg/kg. The pharmacokinetic profile of OKAGERM-4 stands out for its distribution into the vital organs most sensitive to hypoxia: brain, heart, lungs, kidneys. In summary, this allows it to have a comprehensive organoprotective activity which effectively prevents development of the multiple organ dysfunction syndrome that develops in case of acute hypoxic syndrome. I view of the above, it is safe to state that the original compound OKAGERM-4 sufficiently meets modern requirements to antihypoxants and appears worthy of further in-depth studying in terms of its effectiveness and safety as a potential antihypoxant drug.