TOXICO-PHARMACOMETRIC RESEARCH OF A NEW POTENTIAL ANTIHYPOXIC AGENT BASED ON A CITRATOGERMANATE COMPLEX WITH A BENZOTRIAZOLE FRAGMENT
DOI:
https://doi.org/10.11603/1811-2471.2026.v.i2.15713Keywords:
closed-space hypoxia, antihypoxic activity, potential antihypoxic agent, acute toxicity, pharmacometry, citratogermanate complex, bi-exponential model, dose – effectAbstract
SUMMARY. In recent years, the frequency of extreme situations – natural, technogenic, and military – has increased significantly, leading to the development of hypoxic states of varying severity in affected individuals. Unique biologically active substances among germanium coordination compounds based on naturally derived ligands offer promising prospects for the discovery and development of new, safe, and effective agents with antihypoxic activity. In this context, a germanium coordination compound based on citric acid containing a benzotriazole fragment (Maluk-6) was the focus of our investigation.
The aim – to perform a comprehensive toxicological and pharmacometric evaluation of a potential antihypoxic agent using a closed-space hypoxia (CSH) model.
Material and Methods. The compound Maluk-6 was studied. Acute toxicity was determined according to Prozorovsky’s method. Acute hypoxia combined with hypercapnia (CSH) was modelled by placing animals into sealed glass chambers. The test compound (Maluk-6) and the reference drug (ethylmethylhydroxypyridine succinate) were administered intraperitoneally to mice at a dose of 100 mg/kg for preventive purposes. Antihypoxic efficacy was evaluated by monitoring clinical signs, survival time in the chamber (T), antihypoxic protection coefficient (Kp), and the relative increase in survival time (P). To establish the optimal dosing regimen, Maluk-6 was administered intraperitoneally 20 minutes prior to CSH modelling at doses ranging from 100 to 700 mg/kg. Optimal dose parameters were calculated using a defined mathematical model.
Results. It was shown that the median lethal dose (LD50) of Maluk-6 after intraperitoneal administration ranged between 316–1000 mg/kg and was determined to be 708 (620–800) mg/kg, corresponding to hazard class IV. The compound Maluk-6 demonstrated significant clinical and experimental advantages in antihypoxic properties compared with the reference and control groups (according to parameters T, Kp, and P). Based on mathematical modelling (bi-exponential and polynomial functions), optimal dosing parameters were established, including doses corresponding to 50 % efficacy, maximal efficacy, and semi-maximal effect.
Conclusions. Experiments on mice under CSH conditions confirmed the high antihypoxic potential of Maluk-6, which significantly exceeded that of the reference drug (ethylmethylhydroxypyridine succinate) across all studied parameters. The results obtained from the bi-exponential model were consistent with the experimental “dose–effect” curve, confirming the reliability of the pharmacometric analysis.
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