The major feature of COVID-19 is intensive virus-induced inflammation in vital body organs and spatiotemporal dysregulation of pro- and anti-inflammatory cytokines and chemokines synthesis. All this leads to unpredicted clinical progression and high risk of "cytokine storm" development. The "cytokine storm" is the pathogenetic basis for further development of life-threatening complications. Thus, there is a huge need to select effective and safe approaches that allow to control virus-induced inflammation as a part of preventive anti-inflammatory therapy. This article presents toxicological characteristics of the original low-molecular compound XC221GI (1-[2-(1-methylimidazole-4-yl)-ethyl]perhydroazin-2,6-dione) from pre-clinical studies. The obtained results demonstrate that the XC221GI does not have any toxic effect in repeated long-term administration. The compound was well tolerated by all animals. The no-observed-adverse-effect level (NOAEL) was 30 mg/kg per day for dogs and 450 mg/kg per day for rats. There were no effects of XC221GI on blood count, hematopoiesis and hemostasis. As well as no cytotoxic, mutagenic, genotoxic, carcinogenic properties or anaphylactogenic and immunotoxic activity were revealed for XC221GI. All known data enable to classify XC221GI as a low toxic compound and consider its safety profile as reasonably favorable.
Introduction. The study of pharmacokinetics of medicinal substances and evaluation of their pharmacokinetic parameters is a necessary stage of pharmaceutical development of original medicinal agents, allowing to choose the composition and dosage form of the preparation. This is due to obtaining characteristics of all processes that occur in the body of an animal (human), from the absorption of a drug from the place of administration to its excretion from the body.Aim. To conduct a study of the pharmacokinetics of the pharmaceutical substance and the complex compounds based on it to confirm the pharmaceutical development of a drug of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil and to justify the optimal composition of the ready dosage form (GLP).Materials and methods. The study was carried out on male rabbits with a single oral administration of investigated objects in one dose. Plasma concentrations of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil were determined by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic parameters were calculated by extramodel method of statistical moments.Results and discussion. Assay 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil quantification in rabbit blood plasma by HPLC has been developed and validated in the concentration range 10–720 ng/ml in accordance with modern requirements and satisfies them for all indicators. Assay was applicated to analysis of plasma samples obtained from laboratory animals after a single oral administration of a substance and solid dispersion systems of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil in one dose. The main pharmacokinetic parameters of the studied objects were calculated after obtained plasma concentrations of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. It was found that the solid dispersion system with Kollidon 17PF has the greatest relative bioavailability from the examined objects; its relative bioavailability to the substance by oral administration was 583 %.Conclusion. The solid dispersion system method increased the bioavailability of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. Obtained results confirmed correctness of solid dispersion system selection drug e composition and technology development.
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