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Glycopeptide antibiotics are still in demand in clinical practice for treating infections caused by resistant gram-positive pathogens; however, their use is limited due to severe adverse reactions. Their predominant types of side effects are immunoglobulin E-mediated or nonmediated hypersensitivity reactions. Therefore, the development of new glycopeptide antibiotics with improved toxicity profiles remains an important objective in advancing modern antimicrobial agents. We investigated a new eremomycin aminoalkylamide flavancin, its anaphylactogenic properties, influence on histamine levels in blood plasma, pseudoallergic inflammatory reaction on concanavalin A and the change in the amount of flavancin in the blood plasma after administration. It has been shown that flavancin does not demonstrate anaphylactogenic properties. The injection of flavancin resulted in a level of histamine in the blood three times lower than that caused by vancomycin. The therapeutic dose of vancomycin led to a statistically significant increase in the concanavalin A response index compared to flavancin (54% versus 3.7%). Thus, flavancin does not cause a pseudo-allergic reaction. The rapid decrease in flavancin concentration in the blood and the low levels of histamine in the plasma lead us to assume that any pseudoallergic reactions resulting from flavancin application, if they do occur in clinical practice, will be significantly less compared to the use of vancomycin.

Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD 50 ) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD 50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD 50 . The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.

The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing tris (1 H -indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13-1.0 µg/mL) against bacteria that were either sensitive or resistant to antibiotics, including multidrug-resistant clinical isolates. The derivatives combining high antimicrobial activity with relatively low cytotoxicity against human donor fibroblasts HPF-hTERT were subjected to further testing on mice. In vivo they revealed fairly good tolerance and relatively low toxicity. Acute toxicity was evaluated, and the main indicators of toxicity, including LD 50 and LD 10 , were determined. A study of compounds in vivo showed their efficiency in the model of staphylococcal sepsis in mice. The efficiency of compounds may be due to the ability of indolylmethylium salts to form pores in the cytoplasmic membrane of microbial cells and thereby facilitate the penetration of molecules into the pathogen.

A new antitumor multi-target drug anthrafuran, with cellular targets such as topoisomerase I/II and some protein kinases, was obtained in Gause Institute of New Antibiotics and was demonstrated to have a reliable specific effect on different murine and human tumor models by oral administration. In this study, we focused on the evaluation of subchronic toxicity of oral anthrafuran drug formulation (AF) on Chinchilla rabbits. The absence of any changes in the condition or behavior of animals was shown for oral anthrafuran. Changes with reversible and dose-dependent hepato- and nephrotoxicity at low doses, as well as hemato- and gastrointestinal toxicity at high doses, were confirmed pathomorphologically. The identified toxic properties are extremely valuable, since oral anthrafuran does not have the limiting cardio- and myelotoxicity. Anthrafuran with 2 mg/kg/day or 6 mg/kg/day doses was administrated orally over 15 days. Investigations include assessment of the body weight, hematological and serum biochemical parameters and urinalysis, electrocardiography and pathomorphological evaluation of the internal organs. Quantitative data were processed statistically with Student's t -Test, p < 0.05. Revealed during the subchronic study were the favorable toxicological properties of oral anthrafuran as opposed to clinical anthracyclines, oral idarubicin, or parenteral doxorubicin, which allows it to be considered promising for further research.

The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/C max = 219% for P388, TGI max = 91% for Ca755, TGI max = 84% with CR max = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70-100 mg/kg given daily for five days. The LD 50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability.

Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD₅₀ 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.

Hematological toxicity of four combined chemotherapy schemes--TAr, TPAr, EPAr, and IPAr--involving aranose (Ar), cisplatin (P), etoposide (E), irinotecan (I), and topotecan (T) in therapeutic regimes has been studied on healthy mice in comparison to the treatment with Ar in a high therapeutic dose. It is established that Ar alone induces early leucopenia, mostly as a result of lymphocytopenia followed by the absolute and relative neutrophilia; the TAr treatment leads to a moderate neutropenia; whereas the ternary combinations cause a moderate lymphocytopenia. A relatively high hematological toxicity among the ternary combinations was observed for TPAr. The total number of erythrocytes and thrombocytes in the peripheral blood of mice under the action of Ar and all combinations remains on the control level. The inclusion of Ar into the indicated schemes neither modifies the spectrum of hematological toxicity nor increases its level. The observed changes in the peripheral blood were reversible and were not accompanied by any impairment in the state of mice. The obtained results allow the combinations involving P, E, I, T, and Ar to be considered as promising for further investigation.