Study of acute toxicity of γ-cyclodextrin nitrates in vivo

Background. Cyclodextrins and their individual derivatives capable of forming inclusion complexes with poorly soluble physiologically active compounds, increasing their solubility in water and slowing down their metabolism, are used as carriers of various drugs. Previously, cyclodextrin nitrates (NCD) were first proposed by us for these purposes: being organic nitrates, they can serve as a source of exogenous nitric oxide and provide an additional and independent therapeutic effect. It was found that complexes based on them exhibit synergistic antioxidant activity. A necessary stage in the study of the biological effectiveness of water-soluble NCDs, in particular, γ-NCDs, is the assessment of the safety of their use in animals.

Aim. To determine the toxic effect of water-soluble γ-NCD depending on the content of nitrate groups in an acute experiment on mice with a single intraperitoneal administration.

Materials and methods. The studies were conducted on healthy male BDF₁ hybrid mice. Aqueous solutions of low-nitrated γ-NCD with nitrogen content of 2.02 % (1), 1.44 % (2) and 0.84 % (3) were administered intraperitoneally at doses of 200–600, 700–900 and 900–1300 mg / kg, respectively. Clinical signs of animal intoxication, mortality, changes in body weight, food and water consumption have been recorded for 14 days, and macroscopic examination of the internal organs of dead animals was carried out.

Results. The acute toxicity of γ-NCD 1–3 was studied experimentally with a single intraperitoneal injection to laboratory animals in the dose range of 300–600, 750–900 and 1000–1300 mg / kg, respectively. The LD₅₀ value was established: for γ-NCD 1 it was 415 ± 33 mg / kg, for γ-NCD 2 – 800 ± 18 mg / kg, for γ-NCD 3 – 1115 ± 33 mg / kg. The results of the acute toxicity study make it possible to classify γ-NCD 1 and γ-NCD 2 to the class IV of toxicity (low-toxic substances); γ-NCD 3 to the class V of toxicity (practically nontoxic). γ-CD (gamma-cyclodextrin) with a single intraperitoneal injection in doses of 3000 mg / kg, it has no toxic effect and can be classified as toxicity class VI (relatively harmless).

Conclusion. For the first time, toxic dose levels of water-soluble low-nitrated γ-NCDs with nitrogen content from 0.84 to 2.02 % have been established, which allows them to be recommended for further research.