Radioprotective Activity of the Nitric Oxide Synthase Inhibitor T1023. Toxicological and Biochemical Properties, Cardiovascular and Radioprotective Effects

The Ability of the Nitric Oxide Synthases Inhibitor T1023 to Selectively Protect the Non-Malignant Tissues

“…According to these regressions, the estimates for DMF for T1023 (ratio of equal toxic doses values ± T1023) are in the range of 1.4-1.7. These estimates of DMF for acute RSR in γ-ray LI mice are close to the DMF value (1.6) for 30-day survival of total body γ-irradiated mice [18]. This testifies that T1023 hypoxic effect equally effectively increases the radioresistance of both organs critical for the development of acute radiation syndrome (ARS) and other normal somatic tissues.…”

“…Rapid and pronounced vasoconstriction causes reflex changes in cardiac activity (decrease in strength and frequency of contractions) that limit systemic blood flow (for T1023: cardiac output is reduced by 40-50% within 90-120 min). The resulting transient hypoxia promotes to limit alteration under radiation exposure [17,18].…”

“…The prophylactic effect of T1023 against ARS (DMF-1.6-1.9) develops according to physiological mechanisms that are characteristic, among others, for the agonists of α1B-adrenoreceptors and serotonin 5-HT2-receptors [16,18]. Rapid and pronounced vasoconstriction causes reflex changes in cardiac activity (decrease in strength and frequency of contractions) that limit systemic blood flow (for T1023: cardiac output is reduced by 40-50% within 90-120 min).…”

“…Compound T1023 was synthesized in the laboratory of radiation pharmacology of the A. Tsyb MRRC. The methods used in-laboratory of the synthesis, isolation and purification of compound T1023 [18] provided a stable quality of a substance with a content of 1isobutanoyl-2-isopropylisothiourea hydrobromide of more than 95% and a total content of related and extraneous impurities of less than 1% of dry weight. Amifostine in form of powder for preparing injection solution (ethyol; USB Pharma, Brussels, Belgium) was used as a reference drug.…”

“…Such vasotropic activity allows these compounds induce reflex changes in hemodynamics, leading to transient hypoxia, and exerts a preventive radioprotective effect [15][16][17]. In particular, we have shown that the NOS inhibitor 1-isobutanoyl-2-isopropylisothiourea hydrobromide (compound T1023) is highly effective (dose modifying factor (DMF)-1.6-1.9) in the prevention of H-ARS and G-ARS in mice [18]. The data on the T1023 significant radioprotective activity and the relative safety of its effective dose (1/5-1/4 LD10) are the reason for studying its ability to protect normal somatic tissues in models of acute radiation damage to the skin, as well as its radiation modifying effects in RT models.…”