Archives → 2021 → V. 61. № 6 → pp. 632-644
Article
Radioprotective effects of T1082 – phosphate 1-isobutanoyl-2-isopropylisothiurea in Comparisson with its Analogue T1023
M. V. Filimonova, L. I. Shevchenko, V. M. Makarchuk, A. S. Saburova, O. V. Soldatova, A. A. Shitova, A. O. Kosachenko, V. A. Rybachuk, V. O. Saburov, A. S. Filimonov
A. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centerof the Ministry of Health of the Russian Federation, Obninsk, Russia
Abstract
The aim of the research was a comparative study of the toxic properties and radioprotective activity of a new NOS inhibitor T1082, 1-isobutanoyl-2-isopropylisothiourea phosphate, in comparison with its close chemi-cal analogue, known as T1023 – 1-isobutanoyl-2-isopropylisothiourea hydrobromide. The study of toxic properties was carried out according to the acute toxicity test for outbred CD-1 mice with a single intraperitoneal (i/p) and intragastric (i/g) administration. A comparative study of T1082 and T1023 radioprotective activity after i/p administration at doses of 1/18–1/2 LD10 was carried out on male F1 hybrid mice (CBA × × C57BL6j) according to the tests of splenic endocolonies and 30-day survival. The study of T1082 and T1023 effects after i/g administration at doses of 50–150 mg/kg was carried out according to the 30-day survival test. The results of this study showed that the replacement of the salt-forming acid from HBr to H3PO4 does not significantly change the toxic properties, but significantly modifies the padioprotective activity of 1-isobutanoyl-2-isopropyl isothiourea salts. Phosphate salt (T1082) acquires the ability to have an effective radioprotective effect when administered i/p in low doses (1/12–1/8 LD10), at which the hydrobromide salt (T1023) is ineffective or no longer works. The consequences of such features of the T1082 are significant. There is a 2-fold expansion of the range of effective doses – from 1/5–1/3 LD10 (60–90 mg/kg) for T1023 to 1/12–1/3 LD10 (27–90 mg/kg) for T1082. This possibility of using 2–3 times lower doses without loss of radioprotective efficiency gives the T1082 compound significant advantages, first of all, in safety. After i/g administration, T1082 at doses of 50–150 mg/kg implements dose-dependent radioprotective effect, which statistically significantly exceed the effect of equal doses of T1023. Moreover, after i/g administration, the level of T1082 safety increases even more – the therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses of T1082 (ED84–98 – 224 mg/kg) are more than an order of magnitude lower than the maximum tolera-ted doses (1/16–1/10 LD10). The data obtained prove that 1-isobutanoyl-2-isopropylisothiourea phosphate has pronounced advantages over the prototype (T1023), which make it possible to classify the T1082 compound as one of the safest potential radioprotective agents, and indicate its high prospects as a basis for a new radioprotector or a mean of preventing radiation therapy complications.
Keywords
Radioprotective efficacy, irradiation, survival, pharmacological safety, acute toxicity, compound T1023, NOS inhibitor
Current Issue
FAQs
Yes, in this case the paper can be rejected.
Agreement as pdf file signed by all co-authors must be submitted by e-mail together with all materials of the article. Original hard copies of the agreement (two copies) must be sent by post to the address of the Editorial Board.