Federal Budgetary Research Institution-State Research Center of Virology and Biotechnology VECTOR, Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, 630559 Koltsovo, Russia.
The Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Viruses. 2023 Jan 11;15(1):205. doi: 10.3390/v15010205.
Since most of the modern human population has no anti-smallpox immunity, it is extremely important to develop and implement effective drugs for the treatment of smallpox and other orthopoxvirus infections. The objective of this study is to determine the main characteristics of the chemical substance NIOCH-14 and its safety and bioavailability in the body of laboratory animals.
The safety of NIOCH-14 upon single- or multiple-dose intragastric administration was assessed according to its effect on the main hematological and pathomorphological parameters of laboratory mice and rats. In order to evaluate the pharmacokinetic parameters of NIOCH-14 administered orally, a concentration of ST-246, the active metabolite of NIOCH-14, in mouse blood and organs was determined by tandem mass spectrometry and liquid chromatography.
The intragastric administration of NIOCH-14 at a dose of 5 g/kg body weight caused neither death nor signs of intoxication in mice. The intragastric administration of NIOCH-14 to mice and rats at doses of 50 and 150 µg/g body weight either as a single dose or once daily during 30 days did not cause animal death or critical changes in hematological parameters and the microstructure of internal organs. The tissue availability of NIOCH-14 administered orally to the mice at a dose of 50 µg/g body weight, which was calculated according to concentrations of its active metabolite ST-246 for the lungs, liver, kidney, brain, and spleen, was 100, 69.6, 63.3, 26.8 and 20.3%, respectively. The absolute bioavailability of the NIOCH-14 administered orally to mice at a dose of 50 µg/g body weight was 22.8%.
Along with the previously determined efficacy against orthopoxviruses, including the smallpox virus, the substance NIOCH-14 was shown to be safe and bioavailable in laboratory animal experiments.
由于大多数现代人类群体没有抗天花免疫力，因此开发和实施治疗天花和其他正痘病毒感染的有效药物非常重要。本研究的目的是确定化学物质 NIOCH-14 的主要特征及其在实验动物体内的安全性和生物利用度。
根据 NIOCH-14 对实验小鼠和大鼠主要血液学和病理形态学参数的影响，评估其单次或多次口服给药的安全性。为了评估 NIOCH-14 经口给药的药代动力学参数，通过串联质谱法和液相色谱法测定了 NIOCH-14 的活性代谢物 ST-246 在小鼠血液和器官中的浓度。
以 5g/kg 体重的剂量灌胃给予 NIOCH-14 既未导致小鼠死亡，也未引起中毒迹象。以 50 和 150μg/g 体重的剂量单次或每日一次连续 30 天灌胃给予 NIOCH-14 不会导致动物死亡或血液学参数和内部器官微观结构发生重大变化。以 50μg/g 体重的剂量经口给予小鼠的 NIOCH-14 的组织利用度，根据其活性代谢物 ST-246 的浓度计算，对于肺、肝、肾、脑和脾，分别为 100%、69.6%、63.3%、26.8%和 20.3%。以 50μg/g 体重的剂量经口给予小鼠的 NIOCH-14 的绝对生物利用度为 22.8%。
除了先前确定的对正痘病毒（包括天花病毒）的疗效外，实验动物研究还表明物质 NIOCH-14 安全且具有生物利用度。
