Comparative efficacy and the window of radioprotection for adrenergic and serotoninergic agents and aminothiols in experiments with small and large animals

Abstract

This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in experiments on both small and large animals. It presents a hypothesis explaining the decrease in the TI of cystamine and 5-methoxytryptamine (mexamine), and the retention of that of α1-adrenomimetic indralin, and also compares the effects on large and small animals. The considerable differences in the therapeutic indices of catecholamines, serotonin and cystamine are a consequence of specific features of their mechanisms of radioprotective action. Radioprotectors acting via receptor mediation tend to provide a more expanded window of protection. The reduction in the TI of cystamine in larger animals, such as dogs, may be caused by the greater increase in toxicity of aminothiols in relation to the decrease in their optimal doses for radioprotective effect in going from mice to dogs, which is a consequence of the slower metabolic processes in larger animals. The somatogenic phase of intoxication by cystamine is significantly longer than the duration of its radioprotective effect, and increases with irradiation. The decrease in the radioprotective effect and the TI of mexamine in experiments with dogs may be caused by their lower sensitivity to the acute hypoxia induced by the mexamine. This is because of lower gradient in oxygen tension between tissue cells and blood capillaries under acute hypoxia that is determined by lower initial oxygen consumption in a large animal as compared with a small animal. Indralin likely provides optimal radioprotective effects and a higher TI for large animals via the increased specificity of its adrenergic effect on tissue respiration, which supports the development of acute hypoxia in the radiosensitive tissues of large animals. The stimulatory effect of indralin on early post-irradiation haematopoietic recovery cannot provide a high level of radioprotective action for large animals, but it may promote recovery.

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

“…2). This is consistent with published reports indicating that Am and WR can effectively reduce but not block an absorbed radiation dose (Junn et al 2012; Vasin and Ushakov 2015).…”

An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice

“…For example, a decrease in the tryptophan and histidine metabolism, including tryptophan, serotonin, and histamine values, was reported in studies using mouse serum, mouse intestine, and rat urine [25][26][27][28][29]. These metabolites were reported to function as radioprotectors [30][31][32], and we observed that a decrease in these radioprotective metabolites helped explain the radiation-induced damage. We also observed a decrease in the components of the pyrimidine metabolism pathway, such as thymidine, in TBI mice, although several previous studies using mouse serum and urine showed that TBI upregulated the levels of thymidine, reflecting DNA or RNA damage [26,33].…”

1-Isobutanoil-2-isopropylisothiourea Phosphate, T1082: A Safe and Effective Prevention of Radiotherapy Complications in Oncology

“…administration—1/16–1/10 LD 10 ( Table 2 ). Such pharmacological ratios show the advantage of T1082 in comparison with many known radioprotective agents [ 25 ]. This allows for its classification as one of the safest radioprotectors with an emergency, preventive effect.…”

“…In this case, the T1082 therapeutic index (LD 50 /ED 50 ) reaches 30, and its optimal radioprotective doses (ED 84-98 —141–224 mg/kg) are an order of magnitude lower than the maximum tolerated doses—1/16–1/10 LD 10 . These data allow for the classification of T1082 as one of the safest radioprotectors with emergency, preventive action [ 25 ].…”