Protective effect and the therapeutic index of indralin in juvenile rhesus monkeys

Abstract

The radioprotective effect of indralin in rhesus monkeys was examined over 60 d following gamma irradiation. Male and female rhesus macaques (Macaca mulatta) 2–3-years-old and weighing 2.1–3.5 kg were used. Animals were exposed to total-body gamma irradiation from 60Co at a dose of 6.8 Gy (lethal dose, 100% lethality over 30 days). Indralin (40–120 mg kg–1) was administered intramuscularly 5 min prior to radiation exposure. Indralin taken at a dose of 120 mg kg–1 protected five out of six monkeys (compared with the radiation control group, in which all 10 animals died). The average effective dose of indralin in the monkeys exposed to gamma irradiation for 30 min was equal to 77.3 (63.3–94.3) mg kg–1, and the maximum tolerated dose of indralin administered to monkeys was 800 mg kg–1. Indralin reduced radiation-induced injuries in macaques, thus resulting in a less severe course of acute radiation syndrome. Delayed and less pronounced manifestation of the haemorrhagic syndrome of the disease, and milder forms of both leukopenia and anaemia were also noted. The therapeutic index for indralin, expressed as the ratio of the maximum tolerated dose to the average effective dose, was equal to 10. Therefore, indralin has a significant radioprotective effect against radiation and has a high therapeutic index in rhesus monkeys.

Nonhuman primates as models for the discovery and development of radiation countermeasures

“…This agent has been studied in seven species and has shown consistent efficacy [93,94]. Recently, its efficacy was investigated in NHPs exposed to 6.8 Gy of whole-body γ-radiation [93]. In this study, Indralin protected five out of six NHPs compared to the control group, in which all 10 animals died.…”

“…B-190 (indralin) is a small-molecule, adrenomimetic that induces radioprotective effects through activation of α1B-adrenoceptors subtype (a subset of the G-protein-coupled receptors family). This agent has been studied in seven species and has shown consistent efficacy [93,94]. Recently, its efficacy was investigated in NHPs exposed to 6.8 Gy of whole-body γ-radiation [93].…”

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

“…The question arises about whether the radioprotective properties of indralin in experiments in dogs and monkeys [ 64 , 92 ] are high compared with those of mexamine, with the same reduction of blood flow in hematopoietic tissues [ 47 ]. The mechanism for the high level of effectiveness of indralin remains elusive.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status

“…Indralin is an adrenoreceptor agonist, and its radioprotective efficacy is mediated through activation of a1(B)-adrenoreceptors, which are members of a family of G-protein-coupled receptors. The radioprotective efficacy of indralin has been studied in seven species of experimental animals: mice, rats, hamsters, guinea pigs, rabbits, canine, and NHP, and demonstrated consistent efficacy (Vasin et al 1996(Vasin et al , 2014. Recently, its efficacy was investigated in NHP (2-3 years old, weighing 2.1-3.5 kg) using whole-body 60 Co c-radiation.…”

“…Recently, its efficacy was investigated in NHP (2-3 years old, weighing 2.1-3.5 kg) using whole-body 60 Co c-radiation. Animals were exposed to a dose of 6.8 Gy (100% lethality in control over 30 d) (Vasin et al 2014). Indralin (40-120 mg/kg) was administered intramuscularly 5 min before irradiation.…”