I. B. Ushakov

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

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.

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

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.

In Vitro Response of Mitochondrial Succinate Oxidase System to Epinephrine in Human Blood Lymphocytes from Health Individuals and Patients with Neurocirculatory Dystonia

Activities of succinate dehydrogenase (SDH) and α-glycerophosphate dehydrogenase (hyaloplasmic and mitochondrial: α-GPDHH and α-GPDHM) in peripheral blood lymphocytes, and the response of SDH activity to exogenous epinephrine in vitro (the epinephrine test) were studied in 20 healthy subjects and 46 patients with hypertensive neurocirculatory dystonia. Activities of SDH, α-GPDHH, and α-GPDHM in blood lymphocytes and SDH adrenoreactivity in epinephrine test were higher in patients than in healthy controls. Treatment with hypotensive agents (isradipin and pyrroxan) moderated adrenoreactivity. Phytotherapy normalized the baseline activities of succinate oxidase system and α-glycerophosphate pathway in blood lymphocytes.

Pharmacological Analysis of the Therapeutic Effect of Radioprotectors Cystamine and Indralin in the Capacity of Radiomitigators

The therapeutic radiomitigating effect of cystamine and indralin was studied in experiments on mice and rats and pharmacological analysis of these drugs was carried out. The animals were subjected to whole-body 60Co γ-irradiation. The mice were exposed to single (9-10 Gy) or double (8 Gy) irradiation with an interval of 1 month. The rats were exposed to 10 Gy with partial shielding of the upper quarter of the abdomen. In experiments on mice, pretreatment with reserpine abolished the therapeutic effect of cystamine administered repeatedly every 15 min over 1 h after irradiation. Moreover, summation of the radioprotective and therapeutic effects of the radioprotector was revealed under these conditions. In mice and rats, α1-adrenoreceptor blocker terazosin did not abolish the therapeutic effect of indralin administrated after irradiation, but blocked the radioprotective effect of indralin applied prior to irradiation. At the same time, 5-HT2 serotonin receptor blocker tropoxin abolished the therapeutic effect of indralin without affecting its radioprotective activity.

Therapeutic Effect of Long-Term Melatonin Treatment on the Course and Fatal Outcome of Modeled Acute Radiation Sickness

We studied the effect of long-term administration of melatonin to male C57Bl/6 mice starting from day 3 after whole-body γ-irradiation (9.5-10.0 Gy, 7.7-17.1 cGy/min). It was found that replacement of drinking water with melatonin solution (5 mg/liter) did not reduce the amount of fluid intake throughout the period of acute radiation injury. The daily dose of melatonin was 0.9-1.2 mg/kg body weight (this parameter was lower at the peak of the disease and increased during the recovery stage). Melatonin by more than 20% (p<0.05) improved survival of mice exposed to γ-irradiation in a dose of LD97/30, reduced leukopenia during the stage of acute manifestations of the disease and maximum mortality, and increased blood leukocyte count by 40% (p<0.05) by day 12 after irradiation.

Potential Role of Catecholamine Response to Acute Hypoxia in the Modification of the Effects of Radioprotectors

Involvement of hormonal response (catecholamine release) to acute hypoxia induced by radioprotectors in modification of their radioprotective properties was studied in experiments on outbred mature female albino mice, female albino rats, and dogs of both sexes. The response intensity was evaluated by the reduction of radioprotective and toxic properties of indralin (a α1-adrenoceptor agonist and a radioprotector). The radioprotective effect of indralin was measured using lethal doses of whole-body γ-irradiation (60Co) and its acute toxicity was assessed by LD50. It was found that repeated administration of indralin with 30-60-min intervals was followed by weakening of its radioprotective effect. Similar sensitization effect of indralin was observed after pretreatment with cystamine and epinephrine. Comparison of the severity of sensitization after administration of epinephrine and cystamine in the dose providing radioprotective effect showed that the potential aminothiol-induced release of catecholamines can provide optimal long-term radioprotective effect of epinephrine.

Radioprotective Properties of Indralin in Combination with Monizol in the Treatment of Local Acute and Delayed Radiation Injuries Caused by Local Skin γ-Irradiation

Female rats were exposed to local γ-irradiation of the right hindpaw in doses of 30-50 Gy at 131-154 sGy/min dose rate. Radioprotector indralin was administered per os 15 min prior to irradiation, monizol was injected intraperitoneally 5 min after irradiation. Indralin showed marked radioprotective properties both for acute and delayed symptoms of local radiation injuries. In combination with monizol, radioprotective effect of indralin was potentiated to dose reduction factor of 1.4-1.5 both for radiation burn severity reduction and for restriction of postradiational contracture development and amputation of the irradiated limb.

Mitigating Effect of Nitrates (Monizol) on Pharmacodynamic Shifts in the Cardiovascular System Caused by Radioprotector Indralin

We studied the effect of radioprotector indralin (B-190) alone or in combination with monizol on BP and HR in rabbits, reduction of blood supply and spleen weight in rats and (CBA×C57Bl/6)F1 hybrids mice, and on blood loss from a wound on tip of the tail in mice. Being an α1-adrenomimetic, indralin caused hypertensive reaction with the development of bradycardia, reduced blood supply and spleen weight, and sharply reduced blood loss from the wound. Monizol as nitrate reduced BP without affecting HR and reduced blood loss from the wound. Monizol administered prior to indralin eliminated radioprotector-induced hypertensive reaction, reduced bradycardia by more than 2 times, and attenuated the effect of indralin on spleen weight and blood loss from the wound by 1.6-1.8 times. Monizol administered after indralin had no effect on shifts in peripheral blood supply caused by the radioprotector.

Stress Reaction and Biochemical Shock as Interrelated and Unavoidable Components in the Formation of High Radioresistance of the Body in Acute Hypoxia

Stress reactions with activation of the sympathetic-adrenal system due to acute hypoxia reflects the degree of sensitivity of the body to this extreme factor. Succinate dehydrogenase (SDH) activation in cells as an adaptive response to acute hypoxia is closely associated with the degree of disturbance of tissue respiration through a lack of oxygen in the tissues, including the manifestation of “biochemical shock,” which is an unavoidable component of implementation of the protective effect of radioprotectors. In experiments on mice, rats, and dogs, the correlation between the manifestation of the radioprotective effect of acute hypoxia and SDH activation in blood lymphocytes, caused primarily by adrenergic stimulation during stress reactions, is confirmed. The degree of SDH activation in blood lymphocytes by hypoxia of different origins including that induced by radioprotectors may indicate its radioprotective potential irrespective of the differences in the oxygen consumption intensity and the resistance to acute hypoxia in animals and humans.

Hypobaric Interval Hypoxia as a Nonmedication Method for Improving the Functional State of Aerospace Pilots and Astronauts

Maintenance of health of risky profession workers (such as aerospace pilots and astronauts) and rendering them rehabilitative procedures remains to be one of the major medical issues. There is an apparent necessity to seek and adopt effective methods of rehabilitating the workers of risky professions who usually suffer with fatigue, impairment of body tolerance to negative factors, deadaptation, and asthenization (a condition experienced by astronauts with symptoms such as fatigue, irritability, lack of appetite, and sleep disorders) following stressful situations of aerospace flights. These adverse effects could potentially lead to functional and organic diseases in the pilots and astronauts. A method of hypobaric interval hypoxia (HIH) was devised and test validated for the needs of aviation, space, military, preventive, and rehabilitation medicine. The course of HIH treatment consists of ten 1-h daily sessions of exposure to HIH in a hypobaric chamber simulating high altitude of 3,000–5,000 m. In each of the 10-min periods, 7-min hypoxic air breathing alternates with 3-min hyperoxic air mixture breathing with air pressure simulating same altitude. In the first session, the subjects “climb” to 3,000 m; in sessions 2–4, the altitude increases in 500 m steps; and finally the sessions 5–10 are performed at the altitude of 5,000 m. HIH has showed high effectiveness in improving human organism functionality and tolerance to the environmental adverse factors, that is, hypoxia, flight accelerations, and motion sickness, as well as in preventing and correcting the impaired functional states.