Radioprotective properties of indralin combined with cystamine and mexamine

The radioprotective properties of indralin when it is used in combination with cystamine and mexamine are studied in inbred mice and rats. The mice and rats are irradiated with γ rays emitted by ⁶⁰Co at doses of 9.0 and 9.5 Gy, respectively. A combined parenteral administration of indralin and cystamine in mice at doses of 25 mg/kg each is revealed to potentiate the radioprotective properties of indralin up to a level close to the ED₅₀ effect, while the separate application of these drugs in doses of 25 mg/kg each has no or a very weak radioprotective effect. Indralin (50 mg/kg) and mexamine (12 mg/kg) injected intraperitoneally in rats are found to almost completely eliminate the animal mortality caused by gastrointestinal acute radiation syndrome; the mortality in the control radiation group reaches 60% on the seventh day after the animals have been exposed to radiation at a dose of 9.5 Gy. However, if bone-marrow acute radiation syndrome develops under the above condition of super-lethal dose, the radioprotectors have a low radioprotective effect. Under the this condition, the combined application of indralin and mexamine in the same doses has 50% of radioprotective effect reached by applying these radioprotectors separately in double doses.     

Radioprotective properties of indralin combined with cystamine and mexamine

The study of indralin radioprotective properties at its joint application with cystamine and mexamine was carried out in the experiments on inbred mice and rats. The mice and rats were exposed to whole-body y-irradiation at a dose of 9.0 and 9.5 Gy, correspondingly. A combined parenteral administration ofindralin and cystamine at a dose of 25 mg/kg showed ponentiaton of indralin radioprotective properties up to a level of the ED50 effect versus the absence of or a weak radioprotective effect in the case of their separate application. In the experiments on rats, indralin (50 mg/kg) and mexamine (12 mg/kg) injected intraperitoneally almost completely eliminated the animal mortality from the intestinal syndrome of acute radiation sickness amounting in the control radiation group to 60% on the 7th day after exposure to radiation at a dose of 9.5 Gy. However, at the above conditions, radioprotectors at these doses had a low-level radioprotective action at the onset of the bone marrow syndrome of acute radiation sickness. Combined application of indralin and mexamine at the same doses and at the same conditions led to a radiation protection 50% as high as in the case when radioprotectors were applied separately at a double dose.     

Evaluation of the radioprotective action of mexamine based on the cellularity index of the rat thymus

Tie administration of mexamine leads to emigration of thymus cells levelling the radioprotective effect of the compound as determined by total cellularity of the organ. Processes of thymus cell depletion were additive after the effect of mexamine and ionizing radiation. It was found possible to estimate the radioprotective efficiency of mexamine with regard to thymus tissue cellularity diminution after the administration of the preparation.     

Radiation-modifying effect of quinoline derivatives

In experiments with hybrid mice (CBA X C57Bl)F1 and tetrahybrids (CBWA) a study was made of the radio-modifying properties of twelve quinoline derivatives. Among them three preparations, including quipazine [1(2-quinolyl)piperazine], possessed a 50% radioprotective effect. The radioprotective effect of piperazinylcinchonine acid hydrazides was the same as that of mexamine.     

Antiradiation properties of radioprotectors, immunomodulators and agents affecting tissue metabolism in fractionated irradiation

A comparative study was made of the protective efficacy of the per os administered cystamine and mexamine as well as of immunomodulators: decaris and thymoptin, and agents influencing tissue metabolism, such as glutamevite and phosphate concentrate, in conditions of fractionated gamma irradiation at a time interval between fractions of 7 to 1 days. In experiments with (CBA X C57B1/6)F1 and (DBA X C57B1/6)F1 hybrid mice it was shown that with a single exposure cystamine and mexamine protected 40-50% of animals. With a three-fold exposure once a week the efficacy of cystamine was as high as 70%. With exposure every other day the radioprotective efficacy of cystamine and mexamine dropped down to 28.3%. With daily exposure, cystamine was ineffective. Decaris and phosphate concentrate had a slight and transient effect amounting to 10-20%.     

Radioprotective effectiveness and toxicity of 4,5-disubstituted tryptamines

In experiments on mice a study was made of different substituents in the 4th position of the indole ring of 5-methoxytryptamines (5-MOT) on toxicity and radioprotective efficiency of the compounds of this class. It was shown that the administration of the amino-group to a mexamine molecule increased the preparation toxicity; the nitro-group somewhat diminished the toxic properties, and the acetylamino group did not change 5-MOT toxicity. A 5-MOT derivative with a nitro group possessed the strongest radioprotective action. The radioprotective efficiency of these compounds persisted for 1-2 h.     

The effect of different doses of mexamine on systemic hemodynamics

The method of thermodilution was used to study the influence of mexamine on the systemic haemodynamics in rats. The radioprotective and cardiovascular effects of the agent within the dose range (2-11 mg/kg) under study were shown to be relatively independent.     

The use of mexamine to reduce radiation injuries during embryogenesis of Wistar rats

In experiments with 330 Wistar rats experiencing their first pregnancy and 1430 neonatal rats of the first generation a study was made on the toxicity and radioprotective efficiency of a single subcutaneous injection of 10 mg/kg mexamine on days 3, 11 and 19 of pregnancy. The agent caused various abnormalities in pregnancy, delivery and postnatal development of the offspring of nonirradiated animals, and it was almost ineffective when used for the prevention of radiation damages during the antenatal ontogenesis.     

Radioprotective effect of drug combinations on the small intestine

The study of the radioprotective effect of complexes containing small amounts of cystamine or gammaphos mixed with mexamine, gutimine and ethyrone on mouse small intestine showed high efficiency of the drugs as determined by cellularity and DNA-synthesizing activity of intestinal epithelium. This is connected with the influence of the complex mexamine + gutimine + ethyrone on the pharmacodynamics and pharmacokinetics of cystamine and gammaphos.     

The radioprotective properties of the liposomal form of mexamine

Encapsulation of mexamine (5 methoxytryptamine) in large monostratal lecithin-cholesterol liposomes was shown to cause a 1.4-fold reduction of acute toxicity of the preparation and to prolong its radioprotective efficacy from 15 min to 2 h.     

Optimization of the composition of the radioprotective complex APAETP+mexamine and analysis of its action

The method of mathematical theory of experiment was used to find optimum variants of the radioprotective complex APAETP + mexamine. The character of their pharmacological interaction, depending on their dose ratio, was determined. It is suggested that it is conditioned by the specific role of different mechanisms involved in the radioprotective effect.     

State of the free-radical oxidation system in normobaric hypoxia]

The experiments on the rats have revealed that 7-hour action of 10% hypoxic gas mixture (HGM-10) exerts no effect on the parameters of Fe(2+)-induced chemiluminescence and rate of accumulation of TBA-active products in the heart, liver, kidney, brain tissues and blood plasma. Two-week adaptation to intermittent effect of HGM-10 causes some activation of free-radical oxidation recorded in blood plasma and the more pronounced increase in power of the endogenic antioxidant system. It is assumed that the revealed changes in the state of the homeostatic system of free-radical oxidation and antiradical protection of the organism are of importance in the mechanism of the known preventive and curative action of intermittent normobaric hypoxia.     

Radiation protection of mice with hypoxic gas mixtures after administration of anti-hypoxic agents

It is shown that such substances as gutimine, antizol and mexamine increases the resistance of animals to short-term breathing of gas mixtures containing 6 and 5% oxygen. Even if some of them decrease the degree of radioprotective effect of hypoxia, they afford the possibility to safe use of breathing mixtures with lower oxygen content than endured by intact animals, with the resulting increase in radioprotection. Thus the antihypoxic substances can be tested during hypoxiradiotherapy of human tumors.     

Application of the methods of the mathematical theory of experiments to the development of multicomponent radioprotective preparations

A study was made of the possibility of using a mathematical theory of experiment in developing effective many-component radioprotective preparations. The preparations composed of cystamine or S-(omega-aminopropyl)-beta-aminoethyl thiophosphate, as the basis, and mexamine, ethyron and gutimine were used as an example to prove the adequacy of such an approach in solving the problems of optimization of composing the radioprotective complexes according to their efficiency and toxicity.     

Radiosensitivity during the irradiation of animals in an altered gaseous environment. A comparative study on mice and rats of the radiation-protective effect of oxygen-deficient gas mixtures

The radioprotective effect of gas hypoxic mixtures containing 5, 7, 8, 10 and 15% of oxygen on mice and rats was comparatively studied. The dependence of DMF upon oxygen concentration in the mixture was approximated by a hyperbolic function similar to the dependence of the radiomodifying effect of circulatory hypoxia caused by radioprotective agents of the indolylalkylamine series.     

Compensatory and adaptive rearrangement in the human respiratory system under acute hypoxic conditions

Relationships between the parameters of external respiration (minute volume and respiration rate) and those of internal, tissue respiration (oxygen consumption, arteriovenous oxygen difference and efficiency of oxygen uptake) were studied during a period of acute hypoxia and upon its completion. The subjects were exposed to hypoxia for 25 min using oxygen-nitrogen hypoxic gas mixtures (HGMs) differing in oxygen content (8 and 12%, HGM-8 and HGM-12, respectively). From the third to the fifth minutes of exposure to HGM-8, the respiration minute volume (RMV) was found to increase by 51 ± 33% as compared to the background value; however, the body’s oxygen consumption (OC) was 35 ± 22% reduced. Afterwards, OC grew to reach, from the 20th to the 25th min of hypoxia, 108 ± 21% of the background value and 181% of the value determined from the third to the fifth minutes of hypoxia. OC growth was accompanied by an insignificant RMV increase (by 12%) as compared to the level determined from the third to the fifth minutes of hypoxia, whereas the efficiency of oxygen uptake from the arterial blood increased by 75% for the same period. RMV growth from the third to the fifth minutes of hypoxia occurred as expense result of a higher breathing depth; at the same time, the respiration rate decreased as compared to the background value. By the period from the 20th to the 25th min of exposure to HGM-8, the respiration rate increased by 21% as compared to the period from the third to the fifth minutes of hypoxia. The efficiency of oxygen uptake from the arterial blood remained higher than the background value for at least 5 min after completion of the exposure to HGM-8. During the same period, the ventilation equivalent, an indicator of the efficiency of external respiration, i.e., of oxygen supply to the body, was significantly lower than the background value. During the exposure to HGM-12, RMV increased to a lesser extent than on exposure to HGM-8, however, the efficiency of oxygen uptake was higher during exposure to HGM-12; therefore, OC was also higher in the latter case. Therefore, the assumption that, during hypoxia, intensified external respiration (ventilatory response) itself compensates oxygen deficiency in inhaled air is revised. Ventilatory response is only a portion of the entire functional system of respiration (both external and tissue respiration). The role of ventilatory response is important for conditioning the tissue respiration rearrangement to eliminate deficiency of oxygen consumption during hypoxia. The retained higher oxygen uptake from the arterial blood during the period after completion of hypoxic treatment testifies to the adaptive implication of changes in tissue respiration; the same is confirmed by a reduced ventilation equivalent after hypoxia, which is indicative of the growing efficiency of external respiration, i.e., of an improved oxygen supply to the body.     

The late effects of radiation on hematopoietic stem cells and the possibility of their modification]

In experiments with mice it has been found that a radioprotective agent, mexamine (two different forms), administered prior to a whole-body single exposure at a dose of LD0/30 increases the average life of animals and the number of exoCFUs 8 days and has no influence on the number of exoCFUs 12 days. Mexamine does not modify the decrease of haemopoietic colonies in sizes in recipients, mice survived acute radiation sickness being used as donors. The share of CFUs 8 days at the stage of DNA synthesis has been shown to increase with age, as well as in animals which lived for 14 months after irradiation.     

Individual specifics of oxygen consumption by the human organism in hypoxia

Influence of hypoxia on a human organism was studied with the help of hypoxic gas mixtures (HGM) in the first series with 14 % content of oxygen in nitrogen (n = 6), in the second one--with 12 % (n = 10) in the third one--with 8 % (n = 14). Hypoxic exposition in all the series was 25 min. In 6 subjects engaged in all the 3 series, physical working capacity was assessed in two-step test on a veloergometer. In all the 3 series, oxygen consumption by the organism some time after the start of the hypoxic action exceeded the background normnoxic level. Maximal value of this excess on the average was the highest in HGM-12 series--40 +/- 12 %. Maximal increase of the respiration and central blood circulation velocity was the highest in HGM-8 series, 90 +/- 24 and 25 +/- 16 % respectively. Analysis of the EEG parameters, oxygen saturation and rheoencephalographic data indicates the probability of the cerebral metabolic rate of oxygen during hypoxia to beein normal (in most subjects) and even increased (in some subjects). In 3 subjects of 6, whose physical working capacity was assessed, maximal increase of oxygen consumption was observed in HGM-8 series--105 +/- 34 %. Their physical working capacity was higher than of those subjects, who showed maximal increase of oxygen consumption in HGM-12 series. Analysis of increase in oxygen consumption (paradoxical under hypoxic conditions) doesn't allow to ascribe it wholly to an increase of the respiration and central blood circulation. Obviously, the increase of oxygen and energy expenditures for biochemical adaptation to hypoxia, which has common features with adaptation to physical activity plays an important role under hypoxia.     

Electrical activity of the brain and oxygen supply for cognitive-mnestic activity in humans under different degrees of hypoxia

Comparative analysis of the indices of oxygen supply for the body and the brain and the functional state of the brain was carried out in three experimental situations: performance of cognitive-mnestic tests under normoxic (TN) and hypoxic conditions (TH) and exposure to hypoxia in the absence of cognitive tasks (H). Each subject participated in all of the experiments. Hypoxic conditions were created by breathing of a hypoxic gas mixture (HGM) consisting of oxygen and nitrogen for 25 min. The first group (eight subjects) was exposed to moderate hypoxia, with the gas mixture containing 12% O₂ (HGM-12); the second group (eight subjects) was exposed to severe hypoxia, with the gas mixture containing 8% O₂ (HGM-8). The cognitive-mnestic activity (CMA) under both normoxia and hypoxia was continuous and included the following tests: “Arithmetic calculations,” “Memory for numerals,” “Colored figures”, and “Sensorimotor response time.” The CMA efficiency was significantly impaired only under severe hypoxia (HGM-8). The CMA efficiency was higher in some subjects of the first group (HGM-12) in the TH series as compared to that in the TN series. The EEG spectral power (SP) during CMA was decreased as compared to the background in all subjects in the TN series and in most subjects of the first group, exposed to HGM-12, whereas it was increased in all subjects of the second group, exposed to HGM-8. The EEG SP was lower in most subjects of both groups studied in the TH series as compared to that found in the H series. The rheographic index of cerebral blood flow rate was not changed compared to the background in the TN series and was increased in the H and TH series during HGM-8 treatment. The increase in cerebral blood flow was less pronounced in the TH series as compared to the H series in most subjects of the second group (HGM-8). Oxygen consumption by the body was elevated by 10–20% in the TN series. A significant increase in oxygen consumption was found in the subjects of both groups studied during hypoxia treatment (H), and it was greater in HGM-12. The following differences were found between the subjects of the two experimental groups: the increase in oxygen consumption in most subjects of the first group (HGM-12) was higher in the TH series as compared to the H series, whereas, in most subjects of the second group (HGM-8), the increase in oxygen consumption was higher in the H series. The data are discussed from the point of view of synergic and concurrent relationships between different forms of energy expenditure on structural and functional reorganization and organ-specific functions.     

Radioprotective action of a combination of poly I-poly C and mexamine

In experiments on (CBA X C57Bl)F1 mice irradiated with doses of 8-12 Gy a study was made of the effect of a mixture of polyI-polyC (2.5 mg/kg, 2 days before irradiation) and mexamine (30 mg/kg, 5 min before irradiation) on the survival rate of animals and the times of their death. It was shown that polyI-polyC potentiates the protective effect of mexamine not increasing its toxicity. The protective agents used in a combination decrease the "intestinal" death of irradiated animals while used separately fail to produce this effect.