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.

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.

[Combined effect of quercetin and indralin (B-190) in alleviating carboplatin hematologic toxicity].

In experiment conducted on male mice of C57B1/6 line quercetin (80-100 mg/kg injected 60 minutes before carboplatin) or an emergency radioprotector indralin B-190 (50-100 mg/kg injected 5 minutes after carboplatin) decreased the mortality of animals from toxic carboplatin dose of 100 mg/kg from 40% to 10-11% (p < 0.05). In mice receiving both quercetin and B-190 the reduction of carboplatin toxicity evaluated by blood WBC level was even more prominent (p < 0.05). The results were confirmed in rat experiment. In animals receiving both quercetin and B-190 with 50 mg/kg of carboplatin the WBC level was higher (p < 0.05). Quercetin alone had no effect on hematologic toxicity in those settings. Besides, quercetin and B-190 didn't have any effect on RBC level changes.

[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.

[The influence of combined application of quercetin and indralin on post-irradiation repair of hematopoiesis in acute radiation injury].

Experiments on mice-hybrids F1(CBA x C57B1/6) have detected a favorable effect of the associated application of quercetin (30-60 minutes before y-exposure of an animal) and a radioprotectant of urgent action indralin (in the case of its application after y-exposure) on a post-irradiation repair of the hematopoietic tissue in acute radiation sickness after y-exposure at a non-lethal dose of 6.7 Gy, which manifested itself in the accelerated formation of endogenous spleen colonies and spleen mass recovery, as well as in the lesser degree of leukopenia on the 12th and the 16th day after acute radiation injury. Quercetin per se did not have a radio-protective effect.

[Radioprotective properties of a radioprotector of emergency action indraline at its adminisration after irradiation in conditions of local shielding of a rat abdomen].

In experiences on white rats at a gamma-irradiation in a lethal dose LD97/30 in conditions of local schielding of an abdomen (in the field of a liver) and application of a radioprotector indraline after irradiation the expressed efficiency of combined protection up to 87.5% is scored at 31.3% of a survival in local schielding of an abdomen group and absence of effect from a drug.

Effect of radioprotector Indralin on the course of acute GVH disease.

The effect of radioprotector indralin on the graft-versus-host reaction was studied on the model of acute GVH disease induced in mice by intraperitoneal transplantation of 40x10(6)semiallogenic splenocytes. The effect was evaluated by animal mortality from GVH disease. Recipients were male F1(CBAxC57Bl/6) mice exposed to 7 Gy 24 h before transplantation. Donors were male C57Bl/6 mice. Indralin, intraperitoneally injected in a dose of 100 mg/kg 5 min after irradiation attenuated the severity of GVH disease. It eliminated phase I of acute GVH reaction and shifted to the right the dynamics of mortality. Estimated time of 50% mortality (LT50) was prolonged by more than 4 days (the parameter increased by 31.1%). Two (5.7%) animals recovered from acute GVH disease, while all controls died. Indralin treatment after irradiation resulted in a 30% increase in survival of exposed mice.

[The characteristic of radioprotective properties of a radioprotectant B-190 at its administration after radiation].

In experiences on mice F1 (CBAxC57B 1/6) at a gamma-irradiation in a lethal dose LD(35-70/30) the radioprotectant B-190 at administration after an exposure would rise an animal survival--on 35-55%, caused the increase of the amount of endogenic colony in a spleen and of leucocytes in blood on 11th and 30th day of an acute radiation desease accordingly. The drug has the effect in the interval of doses from 75 up to 150 mg/kg b.w. with the rise of radioprotective action on dose reduction factor from 1.1 up to 1.22. alpha(1)-adrenoblockers terasosin in a dose of 15 mg/kg b.w. partially would reduce radioprotective properties of B-190 as radioprotectant or and drug of early therapy of acute radiation desease.

Effect of radioprotector indralin on carboplatinum hemotoxicity.

A decrease in carboplatinum hemotoxicity was detected in experiments on C57B1 mice treated with the drug in combination with indralin (urgent radioprotector). Carboplatinum in a dose of 125 mg/kg, injected intraperitoneally, caused 80-100% death; the median term of death was 6 days (3-17). Single oral dose of indralin (100 mg/kg) during the 1st min or 15 min after carboplatinum injection (125 mg/kg) increased animal survival by 40.0-46.7% by day 20 of the experiment primarily during the period of manifest hemotoxicity (days 7-17), indralin injected 1, 2, or 4 h after carboplatinum exhibited no chemoprotective effect.

Effect of melatonin, ascorbic acid, and succinic acid on the cumulative toxic effect of repeated treatment with gammafos (amifostine).

Daily treatment of outbred albino mice with gammafos in radioprotective doses of 300 and 500 mg/kg for 4 days produced a cumulative toxic effect. This effect was not observed after decreasing the dose of gammafos to 100 mg/kg. Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.

[Comparative effectiveness of antioxidant melatonin and radioprotectors indralin and phenylephrine in local radiation injuries]. / Sravnitel'naia éffektivnost' antioksidanta melatonina i radioprotektorov indralina i mezatona pri mestnykh luchevykh porazheniiakh.

In experiments on mice radioprotective properties of indraline, phenyleprine and melatonin were compared at topical application as an ointment at a place of local exposure of animal hind to a dose of 38.3 Gy of 60Co gamma-quanta. Factor of dose reduction was 1.27-1.32 for indraline (1-10% ointment) and 1.29 for phenyleprine (0.25% ointment). Antioxidants were low efficient at radiation skin burn. At later local radiation injuries, such as hind contracture, the efficiency of indraline was 1.33-1.5, that of phenyleprine was 1.28, and that of melatonine (2 and 5% ointment) was 1.23-1.47.

[Radiation protective efficacy of alpha-adrenomimetics during local gamma irradiation of the skin]. / Protivoluchevaia éffektivnost' alpha-adrenomimetikov pri lokal'nom gamma-obluchenii kozhi.

In experiment with mice and rats radioprotective properties of direct alpha-adrenomimetic drugs: indraline, mesaton (phenylephrine) and naphthyzine (naphazoline) have been investigated by local early and late radiation injuries. The drugs were S. C. and C. administrated at the site of the thigh of the hind of the animal at intervals of 5-8 min locally was irradiated with gamma-60Co-rays in the doses of 26.3-53.7 Gy at a rate of the dose of 1.31-1.54 Gy/min. When S. C. injected the topical effect of the adrenomimetics was higher than the systemic one. In experiment with mice radioprotective efficiency of topical indraline (S. C. 50 and 100 mg/kg) in term of DRF was equal to 1.34 and 1.67 for radiation burn of the skin, 1.56 and 1.91 for 3rd month radiation contracture of the hind and 1.10 and 1.50 for partial amputation of the one. In the same condition the effect of topical mesaton (S. C. 1, 2.5, 5 mg/kg) in term of DRF was accordingly equal to 1.29, 1.49 and 1.62 for early radiation injury, 1.08, 1.20 and 1.46 for 3th month radiation contracture of the hind and 1.0, 1.14, 1.33 for partial amputation of the one; the effect of topical naphthyzine (5 mg/kg) in the term of DRF was 1.36 for early radiation injury. In experiment with rats radioprotective property of systemic indraline (I. M. 100 mg/kg) in the term of DRF was equal to 1.39 for radiation burn of the skin, 1.39 for 6th month radiation contracture of the hind, 1.41 for partial amputation of the one. When C. administrated the effect of topical indraline (5% solution in 50% DMSO or ethyl alcohol solution) in term of DRF was accordingly equal to 1.17 and 1.18 for radiation burn ot the skin, 1.50 and 1.35 for radiation contracture of the hind, 1.41 and 1.28 for amputation of the one. When S. C. administrated the effect of topical and systemic mesaton (2.5 mg/kg) in term of DRF was accordingly equal to 1.30 and 1.04 for radiation burn ot the skin. 1.25 and 1.0 for radiation contracture of the hind, 1.30 and 1.0 for amputation of the one.

[Studies of the radiation-protective effects of indralin on the hematopoietic system of different species of animals]. / Issledovanie radiozashchitnogo éffekta indralina na krovetvornoi sisteme u razlichnykh vidov zhivotnykh.

The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes, thrombocytes and erythrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed.

[Experimental model of heuristic decision making in experiments on rats for pharmacologic screening]. / Eksperimental'naia model' évristicheskikh reshenii v opytakh na krysakh dlia farmakologicheskogo skrininga.

In experiments on 399 rats the authors developed a method permitting the evaluation of the rate and probability of solving the task demanding from the experimental animals to survive after immersion in cold water. Each animal was exposed to stress only once in life. The task was solved by the animals with the probability rate of approximately 80-100% within 2 min. The pharmacological agents with the depriming effects (morphine, aminazine, sodium oxybutyrate, phenazepam) decreased the aim-oriented behavioral reactions of experimental animals. Caffeine (5-10 mg/kg) decreased the reaction time necessary for solving the task and phenazepam (5 mg/kg) blocked the decision made by the exposed rats to eliminate the stress situation. Nootropil and strychnine exerted no effects on the probability and quickness of the exposed rats to solve the stressful task.