Effect of α1-adrenomimetic indralin on oxygen consumption by bone marrow cells in vitro.

In vitro experiments with excessive and normal oxygenation of the culture medium showed unchanged oxygen consumption by mouse bone marrow cells under the influence of radioprotector indralin belonging to α1-adrenomimetics (100 µg/ml). After exhaustion of oxygen in the medium below 10 µM and progressive decrease in cellular respiration, indralin stimulated oxygen consumption by bone marrow cells by 1.5 times. The role of the observed effect of indralin in the realization of its radioprotective properties is discussed.

[The experimental evaluation of antiradiation effectiveness of genistein by survival rates and bone marrow hemopoiesis of mice irradiated by X-rays].

The study was aimed at evaluating the radioprotective effectiveness of genistein administered at different times before or after acute irradiation. Evaluation ofradioprotective efficiency was performed by studying the 30-day survival rate, life expectancy, bone marrow hemapoiesis using the method of endogenous and exogenous colony formation. We have established that genistein at a dose of 200 mg/kg when administered 1 hour prior to irradiation has the highest radioprotective efficiency. In this case, genistein protects mice against death due to X-ray radiation at doses LD(50-90/30), increasing their survival rate by 30-44%, and reduces expression of post radiation disorders of bone marrow hematopoiesis.

[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.

[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.

[Different types of hypoxic preconditioning protect the brain against complete global ischemia].

Different types of hypoxia, including several new models, protect the brain against complete global ischemia. Hypoxic (stay in hermetic chamber without or with consumption of CO2 and H2O exhaled), circulatory (bleeding), hematic (injections of NaNO2, CoCl2, NiCl2) and tissue (histotoxic) hypoxia (K2-malonate injection) increases cerebral ischemic tolerance in early terms (in hours). Intracerebroventricular injections of NaNO2, CoCl2, NiCl2 and K2-malonate in nontoxic doses have weak effects. These substances act by peripheral mechanisms. Increased ischemic tolerance is accompanied by pronounced hypothermia which closely correlates with a neuroprotective effect. This shows using tolerant strategy.

[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.

[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.

[Biochemical and pharmacological mechanisms of different types of hypoxic preconditioning in cerebral ischemia in mice].

Different types of hypoxic preconditioning (hypoxic, circulatory, hemic and tissue hypoxia) increase the tolerance to complete global cerebral ischemia at early terms (hours). Biochemico-pharmacological analysis with the use of selective agonists and antagonists showed the importance of adenosine A1-receptors and K+(ATP)-channels in the mechanisms of the neuroprotective effect and natural tolerance. The general scheme of the investigated mechanisms of different types of hypoxic preconditioning has been proposed.

[The importance of hypothermia in the preconditioning increase of ischemic tolerance to global cerebral ischemia].

Various types of preconditioning including the main hypoxia (hypoxic, circulatory, hematic/hypemic and tissue/histotoxic), agonists of adenosine A-receptors and openers of K(ATP)-channels induce a hypothermia. A-agonists act through A1-receptors, CoCl2 and NiCl2--via endogenous adenosine and activation by it A1-receptors. The developing hypothermia correlates with neuroprotective effect and is important, but not the only mechanism of tolerance increase to global ischemia. At the similar hypothermia the preconditioning effect excels more frequently an influence of external cooling.

[Radioprotective capacity of indralin in reducing radiation injury to salivary glands]. / Protivoluchevye svoistva indralina po snizheniiu tiazhesti luchevogo porazheniia sliunnykh zhelez.

Radioprotective capacity of radioprotector indraline (alpha-1(B)-adrenoagonist) was studied by its effect on early displays of a local radiation injury to salivary glands in white rats after X-ray irradiation of an animal head with a dose of 18.7 Gy. Indraline was found to be capable to reduce a radiation injury to parotid glands registered by reduction of gland mass on 6th day after irradiation. In experiments on rats, radioprotective efficiency of indraline (100 mg/kg) in term of DRF is close to 1.5.

[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.

[The correlation of tolerance to cerebral ischemia and body temperature with glutathione concentration]. / Vzaimosviaz' tolerantnosti k ishemii golovnogo mozga i temperatury tela s kontsentratsiei glutationa.

Methodic approaches for the purposeful changes of glutathione concentration in the brain and liver by administration of glutathione depletors and prodrugs have been modified. Two different depletors (diethylmaleate and buthionine sulfoximine) cause considerable increase of tolerance to the complete global cerebral ischemia and hypothermia development which correlate closely with the decrease of GSH concentration. Five GSH prodrugs (GSH esters and oxothiazolidine carboxilate) and GSH itself usually decrease slightly body temperature but do not influence tolerance to ischemia in the most of series. The increase of tolerance to the complete global cerebral ischemia is connected not with GSH accumulation, but with its decrease. Evidently one of the two opposite GSH effects, sensitizing or protecting one, can predominate in different forms of cerebral ischemia.

[Pharmacologic analysis of the radiation-protecting effect of indraline]. / K farmakologicheskomu analizu protivoluchevogo deistviia indralina.

In comparative studies of the influence of selective alpha 1-adrenoblockager prazosine on radioprotective effect of indraline and mesotone it was found that the mechanism for their radioprotective effect was completely realized via alpha 1-adrenergic action. Calcium blockager nifedipine did not block the indraline effect. It was discussed the issue of classifying of indraline as alpha 1B-adrenomimetic.

[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.

[Radioprotective effect of hydroxy phenylethanolamine phenolic hydroxyl esters]. / Radiozashchitnyi éffekt slozhnykh éfirov po fenol'nym gidroksilam oksifenilétanolaminov.

Experiments are carried out on 3000 mice, irradiated in dose 8 Gy (LD97/30). A number of phenolic hydroxyl esters of phenylephrine, norphenylephrine and epinephrine has the high RPE (70-100%) within 1 h before irradiation. 3-esters of 3-hydroxy phenylethanolamines are active in small doses (19-50 mumol/kg) and protect per os too. RPE of 3-benzoylphenylephrine realizes via alpha 1-adrenoreceptors.

[Radiation-protective effect of agonists of alpha-2 adrenergic receptors. Methyldopa]. / Radiozashchitnyi éffekt agonistov alfa2-adrenoretseptorov. MetilDOFA.

MethylDOPA has the considerable (60-80%) and lasting RPE at both intraperitoneal (0.5-3.8 mmol/kg) and per os (3.8-7.1 mmol/kg) introduction in radiation dose 8 Gr (LD97/30). Optimal time for introduction is 0.5-3.0 hours intraperitoneally and 3-6 hours per os. Evidently, methylDOPA RPE is realized via alpha 2-adrenoceptors.

[Radioprotective effect of alpha 2- adrenoreceptor agonists]. / Radiozashchitnyi éffect agonistov alfa 2- adrenotseptorov.

It is confirmed in experiments with selective antagonists, that radioprotective effects (RPE) of phenylephrine is realised by means of alpha 1--and RPE of clonidine--by means of alpha 2-adrenoceptors (AR). Guanobenz, more selective alpha 2-agonist with another structure, has high RPE too. Chemical analogues of clonidine (alpha-antagonist phentolamine, L-DOPA, DOP-serine), which don't cause selective stimulation of alpha 2-AR, don't protect mice. alpha 2-Agonists are new effective group of radioprotectors.

[The effect of hematoporphyrin derivative on the postradiation recovery of hemopoiesis in mice]. / Vliianie proizvodnogo gematoporfirina na postradiatsionnoe vosstanovlenie krovetvoreniia u myshei.

In experiments with mice exposed to gamma quanta (6.0 Gy) it was shown that a single injection of disodium salt of 2,4-di(alpha-methoxyethyl)deuteroporphyrin IX (50 and 12 mg/kg) both 15 min before and 15 min after irradiation promoted postirradiation regeneration of all bone marrow haemopoiesis compartments. The agent produced a more pronounced stimulatory effect when administered after irradiation.

[Choice of quantitative characteristics of a radiation modifier affinity and the range of its pharmacological action (minireview)]. / O vybore kolichestvennykh kharakteristik srodstva radiomodifikatora i shiroty ego farmakologicheskogo deistviia (minilitobzor).

On the basis of the literature the necessity of using not only DMF and maximal protective or sensitizing effects, but also the affinity and the range of the pharmacological action of radiation modifiers is argued. The affinity is worth while to expressed as ED50 (the dose that produces a half of the maximal effect), and the range of the pharmacological action as a therapeutic index K = LD50/ED50.

[Significance of ED50 and therapeutic indexes of various radiation-protective agent groups]. / Znacheniia ED50 i terapevticheskie indeksy razlichnykh grupp radioprotektorov.

Radioprotective agents are divided in 3 groups: (1) cystamine, AET, cystaphos, gammaphos, and thiogammaphos with ED50 (the dose that gives a half of the maximal protective effect) of 10(3)-10(1.6) mumol/kg and therapeutic index K = LD50/ED50 = 10(0)-10(1.6); (2) 5-methoxytryptamine, phenylephrine, serotonin, and norepinephrine with ED50 = 10(1)-10(0) mumol/kg and K = 10(1.8)-10(2,6); (3) clonidine and isoprenaline with ED50 = 10(-0.5)-10(-0.8) mumol/kg and K = 10(3)-10(4). Possible causes of these differences and advantages of low ED50 and high K are discussed.