[Radioprotective properties of isothiourea derivatives with NO-inhibitory mechanism of action].

The study of the radioprotective activity of S-[2-alkyl (aryl) sulfonyl]-S-ethyl derivatives of (vinyl)-isothiourea in (he model of the survival of mice exposed to gamma-radiation at a dose of 10 Gy has shown that the incorporation of additional sulfur-containing groups does not increase the radioprotective properties of compounds. In contrast to aminoalkil thiols, the effectiveness of the radiation protection action of the isothiourea (ITU) derivatives studied clearly correlates with the NO-inhibitory activity. This fact allowed us to assume that the radioprotective effect of S-substituted ITU caused inhibition of the endogenous synthesis of NO, which promotes the development of circulatory hypoxia, and that a further search for the radioprotective agents in this class of chemicals should be considered as the search for effective inhibitors of NO-synthase (NOS). The theoretical analysis of the conformity of molecular structures to the composition and topology of the active center of NOS-inhibitors allowed us to prognosticate a number of new ITU derivatives with the potential NOS-inhibiting ability. As a result of further theoretical and experimental studies, four S,N-disubstituted ITU derivatives - active non-selective NOS-inhibitors, were first identified and synthesized. These compounds exhibited a pronounced and prolonged vasopressive effects at doses of 0.01-0.05 LD50/15 in the models of severe hemorrhagic and endotoxic shock, and provided 65-100% 30-day survival at doses of 0.2-0.3 LD50/15 in the mice irradiated by gamma-rays at a dose of 10 Gy (LD98/30).The findings suggest the pronounced radioprotective effect of NOS-inhibitors among the ITU-derivatives.

[The study of hypotensive action of dinitrosyl-iron complex with glutathione containing drug oxacom in healthy volunteers].

On the basis of earlier executed studies of hypotensive effect of dinitrosyl iron complexes (DNIC) with glutathione, the drug has been created in industrial conditions named oxacom. Preliminary pharmacological studies of oxacom have not revealed negative qualities. The drug has been now tested in 14 healthy men in whom at single intravenous introduction it caused typical response - a decrease of diastolic as well as systolic arterial pressure on 24-27 mmHg through 3-4 min with subsequent very slow restoration in 8-10 hours. The heart rate after initial rise was quickly normalized. Echocardiography revealed unaltered cardiac output in spite of reduced cardiac filling by 28%. The multilateral analysis of clinical and biochemical data has revealed an absence of essential alterations which could lead to pathological consequences. The drug is recommended for carrying out of the second phase of clinical trial. The comparative study of the efficiency of hypotensive action of oxacom, S-nitrosoglutathione (GS-NO) and sodium nitrite (NO2) in rats has shown that the duration of effect was the greatest at oxacom action.

[Cardiometabolic efficacy and toxicological evaluation of a pharmacological galanin receptor agonist]. / Kardiometabolicheskaia éffektivnost' i toksikologicheskaia kharakteristika farmakologicheskogo agonista retseptorov galanina.

The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [bAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and evaluate its toxicity in BALB /c mice. In anesthetized rats, regional ischemia was simulated by coronary artery occlusion and then coronary blood flow was restored. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25-3.0 mg/kg. The sizes of MI and the activities of creatine kinase-MB (СK-MB) and lactate dehydrogenase (LDH) in blood plasma were estimated. The effect of administration of the optimal dose of G (1.0 mg/kg) on myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr) and lactate was studied. I.v. administration of G to rats at a dose of 1.0 mg/kg slightly affected hemodynamic parameters, but reduced MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion compared to control. These effects were accompanied by a significant improvement in energy state of area at risk (AAR) - an increase in myocardial content of ATP, åAN, PCr and åCr, and combined with a decrease in myocardial lactate level compared with the control. Toxicity of peptide G was studied with a single intraperitoneal injection of 0.5-3.0% solution of the peptide substance to mice. The absence of signs of intoxication and death of animals after G injection in the maximum possible dose did not allow determining the value of the average lethal dose. The results indicate therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and feasibility for further study of its pharmacological properties and mechanisms of action.

[Characteristics of pharmacological and toxic effects of verapamil during cardiac arrhythmia in thyrotoxic and hypothyroid rats].

Aim of this study was to investigate antiarrhythmic and toxic effects of verapamil in mice and rats with thyrotoxicosis and hypothyroidism. We found that changes of thyroid status lead to the increased sensitivity of animals to toxicity of verapamil. At single intraperitoneal introduction of verapamil, LD50 was 118 +/- 7,7 mg/kg for control euthyroid mice, 53 +/- 4,1 mg/kg for hypothyroid mice, and 77 +/- 6,5 mg/kg for thyrotoxic mice. Sensitivity of rat myocardium to arrhythmogenic effects of calcium chloride increased with development of thyrotoxicosis and hypothyroidism. Effective arrhythmogenic dose of CaCl2 was 200 mg/kg for euthyroid rats and 140 mg/kg for rats with thyroid dysfunction. Intravenous introduction of verapamil had antiarrhythmic activity in rats with experimental thyroid dysfunction but at a lower effective dose. Effective preventive dose of verapamil was 3 - 4,5 mg/kg for euthyroid rats and 2 - 2,5 mg/kg for rats with thyrotoxicosis and hypothyroidism. Effective dose of verapamil during rhythm disturbance was 3 mg/kg for control euthyroid rats and 1,5 - 2 mg/kg for rats with abnormal thyroid status. These results provide a basis for the new individual approach for treatment of patients with cardiac arrhythmia combined with thyroid dysfunction.

[Local fibrinolysis of hypertensive intracerebral hematomas].

Authors presented the results of experimental and clinical studies of effects of recombinant prourokinase on brain tissue, its toxicity and safety in intracerebral administration for lysis of hypertensive intracerebral hematomas. Experiments were performed in 64 rabbits. Histological specimens were examined in different periods after injection of prourokinase into white matter and into experimental hematoma. It is revealed that dose of 615 mg/kg causes minimal changes in cerebral tissue. Clinical study was based on analysis of puncture aspiration of intracerebral hematomas with local fibrinolysis performed in 275 patients with hemorrhagic stroke. Dynamics of MRI, clinical and laboratory parameters, coagulation, analysis of aspirated products of lysis were assessed. Authors showed that recombinant prourokinase and the drug "Puroplazan" are effective for local fibrinolysis. The drugs are non-toxic and non-allergenic and do not cause cerebral edema.

[Effect of somatotropin on the course and result of combined radiation and mechanical injury]. / Vliianie somatotropina na techenie i iskhody kombinirovannogo radiatsionno-mekhanicheskogo porazheniia.

In the experiment on rats it was shown that injection of somatotropin (1 ED/kg, i.m. at 1, 3, 5, 7 and 9 days) after combined irradiation and mechanical injury (4.5 Gy, LD50/30 and plural fractures) improved the overall condition of the rats and increased the survival. The drug accelerated the bone regeneration.

[Immunotoxicity assessment in the preclinical study of biologically active compounds]. / Ob otsenke immunotoksichnosti pri doklinicheskom izuchenii biologicheski aktivnykh soedinenii.

The immunotropic action of different drugs was considered on the basis of the modern theory of immunity (theory of network regulation). The immunosuppression and immunostimulation effects were analyzed retrospectively, as well as "disordered" immunity under the action of drugs. A systemic immunomodulated action of different drugs was postulated. Methodical recommendations for the preclinical estimation of immunotoxicity were generalized. A new protocol was proposed, concerning the examination of drug effects on the immune system.

[Study of immunodepressive and allergic effects of xenon]. / Issledovaniia immunodepressornykh i allergiziruiuscchikh svoistv ksenona.

Experimental studies on mice showed that after four 30-min and 60-min inhalations of Xe:O2 (80:20) during 2 weeks, weight indexes of the lymphoid organs (spleen and thymus) increased, phagocytic activity did not change, and primary immune response was moderately stimulated. This indicates that xenon exerted no immunotoxic effects and can be used in patients with diseases associated with primary immunodeficiency. Study of allergic effects on albino guinea pigs showed that on days 14 and 21 of sensitization xenon in the resolving dose possessed no anaphylactogenic activity, caused no specific lysis of leukocytes, and did not modulate the counts of basophils and eosinophils. Xenon did not induce allergic reactions and is not a potential allergen, which is important in patients with panallergy.

[Influence of xenon on reproductive function]. / Vliianie ksenona na reproduktivnuiu funktsiiu.

Wistar rats were used in the study. 15 male rats were exposed to Xe:O2(80:20) mixture for 2 hours twice a week during 10 weeks, and 60 female rats were affected similarly for 2 weeks. The three groups have been formed: 1st group consists of 15 exposed males joined by 30 control female rats, 2nd group includes 30 exposed female rats and 15 control male rats, 15 control male rats and 30 control female rats were in the 3rd group. Xe:O2(80:20) inhalation affect neither fertility and pregnancy indices, which reached 90%, nor body mass gain during pregnancy, nor pre- and postimplantation embryonal death, neonatal body mass and development. Xenon does not impair fine mechanisms of reproductive function, being most safe gas anesthetic with nice prospects for applying in obstetrical clinics.

[Investigation of the teratogenic and embryotoxic action of xenon]. / Issledovaniia teratogennogo i émbriotoksicheskogo deistviia ksenona.

30 Wistar rats inhaled a Xe (80%):O2(20%) mixture for 2 hours twice a week on the 1st to 19th days of pregnancy. On the 20th day of pregnancy 70% rats were exposed to euthanasia, the rest of animals were left for labors to study the postnatal course in the progeny. Inhaling the Xe (80%):O2(20%) mixture did not affect either the changes in body mass of pregnant rats, indices of postimplantating loss of embryos and pregnancy duration or the number of live newborns, their body mass and sizes. Xenon caused neither inhibition of osteal system development nor any malformations. The results of study permit one to look optimistically at the prospects for using Xenon in obstetrical anesthesiology.

[Toxicological characteristics of the antitussive preparation glaucine]. / Toksikologicheskaia kharakteristika protivokashlevogo preparata glautsina.

A toxicological study was made of the antitussive drug glaucinee hydrochloride, an alkaloid of the isoquinoline series (4,5,7,8-tetramethoxyaporphine hydrochloride) isolated from Glaucinum flavum Crantz. of the Papaveraceae family. Upon a single intraperitoneal injection to different laboratory animals the LD50 was found to be equal to 150--180 mg/kg whereas upon intragastric administration, to 510--620 mg/kg. Under the conditions of chronic experiments (intragastric administration to rats in doses of 5, 25 adn 75 mg/kg daily for 3 months) glaucin hydrochloride did not affect the general status of the animals, hematological characteristics, functions of the liver, cardiovascular and excretory systems, and the morphological indicators of the internal organs as shown by electron microscopy. The drug does not possess any allergizing, mutagenic, embryotoxic or teratogenic properties. The data obtained attest to the possibilities of a wide clinical application of glaucin hydrochloride as an antitussive drug.

[Pharmacological properties of adicin, Soviet alpha-acetyldigitoxin]. / Farmakologicheskie svoistva aditsina--otechestvennogo al'fa-atsetildigitoksina.

Adicin, Soviet alpha-acetyldigitoxin, obtained from Digitalis lanata Ehrh., c. Scrophulariaceae after isolation from it of celanid is a highly effective cardiotonic of the digitalis type of action. It exerts a favourable ino- and tonotropic and an adverse chronotropic action on the heart. This action is brought up in varied animal species and can be observed for a long time (over 3 hours). Adicin produces no adverse effect on the coronary blood flow and it is conducive to the improvement of venous circulation. The drug does not differ considerably from acedoxin (Hungarian alpha-acetyldigitoxin) from the standpoint of the cardiotonic effect, cumulative properties, elimination rate, biological activity and toxicity. Adicin is recommended for clinical trials with a purpose of replacing imported drugs.

[Preclinical study of the safety of the new Soviet tranquilizer gindarin]. / Doklinicheskoe izuchenie bezvrednosti novogo otechestvennogo trankvilizatora gindarina.

The Soviet plant tranquilizer gindarin (an isoquinoline series alkaloid I-tetrahydropalmatine) isolated from the tubers of Stephania glabra Miers was subjected to a preclinical study. As regards the toxicity measured during a single administration to the laboratory animals, gindarin may be classified with moderately toxic substances. Daily intragastric administration of gindarin to rats in doses of 20 and 60 mg/kg for 3 months is likely to give rise to the changes in functions of the CNS, liver and blood. In doses of 1--50 mg/kg gindarin does not exhibit any allergizing, mutagenic or teratogenic properties. Administration of the drug in doses of 1--50 mg/kg from the 1st to the 20th day of pregnancy has shown it to produce marked embryotoxic action. In view of this fact gindarin is contraindicated in pregnancy.