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1.
Bull Exp Biol Med ; 168(1): 92-94, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31768777

ABSTRACT

Combined chronic treatment of Ehrlich solid carcinoma (EC) with an NOS inhibitor 1-isobutanoyl-2-isopropylisothiourea hydrobromide (T1023) and a PDK1 inhibitor dichloroacetate was accompanied by statistically significant synergetic antitumor effects manifested in a significant and stable suppression of neoplasm growth (by 55-65%). Separate treatment with T1023 and dichloroacetate induced moderate short-term inhibition of tumor growth (by 30-35%) followed by weakening of tumor sensitivity to these substances. These results attest to synergetic antitumor effects NOS inhibitor T1023 and PDK1 inhibitor dichloroacetate producing antiangiogenic and hypoxia-targeted cytotoxic effects, during their combined administration, which allows overcoming the adaptive potential of the tumors.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Ehrlich Tumor/enzymology , Dichloroacetic Acid/therapeutic use , Nitric Oxide Synthase/antagonists & inhibitors , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors , Animals , Cell Line, Tumor , Female , Mice , Thiourea/analogs & derivatives
2.
Radiats Biol Radioecol ; 55(3): 250-9, 2015.
Article in Russian | MEDLINE | ID: mdl-26310017

ABSTRACT

The study of radioprotective activity of NO-synthase inhibitor, N-S-isothiourea derivative T1023 showed that this compound has a significant therapeutic range of radioprotective activity (5.5-6.0) and its optimal radioprotective dose is 1/4 LD16. The value of its Radiation Dose-Reduction Factor totaled 1.4-1.8. We have demonstrated a pronounced pharmacodynamic interaction of T1023 with some known radioprotectors. The character of the interaction was determined by its vasoactive properties. Combined use of T1023 and cystamine, which causes a decrease in vascular tone, was accompanied by a statistically significant weakening of the radioprotective effect. But, the combined use of T1023 with serotonergic and adrenergic radioprotectors having a pressor action caused a statistically significant increase in the radioprotective effect. Moreover, T1023 combined with such radioprotectors caused the synergistic radioprotective effect even when used at small doses that do not have any radioprotective effect alone. The findings suggest that NOS inhibitors can be effective radioprotectors and are able to create new opportunities for the development of safer radioprotective agents. The very same compound T1023, according to current criteria of pharmacological screening, is certainly promising for further investigations.


Subject(s)
Enzyme Inhibitors/administration & dosage , Radiation Protection , Radiation-Protective Agents/administration & dosage , Thiourea/analogs & derivatives , Animals , Cystamine/administration & dosage , Enzyme Inhibitors/chemical synthesis , Gamma Rays , Humans , Mice , Nitric Oxide Synthase/antagonists & inhibitors , Radiation Dosage , Radiation Injuries, Experimental , Radiation-Protective Agents/chemical synthesis , Thiourea/administration & dosage
3.
Radiats Biol Radioecol ; 55(3): 260-6, 2015.
Article in Russian | MEDLINE | ID: mdl-26310018

ABSTRACT

We studied the effect of T1023, NO-synthase inhibitor, N-acyl-S-alkyl-isothiourea in a single administration at a dose of 75 mg/kg on the growth of transplantable rat sarcoma M-1 and the development of acute skin reactions after the local impact of γ-radiation at the doses of 32 and 36 Gy. The results showed that the T1023 at a single dose had no effect on the growth of sarcoma, and did not modify the radiosensitivity of the tumor and anti-tumor efficacy of γ-rays. However, at both doses T1023 significantly reduced the severity of acute radiation skin reactions. NOS inhibitor did not change the duration of the inflammatory and regenerative processes, but significantly limited the degree of radiation alteration of the deep layers of the skin and underlying tissues. The findings suggest that the hypoxic mechanism of antitumor action allows T1023 to selectively protect the non-malignant tissue during radiation therapy of solid tumors. Therefore, this compound may be regarded as a promising basis for the development of pharmacological prevention of radiotherapy complications.


Subject(s)
Enzyme Inhibitors/administration & dosage , Radiation-Protective Agents/administration & dosage , Sarcoma/drug therapy , Animals , Enzyme Inhibitors/chemical synthesis , Gamma Rays , Humans , Male , Nitric Oxide Synthase/antagonists & inhibitors , Radiation Tolerance/drug effects , Radiation-Protective Agents/chemical synthesis , Rats , Sarcoma/pathology , Sarcoma/radiotherapy , Skin/pathology , Skin/radiation effects
4.
Radiats Biol Radioecol ; 54(5): 500-6, 2014.
Article in Russian | MEDLINE | ID: mdl-25775842

ABSTRACT

We studied the influence on hemodynamics and radioprotective activity of two inhibitors of NO-synthase (NOS)--isothiourea derivatives with different NOS isoform selectivity: T1023--a selective inhibitor of endothelial and inducible NOS; and NTT2--a highly selective inhibitor of neuronal NOS. Both compounds at a dose of 1/7 LD50/15 caused a vasopressive effect and baroreflex response in normal Wistar rats. However, the nature of hemodynamic changes was qualitatively different. T1023 caused a prolonged elevation of vascular tone and reflex shift resulted in a significant and lasting reduction in the systemic blood flow (35-45%), which created conditions for the development of circulatory hypoxia. The use of NTT2 caused a reflex change in hemodynamics accompanied by vasodilation; and systemic blood flow was maintained at the initial level. T1023 effectively protected mice subjected to 10 Gy γ-irradiation and their bone marrow stem cells irradiated with 6 Gy, not yielding to the radioprotective effect of cystamine. NTT2 at these doses did not show any radioprotective effect. The obtained results support the leading mechanism of the radioprotective effect of NOS inhibitors is the induction of hypoxia. With this mechanism of action a significant radioprotective activity can be expected for the inhibitors which effectively suppress primarily endothelial NOS.


Subject(s)
Enzyme Inhibitors/administration & dosage , Nitric Oxide Synthase/blood , Radiation-Protective Agents/administration & dosage , Animals , Gamma Rays , Mice , Nitric Oxide Synthase/antagonists & inhibitors , Protein Isoforms/antagonists & inhibitors , Rats
5.
Radiats Biol Radioecol ; 52(6): 593-601, 2012.
Article in Russian | MEDLINE | ID: mdl-23516890

ABSTRACT

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.


Subject(s)
Nitric Oxide Synthase , Radiation-Protective Agents/administration & dosage , beta-Aminoethyl Isothiourea , Animals , Enzyme Inhibitors/administration & dosage , Gamma Rays , Lethal Dose 50 , Mice , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Radiation-Protective Agents/chemical synthesis , beta-Aminoethyl Isothiourea/administration & dosage , beta-Aminoethyl Isothiourea/analogs & derivatives , beta-Aminoethyl Isothiourea/chemical synthesis
6.
Bull Exp Biol Med ; 150(1): 18-22, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21161041

ABSTRACT

In vivo effect of isothiourea derivatives on NO production was studied by the method of electron paramagnetic resonance spectroscopy with a spin trap. We evaluated the influence of these compounds on hemodynamic parameters in anesthetized rats with hypovolemic shock. A correlation was found between the size of S,N-substituents in isothiourea derivatives (methyl, ethyl, and isopropyl) and NO inhibitory activity of compounds. The antihypotensive effect was more pronounced in compounds with high NO inhibitory activity containing the isopropyl radical.


Subject(s)
Antihypertensive Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Hypotension/drug therapy , Hypotension/etiology , Shock/complications , Thiourea/therapeutic use , Animals , Antihypertensive Agents/chemistry , Electron Spin Resonance Spectroscopy , Enzyme Inhibitors/chemistry , Hemodynamics/drug effects , Male , Nitric Oxide Synthase/antagonists & inhibitors , Rats , Rats, Wistar , Thiourea/chemistry
8.
Biochemistry (Mosc) ; 74(2): 130-6, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19267667

ABSTRACT

Pifithrin alpha (PFTalpha), one of the first known low molecular weight modulators of activity of tumor suppressor p53, increases survival of hemopoietic clonogenic cells (evaluated by the criterion of formation of endogenous spleen CFU-C8 colonies in irradiated animals). This effect appeared when PFTalpha was administered either before or after irradiation. Increase in CFU-C8 was also observed after administration of two PFTalpha analogs, derivatives of 2-amino-4,5,6,7-tetrahydrobenzothiazole. These included a parent compound, 2-ATBT (2-amino-4,5,6,7-tetrahydrobenzothiazole), which is used for synthesis of PFTalpha, and a product of its intramolecular cyclization under physiological conditions, cyclo-PFT (2-(4-methylphenyl)imidazo[2,1-b]-5,6,7,8-tetrahydrobenzothiazole). Earlier we found that many low molecular weight compounds increasing number of CFU-C8 (e.g. isothiourea derivatives) demonstrate NO inhibitory activity. Such activity was also found in 2-ATBT and cyclo-PFT by means of EPR spectroscopy of NO. These compounds caused more than twofold inhibition of NO production in vivo. Thus, it has been demonstrated that PFTalpha and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a role in the mechanism of this effect.


Subject(s)
Benzothiazoles/pharmacology , Hematopoietic Stem Cells/drug effects , Imidazoles/pharmacology , Nitric Oxide/physiology , Radiation-Protective Agents/pharmacology , Toluene/analogs & derivatives , Tumor Suppressor Protein p53/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Survival/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/radiation effects , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Nitric Oxide/biosynthesis , Radiation-Protective Agents/chemical synthesis , Radiation-Protective Agents/chemistry , Spleen/cytology , Spleen/drug effects , Spleen/radiation effects , Structure-Activity Relationship , Toluene/chemical synthesis , Toluene/chemistry , Toluene/pharmacology
9.
Biomed Khim ; 50(5): 471-6, 2004.
Article in Russian | MEDLINE | ID: mdl-15628596

ABSTRACT

In experimental model of hemorrhagic shock, the influence of new hemocorrectors, succinasole and sucksivil (1,4-naphtoquinone) on rabbit myocardial mitochondrial oxidation was studied. Both substances improved function of myocardial mitochondria. Administration of new hemocorrectors increased duration of life of animals subjected to hemorrhagic shock, improved hemodynamics, metabolism, normalized myocaidla mitochondrial functions and increased positive effect of shock therapy.


Subject(s)
Mitochondria, Heart/drug effects , Naphthoquinones/pharmacology , Plasma Substitutes/pharmacology , Shock, Hemorrhagic/metabolism , Succinates/pharmacology , Animals , Male , Mitochondria, Heart/metabolism , Rabbits
10.
Eksp Klin Farmakol ; 66(4): 53-5, 2003.
Article in Russian | MEDLINE | ID: mdl-14558355

ABSTRACT

Succivil, a drug based on the blood substitute succinasol and containing 1,4-naphthoquinone, was studied as a means of restoring the living activity of cells occurring under extremal conditions of alcohol, heliotrin, or combined intoxication. A thorough investigation of the role of the free-radical oxidation in the dynamics of cell damage, in combination with histological, morphological, and biochemical data, showed that the aforementioned extremal intoxication factors lead to disorders in the cell energetics and intracell detoxicant system and to more or less manifested changes in the hemodynamic, biochemical, and physiological parameters. Succivil is capable of reanimating the cells damaged by the extremal factors studied.


Subject(s)
Naphthoquinones/pharmacology , Poisoning/drug therapy , Animals , Benzaldehydes/poisoning , Benzodioxoles , Blood Substitutes/chemistry , Blood Substitutes/pharmacology , Blood Substitutes/therapeutic use , Ethanol/poisoning , Free Radicals/metabolism , Hemodynamics/drug effects , Male , Naphthoquinones/chemistry , Naphthoquinones/therapeutic use , Oxidation-Reduction , Poisoning/metabolism , Poisoning/pathology , Rabbits
11.
Lik Sprava ; (1): 93-4, 2001.
Article in Russian | MEDLINE | ID: mdl-15311705

ABSTRACT

An incriase has been shown in the blood content of lactate, NADH2, pyruvate, activity of lactatedehydrogenase in hypoxic newborn infants, which fact is believed to have a positive character. Under conditions of deficient supply of tissues with oxygen activization of glycolysis is of compensatory character. The results obtained should be regarded as a positive factor aimed to make up for the fund of NADH2, a potential energy product securing ATP synthesis through aerobic mechanism.


Subject(s)
Asphyxia Neonatorum/metabolism , Energy Metabolism/physiology , Glycolysis/physiology , Apgar Score , Humans , Infant, Newborn , L-Lactate Dehydrogenase/analysis , Lactates/analysis , Pyruvates/analysis
12.
Lik Sprava ; (5): 54-5, 2000.
Article in Ukrainian | MEDLINE | ID: mdl-11031451

ABSTRACT

Overall, fifty newborn infants born to mothers with extragenital pathology (diabetes mellitus) were studied for the coagulative link of the homeostasis system as were 20 babies born to essentially healthy mothers. The studies were made by day 1 to 3 and 5 to 7 the babies' life. The conducted studies revealed signs of hypercoagulation presenting with activation of the external and internal route of hemostasis in those infants born to mothers with diabetes mellitus (DM). Toward the period of early neonatal adaptation shifts are still observable in the coagulating system at the expense of stimulation of the first phase of coagulation. The disclosed abnormalities in the coagulative link of the coagulating system in infants born to DM mothers pose a threat of development of thrombohaemorrhagic complications.


Subject(s)
Blood Coagulation , Hemorrhage/blood , Thrombosis/blood , Adult , Blood Coagulation Tests , Diabetes Mellitus/blood , Disease Susceptibility/blood , Female , Humans , Infant, Newborn
13.
Lik Sprava ; (6): 54-7, 2000 Sep.
Article in Ukrainian | MEDLINE | ID: mdl-11452922

ABSTRACT

A study was made on the condition of lipid peroxidation and of the antioxident system of defence in 20 infants born to healthy mothers (control group), 12 babies born to mothers with diabetes mellitus, 15 infants born to mothers with neurocirculatory asthenia and 12 infants born to mothers with congenital heart diseases. In infants born to mothers with diabetes mellitus and cardiovascular pathology, the system of regulation was found to have gotten out of balance, the compensatory-and-adaptive reactions upset. Accumulation of peroxidic products and depletion of the antioxidant system of defence tended to be more readily seen in those babies born to mothers with diabetes mellitus. The results secured attest to the need for employment of drugs endowed with antioxidant activity.


Subject(s)
Glutathione Transferase/blood , Hypoxia/etiology , Lipid Peroxidation , Pregnancy Complications, Cardiovascular , Pregnancy in Diabetics/complications , Superoxide Dismutase/blood , Female , Heart Defects, Congenital/complications , Humans , Infant, Newborn , Neurocirculatory Asthenia/complications , Pregnancy
14.
Fiziol Zh (1994) ; 45(5): 19-23, 1999.
Article in Ukrainian | MEDLINE | ID: mdl-10687059

ABSTRACT

The model of chronic intrauterine hypoxia was made according to the method, devised in physiology and experimental medicine laboratory of Institute of Pediatrics, Obstetrics and Gynecology Ukrainian AM Sci. This method consist in dose narrowing of the basal venous columns from cornua of uterus in rabbits on 14-15 days of pregnancy. The obtained experimental results confirm previous clinical date about disturbances in antistress mechanisms of protection under chronic fetus hypoxia. Evidently, this disturbances are the important pathogenetic links in behinding of newborn rabbits in physical development and, especially, in its lethality.


Subject(s)
Adaptation, Physiological , Fetal Hypoxia/physiopathology , Stress, Physiological/physiopathology , Acid-Base Equilibrium/physiology , Analysis of Variance , Animals , Animals, Newborn , Chronic Disease , Disease Models, Animal , Female , Fetal Hypoxia/blood , Growth/physiology , Lipid Peroxidation/physiology , Pregnancy , Rabbits
15.
Gematol Transfuziol ; 36(2): 25-8, 1991 Feb.
Article in Russian | MEDLINE | ID: mdl-2055408

ABSTRACT

The results are presented of the hemodynamics investigations under the influence of two saline infusion solutions in varying types of hemorrhage. The suggested crystalloid solution succinasol contains sodium succinate (instead of lactate that is present in lactasol) which improves energetic processes in tissues under conditions of circulatory hypoxia. The results of the study of hemodynamics parameters and animal survival rate have shown succinasol advantages as compared to the lactate-saline blood substitute in acute massive hemorrhage and reversible hemorrhagic shock.


Subject(s)
Disease Models, Animal , Hemodynamics/drug effects , Hemorrhage/drug therapy , Lactates/administration & dosage , Plasma Substitutes/administration & dosage , Succinates/administration & dosage , Animals , Crystalloid Solutions , Female , Hemodynamics/physiology , Hemorrhage/physiopathology , Isotonic Solutions , Lactic Acid , Male , Rabbits , Solutions , Succinic Acid
16.
Vrach Delo ; (8): 25-7, 1989 Aug.
Article in Russian | MEDLINE | ID: mdl-2588517

ABSTRACT

The blood concentration of soluble complexes of monomere fibrin (SCMF), fibrin/fibrinogen splitting products (FSP) and sigma-ESB were determined in 11 patients with rheumatic diseases showing an articular syndrome. The authors revealed the diagnostic significance of SCMF in arthritis of any etiology and FSP in rheumatic diseases with systemic manifestations.


Subject(s)
Rheumatic Diseases/diagnosis , Adolescent , Adult , Aged , Evaluation Studies as Topic , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Male , Methods , Middle Aged , Rheumatic Diseases/blood , Solubility
17.
Vrach Delo ; (4): 57-60, 1989 Apr.
Article in Russian | MEDLINE | ID: mdl-2756690

ABSTRACT

The fibrinolytic system of the blood was studied in 46 patients with osteoarthrosis (OA) associated with reactive synovitis or without it, 44 patients with rheumatoid arthritis (RA) without visceral manifestations. It was found that a slowing of enzymatic, nonenzymatic and XIIa-dependent fibrinolysis is typical of RA but not of OA. Products of fibrin breaking in the general blood flow were absent in patients with OA but may be observed in RA. Increase of the level of fibrin monomers (FM) in the blood are observed in OA with reactive synovitis. The concentration of FM in the blood in RA and OA with reactive synovitis is an informative and dynamic sign of the activity of the inflammatory process and efficacy of treatment.


Subject(s)
Arthritis, Rheumatoid/blood , Fibrinolysis , Osteoarthritis/blood , Adult , Aged , Arthritis, Rheumatoid/diagnosis , Diagnosis, Differential , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Humans , Male , Middle Aged , Osteoarthritis/diagnosis , Synovitis/blood , Synovitis/diagnosis
18.
Vrach Delo ; (1): 47-50, 1989 Jan.
Article in Russian | MEDLINE | ID: mdl-2718445

ABSTRACT

The enzymatic, nonenzymatic and XIIa-dependent fibrinolysis was inhibited. In RA without systemic manifestations the main cause of appearance of soluble complexes of monomeric fibrins (SCMF) in the blood is a local activation of coagulation in the inflamed joint tissues. It is suggested that an increase of SCMF concentration in the blood in patients with RA is a reliable and dynamic index of the activity of the inflammatory process.


Subject(s)
Arthritis, Rheumatoid/blood , Fibrin/analysis , Fibrinogen/analysis , Fibrinolysis , Adult , Aged , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/therapy , Combined Modality Therapy , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Male , Middle Aged
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