[Antiaggregation activity of arachidonic acid conjugates with neurotropic peptides proglyprol and semax].

The influence two original derivatives of a therapeutically important peptide, bearing arachidonic acid residue with semax and proglyprol, upon platelet aggregation have been studied in vitro. It is established that both derivatives, in contrast to the parent peptide, possess moderate anti-aggregant properties and produce a dose-dependent decrease in the interplatelet interaction induced by ADP, epinephrine, and arachidonic acid within the concentration range of 0.018 - 1.8 mM. This activity was more pronounced for arachidonoylsemax in comparison with arachidonoylproglyprol.

[Effect of x-ray contrast agents on the thromboresistant properties of vascular walls].

It is established that the x-ray contrast agents urografin, omnipak, and ultravist produce a dose-dependent decrease in the thromboresistant properties of vascular walls in experimental rats. This effect is determined by the individual properties of substances rater than by their belonging to a certain class of ionic or nonionic compounds. Preliminary administration of n3-polyunsaturated fatty acids from fish oil offers a significant protection against the negative action of x-ray contrast agents and retains the antiaggregant activity of the vessel wall intima.

[Cerebrovascular and antiaggregative effects of GABA-docosahexaenoyldopamine conjugate].

The effects of GABA - docosahexaenoyldopamine (DHED) conjugate on the cerebral haemodynamics and thrombocyte aggregation were evaluated and compared to these of docosahexaenoyldopamine alone. The GABA - DHED conjugate was shown to significantly enhance the cerebral circulation in rats with a model of global transient cerebral ischemia, as compared to the intact animals. Administered alone, DHED increased the blood supply of both intact and ischemic brains to an equal extent. The GABA-DHED conjugate demonstrated the antiaggregative activity, but the effect was less expressed than that of DHED alone.

[Effect of RGD-containing peptides on platelet aggregation].

The influence of new synthetic peptides ARGDS-NH2 and RGD-dFK (synthesized by the fermentative method) and VPNLRGDLQVLA (a fragment of the foot-and-mouth virus's surface peptide) on the ADP-induced human platelet aggregation in vitro was studied. All peptides were found to inhibit the human platelet aggregation, but the synthetic peptides (ARGDS-NH2 and RGD-dFK) showed the most pronounced effect. Significant decrease in the platelet aggregation was observed at their concentrations within 0.1-10 mM. ARGDS-NH2 and RGD-dFK inhibited the platelet aggregation stronger than the reference drug pentoxifylline at equivalent concentrations.

[Effects of ionic and non-ionic roentgen-contrast media upon ex vivo hemostasis in rabbits].

The influence of ionic and non-ionic contrast media on the ex vivo hemostasis in rabbits was studied for ionic urografin (76 %), non-ionic ultravist-300, and non-ionic omnipaque-300 intravenously injected in medium and high doses (1.5 ml/kg and 3.0 ml/kg, respectively). Ionic urografin (1.5 ml/kg) almost did not influence the level of hemostasis ex vivo. Non-ionic contrast media (ultravist and omnipaque) in the medium diagnostic dose (1.5 ml/kg) activated the hemostasis, the effect being much more pronounced in the case of omnipaque. Dose-dependent action was observed for both ionic and non-ionic contrast media.

[Effect of the new antimigraine drug serotonin receptor antagonist tropoxin on platelet aggregation].

The effect of the new antimigraine drug tropoxin - the serotonin receptor (5-HT2) antagonist - on the human platelet aggregation in vitro induced by ADP (1 x 10(-5) M) and epinephrine (2.5 x 10(-6) M) was studied. Tropoxin reliably inhibited the ADP-induced platelet aggregation in a concentration range of 0.01 - 7 mg/ml. A significant inhibition effect with respect to the epinephrine-induced platelet aggregation was observed in a drug concentration range of 2 - 7 mg/ml, although a reliable antiaggregant activity was also observed below 2 mg/ml. A bolus administration of tropoxin (10 mg/kg) in rabbits decreased the ADP-induced platelet aggregation ex vivo by a factor of 1.2 - 1.4. The effect appeared 45 min after treatment and was observed during subsequent 30 min.

[Effects of the novel synthetic fatty acid dinitroglycerol esters on aggregation of the human platelets in vitro]. / Deistvie novykh sinteticheskikh dinitroglitserinovykh éfirov zhirnykh kislot na agregatsiiu trombotsitov cheloveka in vitro.

A series of six new synthetic dinitroglycerol esters of fatty acids on the human platelet aggregation was studied in vitro. Inclusion of the dinitroglycerol moiety into the molecule of arachidonic acid deprived this acid from pro-aggregant activity. All six compounds produced moderate (dose-dependent) inhibition of the platelet aggregation process induced by arachidonic acid (1 x 10(-3) M). Platelet aggregation was most significantly affected by dinitroglycerol esters of arachidonic and docosahexaenoic acids. This is probably explained by the influence of these esters on the oxidative metabolism of arachidonic acid to eicosanoids playing the role of proaggregants. In the presence of vessel wall (rat aorta fragments), dinitroglycerol esters of arachidonic and docosahexaenoic acids incubated with platelets (5 min, 37 degrees C) significantly reduced their aggregation induced by arachidonic acid (1 x 10(-3) M) or docosahexaenoic acid (1 x 10(-5) M) under the conditions of endothelial cyclooxygenase suppressed by acetylsalicylic acid (10 mg/ml). The pronounced antiaggregant effect of the synthetic dinitroglycerol esters studied is probably related to their ability to act as NO donors suppressing the activity of thrombocytes (provided that the NO production activity is present in the system).

[Effect of chronic administration of epaden and acetylsalicylic acid on the antithrombotic potential of blood vessel walls in rabbits]. / Vliianie khronicheskogo vvedeniia krolikam épadena i atsetilsalitsilovoi kisloty na protivotromboticheskii potentsial sosudistoi stenki.

The effect of a new domestic polyunsaturated fatty acid (PUFA) concentrate called epaden on the blood coagulation system was studied in comparison with acetylsalicylic acid (ASA). The antithrombotic potential of the blood vessel wall was determined by release of the inhibitors of thrombocyte aggregation, fibrinolysis activators, and anticoagulants in rabbits under immobilization induced stress conditions. In the control group, the immobilization stress resulted in a decrease of the collagen-induced platelet aggregation, a drop in the fibrinogen level, and an increase in the tissue-type plasminogen activator (t-PA) activity. The administration of ASA and epaden reduced a drop in the fibrinogen level caused by the immobilization stress. Animals receiving epaden showed a decrease in the ADP-induced platelet aggregation and an increase in the t-PA activity in comparison with the levels before modeling stressed conditions. No such effect was observed in the group treated with ASA. It is suggested that the additional antithrombotic effect of epaden observed under the immobilization stress conditions is related to a protective action of this substance on the vessel wall.

[Effect of dopamineamides of polyunsaturated fatty acids on blood coagulation system and cerebral circulation]. / Vliianie dofaminamidov polinenasyshchennykh zhirnykh kislot na svertyvaiushchuiu sistemu krovi i mozgovoe krovoobrashchenie.

A series of original dopaminamides of polyunsaturated fatty acids were synthesized and characterized with respect to antiaggregant and cerebrovascular stimulant properties. It was established that dopaminamides of linolic, dimethyllinolic, docosapentaenoic, docosahexaenoic (DHEA) and stearidonic (C18:4 and C18:3) acids decrease ADP and arachidonic acid (AA) induced human thrombocyte aggregation in vitro. The most pronounced antiaggregant effect was observed for DHEA dopaminamide: in a dose of 10 mg/kg, this agent produced a significant decrease in the AA induced thrombocyte aggregation. DHEA per se in the same dose increases the activated partial thromboplastin time (APTT), while not affecting the prothrombin time. The synthesized dopaminamides of arachidonic, eicosapentaenoic, and docosahexaenoic acids stimulate local circulation in the cerebral cortex. The most pronounced cerebrovascular effect was also produced by DHEA dopaminamide.

[Effect of combined administration of acetylsalicylic acid and antioxidants on cellular and plasma hemostasis]. / Vliianie sochetannogo primeneniia atsetilsalitsilovoi kisloty s antioksidantami na kletochnyi i plazmennyi gemostaz.

It was found that upsovit (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg), composition 1 (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg; hypoxen, 50 mg), and composition 2 (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg; hypoxen, 100 mg) inhibit thrombocyte aggregation in vitro. Hypoxen per se induces the aggregation of thrombocytes, but inhibited the ADP aggregation. Intravenous injections of upsovit in rabbits did not influence the ADP aggregation, but inhibited the collagen aggregation, while composition 2 inhibited the aggregation processes of both types. Besides, the intravenous injections of upsovit decreased the thromboplastin time and the activated partial thromboplastin time (APTT) and reduced the protein C activity, while influencing neither the heparin cofactor activity of antithrombin III nor the level of fibrinogen and its degradation products. In contrast, composition II did not change the thromboplastin time, APTT, and the protein C activity, but increased the heparin cofactor activity.

[The effect of the new Russian concentrate of n-3 polyunsaturated fatty acids epaden on thrombocyte functional activity in vitro]. / Vliianie novogo otechestvennogo kontsentrata n-3 polinenasyshchennykh kislot épadena na funktsional'nuiu aktivnost' trombotsitov in vitro.

Epaden, the new domestic concentrate of n-3 polyunsaturated fatty acids (PUFA), is capable of inhibiting in vitro the human thrombocyte aggregation induced by ADP, collagen, and thrombin. It was established that the effect can hardly be related to the action of cyclooxygenase metabolites of eicosapentadienoic acid (entering into the epaden composition). The activity of epaden is probably explained by the effect of lipoxygenase metabolites of the n-3 polyunsaturated fatty acids or by the ligand properties of polyene acids entering into epaden. In addition, epaden is capable of reducing the release of thrombocyte factor 4 and tissue type plasminogen activator inhibitor from activated thrombocytes.

[Effect of chronic epaden administration on the tissue plasminogen activator activity in rabbits]. / Vliianie khronicheskogo vvedeniia épadena na aktivnost' aktivatora plazminogena tkanevogo tipa u krolikov.

The chronic oral administration of epaden (a concentrate of n-3 polyunsaturated fatty acids, n-3 PUFA) to rabbits leads to a decrease in activity of the tissue type plasminogen activator (t-PA) in the blood plasma. In order to elucidate the mechanism of this phenomenon, the epinephrine (adrenaline) stimulated t-PA release in rabbits pretreated with epaden for 4 weeks was compared to that in the control (untreated) group. The epinephrine injections led to a reliable, albeit short-time, increase in the t-PA activity in both test and control groups. Although the base activity of t-PA in the epaden-treated group was lower than that in the control group, the t-PA release in the former group was more pronounced. In addition, the t-PA production was induced by the immobilization shock model in rabbits one month after beginning of the epaden administration (animals in the control group were subject to the shock without epaden pretreatment). In this test, the t-PA release was also more intense in the epaden-treated animals. These results indicate that the dietary epaden administration per os reduces the basal t-PA level, but increases the agonist-induced plasminogen activator production.

Natural eicosanoids in regulation of blood coagulation.

Metabolites of polyunsaturated fatty acids, primarily arachidonic acid, are important physiological regulators of blood coagulation. In contrast to many other substances involved in coagulation, eicosanoids affect virtually all links of hemostasis; they are responsible for blood vessel wall thromboresistance and its acquisition of procoagulant properties in response to various agonists, regulate the extent of cell-to-cell interactions, modulate reactions of plasma hemostasis and blood fibrinolytic activity, and change hemodynamic parameters. Such complex effects of eicosanoids on thrombogenesis suggest that they are unique and extremely important biologically active substances that strongly determine the balance of anticoagulant and procoagulant factors.

[Artificially functionalized polyenoic fatty acids--a new lipid bioregulators]. / Iskusstvenno funktsionalizirovannye polienovye zhirnye kisloty-- novye lipidnye bioreguliatory.

Dopamine, histamine, serotonin, and serotonin analogs were acylated with arachidonic and eicosapentaenoic acids, and the reaction products were named as artificially functionalized fatty acids (AFFA). The amides of arachidonic acid with serotonin, dopamine, and histamine were found to inhibit human platelet aggregation induced by ADP, arachidonic acid and adrenaline. Amides of arachidonic and eicosapentaeonic acids with serotonin and dopamine protect sea urchin early embryos against cytotoxic action of serotonin and histamine antagonists. These effects are not connected with the possible hydrolytic cleavage of AFFA to their constituent polyenoic fatty acids and amines. Arachidonic acid dopaminamide was shown to be a substrate of soybean 15-lipoxygenase, whereas the arachidonic acid amides with serotonin and its derivatives were resistant to this enzyme. Moreover, arachidonic acid serotoninamide turned out to be an irreversible lipoxygenase inhibitor. Considerable amount of hydroxyl radicals (fluorescent assay) were found for the first time to accompany lipoxygenase oxidation of linoleic acid; arachidonic acid serotoninamide blocked this process completely. Therefore, it was concluded that AFFA possess specific biological activity and can be considered as a novel group of lipid bioregulators.

[The effect of the chronic internal administration of the new Russian n-3 polyunsaturated fatty acid concentrate--epaden--on blood coagulation system indices in rabbits]. / Vliianie khronicheskogo vvedeniia vnutr' novogo otechestvennogo kontsentrata n-3 polinenasyshchennykh zhirnykh kislot--épadena na nekotorye pokazateli svertyvaiushchei sistemy krovi u krolikov.

Daily oral 6-week administration of epaden in a dose containing 0.3 g eucosopentanoic acid and 0.05 g docosahexaenoic acid caused decrease in collagen-induced platelet aggregation in rabbits in vivo and in the activity of the tissue type plasminogen activator, as well as reduction in the level of antithrombin III cofactor activity. No changes were encountered in ADP-induced aggregation, in the platelet count, in platelet adhesion to collagen, and in activated partial thromboplastin time.

[The effect of n-3 polyunsaturated fatty acids on the blood coagulation system]. / Vliianie n-3 polinenasyshchennykh zhirnykh kislot na svertyvaiushchuiu sistemu krovi.

The article presents the epidemiologic data on the antithrombotic and antiatherosclerotic effect of n-3 polyunsaturated fatty acids, and the current information on the mechanism of the effect of these compounds on the system of blood coagulation.

[The effect of new synthetic prostanoids on the aggregation activity of human thrombocytes]. / Vliianie novykh sinteticheskikh prostanoidov na agregatsionnuiu aktivnost' trombotsitov cheloveka.

We found that a number of new synthetic prostanoids caused a prominent reduction of human platelet aggregation in the in vitro experiments. Moreover, two of this agents, IOS 3933 and IOS 4732, gives storage stability. Hemoxygenase activity, metabolic homeostasis of bilirubin in brain and transport function of serum albumin in animals receiving cobalt chloride.

[The effect of new synthetic prostanoids on the indices of the blood coagulation system]. / Vliianie novykh sinteticheskikh prostanoidov na nekotorye pokazateli svertyvaiushchei sistemy krovi.

In the experiments on rabbits it was shown, that the administration of prostanoids IOS 3933 caused a reduction of ADP- and collagen induced platelet aggregation, platelet adhesion to collagen and elevation of t-PA level. This prostanoid prevented both a decrease in platelet count and reduction of AT III activity, but did not affect the protein C level during thromboplastin infusion.

[The effect of fluorinated prostaglandins on platelet aggregation]. / Vliianie ftorirovannykh prostaglandinov na agregatsiiu trombotsitov.

The effects of fluorodeoxy prostanoids on platelet aggregability were studied. It was shown that introduction of fluorine into positions 9, 11 or 15 of prostaglandin F2 alpha led to enhanced proaggregation activity. The most active compound among fluorodeoxy analogs was 15-fluoro derivative; bisfluoro analog was moderately active, and 11-fluoro compound had the least activity. In the group of fluorodeoxy prostaglandins E2, a contrary effect was registered. Thus, the most active compound was 1-fluoride and the least, 15-fluoride. The incorporation of fluorine into position 15 of prostacyclin led to insignificantly lower antiaggregatory activity just as this modification of 6-keto-prostaglandin F1 alpha was accompanied by a dramatic increase in its ability to inhibit platelet aggregation.