Synthesis of silicon and germanium containing heteroaromatic sulfides as cholesterol level lowering and vasodilating agents.

Silicon and germanium containing heteroaromatic sulfides have been prepared using phase transfer catalytic (PTC) system thiol / Si or Ge containing alkyl halide / solid KOH / 18- crown-6 / toluene. The target sulfides were isolated in yields up to 92 %. It has been found that 2-{[dimethyl (beta-triethylgermylethyl)-silylmethyl]thio}-1-methylimidazole and 2-{[dimethyl(beta-triphenylsilylethyl) silyl-methyl]thio}benzothiazole are the most active cholesterol level lowering and vasodilating agents.

Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats.

1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

Synthesis, vasodilating, antithrombotic and cardioprotective activity of pyridyl substituted 5-silyl(germyl)isoxazolines-2.

The reactions of [2+3] cycloaddition of pyridylnitrile oxides to vinyl- and allylgermanes proceed regioselectively and afford 5-Ge-substituted isoxazolines-2. We have synthesized 9 new pyridyl substituted 5-Si(Ge)-isoxazolines-2 and investigated their biological activity. The vasodilating, anticoagulant and cardioprotective activities of 5-Si(Ge) substituted isoxazolines-2 have been studied in vitro and in vivo. Substitution of the silicon atom for the germanium one leads to the significant increase in vasodilating, antithrombotic and cardioprotective activity. The insertion of the methylene group between Ge and the isoxazoline ring reduces the vasodilating activity. The most active isoxazoline - 3-(5'-triethylgermyl-3'-isoxazolinyl)pyridine hydrochloride protects the heart from rhythm disturbances and lethality during ischaemia-reperfusion.

[Anti-arrhythmia effect of digoxin antibodies in experimental myocardial infarct (arrhythmogenic action of endogenous digoxin-like factor)]. / Protivoaritmicheskii éffekt antitel k digoksinu pri éksperimental'nom infarkte miokarda (ob aritmogennom deistvii éndogennogo digoksinopodobnogo faktora).

Suggesting endogenous digoxin-like factor (EDLF) to display arrhythmogenic activities in myocardial ischemia (MI), we studied the effect of anti-digoxin antiserum (ADS) on the ventricular fibrillation threshold (VFT) after the coronary ligation in cats and ventricular arrhythmias caused by MI in rats and chloroform-induced hypoxia in mice. Intravenous administration of ADS (5 mg/kg) enhanced VFT in cats with MI from 11.3 +/- 1.6 to 53.3 +/- 8.1 V (M +/- m; p less than 0.01) and significantly reduced ventricular arrhythmias in rats and mice. Our experiments on the isolated electro-stimulated rat atria demonstrated that EDLF is likely not to be an adrenergic cotransmitter in the heart. Possible mechanisms of the arrhythmogenic action of EDLF are discussed.

[Cyclic analogs of bradykinin, containing a carboxyl group]. / Tsiklicheskie analogi bradikinina, soderzhashchie karboksil'nuiu gruppu.

1 alpha-beta-carboxypropionyl-cyclo(9----1 epsilon)-[Lys1, Gly6]bradykinin (Suc-c[Lys1, Gly6]B), 1 alpha-beta-carboxypropionyl-cyclo(10----1 epsilon)kallidin (Suc-cK), cyclo(10 gamma----1 epsilon)-[Glu10]kallidin (c[Glu10]K) and cyclo(11 gamma----1 epsilon)kallidylglutamic acid (cKG) were synthesized. Suc-c[Lys1, Gly6]B and Suc-cK were prepared by acylating the appropriate cyclopeptides with succinic anhydride. c[Glu10]K and cKG were obtained by the classic peptide synthesis, the cyclization being carried out with 61 and 42% yields, respectively. The protecting groups were then eliminated by catalytic hydrogenation. c[Glu10]K and cKG exerted myotropic action on isolated rat uterus (alpha 0.73 and 0.89, pD2 6.61 and 8.61, respectively). cKG displayed direct myotropic activity with respect to electrically stimulated rat vas deferens and guinea-pig ileum, potentiating the contractions (by 100%) in response to electric stimuli. c[Glu10]K and cKG elicit histamine release in isolated rat mast cells (EC30 4.91.10(-5) and 1.47.10(-6) M, respectively). Both cyclopeptides alter arterial pressure following intravenous administration to anaesthetized rats, cats and dogs and affect heart rate. In all assays cKG is more active than c[Glu10]K. Suc-c[Lys1, Gly6]B and Suc-cK do not possess myotropic, histamine-releasing or hypotensive activity, though they were found to elicit a transient increase of bloodflow in cats and dogs.

Synthesis and selective vasodilating properties of esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydro-pyridine-3,5-di- carboxylic acid.

This study presents the synthesis of new 1,4-dihydropyridine (DHP) derivatives which are phenoxy- and alkoxyalkyl esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dica rbo xylic acid and reports on the biological activity of the compounds. It was found that the DHP derivatives showed high affinity to the DHP receptor of rat brain membranes and antagonize potently the potassium depolarization-induced vasospasm in a fashion compatible with the assumption of a calcium entry blockade. The higher vasodilating potency of especially compound III for the cerebral vasculature might represent an improved selectivity profile due to specific substitution patterns of the DHP molecule by increasing lipophilicity. Thus, the new DHP derivatives might be useful as therapeutic agents for hypertension and impaired cerebral microcirculation.

[A transnasal decompression tube and medicamentous stimulation of intestinal motility in the treatment of diffuse appendicular peritonitis in young children]. / Transnazal'nyi dekompressionnyi zond i medikamentoznaia stimuliatsiimotoriki kishechnika v lechenii diffuznogo appendikuliarnogo peritonita u detei rannego vozrasta.

The investigation has shown that best results can be obtained by a combined bilumenal probe for a separate decompression of the stomach and small intestine. Galanthamin gives the best parameters of stimulation of the small intestine peristalsis as compared with Prozerin.

[Effect of totally synthetic racemic prostaglandins F2 alpha and 15 alpha-OH-11-deoxyprostaglandin E1 on small intestine motility in rabbits with dynamic ileus]. / Vliianie total'no-sinteticheskikh ratsemicheskikh prostaglandinov F2alpha i 15alpha-OH-11-dezoksiprostaglandina E1 na motoriku tonkoi kishki krolika v usloviiakh dinamicheskoi neprokhodimosti.

A comparative analysis of the effect of racemic PGF2 alpha--(+/-)PGF2 alpha, 15 alpha OH-II-deoxy-PGE1-(+/-)DPGE1, aceclidine, neostigmine methylsufate, galanthamini hydrobromidum, and pituitrine on the ileum motility was performed in rabbits with dynamic ileus induced by surgical trauma and peritonitis. In the model under study (+/-)PGF2 alpha was similar in its action to neostigmine methylsulfate and aceclidine, with (+/-)DPGE1 having a week effect.

[Experimental study on the effect of 11-deoxyprostaglandin E1 on hormonal balance in animals]. / Eksperimental'noe issledovanie vliianiia 11-dezoksiprostaglandina El na gormonal'nyi balans zhivotnykh.

The effects of prostaglandin F2 alpha and (+/-) 11-deoxyprostaglandin E1 (DPGE) on the levels of progesterone and estradiol in the blood plasma or serum of experimental animals were studied and compared. It was found for the first time that the synthetic analog of natural PGE1, DPGE, is capable to substantially reduce the progesterone level in the blood (rats and cows) and to induce the luteolysis of yellow bodies in the cow ovaries. It was demonstrated that DPGE promotes the resolution of both cyclic and persistent yellow bodies. The pattern of the drug action on rat blood steroid hormones depends on the time of pregnancy and is most pronounced in the last trimester of pregnancy.

[Pharmacokinetics of dioxonium]. / Farmakokinetika dioksoniia

An investigation in the pharmacokinetics of a new peripheral muscle relaxant dioxonium and of its carbon-labeled analogue (with respect to the N-methyl groups) was carried out. An intravenous administration of dioxonium-C14 was found to bring about a biphasic change in radioactivity of the blood plasma. The stoppage of curarization, irrespective of a dioxonium dose, is seen to occur at a definite radioactivity level in the blood plasma. Major radioactivity following introduction of dioxonium-C14 is observed in the organism of the rats in the skeletal muscles and in the kidneys. The drug is eliminated from the organism through the kidneys in an unchanged and pharmacologically active form.