Combined Effect of Hypertension and Alcohol Consumption on the Risk of Death (27­Year Cohort Prospective Study).

Aim      To study the effect of arterial hypertension (AH) in combination with frequent alcohol consumption on the formation of risk for cardiovascular death and all-cause death according to results of a 27-year prospective cohort study.Material and methods  This 27­year prospective cohort study of an unorganized population of the Tomsk city (1546 people aged 20-59 years, including 630 men and 916 women) investigated AH prevalence and alcohol consumption (1988-1991) and analyzed the predictive significance of the effect of AH in combination with frequent alcohol consumption on the formation of risk for all-cause and cardiovascular death. AH was diagnosed at blood pressure ≥140 / 90 mm Hg. Frequent alcohol users were defined as those who consumed alcohol more than once a week.Results The combination of AH and frequent alcohol consumption increased the risk of all-cause death 4.1 times compared to that for persons without these risk factors (p<0.001). This was true for all age groups of the total cohort (higher relative risk, RR, was observed for persons aged 20-39 years) and for men (except for the group aged 40-59 years). RR of cardiovascular death was 5.3 (p<0.001) for frequent alcohol users with AH. It was established that frequent alcohol consumption additionally increased RR of all-cause death for persons with AH (RR 1.89; p<0.05) primarily at the expense of persons aged 20-39 years. Prediction of 27­year survival for frequent alcohol users with AH was 35.3 %.Conclusion      A combination of AH with frequent alcohol consumption considerably increases the risk of all-cause and cardiovascular death. Frequent alcohol consumption significantly impairs the prediction of 27-year survival for persons with AH by additionally (1.9 times) increasing the risk of all-cause death. Binary AH combinations with frequent alcohol consumption exert a more pronounced adverse effect on young men and women.

In vitro cellular effects of perfluorochemicals correlate with their lipid solubility.

Preclinical studies comparing perflubron partial liquid ventilation with conventional mechanical ventilation have indicated that perflubron partial liquid ventilation may exert some anti-inflammatory effects. To assess whether these effects were related to the lipid solubility properties of perflubron rather than to nonspecific biophysical properties of the perfluorocarbon (PFC) liquid phase, we studied the effects of PFCs with varying lipid solubilities on the platelet aggregation response to various procoagulants and the erythrocyte hemolytic response to osmotic stress. In both cases, the degree of the response was directly related to the lipid solubility of the PFC. All the perflubron content of erythrocytes was found to be associated with the membrane compartment. The time to reach a maximum effect on hemolysis with perflubron was relatively slow (2-4 h), which paralleled the time for perflubron to accumulate in erythrocyte membranes. The rate and extent of perflubron partitioning into lecithin liposomes were similar to those of erythrocyte membranes, supporting the hypothesis that perflubron was partitioning into the lipid component of the membranes. Thus some of the potential modulatory effects of perflubron on excessive inflammatory responses that occur during acute lung injury and acute respiratory distress syndrome may be influenced in part by the extent of PFC partitioning into the lipid bilayers of cellular membranes.

[Mechanisms of distribution and elimination of perfluorocarbons upon multiple exposures]. / Mekhanizmy raspredeleniia i vyvedeniia perftoruglerodov pri mnogokratnykh vvedeniiakh.

In clinical practice much more often one meets a necessity of repeated administration of fluorocarbon blood substitutes. The 19F(-)-NMR-spectroscopy has been used to study the kinetics of the blood and tissue fluorocarbon concentration after repeated administration of PFC emulsion. Analysis of the data suggests that redistribution of PFCs between organs and blood after their repeated administration is under control of Ostwald ripening depending on PFC physicochemical properties (water and lipid solubility), emulsion particle diameter etc and does not connect with activity of reticuloendothelial system.

[Perfluorocarbon emulsions and other corpuscular systems influence on neutrophil activity]. / Deistvie emul'sii perftororganicheskikh soedinenii i drugikh korpuskuliarnykh sred na aktivnost' neitrofilov.

Influence of perfluorodecalin, perfluoromethilcyclohexylpiperidine, perfluorotributylamine emulsions on active oxygen form (AOF) generation by neutrophils has been studied. All investigated emulsions stabilized both proxanol 268 and egg yolk phospholipids inhibited PMA-stimulated neutrophil activity. Castor oil emulsion also inhibited the neutrophil activity. Neutrophil response for chemotactic peptide, was unchanged in the presence of all tested emulsions. We suppose that fast hydrophobic attachment of inert submicrone emulsion particles to cell surface provokes alteration of neutrophil plasma membrane function resulting in a decrease of AOF generation.

[Uncoupling of the liver monooxygenase system by perfluorocarbons in vivo]. / Razobshchenie monoksigenaznoi sistemy pecheni perftoruglerodami in vivo.

Administration of a perfluorodecalin (PFD) emulsion, the liver cytochrome P-450 II B1/B2 inducer, to experimental animals is followed by a two-fold increase of the NADPH oxidation rate in liver microsomes. This phenomenon is caused by the presence in the cytochrome P-450 active center of PFD which uncouples microsomal hydroxylation. The high rate of NADPH oxidation in liver microsomes after administration of the fluorocarbon does not decrease the level of reduced pyridine nucleotides in the liver and does not change the glucose concentration in the plasma. It is suggested that the accelerated weight loss in starved animals following PFD administration is due to the energy dissipation in the fluorocarbon uncoupled monooxygenase reactions in the liver.

Application of fluorocarbon emulsions as components of cosmetics and medical ointments.

Localization and accumulation of perfluorochemicals (PFCs) in the skin and internal organs of rats after prolonged surface application of the concentrated PFC emulsion, fluorogel, have been studied by electron microscopy and gas-chromatography. The PFC concentration in skin was about 0.03-0.04 mg per 1 g of tissue. Few aggregates of emulsion particles were detected in derma. The oxygen-dependent favorable effect of fluorogel treatment of thermic burned skin and wound surface was found.

[Interaction of perfluoroctylbromide with liver microsomal monooxygenase]. / Vzaimodeistvie perftorktilbromida s mikrosamal'noi monoksigenazoi pecheni.

Perfluorooctylbromide (PFOB), a constituent component of gas-transporting fluorocarbon emulsions, liberates bromide ions when PFOB undergoes NADPH-dependent metabolism by liver microsomal monooxygenase. The PFOB emulsion injected to rats decreases the liver microsomal cytochrome P-450 level down to 80% of control. Induction of the "phenobarbital" isoforms of cytochrome P-450 (cytochrome P-450 II B1/B2) after administration of PFOB is much weaker than that after administration of the perfluorodecalin emulsion. It is suggested that the anomalous cytochrome P-450-inductive properties of PFOB may be associated with its ability to be metabolized by liver microsomal monooxygenase. In these terms, the generally accepted viewpoint about the biological inertness and unchangeability within the organism of perfluorochemicals containing heteroatoms (N, O, H and others) and double bonds, needs further verification and experiment.

[A new model describing the isolation of fluorocarbons from an organism: dissolution of fluorocarbons in the lipid components of blood]. / Novaia model', opisyvaiushchaia vyvedenie ftoruglerodov iz organizma: rastvorenie ftoruglerodov v lipidnykh komponentakh krovi.

Perfluorodecalin (PFD), intravenously administrated to rabbits in the form of submicron emulsion, quickly disappears from the blood stream and accumulates in the liver, spleen and bone marrow. The expiration rate of PFD from the body can be significantly enhanced by intravenous administration of sunflower oil emulsion. It is supposed that the limit stage of PFD excretion is a fluorocarbon transport from accumulatory organs to the lungs by lipid carriers (lipoproteins, chylomicrons and cell membranes) in which fluorocarbons are physically dissolved.

Effect of perfluorodecalin on activities of hepatic phase II xenobiotic biotransformation enzymes.

The activity of the hepatic phase II enzymes of xenobiotic biotransformation after intravenous administration of perfluorodecalin emulsion to rats was measured. Perfluorodecalin was found to increase the microsomal glutathione S-transferase and UDP-glucuronosyltransferase activities 1.4- and 2.3-fold, respectively. The activity of sulphotransferase was decreased 2-fold. These results show that perfluorodecalin is an inducer of both the enzymes of cytochrome P-450-dependent monooxygenase system [Mishin V. et al (1989) Chem.-Biol. Interactions, 72, 143-155.] and those catalyzing conjugation reactions: microsomal glutathione S-transferase and UDP-glucuronosyltransferase.

[The effect of perfluordecaline on the activity of phase III xenobiotic transformation enzymes]. / Vliianie perftordekalina na aktivnost' fermentov II fazy biotransformatsii ksenobiotikov.

Injection of perfluorodecaline to rats caused an increase of the phase II xenobiotic biotransformation enzyme activities followed by cytochrome P-450 induction. The activities of liver microsomal UDP-glucuronosyl transferase and glutathione transferase increased by 130 and 40%, respectively, against the control level. The increase of the cytosolic glutathione transferase activity was insignificant In contrast, the activity of sulfotransferase decreased about 2-fold. The role of modification of xenobiotic biotransformation enzymes in the biological effect of perfluorodecaline is discussed.

[Formation of biologically active substances during cholesterol oxidation on the surface of fluorocarbon emulsions]. / Poiavlenie biologicheski aktivnykh veshchestv pri okislenii cholesterina na poverkhnosti ftoruglerodnykh émulsii.

Oxidative modification of cholesterol on the surface of fluorocarbon emulsions was studied. The oxidation yielded one primary product--7-peroxycholesterol. It was shown that the obtained cholesterol C7 derivatives possess a high biological activity. It was concluded that the possibility of oxidative modification of plasma substances on the surface of fluorocarbon emulsion particles with the formation of highly active compounds must be taken into account when using the fluorocarbon particles in medicine.

[The effect of a fluorocarbon emulsion--an enzyme inducer of the cytochrome P-450-dependent monooxygenase system of the liver--on the acute toxicity of CCl4 and on the efficacy of the prophylactic use of antidotes in organophosphate pesticide poisoning]. / Vliianie ftoruglerodnoi émul'sii--induktora fermentov tsitokhrom P-450-zavisimosti monooksigenaznoi sistemy pecheni--na ostruiu toksichnost' CCl4 i na éffektivnost' profilakticheskogo primeneniia antidotov pri intoksikatsii fosfororganicheskimi pestitsidami.

The effect of intraperitoneal administration of perfluorocarbon emulsion, an inducer of cytochrome P-450-dependent monoxygenase system of the liver, on the resistance of rodents to the action of CCl4 and organophosphorus pesticides was studied. Perfluorocarbon emulsion potentiated CCl4 toxicity decreasing LD50 from 4.5 to 3.7 mg/kg mouse body weight without changing susceptibility of rats to organophosphorus pesticides. A preliminary administration of perfluorocarbon emulsion effectively increased the protective action of antidotes (atropine + dipyroxime) providing the resistance of the animals to 12-fold, 20-fold and 20-fold LD50 of dichlophos, methaphos and butiphos, respectively.

[Preliminary administration of perfluorocarbon emulsion: a new method of myocardial protection against ischemia]. / Predvaritel'noe vvedenie émul'sii perftoruglerodov--novyi metod protivoishemicheskoi zashchity miokarda.

The study was conducted to determine if myocardium can be protected against ischemic and reperfusion damage by means of the preliminarily injected perfluorocarbon emulsion. Injection of the emulsion into rabbit 1, 12, 24 h prior to ischemia was found to decrease the extent of ischemic and reperfusion damage to myocardium. The cardiotropic effect of the injected emulsion is shown to be dose- and time dependent.

Cholesterol oxidation on fluorocarbon emulsion surface leads to the formation of 7-peroxycholesterol.

Formation of biologically active oxidized derivatives of cholesterol as a result of its oxidation on the surface of fluorocarbon emulsions was studied. A single product of cholesterol oxidation, 7-peroxycholesterol, was found. It was shown that 7-peroxycholesterol and its derivative 7-keto-cholesterol inhibit the rosette formation between human T-lymphocytes and sheep erythrocytes. These substances exert a strong cytostatic action on the growth of procaryotic and eucaryotic cell cultures. Thus, oxidative modification of blood plasma components on the surface of fluorocarbon emulsion particles with the formation of highly active compounds must be taken into account when using the fluorocarbon emulsions in medicine.

[Characteristics of enzyme induction in the liver monooxygenase system of rabbits intravenously administered a fluorocarbon emulsion]. / Osobennosti induktsii fermentov monooksigenaznoi sistemy pecheni krolikov pri vnutrivennom vvedenii ftoruglerodnoi émul'sii.

Intravenous injections to rabbits of perfluorocarbon emulsion containing perfluorodecaline (10 ml/kg, equivalent to 1.3 g of perfluorodecaline per 1 kg of body weight) produced a 2-4-fold increase of cytochrome P-450 content in the liver microsomes within 3-4 weeks. Cytochrome P-450 induction was followed by activation of the liver monoxygenase system evaluated by the rate of antipyrine excretion from the blood. On the 1st day after administration perfluorodecaline caused an insignificant (14%) inhibition of the monoxygenase system.

The phenobarbital-type induction of rat liver microsomal monooxygenases by perfluorodecalin.

Induction of perfluorodecalin (PFD) of the liver microsomal system of metabolism of xenobiotics has been studied and compared with the inductions by phenobarbital (PB) and 3-methylcholanthrene (MC). It has been shown that PFD increases the content of cytochrome P-450, NADPH-cytochrome c reductase activity. Like PB, PFD induces the activities of benzphetamine-N-demethylase, aldrine-epoxidase, 16 beta-androstendion-hydroxylase. Using specific antibodies against cytochromes P-450b and P-450c (which are the main isoenzymes of cytochrome P-450 in the PB- and MC-microsomes respectively), an immunological identity of the cytochrome P-450 isoforms during PFD and PB induction has been found. According to the rocket immunoelectrophoresis the content of cytochrome P-450 in PFD-microsomes, which is immunologically indistinguishable from P-450b, was approximately 70% of the total cytochrome P-450. Two forms of cytochrome P-450 were isolated from the liver microsomes of PFD-induced rats and purified to homogeneity. A comparison of these forms with cytochromes P-450b and P-450e obtained from the PB-induced rat liver microsomes revealed their similarity in a number of properties, e.g., chromotographic behavior on DEAE-Sephacel column, molecular weight determined by sodium dodecyl sulphate (SDS) electrophoresis in polyacrylamide gel, immunoreactivity, peptide mapping, catalytic activity. The data presented demonstrate that PFD induced in rat liver microsomes the cytochrome P-450 forms whose immunological properties and substrate specificity correspond to those of the PB-type cytochrome P-450. These findings suggest that PFD and PB, which differ in their chemical structure, induce in the rat liver microsomes identical forms of cytochrome P-450.