Application of different approaches to generate virtual patient populations for the quantitative systems pharmacology model of erythropoiesis.

In a standard situation, a quantitative systems pharmacology model describes a "reference patient," and the model parameters are fixed values allowing only the mean values to be described. However, the results of clinical trials include a description of variability in patients' responses to a drug, which is typically expressed in terms of conventional statistical parameters, such as standard deviations (SDs) from mean values. Therefore, in this study, we propose and compare four different approaches: (1) Monte Carlo Markov Chain (MCMC); (2) model fitting to Monte Carlo sample; (3) population of clones; (4) stochastically bounded selection to generate virtual patient populations based on experimentally measured mean data and SDs.

Ionol (BHT) produces superoxide anion.

In aqueous medium etiolated wheat seedlings release superoxide anion (O2*-). Interaction of a synthetic antioxidant, butylated hydroxytoluene (BHT, ionol), with oxygen in the aqueous medium is accompanied by O2*- formation. This suggests that under certain conditions BHT behaves as a prooxidant.

A new inhibitor of the CoQ-dependent redox reactions in mitochondria and chromatophores.

The effects of 3,4-dimethoxyphenyl-1-amylketone (DPK) on the CoQ-dependent stages of the electron transport systems in mitochondria and Rhodobacter sphaeroides chromatophores were studied. The two systems contain the complete Q-cycle. The sensitivities of the Q-cycles of two electron transport systems to antimycin, myxothiazole, and other inhibitors are virtually indistinguishable from one another, but these systems have different CoQ reduction processes.

[The effect of inhibitors of the Q-cycle on cyano-resistant oxidation of malate by rat liver mitochondria in the presence of menadione].

Based on the inhibitor analysis data, it has been assumed that the Q-cycle plays a role in the cyano-resistant malate oxidation induced by menadione (90 microM) in rat liver mitochondria. The extent of involvement of Q-cycle transmitters in the cyano-resistant respiration of mitochondria is determined by the mode of the electron supply into the Q-cycle. In the presence of dicumarol, i.

[The use of homeopathy in treating diabetics].

The rationale of homeopathic treatment of diabetes mellitus (DM) with constitutional predisposition is discussed. On the basis of a detailed analysis of one case the author describes the method of homeopathic treatment of diabetes mellitus. The treatment is orientated not only on the treatment of DM but also of concomitant diseases with emphasis in the patients constitution.

[Interaction of menadione and duroquinone with Q-cycle during DT-diaphorase function].

The interaction of quinones (menadione and duroquinone) with DT-diaphorase and mitochondrial electron transport chain translocators at low (120 mosM) and high (400 mosM) values of the medium tonicity in the quinone concentration range of 6-90 microM was studied. It was shown that with a rise in menadione (K3) concentration the number of electron transport carriers interacting with it increase. At K3 concentration of 6 microM the latter is reduced by DT-diaphorase and fully oxidized via the Q-cycle.

[A study of the mechanism of cyanide resistant oxidation of succinate from rat liver mitochondria in the presence of menadione].

Two operation regimes of the electron transport system were found in rat liver mitochondria during the cyanide-resistant succinate oxidation catalyzed by menadione. Under isotonic conditions, the mitochondria were found to contain two electron transport components, one of which was sensitive to mucidin, whereas the other one was inhibited by antimycin A. Both electron transport components were inhibited by thenoyltrifluoroacetone (TTFA).

[The effect of vitamin K deficiency in rats on various enzyme systems participating in energy metabolism].

In alimentary deficiency of vitamin K in rats, accompanied by an increase in the prothrombin time by 30%, activity of kidney creatine kinase and of blood serum alkaline phosphatase was unaltered, while the activity of alkaline phosphatase in small intestinal mucose was decreased by 20% and that of creatine kinase from skeletal muscles--by 10%. In vitamin K-deprived animals the rate of coupling between respiration and mitochondrial phosphorylation was decreased, which might be due to alteration in the NADH-dehydrogenase complex. Menadion reductase activity and cyanide-resistant respiration of mitochondria were unaltered in presence of menadion.

[Stimulation by quinones of cyanide-resistant respiration in rat liver and heart mitochondria].

It was shown that hydrophilic benzo- and naphthoquinones stimulate the cyanide-resistant respiration in liver and muscle mitochondria when succinate or NADH and glutamate or malate are used as oxidation substrates. The substrate-dependent oxygen uptake in the presence of cyanide is initiated by menadione, vicasol, 1.2-naphthoquinone, coenzyme Q0 and duroquinone.

[Energy dissipation in the brown fatty tissue of warm-blooded animals].

The uncoupling mechanism of respiration and phosphorylation in brown adipose tissue as well as factors affecting this process are discussed. An assumption has been suggested and substantiated experimentally that the uncoupling of respiration and phosphorylation in liver mitochondria caused by vitamin K alimentary deficit may have mechanism similar to the unique uncoupling mechanism of brown fat mitochondria.

[Effect of polymyxins B and M on oxygen uptake by rat liver mitochondria].

Polycationic peptide antibiotics, polymixins B and M, are studied for their effect on oxygen uptake by rat liver mitochondria. They both inhibit the process at state 3 and 3p according to Chance. Low concentrations of polymixin M do not affect oxygen uptake by mitochondria at state 4, but its high concentrations inhibit it.

[Inhibition of respiration of mitochondria by o-phenanthroline in a constant magnetic field].

Preincubation of mitochondria treated with chelator of non-heme ferrum o-phenanthroline (0,067-0,267) for 20 min at 18 degrees C in the constant magnetic field of 330 mT brings about a decrease of the intensity of their uncoupled respiration with NAD-dependent substrates by 15-20% as compared to similar mitochondria preparations without the magnetic field effect. The latter is not realized during conjugated respiration with NAD-dependent substrates at uncoupled respiration with succinate, and in the absence of o-phenanthroline as well.

[Effect of the polycationic antibiotic polymyxin B on the respiratory activity of rat liver mitochondria].

the mechanism of the effect of the peptide antibiotic polymixin B on respiration of rat liver mitochondria was studied. It was shown that polymixin B at concentrations of (1,6--2,0) . 10(-3) M inhibits mitochondrial respiration in state 3 and 3u irrespective of the oxidation substrate used and activates oxygen consumption in state 4 at lower concentrations.

[Effect of platinum and palladium compounds on mitochondrial enzymatic systems].

Effect of platinum and palladium complexes on respiration and ATPase activity in bovine heart tissue as well as on respiration of submitochondrial particles was studied. The highest inhibitory activity was exhibited by the complexes of platinum and palladium with pi-ligands in internal coorhdinational sphere such as ethylene-C H4, norbornadiene-C7H8 and allyl-C3H5. The electron density at the central atom of the complex was not responsible for the inhibitory affect of platinum and palladium on mitochondria.

[Induction of a menadione-dependent respiratory shunt by a platinum complex].

Submitochondrial particles (SMP) from the bovine heart were treated with platinum complex--K [C2H4 PtCl3] (Zeize's salt); there occurred a menadion-dependent shunt, this being expressed in menadion stimulation of oxygen consumption under conditions of electron transport block with rotenon. This effect was observed only with the use in the capacity of a substrate of NAD.N2, but not of succinate.

[Inhibition of nonenzymatic ATP hydrolysis by its binding with the cationic detergent micelles].

The rate of ATP hydrolysis is shown to decrease sharply by its binding with mycelles formed from cetyltrimethyl ammonium bromide (CTAB) (pH 9.0, 20 degrees C). Under these conditions only trace amounts of hydrolytic products have been found in the reaction mixture after a two-months standing.

[Inhibitors of the slow stage of proton transfer in the link connecting respiration with mitochondrial phosphorylation].

Electrophilic agents--derivatives of carbonic acids--are found to inhibit respiration, ATP synthesis and reverse electrone transport in intact mitochondria. The inhibition of respiration and ATPase was observed in intact mitochondria at 3 and 3u states (by Chance). Inhibitors concentrations, which caused 50% inhibition, were approximately the same.