Application of vitamin B group permits to shorten the longitude of diclofenac (DF) therapy and to reduce the daytime dose of this drug. All the three schemes of treatment with diclofenac-i.e., diclofenac alone, diclofenac plus two tablets of Gitagamp (composition of vitamin B group), and diclofenac plus four tablets of Gitagamp-enabled to achieve maximum diclofenac concentration in blood within 1 h after its uptake. In the case of diclofenac administration, C max corresponds to 1,137.2±82.4 ng/ml (3.41±0.25 μM); with two tablets of Gitagamp, it corresponds to 1,326.7± 122.5 ng/ml (3.97±0.37 μM), and with four tablets, it corresponds to 2,200.4±111.3 ng/ml (6.59±0.33 μM). Pharmacodynamics and pharmacokinetics data were confirmed in electrochemical experiments with cytochrome P450 3A4 and electrodes nanostructured with gold nanoparticles, stabilized by the synthetic membrane-like surfactant didodecyldimethylammonium bromide. Electrochemical analysis revealed the influence of vitamin B group on the metabolism of the nonsteroidal anti-inflammatory drug diclofenac catalyzed by cytochrome P450 3A4. Riboflavin was found to be the most effective inhibitor of diclofenac hydroxylation by cytochrome P450 3A4, as was demonstrated by comparing the influence of vitamin B group (B1, B2, and B6) at the same (300 μM) concentration. The data obtained provide evidence for the possible regulation of pharmacokinetic parameters and pharmacodynamic effects for DF through the influence of vitamin B group on the catalytic activity of cytochrome P450 3A4.
The review presents the results of a number of experimental and clinical studies proving the prospects of using L-carnitine in the clinic of internal diseases. Due to the antioxidant and antihypoxant properties, the additional use of L-carnitine in addition to the main etiopathogenetic therapy is prescribed by cardiologists, nephrologists, neurologists, gerontologists. Experimental studies we conducted earlier showed no effect of L-carnitine on the activity of the P450 CYP 3A4 system, which reduces the likelihood of drug-drug interaction at the level of metabolism of drugs metabolized by P450 3A4. When using L-carnitine as part of complex pharmacotherapy, the drug has an increased safety profile in comorbid patients taking L-carnitine.
The influence of the biologically active compound taurine on the stability and catalytic properties of the hemoprotein cytochrome P450 3A4 has been investigated. The catalytic properties were analyzed by electrochemical methods (cyclic and square-wave voltammetry) using cytochrome P450 3A4 immobilized on the electrode. Taurine at concentrations in the range 10-70 µM stimulated the electrochemical reduction of cytochrome P450 3A4, and the reduction was the highest (115 ± 3%) in the presence of 50 µM taurine. Taurine pronouncedly attenuated the itraconazol-caused inhibition of the P450 isoenzyme P450 3A4. Taurine protected cytochrome P450 3A4 due to stabilizing it during electrolysis at controlled voltage in the presence of erythromycin as a substrate. This protection was manifested by an increase in the amount of the "residual" reduced form of the hemoprotein (52 ± 5 and 71 ± 8%, respectively).
The electrochemical properties of cytochrome P450 2C9 (CYP2C9) and polymorphic modifications P450 2C9*2 (CYP2C9*2) and P450 2C9*3 (CYP2C9*3) were studied. To analyze the comparative electrochemical and electrocatalytic activity, the enzymes were immobilized on electrodes modified with a membrane-like synthetic surfactant (didodecyldimethylammonium bromide (DDAB)). An adequate choice of the type of modified electrode was confirmed by cyclic voltammetry of cytochromes P450 under anaerobic conditions, demonstrating well-defined peaks of reduction and oxidation of the heme iron. The midpoint potential, Emid, of cytochrome P450 2C9 is −0.318 ± 0.01 V, and Emid = −0.324 ± 0.01 V, and Emid = −0.318 ± 0.03 V for allelic variant 2C9*2 and allelic variant 2C9*3, respectively. In the presence of substrate diclofenac under aerobic conditions, cytochrome P450 2C9 and its polymorphic modifications P450 2C9*2 and P450 2C9*3 exhibit catalytic properties. Stimulation of the metabolism of diclofenac by cytochrome P450 2C9 in the presence of antioxidant medications mexidol and taurine was shown.
A calcium deficiency is detected in more than 80% of children. This is the result of inadequate consumption of milk and dairy products which are the main food sources of calcium. There is a correlation between deficiency of calcium intake with food in childhood and the risk of osteopenia and osteoporosis in subsequent life periods. With insufficient exogenous intake of calcium, its concentration in the blood decreases which stimulates bone resorption. The factors that further limit the consumption of dairy products are lactase deficiency and cow's milk protein allergy. In order to ensure the intake of the necessary amount of calcium, it is advisable to use vitaminmineral complexes in children that contain not only a sufficient amount of calcium and vitamin D but also other micronutrients required for bone formation.
The electrochemical activity of cytochromes P450 (CYP) 3A4, 2C9 and 2D6 on the screen-printed graphite electrode, nanostructured with gold nanoparticles, stabilized by didodecyldimethylammonium bromide was examined. The analysis of CYP catalytic activity was carried out by a variety of electrochemical techniques, such as cyclic voltammetry, square wave voltammetry, amperometry. A sensitive electrochemical CYP-sensor system was proposed as a reliable candidate for investigation of influence of medicinal preparations -ethoxidol (2ethyl-6-methyl-3-hydroxypyridine malate), mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), cytochrome c and L-carnitine -on the CYP redox behavior and electrocatalytic activity. In the presence of antioxidants, the enhancement of electrochemical signal of CYP was registered. It was shown that ethoxidol, in the concentration range with the values of 90-600 µM, stimulates the electrochemical reduction of cytochromes P450, with the maximum stimulating effects for CYP3A4, CYP2C9 and CYP2D6 being estimated, respectively, as 181 ± 15%, 240± 7%, 110± 4% (at 540 µM ethoxidol).
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