The Role of Interleukin-33 in Pathogenesis of Bronchial Asthma. New Experimental Data.

Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and plays an important role in modulating immune system by inducing Th2 immune response via the ST2 membrane receptor. Epithelial cells are the major producers of IL-33. However, IL-33 is also secreted by other cells, e.g., bone marrow cells, dendritic cells, macrophages, and mast cells. IL-33 targets a broad range of cell types bearing the ST2 surface receptor. Many ST2-positive cells, such as Th2 cells, mast cells, basophils, and eosinophils, are involved in the development of allergic bronchial asthma (BA). This suggests that IL-33 directly participates in BA pathogenesis. Currently, the role of IL-33 in pathogenesis of inflammatory disorders, including BA, has been extensively investigated using clinical samples collected from patients, as well as asthma animal models. In particular, numerous studies on blocking IL-33 and its receptor by monoclonal antibodies in asthma mouse model have been performed over the last several years; IL-33- and ST2-deficient transgenic mice have also been generated. In this review, we summarized and analyzed the data on the role of IL-33 in BA pathogenesis and the prospects for creating new treatments for BA.

[Phospholipase D: its role in metabolism processes and disease development]. / Fosfolipaza D: ee rol' v protsessakh metabolizma i razvitii patologicheskikh sostoianii.

Phospholipase D (PLD) is one of the key enzymes that catalyzes the hydrolysis of cell membrane phospholipids. In this review current knowledge about six human PLD isoforms, their structure and role in physiological and pathological processes is summarized. Comparative analysis of PLD isoforms structure is presented. The mechanism of the hydrolysis and transphosphatidylation performed by PLD is described. The PLD1 and PLD2 role in the pathogenesis of some cancer, infectious, thrombotic and neurodegenerative diseases is analyzed. The prospects of PLD isoform-selective inhibitors development are shown in the context of the clinical usage and the already-existing inhibitors are characterized. Moreover, the formation of phosphatidylethanol (PEth), the alcohol abuse biomarker, as the result of PLD-catalyzed phospholipid transphosphatidylation is considered.

[Biologically active substances of cornelian cherry fruits (Cornus mas L.)].

10 samples of fresh-frozen cornelian cherry fruits (Cornus mas L.), collected in the Tambov and the Caucasus regions, were investigated for the total amount and composition of the main biologically active substances (BAS): anthocyanins (AC), proanthocyanidins (OPC), dihydroxycinnamic acids (DHCA), iridoids, organic acids, mono- and disaccharides and antiradical activity in the DPPH-test in vitro. Total phenolics content determined by Folin-Ciocalteu method, was 150-400 mg/100 g fresh fruit weight. The OPC content, estimated by Bate-Smith method, varied from 20-25 mg/100 g of unripe cornelian cherries to 80-430 mg/100 g of mature cornelian cherries. Total AC amount evaluated by pH-differential spectrophotometry was minimal in unripe fruits (11,2 mg/100 g), and maximal in mature fruits (92,2 mg/100 g). Profile of individual AC was determined by HPLC with UV/Vis and ESI-TOF-MS detections. 3-galactosides of cyanidin (19,0-80,3%) and pelargonidin (15,1-75,6%) were found as main anthocyanins. An original methodology for iridoid determination based on HPLC with UV and ESI-TOF-MS detection was developed. The main iridoids were identified as loganic acid, loganin, sweroside and cornuside. Total iridoids content was 130-400 mg/100 g, and loganic acid was predominant in all samples (87,6-94,8%). Only minor amount of the DHCA derivatives (<10 mg/100 g) were found. The malic acid was predominant among organic acids, the total content of which varied from 0,4 to 2,8%. Relatively high amount of ascorbic acid (35-60 mg/100 g) was found. The carbohydrates profile of cornielian cherries was represented by fructose (2,2-3,8%) and glucose (2,5-7,0%). 70% water-ethanol extracts of Cornus mas fruits have showed pronounced antiradical activity in DPPH-test (470,5-932,0 mg TE/100 g). The data on specific minor BAS can be used in the standardization and evaluation of potential biological activity of extracts and dietary supplements based on the cornelian cherry fruits.

[The influence of vitamin B group on monooxygenase activity of cytochrome P450 3A4: pharmacokinetics and electro analysis of catalytic properties].

It was shown that vitamin B group permit to shorten the longitude of diclofenak therapy and to reduce the daytime dose of this drug. All three schemes of diclofenac treatment - only diclofenac, diclofenac plus 2 tablets of Gitagamp (mixture of vitamin B group), and diclofenac plus 4 tablets of Gitagamp--gave maximum value of diclofenal in blood through 1 hour after treatment. In the case of diclofenak treatment without vitamins Cmax corresponds to 1137.2 +/- 82.4 ng/ml, with 2 tablets of Gitagamp--Cmax 1326.7 +/- 122.5 ng/ml, and with 4 tablets--Cmax 2200.4 +/- 111.3 ng/ml. Positive influence of vitamin B group on the decrease of pain syndrome was shown. Pharmacodynamics and pharmacokinetics data were confirmed in electrochemical experiments with cytochrome P450 3A4. For enzyme immobilization screen printed graphite electrodes modified with gold nanoparticles and synthetic membrane-like compound didodecyldimethylammonium bromide (DDAB/Au) were used. Electrochemical analysis reviled the influence of vitamin B group on metabolism of non steroid anti inflammation drug diclofenac catalyzed by cytochrome P450 3A4. Riboflavin was the most effective inhibitor of diclofenac hydroxylation by cytochrome P450 3A4 as was compared at 300 M concentration of vitamin B group (B1, B2, B6). These data confirmed the opportunity of pharmacokinetic parameters regulation and the level of pharmacodynamic effects by the influence of vitamin B group on the catalytic activity of cytochrome P450 3A4.

[The dissolution test in biorelevant media as a prognostic tool for modeling of drug behavior in vivo].

The review deals with the modern tool for modeling of drug behavior in vivo, - the dissolution test in biorelevant media, imitating gastrointestinal fluids. The formulations and preparation methods of fasted state simulation intestinal fluid, FaSSIF and fed state simulation intestinal fluid, FeSSIF, are defined. In addition, the dissolution characteristics of APIs from different BCS classes in biorelevant media are described. Possible applications of biorelevant media in regulatory practice and science are also shown.

[Determination by high performance chromatography, steroid saponins in a biologically active food supplements containing the extract of Tribulus terrestris].

Steroidal saponins are bioactive substances of Tribulus terrestris and can be used to assess the quality of raw materials and processed products from them. For this purpose has been developed the method of qualitative and quantitative determination of steroidal saponins by high performance liquid chromatography with spectrophotometric and mass-selective detection and optimal conditions of sample preparation (70% methanol extraction with sonication and heating); also has been studied steroidal saponins composition of Tribulus terrestris (protodioscin, tribulosaponin B, metilprotodiostsin, terrestrozin H, prototribestin, gracillin and others were found).

[Modern representations of interaction of vitamins].

In article the data of interaction of vitamins among themselves, with various mineral subtances, medicines. The review deals with some new data of the literature on the revealed interactions in manufacture of vitamin complexes, and also in clinicalpractice. The data are systematized according to pharmaceutical, pharmacokinetics and pharmacodynamic interaction of vitamins.

[Cytochrome P4502C9(CYP2C9) gene polymorphism and safety of therapy with warfarin].

Aim of the study was to investigate frequency and influence of alleles CYP2C9*2 and CYP2C9*3 on pharmacokinetics, pharmacodynamics and dosing regimen of warfarin and on development of hemorrhagic complications. We included 84 patients (mean age 62,8 +/- 10,5 years). Duration of follow-up varied between 1 month and 1 year. Carriage of allele variants was determined by polymerase chain reaction, measurement of plasma wafarin concentration was carried out with the help of high performance liquid chromatography. Wild type (CYP2C9*1/*1) was found in 68% of patients; overall frequency of 2C9*1/*1, *l/*3, *2/*2, *3/*3, *2/*3 genotypes was 32%. Average maintenance doses of warfarin for patients with allele variants CYP 2C9 *2 and 2C9 *3 were 3.6 and 3.1 mg/day, respectively, what was significantly lower than in wild type homozygotes (6.1 mg/day). Wild type homozygotes (1) had the highest warfarin clearance (3,51 ml/min). In carriers of 2C9 *2(2) and 2C9 *3(3) warfarin clearance was significantly lower (2.42 and 1.82 ml/min; p1 - 2 = 0,05; p1 - 3 = 0,0008). In carriers of allele variants CYP2C9*2, CYP2C9*3 values of international normalized ratio > 3,0 were met more often, especially in carriers of CYP2C9*3 (in 100% of cases) vs. 28% in wild type homozygotes (p=0,02). Carriers of CYP2C9*3 compared with wild type homozygotes had more hemorrhagic complications (67% and 16%, respectively, p=0,0008). Thus cytochrome P450 2C9 gene polymorphism influences frequency of development of hemorrhagic complications, metabolic clearance, and magnitude of warfarin maintenance dose.

[Importance of genetic polymorphism of cytochrome P450 isoenzymes for the choice and regimes of antidepressant and antipsychotic dosing on an individual basis].

Polymorphism of P450 2D6 (CYP2D6) gene is one of the causes of altered activity of enzymes controlling metabolism of medicinal products (MP), specifically increasing and decreasing biotransformation of xenobiotics. These changes result either in a rise or in a fall of plasma MP; in the former case adverse effects (AE) of MPs are likely to arise, in the latter xenobiotic therapy may prove inefficient. Drug interactions also contribute to variation of MP levels in plasma and undesirable changes of their pharmacological action that may require correction of the therapeutic regime. This paper presents results of original studies and reviews domestic and foreign publications on polymorphism of genes encoding isoenzymes involved in biotransformation processes, such as CYP2D6. This issue is of importance for psychiatric and psychosomatic practice. Algorithms for the rational choice of antidepressants and antipsychotics are proposed with a view to enhancing efficiency and safety of therapy with the use of these MPs.

[The influence of CYP2C9 genetic polymorphism on the pharmacokinetics and pharmacodynamics of warfarin in patients with constant atrial fibrillation].

CYP2C9 is the main enzyme participating in warfarin metabolism, of which genetic polymorphism is typical. The aim of the study was to investigate the influence of having allelic variants CYP2C9*2 and CYP2C9*3 on the pharmacokinetics, dosage regimen, and the rate of hemorrhage in patients with constant atrial fibrillation taking warfarin. Eighty-two patients with constant atrial fibrillation taking warfarin were included in the study. It was shown that in patients with CYP2C9*2 and CYP2C9*3 the clearance of warfarin and its dose were lower, while the episodes of excessive hypocoagulation and hemorrhage associated with warfarin were more frequent than in patients without these allelic variants. Basing on the results of the study, the authors propose an algorithm of choosing the initial warfarin dose depending on CYP2C9 genotype.

[The role of changes in the functional activity and the amount of p-glycoprotein in drug pharmacokinetics].

Data on the structure of P-glycoprotein, the mechanisms of interaction with drugs, the general properties of substrates, the role in the distribution of drugs, and the modulation of their interactions are summarized. Being an ATP-dependent transport agent in the reverse yield, P-glycoprotein participates in the intestinal secretion, limitation of the permeability of histohematic barriers, and the renal and bile excretion of exogenous substrates, thus protecting the organism against xenobiotics. The interactions of drugs on the level of P-glycoprotein either leads to a decrease in these effects, when this transporter is activated by one of the drugs, or causes undesired reactions if P-glycoprotein is inhibited. Poly- or mononucleotide polymorphism of MDRI gene encoding P-glycoprotein can lead to a change in the pharmacokinetics of related substrates. Pharmacotherapy must take into account both the substrate specificity of drugs with respect to P-glycoprotein and the individual features of patients, in particular, race and sex (allele homozygotes versus heterozygotes).

[Clinical significance of the pharmacokinetic interactions between drugs and phytopreparations].

In modern clinics, the pharmacotherapy is frequently accompanied by the administration of phytopreparations (by which are implied any preparations based on or containing plant materials). There are many data indicative of the possible pharmacokinetic interactions between drugs and phytopreparations. Among the most important issues is the ability of components of phytopreparations to induce or inhibit the isoenzymes of cytochrome P-450 and/or glycoprotein P. For this reason, phytopreparations can either increase or decrease the efficacy of jointly admninistared drugs, as well as provoke the development of undesired side reactions.

[The clinical pharmacology of beta-adrenoblockers].

Beta-adrenoblockers (BAB) are highly-effective pharmaceuticals used broadly in treatment of cardial diseases. Response to BABs is known to display interindividual variability; pre-treatment analysis of allelic gene variants responsible for BAB pharmacokinetics, allows dose correction according to the genetic features of an individual patient. Pharmacogenetics is a young science, but it has already proven its practical significance in term of individualization of pharmacotherapy, which in some cases makes it possible to increase the effectiveness of the pharmaceuticals and avoid undesirable effects.

[Interaction of biologically active additives, containing medicinal plants with drugs]. / O vzaimodeistvii biologicheski aktivnykh dobavok, soderzhashchikh lekarstvennye rasteniia, s lechebnymi sredstvami.

For today the biologically active additives (BAA) actively are included into clinical practice as means of "additional" therapy of a number of diseases and their consumption constantly grows. However, majority of the patients do not suspect about an opportunity of interaction between drugs and BAA, containing medicinal plants, and the treating doctors simply underestimate it. The interaction drugs with BAA, containing medicinal plants is investigated not enough. There are separate messages about this interactions of a similar sort, the doctor should take into account this information at realization pharmacotherapy and active image to be interested at the patient about BAA application.