Normalizing effect of energy metabolism regulator (succinic acid) on mitochondrial processes in rat myocardium during hypoxia, cardiac arrhythmia, and salicylate treatment was experimentally shown. A new alternative method for myocardial protection is proposed and its high efficiency in heart diseases of hypoxic and ischemic origin is validated. Address for correspon dence: vkh@pharm.tsu.ru. V. A. Khazanov Coronary disease developing as a result of coronary atherosclerosis is the leading cause of disability and mortality of population of capable age [7]. The progress of atherosclerosis in coronary arteries leads to a discrepancy between the level of coronary bloodflow and myocardial demands for oxygen and substrates associated with augmenting ischemia and hypoxia in cardiomyocytes, this leading to drastic changes in metabolism and energy supply [11]. Inhibition of ATP and creatinine phosphate synthesis associated with this condition leads to disorders in heart rhythm and myocardial contractility.Drug therapy of myocardial ischemia consists in increasing O 2 delivery to the ischemic zone or reducing the O 2 demands of the myocardium. β-Adrenoreceptor blockers, nitrates, angiotensin-converting enzyme inhibitors, calcium antagonists, metabolic drugs, and antiaggregants are used for this purpose [7,8].One of the main drugs for metabolic therapy of coronary disease is trimetazidine (TZ), a selective inhibitor of long-chain 3-ketoacyl-CoA-thiolase [8].It inhibits β-oxidation of fatty acids without inhibition glycolysis, which creates metabolic prerequisites for lactate utilization and reduction of lactoacidosis in the ischemic myocardium. In addition, TZ partially reduces activity of phospholipase A 2 and LPO intensity, which in general leads to improvement of the myocardial function. However, TZ does not completely eliminate the hypoxic type of metabolism. Presumably, blockade of one of the most effective metabolic pathways of energy supply to the myocardium (lipid utilization) limits the potentialities of therapy for the diseases associated with the development of the deficiency of highenergy metabolites [11]. We proposed a principally new pharmacological approach to cardiac protection, consisting in removal of the metabolic limitations of ATP production in the ischemic myocardium without negative impact on the metabolism.We proposed a new class of drugs regulating energy metabolism, optimizing energy supply processes, including those in the ischemic myocardium [11,13]. These drugs provide ATP production in cells at the expense of activity of the rapid metabolic cluster in mitochondria [12,13]. We previously showed that energy metabolism regulators reduced toxicity and increased the efficiency of acetylsalicylic acid (ASA) widely used in cardiology as an antiaggregant [2,7].

Quantitative determination of hydrochlorothiazide (HCTZ) and candesartan (CDS) in human plasma in volunteers was performed using a sensitive, selective and specific LC-MS method which has been developed and validated before the study. The study was performed by means of a liquid chromatograph Shimadzu Prominence equipped with a mass spectrometer LCMS-2020. Analytical column PerfectBond ODS-HD HPLC-column 5 µm 250 × 3.0 mm with a pre-column cartridge PerfectBond ODS-HD 5 µm 10 × 3.0 mm, double source of ionization for LCMS-2020 (electrospray (ESI) and chemical (APCI)) and software LabSol LCMS V5 LCMS2020 systempack were used. The low limit of the quantitative determination for HCTZ and CDS made up 10 ng/ml. m/z for CDS 441.20-positive scan, m/z for HCTZ 295.90-negative scan. The method has been applied to a pharmacokinetic study of 12.5 mg HCTZ and 16 mg CDS tablet in healthy volunteers.

Pegylated hyaluronate-endo-β-N-acetylhexosaminidase considerably potentiates the hemostimulating effects of erythropoietin due to intensification of proliferation and differentiation of erythroid precursors against the background of enhanced secretion of hemopoietins by nonadherent hemopoiesis-inducing environment cells and elevation of serum erythropoietin concentration. The use of the enzyme allows 10-fold reduction of the maximum effective erythropoietin dose.

Immobilized hyaluronidase (nanotechnology method of electron-beam synthesis) exhibited high hepatoprotective activity on the model of Cl4-induced hepatitis. This agent produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects were shown to accompany stimulation of multipotent bone marrow precursors, mobilization of these cells into the peripheral blood, and cell migration to the target organ increasing the number of parenchymal progenitor cells in the liver. The mechanisms for targeted migration of progenitor cells suggest a decrease in SDF-1 production by bone marrow stromal cells and increase in the synthesis of this factor by microenvironmental cells of the liver tissue.

JAK/STAT signaling pathway was examined during functional stimulation of mesenchymal progenitor cells with fibroblast growth factor. The differences were observed in the realizations of the proliferation-differentiation potential of CFU-fibroblasts under blockade of JAKs or during selective inactivation of STAT3. The study revealed stimulating influences of JAKs and STAT3 on mitotic activity of progenitor cells and individual roles of these proteins in the control of their maturation. Blockade of JAKs diminished the level of fibroblast colony formation and the score of actively proliferating CFU-fibroblasts at the background increase of the differentiation rate of progenitor cells. In contrast, STAT3 inhibitor resulted in a coordinated decrease of all examined parameters.