Expanding the possibilities of using sodium-glucose cotransporter 2 inhibitors in patients with heart failure.

OBJECTIVE: Aim: To study the potential mechanisms of the beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, the possibilities of improving the treatment and prognosis of patients with acute heart failure (HF) during their use. PATIENTS AND METHODS: Materials and Methods: The data analysis of literary sources has been conducted regarding the results of existing studies evaluating the clinical benefit and safety of SGLT-2 inhibitors in patients with acute heart failure. CONCLUSION: Conclusions: The peculiarities of the pharmacological action of SGLT-2 inhibitors and the obtained research results expand the possibilities of using this group of drugs, demonstrating encouraging prospects in improving the prognosis of patients hospitalized with acute heart failure.

CLINICAL EFFECTIVENESS OF EMPAGLIFLOZIN IN PATIENTS WITH HEART FAILURE.

OBJECTIVE: The aim: To study the possibilities of increasing the effectiveness of treatment and improving the prognosis of patients with various phenotypes of heart failure when using empagliflozin. PATIENTS AND METHODS: Materials and methods: The analysis of the data regarding the results of existing studies evaluating the clinical benefit and safety of empagliflozin in patients with various phenotypes of heart failure has been conducted. CONCLUSION: Conclusions: In the EMPA-REG OUTCOME study, empagliflozin has demonstrated the ability to improve cardiorenal outcomes and reduce the risk of hospitalization for heart failure in patients with diabetes. The results of the studies (EMPEROR-Preserved, EMPEROR-Reduced, EMPULSE) have shown the clinical advantages of empagliflozin over traditional heart failure therapy, manifested by a reduction in mortality and the number of hospitalizations for heart failure, as well as improvement in quality of life indicators. The clinical benefits of using empagliflozin were observed in patients with chronic heart failure with different left ventricular ejection fraction, as well as in patients with acute heart failure. Empagliflozin is a sodium-glucose co-transporter 2 inhibitor with a convincing evidence base for the treatment of all categories of patients with chronic heart failure, regardless of diabetes status. The results of the conducted studies indicate the unconditional benefit of early initiation of empagliflozin therapy in patients with both chronic and acute heart failure after the stabilization of their condition.

LOOP DIURETICS IN HEART FAILURE: EVIDENCE-BASED CHOICE.

OBJECTIVE: The aim: Of the article is to conduct a comparative evaluation of the effectiveness of torasemide and furosemide in patients with heart failure. PATIENTS AND METHODS: Materials and methods: Analysis of the existing clinical trials and meta-analyzes that combine the results of the completed studies aimed at the investigation of comparative efficacy of furosemide and torasemide in patients with heart failure (НF). CONCLUSION: Conclusions: There is enough convincing evidence to speak about the advantages of torasemide over furosemide both in terms of its pharmacological properties and taking into account the reduction of hospitalizations, functional progress and improvement in the quality of life of patients with НF. The safety profile of torasemide is more favorable, as it is associated with a reduced risk of hypokalemia compared to furosemide. The abovementioned facts favor the use of torasemide in patients with symptomatic НF, as well as the transition from furosemide to torasemide in patients with edema caused by НF, which remain uncontrolled despite receiving optimal doses of furosemide.

DYNAMICS OF DIPHTHERIA INCIDENCE IN THE TRANSCARPATHIAN REGION OF UKRAINE IN THE VACCINATION ERA.

OBJECTIVE: The aim: Was to study the dynamics of the incidence of diphtheria in the Transcarpathian region of Ukraine. PATIENTS AND METHODS: Materials and methods: A retrospective analysis of the data of the state statistical reporting of the Transcarpathian region on the incidence of diphtheria, the carriage of infection, vaccination coverage and the severity of diphtheria immunity was carried out. CONCLUSION: Conclusions: Low coverage of the population with vaccination against diphtheria, registration of an outbreak of diphtheria among international students of the region, and other regions of Ukraine in conditions of increased population migration, are alarming prognostic signs of the possible development of another significant epidemic rise of diphtheria morbidity in Transcarpathia.

Priorities of anti-hyperglycaemic drug therapy in patients with type 2 diabetes and heart failure.

OBJECTIVE: The aim is to explore the possibilities of improving the effectiveness in preventing cardiovascular diseases and heart failure using sodium-glucose co-transporter 2 inhibitors. PATIENTS AND METHODS: Materials and methods: The analysis of the existing clinical and experimental data on the effect of sodium-glucose co-transporter 2 (SGLT-2) inhibitors on the cardiovascular system, the condition of kidneys, cardiovascular risk factors. RESULTS: Review: SGLT-2 inhibitors are the first class of glucose-lowering agents in large-scale studies (EMPA-REG OUTCOME, CANVAS, CVD-REAL, CVD-REAL2) which have demonstrated the ability to improve cardiorenal outcomes and reduce the risk of hospitalization with heart failure in patients with diabetes. In addition to hypoglycaemic action, SGLT-2 inhibitors show a number of pleiotropic effects, which are potentially capable of reducing cardiovascular risk: diuretic effect, decrease in: blood pressure, arterial wall stiffness, waist and body weight, expression of albuminuria, etc. The use of drugs of this class opens great prospects not only in terms of glycaemic control, but also in the prevention of cardiovascular complications of diabetes. CONCLUSION: Conclusions: 1. When choosing glucose-lowering agents in patients with type 2 diabetes, it is necessary to take into account their impact on the risk of development and the course of heart failure. 2. SGLT-2 inhibitors ought to be considered as a preferred method of treatment for type 2 diabetes in patients with heart failure or with a risk of heart failure that meets the latest recommendations of the European and American Diabetes Association.

Enhanced oxidative damage to DNA, lipids, and proteins and levels of some antioxidant enzymes, cytokines, and heat shock proteins in patients infected with influenza H1N1 virus.

Overweight and obesity is becoming widespread enough to generate an acceptable and misleading social status. By 2030, in the USA up to 86 % of adults will be overweight or obese. Some selected statistical data based on the body mass index (BMI) indicated that overweight was not associated with increased mortality, this provoked a conceivable interest. Added to this is the observation that while the prevalence of obesity is dramatically increasing, the cardiovascular mortality and life expectancy in the European Union and USA has improved. When more sensitive indicators of body adiposity and its distribution than the BMI, like the waist-thigh ratio in both sexes and the waist-hip ratio in women are projected on mortality, it becomes obvious that even overweight is associated with an increased health risk. Gaining excessive body fat is a continuous, frequently progressive process. Present obesity epidemic in childhood will manifest with deleterious consequences only in future years when adolescents reach adulthood. Prevention is thus essential even before the overweight sets in. Improved life expectancy observed in large populations despite obesity epidemic, is a favourable medical success in the management of hypertension, of serum lipid disorders and diabetes. While encouraging, when it is observed in large population, it does not take away the potential health risk of a metabolic disorder in an individual who is overweight (Fig. 7, Ref. 25).

Anti-oxidative and anti-inflammatory activities of placental extracts in benzo[a]pyrene-exposed rats.

OBJECTIVE: Placental extracts (PE) have been used for years as a folk remedy in Asian countries. PE mediates alleviation of menopausal symptoms, wound healing, liver regeneration and anti-inflammatory responses. In this study, we evaluated the protective effects of PE on rats exposed to benzo[a]pyrene (BaP). METHODS: The composition of amino acids, sugars and fatty acids in PE was analyzed. The effect of PE on DNA damage was determined by Comet assay, and oxidative damage was determined by measuring the activity of superoxide dismutase and the levels of lipid peroxidation. The effect of PE on cytokines and immunoglobulin levels was determined by western blot analysis. RESULTS: Exposure of rats to BaP significantly increased the Olive Tailmoments compared to controls, while pre-treatment with PE composed of diverse amino acids, monosaccharides and fatty acids significantly decreased the Olive Tailmoments induced by BaP. In addition, oxidative stress induced by BaP was attenuated by pre-treatment with PE. Furthermore, PE pre-treatment significantly decreased the levels of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6. CONCLUSION: Pre-treatment of rats with PE significantly attenuates oxidative damage and immunotoxicity induced by BaP. These findings suggest the further studies regarding the protective effects of PE against environmental toxicants in humans.

Smooth muscle length-dependent PI(4,5)P2 synthesis and paxillin tyrosine phosphorylation.

We studied effects of increasing the length of porcine trachealis muscle on 5.5 microM carbachol (CCh)-evoked phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] synthesis and other parameters of phosphatidylinositol (PI) turnover. PI(4,5)P2 resynthesis rates in muscle held at 1.0 optimal length (L(o)), measured over the first 6 min of CCh stimulation, were 140 +/- 12 and 227 +/- 14% of values found in muscle held at 0.5 L(o) and in free-floating muscle, respectively. Time-dependent changes in cellular masses of PI(4,5)P2, PI, and phosphatidic acid, and PI resynthesis rates, were also altered by the muscle length at which contraction occurred. In free-floating muscle, CCh did not evoke increases in tyrosine-phosphorylated paxillin (PTyr-paxillin), an index of beta1-integrin signaling; however, there were progressive increases in PTyr-paxillin in muscle held at 0.5 and 1.0 L(o) during contraction, which correlated with increases in PI(4,5)P2 synthesis rates. These data indicate that PI(4,5)P2 synthesis rates and other parameters of CCh-stimulated inositol phospholipid turnover are muscle length-dependent and provide evidence that supports the hypothesis that length-dependent beta1-integrin signals may exert control on CCh-activated PI(4,5)P2 synthesis.

Pneumocystis carinii f. sp. carinii synthesizes de novo four homologs of ubiquinone.

Ubiquinone, coenzyme Q, plays a pivotal role in electron transport and is a target for chemotherapy against a number of eukaryotic infectious agents, including Pneumocystis carinii. Coenzyme Q10 was previously identified as the major ubiquinone homolog in P. carinii isolated and purified from rat lungs; CoQ9 was also present. In contrast, CoQ9 and CoQ8 (but not CoQ10) were detected in the lungs of uninfected rat controls. These observations suggested that the pathogen synthesizes CoQ10, and perhaps CoQ9 as well. In the present study, CoQ biosynthesis in P. carinii was examined in greater detail. Radiolabeled mevalonate, a precursor of the CoQ polyprenyl chain, was incorporated in vitro into P. carinii ubiquinones. Incorporation of radiolabeled mevalonate into P. carinii CoQ was not enhanced by treating cells with lovastatin, suggesting that the cells did not transport the drug, or that a lovastatin-insensitive pathway for de novo synthesis of isoprenoids may also function in this organism. Radiolabeled precursors of the ring moiety, including shikimic acid, p-hydroxybenzoic acid, and tyrosine were also incorporated into P. carinii CoQ. Unexpectedly, it was found that not only CoQ9 and CoQ10, but also CoQ7, and CoQ8, were metabolically radiolabeled by all the precursors tested, indicating that the organism synthesizes CoQ7, CoQ8, CoQ9, and CoQ10. Metabolic radiolabeling of ubiquinones in rat lung controls was not detected in experiments using either radioactive mevalonate or p-hydroxybenzoate. Thus the incorporations measured using purified P. carinii preparations were due to the enzymes of the organism.

Neutral lipids, their fatty acids, and the sterols of the marine ciliated protozoon, Parauronema acutum.

The neutral lipids and their fatty acids and the sterol fractions of the marine ciliated protozoon, Parauronema acutum, were characterized. The neutral lipids consisted of triglycerides (30%), sterols (29%), free fatty acids (24%), steryl esters (9%), and diglycerides (8%) and small amounts of fatty alcohols. The fatty acid profiles of these lipids were very similar although quantitative differences were detected. Saturated fatty acids, primarily 14:0, 16:0, and 18:0 constituted 20-30% of the total. Unsaturated fatty acids containing one to three double bonds, primarily 18:1(9), 18:2 (9,12), 18:3 (9, 12, 15) and 20:3 (11, 14, 17), constituted 35-50% of the total. Highly unsaturated fatty acids, 18:4 (6, 9, 12, 15), 20:5 (5, 8, 11, 14, 17) and 22:6 (4, 7, 10, 16, 19), constituted 16-25% of the total. The fatty alcohols consisted of 14:0 (2%), 16:0 (66%), 18:0 (3%), 20:0 (8%), and 22:0 (21%). The sterols of Parauronema acutum consisted of cholesterol (53%), campesterol (32%), desmosterol (7%), and beta-sitosterol (8%).

Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in Pneumocystis carinii organisms.

The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis carinii carinii. In Plasmodium, the primary mechanism of drug action is an irreversible binding to the mitochondrial cytochrome bc(1) complex as an analog of ubiquinone. Blockage of the electron transport chain ultimately inhibits de novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the present study, the effect of atovaquone was examined on Pneumocystis carinii carinii coenzyme Q biosynthesis (rather than electron transport and respiration) by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition at 10 nM and then stimulation up to 0.2 microM, followed by inhibition at 1 microM. Since other naphthoquinone drugs may also act as analogs of ubiquinone, diospyrin and two of its derivatives were also tested for their effects on ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii carinii ubiquinone.

The fatty acid and monosaccharide compositions of three neutral and three phosphorylated glycolipids isolated from Leishmania donovani promastigotes grown in a chemically defined medium.

Several lipids and macromolecular lipoconjugates of Leishmania spp. have now been well characterized; however, the glycolipids of L. donovani have not been thoroughly examined. In the present study, 3 neutral and 3 phosphorylated glycolipids were detected in promastigote forms of the organism grown in a chemically defined medium. The fatty acid and sugar compositions of these glycolipids, isolated and purified by adsorption column chromatography and thin-layer chromatographic procedures, were identified and quantified by gas-liquid chromatography and mass spectrometry. Myristate (14:0), palmitate (16:0), palmitoleate (16:1), stearate (18:0), oleate (18:1), and linoleate (18:2) were the major fatty acids in all 6 glycolipids. Arabinose, mannose, glucose, and galactose were detected in the glycolipids. The biochemical nature of these lipids suggested that the major components in the isolated preparations of the 6 glycolipids are diacylglycerophospholipids, distinct from the major precursors of macromolecular lipoconjugates such as the lipid anchors of cell surface antigens that have been reported. These appear to be terminal products of lipid biosynthesis in this parasite.

Characterizations of Pneumocystis carinii and rat lung lipids: glyceryl ethers and fatty alcohols.

Pneumocystis carinii carinii and rat lung phospholipids contained 3-6% 1-alkyl-2-acyl glycerols composed of the glyceryl ether species, 1-O-octadecyl glycerol (batyl alcohol), 1-O-octadec-9-enyl glycerol (selachyl alcohol), 1-O-hexadecyl glycerol (chimyl alcohol), and 1-O-hexadec-9-enyl glycerol. Of the major phospholipid classes, phosphatidylinositol (PI) and phosphatidylserine contained the highest percentage of alkyl acyl glycerols. Methylprednisolone treatment caused an increase in alkyl acyl PI of rat lung lipids from 12% to 45%. As the PI concentration in lung phospholipids increases in rats treated with methylprednisolone, the increase in alkyl acyl PI was substantial; the proportions of alkyl acyl phosphatidylethanolamine and alkyl acyl lyso phosphatidylcholine (PC) also increased. Pneumocystis phospholipids contained higher proportions of alkyl acyl PC than the phospholipids of the lungs from normal and immunosuppressed uninfected rats. The glyceryl ether compositions of P. carinii carinii PC and lyso PC were similar, which suggests that lyso PC in the organism is derived by phospholipase A2 action on PC. This was not the case for PC and lyso PC of the lung controls. Analysis of the free fatty alcohols, precursors of glyceryl ethers identified only saturated species in P. carinii carinii and rat lung controls. Thus, the introduction of a double bond in the alcohol moiety of glyceryl ethers occurs after formation of the ether linkage between fatty alcohol and the glyceryl backbone.

The membrane lipids of the marine ciliated protozoan Parauronema acutum.

The membrane lipid composition of the marine ciliated protozoan Parauronema acutum was characterized. Phospholipids of P. acutum comprised 75% of the total lipids and consisted of phosphatidyl ethanolamine (33%), phosphatidyl choline and its phosphono analog (24%), phosphatidyl inositol (12%), phosphatidyl serine (8%), an unidentified phosphonolipid (18%) and small amounts of sphingomyelin, phosphatidic acid and lysophospholipid. Neutral sphingolipids comprised 15% of the total ciliate lipids and consisted of two major glycosphingolipids and six minor glycosphingolipids. These contained two kinds of long chain bases, one of which was sphingosine and either glucose or galactose or mixtures of both. The fatty acids of the total lipids of P. acutum consisted primarily of palmitic acid (13%), oleic acid (6%), linoleic acid (25%), alpha-linolenic aid (12%) plus highly unsaturated fatty acids of the omega - 3 family including all-cis 6,9,12,15-octatetraenoic acid (9%), all-cis 5,8,11,14,17-eicosapentaenoic acid (10%) and all-cis 4,7,10,13,16,19,22-docosa-hexaenoic acid (5%). Individual lipids had their own specific fatty acid patterns.

Identification and initial characterizations of free, glycosylated, and phosphorylated ceramides of Paramecium.

Paremecium tetraurelia contains high concentrations of six ethanolamine sphingolipids in the cell surface membrane surrounding somatic cilia. Three have phosphoryl groups and the other three have phosphonyl groups, and each contains either dihydrosphingosine, sphingosine, or phytosphingosine. In the present study, free, phosphorylated, and three major glycosylated ceramides were identified in the neutral sphingolipid fraction of this organism when it was grown on a crude medium. Individual lipids were characterized by specific staining on thin-layer chromatographic plates and the fatty acids derived from them were identified by gas-liquid chromatography and mass spectrometry. Unlike the esterified fatty acid composition of the ciliate's phospholipids, which have only small amounts of fatty acids greater than 20 carbons in length, the neutral sphingolipids mainly contain fatty acids greater than 22 carbons in length as well as high concentrations of long chain hydroxy fatty acids. The sugars, glucose, galactose, and fructose, were identified in total neutral sphingolipid fraction. The long chain bases in the neutral sphingolipid fraction were mainly C18 compounds and were identified as C18 dihydrosphingosine, C20 sphingosine, and isomers of C18 sphingosine. Phytosphingosine was not detected in the neutral sphingolipid fraction obtained from whole cells. Because most of the cell's phytosphingosine-containing ethanolamine sphingolipids are in cilia, the inability to detect phytosphingosine as part of putative precursor ceramide compounds suggests that conversions of the long chain base moiety of ethanolamine phospho- and phosphonosphingolipids occur in situ in the ciliary membrane.

Ubiquinone synthesis by Pneumocystis carinii: incorporation of radiolabeled polyprenyl chain and benzoquinone ring precursors.

Radiolabeled mevalonic acid was incorporated in vitro into Pneumocystis carinii ubiquinone homologs, CoQ9 and CoQ10, demonstrating the isoprenoid branch pathway forming the polyprenyl chain of ubiquinone is functional in the organism. Radiolabeled shikimic acid, tyrosine and p-hydroxybenzoic acid were also incorporated into the two ubiquinone homologs, indicating that P. carinii also possessed the biochemical pathway for de novo synthesis of the CoQ benzoquinone ring.