DEVELOPMENT AND OPTIMIZATION OF CARVEDILOL FORMULATION USING EXPERIMENTAL DESIGN

The aim of this paper was to develop and optimize the carvedilol tablets formulation using the full factorial design. The content of binder (PVP K30), content of disintegrant (crospovidone) and main compression force were used as the independent variables. Tablets were prepared by wet granulation. The percentage of released carvedilol from prepared formulation after 10 minutes was defined as the response. It has been found that formulation with the low content of binding agents (4.8%), high content of disintegrant (4.5%) and compression force of 50 N has the best profile of drug. The optimal formulation was defined based on implementation of pharmaceuticaltechnological tests (testing strength, friability, disintegrating, contents of drug substance, drug release profiles). The stability of the optimal formulation with carvedilol was estimated using the aging tests

ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES OF THE ESSENTIAL OIL AND SOLVENT EXTRACTS OF MENTHA PULEGIUM L.

We report the total phenolic (TPC; expressed as gallic acid equivalents, GAE, per milligram of dry extract weight) and the total flavonoid contents (TFC; expressed as quercetin equivalents, QE, per milligram of dry extract weight) and antimicrobial and antioxidant activities of the essential oil and hexane, diethyl ether, ethyl acetate and methanol extracts of Mentha pulegium L. (Lamiaceae) collected in Serbia. The total phenolic content was in the range of 129.43-388.29 μg GAE/mg, while TFC ranged from 57.81 to 160.94 QE/mg; the highest TPC and TFC were found in the methanol extract. The antimicrobial activity (against five bacteria and two fungi species) of the essential oil and solvent extracts was assessed using disc-diffusion method. However, the studied samples demonstrated a poor antimicrobial potential. The antioxidant activity was screened using five different tests: 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid radical cation decolorization assay (ABTS), total reducing power (TRP), ferric reducing antioxidant power (FRAP) and cupric reducing antioxidant capacity assay (CUPRAC); the methanol extract showed the strongest antioxidant potential. The results of the different antioxidant assays were correlated mutually and with the total flavonoid and total phenolic contents (regression analysis and agglomerative hierarchical clustering). ANTIOKSIDANTNA I ANTIMIKROBNA AKTIVNOST ETARSKOG ULJA I EKSTRAKATA BILJNE VRSTE MENTHA PULEGIUM L.U ovom radu je određen sadržaj ukupnih fenola (TPC; izražen u ekvivalentima galne kiseline, GAE, po miligramu suvog biljnog ekstrakta) i ukupnih flavonoida (TPC; izražen u ekvivalentima kvarcetina, QE, po miligramu suvog biljnog ekstrakta), kao i antimikrobna i antioksidantna aktivnost etarskog ulja i heksanskog, dietil-etarskog, etil-acetatnog i metanolnog ekstrakta biljne vrste Mentha pulegium L. (Lamiaceae; populacija iz Srbije). Sadržaj ukupnih fenola analiziranih uzoraka se kretao u opsegu od 129,43 do 388,29 μg GAE/mg, dok je TFC bio u interval od 57,81 do 160,94 QE/mg; najviše vrednosti za TPC i TFC nađene su za metanolni ekstrakt. Antimikrobna aktivnost (prema pet bakterijskih i dva soja gljivica) etarskog ulja i ekstrakata je određena disk-difuzionom metodom. Proučavani uzorci su imali slabu antimikrobnu aktivnost. Antioksidantna aktivnost je ispitivana pomoću DPPH (2,2-difenil-1-pikrilhidrazil radikal), ABTS (2,2'-azino-bis(3-etilbenzotijazolin-6-sulfonska kiselina radikal katjon), TRP (ukupna redukciona sposobnost), FRAP (sposobnost redukcije feri-jona) i CUPRAC (sposobnost redukcije Cu(II)-jona) metodama; najviši antioksidantni potencijal je imao metanolni ekstrakt. Rezultati različitih metoda za određivanje antioksidantnog potencijala su korelisani međusobno, kao i sa sadržajem ukupnih fenola i flavonoida (regresiona analiza i aglomerativna hijerarhijska klaster analiza). HIGHLIGHTSThe essential oil and hexane, diethyl ether, ethyl acetate and methanol extracts of Mentha pulegium L. collected in Serbia were studied.Their total phenolic content was in the range of 129.43-388.29 μg GAE/mg, while total flavonoid content ranged from 57.81 to 160.94 QE/mg.Solvent extracts (SE) and essential oil of the studied M. pulegium population were poor antimicrobials.Antioxidant activities of SE were studied using five different methods.Differences between the previous and the present results suggest M. pulegium metabolic profile might be influenced by both genetic and environmental factors

Zebrafish Kidney Phagocytes Utilize Macropinocytosis and Ca2+-Dependent Endocytic Mechanisms

Background: The innate immune response constitutes the first line of defense against invading pathogens and consists of a variety of immune defense mechanisms including active endocytosis by macrophages and granulocytes. Endocytosis can be used as a reliable measure of selective and non-selective mechanisms of antigen uptake in the early phase of an immune response. Numerous assays have been developed to measure this response in a variety of mammalian and fish species. The small size of the zebrafish has prevented the large-scale collection of monocytes/macrophages and granulocytes for these endocytic assays. Methodology/Principal Findings: Pooled zebrafish kidney hematopoietic tissues were used as a source of phagocytic cells for flow-cytometry based endocytic assays. FITC-Dextran, Lucifer Yellow and FITC-Edwardsiella ictaluri were used to evaluate selective and non-selective mechanisms of uptake in zebrafish phagocytes. Conclusions/Significance: Zebrafish kidney phagocytes characterized as monocytes/macrophages, neutrophils and lymphocytes utilize macropinocytosis and Ca 2+-dependant endocytosis mechanisms of antigen uptake. These cells do not appear to utilize a mannose receptor. Heat-killed Edwardsiella ictaluri induces cytoskeletal interactions for internalization in zebrafish kidney monocytes/macrophages and granulocytes. The proposed method is easy to implement and should prove especially useful in immunological, toxicological and epidemiological research

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

[Abstract] Aims. Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results. We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66±13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion. Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease

Spring Wheat Leaf Appearance and Temperature: Extending the Paradigm?

Extensive research shows temperature to be the primary environmental factor controlling the phyllochron, or rate of leaf appearance, of wheat (Triticum aestivum L.). Experimental results suggest that soil temperature at crown depth, rather than air temperature above the canopy, would better predict wheat leaf appearance rates. To test this hypothesis, leaf appearance in spring wheat (\u27Nordic\u27) was measured in a 2-year field experiment (Nunn clay loam soil; fine, smectitic, mesic Aridic, Argiustoll) with three planting dates and two soil temperature treatments. One temperature treatment (denoted +3C) consisted of heating the soil at crown depth to 3 °C above the ambient soil temperature (denoted +OC). Main stem cumulative leaf number was measured at least weekly until flag leaf emergence. Leaf appearance was essentially linear with both air and soil growing degree-days (GDD), although there was a stronger linear relationship with soil GDD in the +OC plants than in +3C plants. A weak positive relationship between planting date and the phyllochron was observed. Unexpectedly, we found that heating the soil did not increase the rate of leaf appearance, as the paradigm would predict. To explain these results, we propose extending the paradigm in two ways. First, three processes are involved in leaf appearance: (1) cell division at the shoot apex forms the primordium; (2) cell division in the intercalary meristem forms the cells that then (3) expand to produce the leaf. Cell division is predominately controlled by temperature, but cell expansion is considerably more affected by factors other than temperature, explaining the influence of other factors on the phyllochron. Secondly, the vertical distribution of the two meristems and region of cell expansion occur over a significant distance, where temperature varies considerably, and temperature at a specific point (e.g. crown depth) does not account for the entire temperature regime under which leaves are developing