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In failing hearts, Na + /Ca 2+ exchanger (NCX) overactivity contributes to Ca 2+ depletion, leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca 2+ mishandling, to limit afterdepolarization-related arrhythmias, and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 is a selective NCX inhibitor for all NCX isoforms across species, including human, with no effect on the native voltage-dependent calcium and sodium currents in vitro. Additionally, it showed in vitro and in vivo antiarrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under intravenous infusion at 250,750 or 1500 µg/kg per hour in dogs, which were either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 µg/kg per minute, i.v.). In normal dogs, NCX inhibitor increased cardiac contractility (dP/dt max ) and stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs, NCX inhibitor significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, and +62% at 250, 750, and 1500 µg/kg per hour, respectively) while significantly increasing dP/dt max only at 1500 (+33%). Furthermore, NCX inhibitor significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dt max and SV (+68.8%) but did not change HR, sympathovagal balance, or BRS. Overall, SAR340835, a selective potent NCX inhibitor, displayed a unique therapeutic profile, combining antiarrhythmic properties, capacity to restore systolic function, sympathovagal balance, and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment. SIGNIFICANCE STATEMENT: HF is facing growing health and economic burden. Moreover, patients hospitalized for acute heart failure are at high risk of decompensation recurrence, and no current acute decompensated HF therapy definitively improved outcomes. A new potent, Na + /Ca 2+ exchanger inhibitor SAR340835 with antiarrhythmic properties improved systolic function of failing hearts without creating hypotension, while reducing heart rate and restoring sympathovagal balance. SAR340835 may offer a unique and attractive pharmacological profile for patients with acute heart failure as compared with current inotrope, such as dobutamine., Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The Author(s).)

Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterised in in vitro and in vivo preclinical studies. Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from in vitro metabolic stability studies in human hepatocytes. For human, plasma protein binding was moderate with a fraction unbound of 0.16, whole blood-to-plasma partitioning ratio was 0.8, and danicamtiv showed high permeability and no efflux in a Caco-2 cell line. Danicamtiv metabolism pathways in vitro included CYP-mediated amide-cleavage, N -demethylation, as well as isoxazole- and piperidine-ring-opening. Danicamtiv clearance in vivo was low across species with 15.5, 15.3, 1.6, and 5.7 mL/min/kg in mouse, rat, dog, and monkey, respectively. Volume of distribution ranged from 0.24 L/kg in mouse to 1.7 L/kg in rat. Oral bioavailability ranged from 26% in mouse to 108% in dog. Simple allometric scaling prediction of human plasma clearance, volume of distribution, and half-life was 0.64 mL/min/kg, 0.98 L/kg, and 17.7 h, respectively. Danicamtiv preclinical attributes and predicted human pharmacokinetics supported advancement toward clinical development.

Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P 1 ) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P 1 functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P 1 desensitization have been attributed to endothelial damage, suggesting that drugs with the opposite effect, namely, the ability to activate S1P 1, could help to restore endothelial homeostasis. We found and characterized a biased agonist of S1P 1 , SAR247799, which preferentially activated downstream G protein signaling to a greater extent than β-arrestin and internalization signaling pathways. SAR247799 activated S1P 1 on endothelium without causing receptor desensitization and potently activated protection pathways in human endothelial cells. In a pig model of coronary endothelial damage, SAR247799 improved the microvascular hyperemic response without reducing lymphocyte numbers. Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P 1 -desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P 1 functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P 1 These findings demonstrate that sustained S1P 1 activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aim: To assess the bioequipotency of equimolar doses of idraparinux (2.5 mg) and idrabiotaparinux (3.0 mg)., Method: In a phase I study, 48 healthy male volunteers were randomized to a single subcutaneous injection of idrabiotaparinux or idraparinux, followed by plasma sampling over 27 days. In a prospective substudy of the phase III EQUINOX trial, 228 patients treated for acute symptomatic deep vein thrombosis received idrabiotaparinux or idraparinux once weekly for 6 months. Plasma sampling was performed within 5 days following the last injection. The primary pharmacodynamic endpoint was the inhibition of activated factor X (FXa) activity. Maximal anti-FXa activity (Amax) and area under anti-FXa activity vs. time curve (AAUC) were calculated. Safety and tolerability were also assessed., Results: In both studies, pharmacodynamic anti-FXa vs. time profiles of idrabiotaparinux and idraparinux were superimposable. Ratio estimates (90% confidence intervals [CIs]) for idrabiotaparinux : idraparinux were 0.96 (0.89, 1.04) for Amax and 0.95 (0.87, 1.04) for AAUC in the phase I study, and 1.11 (1.00, 1.22) for Amax and 1.06 (0.96, 1.16) for AAUC at month 6 in the EQUINOX substudy. Idrabiotaparinux and idraparinux were considered bioequipotent because 90% CIs were within the pre-specified interval (0.80, 1.25). Study treatments were well tolerated., Conclusion: Pharmacodynamic parameters reported after single dose in healthy volunteers and after repeated once weekly dosing in patients demonstrated the bioequipotency of idrabiotaparinux and idraparinux based on FXa inhibition. These outcomes support the use of an idrabiotaparinux dose bioequipotent to an idraparinux dose in large clinical trials, and the possibility to substitute idrabiotaparinux to idraparinux for the treatment of venous thromboembolism., (© 2012 Sanofi R&D. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

The high cost and often complex synthesis procedure of new highly selective electrocatalysts (particularly those based on noble metals) for H 2 O 2 production are daunting obstacles to penetration of this technology into the wastewater treatment market. In this work, a simple direct thermal method has been employed to synthesize Sn-doped carbon electrocatalysts, which showed an electron transfer number of 2.04 and outstanding two-electron oxygen reduction reaction (ORR) selectivity of up to 98.0 %. Physicochemical characterization revealed that this material contains 1.53 % pyrrolic nitrogen, which is beneficial for the production of H 2 O 2 , and -C≡N functional group, which is advantageous for H + transport. Moreover, the high volume ratio of mesopores to micropores is known to favor the quick escape of H 2 O 2 from the electrode surface, thus minimizing its further oxidation. A purpose-made gas-diffusion electrode (GDE) was prepared, yielding 20.4 mM H 2 O 2 under optimal electrolysis conditions. The drug diphenhydramine was selected for the first time as model organic pollutant to evaluate the performance of an electrochemical advanced oxidation process. In conventional electro-Fenton process (pH 3), complete degradation was achieved in only 15 min at 10 mA cm -2 , whereas at natural pH 5.9 and 33.3 mA cm -2 , almost overall drug removal was reached in 120 min., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Conducting electrochemical organic synthesis in/on whole water media is undoubtedly a highly green approach, which avoids the usage of organic solvents, and sometimes organic supporting electrolytes. In this review, the electrochemical organic syntheses in/on whole water environment are reviewed, especially including the reactions conducted both in organic solvent and water for comparisons. This review discussed anodic and cathodic reaction, respectively, including the C−H oxidation, hydroxylation, dehydrogenative cross coupling, functionalization of alkenes, cathodic oxidation, hydrogenation, reductive cross coupling, and so on. As the reduction of CO2, conversion biomass, and waste water disposal are frequently performed in water, and have already been reviewed recently. These topics are not included in this review. [ABSTRACT FROM AUTHOR]

The electro-Fenton (EF) process is an advanced oxidation technology with significant potential; however, it is limited by two steps: generation and activation of H 2 O 2 . In contrast to the production of H 2 O 2 via the electrochemical two-electron oxygen reduction reaction (ORR), the electrochemical three-electron (3e - ) ORR can directly activate molecular oxygen to yield the hydroxyl radical (⋅OH), thus breaking through the conceptual and operational limitations of the traditional EF reaction. Therefore, the 3e - ORR is a vital process for efficiently producing ⋅OH in situ, thus charting a new path toward the development of green water-treatment technologies. This review summarizes the characteristics and mechanisms of the 3e - ORR, focusing on the basic principles and latest progress in the in situ generation and efficient utilization of ⋅OH through the modulation of the reaction pathway, shedding light on the rational design of 3e - ORR catalysts, mechanistic exploration, and practical applications for water treatment. Finally, the future developments and challenges of efficient, stable, and large-scale utilization of ⋅OH are discussed based on achieving optimal 3e - ORR regulation and the potential to combine it with other technologies., (© 2024 Wiley-VCH GmbH.)

β-arrestin2, a member of the arrestin family, mediates the desensitization and internalization of most G protein-coupled receptors (GPCRs) and functions as a scaffold protein in signalling pathways. Previous studies have demonstrated that β-arrestin2 expression is dysregulated in malignant tumours, fibrotic diseases, cardiovascular diseases and metabolic diseases, suggesting its pathological roles. Transcription and post-transcriptional modifications can affect the expression of β-arrestin2. Furthermore, post-translational modifications, such as phosphorylation, ubiquitination, SUMOylation and S-nitrosylation affect the cellular localization of β-arrestin2 and its interaction with downstream signalling molecules, which further regulate the activity of β-arrestin2. This review summarizes the structure and function of β-arrestin2 and reveals the mechanisms involved in the regulation of β-arrestin2 at multiple levels. Additionally, recent studies on the role of β-arrestin2 in some major diseases and its therapeutic prospects have been discussed to provide a reference for the development of drugs targeting β-arrestin2., (© 2024 British Pharmacological Society.)

Pharmaceuticals and personal care products (PPCPs) are currently drawing significant attention due to their environmental impact. Electro‐Fenton, one of the advanced oxidation processes (AOPs), is an efficient and comprehensive technology to degrade all kinds of organic pollutants, but the degradation efficiency relies on cathode material. In this work, phosphorus‐doped porous carbon material coated graphite felt (P‐GF) was prepared by adopting phytic acid as a phosphorus source through high temperature solid‐state method. The microstructure and the elements composition of this fabricated material were investigated by SEM, BET and XPS. With phosphorus doping and plenty of carbon porous structures, the hydrophilicity and infiltrating property of the P‐GF had been greatly improved. The prepared P‐GF material enhanced the electrochemical reduction of O2 and could significantly enhance the yield of H2O2. It was used as a cathode to degrade pollutants under a constant potential, and methylparaben (MePa) was chosen as a research model for optimizing the experimental conditions and analyzing the possible degradation pathway. The P‐GF cathode achieved an excellent ability of degrading nearly 100 % of methylparaben within 3 h. The simultaneous removal ability of the P‐GF to four parabens was impressed. Additionally, the P‐GF material exhibited outstanding reusability. [ABSTRACT FROM AUTHOR]

Efficient implementation of a catalyst-integrated cathode-based heterogeneous electro-Fenton (HEF) process usually suffers from the conflict between the optimal potentials of the two targeted reduction reactions (O2 to H2O2 and metal(n+1)+ to metaln+). In addition, the residual H2O2 in the HEF effluent poses a potential environmental risk to aquatic ecosystems and would further make the HEF technology impractical. Herein, a tandem system of dual-cathode HEF and UV radiation is proposed to bypass these issues. In the dual-cathode HEF unit, the air-diffusion cathode (ADC) without aeration and the FeOCl-functionalized graphite felt (FeOCl/GF) perform their respective functions at different operating current densities (100 mA cm−2 for ADC and 5 mA cm−2 for FeOCl/GF) to achieve efficient H2O2 production, ˙OH formation and Fe(III) electroreduction simultaneously. Subsequently, the underutilized H2O2 in the HEF effluent will be reactivated in the UV module to eliminate the risk of oxidant residues while further improving the decontamination efficiency. Importantly, interesting antagonistic and synergistic phenomena governed by the cathodic current density of the ADC in this tandem system were also highlighted by constructing different standalone/coupled processes. The HEF/UV tandem strategy proposed in the present work offers a promising scheme for distributed wastewater treatment due to the demonstrated preeminent process efficiency, as well as the reagent- and residual-oxidant-free green chemistry concept. [ABSTRACT FROM AUTHOR]

Muscle weakness is a hallmark of inherited or acquired myopathies. It is a major cause of functional impairment and can advance to life-threatening respiratory insufficiency. During the past decade, several small-molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review, we provide an overview of the available literature and the mechanisms of action of small-molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin. We also discuss their use in the treatment of skeletal myopathies. The first of three classes of drugs discussed here increase contractility by decreasing the dissociation rate of calcium from troponin and thereby sensitizing the muscle to calcium. The second two classes of drugs directly act on myosin and stimulate or inhibit the kinetics of myosin-actin interactions, which may be useful in patients with muscle weakness or stiffness. [ABSTRACT FROM AUTHOR]

Nowadays, carbon‐based materials applied to the development of chemically modified sensors have been highlighted once they can generate methods with high sensitivity, stability, conductivity, accuracy and low cost. Hence, these sensors have been used in environmental monitoring in aneco‐friendlyy, sensitive, fast, efficient, inexpensive and robust way. In this review, firstly we described about carbon‐based materials and their derivatives, followed by the chemically modified carbon‐based sensors manufacturing overview and their applications in environmental analytical chemistry related to inorganic and organic compounds determinations. Future perspectives on trends of the carbon‐based materials applications in the sensor modifications are also described. [ABSTRACT FROM AUTHOR]

The integrated steel industry is considered as one of the important industrial sectors, and its outputs are inputs for other sectors including construction, engineering, medical and scientific equipment, and defence. Massive production, consumption, and export of steel signify a country's economic index. This review outlines the World's steel production quantities, the processes involved, and wastewater generation from the industry and its treatment. Wastewater generated from steel plants is highly complex and requires intensive treatment before discharge into natural water bodies. Technologies adopted for treating wastewater generated from steel industries are deliberated, focusing on coking wastewater treatment. Microbial mediated processes provide an effective means of degrading the contaminants, but the toxicity of certain compounds during higher pollutant load inhibits its further treatment. However, these processes can be integrated with either electrochemical technologies or advanced oxidation processes (AOPs), which can reduce the toxicity level. Hence, when a highly concentrated and complex mixture of contaminants is considered, an integrated approach is a resourceful option in terms of cost‐effectiveness and treatment efficiency. [ABSTRACT FROM AUTHOR]

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca2+ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations. [ABSTRACT FROM AUTHOR]

Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of Morus alba) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels–Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gastrointestinal side effects. In this study, chalcomoracin was effectively isolated from mulberry leaves, and its α-glucosidase inhibition was studied via enzymatic kinetics, isothermal titration (ITC) and molecular docking. The results showed that chalcomoracin inhibited α-glucosidase through both competitive and non-competitive manners, and its inhibitory activity was stronger than that of 1-doxymycin (1-DNJ) but slightly weaker than that of acarbose. ITC analysis revealed that the combination of chalcomoracin and α-glucosidase was an entropy-driven spontaneous reaction, and the molecular docking results also verified this conclusion. During the binding process, chalcomoracin went into the "pocket" of α-glucosidase via hydrophobic interactions, and it is linked with residues Val544, Asp95, Ala93, Gly119, Arg275 and Pro287 by hydrogen bonds. This study provided a potential compound for the prevention and treatment of diabetes and a theoretical basis for the discovery of novel candidates for α-glycosidase inhibitors. [ABSTRACT FROM AUTHOR]

Environmental problems of great complexity arise from the enormous number of toxic substances that are generated by anthropogenic activities. Seemingly, society encounters new issues every day thus these problems seem to be endless. Now in the face of the COVID‐19 pandemic and the SARS‐CoV‐2 crisis, a large number of emerging treatment compounds generated by pharmaceutical companies worldwide makes future issues even more treacherous. For this reason, there is an increasing need to detect and treat emerging compounds to prevent them from becoming persistent pollutants. This review describes the advances in the use of electrochemical sensors with modified carbon‐based electrodes among other issues, to determine antibiotics, anti‐inflammatories and antidepressants levels in the environment. It further explores technologies suggested for cleaning wastewater polluted by pharmaceutical products using biological or advanced oxidation processes including photolysis, photocatalysis, microwave heating, ultrasound, Fenton, electro‐Fenton, photoelectro‐Fenton and various combined treatments. [ABSTRACT FROM AUTHOR]

Primarily caused by chronic cigarette smoking (CS), emphysema is characterized by loss of alveolar cells comprising lung units involved in gas exchange and inflammation that culminate in airspace enlargement. Dysregulation of sphingolipid metabolism with increases of ceramide relative to sphingosine-1 phosphate (S1P) signaling has been shown to cause lung cell apoptosis and is emerging as a potential therapeutic target in emphysema. We sought to determine the impact of augmenting S1P signaling via S1P receptor 1 (S1P1) in a mouse model of CS-induced emphysema. DBA2 mice were exposed to CS for 4 or 6 mo and treated with pharmacological agonists of S1P1: phosphonated FTY720 (FTY720-1S and 2S analogs; 0.01-1.0 mg/kg) or GSK183303A (10 mg/kg). Pharmacological S1P1 agonists ameliorated CS-induced lung parenchymal apoptosis and airspace enlargement as well as loss of body weight. S1P1 agonists had modest inhibitory effects on CS-induced airspace inflammation and lung functional changes measured by Flexivent, improving lung tissue resistance. S1P1 abundance was reduced in chronic CS-conditions and remained decreased after CS-cessation or treatment with FTY720-1S. These results support an important role for S1P-S1P1 axis in maintaining the structural integrity of alveoli during chronic CS exposure and suggest that increasing both S1P1 signaling and abundance may be beneficial to counteract the effects of chronic CS exposure. [ABSTRACT FROM AUTHOR]

Highly functional 3D biological systems, which are ordinary in this physical world, suggest that traditional planar/flat materials when assembled into 3D variants, can deliver significantly higher levels of functionality and efficiency. Thanks to its set of unique properties, diamond has received significant recognition as the material of choice for a variety of functional platforms, however, implementation of diamond in real‐world applications has lagged behind alternative materials, which offer a greater degree of versatility. In this regard, for applications to benefit from diamond‐specific properties, approaches on fabrication of diamond beyond the common planar form in a practical and scalable manner are required today. Capitalizing on the ability to synthesize diamond over large areas, this study demonstrates fabrication of porous boron‐doped diamond (BDD) in freestanding form and on wafer‐compatible sizes. Porous BDD electrodes deliver robust electrochemical stability and exceptional electrical characteristics. Aiming to utilize the full potential of diamond properties, this study examines the impact of the BDD porous structure on the ability of electrodes to effectively remove organic pollutants from simulated wastewater and to provide enhanced sensitivity/selectivity of biologically active compounds. This study represents an important step in achieving diamond with extended functionality suitable for industrial/commercial scale implementation. [ABSTRACT FROM AUTHOR]

In this study, a new high performance liquid chromatography (HPLC) analysis method was developed for the simultaneous determination of flurbiprofen (F) and thiocolchicoside (T) in pharmaceutical products. A C18 column (Agilent Poroshell 120 EC-C18) was used as the stationary phase. Elution of the analytes was achieved by using gradient elution system. Mobile phase A was an acetate buffer (100 mM, pH 4.8) and mobile phase B was acetonitrile. The flow rate for the method developed was 0.5 ml/min. The temperature of the column compartment was set at 40°C and the injection volume was 5 µl. Monitoring of the analytes was carried out at 248 nm. The method was found linear in the concentration range between 5-100 ppm. The correlation coefficient value was calculated as 0.999 for F and 0.999 for T. The method was found suitable in terms of accuracy, precision, specificity, linearity, and robustness ruggedness. Furthermore, it was applied successfully for the analysis of commercial tablets and gel samples that contains F and T without any time-consuming pre-procedure. The recovery values for Fand T were found as 99.5% and 97.0% in tablet formulations and 98.6% and 99.3% in gel formulations, respectively. All results were acceptable and this confirmed that the method is suitable for its intended use in routine quality control and an assay of drugs. [ABSTRACT FROM AUTHOR]

Mycoplasma is a bacterium that lacks a cell wall around its cell membrane, that makes it naturally resistant to antibiotics such as beta-lactams, which target cell wall synthesis. These bacteria can be parasitic or saprotrophic. Several species of these bacteria are pathogenic in humans, including M. pneumoniae and M. genitalium. Mycoplasma pneumoniae infection occurs worldwide and is more prevalent in colder months. It affects mainly children aged 5 to 9 years. It is spread by close personal contact and has a long incubation period. Ureaplasma urealyticum is spread primarily through sexual contact. Women may be asymptomatic reservoirs. Mycoplasma species are usually sensitive to tetracyclines, macrolides, and the newer quinolones. Tetracycline or erythromycin is recommended for treatment of M. pneumoniae, although effective treatment of the symptoms usually is not accompanied by eradication of the organism from the infected host. The antibiotic-resistant strains of Mycoplasma spp. are increasing worldwide, therefore, the aim of this review was to assess new methods and approaches for treatment of infections caused by Mycoplasma species. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine‐1‐phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so‐called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs. [ABSTRACT FROM AUTHOR]

Aim: Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5‐fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m2 every 3 weeks. However, every 2 weeks administration at 2 mg/m2 demonstrated a favourable toxicity profile. Method: We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m2) and every 3 weeks TOMOX (RTX 3 mg/m2). Results: A three‐compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48‐10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates‐based dose was calculated, leading to less variability in AUC than observed with the actual BSA‐based or fixed doses. Conclusion: These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA. [ABSTRACT FROM AUTHOR]

Arsenite removal from aqueous medium is quite challenging as most of the conventional methods fail to exhibit arsenite removal completely. The present article examines the possibility of electrochemical advanced oxidation processes to remove arsenite from water medium. Anodic oxidation and electro‐Fenton processes failed to remove generated arsenate in the system but found effective to oxidize arsenite completely from its initial concentrations of 1 mg/L and 10 mg/L. Arsenite oxidation is mainly due to in‐situ generated hydrogen peroxide and hydroxyl radicals for anodic oxidation and electro‐Fenton processes. However, peroxicoagulation process was found effective for the oxidation of arsenite as well as removal of arsenic in water. Complete removal of arsenic was observed within 30 min of electrolysis time for pH range in between 3 to 11. Overall, peroxicoagulation is an effective way to remove arsenic from aqueous solution. [ABSTRACT FROM AUTHOR]

Micron‐sized supraparticles, consisting of a plurality of discrete nano‐ and microscale functional units, are assembled and fused by means of a droplet extrusion process. By combining nano magnetite, activated carbon, and conductive carbon with a polymeric binder matrix, particles are obtained which unite good magnetic properties, electrical conductivity, and adsorber activity through the high accessible surface area of the incorporated activated carbon of about 570 m2 g−1, thereby enabling a new approach toward sustainable water treatment processes. Due to the interplay of the components, it is possible to adsorb target substances, dissolved in the water which is demonstrated by the adsorption of the model dye methylene blue. A very fast adsorption kinetic and an adsorption capacity of about 400 mg g−1 is determined. By using the developed composite particles, it is also possible to electrochemically alter substances flowing through a magnetically‐stabilized fluidized‐bed reactor by electrochemically charging/discharging, significantly supported by the magnetic field enabling alternatingly optimum mobility/adsorption phases with contact/charging intervals. The electrochemical conversion can be increased up to 151% depending on the applied flow‐rate and electrical voltage. By applying an external magnetic field, a further increase of electrochemical conversion of up to 70% can be observed. [ABSTRACT FROM AUTHOR]

In this work, the detection and quantification of p‐benzoquinone (BQ) was performed by differential pulse voltammetry (DPV) with a diamond film sensor. The calibration curve and the limits of detection and quantification for BQ were estimated. DPV was compared to high‐performance liquid chromatography (HPLC) analysis, leading to a satisfactory result in terms of stability and sensitive response. As a novel aim, a combined electrochemical method for environmental application has been developed to oxidize and detect BQ using diamond films. A set of galvanostatic electrochemical oxidation experiments with 130 mL of BQ solution were accomplished in order to understand the effect of current density, the concentration of the pollutant and the initial pH using different electrolytes with similar conductivity. The optimal operating conditions were achieved at 33.3 mA cm−2, 100 mg L−1 of BQ at pH 5.0 with 50 mM Na2SO4. Additionally, the evolution of short‐chain carboxylic acids of that test was followed over time in order to suggest a possible degradation route. The results were described and discussed in the light of the existing literature. [ABSTRACT FROM AUTHOR]

Boron‐doped diamond (BDD) electrodes are widely used in electrochemical sensing and water purification owing to their chemical and structural stability under harsh reaction conditions. Water oxidation at BDD electrodes is known to produce reactive oxygen species, but the discharged and surface chemistries involved in these processes have not been studied in depth. Here, we present scanning electrochemical microscopy (SECM) studies of electrogenerated intermediates and products formed on sp2 carbon‐containing BDD electrodes that display stark differences in their reactivity as a function of electrolyte type and pH during water oxidation. The most reactive and abundant species discharged from the electrode were observed at pH 11 in sulfate electrolyte. With the surface interrogation mode of SECM, two kinetically distinct surface intermediates were clearly distinguished, with one forming two orders of magnitude faster than the other but displaying a slower desorption rate. The surface coverage of these species was estimated in the range of 4–7×10−5 mol/cm2 for the first, and 3–4.4×10−5 mol/cm2 for the second one. SECM imaging suggested that regions of increased product evolution have decreased electron transfer kinetics and limited surface sites for intermediate binding. This work establishes methods for studying highly reactive intermediates found in BDD and paves the way for the inspection of other interfaces where solvolysis impacts their reactivity and evolution. [ABSTRACT FROM AUTHOR]

The removal of hazardous organic micropollutants in municipal wastewater treatment plants (WWTP) has become a common concern for public decision‐makers and stakeholders. An advanced electro‐oxidation with boron‐doped diamond (BDD) anode material is proposed to remove acetaminophen as a representative micropollutant in synthetic solution. A customized microfluidic reactor was run in batch mode, and the main operating parameters (i. e. current density, interelectrode distance and solution conductivity) were optimized by minimizing the energy requirement. An optimal current density of 4 mA cm−2 and an optimal interelectrode distance of 500 μm were newly obtained and explained. Mass transport limitation was observed at lower gaps, with a 3.4‐fold decrease in the mass transfer coefficient from 500 μm to 50 μm intervals. In addition, the kinetics of degradation decreased dramatically after a certain electrolysis time. This was attributed to the increase in gas bubble production with treatment time. An increase in the solution conductivity from 0.23 to 2.0 mS cm−1 increased the degradation rate efficiency twofold and decreased the specific energy from 0.88 to 0.17 kWh g−1 at 85 % acetaminophen decay yield. The influence of a real matrix from low‐conductivity reclaimed WWTP (0.86 mS cm−1) highlighted slightly lower kinetics of degradation, but similar energy efficiency until 60 % of pollutant degradation and higher energy efficiency than in conventional macro‐reactors. [ABSTRACT FROM AUTHOR]

Background: Diabetic ketoacidosis at type 1 diabetes diagnosis is a preventable life-threatening complication. Canadian data on the temporal trends of the prevalence of diabetic ketoacidosis at the onset of type 1 diabetes in children are unknown. We aimed to determine the temporal changes in diabetic ketoacidosis prevalence at diabetes diagnosis in Quebec. Methods: We conducted a population-based cohort study of children (aged 1–17 yr) living in Quebec who were diagnosed with diabetes between 2001 and 2014, using multiple health administrative linked databases available at the Institut national de santé publique du Québec through the Quebec Integrated Chronic Surveillance System. We used multivariate Poisson regression analysis with robust error variance to determine trends in the prevalence of diabetic ketoacidosis. Results: We found that 25.6% (1471/5741) of children presented with diabetic ketoacidosis at diabetes diagnosis. The incidence of diabetes was stable at 30 cases per 100 000 children per year during the study period. The age- and sex-standardized rates of diabetic ketoacidosis increased from 22% (95% confidence interval [CI] 17%–26%) in 2001 to 30% (95% CI 24%–36%) in 2014. The relative increase of diabetic ketoacidosis prevalence at diabetes diagnosis over the study period was 2.0% per year (rate ratio 1.02; 95% CI 1.01–1.03). Interpretation: Despite a stable incidence of type 1 diabetes, we found that the prevalence of diabetic ketoacidosis at diabetes onset increased between 2001 and 2014. Our findings are concerning and demonstrate a need to continue to campaign to recognize type 1 diabetes before diabetic ketoacidosis supervenes. [ABSTRACT FROM AUTHOR]

Cancer is a clinical situation caused by uncontrolled cell division and is responsible for a large number of deaths worldwide. Colchicine is a classical antimitotic, tubulin-binding agent (TBA) which is being explored for its antitumor activities, although its tubulin-binding ability leads to some toxicity toward normal cells proliferation. Colchicine derivatives are considered as potent antitumor compounds with less toxicity compared to colchicine. Derivatives with substituted functional groups at A-ring (methoxy), B-ring (acetamide) or C-ring (methoxy) have been synthesized via chemical and microbial routes and show modified bioactivities and altered tropolonic functionality. Earlier reports, in combination with our group’s research findings, suggest that microbial biotransformation is an efficient choice for the production of bioactive colchicine derivatives. This route has gained significant interest in the mass production of regio-specific, cost-effective, safe and eco-friendly derivatives. The present review paper critically analyzes and discusses the development and application of colchicine derivatives as a potent antitumor molecule and their production through a microbial transformation process. The information provided in this review might assist in the stimulation of new ideas regarding the development of alternative therapeutic agent(s) for cancer treatment. [ABSTRACT FROM PUBLISHER]

Heparin mimetics are synthetic and semi-synthetic compounds that are highly sulfated, structurally distinct analogues of glycosaminoglycans. These mimetics are often rationally designed to increase potency and binding selectivity towards specific proteins involved in disease manifestations. Some of the major therapeutic arenas towards which heparin mimetics are targeted include: coagulation and thrombosis, cancers, and inflammatory diseases. Although Fondaparinux, a rationally designed heparin mimetic, is now approved for prophylaxis and treatment of venous thromboembolism, the search for novel anticoagulant heparin mimetics with increased affinity and fewer side effects remains a subject of research. However, increasingly, research is focusing on the non-anticoagulant activities of these molecules. Heparin mimetics have potential as anti-cancer agents due to their ability to: (1) inhibit heparanase, an endoglycosidase which facilitates the spread of tumor cells; and (2) inhibit angiogenesis by binding to growth factors. The heparin mimetic, PI-88 is in clinical trials for post-surgical hepatocellular carcinoma and advanced melanoma. The anti-inflammatory properties of heparin mimetics have primarily been attributed to their ability to interact with: complement system proteins, selectins and chemokines; each of which function differently to facilitate inflammation. The efficacy of low/non-anticoagulant heparin mimetics in animal models of different inflammatory diseases has been demonstrated. These findings, plus clinical data that indicates heparin has anti-inflammatory activity, will raise the momentum for developing heparin mimetics as a new class of therapeutic agent for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: EP217609 is a parenteral antithrombotic compound combining in one molecule an indirect anti-factor Xa inhibitor, a direct thrombin active site inhibitor and a biotin moiety. Aims: The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609. Methods: In this randomised double-blind placebo-controlled study, healthy male subjects were administered intravenously single ascending doses (1, 3 or 10 mg) of EP217609 or placebo. Each treatment group consisted of 10 subjects of whom 8 received EP217609 and 2 received placebo. Results and conclusions: All doses of EP217609 were well tolerated. A total of five treatment-emergent adverse events were reported, all considered unrelated, but no bleedings or other significant adverse events occurred during this study. In both plasma and urine, there was a strong correlation between EP217609 concentrations as measured by anti-factor IIa and Xa specific bioassays indicating that the two pharmacological activities of EP217609 did not dissociate in vivo. EP217609 pharmacokinetics were dose proportional and characterised by a low clearance, a small volume of distribution and a terminal half-life of 20.4 h. The long half-life was reflected in long-lasting, dose-dependent effects on activated and ecarin clotting time, thrombin and prothrombin time, activated partial thromboplastin time, thrombin generation time and anti-factor Xa activity. Pharmacokinetic/pharmacodynamic modelling indicated that the concentration of EP217609 producing 50 % of the pharmacodynamic effect was 3400 and 2210 ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609. What is already known about this subject: • There is a limited number of neutralisable anticoagulants, particularly when rapid neutralisation is required. • Synthetic anti-Xa compounds have predictable pharmacokinetic profiles. However, problems with thrombin rebound remain because of the inability to inhibit clot-bound thrombin. What this study adds: • This manuscript provides a comprehensive investigation of the pharmacokinetics, pharmacodynamics and safety of EP217609, and the results were the basis of future clinical studies in both healthy subjects and patients. • The pharmacokinetic/pharmacodynamic modelling provided information for dose selection in such future studies. [ABSTRACT FROM AUTHOR]

With the development of the new direct oral anticoagulants, many of the unmet needs of the vitamin K antagonists were fulfilled, such as the absence of dietary interactions, few drug interactions, predictable effects and no need for monitoring. However, growing experience with the direct oral anticoagulants indicates there is still room for improvement. Developing antithrombotic agents that optimize their antithrombotic effect while producing little or no risk of bleeding is a long sought after goal. This and other enhanced attributes of candidate drugs are on the horizon. [ABSTRACT FROM AUTHOR]

With an increased number of applications in the field of the avidin-biotin technology, the resulting demand for highly-purified protein avidin has drawn our attention to the purification process of avidin that naturally occurs in chicken egg white. The high-throughput process development (HTPD) methodology was exploited, in order to evaluate purification process alternatives to commonly used ion-exchange chromatography. In a high-throughput format, process parameters for aqueous two-phase extraction, selective precipitation with salts and polyethylene glycol, and hydrophobic interaction and mixed-mode column chromatography experiments were performed. The HTPD strategy was complemented by a high-throughput tandem high-performance liquid chromatography assay for protein quantification. Suitable conditions for the separation of avidin from the major impurities ovalbumin, ovomucoid, ovotransferrin, and lysozyme were identified in the screening experiments. By combination of polyethylene glycol precipitation with subsequent resolubilization and separation in a polyethylene glycol/sulfate/sodium chloride two-phase system an avidin purity of 77% was obtained with a yield >90% while at the same time achieving a significant reduction of the process volume. The two-phase extraction and precipitation results were largely confirmed in larger scale with scale-up factors of 230 and 133, respectively. Seamless processing of the avidin enriched bottom phase was found feasible by using mixed-mode chromatography. By gradient elution a final avidin purity of at least 97% and yield >90% was obtained in the elution pool. The presented identification of a new and beneficial alternative for the purification of the high value protein thus represents a successful implementation of HTPD for an industrially relevant purification task. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:957-973, 2015 [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a prevalent disease with potential serious consequences. Idraparinux and idrabiotaparinux are two kinds of long-acting pentasaccharides. Evidence has shown that idraparinux and idrabiotaparinux are effective anticoagulants. However, up to now, there is no consensus on whether they are better than other anticoagulation methods for long-term VTE treatment. Objective: To evaluate the effect of idraparinux or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment. Methods: We searched Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of science, clinical trial registry web sites (clinical trials,WHO clinical trial registry), Googlescholar, PubMed related articles and companies' web sites electronically up to Dec 30th, 2012 and manually searched the reference lists and conference proceedings. Only randomized controlled trial (RCT) involving adult patients comparing idraparinux and/or idrabiotaparinux versus other anticoagulation methods for long-term VTE treatment was included. Two reviewers evaluated the studies and extracted data independently. Pooled risk ratios (RRs) were calculated as outcome measures and Revman 5.2 software was used to analyze data. Our primary efficacy and safety outcomes were the recurrent VTE and major bleeding rates. Results: We included four RCTs and involved 8584 participants on idraparinux or idrabiotaparinux versus standard warfarin for VTE treatment from 9364 references. We did not perform meta-analysis on the VTE rate because of the significant heterogeneity. We used the fixed effect model to analyze the safety outcomes and demonstrated that idraparinux or idrabiotaparinux decreased major bleeding rate significantly (RR 0.73, 95% CI 0.54 to 0.98, P = 0.04) but had a trend to increase the all cause mortality (RR 1.26, 95% CI 1.00 to 1.57, P = 0.05) compared with warfarin. Conclusions: Until now there is not sufficient evidence to clarify whether idraparinux or idrabiotaparinux is as effective and safe as the standard warfarin treatment for VTE treatment. [ABSTRACT FROM AUTHOR]

Despite the availability of comprehensive evidence-based guidelines there are difficult and controversial areas in the management of venous thromboembolism. Institutions and even countries disagree on the importance of calf vein thrombosis, with some rigorously detecting and treating it and others deliberately not looking for it. The need to treat proximal deep vein thrombosis and pulmonary embolism is accepted but which patients with an unprovoked first event should have long-term anticoagulation has become a difficult clinical decision. We are uncertain how to reduce the incidence of post-thrombotic syndrome seen in a substantial number of patients. How hard to look for an undiagnosed underlying cancer has become a contentious issue particularly in the United Kingdom following the recent publication of a guideline from the National Institute for Health and Clinical Excellence. Whilst we are wrestling with these dilemmas we are entering an era of new anticoagulants and have to solve the logistical problems of introducing them into clinical practice despite cost pressures. These issues will be explored in this review. [ABSTRACT FROM AUTHOR]