Green synthesis of carbon nanotubes functionalized with iron nanoparticles and coffee husk biomass for efficient removal of losartan and diclofenac: Adsorption kinetics and ANN modeling studies.

The presence of emerging contaminants in wastewater poses a global environmental challenge, requiring the development of innovative materials or methods for their treatment. This study focused on the production of green functionalized carbon nanotubes (CNTs) and using them in the adsorption of the pharmaceuticals Losartan (LOS) and Diclofenac (DIC). The efficiency of the methodology was verified by characterization techniques. Elemental composition analysis indicated a significant increase in the iron content after the green functionalization, proving the effectiveness of the method. Thermogravimetric analysis showed similar thermal degradation profiles for pristine CNTs and functionalized CNTs, indicating better post-functionalization thermal stability. BET analysis revealed mesoporous characteristics of CNTs, with increased surface area and pore volumes after functionalization. X-Ray diffraction confirmed the preservation of the lattice structure of the CNTs post-functionalization and post-adsorption, with changes in peak broadening suggesting surface modifications. LOS and DIC adsorption were evaluated via kinetic studies at four different concentrations (0.1-0.4 mmol/L) that were best represented by the pseudo-second order model, suggesting chemisorption mechanisms, with faster and higher uptakes for DIC (0.084-0.261 mmol/g; teq = 5 min) when compared to LOS (0.058-0.235 mmol/g; teq = 20 min). The curves were also studied via artificial neural networks (ANN) and revealed that the best ANN architecture for representing the experimental data is a network with [3 5 5 2] neurons trained using the Bayesian-Regularization algorithm and the Log-sigmoid (hidden layers) and Linear (output layer) transfer functions. The desorption study showed that CaCl2 had better performance in CNT regeneration, reaching its removal capacity above 50% up to 3 cycles, for both pharmaceuticals. These findings reveal the potential of the developed material as a promising adsorbent for targeted removal of pollutants, contributing to advances in the remediation of emerging contaminants and the application of artificial intelligence in adsorption research.

Telmisartán y losartán: las marcadas diferencias entre sus propiedades químicas y farmacológicas pueden explicar la diferencia en la eficacia terapéutica en pacientes hospitalizados con covid-19 / Telmisartan and losartan: marked differences in chemical and pharmacological properties may explain differences in therapeutic efficacy in hospitalized patients with COVID-19

El objetivo de este artículo es comparar las propiedades químicas y farmacológicas del telmisartán y el losartán, y su metabolito activo EXP3174, con el fin de entender por qué el telmisartán es efectivo en pacientes hospitalizados con Covid-19 mientras que el losartán no lo es. Se llevó a cabo una revisión bibliográfica exhaustiva de las propiedades químicas, farmacocinéticas y farmacodinámicas de ambos fármacos y se destacaron las diferencias más importantes que podrían estar relacionadas con su efectividad en pacientes con Covid-19. Se concluyó que las propiedades farmacológicas del telmisartán, como su mayor afinidad por el receptor AT1, su duración de acción prolongada y su capacidad para modular la inflamación podrían explicar su efectividad en pacientes con Covid-19. Por otro lado, las propiedades farmacológicas del losartán, como su menor afinidad por el receptor AT1 y su rápido metabolismo, pueden limitar su efectividad en pacientes con Covid-19. Estos resultados resaltan la importancia de comprender las propiedades químicas y farmacológicas de los medicamentos para identificar posibles candidatos terapéuticos efectivos en el tratamiento de Covid-19. (AU)

The objective of this article is to compare the chemical and pharmacological properties of telmisartan and losartan and their active metabolite EXP3174 to understand why telmisartan is effective in hospitalized patients with COVID-19 while losartan is not. A comprehensive literature review of the chemical, pharmacokinetic and pharmacodynamic properties of both drugs was done to highlight the most important differences that may be related to their efficacy in patients with COVID-19. It was concluded that the pharmacological properties of telmisartan, such as its higher affinity for the AT1 receptor, its long duration of action and its ability to modulate inflammation, could explain its efficacy in patients with COVID-19. On the other hand, the pharmacological properties of losartan, such as its lower affinity for the AT1 receptor and its rapid metabolism, may limit its efficacy in patients with COVID-19. These results highlight the importance of understanding the chemical and pharmacological properties of drugs to identify potential effective therapeutic candidates for the treatment of COVID-19. (AU)

Candesartan, losartan and valsartan Zn(II) complexes interactions with bovine serum albumin.

Background: The pharmacological response and the therapeutic efficacy of a drug depends on the interactions with plasma proteins. Methodology: The interaction of bovine serum albumin (BSA) with the metal complexes of antihypertensive drugs, Zn(II)/sartan complexes (candesartan, valsartan and losartan), was investigated using fluorescence quenching determinations at different temperatures. Results: The binding studies of the compounds with BSA showed static quenching and moderate binding with calculated constants in the range of 104-106 M-1, indicating potent serum distribution via albumins. In all cases, negative values of free energy are indicative of spontaneous processes and the stabilization of BSA/compound complexes through hydrogen bonding and van der Waals forces. The results for the sartans agree with the reported pharmacokinetics studies. Conclusion: It has been determined that the three sartans and the Zn complexes could be transported and distributed by albumin.

Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

High-resolution continuum source graphite furnace atomic absorption spectrometry for screening elemental impurities in drugs to adhere to the new international guidelines.

New guidelines for the limits of elemental impurities in drug products were introduced by the International Council for Harmonization in 2014. While the guidelines define a limit for each element, the complete quantification of the 24 elements included is, in fact, unnecessary. An accurate "pass/fail" test to determine whether the threshold was exceeded or not could be valuable in this context. In this study, a screening procedure using the features of high-resolution continuum source graphite furnace atomic absorption spectrometry for the evaluation of 12 elements in three different drugs was developed. The three-dimensional absorbance spectrum including time and wavelength in the vicinity of the main line of the element allows for a pass/fail decision related to the presence or absence of the element in the sample. Additionally, the bi-dimensional absorbance-wavelength spectrum defines the elements captured in the window when additional peaks are seen in the spectrum. The analysis of the selected drugs included sample digestion, the definition of pyrolysis and atomization temperatures, determination of the limit of detection and other validation parameters for each element. The evaluation of the spectra, both three- and bi-dimensional, revealed that only three elements, Cr, Ni, and Cu, were present in the samples in amounts above the LOD and therefore "fail" in the test. Nevertheless, they were quantified, and the analysis revealed that their levels were below the permitted daily exposure, which are at least 6 times higher than the LOD of the selected elements. Operating in a routine mode, the proposed method is a good option for the evaluation of elemental impurities in drug active ingredients or drug final products.

Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution.

This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method.

Advanced oxidation of antihypertensives losartan and valsartan by photo-electro-Fenton at near-neutral pH using natural organic acids and a dimensional stable anode-gas diffusion electrode (DSA-GDE) system under light emission diode (LED) lighting.

In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED)-type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42 mA/cm2 after 90 min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90 min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (•OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to-metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system.

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents.

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.

Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases.

A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)2].3H2O (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 µM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO4 showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 µM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO4, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 µM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO4 at concentrations higher than 200 µM displays cytotoxic effects. Graphical abstract Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases.

Thermodynamic compatibility between cyclodextrin supramolecular complexes and surfactant.

Supramolecular structures based on cyclodextrins have been extensively used for drug delivery systems over decades. However, combining host and guest molecules in a pharmaceutical formulation is not a trivial process, being one of the majors concern the inclusion complex compatibility with other excipients presented in the final formulation. Herein, experimental and theoretical calculations were used to investigate the competition of sodium dodecyl sulfate (SDS) with atenolol (ATE) or losartan (LOS), antihypertensive drugs widely used in the treatment of hypertension. Our findings, using nuclear magnetic resonance and isothermal titrations calorimetry experiments and molecular dynamic simulations demonstrated that LOS remain included into CD cavity after excipient (SDS) addition, which was not verified for ATE ternary system, being the drug displaced by SDS molecule.

A clean photometric method for the determination of losartan potassium in pharmaceuticals exploiting light scattering effect and employing a multicommuted flow analysis approach.

This paper describes an environmentally friendly procedure for the determination of losartan potassium (Los-K) in pharmaceuticals. The photometric method was based on the light scattering effect due to particles suspension, which were formed by the reaction of Los-K with Cu (II) ions. The method was automated employing a multicommuted flow analysis approach, implemented using solenoid mini-pumps for fluid propelling and a homemade LED based photometer. Under the optimized experimental conditions, the procedure showed a linear relationship in the concentration range of 23.2-417.6mgL-1 (r=0.9997, n=6), a relative standard deviation of 1.61% (n=10), a limit of detection (3.3*σ) estimated to be 12.1mgL-1, and a sampling rate of 140 determinations per hour. Each determination consumed 12µg of copper (II) acetate and generated 0.54mL of waste.

Control of size in losartan/copper(II) coordination complex hydrophobic precipitate.

Reaction of highly soluble orally active, non-peptide antihypertensive drug losartan with copper(II) leads to the spontaneous formation of a very insoluble 2:1 covalent complex, which self assembles in a hydrophobic supramolecular structure of nanometric dimensions. Thermal analysis showed that Los/Cu(II) complex presents intermediate stability in comparison with its precursors KLos and Cu(OAc)2·H2O. Isothermal titration calorimetry indicated complexation to be a stepwise process, driven by enthalpy and entropy. Zeta potential and DLS measurements showed that it is possible to control the size and charge of nanoprecipitates by adjusting the relative concentration of Los(-) and Cu(II).

The coronary endothelium behaves as a functional diffusion barrier for intravascular Angiotensin II.

Diverse intracoronary hormones cause their cardiac effects solely via activation of their coronary endothelial luminal membrane (CELM) receptors. To test this hypothesis for Ang II, we synthesized: a) two large polymers of Ang II (Ang II-POL) and Losartan (Los-POL) which act only in the CELM's AT1R because they cannot cross the endothelial barrier and b) biotin-labeled Ang II (Ang II-Biotin) and Ang II-POL-Biotin to be identified by microscopy in tissues. Sustained coronary perfusion of Ang II (potentially diffusible) or Ang II-POL caused a positive inotropic effect (PIE) and an increase in coronary perfusion pressure (CPP) of equal magnitude that were blocked by Losartan and Los-POL. However, Ang II effects, in contrast to Ang II-POL effects, were transient due to desensitization and resulted in tachyphylaxis to a second administration of Ang II or Ang II-POL. Furthermore, if Ang II and Ang II-POL acted differently on the same receptor; a competition of effects would be expected. This was demonstrated by infusing simultaneously a molar ratio of Ang II:Ang II-POL. As this molar ratio decreased, Ang II-induced desensitization and tachyphylaxis decreased. Intravascularly-administered Ang II-Biotin and Ang II-POL-Biotin remained bound and confined to the endothelium. Our results support the hypothesis and indicate intravascular Ang II, not by mass exchange with the interstitium, but by an action restricted to the CELM's AT1R, causes release of endothelial chemical messengers that exert physiological effects and modulate the effects and metabolism of paracrine Ang II. Endocrine Ang II controls and communicates with its paracrine counterparts solely through endothelial receptors.

Supramolecular interactions between losartan and hydroxypropyl-ß-CD: ESI mass-spectrometry, NMR techniques, phase solubility, isothermal titration calorimetry and anti-hypertensive studies.

In this work, low soluble supramolecular complex between the losartan potassium (Los) and hydroxypropil-ß-cyclodextrin (HPßCD) were characterized throughout phase-solubility, NMR techniques ((1)H and 2D-ROESY) and isothermal titration calorimetry (ITC) in order to attain physical-chemical knowledge of the system. In addition, the hypertensive effect of composition Los/HPßCD was evaluated aiming to obtain a more efficient oral pharmaceutical composition. ESI mass spectrometry and ITC blank experiment demonstrate the presence of Los clusters at 30 mM pure solution. Phase-solubility experiments showed a "Bs" type system, due to the formation of a less soluble complex than pure Los. NMR demonstrated the short distance interactions between the Los and the cyclodextrin, where several possibilities of interactions were observed. ITC data suggest an average 1:1 stoichiometry of Los and the cyclodextrin. The complex demonstrated efficiency in hypertension control, presenting antagonist action on the pressure effect of angiotensin II within 30 h, as compared to Los alone, 6h, indicating that inclusion of Los in HPßCD enhanced the extent and duration of its antagonistic action. In this work, a model of interaction between Los and HPßCD was proposed based on dissociation of self-assembled Los followed by complexation with HPßCD.

Multi-syringe chromatography (MSC) system for the on-line solid-phase extraction and determination of hydrochlorothiazide and losartan potassium in superficial water, groundwater and wastewater outlet samples.

In this paper, a combination of multi-syringe chromatography analysis technique with extraction disks sorbents for the pre-concentration and determination of hydrochlorothiazide and losartan potassium in superficial water, groundwater and wastewater outlet samples has been developed. The system developed was proved for the determination of hydrochlorothiazide and losartan potassium in spiked water samples with recoveries ranging from 95 to 118%. The method involves the on-line enrichment of the targeted analytes from spiked water samples onto a Cation-SR sorbent material. The analytes are subsequently eluted and transported to the monolithic column, Chromolith Flash RP-18e column (25 mmx4.6 mm i.d.). The mobile phase used was 10 mM potassium dihydrogen phosphate (pH 3.0):acetonitrile:methanol (60:30:10 v/v/v), flow-rate 0.8 mL min(-1). UV detection is carried out at 226 nm. Under the optimized chemical and physical variables, the detection limit for hydrochlorothiazide and losartan potassium calculated as 3Syx/b was 0.07 and 0.09 mgL(-1), respectively, for a sample loading volume of 1.0 mL.

A multivariate approach for the simultaneous determination of losartan potassium and hydrochlorothiazide in a combined pharmaceutical tablet formulation.

A convenient new method for the simultaneous determination of losartan potassium and hydrochlorothiazide, with minimum sample pretreatment, is described. The procedure, based on the multivariate analysis of spectral data in the 220-274 nm region by the partial least squares algorithm, is linear in the concentration range 1.06-5.70 mg L(-1) for hydrochlorothiazide and 4.0-22.2 mg L(-1) for losartan. It is simple, rapid and robust, allowing accurate and precise results, with drug recovery rates of 99.3 and 100.4% and relative standard deviations of 1.7 and 1.0% obtained for hydrochlorothiazide and losartan, respectively. The method was applied to the simultaneous determination of both analytes in tablets, and it provided good results which were in statistical agreement with those provided by independent HPLC analyses of the samples. The method has also been successfully applied for the construction of drug dissolution profiles of a commercial pharmaceutical preparation containing both analytes.

Losartan and its interaction with copper(II): biological effects.

Losartan, the potassium salt of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazol, is an efficient antihypertensive drug. The vibrational FTIR and Raman spectra of Losartan (its anionic and protonated forms) are discussed. In addition, the copper(II) complex of Losartan was obtained and characterized as a microcrystalline powder. The metal center is bound to the ligand through the nitrogen atoms of the tetrazolate moiety as determined by vibrational spectroscopy. The compound is a dimer with the metal centers in a tetragonal distorted environment but the presence of a monomeric impurity has been determined by EPR spectroscopy. The antioxidant properties of the complex (superoxide dismutase mimetic activity) and its effect on the proliferation and morphology of two osteoblast-like cells in culture are reported. The new compound exerted more toxic effects on tumoral cells than the copper(II) ion and Losartan.

Losartan potassium, a non-peptide agent for the treatment of arterial hypertension.

In the title compound, potassium 2-butyl-4-chloro-1-[[2'-(5-tetrazolido)biphenyl-4-yl]methyl]-1H-imidazol-5-ylmethanol, K(+) x C(22)H(22)ClN(6)O(-), the imidazole and tetrazole rings are at angles of 85.0 (2) and 51.8 (1) degrees, respectively, to the phenyl rings to which they are attached, while the dihedral angle between the latter two rings is 46.7 (1) degrees. The coordination sphere of the metal cation consists of six tetrazoyl N atoms, the methanol O atom and the pi cloud of one of the phenyl rings. These interactions determine the formation of columns of molecular anions that lie parallel to the b axis, while hydrogen bonding contributes to intercolumnar cohesion. Far from the centre of the columns, the hydrocarbon chain is immersed in a hydrophobic environment.