Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

The acidity constants of the two-fold protonated acyclic 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(9,8aPMEA)±, and its 8-isomer, 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(8,8aPMEA)±, both abbreviated as H2(PA)±, as well as the stability constants of their M(H;PA)+ and M(PA) complexes with the metal ions M2+=Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1M (NaNO3) and 25°C. Application of previously determined straight-line plots of log% MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaWGlbWaa0baaSqaaiaab2eacaqGOaGaaeOuaiaab2cacaqG % qbGaae4taWWaaSbaaeaacaqGZaaabeaaliaabMcaaeaacaqGnbaaaa % aa!4164! $$K_{{\text{M(R-PO}}_{\text{3}} {\text{)}}}^{\text{M}}$$ versus % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGWbGaam4samaaDaaaleaacaqGibGaaeikaiaabkfacaqG % TaGaaeiuaiaab+eammaaBaaabaGaae4maaqabaWccaqGPaaabaGaae % isaaaaaaa!424D! $${\text{p}}K_{{\text{H(R-PO}}_{\text{3}} {\text{)}}}^{\text{H}}$$ for simple phosph(on)ate ligands, % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGsbGaaeylaiaabcfacaqGpbWaa0baaSqaaiaaiodaaeaa % caaIYaGaeyOeI0caaaaa!3F15! $${\text{R-PO}}_3^{2-}$$, where R represents a residue without an affinity for metal ions, proves that for all M(PA) complexes a larger stability is observed than is expected for a sole phosphonate coordination of the metal ion. This increased stability is attributed to the formation of five-membered chelates involving the ether oxygen present in the aliphatic residue (% MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGTaGaae4qaiaabIeadaWgaaWcbaGaaeOmaaqabaGccaqG % TaGaae4taiaab2cacaqGdbGaaeisamaaBaaaleaacaqGYaaabeaaki % aab2cacaqGqbGaae4tamaaDaaaleaacaqGZaaabaGaaeOmaiabgkHi % Taaaaaa!460C! $${\text{-CH}}_{\text{2}} {\text{-O-CH}}_{\text{2}} {\text{-PO}}_{\text{3}}^{{\text{2}}-}$$) of the ligands. The formation degrees of these chelates were calculated; they vary between about 13% for Ca(8,8aPMEA) and 71% for Cu(8,8aPMEA). The adenine residue has no influence on complex stability except in the Cu(9,8aPMEA) and Zn(9,8aPMEA) systems, where an additional stability increase attributable to the adenine residue is observed and equilibria between four different isomers exist. This means (1) an open isomer with a sole phosphonate coordination, M(PA)op, where PA2−=9,8aPMEA2−, (2) an isomer with a five-membered chelate involving the ether oxygen, M(PA)cl/O, (3) an isomer which contains five- and seven-membered chelates formed by coordination of the phosphonate group, the ether oxygen and the N3 site of the adenine residue, M(PA)cl/O/N3, and finally (4) a macrochelated isomer involving N7, M(PA)cl/N7. For Cu(9,8aPMEA) the formation degrees are 15, 30, 48 and 7% for Cu(PA)op, Cu(PA)cl/O, Cu(PA)cl/O/N3 and Cu(PA)cl/N7, respectively; this proves that the macrochelate involving N7 is a minority species. The situation for the Cu(PMEA) system, where PMEA2− represents the parent compound, i.e. the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is quite similar. The relationship between the antiviral activity of acyclic nucleoside phosphonates and the structures of the various complexes is discussed and an explanation is offered why 9,8aPMEA is biologically active but 8,8aPMEA is no

Nickel(II), Copper(II) and Zinc(II) Complexes of 9-[2- (Phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA), the 8-Aza Derivative of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl] adenine (PMEA). Quantification of Four Isomeric Species in Aqueous Solution

The acidity constants of the twofold protonated acyclic nucleotide analogue 9-[2-(phosphonomethoxy)- ethyl]-8-azaadenine, H2(9,8aPMEA)±, as well as the stability constants of the M(H;9,8aPMEA)+ and M(9,8aPMEA) complexes with the metal ions M2+ =Ni2+, Cu2+ or Zn2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1 M (NaNO3) and 25℃. The result for the release of the first proton from H2(9,8aPMEA)+ (pKa= 2.73), which originates from the (N1)H+ site, was confirmed by UV-spectrophotometric measurements. Application of previously determined straight-line plots of log KMM(R-PO3) versus PKH3(R-HPO3)' for simple phosph(on)ate ligands, R- PO-, where R represents a residue without an affinity for metal ions, proves that the primary binding site of 9,8aPMEA2- is the phosphonate group for all three metal ions studied. By stability constant comparisons with related ligands it is shown, in agreement with conclusions reached earlier for the Cu(PMEA) system [PMEA2-=dianion of 9-[2- (phosphonomethoxy)ethyl]adenine], that in total four different isomers are in equilibrium with each other, i.e. (i) an open isomer with a sole phosphonate coordination, M(PA)op, where PA2-=PMEA2-or 9,8aPMEA2-, (ii) an isomer with a 5-membered chelate involving the ether oxygen, M(PA)cl/o, (iii) an isomer which contains 5- and 7-membered chelates formed by coordination of the phosphonate group, the ether oxygen and the N3 site of the adenine residue, M(PA)cl/O/N3, and finally (iv) a macrochelated isomer involving N7, M(PA)cl/]N7. The Cu2+ systems of PMEA2- and 9,8aPMEA2- behave quite alike; the formation degrees for Cu(PA)op, CuM(PA)cl/O, Cu(PA)cl/O/N3 and Cu(PA)cl/N3 are approximately 16, 32, 45 and 7%, respectively, which shows that Cu(PA)cl/N7 is a minority species. In the Ni2+ and Zn2+ systems the open isomer is the dominating one followed by M(PA)cl/O, but there are indications that the other two isomers also occur to some extent

Glyceridic and Unsaponifiable Components of Microencapsulated Sacha Inchi (Plukenetia huayllabambana L. And Plukenetia volubilis L.) Edible Oils

Sacha inchi (Plukenetia huayllabambana L. and Plukenetia volubilis L.) edible oils were microencapsulated and the lipid fraction of the microparticles was characterized. Hi-cap®, Capsule®, Arabic gum, and the binary combination of Arabic gum + maltodextrin and the ternary combination of Arabic gum + maltodextrin + whey protein isolate, were used as coating materials for the encapsulation process using spray-drying. The surface and the total oils obtained from the microparticles were evaluated in terms of fatty acid composition, minor glyceride polar compounds, polymers, oxidized triglycerides, diglycerides, monoglycerides, and free fatty acids, along with their unsaponifiable components, sterols, and tocopherols. Differences between the original oils and the microencapsulated ones were determined. The most remarkable results included the presence of polymers when there were none in the original oils, the slight loss in ¿3-fatty acids, up to 6%, the loss in tocopherols, in some of the cases around 30%, the maintaining of the phytosterol in their initial levels and the presence of cholesterol in the oils encapsulated with whey protein isolate

Ternary Copper(II) Complexes in Solution Formed With 8-Aza Derivatives of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)Ethyl]adenine (PMEA)

The stability constants of the mixed-ligand complexes formed between Cu(Arm)2+, where Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), and the dianions of 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA) and 8-[2-(phosphonomethoxy)ethyl]8-azaadenine (8,8aPMEA) (both also abbreviated as PA2-) were determined by potentiometric pH titrations in aqueous solution (25 °C; I = 0.1 M, NaNO3). All four ternary Cu(Arm)(PA) complexes are considerably more stable than corresponding Cu(Arm)(R-PO3) species, where R-PO3 2- represents a phosph(on)ate ligand with a group R that is unable to participate in any kind of interaction within the complexes. The increased stability is attributed to intramolecular stack formation in the Cu(Arm)(PA) complexes and also to the formation of 5-membered chelates involving the ether oxygen present in the -CH2-O-CH2-PO3 2- residue of the azaPMEAs. A quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PA) species is carried out. For example, about 5% of the Cu(Bpy)(8,8aPMEA) system exist with the metal ion solely coordinated to the phosphonate group, 14% as a 5-membered chelate involving the -CH2-O-CH-2-PO3 2- residue, and 81% with an intramolecular stack between the 8-azapurine moiety and the aromatic rings of Bpy. The results for the other systems are similar though with Phen a formation degree of about 90% for the intramolecular stack is reached. The existence of the stacked species is also proven by spectrophotometric measurements. In addition, the Cu(Arm)(PA) complexes may be protonated, leading to Cu(Arm)(H;PA)+ species for which it is concluded that the proton is located at the phosphonate group and that the complexes are mainly formed by a stacking adduct between Cu(Arm)2+ and H(PA)-. Conclusions regarding the biological properties of these azaPMEAs are shortly indicated

Chemical Characterization of Major and Minor Compounds of Nut Oils: Almond, Hazelnut, and Pecan Nut

The aim of this work was to characterize the major and minor compounds of laboratory-extracted and commercial oils from sweet almond, hazelnut, and pecan nut. Oils from sweet almond, hazelnut, and pecan nut were obtained by means of an expeller system, while the corresponding commercial oils were provided from Vital Âtman (BR). The contents of triacylglycerols, fatty acids, aliphatic and terpenic alcohols, desmethyl-, methyl-, and dimethylsterols, squalene, and tocopherols were determined. Oleic, palmitic, and linoleic acids were the main fatty acids. Desmethylsterols were the principal minor compounds with β-sitosterol being the most abundant component. Low amounts of aliphatic and terpenic alcohols were also found. The major tocopherol in hazelnut and sweet almond oils was α-tocopherol, whereas γ-tocopherol prevailed in pecan nut oil. Principal component analysis made it possible for us to differentiate among samples, as well as to distinguish between commercial and laboratory-extracted oils. Heatmap highlighted the main variables featuring each sample. Globally, these results have brought a new approach on nut oil characterization

Characterization of Glyceridic and Unsaponifiable Compounds of Sacha Inchi (Plukenetia huayllabambana L.) Oils

This work deals with the characterization of the main glyceridic and unsaponifiable components of oils obtained from Sacha inchi (Plukenetia huayllabambana L.) seed ecotypes collected during two harvests in the Department of Amazonas in Peru. The seed-oil yield was 30.3-41.2%; standing out are the high percentages of the ¿3- and ¿6-fatty acids series whose ranges lie within those of the present Regulation for Sacha inchi oils. Triacylglycerols with even equivalent carbon number (ECN; 36-42) were the main components. Minor glyceridic polar compounds such as oxidized triglycerides, diglycerides, monoglycerides, and free fatty acids were determined by high-performance size exclusion chromatography. The low campesterol/stigmasterol ratio (1:6), unusual in the majority of vegetable oils, stands out. Regarding aliphatic hydrocarbons, these oils showed a particular profile for the saturated series of odd and even carbon atom numbers. According to our results Sacha inchi P. huayllabambana oils can be offered as a good alternative to P. volubilis, the species mainly commercialized for this vegetable oil

Simulación para formar en la competencia de valoración preanestésica: diseño común para residentes de primer año de anestesiología y enfermeras de anestesia

Introducción. La valoración preanestésica (VP) es una competencia compleja que debe adquirir el residente de anestesia tempranamente. La incorporación de enfermería especializada en la VP ha demostrado ser segura y eficaz. No existen recomendaciones para el entrenamiento en VP. La simulación puede ser una metodología apropiada para acortar el tiempo de adquisición de la competencia. Objetivo. Describir detalladamente el diseño y aplicación de un taller de simulación para formar residentes de anestesiología y enfermeras posgraduadas en la competencia VP. Sujetos y métodos. Taller de dos horas de duración con casos clínicos en formato video y ejecutados mediante técnica de role-playing. Los componentes fueron dos videos de grabación propia (el primero, de una VP con errores, y el otro, con una VP correctamente realizada), una plantilla para que cada alumno valorara en los videos los componentes técnicos y no técnicos de las competencias de la VP y una encuesta de satisfacción para alumnos e instructores. En el grupo de residentes se añadieron tres escenarios de VP de pacientes complejos. Resultados. Se analizaron las encuestas de los 10 residentes de dos promociones y de 60 enfermeras. La satisfacción de los dos tipos de alumnos y de los instructores sobre el aprendizaje fue muy alta. En el caso de las enfermeras, más del 85% de las alumnas de las promociones que recibieron el taller superaron la estación VP de la evaluación clínica objetiva estructurada (ECOE) frente a sólo el 20% de la promoción anterior. Conclusiones. El taller de VP con formato video y role-playing permite entrenar la competencia VP a residentes de anestesia y enfermeras posgraduadas, mejorando el rendimiento de éstas en la ECOE

Characterization of Glyceridic and Unsaponifiable Compounds of Sacha Inchi ( Plukenetia huayllabambana

This work deals with the characterization of the main glyceridic and unsaponifiable components of oils obtained from Sacha inchi (Plukenetia huayllabambana L.) seed ecotypes collected during two harvests in the Department of Amazonas in Peru. The seed-oil yield was 30.3-41.2%; standing out are the high percentages of the ¿3- and ¿6-fatty acids series whose ranges lie within those of the present Regulation for Sacha inchi oils. Triacylglycerols with even equivalent carbon number (ECN; 36-42) were the main components. Minor glyceridic polar compounds such as oxidized triglycerides, diglycerides, monoglycerides, and free fatty acids were determined by high-performance size exclusion chromatography. The low campesterol/stigmasterol ratio (1:6), unusual in the majority of vegetable oils, stands out. Regarding aliphatic hydrocarbons, these oils showed a particular profile for the saturated series of odd and even carbon atom numbers. According to our results Sacha inchi P. huayllabambana oils can be offered as a good alternative to P. volubilis, the species mainly commercialized for this vegetable oil

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio