Análisis de las interacciones de nirmatrelvir/ritonavir en pacientes ambulatorios en atención primaria / Nirmatrelvir/ritonavir drug-drug interactions in primary care outpatients

Fundamento. Nirmatrelvir/ritonavir es un antiviral oral con un alto potencial de producir interacciones farmacológicas. La población candidata a recibirlo es mayoritariamente vulnerable, con enfermedades crónicas y polimedicada. El objetivo es evaluar la validación farmacéutica previa a la ad-ministración del antiviral.Material y métodos. Las interacciones farmacológicas entre nirmatrelvir/ritonavir y el tratamiento habitual se consulta-ron en fichas técnicas y las herramientas de interacciones de UpToDate® y Universidad de Liverpool®. Se incluyeron las prescripciones validadas por un farmacéutico de atención primaria (abril/2022-abril/2023). Resultados. Se incluyeron 159 pacientes; en 83 se detecta-ron 168 interacciones que podían suponer un cambio en su tratamiento. Las estatinas (25,6%), anticoagulantes (10,7%) y antihipertensivos (10,7%) fueron los grupos terapéuticos más frecuentemente implicados. La suspensión (53,0%) y reducción de dosis (22,6%) fueron los cambios de trata-miento más frecuentes. Conclusiones. La revisión de potenciales interacciones far-macológicas, los ajustes posológicos y las modificaciones del tratamiento habitual del paciente han evitado potenciales to-xicidades, mejorando la seguridad de nirmatrelvir/ritonavir (AU)

Background. The oral antiviral nirmatrelvir/ritonavir inter-acts with a range of drugs. Candidate patients to receive this antiviral agent are usually vulnerable, multipathological and polymedicated. The objective is to evaluate the phar-maceutical validation prior to the administration of the an-tiviral.Material and methods. Drug-drug interactions between nirmatrelvir/ritonavir and patients’ usual treatment medi-cations were checked in product information and in the Up-ToDate® and the University of Liverpool® interaction tools. We included validated prescriptions between April/2022 and April/2023 by a Primary Care pharmacist.Results. Of the 159 study patients, 168 interactions were found in 83 individuals, which may have led to changes of their usual treatment. Statins (25.6%), anticoagulants (10.7%), and antihypertensives (10.7%) were the most fre-quently implicated therapeutic groups. Discontinuation (53.0%) and dose reduction (22.6%) were the most common treatment changes. Conclusions. Our search of potential drug interactions and subsequent dose adjustments and modifications of the pa-tient’s usual treatment has helped avoid potential toxicities ensuring a safe use of nirmatrelvir/ritonavir (AU)

[Nirmatrelvir/ritonavir drug-drug interactions in primary care outpatients]. / Análisis de las interacciones de nirmatrelvir/ritonavir en pacientes ambulatorios en Atención primaria

BACKGROUND: The oral antiviral nirmatrelvir/ritonavir interacts with a range of drugs. Candidate patients to receive this antiviral agent are usually vulnerable, multipathological and polymedicated. The objective is to evaluate the pharmaceutical validation prior to the administration of the antiviral. MATERIAL AND METHODS: Drug-drug interactions between nirmatrelvir/ritonavir and patients' usual treatment medications were checked in product information and in the UpToDate® and the University of Liverpool® interaction tools. We included validated prescriptions between April/2022 and April/2023 by a Primary Care pharmacist. RESULTS: Of the 159 study patients, 168 interactions were found in 83 individuals, which may have led to changes of their usual treatment. Statins (25.6%), anticoagulants (10.7%), and antihypertensives (10.7%) were the most frequently implicated therapeutic groups. Discontinuation (53.0%) and dose reduction (22.6%) were the most common treatment changes. CONCLUSIONS: Our search of potential drug interactions and subsequent dose adjustments and modifications of the patient's usual treatment has helped avoid potential toxicities ensuring a safe use of nirmatrelvir/ritonavir.

Chemical Fingerprinting, Aorta Endothelium Relaxation Effect, and Enzymatic Inhibition of Canelo (Drimys winteri J. R. Forst. & G. Forst, (D.C) A. Gray, Family Winteraceae) Fruits.

Drimys winteri J.R. Forst. & G. Forst (D.C) G. Gray, var. chilensis (canelo) is an endemic tree from Chile. Since pre-Columbian times, it has produced a fruit known as the canelo pepper, (pimienta de canelo) or Foye pepper, which can be used as a spice. The chemical and biological analysis of canelo fruits is reported for the first time in this study, that is, its phenolic fingerprinting by UHPLC-PDA- Q-orbitrap MS, the antioxidant activity, the enzymatic inhibitory activity, and its relaxation effects on rat aorta. The proximal composition and the mineral content (Ca: 1.45 ± 0.03 mg/100 g; Mg: 7.72 ± 0.03 mg/100 g; Fe: 4.54 ± 0.21 mg/100 g; Zn: 2.99 ± 0.02 mg/100 g; Mn: 1.08 ± 0.03 mg/100 g; Cu: 0.82 ± 0.02 mg/100 g; K: 53.03 ± 0.20 mg/100 g; Na: 0.087 ± 0.00 mg/100 g) are also reported. The canelo fruits showed a total phenolic content of 57.33 ± 0.82 mg GAE/g dry weight. In addition, the total flavonoid content was 38.42 ± 1.32 mg equivalent of QE/g dry weight. The antioxidant activity was evaluated by employing DPPH and ABTS methods (IC50 of 6.65 ± 0.5 and 9.5 ± 0.05 µg/mL, respectively), ORAC (25.33 ± 1.2 µmol Trolox/g dry plant) and FRAP (45.56 ± 1.32 µmol Trolox/g dry plant). The enzymatic inhibition of acetylcholinesterase, butyrylcholinesterase, and tyrosinase (IC50: 1.94 ± 0.07, 2.73 ± 0.05, and 9.92 ± 0.05 µg extract/mL, respectively) is also reported. Canelo extract led to an 89% relaxation of rat aorta. Our results confirm that D. winteri fruits are a rich source of secondary metabolites and can inhibit enzymes associated with neurodegenerative diseases; the results also suggest that canelo may induce a potentially hypotensive effect in rat aorta. The study demonstrates the medicinal properties of canelo fruit and spice.

Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[d]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists.

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).

Tratamiento de la COVID-19, ¿qué hemos aprendido? / COVID-19 treatment, what have we learned?

En diciembre de 2019 surgió un nuevo coronavirus, muy virulento y que provocaba un cuadrosevero a nivel respiratorio. La falta de experiencia con esta nueva enfermedad, unida a sugravedad y alta mortalidad, hizo que se utilizaran una gran cantidad de medicamentos sinexperiencia y se investigara sobre nuevas terapias específicas para combatirlo. Los primeros medicamentos que se utilizaron fueron antirretrovirales, usados habitualmente para eltratamiento del virus de la inmunodeficiencia humana, y antiparasitarios, por su actividadinmunosupresora. Además, debido a la neumonía que producía este nuevo virus se utilizabanantibióticos por el riesgo de sobreinfección bacteriana, además de corticoides. Posteriormente, se comenzaron a usar terapias inmunomoduladoras como interferones, anticuerposmonoclonales o moléculas pequeñas dirigidas contra dianas implicadas en el proceso de lainflamación. Durante todo este tiempo surgieron nuevas terapias como remdesivir, cuyaspautas de uso fueron cambiando a lo largo de los meses. En enero de 2022 cambió el paradigma de tratamiento de esta enfermedad, ya que se incluyeron nuevas alternativas tera-péuticas tanto para el tratamiento de esta enfermedad como para su prevención, como sonsotrovimab, casirivimab-imdevimab o nirmatrelvir/ritonavir. Desde este momento, la AgenciaEspañola del Medicamento y Productos Sanitarios publicó una serie de recomendaciones deutilización de estos nuevos medicamentos, que se han ido actualizando hasta la fecha. Eneste artículo hacemos una revisión de los tratamientos utilizados desde el inicio de la pandemia hasta enero de 2023.(AU)

[Off-label use of gabapentinoid drugs: is it necessary a deprescription strategy?] / Gabapentinoides en indicaciones no autorizadas en la ficha técnica: ¿es necesaria una estrategia de desprescripción?

OBJECTIVE: To evaluate gabapentin and pregabalin treatment adequacy to label indications, to analyze off-label use and to identify patients at high risk of respiratory depression. METHOD: An observational, retrospective study was performed. It included patients treated with pregabalin and gabapentin during 2020 in Navarre. RESULTS: A total of 9778 patients were treated with gabapentin or pregabalin during the first two months of 2020. In 56% of the cases, gabapentinoids were prescribed for off-label uses. Sixty percent of patients were taking at least one central nervous system (CNS) depressant drug concomitantly, 33% of them opioids, 20% of them combined opioids with CNS depressants and 4% of them at least one systemic antihistamine. In addition, 11% of the patients had a diagnosis of asthma or COPD. Prevalences remained constant along the year. CONCLUSIONS: It is necessary to implement a gabapentinoid deprescription strategy to improve its use and reduce safety problems.

Genome Editing and Protein Energy Malnutrition.

Protein-energy malnutrition is a state of disordered catabolism resulting from metabolic derangements or starvation. It is associated with chronic disease, hypoglycemia, hypothermia, serious infections, and even an increased prevalence of morbidity and mortality in countries with poor socioeconomic or environmental factors. Adequate food administration is essential to satisfy the main caloric and nutritional demands of humans. The most significant factors seen in the development of protein-energy malnutrition in areas of high incidence, such as underdeveloped countries, are inadequate food and nutrient supplies. It has been well established that one of the strategies to alleviate undernourishment is the biofortification of staple crops. This is because vegetables and plants are significant sources of crucial nutrients for human growth and development. To enhance plant nutrition, recent tactics aim to formulated balanced and diverse diets with acceptable levels of vitamins and minerals that benefit human health. New advances in plant biotechnology and animal productivity could control key enzymes in several metabolic pathways, enriching important nutrients such as iron and vitamins and decreasing the content of disadvantageous compounds such as acrylamide-forming amino acids and phytic acids. Numerous biofortified crops such as rice, maize, and wheat have been created to resolve the problem of nutrition deficiencies. Some examples of these methodologies are genome editing engineered nucleases, transcriptional activator-like effector nucleases, zinc finger nucleases, and clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease which have been created and widely studied for their application, efficiency, and specificity.

Gabapentinoides en indicaciones no autorizadas en la ficha técnica: ¿es necesaria una estrategia de desprescripción? / Off-label use of gabapentinoid drugs: is it necessary a deprescription strategy?

Objetivo: Evaluar la adecuación de los tratamientos con gabapentina y pregabalina a las indicaciones autorizadas, analizar su uso en las no autorizadas e identificar los pacientes con más riesgo de sufrir depresión respiratoria. Método: Estudio observacional retrospectivo que incluyó a los pacientes en tratamiento con gabapentina o pregabalina en 2020 en Navarra. Resultados: Se incluyeron 9778 pacientes en tratamiento con gabapentina o pregabalina durante el primer bimestre de 2020. En el 56% de los casos se prescribieron para indicaciones no autorizadas. El 60% tomaba concomitantemente al menos un depresor del sistema nervioso central (SNC), el 33% algún opiáceo, el 20% opiáceos combinados con depresores del SNC y el 4% algún antihistamínico. El 11% tenía diagnóstico de asma o enfermedad pulmonar obstructiva crónica. Estas prevalencias se mantuvieron constantes durante el resto del año. Conclusiones: Es necesario implementar una estrategia de desprescripción de gabapentinoides para adecuar su uso y disminuir los problemas de seguridad. (AU)

Objective: To evaluate gabapentin and pregabalin treatment adequacy to label indications, to analyze off-label use and to identify patients at high risk of respiratory depression. Method: An observational, retrospective study was performed. It included patients treated with pregabalin and gabapentin during 2020 in Navarre. Results: A total of 9778 patients were treated with gabapentin or pregabalin during the first two months of 2020. In 56% of the cases, gabapentinoids were prescribed for off-label uses. Sixty percent of patients were taking at least one central nervous system (CNS) depressant drug concomitantly, 33% of them opioids, 20% of them combined opioids with CNS depressants and 4% of them at least one systemic antihistamine. In addition, 11% of the patients had a diagnosis of asthma or COPD. Prevalences remained constant along the year. Conclusions: It is necessary to implement a gabapentinoid deprescription strategy to improve its use and reduce safety problems.

Phenolic Fingerprinting and Bioactivity Profiling of Extracts and Isolated Compounds from Gypothamnium pinifolium Phil.

Gypothamnium pinifolium Phil. (Asteraceae) is a small shrub that grows in the Paposo Valley of the II Antofagasta Region of Chile. This initial study is of the high-resolution phenolic fingerprinting, antioxidant activity, the relaxation effects in rat aorta, the inhibitory enzyme potential, plus the antiproliferative activity of the ethyl acetate and n-hexane extract from G. pinifolium and its two major isolated secondary metabolites (one coumarin: 2-nor-1,2-secolycoserone, and one diterpene: ent-labda-8,13-E-diene-15-ol). The study involves using ultra-high-performance liquid chromatography todiode array detection coupled with Q-Orbitrap mass spectrometry analysis (UHPLC-PDA-Orbi-trap-MS), in which various compounds were identified, including specific coumarins. The n-hexane extract showed total phenolic and flavonoid contents of 517.4 ± 12.5 mg GAE/100 g extract and 72.3 ± 3.7 mg QE/100 g extract, respectively. In addition, the antioxidant activity of the n-hexane extract was assessed using in-vitro assays such as bleaching of DPPH and ABTS (IC50: 14.3 ± 0.52 and 2.51 ± 0.43 µg extract/mL, respectively), FRAP (347.12 ± 1.15 µmol Trolox equivalent/g extract), and ORAC (287.3 ± 1.54 µmol Trolox equivalents/g extract). Furthermore, the inhibition against cholinesterases (acetylcholinesterase (AChE) 4.58 ± 0.04 µg/mL, butyrylcholinesterase (BChE) IC50: 23.44 ± 0.03 µg/mL) and tyrosinase (IC50: 9.25 ± 0.15 µg/mL) enzymes of the n-hexane extract, and main compounds (IC50: 1.21 ± 0.03 µg/mL, 11.23 ± 0.02 µg/mL, 3.23 ± 0.12 µg/mL, and 103.43 ± 16.86 µg/mL, correspondingly for the most active coumarin 1) were measured. The antiproliferative potential of the extracts and the two principal compounds against several solid human cancer cells was investigated. All of them showed good activity against cancer cells. Label-free live-cell imaging studies on HeLa cells exposed to the isolated coumarin and the diterpene enabled the observation of cell death and several apoptotic hallmarks. Our results indicate that G. pinifolium Phil. is a valuable source of secondary metabolites with potential activity against noncommunicable diseases.

Guía para la vivienda adecuada en la respuesta a refugiados y migrantes de venezuela en Latino América y el Caribe / Guide for adequate housing in the response to refugees and migrants from Venezuela in Latin America and the Caribbean

Desde el Sector de Alojamiento bajo la Plataforma de Coordinación Interagencial para Refugiados y Migrantes de Venezuela (R4V), en coordinación con otros sectores regionales y organizaciones humanitarias en la región, entendemos el acceso a la vivienda adecuada como algo más que la provisión de un techo y cuatro paredes en momentos de crisis, sino como la oportunidad de reconstruir la palabra "hogar" a través del ejercicio del derecho a vivir con dignidad, protección y seguridad en un entorno saludable que permita a las personas reconstruir lo cotidiano y reactivar sus actividades económicas y sociales; compartiendo así las definiciones de "Vivienda Adecuada" de ONU-Derechos Humanos (ADNUDH) y ONU-Hábitat 1 o las recogidas en el Manual Esfera de 2018 2 . Aquellas poblaciones en situación de movilidad, como son refugiados y migrantes, se encuentran en una situación de mayor vulnerabilidad al dejar sus hogares atrás y ante la violación de sus derechos humanos fundamentales, en particular, el de acceso a la vivienda, exacerbado por situaciones de discriminación, racismo y/o xenofobia; que impiden lograr unas condiciones de vida adecuadas y sostenibles. La vivienda adecuada no provee exclusivamente protección dentro del espacio construido, sino que es un medio para acceder a un mejor nivel de vida. En particular, y dado que en la actualidad las situaciones de desplazamiento tienen una duración mayor que en periodos anteriores, llegando incluso a durar décadas, la ausencia de una vivienda adecuada acrecienta los niveles de pobreza, aumentando la brecha de desigualdad para lograr la integración socioeconómica de las personas refugiadas y migrantes a través del acceso a un trabajo digno, y, en consecuencia, a tener una sensación de seguridad física y económica y a la lograr un sentimiento de comunidad y cohesión social.

UHPLC-MS Metabolomic Fingerprinting, Antioxidant, and Enzyme Inhibition Activities of Himantormia lugubris from Antarctica.

Himantormia lugubris is a Chilean native small lichen shrub growing in the Antarctica region. In this study, the metabolite fingerprinting and the antioxidant and enzyme inhibitory potential from this species and its four major isolated compounds were investigated for the first time. Using ultra-high performance liquid chromatography coupled to quadrupole-Orbitrap mass spectrometry analysis (UHPLC-Q-Orbitrap-MS), several metabolites were identified including specific compounds as chemotaxonomical markers, while major metabolites were quantified in this species. A good inhibition activity against cholinesterase (acetylcholinesterase (AChE) IC50: 12.38 ± 0.09 µg/mL, butyrylcholinesterase (BChE) IC50: 31.54 ± 0.20 µg/mL) and tyrosinase (22.32 ± 0.21 µg/mL) enzymes of the alcoholic extract and the main compounds (IC50: 28.82 ± 0.10 µg/mL, 36.43 ± 0.08 µg/mL, and 7.25 ± 0.18 µg/mL, respectively, for the most active phenolic atranol) was found. The extract showed a total phenolic content of 47.4 + 0.0 mg of gallic acid equivalents/g. In addition, antioxidant activity was assessed using bleaching of DPPH and ORAC (IC50: 75.3 ± 0.02 µg/mL and 32.7 ± 0.7 µmol Trolox/g lichen, respectively) and FRAP (27.8 ± 0.0 µmol Trolox equivalent/g) experiments. The findings suggest that H. lugubris is a rich source of bioactive compounds with potentiality in the prevention of neurodegenerative or noncommunicable chronic diseases.

[Study protocol: A strategy for deprescribing statins and ezetimibe in primary prevention of cardiovascular disease in patients older than 75 years: health outcomes analysis.] / Protocolo del estudio Estrategia de deprescripción de estatinas y ezetimiba en prevención primaria en mayores de 75 años: análisis de los resultados en salud.

OBJECTIVE: The benefit-risk balance of statins and ezetimibe as primary prevention of cardiovascular disease is controversial in elderly patients due to the doubts about their effectiveness and certainty about adverse effects. The aim of this paper was to analyze health outcomes of a statin and ezetimibe deprescription strategy in patients aged 75 or older treated with these drugs for primary prevention of cardiovascular disease. METHODS: An observational ambispective cohort study was made to evaluate health outcomes after the implementation of a strategy for deprescribing statins and ezetimibe in patients aged 75 or older who take these drugs for primary prevention of cardiovascular disease. To avoid the risk of bias due to non-random assignment of patients to different groups, a propensity score will be calculated for each patient using logistic regression. The outcome of interest will be the deprescription or not of statins or ezetimibe. Time to hospital admission or death from any cause and other variables related to health outcomes will be analysed. Groups with and without statin or ezetimibe deprescription will be compared by survival analysis using Cox regression to estimate the hazard ratio. CONCLUSIONS: It is expected to obtain health outcomes of the strategy of deprescribing statins and ezetimibe in primary prevention in patients aged 75 or older. They will provide information on the advisability of continuing the strategy.

OBJETIVO: El balance beneficio-riesgo de estatinas y ezetimiba como prevención primaria de la enfermedad cardiovascular (ECV) resulta controvertido en pacientes de edad avanzada, debido a las dudas sobre su efectividad y las certezas sobre efectos adversos. El objetivo de este estudio fue analizar los resultados en salud de una estrategia de deprescripción de estatinas y ezetimiba en prevención primaria de ECV en pacientes mayores de 75 años. METODOS: Se realizó un estudio ambispectivo de cohortes para evaluar los resultados en salud obtenidos tras la implementación de una estrategia poblacional de deprescripción de estatinas y ezetimiba en pacientes con edad igual o mayor a 75 años que tomaban estos fármacos como prevención primaria de ECV. Para evitar posibles sesgos debidos a la asignación no aleatoria de los pacientes a los distintos grupos, se calculará un índice de propensión para cada paciente utilizando una regresión logística, en la que la variable de resultado será la deprescripción o no de estatinas o ezetimiba. Se analizará el tiempo hasta el ingreso hospitalario o la muerte por cualquier causa y otras variables relacionadas con resultados en salud. Se compararán los grupos con y sin deprescripción de estatina o ezetimiba mediante un análisis de supervivencia utilizando un modelo de riesgos proporcionales de Cox para estimar el hazard ratio. CONCLUSIONES: Se espera obtener información sobre los resultados en salud de la estrategia de deprescripción de estatinas y ezetimiba en prevención primaria en mayores de 75 años que informarán sobre la conveniencia de continuarla.

Protocolo del estudioEstrategia de deprescripción deestatinas y ezetimiba en prevenciónprimaria en mayores de 75 años: análisis de los resultados en salud / Study protocol: A strategy for deprescribing statins and ezetimibe in primary prevention of cardiovascular disease in patients older than 75 years: health outcomes analysis

FUNDAMENTOS: l balance beneficio-riesgo de estatinas y ezetimiba como prevención primaria de la enfermedad cardiovascular (ECV) resulta controvertido en pacientes de edad avanzada, debido a las dudas sobre su efectividad y las certezas sobre efectos adversos. El objetivo de este estudio fue analizar los resultados en salud de una estrategia de deprescripción de estatinas y ezetimiba en prevención primaria de ECV en pacientes mayores de 75 años. MÉTODOS: Se realizó un estudio ambispectivo de cohortes para evaluar los resultados en salud obtenidos tras la implementación de una estrategia poblacional de deprescripción de estatinas y ezetimiba en pacientes con edad igual o mayor a 75 años que tomaban estos fármacos como prevención primaria de ECV. Para evitar posibles sesgos debidos a la asignación no aleatoria de los pacientes a los distintos grupos, se calculará un índice de propensión para cada paciente utilizando una regresión logística, en la que la variable de resultado será la deprescripción o no de estatinas o ezetimiba. Se analizará el tiempo hasta el ingreso hospitalario o la muerte por cualquier causa y otras variables relacionadas con resultados en salud. Se compararán los grupos con y sin deprescripción de estatina o ezetimiba mediante un análisis de supervivencia utilizando un modelo de riesgos proporcionales de Cox para estimar el hazard ratio. CONCLUSIONES: Se espera obtener información sobre los resultados en salud de la estrategia de deprescripción de estatinas y ezetimiba en prevención primaria en mayores de 75 años que informarán sobre la conveniencia de continuarla.(AU)

BACKGROUND: The benefit-risk balance of statins and ezetimibe as primary prevention of cardiovascular disease is controversial in elderly patients due to the doubts about their effectiveness and certainty about adverse effects. The aim of this paper was to analyze health outcomes of a statin and ezetimibe deprescription strategy in patients aged 75 or older treated with these drugs for primary prevention of cardiovascular disease. METHODS: An observational ambispective cohort study was made to evaluate health outcomes after the implementation of a strategy for deprescribing statins and ezetimibe in patients aged 75 or older who take these drugs for primary prevention of cardiovascular disease. To avoid the risk of bias due to non-random assignment of patients to different groups, a propensity score will be calculated for each patient using logistic regression. The outcome of interest will be the deprescription or not of statins or ezetimibe. Time to hospital admission or death from any cause and other variables related to health outcomes will be analysed. Groups with and without statin or ezetimibe deprescription will be compared by survival analysis using Cox regression to estimate the hazard ratio. CONCLUSIONS: It is expected to obtain health outcomes of the strategy of deprescribing statins and ezetimibe in primary prevention in patients aged 75 or older. They will provide information on the advisability of continuing the strategy.(AU)

Phenolic Profile, Antioxidant and Enzyme Inhibition Properties of the Chilean Endemic Plant Ovidia pillopillo (Gay) Meissner (Thymelaeaceae).

Ovidia pillopillo (Lloime) is an endemic species of the Valdivian Forest of Chile. Little is known on the chemistry and biological activity of this plant. In this study, the phenolic profile, antioxidant capacities and enzyme inhibition capacities (against tyrosinase and cholinesterase) of the plant were investigated for the first time. The phenolic profile of the plant was obtained by UHPLC-MS fingerprinting with high resolution, which showed the presence of several flavonoids and coumarins. The antioxidant potential was measured by FRAP and ORAC (45.56 ± 1.32; 25.33 ± 1.2 µmol Trolox equivalents/g dry plant, respectively) plus ABTS and DPPH methods (IC50 = 9.95 ± 0.05 and 6.65 ± 0.5 µg/mL, respectively). Moreover, the flavonoid and phenolic contents were determined (57.33 ± 0.82 and 38.42 ± 1.32, µg of Trolox and quercetin equivalents/100 g dry weight, respectively). The ethanolic extract showed cholinesterase (IC50 = 1.94 ± 0.07 and 2.73 ± 0.05 µg/mL, for AChE and BuChE, respectively) and tyrosinase (4.92 ± 0.05 µg/mL) enzyme inhibition activities. Based on these in vitro studies, in silico simulations were performed, which determined that the major compounds as ligands likely docked in the receptors of the enzymes. These results suggest that Ovidia pillopillo produce interesting special coumarins and flavonoids, which are potential candidates for the exploration and preparation of new medicines.

Alkaloid Profiling, Anti-Enzymatic and Antiproliferative Activity of the Endemic Chilean Amaryllidaceae Phycella cyrtanthoides.

This research aims to identify the alkaloid profile and to evaluate the enzyme inhibitory potential and antiproliferative effects of the Amaryllidaceae plant Phycella cyrtanthoides. The alkaloid extracts from bulbs and leaves were analyzed using ultrahigh performance liquid chromatography orbitrap mass spectrometry (UHPLC-Orbitrap-MS) analysis. A total of 70 alkaloids were detected in the P. cyrtanthoides' extracts. The enzyme inhibition potential against cholinesterases (AChE: acetylcholinesterase, and BChE butyrylcholinesterase) and tyrosinase were studied. Bulbs displayed the best IC50 values against AChE (4.29 ± 0.03 µg/mL) and BChE (18.32 ± 0.03 µg/mL). These results were consistent with docking experiments with selected major compounds in the active sites of enzymes, while no activity was observed against tyrosinase enzyme. Antiproliferative effects were investigated against human cervical (HeLa), lung (A549, SW1573), colon (WiDr), and breast (HBL-100, T-47D) tumor cell lines. Bulbs and leaves were active in all cell lines (GI50 < 2.5 µg/mL). These findings suggest that the endemic Chilean plant P. cyrtanthoides contains diverse types of bioactive alkaloids with antiproliferative activities and inhibitory effects with potential therapeutic applications for neurodegenerative diseases.

Analysis of Carotenoids in Haloarchaea Species from Atacama Saline Lakes by High Resolution UHPLC-Q-Orbitrap-Mass Spectrometry: Antioxidant Potential and Biological Effect on Cell Viability.

Haloarchaea are extreme halophilic microorganisms belonging to the domain Archaea, phylum Euryarchaeota, and are producers of interesting antioxidant carotenoid compounds. In this study, four new strains of Haloarcula sp., isolated from saline lakes of the Atacama Desert, are reported and studied by high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS) for the first time. In addition, determination of the carotenoid pigment profile from the new strains of Haloarcula sp., plus two strains of Halorubrum tebenquichense, and their antioxidant activity by means of several methods is reported. The effect of biomass on cellular viability in skin cell lines was also evaluated by MTT assay. The cholinesterase inhibition capacity of six haloarchaea (Haloarcula sp. ALT-23; Haloarcula sp. TeSe-41; Haloarcula sp. TeSe-51; Haloarcula sp. Te Se-89 and Halorubrum tebenquichense strains TeSe-85 and Te Se-86) is also reported for the first time. AChE inhibition IC50 was 2.96 ± 0.08 µg/mL and BuChE inhibition IC50 was 2.39 ± 0.09 µg/mL for the most active strain, Halorubrum tebenquichense Te Se-85, respectively, which is more active in BuCHe than that of the standard galantamine. Docking calculation showed that carotenoids can exert their inhibitory activity fitting into the enzyme pocket by their halves, in the presence of cholinesterase dimers.

UHPLC-MS Chemical Fingerprinting and Antioxidant, Antiproliferative, and Enzyme Inhibition Potential of Gaultheria pumila Berries.

Gaultheria pumila (Ericaceae) (known as Chaura or Mutilla) is a Chilean native small shrub that produces berry fruits consumed by local Mapuche people. In this study, the chemical fingerprinting and antioxidant, enzyme inhibition, and antiproliferative activities of the berries were investigated for the first time. Thirty-six metabolites were identified in the fruits by ultra-high performance liquid chromatography-photodiode array detection, hyphenated with Orbitrap mass spectrometry analysis (UHPLC-DAD-Orbitrap-MS). Metabolites, included anthocyanins, phenolic acids, flavonoids, iridoids, diterpenes, and fatty acids. Moderate inhibitory activities against acetylcholinesterase (7.7 ± 0.3 µg/mL), butyrylcholinesterase (34.5 ± 0.5 µg/mL), and tyrosinase (3.3 ± 0.2 µg/mL) enzymes were found. Moreover, selected major compounds were subjected to docking assays in light of their experimental inhibition. Results indicated that hydrogen bonding, π-π interaction, and a salt bridge interaction contributed significantly. Gaultheria pumila berries showed a total phenolic content of 189.2 ± 0.2 mg of gallic acid equivalents/g, total flavonoid content of 51.8 ± 0.1 mg quercetin equivalents/g, and total anthocyanin content of 47.3 ± 0.2 mg of cianydin-3-glucoside equivalents/g. Antioxidant activity was assessed using DPPH (92.8 ± 0.1 µg/mL), FRAP (134.1 ± 0.1 µmol Trolox equivalents/g), and ORAC (4251.6 ± 16.9 µmol Trolox equivalents/g) assays. Conversely, Gaultheria pumila showed a scarce antiproliferative potential against several solid human cancer cells. Our findings suggest that Gaultheria pumila berries have several bioactive metabolites with inhibitory effects against acetylcholinesterase, butyrylcholinesterase, and tyrosinase, and have the potential for use in food supplements.

Chemical Profiling, Antioxidant, Anticholinesterase, and Antiprotozoal Potentials of Artemisia copa Phil. (Asteraceae).

Artemisia copa Phil. (Asteraceae) (known as copa-copa) is a native species of Chile used as an infusion in traditional medicine by Atacameños people in the Altiplano, highlands of northern Chile. In this research, we have investigated for the first time the cholinesterase inhibition potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the chemical profiling of the infusions prepared from the aerial parts of A. copa by high resolution spectrometry. In addition, total phenolic, total flavonoid content, antioxidant (DPPH, FRAP, and ORAC) and antiprozoal activity were tested. Artemisia copa showed good inhibitory activity against AChE and BChE (3.92 ± 0.08 µg/ml and 44.13 ± 0.10 µg/ml). The infusion displayed a total phenolics content of 155.6 ± 2.9 mg of gallic acid equivalents/g and total flavonoid content of 5.5 ± 0.2 mg quercetin equivalents/g. Additionally, trypanocidal activity against Trypanosoma cruzi was found (LD50 of 131.8 µg/ml). Forty-seven metabolites were detected in the infusion of A. copa including several phenolic acids and flavonoids which were rapidly identified using ultrahigh performance liquid chromatography orbitrap mass spectrometry analysis (UHPLC-Orbitrap-MS) for chemical profiling. The major compounds identified in the infusions were studied by molecular docking against AChE and BChE. The UHPLC-MS fingerprints generated can be also used for the authentication of these endemic species. These findings reveal that A. copa infusions can be used as beverages with protective effects.