Farmacología

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Active involvement of the general public in pharmacovigilance
(2020-02-12) Romao Matos, Cristiano Filipe; Hunsel, Florence van; Álvarez de Sotomayor Paz, María; Universidad de Sevilla. Departamento de Farmacología
The importance of direct patient reporting has been highlighted by recent European legislation on pharmacovigilance, and in addition, there is also an increasing attention worldwide for this subject. In Europe, the legislation directs member states to take all appropriate measures to encourage patients to report suspected adverse drug reactions (ADR) to the relevant national authorities. The introduction of patient reporting in pharmacovigilance indicates a change in attitude in which patient reporting is valued due to their potential to contribute useful information on drug safety. The aim of this project is to give a better understanding of the role of patients in pharmacovigilance systems. The chosen approach during this project intended to lead to a better understanding of the awareness and perception of the risk involved with medicine use and how patients and healthcare professionals can contribute to optimize the current pharmacovigilance system. For the purpose of this study, the project was divided in several parts, for which specific objectives were designed and described below, together with main results of the thesis. The first study described in Chapter 2 discusses the experiences of patient reporting to pharmacovigilance in Portugal and quantifies consumers motivation for reporting ADRs, investigating patient opinions about reporting with a quantitative analysis in a large group of consumers. The objective was to describe the attitudes and knowledge of the general public regarding spontaneous reporting and the reasons and opinions that can influence consumers adverse drug reaction underreporting. The study reveals that consumers are more likely to do spontaneous report about severe reactions or if they are worried about the symptoms. Also, more altruistic motives as the contribution to research and knowledge, the contribution to improvement of drugs and prevent harm to other people are seen as motives to report ADRs by patients. These motives can be classified in reporting for oneself (severity, worried, problems), reporting for others (share experiences, preventing harm, feeling responsible) or reporting for improvement (research and knowledge, patient information leaflet). It appeared that multiple patient characteristics (gender, age and level of education) had an effect on the motives of patients to report their ADR. In Chapter 3 were described the attitudes toward patient reporting systems, and progress toward implementing such systems among national competent authorities participating in the World Health Organization Programme for International Drug Monitoring. The study shows that most countries accept ADR reports from patients by an official reporting system designed for patients or through the existing system for Healthcare Professionals (HCPs). The main reasons for not having a Patient Reporting System (PRS) are financial restraints and a lack of information/education of patients. Attitudes toward a PRS are positive, but some countries fear 181 that they will not be able to handle an increase in reports. Most countries accept ADR reports from the general public. The lack of resources/budget and the lack of information/education for patients are highlighted as the major obstacles to the implementation of PRS. Chapter 4 focused on patient organizations role to promote patient reporting. In Chapter 4.1, it was studied the role of European patient organizations with the objective of understand the role of European patient organizations as stakeholders to optimize patient involvement in pharmacovigilance. There is a wide range of interest in drug safety issues among patient organizations, which appear to have an important role in encouraging patients to talk with their doctors/pharmacists about ADRs experienced, or to help him/her report the ADRs to the pharmacovigilance systems. A lack of resources, budget, and support from National Competent Authorities (NCAs) are seen as the main barriers to being involved in pharmacovigilance. On the other hand, an important part of the organizations appears to not have any activities or involvement related to pharmacovigilance. Bringing pharmacovigilance stakeholders and patient organizations together could create a more optimal patient reporting culture. Members of a patient organization showed more positive opinions related to pharmacovigilance. They would like to have more information about ADRs related to their medication and a higher intention to have information on how to report when compared to other patients. The other study in Chapter 4 described medicines and attitudes and opinions regarding pharmacovigilance in people with diabetes. The study explored the impact of the patient reports being followed by a patient diabetes association. The objective was to assess risk perception of developing adverse drug reactions and knowledge, attitudes and opinions regarding pharmacovigilance in patients with diabetes and to investigate whether being a member of a patient organization for diabetes had an effect on these factors. Patients followed in a diabetes patient association presented a higher score of risk perception, experiences using the medicines, but also by the information received from the patient organization. Being a member of a patient organization seems to have an important role in increasing risk perception since they presented the highest risk perception scores for medicines related to their disease. Those patients affirmed that their doctor explained the possible ADRs of their medication and they have higher intention to report ADRs in the future if they are serious or unexpected. Patient organizations are well positioned to be a source where patients can obtain reliable information, changing their attitudes and perceptions about the disease and drug treatments. An additional chapter was provided, related with HCPs role as active agents to improve the involvement of patients in pharmacovigilance. Chapter 5.1 objective was to describe the attitudes and knowledge of different community pharmacy professional groups regarding the spontaneous reporting of adverse drug reactions to identify the factors that can influence adverse drug reaction under-reporting. Despite HCPs knowledge of the pharmacovigilance system, only a small 182 percentage of Community pharmacy professionals had reported ADRs, and approximately half did not usually encourage consumers to report possible ADRs. In Chapter 5.2, the objective was to evaluate community pharmacy professionals as role players . Reporting of ADRs is fundamental to pharmacovigilance, and consumer reporting is a significant contribution to creating useful information on drug safety. Community pharmacy professionals can play a major role in pharmacovigilance by reporting ADRs directly or encouraging consumers to report them. Measures to overcome under-reporting as encouraging HCPs and consumers to play an active role in pharmacovigilance, namely continuous education and training should be incorporated to increase the level of risk perception and encourage a better attitude about reporting for both HCPs and consumers. Chapter 6 presents a general discussion about the role of general public in pharmacovigilance, providing recommendations that arose from the results with different points of view of patient participation in pharmacovigilance (national competent authorities, HCPs, patient organizations and patients themselves). In conclusion, this thesis has focused on an overview of the participation of different stakeholders in pharmacovigilance, including HCPs, NCAs, Patient Organizations and patients themselves. Further research and developments for pharmacovigilance systems and for patients themselves arose from the results provided.
Alfabetización en salud y COVID-19 en mayores: aproximación desde la Farmacia Comunitaria
(Pharmaceutical Care España, 2022) Álvarez de Sotomayor Paz, María; Fernández Cuesta, Paula María; Universidad de Sevilla. Departamento de Farmacología
Introducción: La alfabetización en salud son las habilidades cognitivas y sociales que determinan que los individuos puedan acceder, entender y usar la información para promover y mantener su salud. La necesidad de estas habilidades ha sido notable en la pandemia. Método: Se realiza un cuestionario específico a los pacientes mayores de 60 años. Este consta de tres partes: el instrumento HLS-EU-Q16 adaptado a COVID-19, preguntas sobre la actuación del farmacéutico y la herramienta SAHLSA. Resultados: La población era mayoritariamente femenina (75,4%) y su edad era de 79,2±9,4 años. El nivel educativo mayoritario fue de educación primaria (34,4%), predominando éste y el sin estudios en mayores de 80 años. El cuestionario HLS-EU-Q16 reveló que la alfabetización en salud sobre COVID-19 era deficiente (23%), insuficiente (70,5%) y suficiente (6,6%). El cuestionario SAHLSA mostró alfabetización suficiente en el 80%. Mientras que el primer cuestionario no mostró relación con el nivel educativo, ningún bachiller o universitario presentó valores insuficientes en el cuestionario SAHLSA. Por último, los entrevistados consideraron como primer sanitario al que acudir para obtener información fiable al médico (77%), seguido por el farmacéutico (13%). El 75% consideró que el farmacéutico le había ayudado a comprender las precauciones frente a la COVID-19. Conclusiones: Los pacientes presentan dificultades para identificar la información fiable y para encontrar información de tratamientos frente a la COVID. Esta necesidad no está relacionada con el nivel educativo ni con la alfabetización en salud en otras áreas. El farmacéutico puede ser un agente clave en resolver esta necesidad.
Analysis of the implementation of GESIDA quality indicators in the HIV+ cohort PSITAR
(Ibañez & Plaza Asociados, S.L., 2016) Robustillo Cortés, María de las Aguas; Tortajada Goitia, Begoña; Ríos Sánchez, Esmeralda; Talero Barrientos, Elena Mª; Álvarez de Sotomayor Paz, María; Morillo Verdugo, Ramón Alejandro; Universidad de Sevilla. Departamento de Farmacología
Objective: To determine the compliance of quality care indicators (GESIDA) for adult patients living with HIV infection in PSITAR cohort. Methods: Multi-center, prospective observational study. All adult naive patients, that began treatment during 2011 belonging to the PSITAR cohort, were selected. We recorded demographic data, virological parameters at baseline and 48 weeks of treatment and pharmacotherapy variables. The selected indicators were: The compliance of initial antiretroviral therapy with the Spanish national treatment guidelines (GESIDA) for treatment-naive HIV-infected patient (95%), undetectable viral load at 48 weeks (80%), treatment initiation with Abacavir without screening for HLA-B*5701 (0%), treatment modifications within the first year (<30%), adherence treatment measure (95%), study of resistance in the virologic failure (90%) and average expenditure per patient in the first treatment (GESIDA median). Results: In total 108 HIV+ naive patients were included, 83.3% men. The median age was 40.5 years (21-75). The most frequent combination was tenofovir-emtricitabineefavirenz with 61.0%. 28 patients (29.7%) modified their treatment during the first year. Focusing on indicators compliance, starting of treatment with a recommended regimen had 95.4% of compliance, undetectable viral load indicator 74.1%, treatment initiation without Abacavir test 0%, treatment modifications within the first year 25.9%, adherence treatment measure 86.3%, study of resistance in the virologic failure 80% and average expenditure per patient was 8,846 euros. Conclusion: Quality care follow up indicators were fulfilled in their vast majority. The worst accomplished indicators such as undetectable viral load at 48 weeks, evaluation of adherence and study of resistance must be study to examine the possible improvement points.
Argan (Argania spinosa) oil lowers blood pressure and improves endothelial dysfunction in spontaneously hypertensive rats
(Cambridge University Press, 2004) Berrougui, Hicham; Álvarez de Sotomayor Paz, María; Pérez Guerrero, María Concepción; Ettaib, Abdelkader; Hmamouchi, Mohammed; Marhuenda Requena, Elisa; Herrera González, María Dolores; Universidad de Sevilla. Departamento de Farmacología
Traditionally hand-pressed argan oil, obtained from Argania spinosa seeds, is eaten raw in south-west Morocco; its rich composition of tocopherols, MUFA and PUFA make a study of its actions on risk factors for CVD, such as hypertension, interesting. The effects of 7 weeks of treatment with argan oil (10 ml/kg) on the blood pressure and endothelial function of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats were investigated. Systolic blood pressure and heart rate were measured every week by the tailcuff method and endothelial function was assessed by carbachol (10-8 to 10-4M -induced relaxations of aortic rings and small mesenteric arteries pre-contracted with phenylephrine. Argan-oil administration reduced the mean blood pressure of SHR after the fifth week of treatment (P<0.05) and increased (P<0.01) the endothelial responses of arteries from SHR. The NO synthase inhibitor, L-N-ω-nitroarginine (3 × 10-5M) revealed a greater participation of NO in the relaxant effect after the treatment. When cyclooxygenase (COX) was blocked with indomethacin (10-5M), an involvement of COX products in the endothelium-dependent response was characterized. Enzyme immunoassay of thromboxane B2 showed a significant decrease (P< 0.05) in the release of thromboxane A2 in both aorta and small mesenteric artery after argan-oil treatment of SHR. Experiments in the presence of the thromboxane A2-prostaglandin H2 receptor antagonist ICI 192,605 (10-5M) confirmed this result. Results after incubation with the antioxidants superoxide dismutase and catalase suggested that a decreased oxidative stress might contribute to explain the beneficial effects of argan-oil treatment.
Bioavailability of the ferulic acid-derived phenolic compounds of a rice bran enzymatic extract and their activity against superoxide production
(Royal Society of Chemistry, 2017) Pérez Ternero, Cristina; Maciá, Alba; Álvarez de Sotomayor Paz, María; Parrado Rubio, Juan; Motilva, María José; Herrera González, María Dolores; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
ice bran is an exceptional source of such antioxidant molecules as γ-oryzanol and ferulic acid, but their bioavailability and metabolism within this matrix remain unknown. The aims of this work were to describe the oral bioavailability and metabolic pathways of the ferulic acid-derived phenolic compounds contained in a rice bran enzymatic extract (RBEE), and to determine its effect on NADPH oxidase activity. Wistar rats were administered with RBEE and sacrificed at different times over a period of 24 h to obtain plasma. An additional group was used for collection of urine and faeces over a period of 48 h. The phenolic metabolites were determined by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), and plasma pharmacokinetic parameters were calculated. In parallel, aortic rings were incubated in the plasma of rats sacrificed 30 min after RBEE gavage, or in the presence of RBEE, ferulic acid or γ-oryzanol. Endothelin-1-induced superoxide production was recorded by lucigenin-enhanced luminescence. Twenty-five ferulic acid metabolites showing biphasic behaviour were found in the plasma, most of which were found in the urine as well, while in the faeces, colonic metabolism led to simpler phenolic compounds. Superoxide production was abrogated by phenolic compound-enriched plasma and by RBEE and ferulic acid, thus showing the biological potential of RBEE as a nutraceutical ingredient.
Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders
(2011) Álvarez de Sotomayor Paz, María; Rodríguez Rodríguez, Rosalía; Mingorance Gutiérrez, María del Carmen; Justo Gómez, María Luisa; Herrera González, María Dolores; Universidad de Sevilla. Departamento de Farmacología
Development of a taxonomy for pharmaceutical interventions in HIV+ patients based on the CMO model
(Grupo Aula Medica S.L., 2016) Morillo Verdugo, Ramón Alejandro; Villarreal Arévalo, Andrea Lisbeth; Álvarez de Sotomayor Paz, María; Aguas Robustillo-Cortés, María de las; Universidad de Sevilla. Departamento de Farmacología
Objective: To agree on a proposal for pharmaceutical interventions and establish their classification taxonomy according to the CMO-Pharmaceutical Care Model (Capacity-Motivation- Opportunity). Method: A study conducted between March and May, 2016. Two phases of development were defined. A literature review was initially conducted. Then, the DELPHI-Rand-UCLA methodology was used in order to reach a consensus about those interventions selected, and to define the taxonomy. Fifteen (15) experts, specialists in Pharmaceutical Care for HIV+ patients, were selected. This selection was explicitly conducted, following a protocol in order to avoid any bias. An initial proposal was developed according to the interventions extracted from Phase 1. These were tentatively classified according to the CMO Model, in a category based on their design and utility. Three issues were raised from the initial question: Do you agree with the proposed classification? If not, there was an option to re-categorize. Additionally, they were asked about the importance, priority and impact to achieve pharmacotherapeutic objectives that they would assign to it. Interventions were classified according to the degree of agreement. Once a consensus was reached, the final taxonomy was established. Results: Eighteen (18) articles were finally considered. The initial proposal included 20 pharmaceutical interventions with the following classification: seven in Capacity, eight in Motivation, and five in Opportunity. Those interventions considered to have greater importance and priority were: Review and Validation, Safety, and Adherence. The interventions with the greatest impact were: Review and Validation, Coordination, Adherence, and Motivation. On the other hand, the lowest scores for importance were for: Planning and Social Coordination; and in terms of impact: Social Coordination. Conclusions: The taxonomy reached by consensus will allow to classify pharmaceutical interventions with the new model, and therefore to conduct an improved research and patient care.
Efecto de Simvastatina sobre la función vascular: Importancia del endotelio
(1999-06-29) Álvarez de Sotomayor Paz, María; Herrera González, María Dolores; Marhuenda Requena, Elisa; Universidad de Sevilla. Departamento de Farmacología
En las enfermedades cardiovasculares coexisten una serie de factores de riesgo entre los que cabe destacar la elevación de la presión arterial y las disciplinas. Además se ha visto, que la asociación en la misma persona de dos o más factores de riesgo tiene un efecto multiplicativo, más que aditivo sobre el riesgo cardiovascular. En diversos estudios epidemiológicos poblaciones se ha demostrado una relación positiva y significativa entre concentraciones séricas de colesterol y cifras de presión arterial, aunque algunos investigadores consideran esta relación poco relevante desde el punto de vista clínico, hay otros que han sugerido que hipertensión y dislipemia formarían parte de un nuevo síndrome, cuyo origen es poco conocido, pero podía estar determinado por factores genéticos (Williams, 1988). En el estudio Tecumseh (Julius, 1990) con sujetos jóvenes hipertenso, se vio que presentaban de forma significativa concentraciones elevadas de colesterol, triglicéridos e insulina, a la vez que estaba disminuido el colesterol ligado a lipoproteínas de alta densidad (HDL o high density lipoprotein). En este mismo estudio, se recoge que la relación entre la presión arterial y los distintos factores de riesgo para coronariopatías es lineal, incluso en individuos normotensos, de lo que se deduce la existencia de mecanismos comunes para la regulación de los niveles de presión arterial y las diferentes variables metabólicas. Comprender dichos mecanismos será una condición previa para un tratamiento más racional del proceso hipertensivo. Más recientemente, el estudio Tromso (Bonaa, 1991) ha confirmado estos resultados en más de 15.000 sujetos de ambos sexos y ha demostrado que la relación positiva entre los valores de presión arterial y de colesterol total es continua y que las diferencias entre hipertensos y normotensos son secundarias a un desplazamiento hacia la derecha de la curva de concentración de colesterol total en la población hipertensa en relación a la normotensa. Además, la interrelación entre colesterol y presión arterial es más pronunciada en los jóvenes, singularmente en los varones. La introducción de los inhibidores específicos de la 3-hidroxi-3-metilglutaril coenzima A reductasa, entre los que se encuentra simvastatina fue un avance sensacional en la terapéutica de la dislipemia, convirtiéndose en el tratamiento primario de pacientes con concentraciones elevadas de lipoproteínas de baja densidad. Este agente también puso de manifiesto su eficacia para disminuir la mortalidad coronaria según datos de 1994 recogidos en el Scandinavian Simvastatin Survival Study (Scandinavian Simvastatin Survival Study Group, 1994) diseñado para evaluar en hipocolesterolémicos el efecto del tratamiento con simvastatina sobre la mortalidad y morbilidad en pacientes con enfermedad coronaria. En los resultados finales se valoró fundamentalmente la mortalidad total, encontrándose una reducción del 42% en el riesgo de muerte cardiaca, además de disminuir el riesgo de nuevos episodios coronarios y la necesidad de cirugía y angioplastia coronaria. En definitiva se trata del primer ensayo clínico en el que se pone en evidencia la reducción de la mortalidad global tras un tratamiento con simvastatina. Las estrategias encaminadas a combatir factores de riesgo cardiovascular, constituyen uno de los objetivos fundamentales en la actualidad. Y la seguridad de que un fármaco puede modificar de forma significativa los valores de colesterol, actuando a su vez sobre disfunciones comunes a hipercolesterolemia y a hipertensión, es una aportación muy interesante, que puede abrir nuevas perspectivas en el control de los factores de riesgo en la enfermedad cardiovascular. CONCLUSIONES: 1. Simvastatina, fármaco hipocolesterolémico, fue capaz de relajar los anillos de aorta aislada de rata por un mecanismo endotelio-dependiente posiblemente debido a un incremento de la actividad de la NO sintasa. Su actividad inhibidora de la HMG-CoA reductasa parece ser responsable del inicio del efecto vasodilatador, al disminuir la concentración de metabolitos intermediarios de naturaleza isoprenoide. 2. En la acción vasodilatadora de simvastatina, existen otros factores implicados como son los derivados dela vía de la ciclooxigensa, el factor hiperpolarizante dependiente de endotelio, radicales libres con un mayor protagonismo del anión superóxido y la activación del avía de la tirosina kinasa. 3. La arteria mesentérica de rata, vaso que presenta distintas características a los de conductancia, se muestra más sensible a simvastatina, ya que se precisan dosis menores para conseguir el mismo efecto relajante presentando un comportamiento similar al observado en la aorta. La diferencia más significativa está en una acción más evidente sobre los factores contractores de la vía de la ciclooxigenasa. 4. Trabajando con célula endoteliales de aorta bovina, comprobamos que simvastatina induce un incremento de la concentración citosólica de calcio, capaz de provocar una activación de la NO sintas endotelial y de la fosfolipasa A2. Simvastatina libera calcio de los depósitos intracelulares por mecanismos en los que estarían implicados tanto la Ca2+-ATPasa, como la liberación de calcio inducida por calcio, así como una entrada del catión del medio extracelular. Los resultados nos confirman la implicación de la HMG-CoA reductasa, así como el papel de las proteínas Rho en la regulación establecida sobre la concentración de calcio citosólico. 5. La administración de simvastatina en tratamiento crónico a ratas hipertensas, mejoró la función endotelial por estimulación de la NO sintasa, más que por un mecanismo de inhibición de los factores contractores derivados de la ciclooxigenasa. Simvastatina también produce una normalización de la actividad de la bomba Na+/K+, pudiendo atribuir dicho efecto a la regulación de los procesos homeostáticos del calcio en la célula.
Efectos de Oleaster®, un aceite de oliva virgen extra rico en polifenoles, sobre la función vascular en un modelo animal de aterosclerosis
(2017-09-29) Ogalla García, María Elena; Álvarez de Sotomayor Paz, María; Herrera González, María Dolores; Rodríguez Rodríguez, Rosalía; Universidad de Sevilla. Departamento de Farmacología
Según datos obtenidos de la Organización Mundial de la Salud, las enfermedades cardiovasculares y en particular la aterosclerosis, constituyen y lo seguirán haciendo en la próxima década, la primera causa de mortalidad en el mundo. La aterosclerosis implica una lesión arterial caracterizada por la formación de la placa aterosclerótica, un proceso dinámico en el que participan elementos del sistema inmune, moléculas implicadas en procesos inflamatorios y en el que se genera una acumulación de lípidos y proliferación de células musculares y tejido fibroso que producen estenosis en los vasos sanguíneos. Durante las últimas décadas, los cambios en los hábitos alimenticios sobre todo de sociedades desarrolladas, fundamentalmente acompañados por un aumento de la ingesta de grasas saturadas, han contribuido en gran medida a la aparición de un mayor número de casos de enfermedades cardiovasculares como la aterosclerosis. En este sentido, el modelo dietético mediterráneo ha resultado útil en la prevención y tratamiento de esta enfermedad. El componente graso fundamental de la dieta mediterránea es el aceite de oliva, constituido principalmente por ácidos grasos monoinsaturados y gran variedad de moléculas bioactivas como lo compuestos fenólicos y triterpenos, con actividades antioxidantes y ateroprotectoras demostradas. Sin embargo, muchos compuestos fenólicos quedan en el agua de vegetación resultante del propio proceso de obtención del aceite. Oleaster®, es un nuevo aceite de oliva virgen extra obtenido por un novedoso método de extracción, mediante el cual la pérdida de compuestos fenólicos es menor, llegando a alcanzar valores cuatro veces mayores que en otros aceites obtenidos de forma tradicional. La recuperación de compuestos fenólicos que tiene lugar bajo esta nueva forma de obtención de aceite de oliva, posiblemente hace mejorar las propiedades nutracéuticas de este aceite de oliva virgen extra. Para llevar a cabo el estudio se eligió el modelo murino ApoE-/-. Estos ratones transgénicos reproducen muchas de las características del desarrollo de la aterosclerosis en la especie humana, mostrando altos niveles de colesterol y desarrollando una extensa aterosclerosis fibroproliferativa espontánea. OBJETIVOS El mayor contenido fenólico en este aceite presumiblemente debe estar ligado a un aumento de las propiedades biológicas que se le atribuyen, particularmente en la prevención de enfermedades cardiovasculares como la aterosclerosis. El objeto general de este estudio ha sido evaluar el potencial biológico de una dieta suplementada en Oleaster® frente a otro aceite de oliva virgen extra con cantidades normales de estos principios activos en el progreso de la aterosclerosis en un modelo genético de ratones con predisposición al desarrollo de esta enfermedad. Para llevarlo a cabo se establecieron los siguientes objetivos específicos: 1. Evaluar si el alto contenido en polifenoles que proporciona Oleaster® en la dieta aporta beneficios adicionales frente a un aceite de oliva virgen extra convencional, en el desarrollo de la lesión aterosclerótica y la función vascular en aorta de ratones ApoE-/-. 2. Determinar los mecanismos de acción implicados en estos efectos en aorta de ratones ApoE-/-, especialmente aquellos relacionados con la inflamación y el estrés oxidativo. 3. Analizar los efectos de varias dietas con grasa de diferente composición (alto contenido en grasa saturada frente a grasa insaturada del aceite de oliva virgen), sobre las propiedades mecánicas, estructurales y funcionales en arterias de resistencias de ratones ApoE-/-. 4. Estudiar si la modificación de estas propiedades en arterias de resistencia de ratones ApoE-/- están relacionadas o no con el contenido polifenólico aportado por los diversos aceites de oliva. CAPÍTULO I “El contenido fenólico del aceite de oliva virgen extra es esencial para restaurar la disfunción endotelial pero no para prevenir la inflamación vascular en lesiones ateroscleróticas de ratones deficientes en ApoE” El aceite de oliva virgen extra (EVOO) contiene ácidos grasos monoinsaturados y múltiples componentes menores con propiedades biológicas y beneficios para la salud. En este trabajo, se evaluó si una dieta suplementada con Oleaster® (OT), un EVOO obtenido mediante un nuevo procedimiento destinado a aumentar la composición fenólica, proporcionaba beneficios adicionales a los observados en los animales alimentados con una dieta rica en EVOO obtenido de forma tradicional sobre el desarrollo de la aterosclerosis y la función vasomotora en la aorta de ratones ApoE-/-. Los resultados se compararon con los obtenidos en ratones alimentados con EVOO, una dieta estándar (SD) o una dieta rica en grasas (HFD) rica en ácidos grasos saturados. Ambos aceites de oliva virgen extra redujeron la acumulación de macrófagos y la expresión proteica de iNOS, ICAM-1 y VCAM-1, TNFα y NF-κB, independientemente de su contenido fenólico en relación con los valores encontrados en SD. La producción de aniones superóxido se redujo también en la misma medida en ratones ApoE-/- alimentados con EVOO y OT. La función endotelial evaluada mediante la vasodilatación inducida por la ACh y la acumulación de lípidos dentro de la placa aterosclerótica se restablecieron en OT pero no en ratones alimentados con EVOO. Con estos resultados, concluimos que EVOO contribuye a prevenir los marcadores inflamatorios de la progresión de la placa aterosclerótica, pero el contenido en polifenoles no es responsable de este efecto. Sin embargo, estos compuestos sí son capaces de restaurar la función endotelial y de reducir la acumulación de lípidos dentro de la lesión aterosclerótica. CAPÍTULO II “Propiedades estructurales, mecánicas y miogénicas de las pequeñas arterias mesentéricas de ratones ApoE KO: Caracterización y efectos de las dietas de aceite de oliva virgen” El objetivo de este estudio fue analizar las propiedades estructurales, mecánicas, miogénicas y funcionales de las arterias resistentes de ratones ApoE KO en comparación con ratones de tipo salvaje (WT). También se determinó la influencia de la grasa saturada en comparación con las dietas enriquecidas con aceite de oliva virgen en las anomalías de la pared vascular. Para ello se utilizaron ratones macho ApoE KO y WT de 8 semanas de edad, los cuales fueron divididos en los grupos: dieta estándar (SD), dieta alta en grasa (HFD), aceite de oliva virgen (VOO) y aceite de oliva alto en polifenoles (Oleaster®) (OT) (15% p/p). Después de 20 semanas, se analizaron las propiedades estructurales, mecánicas y miogénicas de la arteria mesentérica superior mediante miografía de presión. Para los estudios funcionales, se evaluó la vasodilatación con acetilcolina y la producción de aniones superóxido arterial se midió por fluorescencia de etidio. Se pudo observar cómo el remodelado hipertrófico de las arterias mesentéricas de ratones ApoE-/- fue menor en comparación con los ratones WT, lo que sugiere una alteración en los mecanismos de autorregulación destinados a compensar la progresión de la enfermedad. Sin embargo, la deficiencia de ApoE resultó en un menor deterioro en el tono miogénico en respuesta a la presión intraluminal, además de una mejora de la vasodilatación hiperpolarizante dependiente del endotelio. Además, se ha puesto de manifiesto los efectos beneficiosos del aceite de oliva en contraste con una dieta alta en grasas saturadas en los trastornos de la pared de las arterias mesentéricas de estos animales. Sin embargo, solo la mejora de la función endotelial inducida por el aceite de oliva depende del mayor contenido fenólico. Por tanto, podemos concluir que la estructura de las arterias de resistencia y las respuestas mecánicas, miogénicas y funcionales de los ratones ApoE KO difieren significativamente de los ratones WT, evidenciando la influencia del tipo de dieta en estos trastornos. Estos resultados son particularmente útiles para determinar la contribución de las arterias de resistencia durante el proceso aterosclerótico y para proporcionar nuevos conocimientos sobre el patrón dietético mediterráneo para reducir la carga de la enfermedad aterosclerótica. CONCLUSIONES Como conclusión general, el aceite de oliva virgen extra aporta evidentes beneficios durante el desarrollo de la aterosclerosis, gracias a su contenido en ácidos grasos monoinsaturados. Un aporte mayor en compuestos fenólicos en estos aceites ofrece una protección extra frente al inicio y avance de la enfermedad, favoreciendo eventos tempranos propios de ésta como son la disfunción endotelial y la acumulación lipídica en la íntima arterial.
Efectos sobre la función vascular de l-carnitina y su derivado acilado propionil-l-carnitina
(2003) Bueno Borrego, Rosa María; Herrera González, María Dolores; Álvarez de Sotomayor Paz, María; Pérez Guerrero, María Concepción; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Effects of Dietary Oleacein Treatment on Endothelial Dysfunction and Lupus Nephritis in Balb/C Pristane-Induced Mice
(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Muñoz García, Rocío; Sánchez Hidalgo, Marina; Alcarranza Saucedo, Manuel; Vázquez Román, María Victoria; Álvarez de Sotomayor Paz, María; González Rodríguez, María Luisa; Andrés, María C.; Alarcón de la Lastra Romero, Catalina; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Instituto de Salud Carlos III
Systemic lupus erythematosus (SLE) is a chronic immune-inflammatory disease characterized by multiorgan affectation and lowered self-tolerance. Additionally, epigenetic changes have been described as playing a pivotal role in SLE. This work aims to assess the effects of oleacein (OLA), one of the main extra virgin olive oil secoiridoids, when used to supplement the diet of a murine pristane-induced SLE model. In the study, 12-week-old female BALB/c mice were injected with pristane and fed with an OLA-enriched diet (0.01 % (w/w)) for 24 weeks. The presence of immune complexes was evaluated by immunohistochemistry and immunofluorescence. Endothelial dysfunction was studied in thoracic aortas. Signaling pathways and oxidative-inflammatory-related mediators were evaluated by Western blotting. Moreover, we studied epigenetic changes such as DNA methyltransferase (DNMT-1) and micro(mi)RNAs expression in renal tissue. Nutritional treatment with OLA reduced the deposition of immune complexes, ameliorating kidney damage. These protective effects could be related to the modulation of mitogen-activated protein kinases, the Janus kinase/signal transducer and transcription activator of transcription, nuclear factor kappa, nuclear-factor-erythroid-2-related factor 2, inflammasome signaling pathways, and the regulation of miRNAs (miRNA-126, miRNA-146a, miRNA-24-3p, and miRNA-123) and DNMT-1 expression. Moreover, the OLA-enriched diet normalized endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 overexpression. These preliminary results suggest that an OLA-supplemented diet could constitute a new alternative nutraceutical therapy in the management of SLE, supporting this compound as a novel epigenetic modulator of the immunoinflammatory response.
Effects of pomace olive oil-enriched diets on endothelial function of small mesenteric arteries from spontaneously hypertensive rats
(Cambridge University Press, 2009) Rodríguez Rodríguez, Rosalía; Herrera González, María Dolores; Álvarez de Sotomayor Paz, María; Ruiz Gutiérrez, Valentina; Universidad de Sevilla. Departamento de Farmacología
Pomace olive oil (POM), an olive oil subproduct traditionally used in Spain, is a good source of minor components from the unsaponifiable fraction such as triterpenoids, mainly in the form of oleanolic acid, which induces vascular protection and vasodilatation. Our aim was to evaluate the effects of long-term intake of diets enriched in POM with high concentration in oleanolic acid on endothelial dysfunction associated to hypertension in small mesenteric arteries (SMA) from spontaneously hypertensive rats (SHR). During 12 weeks, rats (six rats per group) were fed either a control 2% maize oil diet (BD), or high-fat diets containing 15% refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in oleanolic acid (POMO; up to 800 parts per million). Endothelial and vascular functions were assessed by relaxing or contracting responses to acetylcholine (ACh) or phenylephrine, respectively. The involvement of endothelium-derived relaxing factors in these responses was evaluated. In contrast to BD, SHR fed high-fat diets showed a biphasic response to ACh related to changes in eicosanoid metabolism. POM enhanced the endothelial function in SMA from SHR by increasing the endothelium-derived hyperpolarising factor (EDHF)-type component, whereas administration of POMO resulted in a similar contribution of NO/EDHF in the endothelial response to ACh. The present study shows that despite the lack of changes in blood pressure, consumption of POM improves endothelial function in SMA from SHR by improving the agonist-mediated EDHF/NO response. Thus, triterpenoids confer a protective role to POM against endothelial dysfunction in hypertension.
Endothelium modulates contractile response to simvastatin in rat aorta
(Walter de Gruyter, 2000) Pérez Guerrero, María Concepción; Álvarez de Sotomayor Paz, María; Herrera González, María Dolores; Marhuenda Requena, Elisa; Universidad de Sevilla. Departamento de Farmacología
Simvastatin is an inhibitor of HMG-CoA reductase used in the treatment of hypercholesterolemia. In the present study simvastatin-induced contraction was observed in rat aortic thoracic rings, this effect increased when the endothelium was removed and when NO synthase was blocked by L-NOARG (3 x 10-5 M). The contractile effect of simvastatin on intact aortic rings diminished when cyclo-oxygenase was inhibited with indomethacin (10-5 M). Also in the presence of endothelium, pretreatment with mevalonate (1 mM), the product of HMGCoA reductase activity, significantly inhibited the contraction. In other experiments carried out on endothelium-removed preparations and in medium containing the calcium antagonist, diltiazem (10-5 and 10-6 M), the contraction dose-response curves were significantly reduced and the same happened in the presence of the inhibitor of sarcoplasmic reticulum Ca-2+ATPase, cyclopiazonic acid (CPA) (3 x 10-6 M). The results suggest that simvastatin might increase intracellular calcium concentration. This effect could lead to an activation of NO synthase and cyclooxygenase pathways in endothelial cells and to contraction in vascular smooth muscle cells. This rise in Ca2+ concentration could be due to an inhibition of isoprenoid synthesis prevented by mevalonate.
Endothelium-dependent vasorelaxation induced by L-carnitine in isolated aorta from normotensive and hypertensive rats
(JPP, 2002) Herrera González, María Dolores; Bueno, Rosario; Álvarez de Sotomayor Paz, María; Pérez Guerrero, María Concepción; Vázquez Cueto, Carmen María; Marhuenda Requena, Elisa; Universidad de Sevilla. Departamento de Farmacología
The aim of this work was to investigate the mechanism of the vasodilatory effect induced by L- carnitine. Relaxation produced by L-carnitine was studied in rat aortic rings with and without functional endothelium, pre-contracted with phenylephrine by adding cumulative doses of L- carnitine (10-7 to 10-3 M). The relaxation evoked by L-carnitine reached higher values in aortic rings from spontaneously hypertensive rats than those obtained in arteries from normotensive rats; no relaxation was produced in de-endothelialized arteries. However, in the presence of NG-nitro-L- arginine (3¬10-5 M, a nitric oxide synthase inhibitor), Ro 68070 (10-4 M, a thromboxane synthetase inhibitor–thromboxane A2/prostaglandin H2 receptor antagonist) or ICI 192605 (10- M, a thromboxane A2 receptor antagonist) the relaxant response to L-carnitine was signiicantly inhibited. These results show that L-carnitine induced endothelium-dependent relaxation in the rat aorta and the mechanism of this relaxation appeared to be mostly mediated by endothelial production of nitric oxide but also could involve prevention of the action of cyclooxygenase endothelial products acting on the thromboxane A2/prostaglandin H2 receptor.
Evaluación del efecto protector de un extracto enzimático de salvado de arroz frente al estado inflamatorio presente en el proceso aterosclerótico
(2017-02-01) Pérez Ternero, Cristina; Álvarez de Sotomayor Paz, María; Herrera González, María Dolores; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. CTS178: Farmacología Cardiovascular
INTRODUCTION Rice bran is a phytochemical-rich layer that surrounds the endosperm of whole grain brown rice. It is produced as a by-product of white rice milling and discarded or designated to animal feeding due to its tendency to rancid reactions that impede its safe consumption. However, there is accumulating evidence that consumption of stabilized rice bran promotes health benefits in humans due to the multifactorial activities of the minor constituents. gamma-oryzanol, the main bioactive molecule in the unsaponificable fraction of rice bran, accounts for well recognized lipid lowering and antioxidant activities. Gamma-oryzanol is cleaved into ferulic acid and sterols by intestinal lipase enzymes. Sterols in the intestine promote cholesterol elimination by competing with cholesterol absorption, while ferulic acid is absorbed and inhibits hepatic cholesterol synthesis by HMG-CoA-reductase. Moreover, ferulic acid has been found to reduce oxidative stress by inducing a more favourable balance between the expression of enzymes related to oxidative stress in favour of the antioxidant defences. In addition to the lipid lowering and antioxidant activities, rice bran is known by its anti-inflammatory actions through reduction of NF-κβ activation. Moreover, rice bran has an important antidiabetic activity related to the normalization of liver enzymes implicated in the metabolism and synthesis of glucose, and to increased secretion of insulin by the pancreas. Prior works of our group showed improvement of several markers of metabolic syndrome and obesity of animals whose diet was supplemented with a rice bran enzymatic extract (RBEE). The enzymatic extraction is carried out at controlled pH and temperature to preserve the activity of the phytochemicals, and allows the stabilization of the original raw material by inactivation of endogenous lipases. The final product is a water-soluble syrup with higher biological quality compared to raw rice bran. There is a net increase in the bioactive components, mainly of gamma-oryzanol and tocotrienols, and the fragmentation of the proteins into peptides of low molecular weight allows the solubilisation of the hydrophobic components by interaction. RBEE supplements to high fat diet improved total cholesterol and HDL cholesterol in Wistar rats. Moreover, RBEE-supplemented diet was able to attenuate hypertension insulin resistance and to improve serum lipids in obese Zucker rats. Moreover, vascular function of the aorta and mesenteric arteries of Zucker rats was improved by increasing the expression of eNOS and calcium activated potassium channels and decreasing vascular oxidative stress and inflammation. Moreover, RBEE supplements attenuated structural changes of adipose tissue and normalized the expression of pro-inflammatory markers such as TNF-alpha, IL-6, IL-1β and iNOS and proinflammatory macrophage polarization of Zucker rats and diet induced obesity-mice. These promising protective cardiometabolic activities derived from diet supplementation with RBEE are of great interest for atherogenesis prevention. Atherosclerosis is the underlying cause for 80% of the deaths caused by cardiovascular diseases. Atherosclerosis is characterized by a low-grade systemic inflammatory and prooxidante state, causing the narrowing of the arteries caused by the accumulation of cholesterol, collagen, vascular smooth muscular cells and other cell types in the vessel wall. These plaques can eventually break causing thrombosis that could block blood flow to tissues, precipitating ischemic events. The process is trigged by small endothelial damages that cause a change in the endothelium, incrementing its permeability to cholesterol and immune cells. Cumulative LDL cholesterol in the arterial wall and its oxidative modifications stimulates monocyte infiltration and foam cell growth by cholesterol phagocytosis. The process is enhanced by oxidative stress and inflammation, which are the underlying cause of other pathologies that come along and potentiate atherosclerosis. Endothelial dysfunction is a predictive factor for atherosclerosis development. Hypercholesterolemia induces the activation of NADPHox reducing the amount of NO available for vasorelaxation, and reduces the activity of eNOS. In further stages of the progression of atherosclerosis, vascular remodelling due to plaque growth, VSMC proliferation and collagen deposition can alter vascular function, both in conductance as well as resistance vessels. Another consequence of hypercholesterolemia is the development of non-alcoholic fatty liver, which can promote atherosclerosis through liberation of proinflammatory cytokines. These prooxidant and proinflammatory stimuli increase vascular apoptosis causing a high cellular turnover that will lead to early cellular senescence, another cause of atherosclerosis promotion. However, macrophage apoptosis could be beneficial to prevent foam cell formation as long as apoptotic bodies are removed and not accumulated in the plaque core. Cellular apoptosis is also induced by dysfunctional mitochondria. Mitochondria are both, source and target of oxidative stress. Reactive oxygen species are key mediators of signalling pathways underlying vascular inflammation in atherosclerosis progression. High oxidative environment causes the modification of mitochondrial DNA leading to dysfunctional proteins and uncoupled mitochondria, which will produce vast amounts of superoxide promoting atherogenesis. Antioxidant-rich foods, such as rice bran can help to abrogate oxidative stress and inflammation. However, to understand the underlying mechanisms and the biological relevance, it is of great importance to investigate the absorption and metabolism of the active molecules. Although gamma-oryzanol is the major phytochemical in rice bran, its appearance in serum was never detected due to its low water solubility, the size of the molecule and more importantly, to pancreatic esterase activity in the intestine which leads to the release of ferulic acid. Diet is the first basic prevention measure as well as the first approach to hyperlipidaemia. Rice bran, rice bran oil and its main bioactive molecules have shown ability to reduce plasma cholesterol and the complications derived from hypercholesterolemia in several clinical studies. Therefore, rice bran and its technological- and qualitatively-improved presentation, the RBEE, appear as promising functional food ingredients for the prevention and treatment of atherosclerosis and atherosclerosis-related disorders. OBJECTIVES Given the biological potential of rice bran for the prevention of cardiovascular diseases and the technological improvement and in the concentration of the bioactive ingredients introduced by the enzymatic extraction, the general objective of this thesis was the study of the effects of diet supplementation with the RBEE on the progression of atherosclerosis in a genetic model of hypercholesterolemia and atherosclerotic plaque development. The specific objectives for this thesis were the following: -To carry out a review of the cardiometabolic and vascular effects of rice bran known to date, as well as its derived preparations and main bioactive molecules. -To study the effect of RBEE on atherogenesis. -To study the hypocholesterolemic mechanism of RBEE. -To study the effects of RBEE consumption on the mechanisms related to the atherosclerotic process: oxidative stress and inflammation. -To study the effects of dietary supplementation with RBEE on endothelial dysfunction in the aorta and resistance arteries. -To study the effects of RBEE consumption on the appearance of functional alterations resulting from the atherosclerotic process, such as steatosis, mitochondrial dysfunction, cellular senescence and apoptosis. -To study the bioavailability of one of the major bioactive molecules of RBEE, ferulic acid. -To identify the bioactive molecules present in the RBEE that are responsible for the observed effects. -To study the antioxidant effects derived from the consumption of ferulic acid in human polymorphonuclear cells. CHAPTER I "Contribution of ferulic acid, gamma-oryzanol and tocotrienols to the cardiometabolic protective effects of rice bran" Rice bran is an excellent nutritional source of bioactive compounds, including phytochemicals such as ferulic acid, gamma-oryzanol, phytosterols and tocols. These bioactive molecules have shown cardiometabolic protection, such as anti-diabetic and anti-hypertensive effects, but more importantly, lipid lowering effects due to cholesterol synthesis downregulation and increased faecal excretion. Moreover, rice bran phytochemicals have been described to mitigate oxidative stress by increasing antioxidant enzymes and by reducing oxygen radical production, and to possess anti-inflammatory activity due to downregulation of NF-κβ activation and reduction of pro-inflammatory cytokines production. This review aims to update and summarize clinical and animal studies, describing the multifactorial activities of rice bran and the individual contribution of its main bioactive compounds, namely, gamma-oryzanol, ferulic acid, phytosterols, triterpenic alcohols and tocotrienols. Technological factors affecting biological activities of the different rice bran-derived preparations are also discussed. CHAPTER II “Rice bran enzymatic extract reduces atherosclerotic plaque development and steatosis in high fat fed ApoE-/- mice.” Here, we aimed to identify RBEE hypolipidemic mechanism and to study the effects of RBEE on the progression of atherosclerosis disease and linked vascular dysfunction and liver steatosis in ApoE-/- mice fed low (LFD) or high (HFD) fat diets. ApoE-/- mice were fed LFD (13% kcal) or HFD (42% kcal) supplemented or not with 1 or 5% RBEE (w/w) for 23 weeks. Then, serum, aorta, liver and faeces were collected and flash frozen for further analysis. RBEE supplementation of HFD improved serum values by augmenting HDL-C and preventing total cholesterol and AST increase. HMG-CoA reductase activity was attenuated (1% and 5% RBEE) and cholesterol excretion increased (5% RBEE). 5% RBEE diet supplementation reduced plaque development regardless of the diet. In HFD-fed mice, both doses of RBEE reduced lipid deposition and macrophage infiltration in the aortic sinus and downregulated ICAM-1 and VCAM-1 expression. None of these effects were observed in mice fed LFD. Liver steatosis was reduced by RBEE supplementation of LFD (1% RBEE) and HFD (1 and 5% RBEE) and nuclear PPAR-α expression upregulated in HDF 5% RBEE group. Regular consumption of RBEE-supplemented HFD reduced plaque development and liver steatosis by decreasing inflammation and hyperlipidemia through a HMG-CoA reductase activity and lipid excretion related mechanism. CHAPTER III “Diet supplementation with rice bran enzymatic extract restores endothelial impairment and wall remodelling of ApoE-/- mice microvessels” Small mesenteric artery resistance and functionality are key factors for the maintenance of blood homeostasis. We attained to evaluate the effects of a rice bran enzymatic extract (RBEE) on structural, mechanic and myogenic alterations and endothelial dysfunction secondary to atherosclerosis disease. Seven week-old ApoE-/- mice were fed on standard (ST) or high fat (HF) diets supplemented or not with 1 or 5 % RBEE (w/w) for 23 weeks. Wild-type C57BL/6J mice fed on ST diet served as controls. Small mesenteric arteries were mounted in a pressure myograph in order to evaluate structural, mechanical and myogenic properties. Vascular reactivity was assessed in the presence of different combinations of inhibitors: L-NAME, indometacin, apamin and charybdotoxin. ApoE-/- mice fed on ST and HF diets showed different structural and mechanical alterations, alleviated by RBEE supplementation of ST and HF diets. C57BL/6J was characterized by increased expression of IKCa (199.3%, p=0.023) and SKCa (133.2%, p=0.026), resulting in higher EDHF participation (p=0.0001). However, NO release was more relevant to ApoE-/- mice vasodilatation. HF diet reduced the amount of NO released due to 2-fold increase of eNOS phosphorylation in the inhibitory residue Thr495 (p=0.034), which was fully counteracted by RBEE supplementation (p=0.028), restoring ACh-induced vasodilatation (p=0.00006). Dihydroethidium fluorescence of superoxide and picrosirius red staining of collagen were reduced by RBEE supplementation of HF diet by 76.91% (p=0.022) and 65.87% (p=0.030), respectively. RBEE supplemented diet reduced vessel remodelling and oxidative stress. Moreover, RBEE supplemented diet increased NO release by downregulating p-eNOSThr495, thus, protecting the endothelial function. CHAPTER IV “Atherosclerosis-related inflammation and oxidative stress are improved by Rice Bran Enzymatic Extract” The objective of this work was to test the antioxidant and anti-inflammatory potential of Rice Bran Enzymatic Extract diet supplementation in atherosclerotic mice. ApoE-/- mice were fed high fat diet supplemented with 1 or 5% rice bran enzymatic extract (RBEE). In parallel, 100 ng/ml-LPS induced human monocytes were treated with 20 µg/ml RBEE, ferulic acid (FA) or gamma-oryzanol (g-Ory). RBEE diet supplements reduced NF-κβ activation, TNF-α, COX-2 and iNOS expression and serum NO-derived metabolites. Additionally, NADPH oxidase subunits were downregulated, resulting in lower superoxide production, as evidenced by lower dihydroethidium fluorescence and oxLDL deposition in the aorta. RBEE, FA and g-Ory reduced pro-inflammatory monocyte (CD14++ CD16+) phenotype and increased non-classical monocytes (CD14- CD16++). A shift towards M2 polarized macrophages was observed, leading to reduced IL-6 and TNF-α mRNA expression. RBEE chronic consumption ameliorates atherosclerosis-related oxidative stress and inflammation showing its potential as nutritional supplement. FA moiety of g-Ory was identified as the main responsible for the actions observed. CHAPTER V “Food supplementation with rice bran enzymatic extract prevents vascular apoptosis and atherogenesis in ApoE-/- mice” Here we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice. Seven weeks-old male ApoE-/- mice were fed high fat diet (HFD) or isocaloric HFD supplemented with 5% (w/w) RBEE for 23 weeks. RBEE treatment reduced total cholesterol (744±63 vs 947±66 mg/dL) and triglycerides (97±16 vs 155±20 mg/dL) and augmented HDL-cholesterol (69±8 vs 35±8 mg/dL). RBEE attenuated macrophage infiltration by 56.69±4.65% and plaque development (7,737±836 vs 12,040±1,001 μm2) in the aortic sinus. In the aorta, RBEE treatment reduced expression of the apoptosis markers p16, p53 and bax/bcl2-ratio. RBEE prevented apoptosis of aortic endothelial cells (2.81±0.71 to 1.14±0.35 apoptotic nuclei/ring for ApoE-/- HFD and ApoE-/- HFD 5% RBEE, respectively). In contrast, MNC of RBEE-fed mice exhibited enhanced apoptosis marker expression with increased p53 and bax/bcl-2 protein levels. Compared to WT, ApoE-/- mice on HFD were characterized by significant telomere shortening in aorta (11±2%) and MNC (73±7%), which was reduced by supplementation with RBEE (aorta: 40±7%; MNC: 105±10%). Expression of telomere repeat-binding factor 2 was increased in RBEE fed mice. Long-term food supplementation with RBEE lowers cholesterol and prevents atherosclerotic plaque development in ApoE-/- mice. Differential regulation of vascular and MNC apoptosis and senescence were identified as potential mechanisms. CHAPTER VI “Bioavailability of the ferulic acid-derived phenolic compounds of a rice bran enzymatic extract. Activity against the superoxide production” The aims of this work were to describe the oral bioavailability and metabolic pathways of the ferulic acid-derived phenolic compounds contained in a rice bran enzymatic extract (RBEE), and to determine its activity upon NADPH oxidase activity. Wistar rats were administrated 10 g RBEE per kg and sacrificed at different times over a period of 24 h to obtain plasma. Urine and faeces were collected for 48 h. The phenolic metabolites were determined by liquid chromatography (UHPLC-MS/MS), and plasma pharmacokinetic parameters were calculated. In parallel, aortic rings were incubated in the plasma of rats sacrificed 30 min after water or RBEE gavage, or in HEPES-KHS in the presence of RBEE, ferulic acid or gamma-oryzanol, respectively. Endothelin-1-induced superoxide production was recorded by lucigenin enhanced luminescence. Twenty-five ferulic acid metabolites were found in the plasma showing a biphasic behaviour. Most of the urine metabolites were the same as those found in the plasma while in the faeces, colonic metabolism led to the simple phenol compounds. Finally, superoxide production was abrogated by phenolic compounds-enriched plasma and by RBEE and ferulic acid showing the biological potential of RBEE as a nutraceutical ingredient due to the benefits derived from NADPH oxidase inhibition. CHAPTER VII “Ferulic acid, a bioactive component of rice bran, improves oxidative stress and mitochondrial biogenesis and dynamics in mice and in human mononuclear cells” The objective of this work was to characterize the molecular effects of rice bran and its components on vascular oxidative stress and mitochondrial dysfunction during atherogenesis in mice and in humans. ApoE-/- mice were fed a high-fat, high-cholesterol diet (HFD) or HFD supplemented with 5% rice bran enzymatic extract (RBEE) for 21 weeks. RBEE prevented development of atherosclerotic plaques and oxidative stress in mouse aorta, as exemplified by increased GSH/GSSG ratio, reduced peroxiredoxin-SO3 and reduced lipid peroxidation. RBEE prevented the HFD-mediated downregulation of mRNA expression of markers of mitochondrial biogenesis (Pgc-1α, Pgc-1β, Nrf-1) and dynamics (Mfn1, Mfn2, Fis1, Beclin-1). Moreover, RBEE increased p-AMPK leading to increased deacetylation of PGC-1α. Analysis of the bioactive components of RBEE in bovine aortic endothelial cells identified ferulic acid as the component responsible for the observed effects. Ferulic acid metabolites such as sulfonates and glucuronides significantly increased in murine liver and kidney after treatment. To confirm these findings in humans, the kinetics of ferulic acid and its metabolites were determined in healthy volunteers who consumed 500 mg ferulic acid/day for 15 days. Ferulic acid intake reduced NADPH oxidase activity, superoxide release, apoptosis and necrosis and increased PGC-1α and MFN1 mRNA expression in human peripheral blood mononuclear cells. Moreover, differentiation and proliferation of endothelial progenitor cells were improved. Ferulic acid was identified as a major active component of rice bran, which improved mitochondrial biogenesis and dynamics and reduced oxidative stress in mouse aorta and human mononuclear cells. CONCLUSION The results obtained in this thesis suggest that the supplementation of a high fat and high cholesterol diet with RBEE improves the pro-inflammatory and prooxidant state present in atherosclerosis, preventing its progress and other alterations associated with atherosclerosis: vascular dysfunction and remodelling, steatosis, apoptosis, cellular senescence and mitochondrial dysfunction.
Identificación del indice de complejidad de farmacoterapia total, como factor asociado de la adherencia al tratamiento antirretroviral en pacientes VIH+
(2019-09-27) Manzano García, Mercedes; Álvarez de Sotomayor Paz, María; Pérez Guerrero, María Concepción; Universidad de Sevilla. Departamento de Farmacología
Impact of Frailty on Outcomes of First-Line Pembrolizumab Monotherapy in a Real-World Population with Advanced Non-Small Cell Lung Cancer
(MDPI, 2023) Jiménez Galán, Rocío; Prado-Mel, Elena; Álvarez de Sotomayor Paz, María; Abdel-Kader Martín, Laila; Universidad de Sevilla. Departamento de Farmacología
ICIs have been able to improve overall survival in advanced-stage lung cancer. The benefit of this therapy is limited in patients with poor ECOG PS. However, this scale is imprecise and can be influenced by different factors, such as frailty. Cancer patients have a high risk of frailty independently of age. In this observational, single-center, retrospective study, we investigated the effect of frailty on the effectiveness of pembrolizumab in first-line use in a cohort of 101 patients with metastatic NSCLC. Frailty was determined using a frailty score system developed by Sakakida et al. Univariate and multivariate analysis was performed to determine the prognostic role of frailty on OS and PFS. Median OS was significantly higher in patients with low frailty compared with intermediate and high frailty (23.8 vs. 7.0 and 1.8 months, respectively; p < 0.001). Median PFS was also significantly higher in patients with low frailty compared with intermediate and high frailty (10.5 vs. 3.9 and 1.6 months; p < 000.1, respectively). Frailty was the only variable that showed significant differences in OS and PFS. Multivariate analysis confirms frailty as an independent predictor of OS and PFS. Frailty assessment could help to select which patients are candidates for ICIs in NSCLC.
Interés terapéutico de las estatinasen el tratamiento de la aterosclerosis
(Universidad de Granada: Facultad de Farmacia, 1999) Pérez Guerrero, María Concepción; Álvarez de Sotomayor Paz, María; Herrera González, María Dolores; Marhuenda Requena, Elisa; Universidad de Sevilla. Departamento de Farmacología
Los inhibidores de la HMG-Co A reductasa o estatinas, son fármacos muy utilizados en el tratamiento de la hipercolesterolemia, ya que consiguen disminuir la concentración plamática de lipoproteína de baja densidad (LDL) regulando la síntesis endógena de colesterol y por tanto, de receptores para LDL. Recientemente se ha comprobado como el tratamiento prolongado con estos fármacos disminuyen la mortalidad y morbilidad cardiovascular. Este fenómeno puede explicarse por los efectos beneficiosos directos de las estatinas en el desarrollo de la placa de ateroma. Las estatinas disminuyen la proliferación y migración de células de musculatura lisa vascular e inducen apoptosis de estas células. También previenen la oxidación de LDL y la formación de células espumosas, reducen la respuesta inflamatoria asociada a la aterosclerosis, normalizan los fenómenos de coagulación y fibrinolisis y por último mejoran significativamente la función endotelial. Todas estas propiedades parecen estar mediadas compuestos isoprenoides intermediarios de la ruta metabólica de la HMG-Co A reductasa, y son indepen- dientes de la concentración de colesterol en el medio. Por tanto, las estatinas también podrían ser utilizadas en enfermedades asociadas a disfunción endotelial indepen- dientemente de las cifras analíticas de LDL, tal y como sucede en la hipertensión
Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats
(Cambridge University Press, 2009) Mingorance Gutiérrez, María del Carmen; González del Pozo, María; Herrera González, María Dolores; Álvarez de Sotomayor Paz, María; Universidad de Sevilla. Departamento de Farmacología
Propionyl-l-carnitine (PLC) is an SCFA esterified to carnitine that plays an important role in fatty acid oxidation and energy expenditure, in addition to having a protective effect on the endothelium. In order to evaluate the effect of PLC on an animal model of obesity, insulin resistance and, consequently, endothelial dysfunction, lean and obese Zucker rats (OZR) received either vehicle- or PLC-supplemented drinking water (200mg/kg per d) for 20 weeks. Body weight, food intake, systolic blood pressure and heart rate were controlled weekly and an oral glucose tolerance test was performed. Fasting glucose, TAG, cholesterol, HDL, NEFA, adiponectin and insulin were analysed in serum. Visceral adipose tissue and liver were weighed and liver TAG liver composition was evaluated. Endothelial and vascular functions were assessed in the aorta and small mesenteric arteries by response to acetylcholine, sodium nitroprusside and phenylephrine (Phe); NO participation was evaluated after incubation with the NO synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME) and endothelial NOS protein expression by Western blotting. PLC decreased body-weight gain, food intake, adiposity, insulin serum concentration and TAG liver content and improved insulin resistance. Aortae from OZR receiving either vehicle or PLC exhibited a lower contractile response to Phe. PLC-treated OZR showed an enhanced release of endothelial NO upon the adrenergic stimulation. The protection of vascular function found after treatment with PLC in an animal model of insulin resistance supports the necessity of clinical trials showing the effect of l-carnitine supplements on metabolic disorders.
Perfluorohexyloctane in dry eye disease: A systematic review of its efficacy and safety as a novel therapeutic agent
(Elsevier, 2023) Ballesteros Sánchez, Antonio; Hita Cantalejo, María Concepción de; Sánchez González, María del Carmen; Jansone-Langine, Zane; Álvarez de Sotomayor Paz, María; Culig, Josip; Sánchez González, José María; Universidad de Sevilla. Departamento de Física de la Materia Condensada; Universidad de Sevilla. Departamento de Farmacología
Perfluorohexyloctane (F6H8), a physically and chemically inert synthetic compound, has recently emerged as a promising candidate for the treatment of DED due to its unique properties. A systematic review that only include full-length randomized controlled studies (RCTs), reporting the effects of F6H8 in three databases, PubMed, Scopus and Web of Science, was performed according to the PRISMA statement. The search period was performed between June 1, 2023, and June 21, 2023. The Cochrane risk of bias tool was used to analyze the quality of the studies selected. A total of six RCTs were included in this systematic review. F6H8 tear substitutes treatment achieved a higher improvement than control group interventions in most of the reported variables. The mean differences between both groups were in favor of F6H8 and were as follow: eye dryness score (EDS) base on a visual analogue scale (VAS) of −6.12 ± 4.3 points, ocular surface disease index (OSDI) questionnaire score of −2.8 ± 2.3 points, lipid layer thickness (LLT) of 11.4 ± 10.4 μm, total corneal fluorescein staining (tCFS) of −0.8 ± 0.3 points and ocular treatment-emergent adverse events (TEAEs) of −0.66 ± 1.7. Tear film break-up time (TBUT) was the only variable in favor of control group with a mean of −0.5 ± 0.4 s. Patient satisfaction after F6H8 tear substitutes treatment was high. Therefore, F6H8 tear substitutes improve dry eye symptoms and signs with a satisfactory tolerability and could be recommended in patients with DED.

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Examinando Farmacología por Autor "Álvarez de Sotomayor Paz, María"