Antihypertensive Mechanism of Lactoferrin-Derived Peptides: Angiotensin Receptor Blocking Effect

Texto del artículo, no incluye figuras ni tablas.Looking for antihypertensive mechanisms beyond ACE inhibition, we assessed whether lactoferrin (LF)-derived peptides can act as receptor blockers to inhibit vasoconstriction induced by angiotensin II or endothelin-1. The lactoferricin B (LfcinB)-derived peptide LfcinB20–25 (RRWQWR), the low molecular weight LF hydrolysate (LFH < 3 kDa), and two peptides identified in LFH < 3 kDa (LIWKL and RPYL) were tested in ex vivo assays of vasoactive responses. The peptide RPYL was tested in radioligand receptor binding assays. Both LFH < 3 kDa and individual peptides inhibited angiotensin II-induced vasoconstriction. RPYL showed the highest ex vivo inhibitory effect and also inhibited binding of [125I]-(Sar1,Ile8)-angiotensin II to AT1 receptors. By contrast, neither LFH < 3 kDa nor RPYL inhibited endothelin-1 and depolarization-induced vasoconstrictions. In conclusion, LF-derived peptides selectively inhibit angiotensin II-induced vasoconstriction by blocking angiotensin AT1 receptors. Therefore, inhibition of angiotensin II-induced vasocontriction is suggested as a mechanism contributing along with ACE inhibition to the antihypertensive effect of some LF-derived peptides.This work was supported by Grants AGL2010-21009 from Ministerio de Educación y Ciencia – FEDER, Consolider Ingenio 2010, Fun-C-Food, CSD2007-00063, and network RETICS INVICTUS – RD12/0014/0004 from Instituto de Salud Carlos III. R. Fernández-Musoles is the recipient of a fellowship from Ministerio de Educación y Ciencia (BES-2008-004472).Peer reviewe

Evaluation and synthesis of 7-arylhydroxymethyltriazolopyridines as potential cardiovascular agents

7-Arylhydroxymethyltriazolopyridines 3a-c and 4a-d were synthesized by regioselective lithiation of [1,2,3]triazolo[1,5-a]pyridines 1 and 2 and subsequent trapping of the 7-lithioderivatives formed using aryl aldehydes as electrophiles. The structural relationship between compounds 3a-c and 4a-d and arylethanolamines suggested their consideration as potential cardiovascular agents. A preliminary evaluation as vascular smooth muscle relaxants was carried out. These compounds did not act as α1-adrenoceptor antagonists and were unable to block calcium entry through voltage-dependent calcium channels.Abarca Gonzalez, Belen, [email protected] ; Ballesteros Campos, Rafael, [email protected] ; Ivorra Insa, Maria Dolores, [email protected] ; Valiente Bautista, Miguel, [email protected]

Detección de prescripciones potencialmente inapropiadas en pacientes ancianos: estudio descriptivo en dos farmacias comunitarias

Introducción: Los ancianos son un grupo de pacientes heterogéneos a los que se les prescribe un número elevado de medicamentos. Esto conlleva a prescripciones potencialmente inapropiadas.Objetivo: Analizar la farmacoterapia del paciente anciano desde la farmacia comunitaria para detectar prescripciones potencialmente inapropiadas (Beers 2012 y STOPP) y prescripciones potencialmente omitidas (START), determinando su prevalencia.Metodología: Estudio descriptivo, observacional en el que se incluyeron pacientes mayores de 65 años de atención primaria que llevaban al menos un tratamiento crónico. Se verificó la idoneidad de la medicación según los criterios Beers 2012 y STOPP &amp; START.Resultados: Se incluyeron 223 pacientes con una edad media de 75 años. En total se prescribieron 1.558 medicamentos, con una media de 7 medicamentos por paciente. El 67 % de los pacientes eran polimedicados. Con Beers 2012 se detectaron 246 prescripciones inapropiadas y el criterio que más se repitió fue el de benzodiazepinas de acción corta, intermedia y larga (36 %). Con STOPP se detectaron 146 prescripciones inapropiadas. El criterio más frecuente fue IBP a dosis plenas durante más de 8 semanas (14 %). Con START se detectaron 103 prescripciones potencialmente omitidas, siendo antiagregantes plaquetarios en diabetes mellitus la más frecuente (11,6 %).Conclusiones: Los criterios Beers 2012 y STOPP-START, suponen una herramienta de utilidad en la detección de los posibles problemas relacionados con los medicamentos en una farmacia comunitaria. En ningún caso suponen una prohibición en la utilización de dichos medicamentos, puesto que su prescripción dependerá de las características del paciente en concreto y del juicio clínico del médico prescriptor

Red de innovación docente interuniversitaria en Farmacología

Se ha formado una red interuniversitaria con objeto de crear un espacio común para compartir e intercambiar las experiencias, los resultados de investigación y el material elaborado en diferentes aspectos de innovación docente (nuevas tecnologías, metodologías, sistemas de evaluación, …) en el proceso de enseñanza-aprendizaje en Farmacología en diferentes grados/posgrados de Ciencias de la Salud (Enfermería, Farmacia, Medicina, Veterinaria, Ciencias Biomédicas, Óptica, Nutrición y Dietética, ...). Además del grupo de innovación docente de la Universitat de València, participan en la red un total de 45 profesores pertenecientes a 13 Universidades: U. de Alicante, U. Autónoma de Barcelona, U. de Barcelona, U. Pompeu Fabra (Barcelona), U. CEU Cardenal Herrera, U. Complutense de Madrid, U. Francisco de Vitoria (Madrid), U. de Granada, U. de Málaga, U. País Vasco, U. de Salamanca y U. de Sevilla. Todos los profesores que integran la red han participado y tienen experiencia en diferentes proyectos de innovación docente convocados por las Universidades a las que pertenecen. Se ha iniciado el proyecto con la creación de una plataforma Moodle común para intercambiar experiencias docentes

Herramientas para evaluar la adecuación de la prescripción en ancianos

El envejecimiento es un proceso complejo. Con la edad se van produciendo importantes cambios fisiológicos y aumenta la incidencia de múltiples patologías orgánicas y sistémicas. A los pacientes ancianos se les prescribe un elevado número de medicamentos. Además, son los que realizan un mayor número de visitas médicas e ingresos hospitalarios. Los ancianos son el grupo poblacional con mayor grado de polimedicación. La polimedicación genera un elevado coste para el Sistema Nacional de Salud (SNS) y puede además incrementar el número de reacciones adversas medicamentosas e interacciones. La prescripción inapropiada de fármacos es un problema frecuente en los mayores, que contribuye al aumento del riesgo de reacciones adversas a medicamentos (RAM). En los últimos años, se han desarrollado varias herramientas para detectar la prescripción potencialmente inadecuada en ancianos. El objetivo de esta revisión consiste en describir dos de estas herramientas: los criterios americanos de BEERS y los criterios europeos STOPP (Screening Tool of Older Person’s Prescriptions)/ START (Screening Tool to Alert doctors to Right i.e. appropriate, indicated Treatment). Los criterios STOPP aportan el valor añadido de detectar no sólo la prescripción inadecuada por determinados fármacos, sino también por falta de prescripción de medicamentos indicados. Los criterios STOPP/START pueden convertirse en una buena herramienta para mejorar la prescripción en los pacientes mayores

Contraceptive methods

El objetivo de nuestro estudio ha sido aumentar conocimientos y corregir errores, sobre el uso de métodos anticonceptivos y prevención de E.T.S. en una muestra de 30 alumnos de 3º de E.S.O. de un instituto de la provincia de Alicante. Pensamos que ante una necesidad tan evidente podíamos obtener resultados satisfactorios si utilizábamos una pedagogía participativa que atrajese a los alumnos. De este modo, por medio del paradigma sociocrítico conseguimos implicar a la muestra para que tomasen conciencia de sus propias necesidades. Se impartieron charlas a los alumnos sobre distintos temas de interés que más tarde serían evaluados. La metodología utilizada fue el test-retest. Se distribuyó un primer cuestionario antes de la primera charla para adaptar nuestra ponencia a las necesidades de la muestra, y un segundo test, de iguales características al primero, después de la última charla para evaluar los conocimientos adquiridos. Los alumnos tenían mayores problemas en aspectos como qué es la sexualidad, dónde acudir para informarnos sobre sexualidad, diferencia entre sexualidad y reproducción, dónde comprar preservativos, qué hacer ante la ruptura de un preservativo, utilización de lubricantes, vías de transmisión de las E.T.S., etc. En estos aspectos se consiguió un porcentaje de éxito en base a nuestros objetivos considerablemente elevado.The aim of our study was to increase knowledge and correct errors in the use of contraceptive methods and prevention of Sexual Transmission Diseases (STD) in a sample of 30 students in the 3rd year of ESO (GCE) from a school in the Alicante area. We considered that faced with such an evident need we could obtain very satisfactory results should we use an appealing pedagogical participation which attracted the students. So by means of a critical paradigm we managed to get them involved in the event, concerned of their own needs. Lectures on different interesting topics were given to the students, to be evaluated later on. The method used was that of the test/re-test. A questionnaire was provided before the first lecture so that we could adapt our information to their shown expressed needs; and a second questionnaire of equal characteristics was provided after the last lecture to evaluate their acquired knowledge. The students' major problems were in knowing: what sexuality means and where to go to get information about it; what is the difference between sexuality and reproduction; where to obtain sheaths; what to do if they get torn; use of lubricants, and means of sexual transmission of diseases (STD). According to our expectation the degree of success was really high

Abacavir increases purinergic P2X7 receptor activation by ATP: does a pro-inflammatory synergism underlie its cardiovascular toxicity?

16 p.-9 fig.-1 tab.The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.This work was supported by Ministerio de Economía y Competitividad and the European Regional Development fund of the European Union (FEDER) (SAF2015–67678-R, RTI2018-094436-B-I00 and CTQ2017-88353-R), Ministerio de Sanidad y Consumo (CB06/04/0071, CIBERehd) and Generalitat Valenciana (PROMETEOII/2014/035 and PROMETEO 2018/141), along with an unrestricted grant from GILEAD S.L. VCD and ASL were funded by VALI + D program from Generalitat Valenciana (grants number ACIF/2015/316 and ACIF/2016/119, respectively) and PGM by FPU program from Ministerio de Educación, Cultura y Deporte (grant number FPU16/06064) and MABR by FPU program from Ministerio de Ciencia, Innovación y Universidades (grant number FPU17/04249).Peer reviewe

2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure-activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index <= 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission