Seguimiento farmacoterapéutico a pacientes polimedicados / Pharmaceutical care to polimedicated patients

Los servicios profesionales farmacéuticos asistenciales contribuyen a un mejor control de los problemas de salud, sobre todo en pacientes polimedicados, y a una optimización de los recursos sanitarios, lo cual conlleva una menor prescripción de medicamentos y un menor número de visitas a los centros sanitarios. Formaron parte de este estudio 78 pacientes, siendo el sexo femenino el más prevalente, con una edad media 72,49 ± 13,92 años; de ellos, 60 pacientes eran mayores de 65 años y, por tanto, considerados pacientes geriátricos. Fueron incluidos en un servicio de sistemas personalizados de dosificación y, posteriormente, se realizó un seguimiento farmacoterapéutico. Se detectaron 450 problemas relacionados con los medicamentos siendo los más frecuentes los asociados al paciente: falta de conocimiento de uso, mala adherencia terapéutica, errores en la administración…, siendo la probabilidad de presentarlos mayor en el sexo masculino. Asociados a estos problemas con los medicamentos se detectaron 160 resultados negativos asociados a la medicación; solo 5 de ellos no fueron resueltos durante la fase estudio, los más frecuentes fueron los de inefectividad no cuantitativa, es decir, aquellos que no se resuelven con una modificación de la dosis farmacológica sino incluyendo o eliminando otros principios activos. En conclusión, el servicio de sistema personalizado de dosificación precisa de una revisión de la medicación como, por ejemplo, el seguimiento farmacoterapéutico, ya que ambos permiten optimizar el tratamiento de los pacientes polimedicados, así como, un aumento del control de los problemas de salud.(AU)

Professional pharmaceutical care services contribute to better health problem control, especially in polymedicated patients, and to the optimization of health resources, which leads to less medication prescription and fewer visits to healthcare centers. This study included 78 patients, with the female sex being the most prevalent, with an average age of 72.49 ± 13.92 years; of these, 60 patients were over 65 years of age and, herefore, considered geriatric patients. They were included in a personalized medication dispensing service and, subsequently, a pharmacotherapeutic follow-up was carried out. 450 medication-related problems were detected, the most frequent of which were associated with the patient: lack of knowledge of use, poor therapeutic adherence, administration errors, etc., with the probability of presenting them being higher in the male sex. Associated with these medication problems, 160 negative medication-related results were detected; only 5 of them were not resolved during the study phase, the most frequent being those of non-quantitative ineffectiveness, that is, those that are not resolved with a modification of the pharmacological dose but by including or eliminating other active ingredients. In conclusion, the personalized medication dispensing service requires a medication review, such as pharmacotherapeutic follow-up, as both allow the optimization of the treatment of polymedicated patients, as well as an increase in the control of health problems.(AU)

Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain.

AIMS: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. METHODS: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. RESULTS: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. CONCLUSION: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

El valor añadido de los servicios profesionales farmacéuticos asistenciales. Un caso de SFT / The added value of Professional Pharmaceutical Assistance Services. A case of pharmaceutical care

Presentación del caso: paciente de 62 años, dependiente, con buena adherencia terapéutica y presencia de enfermedades psiquiátricas que limitan su calidad de vida. Su hijo, cuidador desde que le diagnosticaron el trastorno de la personalidad, acude a la farmacia solicitando ayuda para abordar la situación. Estudio y evaluación del caso: se evaluó el estado de salud de la paciente y se detectaron posibles resultados negativos asociados a la medicación (RNM) que limitaban su calidad de vida. Intervención: se derivó a su médico de atención primaria con un informe de interconsulta multidisciplinar indicado los posibles RNM y las posibles modificaciones. Resultados: el médico de atención primaria aceptó la intervención y comenzó con una deprescripción progresiva de benzodiacepinas, con respecto a la sintomatología extrapiramidal se confirmó el RNM y se derivó a su especialista en psiquiatría. Tras mejorar significativamente su calidad de vida, se abordaron sus enfermedades cardiovasculares. Para ello se indicaron medidas higiénico- sanitarias que disminuyeran su riesgo cardiovascular. Conclusiones: la coordinación de los diferentes profesionales sanitarios permite un aumento de la autonomía del paciente, una deprescripción de medicamentos y una optimización de recursos sanitarios, traduciéndose como una mejora en su calidad de vida (AU)

Efectos de la COVID-19 en el consumo de antidepresivos en la provincia de Santa Cruz de Tenerife, Islas Canarias / Effects of COVID-19 on the consumption of antidepressants in the Province of Santa Cruz de Tenerife, Canary Islands

Fundamento: en este trabajo se analiza el impacto de la COVID-19 en el consumo de antidepresivos durante el primer año de la pandemia (2020) tomando como línea de base las tendencias de prescripción durante los 4 años anteriores (2016-2019) en la provincia de Santa Cruz de Tenerife y las cuatro islas que la conforman. Métodos: los datos de ventas en las farmacias comunitarias se tomaron como base de datos agregados. La dosis por 1000 habitantes y día se utilizó como indicador de consumo.Resultados: en las islas de El Hierro y La Gomera, el aumento de población no justifica por sí solo los incrementos relevantes observados en el consumo de antidepresivos y, posiblemente, la COVID-19 y sus consecuencias sobre la salud de la población podrían ser responsables de dichos aumentos. En la isla de Tenerife el incremento de población podría justificar, en gran medida, el ligero aumento de consumo observado. La isla de La Palma presenta un aumento de tan solo un 1,40 %, pero menor al valor esperado tomando como línea de base el periodo 2016-2019. Todas las islas presentan las mismas tendencias en el consumo de los diferentes subgrupos de antidepresivos y principios activos, aunque con ligeras variaciones, con la excepción de la isla de la Palma que presenta un comportamiento y tendencias estadísticamente diferentes.Conclusiones: las diferencias de prescripción observadas podrían estar relacionadas con las características sociosanitarias y demográficas de cada una de las islas. (AU)

Atención multidisciplinar: farmacia comunitaria y medicina familiar / Multidisciplinary care: community pharmacy and family medicine

Presentación del caso: paciente de 67 años, con una mala adherencia terapéutica. Se le ofrece formar parte del servicio de Sistema Personalizados de Dosificación (SPD); servicio que se convierte en la puerta de entrada para otro servicio asistencial de la farmacia comunitaria, el seguimiento farmacoterapéutico. Estudio y evaluación del caso: la evaluación del estado inicial de salud demuestra que algunos de los problemas de salud podrían estar relacionados con un Resultado Negativo Asociado a la Medicación (RNM). Se detectan fallos de inefectividad al tratamiento antihipertensivo y de seguridad al tratamiento antipsicótico. Intervención: se deriva al equipo de atención primaria con un informe de los resultados del servicio de seguimiento farmacoterapéutico y una propuesta de modificación de la farmacoterapia. Resultados: se añadió un nuevo principio activo para controlar la presión arterial, que provocó una reacción adversa, lo que derivó en su sustitución por otro. Por otro lado, se confirmaron reacciones adversas asociadas al tratamiento antipsicótico, por lo que se inició una deprescripción gradual del tratamiento. Conclusiones: la coordinación entre los diferentes profesionales de salud resultó esencial. El farmacéutico comunitario detectó Problemas Relacionado con los Medicamentos (PRM) y RNM que afectan negativamente a la calidad de vida de los pacientes polimedicados. (AU)

Mini viral RNAs act as innate immune agonists during influenza virus infection.

The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors1. However, it is generally accepted that a strong innate immune dysregulation known as 'cytokine storm' contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype2-4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression5. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-ß. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.

RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation.

In this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFα-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MΦ) and progressive loss of iPS-MΦ production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases.

Caspase-8 inhibition represses initial human monocyte activation in septic shock model.

In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1ß and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source.

Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system.

Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.

Relevance of chronic stress and the two faces of microglia in Parkinson's disease.

This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson's disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD.

Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model.

Increasing evidence involves sustained pro-inflammatory microglia activation in the pathogenesis of different neurodegenerative diseases, particularly Parkinson's disease (PD). We recently uncovered a completely novel and unexpected role for caspase-8 and its downstream substrates caspase-3/7 in the control of microglia activation and associated neurotoxicity to dopaminergic cells. To demonstrate the genetic evidence, mice bearing a floxed allele ofCASP8 were crossed onto a transgenic line expressing Cre under the control of Lysozyme 2 gene. Analysis of caspase-8 gene deletion in brain microglia demonstrated a high efficiency in activated but not in resident microglia. Mice were challenged with lipopolysaccharide, a potent inducer of microglia activation, or with MPTP, which promotes specific dopaminergic cell damage and consequent reactive microgliosis. In neither of these models, CASP8 deletion appeared to affect the overall number of microglia expressing the pan specific microglia marker, Iba1. In contrast, CD16/CD32 expression, a microglial pro-inflammatory marker, was found to be negatively affected upon CASP8 deletion. Expression of additional proinflammatory markers were also found to be reduced in response to lipopolysaccharide. Of importance, reduced pro-inflammatory microglia activation was accompanied by a significant protection of the nigro-striatal dopaminergic system in the MPTP mouse model of PD.

Collateral Damage: Contribution of Peripheral Inflammation to Neurodegenerative Diseases.

Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson's disease, especially through the so called gut-brain axis.

Evaluation of a method for murine monocyte isolation by bone marrow depletion.

The study of monocyte activation and differentiation has great applications in sepsis, chronic inflammatory diseases, and cancer studies. However, despite the existence of well-established protocols for monocyte purification from human blood, the isolation of murine monocytes that can be subsequently activated has not yet been fully optimized. Here we evaluate a recently developed commercial procedure for obtaining monocytes from the bone marrow based on immunomagnetic depletion of non-monocytic cells. Moreover, we compare the advantages and disadvantages of this approach relative to other existing procedures. We found that monocytes isolates generated using this technique had equal purity to those attained via depletion from peripheral blood; however, higher yields were achieved. Furthermore, isolates from this technique have lower levels of macrophage contamination than those reported in samples generated by culturing bone marrow extracts with macrophage colony-stimulating factor (M-CSF). In addition, we demonstrate that the purified monocytes are sensitive to lipopolysaccharide (LPS)-mediated activation and, therefore, are useful for studies aimed at elucidating the molecular mechanisms involved in monocyte activation and differentiation.

Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation.

Inflammatory response induced by microglia plays a critical role in the demise of neuronal populations in neuroinflammatory diseases. Although the role of toll-like receptor 4 (TLR4) in microglia's inflammatory response is fully acknowledged, little is known about endogenous ligands that trigger TLR4 activation. Here, we report that galectin-3 (Gal3) released by microglia acts as an endogenous paracrine TLR4 ligand. Gal3-TLR4 interaction was further confirmed in a murine neuroinflammatory model (intranigral lipopolysaccharide [LPS] injection) and in human stroke subjects. Depletion of Gal3 exerted neuroprotective and anti-inflammatory effects following global brain ischemia and in the neuroinflammatory LPS model. These results suggest that Gal3-dependent-TLR4 activation could contribute to sustained microglia activation, prolonging the inflammatory response in the brain.

Primary phagocytosis of viable neurons by microglia activated with LPS or Aß is dependent on calreticulin/LRP phagocytic signalling.

BACKGROUND: Microglia are resident brain macrophages that can phagocytose dead, dying or viable neurons, which may be beneficial or detrimental in inflammatory, ischaemic and neurodegenerative brain pathologies. Cell death caused by phagocytosis of an otherwise viable cell is called 'primary phagocytosis' or 'phagoptosis'. Calreticulin (CRT) exposure on the surface of cancer cells can promote their phagocytosis via LRP (low-density lipoprotein receptor-related protein) on macrophages, but it is not known whether this occurs with neurons and microglia. METHODS: We used primary cultures of cerebellar neurons, astrocytes and microglia to investigate the potential role of CRT/LRP phagocytic signalling in the phagocytosis of viable neurons by microglia stimulated with lipopolysaccharide (LPS) or nanomolar concentrations of amyloid-ß peptide1-42 (Aß). Exposure of CRT on the neuronal surface was investigated using surface biotinylation and western blotting. A phagocytosis assay was also developed using BV2 and PC12 cell lines to investigate CRT/LRP signalling in microglial phagocytosis of apoptotic cells. RESULTS: We found that BV2 microglia readily phagocytosed apoptotic PC12 cells, but this was inhibited by a CRT-blocking antibody or LRP-blocking protein (receptor-associated protein: RAP). Activation of primary rat microglia with LPS or Aß resulted in loss of co-cultured cerebellar granule neurons, and this was blocked by RAP or antibodies against CRT or against LRP, preventing all neuronal loss and death. CRT was present on the surface of viable neurons, and this exposure did not change in inflammatory conditions. CRT antibodies prevented microglia-induced neuronal loss when added to neurons, while LRP antibodies prevented neuronal loss when added to the microglia. Pre-binding of CRT to neurons promoted neuronal loss if activated microglia were added, but pre-binding of CRT to microglia or both cell types prevented microglia-induced neuronal loss. CONCLUSIONS: CRT exposure on the surface of viable or apoptotic neurons appears to be required for their phagocytosis via LRP receptors on activated microglia, but free CRT can block microglial phagocytosis of neurons by acting on microglia. Phagocytosis of CRT-exposing neurons by microglia can be a direct cause of neuronal death during inflammation, and might therefore contribute to neurodegeneration and be prevented by blocking the CRT/LRP pathway.

Enfermedad de la válvula áortica: resultados a 3 años de la cirugía de Ross / Ross procedure for aortic valve disease: 3 years of follow-up

Se analizan los resultados en 54 pacientes con enfermedad de la válvula áortica sometidos a cirugía de Ross. En 52 de ellos se pudo efectuar exitosamente. La morbimortalidad del procedimiento fue baja. En el seguimiento a 3 años, la sobrevida fue del 100 por ciento y la ausencia de eventos tromboembólicos e infecciosos relacionados con la válvula también fue del 100 por ciento. Un paciente debió ser reoperado por disfunción del autoinjerto

Enfermedad de la válvula áortica: resultados a 3 años de la cirugía de Ross / Ross procedure for aortic valve disease: 3 years of follow-up

Se analizan los resultados en 54 pacientes con enfermedad de la válvula áortica sometidos a cirugía de Ross. En 52 de ellos se pudo efectuar exitosamente. La morbimortalidad del procedimiento fue baja. En el seguimiento a 3 años, la sobrevida fue del 100 por ciento y la ausencia de eventos tromboembólicos e infecciosos relacionados con la válvula también fue del 100 por ciento. Un paciente debió ser reoperado por disfunción del autoinjerto (AU)

Descalcificación manual de válvula aórtica en pacientes con estenosis aórtica degenerativa senil / Aortic manual valve debridement of degenerative aortic valve stenosis

Se presentan los resultados a 98 meses de la descalcificación de la válvula aórtica en 103 pacientes portadores de estenosis aórtica degenerativa senil. 1) La descalcificación manual de la válvula aórtica es una técnica quirúrgica con baja mortalidad hospitalaria y una menor incidencia de complicaciones perioperatorias respecto de otras técnicas. 2) En el seguimiento alejado fue baja la incidencia de eventos tromboembólicos e infecciosos; ningún paciente requirió anticoagulación temporal o definitiva por el procedimiento. La incidencia de reoperación fue la complicación más frecuente. 3) Esta técnica puede ser considerada en pacientes seniles, especialmente con anillos aórticos pequeños, con indicación de revascularización miocárdica asociada y/o aquellos con contraindicación de anticoagulación temporal o definitiva

Descalcificación manual de válvula aórtica en pacientes con estenosis aórtica degenerativa senil / Aortic manual valve debridement of degenerative aortic valve stenosis

Se presentan los resultados a 98 meses de la descalcificación de la válvula aórtica en 103 pacientes portadores de estenosis aórtica degenerativa senil. 1) La descalcificación manual de la válvula aórtica es una técnica quirúrgica con baja mortalidad hospitalaria y una menor incidencia de complicaciones perioperatorias respecto de otras técnicas. 2) En el seguimiento alejado fue baja la incidencia de eventos tromboembólicos e infecciosos; ningún paciente requirió anticoagulación temporal o definitiva por el procedimiento. La incidencia de reoperación fue la complicación más frecuente. 3) Esta técnica puede ser considerada en pacientes seniles, especialmente con anillos aórticos pequeños, con indicación de revascularización miocárdica asociada y/o aquellos con contraindicación de anticoagulación temporal o definitiva (AU)