Drogodependencias: XX Curso de Actualización para Postgraduados en Farmacia

El consumo de drogas es un fenómeno multicausal en el que incide una serie de factores del ámbito personal, familiar, social, y cultural. En los últimos años, asistimos a cambios tanto en la oferta de drogas como en los patrones de consumo. Así, mientras en los años 80 y primeros 90 la droga emblemática era la heroína, hoy en día su consumo se ha estabilizado, e incluso ha disminuido. Las nuevas formas de estar en sociedad afectan a grupos de jóvenes aceptablemente integrados en su medio familiar y social. A día de hoy, debe considerarse el consumo de otras drogas, fundamentalmente las llamadas drogas de síntesis, y la adopción de nuevos patrones en el consumo de algunas ya establecidas, como es el alcohol. En este marco se está haciendo frente al fenómeno del consumo de drogas desde diferentes perspectivas que se extienden desde la investigación científica hasta la prevención, la reducción de daños y la asistencia al drogodependiente. Entre las estrategias del nuevo Plan Nacional Sobre Drogas (PND) destaca la de normalizar las redes asistenciales a drogodependientes, integrándolas de forma coordinada en los sistemas públicos de salud y sistemas sociales. Se pretende que los diferentes recursos que formen parte del denominado sistema de asistencia e integración social de drogodependientes se caractericen por su profesionalización, interdisciplinariedad y fácil accesibilidad. En este sentido, hay que destacar la participación activa de algunos profesionales farmacéuticos en distintos programas de actuación, prevención y reducción de daños producidos por drogas. Por otra parte, se están realizando esfuerzos importantes en la investigación básica y clínica dirigidos a desentrañar los mecanismos que operan en la adicción a drogas. Los capítulos que componen este texto son el resultado del trabajo coordinado entre investigadores, docentes, farmacéuticos comunitarios, psicólogos, psiquiatras y otros profesionales implicados en la problemática de las drogodependencias. Su lectura permitirá conocer la actual situación respecto al consumo de drogas, los mecanismos neurobiológicos implicados en la drogadicción, la farmacología y la toxicología de las diferentes drogas, los riesgos asociados a su consumo, y los recursos disponibles que atienden a la población drogodependiente. Agradecemos la participación de los profesionales que asisten desde diferentes ámbitos a las personas afectadas directa o indirectamente por los problemas derivados del consumo de drogas, que ha hecho posible integrar aspectos básicos y prácticos de un tema tan complejo como es el de las drogodependencias

Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease

Abstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated. EXPERIMENTAL APPROACH: Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS: Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS: Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Efecto neuroprotector del sildenafilo frente a la isquemia química inducida por la toxina mitocondrial malonato

Phosphodiesterase 5 inhibitors (PDE5i) have recently been reported to exert beneficial effects against ischemia-reperfusion injury in several organs but their neuroprotective effects in brain stroke models are scarce. The present study was undertaken to assess the effects of sildenafil against cell death caused by intrastriatal injection of malonate, an inhibitor of succinate dehydrogenase; which produces both energy depletion and lesions similar to those seen in cerebral ischemia. Our data demonstrate that sildenafil (1.5 mg/kg p.o.), given 30 min before malonate (1.5 ìmol/2 ìl), significantly decreased the lesion volume caused by this toxin. This protective effect cannot be attributed to any effect on reactive oxygen species production. By contrast, our results suggest that inhibition of malonate-induced activation of calpain/p25/cdk5 and ASK-1/MKK3/6/p38 pathways play a key role in the neuroprotective effects of this PDE5i. Sildenafil also increased the expression of two antiapoptotic proteins, namely Bcl-2 and Bcl-xL, as well as the phosphorylation of the prosurvival factor MEF2; effects that might, as well, contribute to prevent the cell death caused by malonate. The neuroprotective effect of sildenafil was not only preventive but also therapeutic. Thus, sildenafil protected hippocampal slices subjected to oxygen and glucose deprivation (OGD) when administered during reoxygenation and also reduced tissue damage caused by malonate if administered up to 3 hours after the injection of the mitochondrial toxin

Estudio de las principales vías responsables del efecto terapéutico del sildenafilo sobre el deterioro cognitivo del ratón de senescencia acelerada SAMP8

Aging is associated with a deterioration of cognitive performance particularly of learning and memory and with increased risk of neurodegenerative disorders. Undoubtedly, identifying the key markers and how they interact to turn benign aging into pathologic seems a crucial step for the development of therapeutic strategies to prevent or hinder the progression of aging and neurodegenerative diseases. The senescence-accelerated mouse (SAM) is comprised of 14 strains derived from selective inbreeding of the AKR/J strain. One of these substrains, the senescence-accelerated mouse prone-8 (SAMP8) strain manifests irreversible advancing senescence and shares similar characteristics with aged humans. Interestingly, SAMP8 mice also exhibit age-related learning and memory deficits, increased expression of hyperphosphorylated tau as well as amyloid-like deposits in the brain. Given such features, SAMP8 mice have been proposed as one plausible age-associated Alzheimer¿s disease (AD) animal model and a suitable rodent model for studying the molecular mechanisms underlying cognitive impairment in aged subjects. Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor initially approved for the treatment of erectile dysfunction and nowadays also for pulmonary arterial hypertension. Several studies have shown that sildenafil improves memory in rats and mice. Moreover, recent investigations have demonstrated that sildenafil also restores the cognitive function in a transgenic mouse model of AD. Based on these premises, the aim of the present work was to explore whether sildenafil could reverse the memory impairments shown by SAMP8 mice as well as the underlying mechanisms. In particular, we focused our study on the effects of sildenafil on tau and amyloid pathology, the two main histopatological hallmarks of Alzheimer's disease

Estudio de las principales vías responsables del efecto terapéutico del sildenafilo sobre el deterioro cognitivo del ratón de senescencia acelerada SAMP8

Aging is associated with a deterioration of cognitive performance particularly of learning and memory and with increased risk of neurodegenerative disorders. Undoubtedly, identifying the key markers and how they interact to turn benign aging into pathologic seems a crucial step for the development of therapeutic strategies to prevent or hinder the progression of aging and neurodegenerative diseases. The senescence-accelerated mouse (SAM) is comprised of 14 strains derived from selective inbreeding of the AKR/J strain. One of these substrains, the senescence-accelerated mouse prone-8 (SAMP8) strain manifests irreversible advancing senescence and shares similar characteristics with aged humans. Interestingly, SAMP8 mice also exhibit age-related learning and memory deficits, increased expression of hyperphosphorylated tau as well as amyloid-like deposits in the brain. Given such features, SAMP8 mice have been proposed as one plausible age-associated Alzheimer¿s disease (AD) animal model and a suitable rodent model for studying the molecular mechanisms underlying cognitive impairment in aged subjects. Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor initially approved for the treatment of erectile dysfunction and nowadays also for pulmonary arterial hypertension. Several studies have shown that sildenafil improves memory in rats and mice. Moreover, recent investigations have demonstrated that sildenafil also restores the cognitive function in a transgenic mouse model of AD. Based on these premises, the aim of the present work was to explore whether sildenafil could reverse the memory impairments shown by SAMP8 mice as well as the underlying mechanisms. In particular, we focused our study on the effects of sildenafil on tau and amyloid pathology, the two main histopatological hallmarks of Alzheimer's disease

Drogodependencias: XX Curso de Actualización para Postgraduados en Farmacia

El consumo de drogas es un fenómeno multicausal en el que incide una serie de factores del ámbito personal, familiar, social, y cultural. En los últimos años, asistimos a cambios tanto en la oferta de drogas como en los patrones de consumo. Así, mientras en los años 80 y primeros 90 la droga emblemática era la heroína, hoy en día su consumo se ha estabilizado, e incluso ha disminuido. Las nuevas formas de estar en sociedad afectan a grupos de jóvenes aceptablemente integrados en su medio familiar y social. A día de hoy, debe considerarse el consumo de otras drogas, fundamentalmente las llamadas drogas de síntesis, y la adopción de nuevos patrones en el consumo de algunas ya establecidas, como es el alcohol. En este marco se está haciendo frente al fenómeno del consumo de drogas desde diferentes perspectivas que se extienden desde la investigación científica hasta la prevención, la reducción de daños y la asistencia al drogodependiente. Entre las estrategias del nuevo Plan Nacional Sobre Drogas (PND) destaca la de normalizar las redes asistenciales a drogodependientes, integrándolas de forma coordinada en los sistemas públicos de salud y sistemas sociales. Se pretende que los diferentes recursos que formen parte del denominado sistema de asistencia e integración social de drogodependientes se caractericen por su profesionalización, interdisciplinariedad y fácil accesibilidad. En este sentido, hay que destacar la participación activa de algunos profesionales farmacéuticos en distintos programas de actuación, prevención y reducción de daños producidos por drogas. Por otra parte, se están realizando esfuerzos importantes en la investigación básica y clínica dirigidos a desentrañar los mecanismos que operan en la adicción a drogas. Los capítulos que componen este texto son el resultado del trabajo coordinado entre investigadores, docentes, farmacéuticos comunitarios, psicólogos, psiquiatras y otros profesionales implicados en la problemática de las drogodependencias. Su lectura permitirá conocer la actual situación respecto al consumo de drogas, los mecanismos neurobiológicos implicados en la drogadicción, la farmacología y la toxicología de las diferentes drogas, los riesgos asociados a su consumo, y los recursos disponibles que atienden a la población drogodependiente. Agradecemos la participación de los profesionales que asisten desde diferentes ámbitos a las personas afectadas directa o indirectamente por los problemas derivados del consumo de drogas, que ha hecho posible integrar aspectos básicos y prácticos de un tema tan complejo como es el de las drogodependencias

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB and BDNF

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD