Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis

Brain tyrosinase; Neuromelanin production; Parkinson’sTirosinasa cerebral; Producció de neuromelanina; ParkinsonTirosinasa cerebral; Producción de neuromelanina; ParkinsonIn Parkinson's disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD

Causas de falta de respuesta primaria y pérdida de respuesta secundaria a inhibidores del factor de necrosis tumoral alfa en la artritis reumatoide

La artritis reumatoide (AR) es una enfermedad inflamatoria sistémica crónica que requiere tratamiento a largo plazo. Dado que el daño articular en pacientes con AR habitualmente es progresivo y éstos requieren tratamiento durante largos periodos de tiempo, es necesario un seguimiento a largo plazo para evaluar la eficacia y la seguridad de los tratamientos e intervenciones. Los fármacos biológicos han supuesto un gran avance terapéutico en el tratamiento de las enfermedades inflamatorias inmunomediadas. La European League Against Rheumatism (EULAR) define la falta de respuesta primaria como una reducción ≤0,6 del Disease Activity Score (DAS) en 28 articulaciones, valorando la velocidad de sedimentación glomerular (DAS28‑VSG) inicial tras 12-24 semanas de tratamiento y la pérdida de respuesta secundaria como un aumento en DAS28-VSG >0,6 o un aumento de actividad de la enfermedad. Uno de los pilares del tratamiento de la AR en la actualidad son los inhibidores del factor de necrosis tumoral alfa (iTNFα); sin embargo, se ha descrito que un 33% de los pacientes con AR no responden inicialmente a estos fármacos, y hasta el 30% pierden la respuesta clínica inicial con el tiempo. Esta variabilidad e incapacidad de predecir la respuesta a los iTNFα se ha descrito como intrínseca a la terapia biológica para la AR. Identificar a los pacientes con mayor probabilidad de presentar pérdida de respuesta, tanto primaria como secundaria, podría permitir que un número significativo de ellos alcanzara su objetivo terapéutico realizando los ajustes adecuados. Así, el objetivo principal de este estudio es la revisión de la evidencia que incluya información sobre las causas de falta o pérdida de respuesta, así como de los factores que influyen en la predicción de la respuesta a los iTNFα en la AR. Palabras clave: Artritis reumatoide, agente biológico, monitorización farmacocinética

Monitorización de agentes biológicos en la artritis reumatoide

Los fármacos biológicos se han convertido en agentes clave para el tratamiento de las enfermedades inflamatorias inmunomediadas (IMID). Sin embargo, la terapia biológica está condicionada por la gran variabilidad farmacocinética (PK) inter/ intraindividual. La monitorización terapéutica (TDM), basada en las concentraciones de fármaco biológico y los anticuerpos antifármaco, es una herramienta apropiada para la optimización del tratamiento de las IMID con el objetivo de individualizar la posología para cada paciente. Así, la determinación de concentraciones plasmáticas de los agentes biológicos, junto con la interpretación de los valores clínicos y analíticos, permitiría una evaluación global del estado del paciente, optimizar la exposición al fármaco y mejorar la respuesta clínica. La monitorización de concentraciones plasmáticas se puede realizar en caso de no respuesta (TDM reactiva) o en caso de remisión para mantener una exposición al fármaco adecuada (TDM proactiva). En este artículo se resume la información disponible sobre la TDM de los agentes biológicos para la optimización del tratamiento de la artritis reumatoide (AR). A pesar de la evidencia disponible sobre la asociación entre las concentraciones séricas de fármacos y el resultado clínico en AR, se requieren más datos PK y de coste-efectividad que permitan obtener más información para consolidar la TDM como una intervención en reumatología. Palabras clave: Artritis reumatoide, agente biológico, monitorización farmacocinética

Posaconazole achieves prompt recovery of voriconazole-induced liver injury in a case of invasive aspergillosis

Azole antifungals have frequently been linked to the presence of hepatotoxicity, but there is scarce information on cross-toxicity between these drugs or on the possibility of using some of them when this type of toxicity occurs. We report the case of a 64-year-old man with invasive aspergillosis (IA) leading to spondylodiscitis with neurological involvement. Early management included intravenous (iv) voriconazole, which had to be interrupted after 1 week due to liver damage. Therapeutic drug monitoring (TDM) of voriconazole showed that the plasma concentration was within the therapeutic range. However, it was replaced by a combination therapy of oral posaconazole plus iv caspofungin. Posaconazole allowed normalization of liver enzymes. After finishing posaconazole monotherapy on an outpatient basis, the patient made a full recovery. This case report provides further evidence that oral posaconazole is safe and effective as rescue therapy after the appearance of voriconazole-induced liver toxicity

Community-acquired pneumonia caused by methicillin-resistant Staphylococcus aureus in critically-ill patients: systematic review

INTRODUCTION: Community-acquired pneumonia (CAP) is associated with high morbidity and mortality rates. Despite methicillin-resistant Staphylococcus aureus (MRSA) having often been associated with nosocomial pneumonia, the condition of some MRSA CAP patients is severe enough to warrant their being admitted to ICU. OBJECTIVE: The purpose of this study is to conduct a systematic review of the literature on antibiotic treatment of MRSA CAP in critically-ill patients. MATERIAL AND METHODS: An online search was conducted for locating articles on MRSA CAP in critically ill patients. Relevant publications were identified in PUBMED, the BestPractice database, UpToDate database and the Cochrane Library for articles published in English within the December 2001 - April 2016 time frame. RESULTS: A total of 70 articles were found to have been published, 13 (18.8%) having been included and 57 (81.4%) excluded. Cohort studies were predominant, having totaled 16 in number (20.7%) as compared to one sole cross-sectional study (3.5%). CONCLUSIONS: The experience in the treatment of MRSA CAP in patients requiring admission to ICU is quite limited. Vancomycin or linezolid seem to be the treatments of choice for MRSA CAP, although there not be any specific recommendation in this regard. It may be useful to use alternative routes, such as administration via aerosolized antibiotics, continuous infusion or in association with other antibiotic

Real-world effectiveness and persistence of reference etanercept versus biosimilar etanercept GP2015 among rheumatoid arthritis patients: A cohort study

Although several randomized clinical trials have confirmed that there is no difference in efficacy between etanercept and its biosimilar versions in the treatment of rheumatoid arthritis (RA), limited real-world evidence is available. We conducted a cohort study to compare the effectiveness and treatment persistence between the reference etanercept (ETN) and the biosimilar GP2015 in RA patients in a real-life setting. Adults with a diagnosis of RA who initiated treatment with ETN or GP2015, between January 2007 and December 2019, were included. The follow-up period was 52 weeks. The primary outcome was the mean of change in the DAS28-CRP values and the adjusted mean difference from baseline to 52 weeks between ETN and GP2015. Other effectiveness endpoints assessed were the rate of patients who achieved remission or low disease activity (LDA) at week 52, who showed a reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 and rate of good responder patients (those meeting both effectiveness measures) at week 52. Treatment effectiveness over time (baseline, 26 and 52 weeks) was compared between the ETN and GP2015 groups using mixed effects models. Treatment persistence (probability of maintaining the same treatment over time) was also evaluated and shown using Kaplan-Meier survival curves. A total of 115 RA patients were included (ETN, n = 90; GP2015, n = 25). No differences were observed in the primary outcome: DAS28-CRP score decreased from baseline to week 52 [5.1 to 2.7 (mean of change -2.37) in ETN group and 5.0 to 2.2 (mean of change -2.84) in GP2015 group, p-value = 0.372] and the adjusted mean difference was -0.37 (-1.03 to 0.29). No differences were also observed in the other effectiveness endpoints assessed among patients treated with ETN or GP2015: rate of patients who achieved remission (54.1% vs. 66.7%, p-value = 0.303) and LDA (71.6% vs. 80.9%, p-value = 0.391) at week 52, reduction of DAS28-CRP value greater than or equal to 1.2 from baseline to week 52 (75.6% vs. 80.9%, p-value = 0.613) and rate of good responder patients (58.1% vs. 76.1%, p-value = 0.202). Drug survival was 82% and 80% for ETN and GP2015, respectively (log-rank p-value = 0.804). Etanercept and its biosimilar GP2015 show similar effectiveness and treatment persistence in RA patients in a real-life setting

Best practices for interdisciplinary care of uncontrolled severe asthma patients (TEAM project)

As one of the most prevalent chronic respiratory diseases, asthma imposes a heavy health and socioeconomic burden on society, particularly in the case of patients who fail to appropriately control the disease. For this reason, improving the clinical management of patients with severe uncontrolled asthma should be a priority for any healthcare system.At a time when healthcare models for chronic disease management and personalized medicine are undergoing a major overhaul, the project presented in this study seeks to lay the foundations for an interdisciplinary care model for patients with severe uncontrolled asthma. The work carried out reinforces the general perception that it is paramount to optimize coordination between different levels of care, encourage collaboration and an interdisciplinary approach, and promote an integrated care model that makes it possible to adapt the care of patients with severe uncontrolled asthma in a more personalized manner. Under this project, a series of interdisciplinary working groups were created, made up of specialist hospital pharmacists, pneumologists and allergists, to identify and prioritize a number of best practices, and classify them in terms of their potential impact on the improvement of the quality of care and the health outcomes of patients with severe uncontrolled asthma, and their feasibility. The authors' ambition is that the conclusions drawn from this study should help other interdisciplinary teams improve the care provided to patients suffering from severe uncontrolled asthma

Factors associated to potentially inappropriate prescribing in older patients according to STOPP/START criteria: MoPIM multicentre cohort study

Objectives: The objectives of the present analyses are to estimate the frequency of potentially inappropriate prescribing (PIP) at admission according to STOPP/START criteria version 2 in older patients hospitalised due to chronic disease exacerbation as well as to identify risk factors associated to the most frequent active principles as potentially inappropriate medications (PIMs). Methods: A multicentre, prospective cohort study including older patients (≥65) hospitalized due to chronic disease exacerbation at the internal medicine or geriatric services of 5 hospitals in Spain between September 2016 and December 2018 was conducted. Demographic and clinical data was collected, and a medication review process using STOPP/START criteria version 2 was performed, considering both PIMs and potential prescribing omissions (PPOs). Primary outcome was defined as the presence of any most frequent principles as PIMs, and secondary outcomes were the frequency of any PIM and PPO. Descriptive and bivariate analyses were conducted on all outcomes and multilevel logistic regression analysis, stratified by participating centre, was performed on the primary outcome. Results: A total of 740 patients were included (mean age 84.1, 53.2% females), 93.8% of them presenting polypharmacy, with a median of 10 chronic prescriptions. Among all, 603 (81.5%) patients presented at least one PIP, 542 (73.2%) any PIM and 263 (35.5%) any PPO. Drugs prescribed without an evidence-based clinical indication were the most frequent PIM (33.8% of patients); vitamin D supplement in older people who are housebound or experiencing falls or with osteopenia was the most frequent PPO (10.3%). The most frequent active principles as PIMs were proton pump inhibitors (PPIs) and benzodiazepines (BZDs), present in 345 (46.6%) patients. This outcome was found significantly associated with age, polypharmacy and essential tremor in an explanatory model with 71% AUC. Conclusions: PIMs at admission are highly prevalent in these patients, especially those involving PPIs or BZDs, which affected almost half of the patients. Therefore, these drugs may be considered as the starting point for medication review and deprescription

Impact of non-persistence on healthcare resource utilization and costs in patients with immune-mediated rheumatic diseases initiating subcutaneous TNF-alpha anhibitors: a before-and-after study

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are chronic progressive immune-mediated rheumatic diseases (IMRD) that can cause a progressive disability and joint deformation and thus can impact in healthcare resource utilization (HCRU) and costs. The main outcome of the study was to assess the effect of non-persistence to treatment with subcutaneous tumor necrosis factor-alpha inhibitors (SC-TNFis) on HCRU costs in naïve patients with IMRD who started treatment with adalimumab, etanercept, golimumab or certolizumab pegol during 12 months after initiation of treatment. The impact of persistence and non-persistence of SC-TNFis on HCRU costs was compared between 12 months before and 12 months after initiating SC-TNFis. Persistence was defined as the duration of time from initiation to discontinuation of therapy. The study was conducted in an acute care teaching hospital in Barcelona, Spain. Data for the period between 2015 and 2018 were extracted from the hospital cost management control database. HCRU costs comprised outpatient care, outpatient specialized rheumatology care, in-patient care, emergency care, laboratory testing and other non-biological therapies. The study population included 110 naïve SC-TNFis patients, divided into the cohorts of persistent (n = 85) and non-persistent (n = 25) patients. Fifty-six percent of patients were women, with a mean (standard deviation) age of 47.6 (14.8) years. Baseline clinical features and HCRU costs over the 12 months before the index prescription were similar in the two study groups. Before-and-after differences in mean (standard deviation) HCRU costs were significantly higher in the non-persistence group as compared to the persistence group for outpatient rheumatology care (€110.90 [234.56] vs. €20.80 [129.59], p = 0.023), laboratory testing (-€193.99 [195.88] vs. -€241.3 [217.88], p = 0.025), other non-biological drugs (€3849.03 [4046.14] vs. -€10.90 [157.42], p < 0.001) and total costs (€3268.90 [4821.55] vs. -€334.67 (905.44), p < 0.001). Treatment persistence with SC-TNFis may be associated with HCRU cost savings in naïve IMRD patients. Prescribing SC-TNFis with the best long-term persistence is beneficial