Concordancia del tratamiento en vida real con las recomendaciones de ficha técnica y guías de práctica clínica en pacientes monoinfectados con hepatitis crónica por virus C tratados con antivirales directos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 3-07-2017Esta tesis tiene embargado el acceso al texto completo hasta el 03-01-201

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study)

Lymphopenia; Multiple sclerosis; PharmacovigilanceLinfopenia; Esclerosis múltiple; FarmacovigilanciaLimfopènia; Esclerosi múltiple; FarmacovigilànciaBackground: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. Objective: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. Methods: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. Results: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade ≤ 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. Conclusions: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk

SENTIA: a systematic online monitoring registry for children and adolescents treated with antipsychotics

INTRODUCTION: Despite drastic increases in antipsychotic prescribing in youth, data are still limited regarding their safety in this vulnerable population, necessitating additional tools for capturing long-term, real world data. METHODS: We present SENTIA (SafEty of NeurolepTics in Infancy and Adolescence; https://SENTIA.es), an online registry created in 2010 to track antipsychotic adverse effects in Spanish youth <18 years old currently taking or initiating with any antipsychotic treatment. SENTIA collects information on sociodemographic, diagnostic and treatment characteristics, past personal medical/psychiatric history, healthy lifestyle habits and treatment adherence. Additionally, efficacy and adverse effect data are recorded including the Children’s Global Assessment Scale; Clinical Global Impressions scale for Severity and Improvement, the Safety Monitoring Uniform Report Form, Simpson-Angus Scale, Abnormal Involuntary Movement Scale, vital signs, blood pressure, and EKG. Finally, fasting blood is drawn for hematology, electrolytes, renal, liver and thyroid function, glucose, insulin, lipid, prolactin and sex hormone levels. Initially, a diagnostic interview and several psychopathology scales were also included. Patients are assessed regularly and followed even beyond stopping antipsychotics. RESULTS: Since 01/17/2011, 85 youth (11.5 ± 2.9 (range = 4-17) years old, 70.6% male) have been included at one inaugural center. After a mean duration of 17 ± 11 (range = 1-34) months, 78.8% are still actively followed. For feasibility reasons, the diagnostic interview and detailed psychopathology scales were dropped. The remaining data can be entered in <30 minutes. Several additional centers are currently being added to SENTIA. CONCLUSIONS: Implementation of a systematic online pharmacovigilance system for antipsychotic adverse effects in youth is feasible and promises to generate important information

Bronchopulmonary penetration of isavuconazole in lung transplant recipients

Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung.This work was partially supported and funded by Pfizer (grant 54685521). Pfizer had no role in the study’s design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publicationS

Bronchopulmonary Penetration of Isavuconazole in Pulmonary Transplant Recipients (PBISA01): Protocol for a Phase IV Clinical Trial With a Single Treatment Arm

Background: Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD. Objective: The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD. Methods: A total of 12 patients aged ≥18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method. Results: Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022. Conclusions: There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA. Trial registration: European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES. International registered report identifier (irrid): DERR1-10.2196/37275.This work is supported funded by Pfizer (grant 54685521). Pfizer will have no role in the study’s design; the collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.S

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection : A Spanish, Multicenter, Cohort Study

We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users

Evaluation of two treatment strategies for the prevention of preterm birth in women identified as at risk by ultrasound (PESAPRO Trial): Study protocol for a randomized controlled trial

Background: Premature birth is considered one of the main problems in modern Obstetrics. It causes more than 50 % of neonatal mortality; it is responsible for a large proportion of infant morbidity and incurs very high economic costs. Cervical length, which can be accurately measured by ultrasound, has an inverse relationship with the risk of preterm birth. As a result, having an effective intervention for asymptomatic patients with short cervix could reduce the prematurity. Although recently published data demonstrates the effectiveness of vaginal progesterone and cervical pessary, these treatments have never been compared to one another. Methods/Design: The PESAPRO study is a noncommercial, multicenter, open-label, randomized clinical trial (RCT) in pregnant women with a short cervix as identified by transvaginal ultrasonography at 19 to 22 weeks of gestation. Patients are randomized (1:1) to either daily vaginal progesterone or cervical pessary until the 37th week of gestation or delivery; whichever comes first. During the trial, women visit every 4 weeks for routine questions and tests. The primary outcome is the proportion of spontaneous preterm deliveries before 34 weeks of gestation. A sample size of 254 pregnant women will be included at 29 participating hospitals in order to demonstrate noninferiority of placing a pessary versus vaginal progesterone. The first patient was randomized in August 2012, and recruitment of study subjects will continue until the end of December 2015. Discussion: This trial assesses the comparative efficacy and safety between two accepted treatments, cervical pessary versus vaginal progesterone, and it will provide evidence in order to establish clinical recommendationsThe study has been funded by two national grants from the Spanish Ministry of Health and ISCIII

Riesgos de las plantas medicinales en uso concomitante con medicamentos

El consumo de plantas medicinales ha crecido en nuestro medio en los últimos años y es frecuente su utilización en combinación con medicamentos prescritos por los médicos. Existe la falsa percepción de que los productos a base de plantas son inocuos e incluso ventajosos por su supuesto carácter "natural", razonamiento poco compatible con el hecho de que su efecto terapéutico se atribuya a su contenido en principios activos con actividad farmacológica. Se han descrito algunas interacciones de relevancia clínica entre plantas y medicamentos por lo que resulta imprescindible incorporar a la historia clínica el interrogatorio sobre tales hábitos, especialmente en aquellos pacientes tratados con medicamentos en los que las posibles interacciones impliquen consecuencias clínicas. Debemos considerar estos productos como posible origen de síntomas, reacciones adversas e interacciones medicamentosas en los pacientes. La notificación de estas sospechas al Sistema Español de Farmacovigilancia puede ser una herramienta para mejorar el conocimiento sobre estos productos