Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method

Fabry disease is a lysosomal storage disease arising from a deficiency of the enzyme α-galactosidase A (GLA). The enzyme deficiency results in an accumulation of glycolipids, which over time, leads to cardiovascular, cerebrovascular, and renal disease, ultimately leading to death in the fourth or fifth decade of life. Currently, lysosomal storage disorders are treated by enzyme replacement therapy (ERT) through the direct administration of the missing enzyme to the patients. In view of their advantages as drug delivery systems, liposomes are increasingly being researched and utilized in the pharmaceutical, food and cosmetic industries, but one of the main barriers to market is their scalability. Depressurization of an Expanded Liquid Organic Solution into aqueous solution (DELOS-susp) is a compressed fluid-based method that allows the reproducible and scalable production of nanovesicular systems with remarkable physicochemical characteristics, in terms of homogeneity, morphology, and particle size. The objective of this work was to optimize and reach a suitable formulation for in vivo preclinical studies by implementing a Quality by Design (QbD) approach, a methodology recommended by the FDA and the EMA to develop robust drug manufacturing and control methods, to the preparation of α-galactosidase-loaded nanoliposomes (nanoGLA) for the treatment of Fabry disease. Through a risk analysis and a Design of Experiments (DoE), we obtained the Design Space in which GLA concentration and lipid concentration were found as critical parameters for achieving a stable nanoformulation. This Design Space allowed the optimization of the process to produce a nanoformulation suitable for in vivo preclinical testing

Hospital-acquired influenza infections detected by a surveillance system over six seasons, from 2010/2011 to 2015/2016

In addition to outbreaks of nosocomial influenza, sporadic nosocomial influenza infections also occur but are generally not reported in the literature. This study aimed to determine the epidemiologic characteristics of cases of nosocomial influenza compared with the remaining severe cases of severe influenza in acute hospitals in Catalonia (Spain) which were identified by surveillance. An observational case-case epidemiological study was carried out in patients aged ≥18 years from Catalan 12 hospitals between 2010 and 2016. For each laboratory-confirmed influenza case (nosocomial or not) we collected demographic, virological and clinical characteristics. We defined patients with nosocomial influenza as those admitted to a hospital for a reason other than acute respiratory infection in whom ILI symptoms developed ≥48 h after admission and influenza virus infection was confirmed using RT-PCR. Mixed-effects regression was used to estimate the crude and adjusted OR. One thousand seven hundred twenty-two hospitalized patients with severe laboratory-confirmed influenza virus infection were included: 96 (5.6%) were classified as nosocomial influenza and more frequently had > 14 days of hospital stay (42.7% vs. 27.7%, P <.001) and higher mortality (18.8% vs. 12.6%, P <.02). The variables associated with nosocomial influenza cases in acute-care hospital settings were chronic renal disease (aOR 2.44 95% CI 1.44-4.15) and immunodeficiency (aOR 1.79 95% CI 1.04-3.06). Nosocomial infections are a recurring problem associated with high rates of chronic diseases and death. These findings underline the need for adherence to infection control guidelines

Cut-offs and response criteria for the Hospital Universitario la Princesa Index (HUPI) and their comparison to widely-used indices of disease activity in rheumatoid arthritis

Objective To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if =2, low disease activity if >2 and =5), moderate if >5 and <9 and high if =9. HUPI''s AUC to discriminate between low-moderate activity was 0.909 and between moderate-high activity 0.887. DAS28''s AUCs were 0.887 and 0.846, respectively; both indices had higher accuracy than SDAI (AUCs: 0.832 and 0.756) and CDAI (AUCs: 0.789 and 0.728). HUPI discriminates remission better than DAS28-ESR in early arthritis, but similarly to SDAI. The HUPI cut-off for minimal clinical improvement was established at 2 and for relevant clinical improvement at 4. Response criteria were established based on these cut-off values. Conclusions The cut-offs proposed for HUPI perform adequately in patients with either early or long term arthritis

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with &gt;80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Cómo y cuándo derivar un paciente con cefalea primaria y neuralgia craneofacial desde Urgencias y Atención Primaria: recomendaciones del Grupo de Estudio de Cefalea de la Sociedad Española de Neurología

Introducción: Cuando tras una correcta anamnesis y exploración neurológica se diagnostica a un paciente con una cefalea primaria o una neuralgia craneofacial en urgencias o atención primaria y se decide derivar a neurología por complejidad es útil conocer si además se deberían solicitar exploraciones complementarias y la preferencia (urgente, preferente o normal) con la que se debería derivar para que el paciente llegue a la consulta del neurólogo sin demoras innecesarias en pacientes con dolores incapacitantes o con sospecha de organicidad. Por este motivo, el Grupo de Estudio de Cefalea de la Sociedad Española de Neurología, ha decidido crear unas recomendaciones consensuadas que establezcan un protocolo de derivación de pacientes con cefalea y/o neuralgias craneofaciales. Desarrollo: Se ha contactado con neurólogos jóvenes con interés y experiencia en cefalea y con la Junta Directiva del Grupo de Estudio de Cefalea de la Sociedad Española de Neurología que han desarrollado este documento que, por razones prácticas, se ha dividido en 2 artículos. Esta primera centrada en las cefaleas o neuralgias craneofaciales primarias y una segunda que se focaliza en las cefaleas secundarias. El enfoque es práctico con tablas que resumen los criterios de derivación con exploraciones complementarias y otros especialistas a los que derivar, para que sea útil y facilite su uso en nuestra práctica asistencial diaria. Conclusiones: Esperamos ofrecer una guía y herramientas para mejorar la toma de decisiones ante un paciente con cefalea, valorando exploraciones a priorizar y qué circuitos seguir para así evitar la duplicación de consultas y retrasos en el diagnóstico y en el tratamiento

Headache: pregnancy and breastfeeding. Recommendations of the Spanish Society of Neurology's Headache Study Group.

Headache is one of the most common neurological complaints, and is most frequent during reproductive age. As a result, we are routinely faced with pregnant or breastfeeding women with this symptom in clinical practice. It is important to know which pharmacological choices are the safest, which should not be used, and when we should suspect secondary headache. To this end, the Spanish Society of Neurology's Headache Study Group has prepared a series of consensus recommendations on the diagnostic and therapeutic algorithms that should be followed during pregnancy and breastfeeding. This guide was prepared by a group of young neurologists with special interest and experience in headache, in collaboration with the Group's Executive Committee. Recommendations focus on which drugs should be used for the most frequent primary headaches, both during the acute phase and for prevention. The second part addresses when secondary headache should be suspected and which diagnostic tests should be performed in the event of possible secondary headache during pregnancy and breastfeeding. We hope this guide will be practical and useful in daily clinical practice and that it will help update and improve understanding of headache management during pregnancy and breastfeeding, enabling physicians to more confidently treat these patients