Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization.

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19. ONE-SENTENCE SUMMARY: Plitidepsin, an inhibitor of SARS-Cov-2 in vitro , is safe and positively influences the outcome of patients hospitalized with COVID-19.

Gas venoso portal hepático, un hallazgo radiológico potencialmente grave / Hepatic portal venous gas, a potentially serious radiological finding

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Esófago negro (necrosis aguda esofágica) / Black oesophagus (acute oesophageal necrosis)

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Riesgo de mortalidad total y cardiovascular según la clasificación propuesta por las guías KDIGO en pacientes con diabetes tipo 2 / Total and cardiovascular mortality risk according to KDIGO guidelines classification in type 2 diabetic patients

Antecedentes y objetivo: El objetivo del estudio fue comprobar la validez de la clasificación de riesgo KDIGO 2012 para predecir mortalidad total (MT) y cardiovascular (MCV) en diabetes mellitus tipo 2 (DM2). Materiales y métodos: Estudio de cohortes prospectivo incluyendo pacientes con DM2. Los puntos finales clínicos fueron MT y MCV. La principal variable predictora fue la clasificación KDIGO, una variable que recoge 4 niveles de riesgo en dependencia de una combinación de la tasa de filtración glomerular y la excreción de albúmina urinaria. La evaluación del poder predictivo se realizó con el índice de mejora de discriminación integrada (IDI). Resultados: Se incluyeron 453 pacientes (39,3% varones, edad 64,9 [DE 9,3] años y evolución de DM2 de 10,4 [DE 7,5] años). Durante una mediana de 13 años de seguimiento, hubo incremento significativo de la tasa/1000 pacientes-año de MT (26,5 vs. 45,1 vs. 79,2 vs. 109,8; p<0,001) y de MCV (8,1 vs. 17,4 vs. 24,7 vs. 57,5; p<0,001) en las sucesivas categorías de riesgo KDIGO. En análisis multivariante también hubo incremento de riesgo de MT (HR[riesgo moderado]=1,29; HR[riesgo alto]=1,83; HR[riesgo muy alto]=2,15; p=0,016) y MCV (HR[riesgo moderado]=1,73; HR[riesgo alto]=2,27; HR[riesgo muy alto]=4,22; p=0,007) en las sucesivas categorías. La clasificación KDIGO mejoró la predicción de MT (IDI=0,00888; p=0,047) y MCV (IDI=0,01813; p=0,035). Conclusiones: La clasificación de riesgo según guías KDIGO 2012 puede estratificar eficazmente el riesgo de MT y MCV en pacientes con DM2

Background and aims: Our aim was to assess the usefulness of KDIGO 2012 risk classification to predict total and cardiovascular mortality in type 2 diabetes mellitus (DM2). Material and methods: Prospective cohort study that included DM2 patients. Clinical end-points were total and cardiovascular mortality. The main predictive variable was KDIGO risk classification, which is a combination of urinary albumin excretion and glomerular filtration rate. The predictive value was evaluated by the integrated discrimination improvement (IDI) index. Results: 453 patients (39.3% males, aged 64.9 [SD 9.3] and with a mean diabetes duration of 10.4 [SD 7.5] years) were included. During a median follow-up of 13 years, mortality rates per 1000 patients/year (26.5 vs. 45.1 vs. 79,2 vs. 109,8; p<0,001) and cardiovascular mortality (8.1 vs. 17.4 vs. 24.7 vs. 57.5; p<0,001) were progressively increased in successive KDIGO categories. In the multivariate analysis, there was also a progressive increase of mortality risk (HR[moderate risk]=1.29; HR[high risk])=1.83; HR[very high risk]=2.15; p=.016) and cardiovascular mortality risk (HR[moderate risk]=1.73; HR[high risk]=2.27; HR[very high risk]=4.22; p=.007) in the successive categories. KDIGO classification was able to improve the mortality risk prediction (IDI=0.00888; p=.047) and cardiovascular mortality risk prediction (IDI=0.01813; p=.035). Conclusions: KDIGO risk classification can effectively stratify total and cardiovascular mortality risk in DM2 patients

Evaluación de la eficacia y la seguridad de un protocolo de manejo de pacientes con diabetes descompensada por glucocorticoides durante la hospitalización / Assessment of the efficacy and safety of a protocol to manage glucocorticoid-induced hyperglycemia in diabetic patients during hospital stay

Introducción: No existen protocolos consensuados de manejo hospitalario de las descompensaciones hiperglucémicas inducidas por dosis farmacológicas de glucocorticoides (GC). Nuestro objetivo fue evaluar la eficacia y la seguridad de un protocolo de insulinización específico para corticoides (PC) frente a un protocolo general (PG) en diabetes descompensada por GC (DDG). Materiales y métodos: Estudio experimental con grupo control, no aleatorizado, en pacientes con DDG ingresados en neumología. Se compararon 2 protocolos (PC y PG), ambos basados en terapia basal-bolo pero con diferentes dosis y distribución de insulina. Se evaluó la diferencia de glucemia media (GM) durante la hospitalización entre el PC y el PG, así como el riesgo de presentar una GM > 200mg/dl, ajustado para potenciales factores de confusión (relacionados con el paciente y con la terapia de GC empleada). Resultados: Se incluyó a 131 pacientes, 60 asignados al PG y 71 al PC. Un 74% de los pacientes estaban ingresados por exacerbación de enfermedad pulmonar obstructiva crónica. Hubo diferencia significativa en la dosis total de insulina entre el PG y el PC (29,4 vs. 57,4 unidades; p < 0,0001). La diferencia ajustada de GM (PC-PG) fue de -14,8 (IC del 95%, -26,2 a -3,3) mg/dl. Los pacientes del PC tuvieron menor riesgo ajustado de presentar GM > 200mg/dl durante la hospitalización (OR = 0,31; IC del 95%, 0,11-0,91; p = 0,033). No hubo diferencias en el riesgo de hipoglucemia grave entre el PG y el PC (0% vs. 1,4%; p = 0,36). Conclusiones: El protocolo estudiado ha demostrado reducir la GM de pacientes con DDG durante la hospitalización sin comprometer su seguridad

Introduction: There are no agreed protocols on hospital management of hyperglycemic decompensation induced by pharmacological doses of glucocorticoids (GCs). The study objective was to assess the efficacy and safety of an insulin therapy protocol specific for patients treated with glucocorticoids (CP) as compared to a general protocol (GP) in diabetes decompensation secondary to glucocorticoids. Materials and methods: An experimental study in patients with glucocorticoids-induced decompensated diabetes admitted to a respiratory ward including a non-randomized control group. Two protocols (CP and GP), both based on basal-bolo insulin regimens, but with different insulin doses and distribution, were compared. The difference in mean blood glucose (MBG) levels between both protocols was measured during hospital stay, as was the risk of having MBG levels > 200mg/dL, adjusted for potential confounding factors (related to patients and to the glucocorticoid therapy used). Results: A total of 131 patients were included, 60 assigned to the GP and 71 to the CP groups. Seventy-four percent of patients had been admitted due to COPD exacerbation. There was a significant difference in the total daily insulin dose used between the CP and GP groups (29.4 vs. 57.4 IU; P<.0001). The adjusted difference in MBG levels (CP-GP) was -14.8 (95% CI, -26.2 to -3.3) mg/dL. Patients in the CP group had a lower adjusted risk of having MBG levels >200mg/dL during hospital admission (OR=0.31; 95% CI, 0.11-0.91; P=.033). There were no differences in the risk of severe hypoglycemia between the CP and GP groups (0% vs. 1.4%; P=.36). Conclusions: The study protocol has been shown to decrease MBG levels in patients with glucocorticoids-induced decompensation of diabetes during hospital admission without compromising their safety

Total and cardiovascular mortality risk according to KDIGO guidelines classification in type 2 diabetic patients. / Riesgo de mortalidad total y cardiovascular según la clasificación propuesta por las guías KDIGO en pacientes con diabetes tipo 2.

BACKGROUND AND AIMS: Our aim was to assess the usefulness of KDIGO 2012 risk classification to predict total and cardiovascular mortality in type 2 diabetes mellitus (DM2). MATERIAL AND METHODS: Prospective cohort study that included DM2 patients. Clinical end-points were total and cardiovascular mortality. The main predictive variable was KDIGO risk classification, which is a combination of urinary albumin excretion and glomerular filtration rate. The predictive value was evaluated by the integrated discrimination improvement (IDI) index. RESULTS: 453 patients (39.3% males, aged 64.9 [SD 9.3] and with a mean diabetes duration of 10.4 [SD 7.5] years) were included. During a median follow-up of 13 years, mortality rates per 1000 patients/year (26.5 vs. 45.1 vs. 79,2 vs. 109,8; p<0,001) and cardiovascular mortality (8.1 vs. 17.4 vs. 24.7 vs. 57.5; p<0,001) were progressively increased in successive KDIGO categories. In the multivariate analysis, there was also a progressive increase of mortality risk (HR[moderate risk]=1.29; HR[high risk])=1.83; HR[very high risk]=2.15; p=.016) and cardiovascular mortality risk (HR[moderate risk]=1.73; HR[high risk]=2.27; HR[very high risk]=4.22; p=.007) in the successive categories. KDIGO classification was able to improve the mortality risk prediction (IDI=0.00888; p=.047) and cardiovascular mortality risk prediction (IDI=0.01813; p=.035). CONCLUSIONS: KDIGO risk classification can effectively stratify total and cardiovascular mortality risk in DM2 patients.

Assessment of the efficacy and safety of a protocol to manage glucocorticoid-induced hyperglycemia in diabetic patients during hospital stay. / Evaluación de la eficacia y la seguridad de un protocolo de manejo de pacientes con diabetes descompensada por glucocorticoides durante la hospitalización.

INTRODUCTION: There are no agreed protocols on hospital management of hyperglycemic decompensation induced by pharmacological doses of glucocorticoids (GCs). The study objective was to assess the efficacy and safety of an insulin therapy protocol specific for patients treated with glucocorticoids (CP) as compared to a general protocol (GP) in diabetes decompensation secondary to glucocorticoids. Materials and methods An experimental study in patients with glucocorticoids-induced decompensated diabetes admitted to a respiratory ward including a non-randomized control group. Two protocols (CP and GP), both based on basal-bolo insulin regimens, but with different insulin doses and distribution, were compared. The difference in mean blood glucose (MBG) levels between both protocols was measured during hospital stay, as was the risk of having MBG levels > 200mg/dL, adjusted for potential confounding factors (related to patients and to the glucocorticoid therapy used). RESULTS: A total of 131 patients were included, 60 assigned to the GP and 71 to the CP groups. Seventy-four percent of patients had been admitted due to COPD exacerbation. There was a significant difference in the total daily insulin dose used between the CP and GP groups (29.4 vs. 57.4 IU; P<.0001). The adjusted difference in MBG levels (CP-GP) was -14.8 (95% CI, -26.2 to -3.3) mg/dL. Patients in the CP group had a lower adjusted risk of having MBG levels >200mg/dL during hospital admission (OR=0.31; 95% CI, 0.11-0.91; P=.033). There were no differences in the risk of severe hypoglycemia between the CP and GP groups (0% vs. 1.4%; P=.36). CONCLUSIONS: The study protocol has been shown to decrease MBG levels in patients with glucocorticoids-induced decompensation of diabetes during hospital admission without compromising their safety.