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.

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.

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.

Impact of uric acid levels on the risk of long-term cardiovascular mortality in patients with type 2 diabetes mellitus. / Influencia de los niveles de ácido úrico sobre el riesgo de mortalidad cardiovascular a largo plazo en pacientes con diabetes de tipo 2.

BACKGROUND: Hyperuricemia is associated to cardiovascular disease. However, the contribution of uric acid (UA) to cardiovascular mortality in diabetic patients is controversial. OBJECTIVE: To assess the impact of UA levels on the risk of cardiovascular mortality risk in a cohort of patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: A prospective cohort study on outpatients with T2DM. The clinical endpoint was cardiovascular death. Anthropometric, demographic, clinical, and biochemical variables were collected, including UA levels, urinary albumin excretion and estimated glomerular filtration rate. The independent contribution of UA levels to cardiovascular mortality was assessed using multivariate Cox regression models, progressively adjusted for potential confounders. RESULTS: A total of 452 patients with a mean age of 65.9 (SD 9.5) years were enrolled. Mean UA level was 4.2mg/dL. Quartiles of UA levels were Q1 < 3.3; Q2: 3.3-4.2; Q3: 4.3-5.1; Q4 > 5.1mg/dL. UA levels significantly correlated with estimated glomerular filtration rate (Rho=-0.227; p<0.001). During a median follow-up time of 13 years, cardiovascular mortality rates were higher in Q4 of the UA distribution (Q1: 10.7; Q2: 11.7; Q3: 10.7; Q4: 21.6 per 1000 patient-years; p = 0.027). UA was a predictor of cardiovascular mortality in the univariate analysis (HR1mg/dL = 1.30; p=0.002), but not in a multivariate analysis adjusted for urinary albumin excretion and eGFR (HR1mg/dL=1.20; p=0.12). DISCUSSION AND CONCLUSIONS: High UA levels are associated to cardiovascular mortality in patients with T2DM. However, the role of UA may be mediated by impaired kidney function in patients with hyperuricemia.

[Recommendations for the management of emergencies in patients with diabetes, acute metabolic complications of diabetes, and steroid-related hyperglycemia]. / Recomendaciones de manejo de la diabetes, de sus complicaciones metabólicas agudas y de la hiperglucemia relacionada con corticoides en los servicios de urgencias.

EN: Persons with diabetes make up a large percentage of patients attended in the emergency department. Most will be discharged, but patients who remain under observation in wards managed by the emergency department or who wait are waiting to be admitted to a conventional ward must receive appropriate, protocol-guided treatment for their diabetes. Situations of hyper- or hypoglycemia must be avoided because both worsen prognosis. Emergency physicians must correctly and efficiently prevent, diagnose, and manage acute metabolic complications of diabetes such as simple hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state. They must also be ready to prescribe and properly administer intravenous insulin to critically ill patients. Hyperglycemia induced by treatment with steroids deserves special mention. If this complication develops, the hyperglycemia is intense, influenced by increased insulin resistance and gluconeogenesis in the liver. Thus, it usually appears after meals and is dependent on steroid dose, duration of treatment, and individual predisposition. The recommendations in this paper elaborated by consensus of the Spanish Society of Emergency Medicine (SEMES) experts, are the first to be written specifically for use in emergency departments in Spain. They give a detailed, in-depth overview of emergencies related to diabetes and diabetic complications.

ES: Un alto porcentaje de los pacientes atendidos en urgencias son diabéticos. La mayoría serán dados de alta. Sin embargo, los que se quedan en observación, ingresados en unidades dependientes de urgencias o los que quedan pendientes de ingreso en hospitalización convencional deben recibir un tratamiento correcto y protocolizado en cuanto a su diabetes, que evite tanto la hiper como la hipoglucemia, ya que ambas son situaciones que empeorarán el pronóstico del paciente. Por otro lado, los urgenciólogos deben prevenir, diagnosticar y manejar de una manera correcta y eficiente las complicaciones metabólicas agudas de la diabetes como son la hiperglucemia simple, la cetoacidosis diabética, la situación hiperosmolar y la hipoglucemia, así como las indicaciones y la forma de administración de insulina intravenosa en los pacientes críticos. Una mención aparte requiere también la hiperglucemia reactiva al tratamiento corticoideo. Esta hiperglucemia, en el caso de aparecer, es intensa y está influenciada por el aumento de la resistencia a la insulina y de la neoglucegénesis hepática que provocan los corticoides, por lo que será de predominio postprandial. Depende de la dosis y duración del tratamiento corticoideo además de una predisposición individual. Las recomendaciones que aquí se exponen, procedentes del consenso alcanzado por el grupo de expertos de la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES), son las primeras redactadas en España dirigidas exclusivamente a los servicios de urgencias y que hacen una revisión pormenorizada y profunda sobre todas las situaciones que pueden encontrarse en cuanto a la diabetes y sus complicaciones.

[Predictors of mean blood glucose control and its variability in diabetic hospitalized patients]. / Factores predictores del control glucémico promedio yde su variabilidad en pacientes diabéticos ingresadosen el hospital.

INTRODUCTION: This study was intended to assess the effectiveness and predictors factors of inpatient blood glucose control in diabetic patients admitted to medical departments. MATERIAL AND METHODS: A retrospective, analytical cohort study was conducted on patients discharged from internal medicine with a diagnosis related to diabetes. Variables collected included demographic characteristics, clinical data and laboratory parameters related to blood glucose control (HbA1c, basal plasma glucose, point-of-care capillary glucose). The cumulative probability of receiving scheduled insulin regimens was evaluated using Kaplan-Meier analysis. Multivariate regression models were used to select predictors of mean inpatient glucose (MHG) and glucose variability (standard deviation [GV]). RESULTS: The study sample consisted of 228 patients (mean age 78.4 (SD 10.1) years, 51% women). Of these, 96 patients (42.1%) were treated with sliding-scale regular insulin only. Median time to start of scheduled insulin therapy was 4 (95% CI, 2-6) days. Blood glucose control measures were: MIG 181.4 (SD 41.7) mg/dL, GV 56.3 (SD 22.6). The best model to predict MIG (R(2): .376; P<.0001) included HbA1c (b=4.96; P=.011), baseline plasma glucose (b=.056; P=.084), mean capillary blood glucose in the first 24hours (b=.154; P<.0001), home treatment (versus oral agents) with basal insulin only (b=13.1; P=.016) or more complex (pre-mixed insulin or basal-bolus) regimens (b=19.1; P=.004), corticoid therapy (b=14.9; P=.002), and fasting on admission (b=10.4; P=.098). CONCLUSION: Predictors of inpatient blood glucose control which should be considered in the design of DM management protocols include home treatment, HbA1c, basal plasma glucose, mean blood glucose in the first 24hours, fasting, and corticoid therapy.

Generalised weakness in a young patient: a cause for concern?

Muscular weakness in young patients is usually due to mild, self-limiting causes. Nonetheless, it is important to remember other, more serious aetiologies which can cause this clinical picture. Thyrotoxic hypokalaemic periodic paralysis (THPP) is a rare disease in Europe and the USA, with fatal cardiovascular and respiratory complications. It is characterised by recurrent episodes of generalised muscular weakness, especially in the legs, with an associated hypokalaemia and hyperthyroidism. Diagnosis is based on clinical history, laboratory tests and an ECG. Early treatment focused on cautious correction blood potassium and non-cardiac selective ß-blockers. Additionally, it is imperative to normalise thyroid function to prevent relapses. We present a young, healthy man to the emergency department with episodes of intermittent leg weakness. The history and the ECG findings allowed for the diagnosis of THPP to be reached with early treatment causing remission.

Alternativas terapéuticas para la insuficiencia cardíaca en los ancianos: [revisión] / Therapeutic alternatives for treating heart failure in elderly patients: [review]

La insuficiencia cardíaca (IC) es una importante causa de mortalidad en todo el mundo y el principal motivo de hospitalización de origen no quirúrgico en muchos países. Existe un gran número de variables predictivas acerca del pronóstico de pacientes con IC, una de ellas es la edad. Además, la comorbilidad por causa no cardíaca dificulta el tratamiento en un importante grupo de pacientes ancianos con IC y casi la mitad de los pacientes con síntomas de IC presenta una fracción de eyección del ventrículo izquierdo conservada. Sin embargo, los ensayos clínicos en IC no se han centrado ni en el grupo de pacientes ancianos ni en aquellos con fracción de eyección conservada. Por esta razón no se han establecido recomendaciones específicas para este grupo. Este artículo revisará los estudios más importantes sobre IC realizados en los últimos años y analizará los resultados en pacientes de edad igual o superior a 65 años. Esta revisión incluye los betabloqueantes, inhibidores de la enzima convertidora de angiotensina, antagonistas del receptor de la angiotensina, antagonistas de los receptores de la aldosterona, nitratos más hidralazina, digoxina, estatinas, el desfibrilador automático implantable y la resincronización cardíaca.