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1. Potential protective role of let-7d-5p in atherosclerosis progression reducing the inflammatory pathway regulated by NF-κB and vascular smooth muscle cells proliferation

Author

Aroca-Esteban, Javier, Souza-Neto, Francisco V., Aguilar-Latorre, Carlota, Tribaldo-Torralbo, Alba, González-López, Paula, Ruiz-Simón, Rubén, Álvarez-Villareal, Marta, Ballesteros, Sandra, de Ceniga, Melina Vega, Landete, Pedro, González-Rodríguez, Águeda, Martín-Ventura, José L., de las Heras, Natalia, Escribano, Óscar, and Gómez-Hernández, Almudena

Published
2024
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3. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Author

Varona, Jose F, Landete, Pedro, Lopez-Martin, Jose A, Estrada, Vicente, Paredes, Roger, Guisado-Vasco, Pablo, de Orueta, Lucia Fernandez, Torralba, Miguel, Fortun, Jesus, Vates, Roberto, Barberan, Jose, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemi, Porras, Lourdes, Gijon, Paloma, Monereo, Alfonso, Abad, Daniel, Zuñiga, Sonia, Sola, Isabel, Rodon, Jordi, Vergara-Alert, Julia, Izquierdo-Useros, Nuria, Fudio, Salvador, Pontes, Maria Jose, de Rivas, Beatriz, de Velasco, Patricia Giron, Nieto, Antonio, Gomez, Javier, Aviles, Pablo, Lubomirov, Rubin, Belgrano, Alvaro, Sopesen, Belen, White, Kris M, Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G, Jolly, Clare, Towers, Greg J, Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L, Rodriguez, M Luis, Enjuanes, Luis, Fernandez-Sousa, Jose M, Krogan, Nevan J, Jimeno, Jose M, and Garcia-Sastre, Adolfo

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Infectious Diseases, Cancer, Lung, Clinical Trials and Supportive Activities, Patient Safety, Prevention, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Adult, Aged, COVID-19, Cell Line, Tumor, Depsipeptides, Drug Evaluation, Preclinical, Female, Hospitalization, Humans, Kaplan-Meier Estimate, Length of Stay, Male, Middle Aged, Neutropenia, Peptides, Cyclic, SARS-CoV-2, Treatment Outcome, Viral Load, COVID-19 Drug Treatment, Biological sciences, Biomedical and clinical sciences
Abstract

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.

Published
2022

7. Role of Sleep Apnea and Long-Term CPAP Treatment in the Prognosis of Patients With Melanoma: A Prospective Multicenter Study of 443 Patients

Author

Gómez-Olivas, Jose Daniel, Campos-Rodriguez, Francisco, Nagore, Eduardo, Martorell, Antonio, García-Rio, Francisco, Cubillos, Carolina, Hernandez, Luis, Bañuls, Jose, Arias, Eva, Ortiz, Pablo, Cabriada, Valentin, Gardeazabal, Juan, Montserrat, Josep Maria, Carrera, Cristina, Masa, Juan Fernando, Gomez de Terreros, Javier, Abad, Jorge, Boada, Adam, Mediano, Olga, Castillo-Garcia, Marta, Chiner, Eusebi, Landete, Pedro, Mayos, Mercedes, Fortuna, Ana, Barbé, Ferrán, Sanchez-de-la-Torre, Manuel, Cano-Pumarega, Irene, Perez-Gil, Amalia, Gomez-Garcia, Teresa, Cullen, Daniela, Somoza, Maria, Formigon, Manuel, Aizpuru, Felipe, Oscullo, Grace, Garcia-Ortega, Alberto, Almendros, Isaac, Farré, Ramón, Gozal, David, and Martinez-Garcia, Miguel Angel

Published
2023
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8. Effect of the Early Combination of Continuous Positive Airway Pressure and High-Flow Nasal Cannula on Mortality and Intubation Rates in Patients With COVID-19 and Acute Respiratory Distress Syndrome. The DUOCOVID Study

Author

Teran-Tinedo, Jose Rafael, Gonzalez-Rubio, Jesus, Najera, Alberto, Lorente-Gonzalez, Miguel, Cano-Sanz, Eduardo, De La Calle-Gil, Isabel, Ortega-Fraile, Maria Ángeles, Carballo-López, Daniel, Hernández-Nuñez, Joaquín, Churruca-Arróspide, Maria, Zevallos-Villegas, Annette, López-Padilla, Daniel, Puente-Maestú, Luis, Navarro-Lopez, Juan D., Jimenez-Diaz, Lydia, and Landete, Pedro

Published
2023
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11. A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19.

Author

Landete, Pedro, Caliman-Sturdza, Olga-Adriana, Lopez-Martin, Jose A, Preotescu, Liliana, Luca, Mihaela-Catalina, Kotanidou, Anastasia, Villares, Paula, Iglesias, Shirley-Patricia, Guisado-Vasco, Pablo, Saiz-Lou, Elena-Maria, Farinas-Alvarez, Maria del Carmen, Lucas, Esperanza Merino de, Perez-Alba, Eduardo, Cisneros, Jose-Miguel, Estrada, Vicente, Hidalgo-Tenorio, Carmen, Poulakou, Garyfallia, Torralba, Miguel, Fortun, Jesus, and Garcia-Ocana, Paula

Subjects
*COMBINATION drug therapy, *PATIENT safety, *RESEARCH funding, *STATISTICAL sampling, *HOSPITAL care, *OXYGEN therapy, *TERMINATION of treatment, *RANDOMIZED controlled trials, *DESCRIPTIVE statistics, *INVERTEBRATES, *PEPTIDES, *ANTIVIRAL agents, *DRUG efficacy, *RESEARCH, *CONFIDENCE intervals, *COVID-19, *MARINE animals, *DEXAMETHASONE, *EVALUATION, *ADULTS
Abstract

Background Plitidepsin has shown potent preclinical activity against severe acute respiratory syndrome coronavirus 2 and was generally well tolerated in a phase I trial of hospitalized patients with coronavirus disease 2019 (COVID-19). NEPTUNO, a phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients. Methods Included patients had documented severe acute respiratory syndrome coronavirus 2 infection, required oxygen therapy, and had adequate organ function. The planned sample size was 609 patients. Patients were randomized 1:1:1 to at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, for 3 days) or standard of care (control). The primary endpoint was the time to sustained withdrawal of supplemental oxygen. Secondary endpoints included time to sustained hospital discharge, clinical status, duration of oxygen support, percentage of patients requiring admission to the intensive care unit, and safety. Results After randomizing 205 patients, NEPTUNO was discontinued due to a notable drop in COVID-19–related hospitalizations. Available data suggest a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms (hazard ratio, 1.37; 95% confidence interval,.96–1.96; P =.08 for plitidepsin 1.5 mg vs control; hazard ratio, 1.06; 95% confidence interval,.73–1.53; P =.78 for plitidepsin 2.5 mg vs control). Plitidepsin was generally well tolerated. Conclusions Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted. Results from this phase III trial suggest that plitidepsin, a first-in-class antiviral, may have a positive benefit-risk ratio in the management of hospitalized patients requiring oxygen therapy for moderate COVID-19. [ABSTRACT FROM AUTHOR]

Published
2024
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16. COVID-19 severity associates with pulmonary redistribution of [CD1c.sup.+] DCs and inflammatory transitional and nonclassical monocytes

Author

Sanchez-Cerrillo, Ildefonso, Landete, Pedro, Aldave, Beatriz, Sanchez-Alonso, Santiago, Sanchez-Azofra, Ana, Marcos-Jimenez, Ana, Avalos, Elena, Alcaraz-Serna, Ana, de los Santos, Ignacio, Mateu-Albero, Tamara, Esparcia, Laura, Lopez-Sanz, Celia, Martinez-Fleta, Pedro, Gabrie, Ligia, del Campo Guerola, Luciana, de la Fuente, Hortensia, Calzada, Maria J., Gonzalez-Alvaro, Isidoro, Alfranca, Arantzazu, Sanchez-Madrid, Francisco, Munoz-Calleja, Cecilia, Soriano, Joan B., Ancochea, Julio, and Martin-Gayo, Enrique

Subjects
Epidemics -- Control -- Spain, Dendritic cells -- Health aspects, Immune response -- Observations, COVID-19 -- Complications and side effects -- Care and treatment, Health care industry
Abstract

SARS-CoV-2 is responsible for the development of coronavirus disease 2019 (COVID-19) in infected individuals, who can either exhibit mild symptoms or progress toward a life-threatening acute respiratory distress syndrome (ARDS). Exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of [CD8.sup.+] T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. Here, we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood and lung of COVID-19 patients with different clinical severity in comparison with healthy individuals. Furthermore, these subpopulations and their association with antiviral effector [CD8.sup.+] T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Our results indicate that inflammatory transitional and nonclassical monocytes and [CD1c.sup.+] conventional dendritic cells preferentially migrate from blood to lungs in patients with severe COVID-19. Thus, this study increases the knowledge of specific myeloid subsets involved in the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies for fighting SARS-CoV-2 infection., Introduction The new SARS-CoV-2 virus causing coronavirus disease 2019 (COVID-19) has unleashed the current pandemic. Individuals infected with this pathogen can either remain asymptomatic or progress from mild to severe [...]

Published
2020
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18. Unmet therapeutic goals and potential treatable traits in a population of patients with severe uncontrolled asthma in Spain. ENEAS study

Author

Pérez de Llano, Luis, Martínez-Moragón, Eva, Plaza Moral, Vicente, Trisan Alonso, Andrea, Sánchez, Carlos Almonacid, Callejas, Francisco Javier, Vera, Elisabeth, Soto Campos, Jose Gregorio, Martinez Rivera, Carlos, Alcázar Navarrete, Bernardino, Urrutia Landa, Isabel, Garcia Rivero, Juan Luis, Padilla Galo, Alicia, Alvarez Gutierrez, Francisco, Landete, Pedro, Ramos González, Jacinto, Aracil, Cleofé Fernández, Carretero Gracia, José Ángel, Lluch, Inmaculada, Puente, Luis, Andujar-Espinosa, Ruben, and Cosío, Borja Garcia

Published
2019
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19. Clasificación del neumomediastino según su etiología: aclaraciones sobre la nomenclatura

Author

Lorente-González, Miguel, primary, Terán-Tinedo, José R., additional, Zevallos-Villegas, Annette, additional, Laorden, Daniel, additional, Suárez-Ortiz, Miguel, additional, Ortega-Fraile, Ma. Ángeles, additional, Cano-Sanz, Eduardo, additional, Hernández-Núñez, Joaquín, additional, Villén-Villegas, Tomás, additional, Saiz-Lou, Elena Ma., additional, and Landete, Pedro, additional

Published
2023
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22. Sleep apnea-COPD overlap syndrome is associated with larger left carotid atherosclerotic plaques

Author

Instituto de Salud Carlos III, European Commission, Sociedad Española de Neumología y Cirugía Torácica, Landete, Pedro, Fernández-García, Carlos Ernesto, Muñoz, José M., Friera, Alfonsi, Ancochea, Julio, González-Rodríguez, Águeda, García-Monzón, Carmelo, Instituto de Salud Carlos III, European Commission, Sociedad Española de Neumología y Cirugía Torácica, Landete, Pedro, Fernández-García, Carlos Ernesto, Muñoz, José M., Friera, Alfonsi, Ancochea, Julio, González-Rodríguez, Águeda, and García-Monzón, Carmelo

Abstract

[Background]: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself., [Methods]: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated., [Results]: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients., [Conclusions]: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke.

Published
2023

23. Table3_Sleep apnea-COPD overlap syndrome is associated with larger left carotid atherosclerotic plaques.docx [Dataset]

Author

Landete, Pedro, Fernández-García, Carlos Ernesto, Muñoz, José M., Friera, Alfonsi, Ancochea, Julio, González-Rodríguez, Águeda, García-Monzón, Carmelo, Landete, Pedro, Fernández-García, Carlos Ernesto, Muñoz, José M., Friera, Alfonsi, Ancochea, Julio, González-Rodríguez, Águeda, and García-Monzón, Carmelo

Abstract

[Background]: Little is known about whether the overlap syndrome (OS) combining features of chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome increases the risk of stroke associated with COPD itself., [Methods]: We prospectively studied 74 COPD patients and 32 subjects without lung disease. Spirometry and cardiorespiratory polygraphy were used to assess the pulmonary function of the study population and ultrasound measurements of intima media thickness (IMT) as well as the volume of plaques in both carotid arteries were also evaluated., [Results]: Polygraphic criteria of OS were met in 51% of COPD patients. We found that 79% of patients with OS and 50% of COPD patients without OS had atherosclerotic plaques in the left carotid artery (p = 0.0509). Interestingly, the mean volume of atherosclerotic plaques was significantly higher in the left carotid artery of COPD patients with OS (0.07 ± 0.02 ml) than in those without OS (0.04 ± 0.02 ml, p = 0.0305). However, regardless of the presence of OS, no significant differences were observed in both presence and volume of atherosclerotic plaques in the right carotid artery of COPD patients. Adjusted-multivariate linear regression revealed age, current smoking and the apnea/hypopnea index (OR = 4.54, p = 0.012) as independent predictors of left carotid atherosclerotic plaques in COPD patients., [Conclusions]: This study suggests that the presence of OS in COPD patients is associated with larger left carotid atherosclerotic plaques, indicating that OS might be screened in all COPD patients to identify those with higher risk of stroke.

Published
2023

28. Plitidepsin in adult patients with COVID-19 requiring hospital admission: A long-term follow-up analysis

Author

Varona, Jose F., primary, Landete, Pedro, additional, Paredes, Roger, additional, Vates, Roberto, additional, Torralba, Miguel, additional, Guisado-Vasco, Pablo, additional, Porras, Lourdes, additional, Muñoz, Patricia, additional, Gijon, Paloma, additional, Ancochea, Julio, additional, Saiz, Elena, additional, Meira, Fernanda, additional, Jimeno, Jose M., additional, Lopez-Martin, Jose A., additional, and Estrada, Vicente, additional

Published
2023
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29. Obstructive sleep apnea: The key for a better asthma control?

Author

Cisneros, Carolina, primary, Iturricastillo, Gorane, additional, Martínez–Besteiro, Elisa, additional, Eiros, José María, additional, Marcos, Celeste, additional, Múgica, Victoria, additional, Melero, Carlos, additional, Martínez-Meca, Ana, additional, Landete, Pedro, additional, and Zamora, Enrique, additional

Published
2023
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31. El neumomediastino como complicación de la neumonía por SARS-CoV-2

Author

Lorente-González, Miguel, primary, Terán-Tinedo, José R., additional, Zevallos-Villegas, Annette, additional, Laorden, Daniel, additional, Suárez-Ortiz, Miguel, additional, Ortega-Fraile, Ma. Ángeles, additional, Cano-Sanz, Eduardo, additional, Hernández-Núñez, Joaquín, additional, Villén-Villegas, Tomás, additional, Saiz-Lou, Elena M., additional, and Landete, Pedro, additional

Published
2022
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35. Clinical Findings and Outcomes From Subjects With COVID-19 Pneumonia in an Intermediate Respiratory Care Unit

Author

Laorden, Daniel, primary, Gholamian-Ovejero, Soraya, additional, Terán-Tinedo, José Rafael, additional, Lorente-González, Miguel, additional, Cano-Sanz, Eduardo, additional, Ortega-Fraile, María Ángeles, additional, Alejos, Roberto-Martínez, additional, Hernández-Nuñez, Joaquín, additional, De La Calle-Gil, Isabel, additional, Navarro-Casado, Rosalía, additional, Neria, Fernando, additional, Zevallos-Villegas, Annette, additional, Mariscal-Aguilar, Pablo, additional, Suarez-Ortiz, Miguel, additional, Plaza-Moreno, María Cristina, additional, Carballo-López, Daniel, additional, Gallego-Rodríguez, Berta, additional, Calderón-Alcala, Mariara, additional, Latif-Essa, Aylaf, additional, Churruca-Arróspide, María, additional, Valle-Falcones, Manuel, additional, Saiz-Lou, Elena María, additional, Rodríguez-Calle, Carmen, additional, Funes-Moreno, Clotilde, additional, Villén-Villegas, Tomas, additional, and Landete, Pedro, additional

Published
2022
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36. SARS-CoV-2 Pneumonia, Acute Pulmonary Infarction Secondary to Acute Pulmonary Embolism, Secondary Spontaneous Pneumothorax and Subacute Invasive Pulmonary Aspergillosis: Are They Related to Each Other?

Author

Lorente-González, Miguel, primary, García-Fadul, Christian, additional, Gijón-Herreros, Natalia, additional, Terán-Tinedo, José Rafael, additional, Zevallos-Villegas, Annette, additional, Laorden, Daniel, additional, and Landete, Pedro, additional

Published
2022
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37. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), Swiss National Science Foundation, Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin; Thorne, Lucy G.; Jolly, Claire; Towers, Greg J.; Zuliani-Alvarez, Lorena; Bouhaddou, Mehdi; Obernier, Kirsten; Enjuanes Sánchez, Luis CSIC ORCID ; Fernández-Sousa, José M.; Plitidepsin – COVID - 19 Study Group; Krogan, Nevan J.; Jimeno, José M.; García-Sastre, Adolfo, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo

Abstract

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.

Published
2022

38. Increased oxygen desaturation time during sleep is a risk factor for NASH in patients with obstructive sleep apnea: A prospective cohort study

Author

Instituto de Salud Carlos III, European Commission, Sociedad Española de Neumología y Cirugía Torácica, Fundación Francisco Cobos, Landete, Pedro, Fernández-García, Carlos Ernesto, Aldave-Orzaiz, Beatriz, Hernández-Olivo, Marta, Acosta-Gutiérrez, Carmen M., Zamora-García, Enrique, Ancochea, Julio, González-Rodríguez, Águeda, García-Monzón, Carmelo, Instituto de Salud Carlos III, European Commission, Sociedad Española de Neumología y Cirugía Torácica, Fundación Francisco Cobos, Landete, Pedro, Fernández-García, Carlos Ernesto, Aldave-Orzaiz, Beatriz, Hernández-Olivo, Marta, Acosta-Gutiérrez, Carmen M., Zamora-García, Enrique, Ancochea, Julio, González-Rodríguez, Águeda, and García-Monzón, Carmelo

Abstract

[Introduction]: Given that obstructive sleep apnea (OSA) is commonly associated with metabolic disorders, in this prospective study, we sought to determine the prevalence and risk factors for hepatosteatosis, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis in patients with clinical and polygraphic criteria of OSA (n = 153) and in subjects with normal lung function parameters (NLP, n = 43). [Methods]: Hepatosteatosis, NASH, and advanced liver fibrosis were determined by blood-based non-invasive tools, such as the fatty liver index and the hepatic steatosis index, a serum lipidomic (OWLiver™) test, and three distinct fibrosis algorithms, respectively. Logistic regression models adjusted by potential confounders were performed to evaluate risk factors. [Results]: Insulin resistance and dyslipidemia were more frequent in patients with OSA than in subjects with NLP. The prevalence of hepatosteatosis was significantly higher in patients with OSA than in subjects with NLP. NASH was also found more frequently in patients with OSA than in subjects with NLP. In contrast, advanced liver fibrosis was rarely detected in the entire study population, and no significant differences were observed between patients with OSA and subjects with NLP. Besides male gender, increased body mass index (BMI), and presence of type 2 diabetes, percentage of sleep time with oxygen saturation <90% (Tc90%) was the only polygraphic variable significantly associated with NASH in patients with OSA. [Conclusions]: This study shows that hepatosteatosis and NASH are highly prevalent in patients with OSA and indicates that those with a Tc90% higher than 10% are at increased risk for NASH.

Published
2022

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

Author

Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Vergara-Alert, Júlia, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, Belgrano, Álvaro, Sopesén, Belén, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis CSIC ORCID, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, McGovern, Briana L., Rodríguez, M. Luis, Enjuanes Sánchez, Luis, Producció Animal, Sanitat Animal, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), National Institute of Allergy and Infectious Diseases (US), and Swiss National Science Foundation

Subjects
Adult, Male, Neutropenia, Health, Toxicology and Mutagenesis, Clinical Trials and Supportive Activities, Plant Science, Kaplan-Meier Estimate, Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell Line, Clinical Research, Depsipeptides, Humans, Lung, Aged, Cancer, Cyclic, Tumor, Ecology, SARS-CoV-2, Prevention, COVID-19, Evaluation of treatments and therapeutic interventions, Length of Stay, Viral Load, Middle Aged, Preclinical, COVID-19 Drug Treatment, Hospitalization, Treatment Outcome, Infectious Diseases, Good Health and Well Being, 6.1 Pharmaceuticals, Drug Evaluation, Female, Patient Safety, Peptides
Abstract

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., This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).

Published
2022

41. Increased Oxygen Desaturation Time During Sleep Is a Risk Factor for NASH in Patients With Obstructive Sleep Apnea: A Prospective Cohort Study

Author

Landete, Pedro, primary, Fernández-García, Carlos Ernesto, additional, Aldave-Orzaiz, Beatriz, additional, Hernández-Olivo, Marta, additional, Acosta-Gutiérrez, Carmen M., additional, Zamora-García, Enrique, additional, Ancochea, Julio, additional, González-Rodríguez, Águeda, additional, and García-Monzón, Carmelo, additional

Published
2022
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42. Clinical Characteristics and Respiratory Care in Hospitalized Vaccinated SARS-CoV-2 Patients

Author

Teran-Tinedo, Jose Rafael, primary, Gonzalez-Rubio, Jesus, additional, Najera, Alberto, additional, Castany-Faro, Andrea, additional, Contreras de Blas, Maria de las Nieves, additional, Garcia, Isabel Maria, additional, Lopez-Mellado, Lourdes, additional, Lorente-Gonzalez, Miguel, additional, Perez-Garvin, Patricia, additional, Sacristan-Crespo, Galaxia, additional, Suarez-Ortiz, Miguel, additional, Jimenez-Diaz, Lydia, additional, Navarro-Lopez, Juan D., additional, and Landete, Pedro, additional

Published
2022
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46. Improving Adherence and Quality of Life of CPAP for Obstructive Sleep Apnea With An Intervention Based On Stratification and Personalization of Care Plans: A Randomized Controlled Trial

Author

Rudilla, David, primary, Perelló, Salvador, additional, Landete, Pedro, additional, Zamora, Enrique, additional, Vázquez, María, additional, Sans, Lluisa, additional, Tomás, Jose Manuel, additional, Martín, Jose Luis R, additional, Leonardi, Jennifer, additional, Rubinos, Gema, additional, and Ancochea, Julio, additional

Published
2021
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47. Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization

Author

PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., García-Sastre, Adolfo, PharmaMar, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Grifols, YoMeCorono, National Institutes of Health (US), Roddenberry Foundation, Defense Advanced Research Projects Agency (US), Center for Research for Influenza Pathogenesis (US), Centers of Excellence for Influenza Research and Surveillance (US), JPB Foundation, Swiss National Science Foundation, López-Martín, José A. [0000-0001-7530-3207], Varona, José F., Landete, Pedro, López-Martín, José A., Estrada, Vicente, Paredes, Roger, Guisado Vasco, P., Fernández de Orueta, Lucía, Torralba, Miguel, Fortún, Jesús, Vates, Roberto, Barberán, José, Clotet, Bonaventura, Ancochea, Julio, Carnevali, Daniel, Cabello, Noemí, Porras, Lourdes, Gijón, Paloma, Monereo, Alfonso, Abad, Daniel, Zúñiga Lucas, Sonia, Solá Gurpegui, Isabel, Rodón, Jordi, Izquierdo-Useros, Núria, Fudio, Salvador, Pontes, María José, Rivas, Beatriz de, Girón de Velasco, Patricia, Sopesén, Belén, Nieto, Antonio, Gómez, Javier, Avilés, Pablo, Lubomirov, Rubin, White, Kris M., Rosales, Romel, Yildiz, Soner, Reuschl, Ann-Kathrin, Thorne, Lucy G., Jolly, Claire, Towers, Greg J., Zuliani-Alvarez, Lorena, Bouhaddou, Mehdi, Obernier, Kirsten, Enjuanes Sánchez, Luis, Fernández-Sousa, José M., Plitidepsin – COVID - 19 Study Group, Krogan, Nevan J., Jimeno, José M., and García-Sastre, Adolfo

Abstract

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.

Published
2021

49. IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Author

Galván-Román, José María, primary, Rodríguez-García, Sebastián C., additional, Roy-Vallejo, Emilia, additional, Marcos-Jiménez, Ana, additional, Sánchez-Alonso, Santiago, additional, Fernández-Díaz, Carlos, additional, Alcaraz-Serna, Ana, additional, Mateu-Albero, Tamara, additional, Rodríguez-Cortes, Pablo, additional, Sánchez-Cerrillo, Ildefonso, additional, Esparcia, Laura, additional, Martínez-Fleta, Pedro, additional, López-Sanz, Celia, additional, Gabrie, Ligia, additional, del Campo Guerola, Luciana, additional, Suárez-Fernández, Carmen, additional, Ancochea, Julio, additional, Canabal, Alfonso, additional, Albert, Patricia, additional, Rodríguez-Serrano, Diego A., additional, Aguilar, Juan Mariano, additional, del Arco, Carmen, additional, de los Santos, Ignacio, additional, García-Fraile, Lucio, additional, de la Cámara, Rafael, additional, Serra, José María, additional, Ramírez, Esther, additional, Alonso, Tamara, additional, Landete, Pedro, additional, Soriano, Joan B., additional, Martín-Gayo, Enrique, additional, Fraile Torres, Arturo, additional, Zurita Cruz, Nelly Daniela, additional, García-Vicuña, Rosario, additional, Cardeñoso, Laura, additional, Sánchez-Madrid, Francisco, additional, Alfranca, Arantzazu, additional, Muñoz-Calleja, Cecilia, additional, González-Álvaro, Isidoro, additional, Alvarado, Teresa, additional, Martínez, Pablo, additional, Javier de la Cuerda Llorente, Francisco, additional, Arco, Carmen del, additional, Villalba, Natalia, additional, Negro, Mónica, additional, Contreras, Elvira, additional, Rey, Ana del, additional, Santiago, Cristina, additional, Junquera, Manuel, additional, Caminero, Raquel, additional, Val, Francisco Javier, additional, González, Sonia, additional, Caño, Marta, additional, López, Isabel, additional, von Wernitz, Andrés, additional, Retana, Bárbara, additional, Guerra, Iñigo, additional, Sorando, Jorge, additional, Chao, Lydia, additional, Cárdenas, María José, additional, Espiga, Verónica, additional, Chicharro, Pablo, additional, Rodríguez, Pedro, additional, Alday, Iñigo Hernando, additional, Sampedro, Miguel, additional, Prada, Jorge, additional, Aldama, Eukene Rojo, additional, Real, Yolanda, additional, Caldas, María, additional, Casabona, Sergio, additional, Lanas-Gimeno, Aitor, additional, Camara, Rafael de la, additional, Alvárez, Angela Figuera, additional, Aguadol, Beatriz, additional, Morell, Alberto, additional, Zurriaga, Amparo Ibáñez, additional, Abanades, María Pérez, additional, García, Silvia Ruiz, additional, Aranda, Tomás Gallego, additional, Ruiz, María, additional, Nieto, Concepción Martínez, additional, Aspa, Javier, additional, Guerola, Luciana del Campo, additional, Fernández, Elena, additional, Calzada, Ma José, additional, Tejedor, Reyes, additional, Iglesias, Judit, additional, Suarez, Fernando, additional, Sánchez, Juan Antonio, additional, Abad, Beatriz, additional, Suarez, Carmen, additional, Santos, Ignacio de los, additional, Galván-Román, José María, additional, Roy, Emilia, additional, Sanz, Jesus, additional, Sanchez, Eduardo, additional, Moldenhauer, Fernando, additional, Casado, Pedro, additional, Curbelo, Jose, additional, Gutierrez, Angela, additional, Bautista, Azucena, additional, Giménez, Nuria Ruiz, additional, Fernandez, Angelica, additional, Parra, Pedro, additional, Moyano, Berta, additional, Barrios, Ana, additional, Real de Asua, Diego, additional, Sanchez, Beatriz, additional, Saez, Carmen, additional, Ciudad, Marianela, additional, Navas, Desiré, additional, Domingo, Laura Cardeñoso, additional, Torresano, María del Carmen Cuevas, additional, García, Diego Domingo, additional, Cavero, Teresa Alarcón, additional, Blanco, Alicia García, additional, Ramírez, Alexandra Martín, additional, Semiglia Chong, María Auxiliadora, additional, Cobos, Ainhoa Gutiérrez, additional, Fraile Torres, Arturo Manuel, additional, Sanchez-Gonzalez, Carmen, additional, Perpén, Antonio Fernádez, additional, Pérez, Carolina Díaz, additional, Soriano, Joan, additional, Cisneros, Carolina, additional, Castillo, Elena García, additional, García Pérez, Francisco Javier, additional, Girón, Rosa María, additional, Marcos, Celeste, additional, Zamora, Enrique, additional, García, Patricia García, additional, Castañeda, Santos, additional, Rodríguez-García, Sebastián, additional, Cubas, Irene Llorente, additional, Tomero, Eva G., additional, Castañeda, Noelia García, additional, Ortiz, Ana Ma, additional, Valero, Cristina, additional, Uriarte, Miren, additional, and Montes, Nuria, additional

Published
2021
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50. Clinical features and radiological manifestations of COVID-19 disease

Author

Landete, Pedro, primary, Loaiza, Carlos Andrés Quezada, additional, Aldave-Orzaiz, Beatriz, additional, Muñiz, Susana Hernández, additional, Maldonado, Antonio, additional, Zamora, Enrique, additional, Cerna, Allan Charles Sam, additional, Cerro, Elia del, additional, Alonso, Raquel Cano, additional, and Couñago, Felipe, additional

Published
2020
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