RESUMEN
The 'flu, caused mostly by influenza A and B viruses, represents a major public health issue. Despite vaccines and antiviral drugs, the therapeutic arsenal is still suboptimal. Recently, several studies have reported the antiviral and anti-inflammatory properties of several host metabolites. Now, we show that a metabolite (called here "C2") has a potent anti-influenza activity by blocking the viral replication and by limiting the downstream pro-inflammatory signalling. These results pave the way for the development of innovative metabolic therapy against influenzal pneumonia.
Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Neumonía , Antivirales/uso terapéutico , Humanos , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Neumonía/tratamiento farmacológico , Neumonía/prevención & control , Replicación ViralRESUMEN
Micropollutants like pharmaceuticals, hormones and pesticides are still found in treated municipal wastewater. An effective way to degrade micropollutants is to use oxidants such as ozone or hydroxyl radicals. We designed an innovative experimental protocol combining batch experiments and a study of a full-scale WWTP to understand and predict the removal via ozonation of typical micropollutants present in secondary treated effluents. First, the direct and indirect ozonation of 47 organic micropollutants was scrutinized, then a model was developed and calibrated to simulate the ozone transfers and the oxidation of the selected micropollutants. The kinetic rate constants between micropollutants and ozone or hydroxyl radicals (OHâ) were determined for 47 micropollutants found in secondary treated effluent. We classified the micropollutants into low- (kO3 between 1.50 and 4.47 × 102 L mol-1. s-1), medium- (kO3 between 1.31 × 103 and 4.92 × 103 L mol-1. s-1) and high-oxidizable groups (kO3 between 9.44 × 104 and 8.18 × 106 L mol-1. s-1) according to their reactivity with ozone, and identified the major degradation pathways for all 47 micropollutants. Micropolluants of the low- and medium-oxidizable groups were largely eliminated by the indirect pathway, at 96% and 84% on average, respectively. In contrast, micropollutants of high-oxidizable group were largely eliminated by the direct pathway, at 98% on average. The model successfully simulated the direct and indirect ozonation of the 47 micropollutants in batch experiments and confirmed the predominant pathways for each group. Finally, the model was applied to the full-scale ozonation process operated at an ozone dose ranging from 0.5 to 1.6 gO3. gDOC-1. The model was found to reliably simulate the ozonation-process removal efficiencies for 4 micropollutants (imidacloprid, fenofibric acid, metronidazole and ketoprofen).
Asunto(s)
Oxidantes/química , Ozono/química , Aguas Residuales/química , Contaminantes Químicos del Agua/análisis , Purificación del Agua/métodos , Radical Hidroxilo/química , Cinética , Modelos Teóricos , Oxidación-ReducciónRESUMEN
No disponible
Asunto(s)
Humanos , Masculino , Anciano , Enfisema Mediastínico/diagnóstico por imagen , Enfermedad Crítica , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Enfisema Mediastínico/complicaciones , Respiración Artificial , Infecciones por Coronavirus/terapia , Neumonía Viral/terapiaRESUMEN
The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.
Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/metabolismo , Citosina/sangre , Metaboloma , Metabolómica/métodos , Niacinamida/sangre , Neumonía Viral/epidemiología , Neumonía Viral/metabolismo , Triptófano/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Diagnóstico Precoz , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Pronóstico , Reproducibilidad de los Resultados , SARS-CoV-2 , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Nonclinical studies are fundamental for the development of inhaled drugs, as for any drug product, and for successful translation to clinical practice. They include in silico, in vitro, ex vivo and in vivo studies and are intended to provide a comprehensive understanding of the inhaled drug beneficial and detrimental effects. To date, animal models cannot be circumvented during drug development programs, acting as surrogates of humans to predict inhaled drug response, fate and toxicity. Herein, we review the animal models used during the different development stages of inhaled pharmaceuticals and biopharmaceuticals, highlighting their strengths and limitations.
Asunto(s)
Aerosoles/administración & dosificación , Aerosoles/farmacología , Productos Biológicos/administración & dosificación , Productos Biológicos/farmacología , Modelos Animales , Administración por Inhalación , Aerosoles/farmacocinética , Animales , Productos Biológicos/farmacocinética , Evaluación Preclínica de Medicamentos/métodos , Humanos , Orofaringe/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Roedores , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Síndrome Respiratorio Agudo Grave , Betacoronavirus , COVID-19 , Humanos , Evasión Inmune , ARN , SARS-CoV-2RESUMEN
Acute and chronic respiratory diseases account for major causes of illness and deaths worldwide. Recent developments of biotherapeutics opened a new era in the treatment and management of patients with respiratory diseases. When considering the delivery of therapeutics, the inhaled route offers great promises with a direct, non-invasive access to the diseased organ and has already proven efficient for several molecules. To assist in the future development of inhaled biotherapeutics, experimental models are crucial to assess lung deposition, pharmacokinetics, pharmacodynamics and safety. This review describes the animal models used in pulmonary research for aerosol drug delivery, highlighting their advantages and limitations for inhaled biologics. Overall, non-clinical species must be selected with relevant scientific arguments while taking into account their complexities and interspecies differences, to help in the development of inhaled medicines and ensure their successful transposition in the clinics.
Asunto(s)
Aerosoles/administración & dosificación , Preparaciones Farmacéuticas/administración & dosificación , Terapia Respiratoria/métodos , Administración por Inhalación , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Modelos AnimalesRESUMEN
The objective of this study was to determine how clinicians make use of the modern multiplex PCR assays (MPAs) to manage patients hospitalized for community-acquired pneumonia (CAP). We studied the use of MPAs in 1648 patients hospitalized for CAP over a 3-year period at the moment of the setup of the new PCR assay. We observed that the use of MPAs for the identification of multiple respiratory pathogens marks a radical change in the investigation of CAP etiology. Surprisingly, the contribution of MPAs to the medical decision-making process varies drastically according to the units of care.
Asunto(s)
Toma de Decisiones Clínicas/métodos , Reacción en Cadena de la Polimerasa Multiplex , Neumonía/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/etiología , Infecciones Comunitarias Adquiridas/terapia , Estudios Transversales , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Neumonía/diagnóstico , Neumonía/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Bronchoscopy during mechanical ventilation of patients' lungs significantly affects ventilation because of partial obstruction of the tracheal tube, and may thus be omitted in the most severely ill patients. It has not previously been possible to reduce the external diameter of the bronchoscope without reducing the diameter of the suction channel, thus reducing the suctioning capacity of the device. We believed that a better-designed bronchoscope could improve the safety of bronchoscopy in patients whose lungs were ventilated. We designed a flexible bronchoscope prototype with a drumstick-shaped head consisting of a long, thin proximal portion; a short and large distal portion for camera docking; and a large suction channel throughout the length of the device. The aims of our study were to test the impact of our prototype on mechanical ventilation when inserted into the tracheal tube, and to assess suctioning capacity. We first tested the efficiency of the suction channel, and demonstrated that the suction flow of the prototype was similar to that of conventional adult bronchoscopes. We next evaluated the consequences of bronchoscopy when using the prototype on minute ventilation and intrathoracic pressures during mechanical ventilation: firstly, in vitro using a breathing simulator; and secondly, in vivo using a porcine model of pulmonary ventilation. The insertion of adult bronchoscopes into the tracheal tube immediately impaired the protective ventilation strategy employed, whereas the prototype preserved it. For the first time, we have developed an innovative flexible bronchoscope designed for bronchoscopy during invasive mechanical ventilation, that both preserved the protective ventilation strategy, and enabled efficient suction flow.
Asunto(s)
Broncoscopios , Broncoscopía/instrumentación , Respiración Artificial/métodos , Adulto , Manejo de la Vía Aérea , Animales , Simulación por Computador , Diseño de Equipo , Femenino , Tecnología de Fibra Óptica , Humanos , Intubación Intratraqueal , Masculino , Síndrome de Dificultad Respiratoria/terapia , Succión , PorcinosRESUMEN
Flexible bronchoscopy is essential for appropriate care during mechanical ventilation, but can significantly affect mechanical ventilation of the lungs, particularly for patients with acute respiratory distress syndrome. We aimed to describe the consequences of bronchoscopy during lung-protective ventilation in a bench study, and thereby to determine the optimal diameter of the bronchoscope for avoiding disruption of the protective-ventilation strategy during the procedure. Immediately following the insertion of the bronchoscope into the tracheal tube, either minute ventilation decreased significantly, or positive end-expiratory pressure increased substantially, according to the setting of the inspiratory pressure limit. The increase in end-expiratory pressure led to an equivalent increase in the plateau pressure, and lung-protective ventilation was significantly altered during the procedure. We showed that a bronchoscope with an external diameter of 4 mm (or less) would allow safer bronchoscopic interventions in patients with severe acute respiratory distress syndrome.
Asunto(s)
Broncoscopía/instrumentación , Modelos Biológicos , Respiración Artificial , Síndrome de Dificultad Respiratoria/fisiopatología , Adulto , Diseño de Equipo , Tecnología de Fibra Óptica , Humanos , Respiración con Presión Positiva , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Sistema Respiratorio/metabolismo , Administración por Inhalación , Aerosoles , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Cetuximab , Sistemas de Liberación de Medicamentos , Femenino , Antígenos de Histocompatibilidad Clase I/genética , Neoplasias Pulmonares/tratamiento farmacológico , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Desnudos , Receptores Fc/genéticaRESUMEN
A single-use flexible bronchoscope with a large suction channel has become available recently and we have evaluated this innovative device. Firstly, bronchoalveolar lavage was performed and quantified in ventilated piglets. Next, the bronchoscope was evaluated in three intensive care units and a satisfaction questionnaire was carried out. Sixteen bronchoalveolar lavages were performed in piglets with a recovery rate of 83 (79-86 [72-89])% of the instilled volume. Quality and performance of all devices tested was identical. The medical satisfaction questionnaire was as follows: 'acceptable' to 'very good' for quality of aspiration, manoeuvrability and quality of vision; 'very good' to 'perfect' for setting up and insertion. This encouraging preliminary evaluation demonstrates the effectiveness of this new single-use device, which may obviate the need for disinfection procedures and, thereby, eradicate a potential vector of patient cross-contamination.
Asunto(s)
Lavado Broncoalveolar/instrumentación , Lavado Broncoalveolar/métodos , Broncoscopios/normas , Broncoscopía/instrumentación , Respiración Artificial , Animales , Broncoscopía/normas , Diseño de Equipo , Reproducibilidad de los Resultados , Succión , Encuestas y Cuestionarios , PorcinosRESUMEN
UNLABELLED: Amiodarone-induced pulmonary toxicity (APT) is a serious adverse event that can lead to death. The aims of our study are to determine factors associated with mortality and to describe outcome and sequelae of patients with APT. METHODS: Forty-six patients with APT were divided into two groups according to survival at day 90 for a clinical, functional, biological and radiological comparaison. We then evaluated the evolution of 15 survivors at a median of three months [1-6 months] and/or 12 months [8-36 months]. RESULTS: Mortality of APT at day 90 was 37% (17 patients) and was linked to the speed of onset of symptoms and a high HRCT alveolar score. Angiotensin system antagonist treatment was prescribed significantly more in the survival group (p = 0.042, HR 0.34 (95% CI 0.12-0.96)). In surviving patients, dyspnea, vital capacity and HRCT alveolar score improved significantly while HRCT fibrosis score deteriorated gradually during the first six months. At the end of the study, all the surviving patients presented functional and/or radiological sequelae. CONCLUSIONS: Severity of APT is linked to the extent and speed of onset of pulmonary damage. After the initial episode, the patients who survived improved slowly but with persistent sequelae.