RESUMEN
The normative role of the World Health Organization (WHO) involves creating evidence-based, principled guidelines to guide its Member States in making well-informed public health decisions. While these guidelines often need to be adapted to ensure contextual relevance, foster better implementation and adherence, adapting existing guidelines is more efficient than creating new ones. Here we describe the adaptation of the WHO coronavirus disease 2019 (COVID-19) living guideline on pharmacological interventions for the Caribbean using the grading of recommendations, assessment, development and evaluation (GRADE)-ADOLOPMENT method. The Caribbean Public Health Agency and the Pan American Health Organization led the effort, assembling a diverse panel of 16 experts from seven Caribbean countries and territories. The adaptation process, involving 15 steps, was guided by an experienced methodologist and included selecting relevant clinical questions and prioritizing them based on regional needs. The panel evaluated the latest WHO guidelines and integrated additional local data. They adjusted the direction and strength of several recommendations to better fit the Caribbean context, considering local values and preferences, resources, accessibility, feasibility and impact on health equity. Ultimately, we changed the direction of two recommendations and the strength of five, tailoring them to regional realities. This effort highlights the importance of adapting global guidelines to local settings, improving their applicability and effectiveness. The adaptation process also serves as a valuable opportunity for skill transfer and capacity-building in guideline development. Continued research is needed to assess the impact of these adaptations on health-care outcomes in the Caribbean.
Le rôle normatif de l'Organisation mondiale de la santé (OMS) consiste à élaborer des lignes directrices fondées sur des données scientifiques et sur des principes afin d'aider ses États membres à prendre des décisions éclairées en matière de santé publique. Bien qu'elles nécessitent souvent des adaptations pour garantir leur pertinence par rapport à des contextes précis et pour favoriser une meilleure mise en Åuvre et adhésion, il est plus efficace d'adapter les lignes directrices existantes que d'en créer de nouvelles. La présente publication décrit l'adaptation de la ligne directrice évolutive de l'OMS sur les interventions pharmacologiques dans le cadre de la maladie à coronavirus (COVID-19) pour les Caraïbes en appliquant la méthodologie GRADE (classement des recommandations, de l'appréciation, du développement et de l'évaluation)-ADOLOPMENT. L'Agence de santé publique des Caraïbes et l'Organisation panaméricaine de la Santé ont dirigé les travaux en réunissant un groupe diversifié de 16 experts issus de sept pays et territoires des Caraïbes. Le processus d'adaptation, comptant 15 étapes et encadré par un méthodologiste expérimenté, a consisté à sélectionner des questions cliniques pertinentes et à les classer par ordre de priorité selon les besoins régionaux. Ce groupe a évalué les dernières lignes directrices de l'OMS et a intégré des données locales supplémentaires. Il a ensuite ajusté l'orientation et le poids de plusieurs recommandations afin de mieux les adapter au contexte des Caraïbes, en tenant compte des valeurs et des préférences locales, des ressources, de l'accessibilité, de la faisabilité et de l'impact sur l'équité en matière de santé. En fin de compte, l'orientation de deux recommandations et le poids de cinq autres ont été modifiés, en les adaptant aux réalités régionales. Cet effort souligne l'importance d'adapter des lignes directrices mondiales aux contextes locaux, afin d'en améliorer l'applicabilité et l'efficacité. Le processus d'adaptation représente également une occasion précieuse de transfert de compétences et de renforcement des capacités en matière d'élaboration de lignes directrices. Des recherches continues s'imposent pour évaluer l'impact de ces adaptations sur les résultats des soins de santé dans les Caraïbes.
La función normativa de la Organización Mundial de la Salud (OMS) consiste en elaborar directrices basadas en pruebas y principios para orientar a sus Estados Miembros en la toma de decisiones de salud pública bien fundamentadas. Aunque con frecuencia es necesario adaptar estas directrices para garantizar su pertinencia contextual y fomentar una mejor implementación y observancia, la adaptación de directrices existentes es más eficiente que la creación de otras nuevas. Aquí describimos la adaptación de la directriz vigente de la OMS sobre la enfermedad por coronavirus (COVID-19) relativa a las intervenciones farmacológicas para el Caribe utilizando el método de clasificación de valoración, elaboración y evaluación de las recomendaciones (GRADE)-ADOLOPMENT. La Agencia de Salud Pública del Caribe y la Organización Panamericana de la Salud lideraron la iniciativa, que reunió a un variado grupo de 16 expertos de siete países y territorios caribeños. El proceso de adaptación, que comprendió 15 pasos y fue guiado por un metodólogo experimentado, incluyó la selección de preguntas clínicas pertinentes y su priorización en función de las necesidades regionales. El grupo evaluó las últimas directrices de la OMS e integró datos locales adicionales. Ajustaron la orientación y la fuerza de varias recomendaciones para adaptarlas mejor al contexto caribeño, teniendo en cuenta los valores y preferencias locales, los recursos, la accesibilidad, la viabilidad y el impacto en la equidad sanitaria. Finalmente, cambiamos la orientación de dos recomendaciones y la fuerza de cinco para adaptarlas a las realidades regionales. Esta iniciativa destaca la importancia de adaptar las directrices mundiales a los contextos locales, lo que mejora su aplicabilidad y eficacia. El proceso de adaptación también constituye una valiosa oportunidad para la transferencia de conocimientos y el desarrollo de capacidades en la elaboración de directrices. Es necesario seguir investigando para evaluar el impacto de estas adaptaciones en los resultados de la atención sanitaria en el Caribe.
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COVID-19 , Guías de Práctica Clínica como Asunto , SARS-CoV-2 , Organización Mundial de la Salud , Humanos , COVID-19/epidemiología , Región del Caribe/epidemiología , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. METHODS: This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. FINDINGS: The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. INTERPRETATION: SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. FUNDING: National Institutes of Health.
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COVID-19 , Hospitalización , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , COVID-19/mortalidad , Anciano , Hospitalización/estadística & datos numéricos , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Resultado del Tratamiento , Brasil/epidemiologíaRESUMEN
BACKGROUND: Algae-derived nutraceuticals, such as spirulina, have been reported to have biological activities that may minimize clinical consequences to COVID-19 infections. OBJECTIVES: This study aimed to determine whether spirulina is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. METHODS: The TOGETHER trial is a placebo-controlled, randomized, platform trial conducted in Brazil. Eligible participants were symptomatic adults with a positive rapid test for SARS-CoV-2 older than 50 y or with a known risk factor for disease severity. Patients were randomly assigned to receive placebo or spirulina (1 g twice daily for 14 d). The primary end point was hospitalization defined as either retention in a COVID-19 emergency setting for >6 h or transfer to tertiary hospital owing to COVID-19 at 28 d. Secondary outcomes included time-to-hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to compare spirulina with placebo. RESULTS: We recruited 1126 participants, 569 randomly assigned to spirulina and 557 to placebo. The median age was 49.0 y, and 65.3% were female. The primary outcome occurred in 11.2% in the spirulina group and 8.1% in the placebo group (odds ratio [OR]: 1.24; 95% credible interval: 0.84, 1.86). There were no differences in emergency department visit (OR: 1.21; 95% credible interval: 0.81, 1.83), nor time to symptom relief (hazard ratio: 0.90; 95% credible interval: 0.79, 1.03). Spirulina also not demonstrate important treatment effects in the prespecified subgroups defined by age, sex, BMI, days since symptom onset, or vaccination status. CONCLUSIONS: Spirulina has no any clinical benefits as an outpatient therapy for COVID-19 compared with placebo with respect to reducing the retention in an emergency setting or COVID-19-related hospitalization. There are no differences between spirulina and placebo for other secondary outcomes. This trial was registered at clinicaltrials.gov as NCT04727424.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Suplementos Dietéticos , Hospitalización , SARS-CoV-2 , Spirulina , Humanos , Masculino , Femenino , Persona de Mediana Edad , COVID-19/prevención & control , COVID-19/epidemiología , Anciano , Brasil , Método Doble Ciego , Resultado del TratamientoRESUMEN
Propolis is a natural resinous mixture produced by honeybees with numerous biological activities. Considering the recently reported potential of propolis as an adjuvant in COVID-19 treatment, a methodology for the fractionation of the hexane extract of Brazilian green propolis (HEGP) was developed for the obtention of prenylated biomarkers by countercurrent chromatography. The inhibition of the interaction between the receptor binding domain (RBD) of spike and ACE2 receptor was evaluated by the Lumitáµá´¹ immunoassay. Fractionation of HEGP was performed by both normal (CCC1 and CCC2, with extended elution) and reversed (CCC3) phase elution-extrusion modes with the solvent system hexane-ethanol-water 4:3:1. The normal elution mode of CCC1 (471 mg HEGP in a 80 mL column volume, 1.6 mm id) was scaled-up (CCC5, 1211 mg HEGP in a 112 mL column volume, 2.1 mm id), leading to the isolation of 89.9 mg of artepillin C, 1; 52.7 mg of baccharin, 2; and 26.6 mg of chromene, with purities of 93 %, 83 % and 88 %, respectively, by HPLC-PDA. Among the isolated compounds, artepillin C, 1, and baccharin, 2, presented the best results in the Lumitáµá´¹ immunoassay, showing 67% and 51% inhibition, respectively, at the concentration of 10 µM. This technique proved to be of low operational cost and excellent reproducibility.
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Enzima Convertidora de Angiotensina 2 , Distribución en Contracorriente , Própolis , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Própolis/química , Distribución en Contracorriente/métodos , SARS-CoV-2/efectos de los fármacos , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/aislamiento & purificación , Biomarcadores/metabolismo , COVID-19 , Unión Proteica , Tratamiento Farmacológico de COVID-19 , Fenilpropionatos/química , Fenilpropionatos/aislamiento & purificaciónRESUMEN
To evaluate the safety and the potential antiviral treatment of inhaled enriched heparin in patients with COVID-19. The specific objectives were to investigate the anticoagulation profile, antiviral and anti-inflammatory effects, and respiratory evolution of inhaled enriched heparin. We conducted a randomized, triple-blind, placebo-controlled Phase I/II clinical trial in hospitalized adults with COVID-19 receiving inhalation of enriched heparin or saline (placebo) every 4 h for 7 days. Among the 27 patients who completed the study, no changes in blood coagulation parameters were observed, indicating the safety of inhaled enriched heparin. The group receiving enriched heparin showed a significant reduction in the need for supplemental oxygen and improvement in respiratory parameters, such as the PaO2/FiO2 ratio. Inhalation of enriched heparin is shown to be safe and has also demonstrated potential therapeutic benefits for patients with COVID-19. These promising results justify the continuation of the study to the next phase, Phase II/III, to further evaluate the therapeutic efficacy of inhaled enriched heparin in the treatment of COVID-19-associated viral pneumonia.Trial registration: ClinicalTrials.gov. 08/02/2021. Identifier: NCT04743011.
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Anticoagulantes , Tratamiento Farmacológico de COVID-19 , COVID-19 , Heparina , Humanos , Heparina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Administración por Inhalación , Anciano , COVID-19/virología , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Nebulizadores y Vaporizadores , SARS-CoV-2 , Adulto , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-ß2-Glycoprotein-I (aß2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS: Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION: These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.
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Anticuerpos Antifosfolípidos , COVID-19 , Colecalciferol , Humanos , Masculino , Colecalciferol/uso terapéutico , Colecalciferol/administración & dosificación , Femenino , Persona de Mediana Edad , Método Doble Ciego , COVID-19/inmunología , Anticuerpos Antifosfolípidos/sangre , Anciano , Adulto , Índice de Severidad de la Enfermedad , Hospitalización/estadística & datos numéricos , SARS-CoV-2/inmunología , Tratamiento Farmacológico de COVID-19 , Vitaminas/uso terapéutico , Vitaminas/administración & dosificación , Anticuerpos Anticardiolipina/sangre , Brasil , Inmunoglobulina G/sangre , beta 2 Glicoproteína I/inmunología , Resultado del TratamientoRESUMEN
PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.
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COVID-19 , Sistema Calicreína-Quinina , SARS-CoV-2 , Humanos , Masculino , Femenino , Persona de Mediana Edad , COVID-19/terapia , COVID-19/mortalidad , Método Doble Ciego , Anciano , Respiración Artificial , Brasil/epidemiología , Oligonucleótidos Antisentido/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Resultado del TratamientoRESUMEN
The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP-1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP-1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP-1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.
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Amidas , Antivirales , Proteasas 3C de Coronavirus , Ácido Gálico , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas , SARS-CoV-2 , Humanos , Células Vero , Chlorocebus aethiops , Ácido Gálico/farmacología , Ácido Gálico/síntesis química , Ácido Gálico/química , Ácido Gálico/análogos & derivados , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Animales , Relación Estructura-Actividad , Amidas/farmacología , Amidas/síntesis química , Amidas/química , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Simulación por Computador , Tratamiento Farmacológico de COVID-19 , Concentración 50 Inhibidora , Supervivencia Celular/efectos de los fármacosRESUMEN
INTRODUCTION: Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19. METHODS: C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg-1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air. RESULTS: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1ß by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017). CONCLUSION: Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Ratones Endogámicos C57BL , SARS-CoV-2 , Humanos , Animales , Masculino , Persona de Mediana Edad , Femenino , Ratones , Método Doble Ciego , SARS-CoV-2/efectos de los fármacos , Anciano , Adulto , Citocinas/metabolismo , Hospitalización , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismoRESUMEN
OBJECTIVE: In this study, we present the findings from a cohort of patients with COVID-19 with acute respiratory distress syndrome who underwent standard therapy, including prone positioning, with or without adjunctive inhalation of nitric oxide. Our investigation sought to determine whether inhaled nitric oxide administration yielded clinical enhancement in this population. Remarkably, nitric oxide administration elevated the PaO2/FiO2 ratio, which is indicative of improved oxygenation. Despite this improvement, discernible mortality benefits did not emerge in association with the inhaled nitric oxide treatment. To evaluate the responsiveness of COVID-19 acute respiratory distress syndrome patients to inhaled nitric oxide as part of their standard therapy. METHODS: This retrospective cohort study included critically ill adult patients with confirmed COVID-19 treated between March 2020 and May 2021. Eligible patients with moderate-to-severe acute respiratory distress syndrome due to COVID-19 were subsequently categorized into two groups based on inhaled nitric oxide use throughout their stay in the intensive care unit. The primary endpoints were overall mortality and improvement in oxygenation parameters 6 hours after inhaled nitric oxide use. RESULTS: A total of 481 patients admitted to the intensive care unit due to COVID-19 acute respiratory distress syndrome were screened, 105 of which were included. Among the 105 patients, inhaled nitric oxide therapy was used in 33 patients, will 72 did not undergo inhaled nitric oxide therapy. No significant difference in mortality was observed between the groups (67% for the treatment and 82% for the no-treatment groups respectively, p=0.173). Among the patients who used inhaled nitric oxide, 17 (51%) were considered responsive to therapy. There was no significant difference in the length of stay in the intensive care unit (p=0.324) or total hospitalization time (p=0.344). CONCLUSION: Inhaled nitric oxide rescue therapy improved oxygenation in patients with COVID-19 with moderate-to-severe acute respiratory distress syndrome but did not affect mortality.
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COVID-19 , Óxido Nítrico , Síndrome de Dificultad Respiratoria , Humanos , Óxido Nítrico/administración & dosificación , Óxido Nítrico/uso terapéutico , Estudios Retrospectivos , Administración por Inhalación , Masculino , Femenino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/mortalidad , COVID-19/complicaciones , Anciano , Unidades de Cuidados Intensivos , Tratamiento Farmacológico de COVID-19 , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , SARS-CoV-2 , AdultoRESUMEN
In severe COVID-19 cases, an exacerbated inflammatory response triggers a cytokine storm that can worsen the prognosis. Compounds with both antiviral and anti-inflammatory activities show promise as candidates for COVID-19 therapy, as they potentially act against the SARS-CoV-2 infection regardless of the disease stage. One of the most attractive drug targets among coronaviruses is the main protease (MPro). This enzyme is crucial for cleaving polyproteins into non-structural proteins required for viral replication. The aim of this review was to identify SARS-CoV-2 MPro inhibitors with both antiviral and anti-inflammatory properties. The interactions of the compounds within the SARS-CoV-2 MPro binding site were analyzed through molecular docking when data from crystallographic structures were unavailable. 18 compounds were selected and classified into five different superclasses. Five of them exhibit high potency against MPro: GC-376, baicalein, naringenin, heparin, and carmofur, with IC50 values below 0.2 µM. The MPro inhibitors selected have the potential to alleviate lung edema and decrease cytokine release. These molecules mainly target three critical inflammatory pathways: NF-κB, JAK/STAT, and MAPK, all previously associated with COVID-19 pathogenesis. The structures of the compounds occupy the S1/S2 substrate binding subsite of the MPro. They interact with residues from the catalytic dyad (His41 and Cys145) and/or with the oxyanion hole (Gly143, Ser144, and Cys145), which are pivotal for substrate recognition. The MPro SARS-CoV-2 inhibitors with potential anti-inflammatory activities present here could be optimized for maximum efficacy and safety and be explored as potential treatment of both mild and severe COVID-19.
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Antiinflamatorios , Antivirales , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus , SARS-CoV-2 , Humanos , Antiinflamatorios/farmacología , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Simulación del Acoplamiento Molecular , COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , AnimalesRESUMEN
Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Péptidos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Humanos , Animales , SARS-CoV-2/efectos de los fármacos , COVID-19/virología , Ratones , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Péptidos/farmacología , Péptidos/química , Péptidos/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Antivirales/farmacología , Antivirales/química , Línea Celular , Neumonía/tratamiento farmacológico , Neumonía/virología , Neumonía/prevención & control , Pulmón/virología , Pulmón/patología , FemeninoRESUMEN
BACKGROUND: Patients with Hematological Malignancies (HM) are at a high risk of mortality from Coronavirus disease 2019 (COVID-19). The available antivirals were different between China and other countries. In China, azvudine was obtained for emergency use to treat adult COVID-19 patients with moderate symptoms in July 2022. While nirmatrelvir-ritonavir was well-known and used in many countries. The purpose of the present study was to assess whether there was any difference in the efficacy and safety of the two drugs. METHODS: This study was a prospective observational study of patients with HM who developed COVID-19. Patients were divided into three treatment groups: nirmatrelvir-ritonavir, azvudine, and observation. Treatment outcomes, first nucleic acid test negative time, hospitalization time, and the conversion rate of mild or moderate disease to severe disease were recorded. RESULTS: First nucleic acid test negative time (23.5 days vs. 34 days, p = 0.015), hospitalization time (p = 0.015), and conversion rate (31.8 % vs. 8 %, p = 0.046) were statistically different between the nirmatrelvir-ritonavir and observation groups. First nucleic acid test negative time (20 days vs. 34 days, p = 0.009) and hospitalization time (p = 0.026) were statistically different between the azvudine and observation groups. ECOG score and liver disease were significantly associated with the conversion rate from mild or moderate disease to severe disease using multivariate analysis (p < 0.05). CONCLUSIONS: The authors found no significant differences existed in outcome measures between patients with HM and COVID-19 who were treated with nirmatrelvir-ritonavir or azvudine.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Neoplasias Hematológicas , Ritonavir , Humanos , Masculino , Ritonavir/uso terapéutico , Persona de Mediana Edad , Antivirales/uso terapéutico , Femenino , Estudios Prospectivos , Neoplasias Hematológicas/tratamiento farmacológico , Resultado del Tratamiento , Adulto , Anciano , SARS-CoV-2 , COVID-19RESUMEN
There is limited evidence about the use of medications among pregnant women with COVID-19, as well as risk factors for hospitalization due to COVID-19 in pregnancy. We aimed to describe the use of medications among SARS-CoV-2-positive pregnant women at the time around infection and identify predictors for hospitalization due to COVID-19 in two hospitals in Brazil. This is a hospital record-based study among pregnant women with positive SARS-CoV-2 tests between March 2020 and August 2022 from two Brazilian hospitals. Characteristics of sociodemographic, obstetrical, and COVID-19 symptoms were extracted retrospectively. The prevalence use of medications was based on self-reported use, and this was administered at the hospital. Logistic regression was used to estimate predictors of hospitalization due to COVID-19. There were 278 pregnant women included in the study, of which 41 (14.7%) required hospitalization due to COVID-19. The remaining 237 (85.3%) had mild symptoms or were asymptomatic. Most of the women had the infection in the third trimester (n = 149; 53.6%). The most prevalent medications used across all trimesters were analgesics (2.4% to 20.0%), antibacterials (15.0% to 23.1%), and corticosteroids (7.2% to 10.4%). Pre- or gestational hypertensive disorder (odds ratio (OR) 4.94, 95% confidence interval (CI) 1.65, 14.87) and having at least one dose of vaccine against SARS-CoV-2 (OR 0.13, 95% CI 0.04, 0.39) were associated with hospitalization due to COVID-19. Analgesics, antibacterials, and corticosteroids were the most frequently used medications among pregnant women with COVID-19. Women with hypertensive disorders have almost a five-fold increased risk of hospitalization due to COVID-19. Vaccination was the strongest protective factor for severe COVID-19. The COVID-19 vaccination among pregnant women should be promoted, and pregnant women diagnosed with COVID-19 who have hypertensive disorders should be closely monitored.
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COVID-19 , Hospitalización , Complicaciones Infecciosas del Embarazo , SARS-CoV-2 , Humanos , Embarazo , Femenino , Brasil/epidemiología , Hospitalización/estadística & datos numéricos , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , COVID-19/epidemiología , Adulto , Estudios Retrospectivos , Factores de Riesgo , Tratamiento Farmacológico de COVID-19 , Adulto Joven , Antibacterianos/uso terapéuticoRESUMEN
OBJECTIVE: The quality of care and safety for Telemedicine-discharged patients with suspected respiratory infections are closely related to low rates of prescriptions of unjustified and high-risk medications. This retrospective study aimed to assess adherence to the current COVID-19 guidelines in direct-to-consumer telemedicine encounters at a large center using multidrug stewardship protocols. METHODS: A quarterly electronic survey utilizing medical records of individual physician care assessed various quality indicators. Physicians received ongoing adaptive feedback based on personal metrics, with Telemedicine Center recommendations derived from the 2020 Infectious Diseases Society of America guidelines. The study included all consecutive adults with new respiratory symptoms in the last 14 days who sought spontaneous Telemedicine consultations between March 2020 and August 2021. This study analyzed patients with suspected or confirmed COVID-19 and other airway infections. RESULTS: Of the 221,128 evaluated patients, 42,042 (19%) had confirmed COVID-19; 104,021 (47%) were suspected to have COVID-19; and, 75,065 (33%) had other diagnoses. Patients with suspected or confirmed COVID-19 had a mean (+DP) age of 35±12 years. A total of 125,107 (85.65%) patients were managed at home, 2,552 (1.74%) were referred for non-urgent in-office reassessment, and 17,185 (11.7%) were referred to the emergency department for whom there was no further treatment recommendation. The antibiotic rate in confirmed or suspected COVID-19 cases was 0.46%/0.65% and that for non-evidence-based prescriptions was 0.01%/0.005%. CONCLUSION: Guideline training and Telemedicine consultation feedback may lead to lower antibiotic and antimicrobial prescriptions in suspected and confirmed COVID-19 cases. Multidrug stewardship protocols may improve guideline adherence and reinforce the quality of care and safety in Telemedicine encounters.
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COVID-19 , Adhesión a Directriz , Telemedicina , Humanos , Estudios Retrospectivos , Adhesión a Directriz/estadística & datos numéricos , Telemedicina/estadística & datos numéricos , Telemedicina/normas , Adulto , Femenino , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Programas de Optimización del Uso de los Antimicrobianos/normasRESUMEN
SARS-CoV-2 is recently emerged virus, which caused millions of deaths, all over the world. To tackle COVID-19 pandemic, there is an utmost need for in-depth analysis of viral replication. We aimed to examine viral load in SARS-CoV-2 patients during first two waves of COVID-19 in Pakistan. 225,615 suspected subjects from 75 different regions of Pakistan were selected in the study. SARS-CoV-2 RNAs were detected via real time PCR. During first wave (period of June-July, 2020) of COVID-19 the prevalence of SARS-CoV-2 was 20.38%. However, during second wave (period of November-December, 2020) of COVID-19, the rate of prevalence was 9.41%. During first wave of COVID-19 96.31% of participants remained PCR positive for 14 to 21 days, 3.39% of subjects showed positive results for 22 to 35 days, while delayed Ct values were observed among 0.26% of participants for 36 to 49 days. However, during second wave of COVID-19 89.31% of the subjects exhibited symptoms and showed real-time PCR positive results for 14 to 21 days, 9.42% showed positive results for 22 to 35 days, while significantly delayed Ct value results were observed among 1.026% of participants for 36 to 63 days (3.95 times higher than first wave). In contrast to first wave of COVID-19, the factors that were different in second wave were neither viral (different strains) nor host (same population). But treatment factors changed significantly. As during second wave besides azithromycin, corticosteroid dexamethasone consumption was increased consequently causing delayed Ct value negativity. This suggests that corticosteroid treatment might be linked with delayed Ct value or viral clearance. This study is crucial for re-considering effective therapeutic options against COVID-19.
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COVID-19 , SARS-CoV-2 , Carga Viral , Humanos , Pakistán/epidemiología , Carga Viral/efectos de los fármacos , Masculino , Femenino , Tratamiento Farmacológico de COVID-19 , Adulto , ARN Viral/análisis , Persona de Mediana Edad , Factores de Tiempo , Corticoesteroides/uso terapéutico , Adulto Joven , Pandemias , Adolescente , Reacción en Cadena en Tiempo Real de la Polimerasa , Prueba de Ácido Nucleico para COVID-19RESUMEN
Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus , Ivermectina , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , SARS-CoV-2 , Ivermectina/química , Ivermectina/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Humanos , Antivirales/química , Antivirales/farmacología , Unión Proteica , Sulfonamidas/química , Sulfonamidas/farmacología , Sitios de Unión , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
AIMS: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE). MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction. KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as ß2 integrin, PI3K, and PAD2 due to its intermolecular coupling. SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.