Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.877
Filtrar
2.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802761

RESUMEN

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , /inmunología , Anticuerpos Monoclonales Humanizados/química , /inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/fisiopatología , Humanos , Interleucina-6/antagonistas & inhibidores , Interleucina-6/fisiología
3.
J Immunother Cancer ; 9(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33837054

RESUMEN

The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/antagonistas & inhibidores , /aislamiento & purificación , /epidemiología , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Pandemias , /fisiología
4.
Medicine (Baltimore) ; 100(12): e25173, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761696

RESUMEN

RATIONALE: Bacterial and fungal infections in Coronavirus Disease-19 (COVID-19) patients have been inadequately investigated and reported thus far. The safety profile of tocilizumab (TCZ) administration in candidemia patient still debatable. PATIENT CONCERNS: A 54 year-old woman presenting with weakness on the left side of her body was diagnosed with COVID-19. After 7 days of admission, her condition worsened and developed respiratory distress and was having respiratory distress despite standard treatment. DIAGNOSES: Acute respiratory distress syndrome (ARDS) in COVID 19 was diagnoses based on real time-PCR swab, deterioration of PaO2/FiO2 and increased of acute phase reactants. INTERVENTIONS: Anti Interleukin-6 (IL-6) was considered to tackle her inflammatory condition. Prior to TCZ administration, blood culture was performed and the result came with Candida tropicalis in the absence of bacterial growth. OUTCOMES: No major complications associated with intravenous antifungal or TCZ occurred. After 40 days of hospitalization, the patient's clinical condition improved and was finally discharged. LESSONS: This case underscores the safety profile of giving TCZ in candidemia as a secondary infection in severe COVID-19 patient.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antifúngicos/uso terapéutico , /tratamiento farmacológico , Candidemia/complicaciones , Candidemia/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/efectos adversos , Candida tropicalis , Coinfección , Femenino , Humanos , Micafungina/uso terapéutico , Persona de Mediana Edad
5.
Cochrane Database Syst Rev ; 3: CD013881, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33734435

RESUMEN

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Sesgo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto
6.
BMC Infect Dis ; 21(1): 241, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33673818

RESUMEN

BACKGROUND: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. METHOD: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation. CONCLUSION: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Síndrome de Liberación de Citoquinas , Hipoxia , Interleucina-6/antagonistas & inhibidores , Neumonía Viral , /epidemiología , /fisiopatología , Ensayos de Uso Compasivo/estadística & datos numéricos , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/terapia , Femenino , Humanos , Hipoxia/etiología , Hipoxia/terapia , India/epidemiología , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Neumonía Viral/sangre , Neumonía Viral/etiología , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Respiración Artificial/métodos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento
7.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670304

RESUMEN

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Lisosomas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Antivirales/farmacocinética , Antivirales/uso terapéutico , /metabolismo , Clorpromazina/farmacocinética , Clorpromazina/farmacología , Clorpromazina/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , Fluvoxamina/farmacocinética , Fluvoxamina/farmacología , Fluvoxamina/uso terapéutico , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Interleucina-1/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/virología , Lisosomas/inmunología , Lisosomas/metabolismo , Lisosomas/virología , /fisiología , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Replicación Viral/efectos de los fármacos
9.
Eur J Pharmacol ; 899: 174031, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33722593

RESUMEN

Interleukin 6 (IL-6), which is involved in the cytokine storm phenomenon, is a therapeutic target in COVID-19, but monoclonal receptor antibody therapeutic agents such as tocilizumab have demonstrated mixed results. Could Vitamin D, which modulates IL-6, be more effective than currently deployed IL-6 antagonists, including tocilizumab, thereby presenting a useful therapeutic option in COVID-19? A narrative review of published trials examining the effect of Vitamin D administration in COVID-19 patients was conducted, and the theoretical basis for the use of tocilizumab as an IL-6 antagonist was compared with the immunomodulatory effect of Vitamin D on IL-6 production. Four of the six included studies reported a positive effect of Vitamin D on outcomes. While tocilizumab non-selectively blocks both anti-inflammatory and pro-inflammatory actions of IL-6, Vitamin D lowers immune cell IL-6 production, potentially reducing pro-inflammatory effects, but does not specifically target IL-6 receptors, avoiding any deleterious effect on the anti-inflammatory actions of IL-6. Vitamin D may have advantages over tocilizumab as an IL-6 immunomodulator, and, given that it is safe if administered under clinical supervision, there is a strong rationale for its use.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/sangre , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/terapia , Humanos , Interleucina-6/antagonistas & inhibidores
10.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33670858

RESUMEN

Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure with multiple sulfate groups. The aim of the present study was to uncover the type of binding between critical positions in the human IL-6 structure available for binding dPGS and compare it with heparin sulfate binding. We studied these interactions by performing docking simulations of dPGS and heparins with human IL-6 using AutoDock Vina. These molecular docking analyses indicate that the two ligands have comparable affinities for the positively charged positions on the surface of IL-6. All-atom molecular dynamics simulations (MD) employing Gromacs were used to explore the binding sites and binding strengths. Results suggest two major binding sites and show that the strengths of binding are similar for heparin and dPGS (-5.5-6.4 kcal/ mol). dPGS or its analogs could be used in the therapeutic intervention in sepsis and inflammatory disorders to reduce unbound IL-6 in the plasma or tissues and its binding to the receptors. We propose that analogs of dPGS could specifically block IL-6 binding in the desired signaling mode and would be valuable new probes to establish optimized therapeutic intervention in inflammation.


Asunto(s)
Dendrímeros/química , Glicerol/farmacología , Interleucina-6/antagonistas & inhibidores , Modelos Moleculares , Polímeros/farmacología , Antiinflamatorios/farmacología , Heparina , Humanos , Inflamación , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica
11.
Inflamm Res ; 70(4): 389-405, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33608746

RESUMEN

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1ß. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF. RESULTS: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application. CONCLUSION: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.


Asunto(s)
/epidemiología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Animales , Antirreumáticos/uso terapéutico , Citocinas/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inmunización Pasiva , Inmunosupresores/uso terapéutico , Inmunoterapia , Inflamación/tratamiento farmacológico , Interferones/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Janus Quinasa 1/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Respiratoria/terapia , Factor de Transcripción STAT1/antagonistas & inhibidores , Transducción de Señal
12.
Braz J Anesthesiol ; 71(1): 79-83, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33518836

RESUMEN

The management of acute hypoxemic respiratory failure and the effect of antiviral drugs in patients with severe COVID-19 have been debated. This case presents the management of a 64-year-old man COVID-19 patient admitted to the Intensive Care Unit with fever, fatigue, shortness of breath and hemophagocytic lymphohistiocytosis syndrome. Helmet mask was successfully used to treat his hypoxemic respiratory failure without any aerosol problems. Tocilizumab, an antagonist interleukin-6, was intravenously infused as an alternative drug. After administration, the high level of IL-6, CRP, ferritin, D-dimer, triglyceride, and H-scores decreased, and the patient observed good clinical and laboratory improvements. In this case report, we describe the effect of noninvasive ventilation delivered by helmet mask and antiviral drugs, and the intravenous administration of tocilizumab in a patient with hemophagocytic lymphohistiocytosis syndrome and COVID-19.


Asunto(s)
/complicaciones , Linfohistiocitosis Hemofagocítica/complicaciones , Máscaras , Ventilación no Invasiva/métodos , Insuficiencia Respiratoria/terapia , Anticuerpos Monoclonales Humanizados/administración & dosificación , Humanos , Inyecciones Intravenosas , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/sangre
13.
Int J Med Sci ; 18(6): 1356-1362, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33628091

RESUMEN

Cytokine release syndrome (CRS) may be the key factor in the pathology of severe coronavirus disease 2019 (COVID-19). As a major driver in triggering CRS in patients with COVID-19, interleukin-6 (IL-6) appears to be a promising target for therapeutics. The results of inhibiting both trans- and classical- signaling with marketed IL-6 inhibitors (tocilizumab, siltuximab and sarilumab) in severe COVID-19 patients are effective based on several small studies and case reports thus far. In this review, we described the evidence of the IL-6 response in patients with COVID-19, clarified the pathogenesis of the role of IL-6-mediated CRS in severe COVID-19, and highlighted the rationale for the use of anti-IL-6 agents and key information regarding the potential features of these IL-6 inhibitors in COVID-19 patients.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Interleucina-6/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , /metabolismo , Síndrome de Liberación de Citoquinas/metabolismo , Humanos , Interleucina-6/antagonistas & inhibidores
14.
Biosci Biotechnol Biochem ; 85(5): 1170-1174, 2021 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-33590853

RESUMEN

Interleukin-6 (IL-6) binds to the IL-6 receptor (IL-6R) subunit, related to autoimmune diseases and cytokine storm in COVID-19. In this study, we performed systematic evolution of ligands by exponential enrichment and identified a novel RNA aptamer. This RNA aptamer not only bound to IL-6R with a dissociation constant of 200 n m, but also inhibited the interaction of IL-6R with IL-6.


Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/antagonistas & inhibidores , Aptámeros de Nucleótidos/química , Secuencia de Bases , Síndrome de Liberación de Citoquinas/etiología , ADN Viral/efectos de los fármacos , Humanos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Técnica SELEX de Producción de Aptámeros
16.
RMD Open ; 7(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33455920

RESUMEN

BACKGROUND: The recent outbreak of COVID-19 has raised concerns in the rheumatology community about the management of immunosuppressed patients diagnosed with inflammatory rheumatic diseases. It is not clear whether the use of biological agents may suppose a risk or protection against SARS-CoV-2 infection; however, it has been suggested that severe respiratory forms of COVID-19 occur as a result of exacerbated inflammation status and cytokine production. This prompted the use of interleukin 6 (IL-6) (tocilizumab and sarilumab) and IL-1 inhibitors (anakinra) in severe COVID-19 disease and more recently JAK1/2 inhibitor (baricitinib). Therefore, patients with rheumatic diseases provide a great opportunity to learn about the use of biological agents as protective drugs against SARS-CoV-2. OBJECTIVES: To estimate COVID-19 infection rate in patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) for inflammatory rheumatic diseases (RMD), determine the influence of biological agents treatment as risk or protective factors and study the prognosis of patients with rheumatic diseases receiving biological agents compared to the general population in a third-level hospital setting in León, Spain. METHODS: We performed a retrospective observational study including patients seen at our rheumatology department who received bDMARDs for rheumatic diseases between December 1st 2019 and December 1st 2020, and analysed COVID-19 infection rate. All patients who attended our rheumatology outpatient clinic with diagnosis of inflammatory rheumatic disease receiving treatment with biological agents were included. Main variable was the hospital admission related to COVID-19. The covariates were age, sex, comorbidities, biological agent, duration of treatment, mean dose of glucocorticoids and need for intensive care unit . We performed an univariate and multivariate logistic regression models to assess risk factors of COVID-19 infection. RESULTS: There were a total of 4464 patients with COVID-19 requiring hospitalisation. 40 patients out of a total of 820 patients with rheumatic diseases (4.8%) receiving bDMARDs contracted COVID-19 and 4 required hospital care. Crude incidence rate of COVID-19 requiring hospital care among the general population was 3.6%, and it was 0.89% among the group with underlying rheumatic diseases. 90% of patients receiving bDMARDS with COVID-19 did not require hospitalisation. Out of the 4464 patients, 869 patients died, 2 of which received treatment with biological agents. Patients with rheumatic diseases who tested positive for COVID-19 were older (female: median age 60.8 IQR 46-74; male: median age 61.9 IQR 52-70.3) than those who were negative for COVID-19 (female: median age 58.3 IQR 48-69; male: median age 56.2 IQR 47-66), more likely to have hypertension (45% vs 26%, OR 2.25 (CI 1.18-4.27),p 0.02), cardiovascular disease (23 % vs 9.6%, OR 2.73 (1.25-5.95), p 0.02), be smokers (13% vs 4.6%, OR 2.95 (CI 1.09-7.98), p 0.04), receiving treatment with rituximab (20% vs 8%, 2.28 (CI 1.24-6.32), p 0.02) and a higher dose of glucocorticoids (OR 2.5 (1.3-10.33, p 0.02) and were less likely to be receiving treatment with IL-6 inhibitors (2.5% vs 14%, OR 0.16, (CI 0.10-0.97, p 0.03). When exploring the effect of the rest of the therapies between groups (affected patients vs unaffected), we found no significant differences in bDMARD proportions. IL-1 inhibitors, IL-6 inhibitors, JAK inhibitors and belimumab-treated patients showed the lowest incidence of COVID-19 among adult patients with rheumatic diseases. We found no differences in sex or rheumatological disease between patients who tested positive for COVID-19 and patients who tested negative. CONCLUSIONS: Overall, the use of biological disease-modifying antirheumatic drugs (bDMARDs) does not associate with severe manifestations of COVID-19. Patients with rheumatic disease diagnosed with COVID-19 were more likely to be receiving a higher dose of glucocorticoids and treatment with rituximab. IL-6 inhibitors may have a protective effect.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Factores Biológicos/uso terapéutico , Brotes de Enfermedades , Glucocorticoides/uso terapéutico , Sustancias Protectoras/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Rituximab/uso terapéutico , /aislamiento & purificación , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Humanos , Interleucina-6/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , /inmunología , España/epidemiología , Resultado del Tratamiento
17.
Aging (Albany NY) ; 13(2): 1571-1590, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33465050

RESUMEN

The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as 'cytokine storm', that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission. Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies. The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis. Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and 'inflammaging' - the inflammatory underpinning of aging and frailty.


Asunto(s)
Cannabis , Síndrome de Liberación de Citoquinas , Interleucina-6/antagonistas & inhibidores , Extractos Vegetales/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios/farmacología , Cannabinoides/farmacología , Línea Celular , Fibroblastos/efectos de los fármacos , Humanos , Inflamación/virología , Piel/efectos de los fármacos , Técnicas de Cultivo de Tejidos
18.
J Intern Med ; 289(5): 738-746, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33511686

RESUMEN

BACKGROUND: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues. METHODS: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response. RESULTS: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response. CONCLUSIONS: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Biomarcadores Farmacológicos/análisis , Monitoreo de Drogas/métodos , Interleucina-6 , Neumonía Viral , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , /epidemiología , /terapia , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacocinética , Infusiones Intravenosas , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Italia/epidemiología , Masculino , Oximetría/métodos , Terapia por Inhalación de Oxígeno/métodos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Neumonía Viral/etiología , Valor Predictivo de las Pruebas , Pruebas de Función Respiratoria/métodos , Resultado del Tratamiento
19.
Cytokine ; 138: 155393, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33333393

RESUMEN

COVID-19 is a public health emergency of international concern with millions confirmed cases globally including in Indonesia with more than two hundred thousand confirmed cases to date COVID-19. (1) COVID-19 has wide clinical manifestation ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitates mechanical ventilation and support in an ICU, to MODS. (2) Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease. (3)-(5) Severe COVID-19 is associated with increased plasma concentrations of IL-6, resulting in cytokine storm. (6) Tocilizumab, an interleukin-6 inhibitor, might alleviates the cytokine storm, prevents significant lungs and organs damage, thus improving clinical outcomes. (7) Therefore, tocilizumab, might be one of the promising therapies for severe COVID-19. (8) However there were limited studies regarding the efficacy in COVID-19 patients, especially with control group. We would like to report our experience in using tocilizumab as treatment in severe COVID-19 patients in Indonesia, which is the first in Indonesia to the best of our knowledge.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Femenino , Humanos , Indonesia , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
20.
Eur Cytokine Netw ; 31(3): 81-93, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-33361013

RESUMEN

Coronavirus disease (COVID-19) reached pandemic proportions at the beginning of 2020 and continues to be a worldwide concern. End organ damage and acute respiratory distress syndrome are the leading causes of death in severely or critically ill patients. The elevated cytokine levels in severe patients in comparison with mildly affected patients suggest that cytokine release syndrome (CRS) occurs in the severe form of the disease. In this paper, the significant role of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, and their mechanism of action in the CRS cascade is explained. Potential therapeutic approaches involving anti-IL-6 and anti-TNF-alpha antibodies to fight COVID-19 and reduce mortality rate in severe cases are also discussed.


Asunto(s)
Anticuerpos/uso terapéutico , Síndrome de Liberación de Citoquinas , Interleucina-6/antagonistas & inhibidores , Pandemias , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , /sangre , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/mortalidad , Humanos , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...