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1.
BMJ Case Rep ; 14(1)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33419750

RESUMEN

As of 28 October 2020, there are over 44 000 000 confirmed COVID-19 infections and over 1 000 000 deaths worldwide, including 945 367 infections and 45 765 deaths in the UK. Acute respiratory distress syndrome occurs in 50% of patients with secondary haemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome characterised by a surge of cytokines, including interleukin 6 (IL-6). Here we describe the case of the first patient with severe COVID-19 pneumonia successfully treated with tocilizumab, a humanised monoclonal antibody against the IL-6 receptor, in the UK. Early treatment (after 7-10 days from the onset of symptoms) with tocilizumab could (1) reduce the risk of requiring non-invasive or invasive ventilation; (2) offer a chance of survival to people who are not fit for escalation or have refused to be ventilated; and (3) potentially increase the chance of survival in some patients who are already ventilated but fail to improve with supportive treatment.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Hipoxia/terapia , Anciano , /fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Hipertensión/complicaciones , Hipoxia/fisiopatología , Masculino , Terapia por Inhalación de Oxígeno , Receptores de Interleucina-6/antagonistas & inhibidores , Índice de Severidad de la Enfermedad
2.
Pharmacol Res Perspect ; 9(1): e00705, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33421347

RESUMEN

Drug-drug interaction (DDI) is a common clinical problem that has occurred as a result of the concomitant use of multiple drugs. DDI may occur in patients under treatment with medications used for coronavirus disease 2019 (COVID-19; i.e., chloroquine, lopinavir/ritonavir, ribavirin, tocilizumab, and remdesivir) and increase the risk of serious adverse reactions such as QT-prolongation, retinopathy, increased risk of infection, and hepatotoxicity. This review focuses on summarizing DDIs for candidate medications used for COVID-19 in order to minimize the adverse reactions.


Asunto(s)
Antivirales/uso terapéutico , /tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Cloroquina/uso terapéutico , Interacciones Farmacológicas , Humanos , Lopinavir/uso terapéutico , Ribavirina/uso terapéutico , Ritonavir/uso terapéutico
3.
BMJ ; 372: m4447, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397652

RESUMEN

Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/terapia , Terapia por Ejercicio/métodos , Antígeno HLA-B27/sangre , Humanos , Interleucina-17 , Interleucinas , Imagen por Resonancia Magnética , Espondilitis Anquilosante/clasificación , Espondilitis Anquilosante/fisiopatología
4.
Medicine (Baltimore) ; 100(1): e23582, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429732

RESUMEN

ABSTRACT: COVID-19 is causing a high influx of patients suffering from serious respiratory complications leading the necessity to find effective therapies. These patients seem to present with cytokine perturbation and high levels of IL6. Tocilizumab and sarilumab could be effective in this condition.We retrospectively collected data about 112 consecutive hospitalized in a single center.Fifty (IL6 group) treated with tocilizumab (8 mg/kg intravenously [IV], 2 infusions 12 hours apart) or sarilumab 400 mg IV once and 62 treated with the standard of care but not anti-cytokine drugs (CONTROL group).To determine whether anti-IL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality in COVID-19 pneumonia.To date 84% (42/50) of IL6 group patients have already been discharged and only 2/50 are still recovered and intubated in intensive care. Six/fifty patients (12%) died: 5/6 due to severe respiratory failure within a framework of severe acute respiratory distress syndrome (ARDS), 1 suffered an acute myocardial infarction, and 1 died of massive pulmonary thromboembolism. There were no adverse treatment events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate (12% versus 43%), for the same number of complications and days of hospitalization.Anti-IL6 drugs seem to be effective in the treatment of medium to severe forms of COVID-19 pneumonia reducing the risk of mortality due to multi-organ failure, acting at the systemic level and reducing inflammation levels and therefore microvascular complications. However, it is essential to identify the best time for treatment, which, if delayed, is rendered useless as well as counterproductive. Further studies and ongoing clinical trials will help us to better define patients eligible as candidates for more aggressive intervention.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía Viral/virología , Pronóstico , Estudios Retrospectivos
5.
Theranostics ; 11(1): 316-329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391477

RESUMEN

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Asunto(s)
Antiinflamatorios/uso terapéutico , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Inmunosupresores/uso terapéutico , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , /inmunología , Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Humanos , Inmunosupresores/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
6.
Medicine (Baltimore) ; 100(1): e24018, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429766

RESUMEN

INTRODUCTION: Pembrolizumab, a monoclonal antibody targeting programmed cell death-1 (PD-1), is approved as a therapy for unresectable or metastatic melanoma. Immunotherapy-associated pneumonitis is an uncommon event. PATIENT CONCERNS: A 73-year-old man was admitted to our hospital with a history of melanoma on the left side of the face (resected in December 2012) and metastasis to the left lung upper lobe (resected in November 2016). Recurrence of metastasis to the bilateral lungs and left pleura was detected in April 2018. A complete response was achieved following treatment with pembrolizumab, with lower limb rashes the only adverse events occurring during therapy. The patient was readmitted in March 2019 with a productive cough, shortness of breath, and mild fever, and sputum culture identified Escherichia coli. DIAGNOSIS: A diagnosis of pneumonia was made, and although cough and shortness of breath responded to ceftazidime and levofloxacin, but fever and poor appetite persisted. Computed tomography showed no improvement in the bilateral lower lobe lesions. Prednisone was initiated based on a clinical diagnosis of immunotherapy-related pneumonitis. The response to prednisone confirmed the diagnosis. INTERVENTIONS: The patient first received ceftazidime and levofloxacin, but the symptoms persisted. Prednisone was initiated based on a clinical diagnosis of immunotherapy-related pneumonitis. OUTCOME: Complete resolution of the bilateral lung lesions occurred after 45 days of prednisone therapy. CONCLUSION: This case report highlights that both pneumonitis and bacterial pneumonia can occur as complications of anti-PD-1 immunotherapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia/efectos adversos , Melanoma/tratamiento farmacológico , Neumonía Bacteriana/etiología , Neumonía/etiología , Anciano , Tos/etiología , Disnea/etiología , Fiebre/etiología , Humanos , Inmunoterapia/métodos , Inmunoterapia/normas , Masculino , Melanoma/complicaciones , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/fisiopatología , Neumonía/fisiopatología , Neumonía Bacteriana/fisiopatología
7.
Nihon Yakurigaku Zasshi ; 156(1): 47-51, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390481

RESUMEN

Antibody-drug conjugates (ADCs) combine the specific antibody and cytotoxic agent by a linker and represent a promising drug class with a wider therapeutic window than conventional chemotherapeutic agents by substantiating efficient and specific drug delivery to antigen-expressing tumor cells. However, there are rooms for improvement in terms of efficacy, safety, physicochemical property; therefore, the development of promising ADC drugs across multiple indications are eagerly awaited. In 2015, Daiichi Sankyo initiated the first-in-human study of HER2 ADC, trastuzumab deruxtecan (T-DXd, ENHERTU®) which possesses DNA topoisomerase I inhibitor, exatecan derivative and proprietary linker, in Japan. Based on the provocative results in phase 1 study, the global development program has been accelerated to show the high and durable efficacy in patients with HER2 positive breast cancer pretreated with trastuzumab emtansine. As a result, T-DXd was approved based on single arm phase 2 study in the US (Dec 2019) and Japan (March 2020) by leveraging the breakthrough designation and conditional early approval system, respectively, at the first time for the HER2 positive breast cancer. In addition, T-DXd was recently approved in gastric cancer through Sakigake designation in Japan based on a randomized phase 2 study. T-DXd is also being developed in the earlier lines or other indications where no anti-HER2 therapies were approved to date. Combination studies with other agents, such as immune checkpoint inhibitors are underway. In the near future, we hope that more patients worldwide can enjoy the therapeutic benefits of T-DXd through our continuous efforts to expand its indications.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivados , Humanos , Inmunoconjugados , Japón , Receptor ErbB-2/uso terapéutico , Trastuzumab/uso terapéutico
8.
Support Care Cancer ; 29(1): 117-125, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32318871

RESUMEN

PURPOSE: In REVEL, patients with advanced non-small-cell lung cancer (aNSCLC) and patients with increased tumor aggressiveness (rapid disease progression (RDP), platinum-refractory disease (PRD), and high symptom burden (HSB)) benefited from second-line treatment with ramucirumab plus docetaxel over placebo plus docetaxel. This post hoc analysis describes healthcare resource utilization (HCRU) associated with the treatment. METHODS: aNSCLC patients who had progressed during or after first-line platinum-based chemotherapy were randomized to receive docetaxel and either ramucirumab or placebo until disease progression, unacceptable toxicity, withdrawal, or death. HCRU included hospitalizations, transfusions, and concomitant medications. Categorical variables (counts and percentages) were compared using Fisher's exact test. Continuous variables (mean, standard deviation (SD), median, minimum, and maximum) were compared using the Wilcoxon rank sum test. RESULTS: Patient characteristics were largely similar between treatment arms. Within the intent-to-treat (ITT) population (n = 1253), the mean treatment duration was 19.7 and 16.9 weeks in the ramucirumab and control arms, respectively; 51.0% versus 54.9% of patients received subsequent anticancer therapy, respectively. Hospitalization rates were 41.9% versus 42.6% (p = 0.863), mean length of hospital stay was 14.5 days versus 11.3 days (p = 0.066), transfusion rates were 9.9% versus 12.3% (p = 0.206), and use of granulocyte colony-stimulating factors was 41.8% versus 36.6% (p = 0.063), respectively. No significant difference was observed in HCRU between treatment arms in both ITT population and in aggressive disease subgroups including RDP (n = 209), PRD (n = 360), and HSB (n = 497). CONCLUSION: In REVEL, the addition of ramucirumab to docetaxel did not increase HCRU among patients with aggressive aNSCLC disease. These results may help inform economic evaluation of treatment for patients with aNSCLC.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Aceptación de la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Platino (Metal)/uso terapéutico , Taxoides/uso terapéutico
9.
J Infect Chemother ; 27(1): 76-82, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33051144

RESUMEN

INTRODUCTION: The severity of coronavirus disease (COVID-19) in Japanese patients is unreported. We retrospectively examined significant factors associated with disease severity in symptomatic COVID-19 patients (COVID-Pts) admitted to our institution between February 20 and April 30, 2020. METHODS: All patients were diagnosed based on the genetic detection of severe acute respiratory syndrome coronavirus 2. Information on the initial symptoms, laboratory data, and computed tomography (CT) images at hospitalization were collected from the patients' records. COVID-Pts were categorized as those with critical or severe illness (Pts-CSI) or those with moderate or mild illness (Pt-MMI). All statistical analyses were performed using R software. RESULTS: Data from 61 patients (16 Pt-CSI, 45 Pt-MMI), including 58 Japanese and three East Asians, were analyzed. Pt-CSI were significantly older and had hypertension or diabetes than Pt-MMI (P < 0.001, 0.014 and < 0.001, respectively). Serum albumin levels were significantly lower in Pt-CSI than in Pt-MMI (P < 0.001), whereas the neutrophil-to-lymphocyte ratio and C-reactive protein level were significantly higher in Pt-CSI than in Pt-MMI (P < 0.001 and P < 0.001, respectively). In the CT images of 60 patients, bilateral lung lesions were more frequently observed in Pt-CSI than in Pt-MMI (P = 0.013). Among the 16 Pt-CSI, 15 received antiviral therapy, 12 received tocilizumab, five underwent methylprednisolone treatment, six received mechanical ventilation, and one died. CONCLUSIONS: The illness severity of Japanese COVID-Pts was associated with older age, hypertension and/or diabetes, low serum albumin, high neutrophil-to-lymphocyte ratio, and C-reactive protein.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/terapia , Femenino , Humanos , Japón/epidemiología , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Neutrófilos , Pandemias , Neumonía Viral/terapia , Respiración Artificial , Estudios Retrospectivos , Factores de Riesgo , Albúmina Sérica/análisis , Tomografía Computarizada por Rayos X , Adulto Joven
10.
Eur J Hosp Pharm ; 28(1): 22-27, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32912961

RESUMEN

BACKGROUND: In December 2019 a novel coronavirus designated SARS-CoV-2 was identified, and the disease COVID-19 has caused many deaths. SARS-CoV-2 infection has been associated with the development of cytokine storm (including interleukin 6 (IL-6)), which can cause lung damage and lack of oxygen. Tocilizumab (TCZ) inhibits ligand binding to the IL-6 receptor and may be a potential treatment for the hyperinflammation symptoms of COVID-19. However, data regarding the efficacy of TCZ in COVID-19 are lacking. The rapid spread of the pandemic in France, especially in the Paris region, constrained us to the off-label use of TCZ in patients with severe clinical conditions. METHODS: A single-centre observational cohort study of 44 patients infected with COVID-19 was carried out between 6 April and 21 April 2020 in Groupe Hospitalier Intercommunal Le Raincy-Montfermeil (GHILRM). Twenty-two patients diagnosed with COVID-19 were treated with TCZ and were compared with 22 patients not treated with TCZ matched for age, gender and length of hospital stay for COVID-19. Respiratory rate and oxygen supplementation as well as laboratory parameters (such as C-reactive protein (CRP), aspartate aminotransferase and alanine aminotransferase) were collected at baseline and during 14 days of follow-up. Our primary objective was to assess the efficacy of TCZ on respiratory clinical conditions. FINDINGS: The average respiratory rate was lower in the TCZ group than in the control group (21.5 vs 25.5 breaths/min at day 14, 95% CI -7.5 to -0.4; p=0.03). Treated patients tended to be intubated less during the course of the disease (2/22 vs 6/22, 95% CI -0.4 to 0.1; p=0.12). In each group, 10 patients no longer required oxygen therapy. We found a significant decrease in CRP in treated patients on day 7 (p=0.04). TCZ caused cytolysis in more than half (14/22) of the patients but without clinical impact. INTERPRETATION: There was a significant difference in the respiratory rate on day 14 of follow-up, with a greater decrease observed in the treated group. Fewer patients required mechanical ventilation in the TCZ group, especially among patients with more extensive CT lung damage, than in the control group. The same number of patients were weaned off oxygen on day 14 in the two groups, while the patients in the TCZ group had more severe impairment at inclusion. We consider that TCZ showed significant control of the biological inflammatory syndrome, suggesting that it may limit the effect of the cytokine storm. Our study seems to indicate the efficacy of TCZ, particularly in patients with severe initial pulmonary impairment. Selecting the best candidates and the best timing for TCZ therapy needs to be determined in randomised clinical trials.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , /tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/análisis , Estudios de Cohortes , Creatinina/sangre , Femenino , Humanos , Intubación Intratraqueal , Tiempo de Internación , Pulmón/patología , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado , Terapia por Inhalación de Oxígeno , Respiración Artificial , Frecuencia Respiratoria , Resultado del Tratamiento
11.
Biomed Pharmacother ; 133: 110825, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378989

RESUMEN

BACKGROUND: Since December 2019, COVID-19 has spread to almost every corner of the world. In theory, tocilizumab and favipiravir are considered to be reliable drugs for the treatment of COVID-19 with elevated IL-6. We aimed to assess the efficacy and safety of tocilizumab combined with favipiravir in patients with COVID-19. METHODS: This was a multicenter trial in adults with COVID-19. Patients were randomly assigned (3:1:1) to a 14-day combination of favipiravir combined with tocilizumab (combination group), favipiravir, and tocilizumab. The primary outcome was the cumulative lung lesion remission rate (lung CT examination indicated absorption of lung inflammation). RESULTS: Between Feb 2 and March 15, 2020, 26 patients were recruited; 14 were randomly assigned to the combination group, 7 were assigned to the favipiravir group and 5 were assigned to the tocilizumab group. The cumulative lung lesion remission rate at day 14 was significantly higher in combination group as compared with favipiravir group (P = 0.019, HR 2.66 95 % CI [1.08-6.53]). And there was also a significant difference between tocilizumab and favipivavir (P = 0.034, HR 3.16, 95 % CI 0.62-16.10). In addition, there was no significant difference between the combination group and the tocilizumab group (P = 0.575, HR 1.28 95 %CI 0.39-4.23). Furthermore, combined therapy can also significantly relieve clinical symptoms and help blood routine to return to normal. No serious adverse events were reported. CONCLUSION: Tocilizumab combined with or without favipiravir can effectively improve the pulmonary inflammation of COVID-19 patients and inhibit the deterioration of the disease.


Asunto(s)
Amidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Pirazinas/uso terapéutico , /efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Amidas/administración & dosificación , Amidas/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antivirales/administración & dosificación , Antivirales/efectos adversos , /patología , Quimioterapia Combinada , Femenino , Humanos , Interleucina-6/sangre , Estimación de Kaplan-Meier , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Receptores de Interleucina-6/antagonistas & inhibidores , Respiración Artificial/estadística & datos numéricos , Tamaño de la Muestra , Resultado del Tratamiento
12.
N Engl J Med ; 384(1): 20-30, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33332779

RESUMEN

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , /tratamiento farmacológico , Adulto , Anciano , /mortalidad , Progresión de la Enfermedad , Femenino , Hospitalización , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Neumonía Viral/tratamiento farmacológico , Respiración Artificial , Tasa de Supervivencia
13.
Jpn J Clin Oncol ; 51(1): 20-27, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33241322

RESUMEN

Recently, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have improved the overall survival of various types of cancers including advanced gastric cancer (AGC). Until now, two ant-PD-1 inhibitors were approved for AGC in Japan: nivolumab as third- or later-line treatment for AGC and pembrolizumab for previously treated patients with microsatellite instability-high tumours. However, a limited number of patients achieved clinical benefit, highlighting the importance of the better selection of patients or additional treatment to overcome resistance to PD-1/PD-L1 blockade. This review focused on pivotal clinical trials, biomarkers and novel combination therapy of immune checkpoint inhibitors forAGC.


Asunto(s)
/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Inmunoterapia , Inestabilidad de Microsatélites , Nivolumab/uso terapéutico , Neoplasias Gástricas/genética
14.
Med Intensiva ; 45(1): 27-34, 2021.
Artículo en Inglés, Español | MEDLINE | ID: mdl-32919796

RESUMEN

OBJECTIVE: Information from critically ill coronavirus disease 2019 (COVID-19) patients is limited and in many cases coming from health systems approaches different from the national public systems existing in most countries in Europe. Besides, patient follow-up remains incomplete in many publications. Our aim is to characterize acute respiratory distress syndrome (ARDS) patients admitted to a medical critical care unit (MCCU) in a referral hospital in Spain. DESIGN: Retrospective case series of consecutive ARDS COVID-19 patients admitted and treated in our MCCU. SETTING: 36-bed MCCU in referral tertiary hospital. PATIENTS AND PARTICIPANTS: SARS-CoV-2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal/pharyngeal swabs. INTERVENTIONS: None MAIN VARIABLES OF INTEREST: Demographic and clinical data were collected, including data on clinical management, respiratory failure, and patient mortality. RESULTS: Forty-four ARDS COVID-19 patients were included in the study. Median age was 61.50 (53.25 - 67) years and most of the patients were male (72.7%). Hypertension and dyslipidemia were the most frequent co-morbidities (52.3 and 36.4% respectively). Steroids (1mg/Kg/day) and tocilizumab were administered in almost all patients (95.5%). 77.3% of the patients needed invasive mechanical ventilation for a median of 16 days [11-28]. Prone position ventilation was performed in 33 patients (97%) for a median of 3 sessions [2-5] per patient. Nosocomial infection was diagnosed in 13 patients (29.5%). Tracheostomy was performed in ten patients (29.4%). At study closing all patients had been discharged from the CCU and only two (4.5%) remained in hospital ward. MCCU length of stay was 18 days [10-27]. Mortality at study closing was 20.5% (n 9); 26.5% among ventilated patients. CONCLUSIONS: The seven-week period in which our MCCU was exclusively dedicated to COVID-19 patients has been challenging. Despite the severity of the patients and the high need for invasive mechanical ventilation, mortality was 20.5%.


Asunto(s)
/complicaciones , /etiología , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , /mortalidad , Comorbilidad , Enfermedad Crítica , Infección Hospitalaria/epidemiología , Diabetes Mellitus/epidemiología , Dislipidemias/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Posición Prona , Respiración Artificial/métodos , Respiración Artificial/estadística & datos numéricos , Estudios Retrospectivos , España/epidemiología , Esteroides/uso terapéutico , Traqueostomía/estadística & datos numéricos
15.
Clin Nucl Med ; 46(2): e121-e122, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-32969909

RESUMEN

ABSTRACT: A 58-year-old man with previous melanoma of the left leg underwent whole-body 18F-FDG PET/CT to stage metastatic disease prior to commencing pembrolizumab. Follow-up FDG PET/CT after 3 months of treatment showed partial metabolic response of soft tissue and nodal metastases and diffuse increased thyroid and colonic uptake, suggestive of thyroiditis and colitis. Pembrolizumab was ceased, and a repeat FDG PET/CT scan showed regression of uptake in the thyroid gland and colon, in keeping with resolution of inflammatory change. Immune-related adverse events induced by Immune checkpoint inhibitors, such as pembrolizumab, should be recognized-cessation of treatment often leads to resolution.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Colitis/inducido químicamente , Colitis/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tiroiditis/inducido químicamente , Tiroiditis/diagnóstico por imagen , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Persona de Mediana Edad
16.
J Med Virol ; 93(2): 831-842, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32672860

RESUMEN

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Síndrome de Liberación de Citoquinas/prevención & control , Factores Inmunológicos/uso terapéutico , /patogenicidad , Administración Intravenosa , Adulto , Temperatura Corporal/efectos de los fármacos , Proteína C-Reactiva/metabolismo , /mortalidad , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/virología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Interferón beta/efectos adversos , L-Lactato Deshidrogenasa/sangre , Masculino , Persona de Mediana Edad , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Frecuencia Respiratoria/efectos de los fármacos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
17.
J Med Virol ; 93(2): 1023-1028, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32860432

RESUMEN

BACKGROUND: We sought to evaluate the effect of tocilizumab (TCB), a recombinant humanized monoclonal antibody against soluble interleukin-6 receptors, in patients hospitalized for coronavirus disease 2019 (COVID-19). METHODS: We included all patients with laboratory-confirmed COVID-19 who had completed hospitalization between March 10, 2020 and April 10, 2020 with follow-up through April 20, 2020. Patients who received TCB in addition to standard of care within 48 h of admission were matched in a 1:2 fashion to a similar cohort who received standard of care alone. Clinical outcomes were compared between matched groups. The primary outcome was de-escalation in oxygen therapy. Secondary outcomes were in-hospital death, septic shock, and acute kidney injury (AKI) requiring hemodialysis. RESULTS: Out of 77 patients who received TCB in addition to standard of care, 34% (n = 26) received TCB within 48 h of admission. One-to-two propensity matching identified 20 versus 40 patients in the TCB and no-TCB treatment arms. In the TCB group, an improvement in oxygenation was observed in 80% (n = 16) of the patients by 7 days post TCB administration. After matching, there was no difference in clinical outcomes between TCB and no-TCB patients. In-hospital death: 10% versus 8%; p = .823, septic shock: 10% versus 11%, p = .912, AKI requiring hemodialysis (10% vs. 13%; p = .734). CONCLUSIONS: Early treatment with TCB in patients admitted for COVID-19 led to an improvement in their oxygen status during hospitalization. This change however did not translate into improved survival when compared to a matched cohort with a similar clinical profile.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , /terapia , Hospitalización/estadística & datos numéricos , Lesión Renal Aguda/virología , Adulto , Anciano , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Diálisis Renal , Estudios Retrospectivos , Choque Séptico/virología , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
19.
JAMA Intern Med ; 181(1): 41-51, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33080002

RESUMEN

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Mortalidad Hospitalaria , Insuficiencia Respiratoria/terapia , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anticoagulantes/uso terapéutico , Estudios de Cohortes , Enfermedad Crítica , Intervención Médica Temprana , Femenino , Hospitalización , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Mortalidad , Puntuaciones en la Disfunción de Órganos , Posicionamiento del Paciente , Posición Prona , Modelos de Riesgos Proporcionales , Receptores de Interleucina-6/antagonistas & inhibidores , Respiración Artificial , Insuficiencia Respiratoria/fisiopatología , Adulto Joven
20.
JAMA Intern Med ; 181(1): 24-31, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33080005

RESUMEN

Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, Setting, and Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main Outcome and Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos/estadística & datos numéricos , Respiración Artificial/estadística & datos numéricos , Insuficiencia Respiratoria/terapia , Anciano , Análisis de los Gases de la Sangre , Proteína C-Reactiva/metabolismo , /fisiopatología , Progresión de la Enfermedad , Terminación Anticipada de los Ensayos Clínicos , Femenino , Fiebre , Hospitalización , Humanos , Italia , Masculino , Inutilidad Médica , Persona de Mediana Edad , Receptores de Interleucina-6/antagonistas & inhibidores , Insuficiencia Respiratoria/fisiopatología
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