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1.
s.l; CONETEC; mar. 2021.
No convencional en Español | BRISA/RedTESA | ID: biblio-1151444

RESUMEN

INTRODUCCIÓN: En Argentina, cada año se presentan aproximadamente 1.400 casos nuevos y mueren 550 personas por melanoma; en 2011 y 2015 se estimaron entre 2,2 y 1,3 años de vida potenciales perdidos ajustados por edad/10.000 habitantes (para varones y mujeres respectivamente) por melanoma para nuestro país. Los factores de riesgo para el melanoma incluyen el tipo de piel, antecedentes de melanoma previo, múltiples lunares clínicamente atípicos o nuevos displásicos, antecedentes familiares de melanoma y, raramente, mutaciones genéticas hereditarias. El pronóstico es muy bueno para pacientes que presentan enfermedad localizada y tumores primarios de 1 mm o menos de grosor, con una supervivencia a 5 años alcanzada en más del 90% de los pacientes. Para pacientes con melanomas localizados de más de 1 mm de grosor, las tasas de supervivencia varían de 50% a 90%, dependiendo del grosor del tumor, la ulceración y la frecuencia mitótica. Para pacientes en estadio III, las tasas de supervivencia a 5 años varían de 20% a 70%, dependiendo principalmente de la carga tumoral nodal. La supervivencia a largo plazo en pacientes con melanoma metastásico distante (estadio IV) ha sido inferior al 10%. DESCRIPCIÓN DE LA TECNOLOGÍA: El pembrolizumab, al igual que nivolumab, es un anticuerpo monoclonal que actúa como un inhibidor del punto de control inmunológico al unirse al receptor de PD-1 en las células T y bloquear la interacción de PD-1 con ligandos de PD-1. OBJETIVO: El objetivo de este documento es evaluar la eficacia, seguridad, recomendaciones y aspectos económicos de pembrolizumab en primera línea para melanoma avanzado, metastásico o irresecable, sin mutación BRAF. METODOLOGÍA: Se realizó un meta-análisis en red de elaboración propia a partir de cinco ensayos controlados aleatorizados, y se incluyeron tres guías de práctica clínica, trece políticas de cobertura, tres evaluaciones de tecnologias sanitarias, un análisis de costo-efectividad y se elaboró un análisis de impacto presupuestario con datos de nuestro país para responder las preguntas de investigación. RESULTADOS: Luego de realizar la estrategia de búsqueda exhaustiva de estudios siguiendo los criterios estabelecidos en el apartado metodológico, se procedió a la eliminación de artículos que no cumplían con los critérios de interés planteados en la pregunta PICO, tanto a través de la lectura del título y del resumen (en uma primera instancia) como de la lectura crítica completa de los trabajos potencialmente relevantes (segunda instancia). Debido a la falta de comparaciones directas entre algunos tratamientos para los estudios incluidos, o bien dado que los meta-análisis en red no utilizaron GRADE para la valoración de la calidad de la evidencia, se decidió realizar un meta-análisis en red de elaboración propia para algunas comparaciones. Se seleccionaron finalmente para el reporte un total de cinco ensayos controlados aleatorizados, tres guías de práctica clínica, trece políticas de cobertura, tres evaluaciones de tecnologías sanitarias y un análisis de costo-efectividad. CONCLUSIONES: El grupo de trabajo concluyó que pembrolizumab probablemente reduce la mortalidad de manera significativa en comparación con dacarbazina, mientras que es incierto si tiene menos efectos adversos en comparación con este estándar. Pembrolizumab reduce significativamente la mortalidad, aunque podría tener mayores efectos adversos en comparación con monoterapia con ipilimumab. La magnitude del beneficio sobre la mortalidad con pembrolizumab parece ser similar a la obtenida con nivolumab y podría tener menores efectos adversos. Al analizar la comparación de pembrolizumab con la combinación de nivolumab + ipilimumab, se concluyó que ambas opciones son similares en cuanto al efecto sobre la mortalidad, pero es probable que la asociación de nivolumab con ipilimumab se asocie a mayor tasa de efectos adversos. Un estudio de costo-efectividad del Instituto Nacional del Cáncer de Argentina estimó que, considerando el umbral de costo efectividad propuesto por la Organización Mundial de la Salud (de baja aceptabilidad como referencia en la actualidad), existiría una probabilidad del 73% que pembrolizumab o nivolumab sea costo-efectivo en nuestro país en la indicación evaluada: sin embargo, remarca que este resultado puede no ser válido para toda Argentina debido a la inequidad existente entre las provincias. El análisis de impacto presupuestario de elaboración propia dio como resultado un incremento de los costos para la inclusión de pembrolizumab o nivolumab solo o combinado e ipilimumab. Las guías de práctica clínica de las principales sociedades científicas internacionales y una guía nacional recomiendan el tratamiento con pembrolizumab en la indicación evaluada como una opción, al igual que nivolumab solo y combinado con ipilimumab. Respecto a políticas de cobertura, todos los países de altos ingresos y sólo dos países de Latinoamérica relevados brindan cobertura a pembrolizumab en la indicación evaluada.


Asunto(s)
Humanos , Melanoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Evaluación de la Tecnología Biomédica , Análisis Costo-Beneficio
2.
Nat Commun ; 12(1): 1891, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767178

RESUMEN

Monoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , Enfermedad del Virus de Marburg/tratamiento farmacológico , Marburgvirus/efectos de los fármacos , Adenosina Monofosfato/uso terapéutico , Alanina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Macaca mulatta , Enfermedad del Virus de Marburg/prevención & control , Carga Viral/efectos de los fármacos
3.
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
5.
Adv Exp Med Biol ; 1286: 49-64, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33725344

RESUMEN

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer worldwide. It metastasizes rapidly and has a poor prognosis. The first-line treatment for most patients is a combination of chemotherapy and radiation. In many subjects, using targeted treatments alongside chemoradiation has shown a better outcome in terms of progression and quality of life for patients. These targeted treatments include small biological inhibiting molecules and monoclonal antibodies. In this review, we have assessed studies focused upon the treatment of non-small cell lung cancer. Some therapies are approved, such as bevacizumab and atezolizumab, while some are still in clinical trials, such as ficlatuzumab and ipilimumab, and others have been rejected due to inadequate disease control, such as figitumumab.


Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Calidad de Vida
6.
Sheng Wu Gong Cheng Xue Bao ; 37(2): 513-529, 2021 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-33645152

RESUMEN

Bispecific antibody (BsAb) has two different antigen-binding sites, divided into the "IgG-like" format and the "non-IgG-like" format. Different formats have different characteristics and applications. BsAb has higher sensitivity and specificity than conventional antibodies, with special functions such as recruitment of immune cells and blocking of dual signaling pathways, playing an important role in immune-diagnosis and therapy. With the deterioration of the global environment and the irregular living habits of people, the incidence of tumor is becoming higher and higher. Tumor becomes the most serious fatal disease threatening human health after cardiovascular disease. There are 12 million estimated new tumor cases each year worldwide. The major clinical treatments of tumor are surgical resection, chemoradiotherapy, target therapy. Tumor immunotherapy is a novel approach for tumor treatment in recent years, and activates human immune system to control and kill tumor cells. Although the traditional monoclonal antibodies have already acquired some therapeutic effects in tumor targeted therapy and immunotherapy, they induce drug resistance resulted from the heterogeneity and plasticity of tumors. Binding to two target antigens at the same time, BsAb has been used in the clinical treatment of tumors and obtained promising outcomes. This review elaborates the research progress and applications of bispecific antibody in clinical tumor therapy.


Asunto(s)
Anticuerpos Biespecíficos , Neoplasias , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Humanos , Inmunoterapia , Neoplasias/terapia
8.
Medicine (Baltimore) ; 100(9): e24372, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33655912

RESUMEN

RATIONALE: Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody. PATIENT CONCERNS: A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia. DIAGNOSIS: Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed. INTERVENTIONS: The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26. OUTCOMES: Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life. CONCLUSION: Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Dipeptidil Peptidasa 4/inmunología , Inhibidores de la Dipeptidil-Peptidasa IV/inmunología , Inmunoglobulina G/inmunología , Dermatomiositis/inmunología , Humanos , Masculino , Persona de Mediana Edad
9.
N Engl J Med ; 384(11): 1003-1014, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33730454

RESUMEN

BACKGROUND: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 µg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos ampliamente neutralizantes/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , VIH-1 , Adolescente , Adulto , África del Sur del Sahara/epidemiología , Américas/epidemiología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos ampliamente neutralizantes/efectos adversos , Método Doble Ciego , Europa (Continente)/epidemiología , Femenino , Anticuerpos Anti-VIH/efectos adversos , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , Humanos , Incidencia , Masculino , Prueba de Estudio Conceptual , Adulto Joven
10.
Adv Exp Med Biol ; 1303: 1-12, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33788184

RESUMEN

The mechanisms driving corticosteroid insensitivity in asthma are still unclear although evidence points toward a potential role of lung mast cells. Indeed, a number of in vitro studies using various cell types showed that different mediators produced by activated mast cells, including cytokines, have the capacity to interfere with the therapeutic action of corticosteroids. In patients with severe allergic refractory asthma, the anti-IgE monoclonal antibody (mAb), Omalizumab, has been shown to be associated with a marked reduction in inhaled and systemic use of corticosteroids, further suggesting a key role of mast cells in the poor response of patients to these drugs. The present chapter will discuss the possible underlying mechanisms by which mast cells could contribute to reducing corticosteroid sensitivity seen in patients with severe asthma.


Asunto(s)
Asma , Mastocitos , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Asma/tratamiento farmacológico , Humanos
12.
BMC Neurol ; 21(1): 77, 2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33596839

RESUMEN

BACKGROUND: Cerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations. METHODS: We performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks. RESULTS: We identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months. CONCLUSIONS: Single-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Bevacizumab/administración & dosificación , Edema Encefálico/tratamiento farmacológico , Lesiones Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Encéfalo/patología , Traumatismos por Radiación/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Bevacizumab/uso terapéutico , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/etiología , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/etiología , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Dexametasona/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Glioma/radioterapia , Glucocorticoides/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Necrosis , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
14.
Int J Mol Sci ; 22(4)2021 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-33572274

RESUMEN

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become a worldwide pandemic. Symptoms range from mild fever to cough, fatigue, severe pneumonia, acute respiratory distress syndrome (ARDS), and organ failure, with a mortality rate of 2.2%. However, there are no licensed drugs or definitive treatment strategies for patients with severe COVID-19. Only antiviral or anti-inflammatory drugs are used as symptomatic treatments based on clinician experience. Basic medical researchers are also trying to develop COVID-19 therapeutics. However, there is limited systematic information about the pathogenesis of COVID-19 symptoms that cause tissue damage or death and the mechanisms by which the virus infects and replicates in cells. Here, we introduce recent knowledge of time course changes in viral titers, delayed virus clearance, and persistent systemic inflammation in patients with severe COVID-19. Based on the concept of drug reposition, we review which antiviral or anti-inflammatory drugs can effectively treat COVID-19 patients based on progressive symptoms and the mechanisms inhibiting virus infection and replication.


Asunto(s)
/patología , /metabolismo , Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Humanos , /fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Carga Viral , Internalización del Virus
18.
Ann Hematol ; 100(4): 1065-1077, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33599794

RESUMEN

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Grupo de Ascendencia Continental Asiática/psicología , Peso Corporal , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Subcutáneas , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/etnología , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Neutropenia/inducido químicamente , Satisfacción del Paciente , Supervivencia sin Progresión , República de Corea/epidemiología , Taiwán/epidemiología , Adulto Joven
19.
Lancet Haematol ; 8(4): e254-e266, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33631112

RESUMEN

BACKGROUND: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. METHODS: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. FINDINGS: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. INTERPRETATION: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. FUNDING: TG Therapeutics.


Asunto(s)
Adenina/análogos & derivados , Anticuerpos Monoclonales/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/uso terapéutico , Administración Intravenosa , Administración Oral , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Israel/epidemiología , Masculino , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Seguridad , Resultado del Tratamiento , Estados Unidos/epidemiología
20.
Food Chem Toxicol ; 150: 112087, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33640537

RESUMEN

Coronavirus disease-19 (COVID-19) is a complex disease that causes illness ranging from mild to severe respiratory problems. It is caused by a novel coronavirus SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2) that is an enveloped positive-sense single-stranded RNA (+ssRNA) virus belongs to coronavirus CoV family. It has a fast-spreading potential worldwide, which leads to high mortality regardless of lows death rates. Now some vaccines or a specific drug are approved but not available for every country for disease prevention and/or treatment. Therefore, it is a high demand to identify the known drugs and test them as a possible therapeutic approach. In this critical situation, one or more of these drugs may represent the only option to treat or reduce the severity of the disease, until some specific drugs or vaccines will be developed and/or approved for everyone in this pandemic. In this updated review, the available repurpose immunotherapeutic treatment strategies are highlighted, elucidating the crosstalk between the immune system and SARS-CoV-2. Despite the reasonable data availability, the effectiveness and safety of these drugs against SARS-CoV-2 needs further studies and validations aiming for a better clinical outcome.


Asunto(s)
Antivirales/farmacología , Inflamación/etiología , /efectos de los fármacos , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , /inmunología , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interferones/farmacología , Interferones/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , /inmunología
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