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5.
J Popul Ther Clin Pharmacol ; 27(S Pt 1): e14-e25, 2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32650355

RESUMO

COVID-19 disease is the most recent pandemic, since it has affected more than four and a half million people and caused more than 300,000 deaths. It is a very complex systemic disease in terms of pathogenesis, treatment, and prognosis. Pharmacological treatment may include antiviral and antimalarial drugs, antibiotics, monoclonal antibodies, corticosteroids as well as low-molecular-weight heparins to prevent the evolution of the disease from reaching the severe inflammatory phase that can lead to respiratory complications, multiple organ failure, disseminated intravascular coagulation (DIC), and finally death. Therefore, pending the development of the much sought-after vaccine, there needs to be a multidisciplinary approach to tackling this disease, and it is essential to use different medical treatments at the correct pathogenic moment. The aim of this article is to evaluate the rationale and reason behind the use of antirheumatic drugs, by expert point of view, in the various phases of the disease. Another important aspect in the management of the disease is to identify patients at high risk, both to change their lifestyle and to correct the state of their health through non-pharmacological measures for improving their immuno-balance. Our literature review reveals the important role and the therapeutic potential of antirheumatic agents in preventing the progression of the disease and aiding recovery from the disease. However, there is a lack of clinical evidence to support the use of these agents, indicating that further randomized controlled studies are required.


Assuntos
Antirreumáticos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antimaláricos/uso terapêutico , Infecções por Coronavirus/patologia , Humanos , Pandemias , Pneumonia Viral/patologia
8.
Dermatol Online J ; 26(3)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32609449

RESUMO

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon skin condition that can be inherited or may occur sporadically with multiple red-brown, thin plaques in a photodistribution. The condition more often affects middle-aged women and is often recalcitrant to therapy. In rare literature reports, systemic medications can trigger exacerbation or promote inflammation in pre-existing lesions of DSAP. We present a novel case of chemotherapy-associated DSAP inflammation in a 66-year-old woman after triple therapy with durvalumab (PD-L1 inhibitor), olaparib (PARP inhibitor) and paclitaxel, showing similarities to primary lichen planus-like eruption from immune checkpoint inhibitors.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inflamação/diagnóstico , Erupções Liquenoides/diagnóstico , Paclitaxel/efeitos adversos , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Poroceratose/patologia , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Diagnóstico Diferencial , Erupção por Droga , Feminino , Humanos , Inflamação/induzido quimicamente , Poroceratose/complicações , Pele/patologia
10.
Cell Rep ; 32(3): 107918, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32668215

RESUMO

Coronavirus disease 2019 (COVID-19) has become a worldwide threat to humans, and neutralizing antibodies have therapeutic potential. We have purified more than 1,000 memory B cells specific to SARS-CoV-2 S1 or its RBD (receptor binding domain) and obtain 729 paired heavy- and light-chain fragments. Among these, 178 antibodies test positive for antigen binding, and the majority of the top 17 binders with EC50 below 1 nM are RBD binders. Furthermore, we identify 11 neutralizing antibodies, eight of which show IC50 within 10 nM, and the best one, 414-1, with IC50 of 1.75 nM. Through epitope mapping, we find three main epitopes in RBD recognized by these antibodies, and epitope-B antibody 553-15 could substantially enhance the neutralizing abilities of most of the other antibodies. We also find that 515-5 could cross neutralize the SARS-CoV pseudovirus. Altogether, our study provides 11 potent human neutralizing antibodies for COVID-19 as therapeutic candidates.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Receptores Virais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Infecções por Coronavirus/terapia , Mapeamento de Epitopos , Epitopos/imunologia , Humanos , Memória Imunológica/imunologia , Testes de Neutralização , Pandemias , Pneumonia Viral/terapia , Domínios Proteicos/imunologia
11.
Anticancer Res ; 40(7): 3793-3799, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620618

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer worldwide. Our study focused on the axon guidance receptor roundabout guidance receptor 1 (ROBO1) as a target for monoclonal antibody therapy of HNSCC. We previously showed that saporin-conjugated anti-ROBO1 (B5209B) immunotoxin (IT-ROBO1) enhanced cytotoxic effects on HNSCC cells in combination with the photosensitizer aluminum phthalocyanine disulphonate (AlPcS2a) and illumination. We examined the effects of this combination therapy in a mouse xenograft model. MATERIALS AND METHODS: IT-ROBO1 was intraperitoneally administered to HSQ-89 (derived from Japanese maxillary sinus squamous carcinoma, RCB0789; RIKEN, Tsukuba, Japan) xenografted mice. After 3 days, AlPcS2a was injected subcutaneously around the tumor and the area was illuminated at 650 nm for 30 min. The growth of the tumor was evaluated and the effects on the tumor were examined. RESULTS: Pronounced anti-tumor effects were elicited by the administration of IT-ROBO1 and AlPcS2a with light illumination on tumor size and pathological characteristics. CONCLUSION: The results showed that photosensitizer treatment with illumination robustly enhanced the antitumor effect of the IT-ROBO1 immunotoxin.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunotoxinas/metabolismo , Seio Maxilar/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Receptores Imunológicos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Seio Maxilar/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bull Cancer ; 107(5S): S6-S16, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620209

RESUMO

Until 2014, no new therapeutic agent have been approved by authorities in more than 2 decades for bladder cancer. But the panel of treatments has expended in recent years with the emergence of at least 3 different therapeutic classes. First, the immune checkpoint inhibitors that have demonstrated an overall survival benefit in metastatic patients after failure of platinum based chemotherapy. They are therefore currently evaluated alone or in combination with chemotherapy in multiple studies at earlier stages (localized and meta-static). The second and third therapeutic classes are the targeted therapies (especially FGFR inhibitor) and the antibody-drug conjugates with promising results in early clinical trials. In this article, we review all the current and future studies conducted in urothelial carcinoma of the bladder.


Assuntos
Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Carcinoma de Células de Transição/secundário , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Terapias em Estudo
13.
Bull Cancer ; 107(5S): eS8-eS15, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620213

RESUMO

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. METHODS/DESIGN: NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. DISCUSSION: NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Terapia Neoadjuvante , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/uso terapêutico
15.
Medicine (Baltimore) ; 99(28): e21273, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664183

RESUMO

BACKGROUND: The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors. OBJECTIVE: To evaluate the efficacy and safety of durvalumab in combination with tremelimumab compared with either drug alone. METHODS: The online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) were searched for potential clinical studies up to Nov 26, 2019. Eligible studies were prospective and registered clinical trials. Pooled odds ratios for objective response rate and disease control rate and pooled risk ratios for treatment-related adverse events were meta-analyzed. A random-effect model was used due to the synthesis of different cancer types. RESULTS: Overall, 5 studies were eligible for systematic review, 3 of which were further meta-analyzed. Durvalumab plus tremelimumab was superior to tremelimumab monotherapy in improving disease control rate in head and neck squamous cell carcinoma. However, there were no significant differences between dual immunotherapy and mono-immunotherapy in pancreatic ductal adenocarcinoma and gastric and gastroesophageal junction adenocarcinoma. Additionally, pooled analyses illustrated that no significant differences in treatment-related adverse events were displayed between the 2 groups. CONCLUSION: Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
16.
Lancet ; 396(10245): 147-148, 2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32682464
17.
Euro Surveill ; 25(28)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32700671

RESUMO

BackgroundA novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2.AimThe cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed.MethodsThe SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein.ResultsAn immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format.ConclusionThe cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.


Assuntos
Anticorpos Monoclonais/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Sequência de Aminoácidos , Animais , Betacoronavirus/genética , Western Blotting , Células COS , Chlorocebus aethiops , Sequência Conservada , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Reações Cruzadas/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Imunofluorescência/métodos , Genoma Viral , Camundongos , Pandemias , Peptidil Dipeptidase A/imunologia , Plasmídeos , Pneumonia Viral/genética , Proteínas Recombinantes/imunologia , Vírus da SARS/genética , Alinhamento de Sequência , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Transfecção , Células Vero , Integração Viral
18.
Lancet ; 396(10245): 186-197, 2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32682484

RESUMO

BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile. FUNDING: Amgen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Doença Crônica , Dexametasona/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Resultado do Tratamento , Adulto Jovem
19.
J Exp Med ; 217(11)2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32692348

RESUMO

The emergence of SARS-CoV-2 and the ensuing explosive epidemic of COVID-19 disease has generated a need for assays to rapidly and conveniently measure the antiviral activity of SARS-CoV-2-specific antibodies. Here, we describe a collection of approaches based on SARS-CoV-2 spike-pseudotyped, single-cycle, replication-defective human immunodeficiency virus type-1 (HIV-1), and vesicular stomatitis virus (VSV), as well as a replication-competent VSV/SARS-CoV-2 chimeric virus. While each surrogate virus exhibited subtle differences in the sensitivity with which neutralizing activity was detected, the neutralizing activity of both convalescent plasma and human monoclonal antibodies measured using each virus correlated quantitatively with neutralizing activity measured using an authentic SARS-CoV-2 neutralization assay. The assays described herein are adaptable to high throughput and are useful tools in the evaluation of serologic immunity conferred by vaccination or prior SARS-CoV-2 infection, as well as the potency of convalescent plasma or human monoclonal antibodies.


Assuntos
Anticorpos Neutralizantes/análise , Anticorpos Antivirais/análise , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunoensaio/métodos , Pneumonia Viral/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/genética , Linhagem Celular , Quimera/genética , Quimera/imunologia , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Células HEK293 , HIV-1/genética , HIV-1/imunologia , Humanos , Testes de Neutralização/métodos , Pandemias , Pneumonia Viral/virologia , Recombinação Genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/imunologia
20.
Int J Med Sci ; 17(12): 1803-1810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714083

RESUMO

Since the end of 2019, a new type of coronavirus pneumonia (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout the world. Previously, there were two outbreaks of severe coronavirus caused by different coronaviruses worldwide, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This article introduced the origin, virological characteristics and epidemiological overview of SARS-CoV-2, reviewed the currently known drugs that may prevent and treat coronavirus, explained the characteristics of the new coronavirus and provided novel information for the prevention and treatment of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Cloroquina/análogos & derivados , Cloroquina/uso terapêutico , Clorpromazina/uso terapêutico , Coronavirus/genética , Infecções por Coronavirus/genética , Ciclofilinas/antagonistas & inibidores , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Medicamentos de Ervas Chinesas/uso terapêutico , Endocitose/efeitos dos fármacos , Humanos , Soros Imunes , Indutores de Interferon/uso terapêutico , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Pneumonia Viral/genética , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Vacinas Virais/uso terapêutico
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