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1.
J Drugs Dermatol ; 18(10): 1047, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603633

RESUMO

To the Editor: Acrodermatitis continua of Hallopeau (ACH) is a relatively rare chronic disorder with clinical findings of pustules and erythematous plaques on the digits.1 Although it is a variant of pustular psoriasis, it can be resistant to multiple lines of therapy. We describe for the first time a patient with recalcitrant ACH successfully treated with brodalumab, an interleukin-17 receptor A (IL-17RA) blocking antibody.


Assuntos
Acrodermatite/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Acrodermatite/imunologia , Anticorpos Monoclonais Humanizados , Esquema de Medicação , Resistência a Medicamentos , Dedos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Resultado do Tratamento
2.
Anticancer Res ; 39(10): 5645-5652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570462

RESUMO

BACKGROUND/AIM: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. PATIENTS AND METHODS: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. RESULTS: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). CONCLUSION: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Panitumumabe/administração & dosagem
3.
Expert Opin Investig Drugs ; 28(11): 931-940, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31549891

RESUMO

Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.


Assuntos
Antiasmáticos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Asma/tratamento farmacológico , Adolescente , Adulto , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Asma/imunologia , Asma/fisiopatologia , Citocinas/imunologia , Humanos , Índice de Gravidade de Doença
4.
Lancet ; 394(10200): 793-804, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31478503

RESUMO

Antibody-drug conjugates (ADCs) are immunoconjugates comprised of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. The ADC is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, five ADCs have received market approval and over 100 are being investigated in various stages of clinical development. In this Therapeutics paper, we review recent clinical experience with the approved ADCs and other promising late-stage candidates on the horizon, following an overview of the biology and chemistry of ADCs and how the individual components of an ADC (antibody [or target], linker and conjugation chemistry, and cytotoxic payload) influence its activity. We briefly discuss opportunities for enhancing ADC efficacy, drug resistance, and future perspectives for this novel antibody-based molecular platform, which has great potential to make a paradigm shift in cancer chemotherapy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Imunoconjugados , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia
5.
Expert Opin Drug Saf ; 18(11): 1031-1041, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479282

RESUMO

Introduction: Psoriasis is a chronic inflammatory disease and affects about 10% of the world's population. Psoriasis is associated with a number of comorbidities. Biologic therapies for the treatment of moderate-severe plaque psoriasis include tumor necrosis factor α inhibitors (TNFi), and newer molecules targeting IL-12 and 23, blocking p40 subunit, or targeting subunit p19 of IL-23 and other molecules blocking IL-17A, or directed against the IL-17 receptor. Areas covered: Anti-interleukin drugs show great improvement in disease control and on the other hand are not affected by important adverse reactions of older compounds. Approach to chronic disease affected patients, in particular, and to patients with multiple comorbidities is revolutionized by novel molecules that are safer and more manageable. Expert opinion: A recent work suggests that pro-fibrogenic cytokines, IL-17, might be important player of liver damage and even in regulation of obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Choosing to interfere with IL-23/Il-17 axis, definitely, is like acting against psoriatic march and in a parallel way against its comorbidities.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Produtos Biológicos/imunologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/imunologia , Humanos , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença
7.
J Drugs Dermatol ; 18(9): 940-942, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31524352

RESUMO

Prurigo nodularis (PN) is a disease in which chronic scratching and picking of the skin due to intense pruritis results in papulonodules, notably in areas that are accessible to the patient. The pathophysiology is hypothesized to be mediated by a Th2 helper cell response, similar to that seen in atopic dermatitis, therefore, treatment of PN with dupilumab would be expected to elicit a therapeutic response. We demonstrated that treatment of PN with dupilumab significantly decreased pruritis and the size and number of new lesions after 2 months of treatment. J Drugs Dermatol. 2019;18(9):940-942.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Prurigo/tratamento farmacológico , Prurido/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Injeções Subcutâneas , Prurigo/diagnóstico , Prurigo/patologia , Prurido/diagnóstico , Prurido/patologia , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento
8.
Expert Rev Clin Pharmacol ; 12(10): 947-951, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31524530

RESUMO

Introduction: In September of 2018, the United States Federal Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for advanced cutaneous squamous cell carcinoma (CSCC). Cemiplimab is an intravenous human monoclonal antibody directed against programmed cell death-1 receptor (PD-1). Cemiplimab blocks T-cell inactivation and enhances the immune system's anti-tumor response. Areas Covered: We review CSCC and the studies leading to cemiplimab's approval, including common side effects and safety issues experienced during the clinical trials. Expert Opinion: Immunotherapy, specifically checkpoint inhibitors, represents an increasingly utilized class of medications that is proving to be an effective treatment option for those with certain cancers. Over time, immunotherapy is likely to be the standard of care for immune-sensitive tumors. There are many challenges that the field faces, including the identification of reliable biomarkers to better predict response, decreasing toxicity, and the potential treatment of organ transplant patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Resultado do Tratamento
9.
Expert Opin Investig Drugs ; 28(10): 821-826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526130

RESUMO

Introduction: The conventional management of most patients with metastatic urothelial carcinoma (UC) is platinum-based chemotherapy followed by immunotherapy. Erdafitinib is an option in post-platinum patients with activating mutations in fibroblast growth factor receptor (FGFR)-3 and -2. Salvage therapy with taxanes or vinflunine has demonstrated minimal efficacy. Enfortumab Vedotin (EV), a monoclonal antibody-drug conjugate (ADC) targeting nectin-4 is under investigation in patients with advanced UC. Areas covered: This review describes the epidemiology and unmet needs of patients with metastatic UC and is focused specifically on heavily treated patients. We explore the rationale for targeting nectin 4 and the clinical development of EV; efficacy and safety data from the completed phase I and II studies are examined. Ongoing trials to definitively assess clinical outcomes in comparison to current therapy and trials exploring EV in combination are also highlighted. Expert opinion: There is an unmet need for new therapies in most patients with advanced UC and who progress after platinum and immunotherapy. EV has shown promising efficacy and safety in this population in phase 1 and 2 trials including those with poor prognostic factors such as liver metastases. Ongoing trials exploring this agent in combination will continue to advance the treatment of UC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/imunologia , Moléculas de Adesão Celular/imunologia , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Imunoterapia/métodos , Metástase Neoplásica , Oligopeptídeos/imunologia , Prognóstico , Neoplasias Urológicas/imunologia
10.
Anticancer Res ; 39(9): 4987-4993, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519605

RESUMO

BACKGROUND/AIM: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment. PATIENTS AND METHODS: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history. RESULTS: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients. CONCLUSION: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Docetaxel/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
11.
Anticancer Res ; 39(9): 5165-5170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519629

RESUMO

BACKGROUND/AIM: Daratumumab is a promising novel agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its efficacy and toxicity profiles in real-world patients, especially in the Asian population. PATIENTS AND METHODS: This was a multicenter, retrospective, longitudinal cohort study set between January 2017 and April 2019. We collected and analyzed clinical and survival data of 21 patients treated with daratumumab monotherapy. All patients were previously exposed to proteasome inhibitors and immunomodulatory drugs. RESULTS: The overall response rate was 42.1%, including one complete remission (4.8%) and three very good partial responses (14.3%). The cycles of daratumumab delivered were three (range=1-10 cycles) and the median progression-free survival was 6 months, while the overall survival was not reached. Infusion reaction was observed in nine patients (42.9%), and one discontinued permanently. Fatigue was the most common adverse event (52.4%), and there were five cases of documented infection during daratumumab treatment, two of them leading to the death of the patient. CONCLUSION: Daratumumab monotherapy showed fairly promising activity with modest tolerance in heavily treated Asian RRMM patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ásia , Linhagem Celular Tumoral , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
13.
Lancet ; 394(10201): 831-839, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31402114

RESUMO

BACKGROUND: Antibodies targeting interleukin (IL)-23 and IL-17A effectively treat moderate-to-severe psoriasis. ECLIPSE is the first comparator study of an IL-23p19 inhibitor, guselkumab, versus an IL-17A inhibitor, secukinumab. The primary objective of this study was to show superiority of clinical response at week 48 for guselkumab versus secukinumab. METHODS: In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA), eligible patients were aged 18 years or older, had moderate-to-severe plaque-type psoriasis, and were candidates for phototherapy or systemic therapy. Eligible patients were randomly assigned with permuted block randomisation using an interactive web response system to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks). The primary endpoint, the proportion of patients in the intention-to-treat population who achieved 90% reduction or more from baseline of Psoriasis Area and Severity Index (PASI 90 response) at week 48, and major secondary endpoints (the proportions of patients in the guselkumab group and in the secukinumab group who achieved a PASI 75 response at both weeks 12 and 48, a PASI 90 response at week 12, a PASI 75 response at week 12, a PASI 100 response at week 48, an Investigator's Global Assessment [IGA] score of 0 [cleared] at week 48, and an IGA score of 0 or 1 [minimal] at week 48) were to be tested in a fixed sequence to control type I error rate. Safety was evaluated in patients who received one or more doses of study drug from week 0 to 56. The study is registered with ClinicalTrials.gov, NCT03090100. FINDINGS: This study was done between April 27, 2017, and Sept 20, 2018. 1048 eligible patients were enrolled and, of these, 534 were assigned to receive guselkumab and 514 to receive secukinumab. The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p<0·0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p=0·0616). Consequently, formal statistical testing was not done for subsequent major secondary endpoints. Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations. INTERPRETATION: Guselkumab showed superior long-term efficacy based on PASI 90 at week 48 when compared with secukinumab for treating moderate-to-severe psoriasis. This finding could assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis. FUNDING: This study was funded by Janssen Research & Development.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Produtos Biológicos/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Produtos Biológicos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
14.
Hautarzt ; 70(9): 684-690, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31468071

RESUMO

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer in which Merkel cell polyomavirus infection and chronic exposure to ultraviolet radiation are key risk factors. Immune checkpoint inhibition has revolutionized the treatment of locally advanced, inoperable and metastatic MCC. AIM: To outline the modern management of MCC based on advances in our understanding of MCC tumour biology and the development of immune checkpoint inhibitors, namely inhibitors of programmed cell death protein (PD)-1- and PD­1 ligand 1 (PD-L1). METHODS: A review of the scientific literature listed in PubMed. RESULTS: First line therapy with the PD-L1 blocking antibody avelumab is associated with a response rate of 62%. In the second line setting, for example after chemotherapy, the response rate only reaches 33%. However, in patients who responded in the second line setting, 69% remained relapse free after 2 years. Treatment responses occurred on average after 6.1 weeks of therapy. First line treatment with pembrolizumab (anti-PD­1 antibody) is associated with a 2-year survival rate of 69% and the median survival rate has not been reached. Whilst the various chemotherapy regimens are associated with similar response rates, these are typically short lived. DISCUSSION: Checkpoint inhibition offers an effective treatment option for patients with MCC. Avelumab is currently licensed as a treatment for metastatic disease. Chemotherapy remains an option to reduce tumor load, or in the context of resistance and/or contraindications to immune checkpoint therapy. Adjuvant and neoadjuvant use of checkpoint inhibition in MCC may represent a future treatment strategy pending the results of on-going clinical trials.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Célula de Merkel/patologia , Humanos , Recidiva Local de Neoplasia , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Raios Ultravioleta
15.
J Drugs Dermatol ; 18(8): 804-813, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424712

RESUMO

Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week 16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator's Global Assessment and pain or discomfort assessed by the European Quality of Life-5 Dimensions 3 level questionnaire. A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints. Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups. Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White, Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications. ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Adulto , Afro-Americanos/estatística & dados numéricos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Dermatite Atópica/diagnóstico , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
16.
J Drugs Dermatol ; 18(8): 822-823, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424714

RESUMO

Guttate psoriasis is an acute subtype of plaque psoriasis characterized by eruption of small, scaly plaques, and papules, 5 to 10 mm in size over the trunk and proximal extremities.1 It often arises in children and young adults concomitantly with or shortly after a streptococcal throat infection or tonsillitis. Patients with chronic plaque psoriasis can also experience guttate flares following streptococcal throat infections.1,2 Controlling guttate psoriasis with topical corticosteroids is difficult to achieve due to numerous widespread lesions. Other treatment options include phototherapy and short term use of cyclosporine or methotrexate, as guttate variants of psoriasis can remit with these treatments.1,2 Guselkumab, an inhibitor of the p19 cytokine subunit of interleukin-23 and interleukin-39, produces dramatic resolutions of plaque psoriasis with long lasting effects.3 This case report describes a patient with a guttate variant of plaque psoriasis that resolved after a single administration of guselkumab and continues to remain clear more than 6 months after treatment with guselkumab.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Injeções Subcutâneas , Resultado do Tratamento , Adulto Jovem
17.
Lancet ; 394(10203): 1030-1040, 2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31427046

RESUMO

BACKGROUND: Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. METHODS: The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. FINDINGS: Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterly fremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI -3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. INTERPRETATION: Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. FUNDING: Teva Pharmaceuticals.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Transtornos de Enxaqueca/prevenção & controle , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Peptídeo Relacionado com Gene de Calcitonina/agonistas , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Expert Rev Clin Pharmacol ; 12(9): 851-857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31460804

RESUMO

Introduction: The interleukin (IL)-23 and IL-17 pathway is closely related to the pathogenesis of psoriasis. This pathway is considered to be an important target for treating psoriasis. Risankizumab can selectively inhibit IL-23p19 subunit and for the treatment of psoriasis. This article aims to review risankizumab and provides reference for clinicians. Areas covered: The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, safety of risankizumab was introduced in this paper. A PubMed search using the terms 'risankizumab,' 'IL-23,' 'p19 subunit,' and 'psoriasis,' was performed, and the results were screened for the most relevant English language publications. Expert opinion: Risankizumab is a humanized IgG monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. Clinical trials showed that risankizumab was significantly more effective than ustekinumab. Risankizumab was well tolerated, upper respiratory tract infection was the common adverse reactions. Therefore, the market of risankizumab provides an important therapeutic means for psoriasis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Humanos , Interleucina-23/imunologia , Psoríase/imunologia , Psoríase/patologia , Ustekinumab/administração & dosagem
19.
J Dermatol ; 46(9): 752-758, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342560

RESUMO

The 52-week results from the CLEAR (NCT02074982) study showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient-reported outcomes, with comparable safety profile in subjects with moderate to severe psoriasis. Here, we analyzed the efficacy and safety of secukinumab in Asian subjects from the CLEAR study. In this double-blind, phase IIIb study, eligible subjects with moderate to severe plaque psoriasis were randomized (1:1) to receive s.c. injection of secukinumab 300 mg or ustekinumab as per label. Of 62 subjects included in Asian subanalyses, 23 were randomized to secukinumab and 39 to ustekinumab. A significantly higher proportion of subjects achieved 90% or more improvement in Psoriasis Area and Severity Index (PASI 90) with secukinumab versus ustekinumab at week 16 (78.3% vs 35.9%, P = 0.0010) and at week 52 (60.9% vs 33.3%, P = 0.0196). Similarly, a higher proportion of subjects achieved PASI 100 with secukinumab versus ustekinumab at week 16 (43.5% vs 10.3%, P = 0.0029) and at week 52 (30.4% vs 12.8%, P = 0.0704). The median time to achieve 50% improvement in baseline PASI was 2.8 weeks in the secukinumab group versus 6.3 weeks in the ustekinumab group. The safety profile of secukinumab was in line with the known profile and no deaths occurred. Overall, 95.7% and 84.6% of subjects remained on secukinumab and ustekinumab, respectively. Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns were identified, in Asian subjects with moderate to severe plaque psoriasis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Ustekinumab/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Grupo com Ancestrais do Continente Asiático , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/patologia , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/patologia , Fatores de Tempo , Ustekinumab/efeitos adversos
20.
Einstein (Sao Paulo) ; 17(4): eRC4599, 2019 Jul 10.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31291386

RESUMO

Case report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Imunossupressores/administração & dosagem , Adolescente , Anticorpos Monoclonais Humanizados , Brasil , Feminino , Humanos , Imunossupressão , Injeções Subcutâneas , Interleucina-13 , Interleucina-4 , Qualidade de Vida , Índice de Gravidade de Doença
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