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1.
BMJ Open ; 13(2): e066057, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36725094

RESUMO

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.


Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Resultado do Tratamento , Índice de Gravidade de Doença
8.
J Dermatolog Treat ; 34(1): 2160196, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36629859

RESUMO

OBJECTIVES: To describe the results of a structured literature review of real-world outcomes with ixekizumab in patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). METHODS: Literature databases, conference proceedings and additional sources were searched for relevant publications. Real-world studies of ≥25 ixekizumab-treated patients with PsO and/or PsA were included. Data on clinical effectiveness, treatment persistence/patterns, economic outcomes, patient-reported outcomes (PROs) and safety were extracted. RESULTS: Fifty-one publications were included. Most studies focused on patients with PsO, and the number of publications with a focus on PROs was low. Studies of treatment patterns found that in general, ixekizumab had similar or better persistence versus other biologics, and rates or risk of switching similar to or less than comparator drugs. Adherence to ixekizumab was high, and patients were less likely to discontinue ixekizumab than other biologics. Ixekizumab was effective in the real world, with a safety profile consistent with that reported in clinical trials. CONCLUSIONS: Real-world use of ixekizumab in PsO and PsA is effective and safe, with generally high treatment persistence and adherence. Further work is required to determine the impact of ixekizumab on PROs in PsO, and to gather more data on real-world use of ixekizumab in PsA.


Assuntos
Artrite Psoriásica , Produtos Biológicos , Psoríase , Humanos , Artrite Psoriásica/tratamento farmacológico , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos/uso terapêutico
9.
Br J Dermatol ; 188(1): 22-31, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36689515

RESUMO

BACKGROUND: BE SURE 1-year results demonstrated the superior efficacy of bimekizumab compared with adalimumab with no unexpected safety findings. OBJECTIVES: To provide efficacy and safety data over 2 years of bimekizumab treatment compared with adalimumab from BE SURE and the BE BRIGHT open-label extension (OLE) in patients with moderate-to-severe plaque psoriasis. METHODS: The 56-week double-blinded BE SURE phase III randomized controlled trial randomized patients 1 : 1 : 1 to bimekizumab 320 mg every 4 weeks (Q4W), bimekizumab 320 mg Q4W to week 16 then every 8 weeks (Q8W), or adalimumab 40 mg every 2 weeks to week 24 then bimekizumab 320 mg Q4W. After completing BE SURE, patients could enter the ongoing BE BRIGHT OLE, with possible dosing adjustments based on Psoriasis Area and Severity Index (PASI). The primary outcome in BE BRIGHT was incidence of treatment-emergent adverse events (TEAEs); safety data are reported by study period through week 104. Efficacy data are reported for the intention-to-treat population through week 104 by initial randomization group, with ≥ 90% improvement from baseline PASI (PASI 90) and 100% improvement (PASI 100) as key outcomes. RESULTS: Of the patients randomized to bimekizumab, 158 were assigned to Q4W, and 161 to Q4W/Q8W. At week 104, PASI 90 was achieved by 91.2% and 89.7%, and PASI 100 was achieved by 72.3% and 68.1%, for Q4W and Q4W/Q8W, respectively; comparable to week 16 results. Among the 159 patients randomized to adalimumab, responses rapidly and substantially increased after the week 24 bimekizumab switch; at week 104, 96.9% and 70.2% of patients achieved PASI 90 and PASI 100 respectively. Through weeks 24-104, the three most common TEAEs in any bimekizumab-treated group were nasopharyngitis, oral candidiasis and upper respiratory tract infection. Rates of serious TEAEs were low. CONCLUSIONS: Clinical responses observed through week 16 of BE SURE in patients randomized to bimekizumab were sustained through 104 weeks of treatment, regardless of Q4W or Q8W maintenance dosing. Response rates were also sustained through week 104 in patients who switched from adalimumab to bimekizumab at week 24, and were similar to those observed in the bimekizumab groups. Bimekizumab was well tolerated with no new safety signals.


Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Psoríase/tratamento farmacológico , Nível de Saúde , Resultado do Tratamento , Método Duplo-Cego , Índice de Gravidade de Doença
10.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36669791

RESUMO

BACKGROUND: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. METHODS: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. RESULTS: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). CONCLUSIONS: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02043665.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Vírus Oncolíticos , Masculino , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos
11.
Immunotherapy ; 15(2): 71-75, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36628567

RESUMO

Trousseau's syndrome is a relatively rare reported event in immunotherapy-related clinical trials, mostly occurring in the early period of immune checkpoint inhibitor (ICI) therapy. Here, we report an unusual case of late and lethal Trousseau's syndrome during pembrolizumab maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. The patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseau's syndrome when patients are treated with ICIs.


In clinical practice, symptoms associated with abnormal coagulation or fibrinolytic function in malignant tumors are known as Trousseau's syndrome. Its main clinical features include cerebral infarction, myocardial infarction, peripheral arterial embolism, etc. Trousseau's syndrome is a relatively rare reported event in immune checkpoint inhibitors (ICIs)-related clinical studies, mostly occurring in the early period of ICI therapy. Here, we report an unusual case of late and lethal Trousseau's syndrome during pembrolizumab, one of the ICI agents, maintenance therapy in a lung adenocarcinoma harboring tumor protein p53 (TP53) mutation. This patient has experienced severe coagulation abnormalities manifesting as cerebral infarction, partial infarction of both kidneys and spleen after 23 cycles of pembrolizumab use and was resistant to anticoagulants. The late occurrence of coagulation abnormalities in this case reveals a possible correlation between TP53 mutations and Trousseau's syndrome when patients are treated with ICIs.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/tratamento farmacológico , Anticoagulantes/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico
13.
Ann Intern Med ; 176(1): JC5, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36592464

RESUMO

SOURCE CITATION: Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, et al. Effect of tocilizumab on disease activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: a randomized clinical trial. JAMA. 2022;328:1053-62. 36125471.


Assuntos
Arterite de Células Gigantes , Polimialgia Reumática , Humanos , Glucocorticoides/uso terapêutico , Polimialgia Reumática/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/induzido quimicamente
14.
Trials ; 24(1): 22, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627711

RESUMO

BACKGROUND: Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression. METHODS: Patients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively. DISCUSSION: DISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, NCT04882098 . Registered on 11 May 2021.


Assuntos
Antirreumáticos , Artrite Psoriásica , Adulto , Humanos , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/efeitos adversos , Resultado do Tratamento , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como Assunto
16.
Clin Nucl Med ; 48(2): 168-169, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607365

RESUMO

ABSTRACT: Høilund-Carlsen and colleagues raise concern regarding the reliability of amyloid PET to exclude Alzheimer disease. We present additional studies of amyloid PET and discuss the diagnostic challenges in Alzheimer disease. We discuss the limitations of amyloid in diagnosis and evaluation of therapy response in AD.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Reprodutibilidade dos Testes , Anticorpos Monoclonais Humanizados/efeitos adversos , Amiloide , Peptídeos beta-Amiloides
17.
Clin Drug Investig ; 43(1): 45-59, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36482037

RESUMO

BACKGROUND AND OBJECTIVE: Several studies on use of erenumab for migraine treatment have been published over recent years. However, its long-term safety and effectiveness have not been consistently established in the literature yet. We aimed to perform a qualitative and quantitative analysis of the long-term safety and effectiveness of erenumab for the treatment of migraine headaches. METHODS: Long-term follow-up was defined as ≥ 1 year. PubMed, Embase and Cochrane Library were systematically searched from inception to 14 June 2022 for studies meeting the inclusion criteria. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Fourteen studies, comprising 3574 patients, were included. The total follow-up period ranged from 48 to 268 weeks (i.e., 1 year to 5.6 years). Pooled estimate rates for all adverse events (AEs) were 63% (95% CI 46-78); for serious AEs, 3% (95% CI 1-7); and for AEs leading to discontinuation of erenumab, 3% (95% CI 2-5). Reduction in monthly migraine days (MMDs) was -6.98 (95% CI -8.90 to -5.05) and in migraine-specific medication days (MSMDs) was - 6.09 (95% CI - 9.43 to - 2.75). More than half (57%; 95% CI 51-63) and around one-third (35%; 95% CI 28-42) of patients presented with reductions of ≥ 50% and ≥ 75% in MMDs, respectively. Headache Impact Test-6 (HIT-6) score was decreased by -9.68 points (95% CI - 12.03 to - 7.34). Nine studies were considered of poor methodological quality and five of fair quality. CONCLUSIONS: Erenumab has a favorable safety profile, with a low incidence of serious AEs, and sustained efficacy over ≥1 year of follow-up in the treatment of migraine.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca , Humanos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Transtornos de Enxaqueca/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos
18.
Drug Ther Bull ; 61(1): 6, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36543342

RESUMO

Overview of: Medicines and Healthcare products Regulatory Agency. Dupilumab (Dupixent▼): risk of ocular adverse reactions and need for prompt management. Drug Safety Update 2022;16(4): 1.


Assuntos
Anticorpos Monoclonais Humanizados , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos
19.
J Dermatol ; 50(2): 195-202, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36514850

RESUMO

Risankizumab, a humanized immunoglobin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit, is approved in Japan to treat numerous indications, including generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). Both GPP and EP are severe forms of psoriasis that have limited treatment options. In IMMspire (A Study to Assess Efficacy and Safety of Two Different Dose Regimens of Risankizumab Administered Subcutaneously in Japanese Subjects With Generalized Pustular Psoriasis or Erythrodermic Psoriasis) (NCT03022045), a phase 3, randomized, multicenter study in Japan, we evaluated the efficacy and safety of risankizumab for Japanese adults with GPP or EP. Patients were randomized (1:1) to receive open-label risankizumab 75 mg or 150 mg at weeks 0 and 4 and every 12 weeks thereafter through week 160. The primary efficacy end point was GPP or EP clinical response at week 16. Other efficacy end points included GPP or EP clinical response, ≥90% improvement from baseline in the Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index of 0 or 1 (DLQI 0/1) through 180 weeks (last follow-up visit). Safety was assessed throughout. A total of 17 patients (eight with GPP and nine with EP) were enrolled. All patients achieved the primary end point of GPP or EP clinical response at week 16. Among patients continuing risankizumab treatment, achievement of GPP or EP clinical response, PASI 90 and DLQI 0/1 were generally sustained throughout the treatment. The safety profile remained consistent with the safety profiles noted in previous risankizumab studies. Risankizumab demonstrated clinically meaningful efficacy at week 16, with durable efficacy and a favorable long-term safety profile in Japanese patients with GPP or EP.


Assuntos
Psoríase , Adulto , Humanos , Seguimentos , Resultado do Tratamento , Índice de Gravidade de Doença , Anticorpos Monoclonais/uso terapêutico , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos
20.
Clin Neuropharmacol ; 46(1): 6-16, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36542785

RESUMO

OBJECTIVE: The aim of this study was to assess the efficacy of different dosage regimens of tanezumab among individuals living with chronic low back pain (CLBP). METHODS: PubMed, Embase, The Cochrane Library, and other databases were searched from inception until August 2021. Randomized controlled trials investigating the efficacy and safety of tanezumab in individuals with CLBP were included. Data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The measurements include low back pain intensity and Roland-Morris Disability Questionnaire. The incidence of adverse events and serious adverse events was set to assess the safety of tanezumab for CLBP. RESULTS AND DISCUSSION: Three high-quality randomized controlled trials with 3414 patients were finally included in our analysis. Tanezumab, respectively, led to a notable decrease compared with placebo in low back pain intensity (mean difference, -0.62; 95% confidence interval [CI], -0.77 to -0.46; P < 0.01) and Roland-Morris Disability Questionnaire (mean difference, -0.64; 95% CI, -0.80 to -0.47; P = 0.01). In addition, no significant difference existed between tanezumab and placebo groups (risk ratio, 1.10; 95% CI, 0.81-1.49; P = 0.55) in the adverse events and (risk ratio, 1.06; 95% CI, 0.34-3.27; P = 0.93) serious adverse events. CONCLUSIONS: Intravenous and subcutaneous tanezumab injections as treatment for improving CLBP have promising clinical application as its great improvement on all efficacy and its controllable safety issues. Furthermore, intravenous and subcutaneous tanezumab injections were proved to achieve excellent and long-term curative effect on CLBP through our subgroup analysis and comparison.


Assuntos
Dor Crônica , Dor Lombar , Humanos , Administração Intravenosa , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Dor Crônica/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Dor Lombar/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto
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