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1.
Clin Exp Rheumatol ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32662413

RESUMO

OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.

2.
Rheumatol Int ; 40(5): 747-755, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32040761

RESUMO

Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p < 0.0001). DAS28-dcrit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.

3.
PLoS One ; 14(5): e0217412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31136632

RESUMO

OBJECTIVES: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. METHODS: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. RESULTS: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. CONCLUSIONS: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).


Assuntos
Artrite Reumatoide/psicologia , Depressão/epidemiologia , Idoso , Artrite Reumatoide/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
4.
Arthritis Care Res (Hoboken) ; 69(1): 58-66, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27482854

RESUMO

OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.


Assuntos
Artrite Reumatoide/psicologia , Depressão/diagnóstico , Escalas de Graduação Psiquiátrica/normas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inquéritos e Questionários/normas
5.
Inflamm Res ; 59(5): 379-89, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19902332

RESUMO

OBJECTIVE: MMP-13 is highly upregulated in arthritis and therefore strongly implicated in the pathogenesis of osteoarthritis (OA). Selective inhibition of MMP-13 may provide the desired cartilage degradation protection, while overcoming the musculoskeletal toxicity seen with nonselective inhibition of MMPs. METHODS: Activity and selectivity of novel MMP-13 inhibitors were determined in enzymatic and collagenase assays. Inhibition kinetics and competitive binding experiments were performed. The inhibition of collagen degradation was studied in cartilage explants from OA patients and in bovine and human articular cartilage systems. RESULTS: We have identified a new class of very potent and highly selective non-zinc-binding MMP-13 inhibitors. Selective MMP-13 inhibitors completely blocked type II collagen degradation in bovine explants and showed up to 80% inhibition in human OA cartilage. CONCLUSIONS: These results indicate MMP-13 as the primary collagenase in the human OA cartilage and in the IL-1/OSM-induced cartilage degradation process and suggest that selective MMP-13 inhibitors may be a potential treatment of OA.


Assuntos
Cartilagem Articular/enzimologia , Cartilagem Articular/patologia , Colágeno/metabolismo , Inibidores de Metaloproteinases de Matriz , Osteoartrite/patologia , Animais , Cartilagem Articular/citologia , Bovinos , Células Cultivadas , Humanos , Interleucina-1/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite/enzimologia , Técnicas de Cultura de Tecidos
6.
Stem Cells Dev ; 18(6): 881-92, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19327011

RESUMO

Mesenchymal stromal cells (MSC) are an attractive source for cell therapy and tissue engineering of joint cartilage. Common chondrogenic in vitro protocols, however, induce hypertrophic markers like COL10A1, matrix metalloproteinase 13 (MMP13), and alkaline phosphatase (ALP) reminiscent of endochondral bone formation. To direct MSC toward articular chondrocytes more specifically, a better understanding of the regulatory steps is desirable. Proteases are important players in matrix remodeling, display inhibitory effects on growth plate development and MMP13 inhibition prevented hypertrophy of bovine chondrocytes. The aim of this study was to evaluate whether the activity of proteases and MMPs, especially MMP13, is crucial for the transition of MSC toward mature chondrocytes and could allow to selectively influence aspects of early and late chondrogenic differentiation. Protease inhibitors were added during MSC chondrogenesis and stage-specific markers were assessed by histology, qPCR, and ALP quantification. Chondrogenesis was little affected by leupeptin, pepstatin, or aprotinin. In contrast, broad spectrum pan-MMP inhibitors dose dependently suppressed proteoglycan deposition, collagen type II and type X staining, ALP activity, and reduced SOX9 and COL2A1 expression. A selective MMP13 inhibitor allowed chondrogenesis and showed only weak effects on ALP activity. In conclusion, transition of MSC toward mature chondrocytes in vitro depended on molecules suppressed by pan-MMP inhibitors identifying chondrogenic differentiation of MSC as a sophistically regulated process in which catabolic enzymes are capable to directly influence cellular fate. In future therapeutic applications of diseased joints, the tested MMP13-specific inhibitor promises suppression of collagen type II degradation without imposing a risk to impair MSC-driven regeneration processes.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Células-Tronco Mesenquimais/citologia , Inibidores de Proteases/farmacologia , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Tecido Adiposo/citologia , Fosfatase Alcalina/metabolismo , Domínio Catalítico , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Estromais/enzimologia
7.
J Med Chem ; 46(3): 356-8, 2003 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-12540234

RESUMO

New and potent inhibitors of neuraminidase, a key enzyme in the influenza virus activity, have been discovered in dynamic combinatorial libraries based on ketones and amines as building blocks. Selective synthesis of a number of inhibitors among multiple theoretically possible combinations of building blocks is driven by the presence of the target enzyme.


Assuntos
Inibidores Enzimáticos/química , Cetonas/química , Neuraminidase/antagonistas & inibidores , Aminas/química , Técnicas de Química Combinatória , Bases de Dados Factuais , Ligantes , Neuraminidase/química , Relação Estrutura-Atividade
8.
Proc Natl Acad Sci U S A ; 99(6): 3382-7, 2002 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-11891312

RESUMO

Neuraminidase, a key enzyme responsible for influenza virus propagation, has been used as a template for selective synthesis of small subsets of its own inhibitors from theoretically highly diverse dynamic combinatorial libraries. We show that the library building blocks, aldehydes and amines, form significant amounts of the library components resulting from their coupling by reductive amination only in the presence of the enzyme. The target amplifies the best hits at least 120-fold. The dynamic libraries synthesized and screened in such an in vitro virtual mode form the components that possess high inhibitory activity, as confirmed by enzyme assays with independently synthesized individual compounds.


Assuntos
Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Vírus da Influenza A/enzimologia , Neuraminidase/antagonistas & inibidores , Aldeídos/química , Aldeídos/metabolismo , Aminas/química , Aminas/metabolismo , Sítios de Ligação , Vírus da Influenza A/classificação , Estrutura Molecular , Neuraminidase/química , Neuraminidase/metabolismo , Termodinâmica
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