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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.

3.
Curr Med Res Opin ; 35(12): 2079-2087, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31355677

RESUMO

Objectives: To compare the efficacy of emicizumab prophylaxis with that of factor VIII (FVIII) prophylaxis in patients with hemophilia A without inhibitors using two approaches: network meta-analyses (NMA) and additional sub-group analyses from the HAVEN 3 trial.Methods: The NMA used data from trials identified using a systematic literature review and compared bleed rates in patients receiving emicizumab prophylaxis and patients receiving FVIII prophylaxis using a Bayesian, random effects generalized linear model with log link Poisson likelihood. Additional sub-groups of the HAVEN 3 trial included here were defined as patients whose dose-taking behavior met either European label or World Federation of Hemophilia guidelines. A negative binomial regression model was used to conduct an intra-patient comparison of bleed rates within the sub-groups, during treatment with FVIII prophylaxis before entering HAVEN 3 and treatment with emicizumab prophylaxis during HAVEN 3.Results: Four studies were included in the base-case NMA. Evidence showed that the total treated bleed rate was lower with emicizumab prophylaxis compared with FVIII prophylaxis (rate ratio [RR] = 0.36 [95% credible interval (CrI) = 0.13-0.95]). Similar associations were observed in sensitivity analyses. The additional HAVEN 3 analyses also showed lower rates of treated bleeds with emicizumab prophylaxis than with FVIII prophylaxis (RRs [95% confidence interval (CI)] = 0.380 [0.186-0.790] and 0.472 [0.258-0.866] in two sub-groups). These results confirm the original HAVEN 3 intra-patient comparison findings.Conclusions: Combined findings from NMA and additional sub-group analyses of HAVEN 3 support the superiority of emicizumab prophylaxis over FVIII prophylaxis in patients with hemophilia A without inhibitors.


Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Fator VIII , Hemofilia A/tratamento farmacológico , Hemorragia , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Quimioprevenção/métodos , Coagulantes/administração & dosagem , Coagulantes/efeitos adversos , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Hemofilia A/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Metanálise em Rede , Medição de Risco/métodos , Resultado do Tratamento
4.
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
5.
Patient Prefer Adherence ; 11: 1253-1264, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28790807

RESUMO

OBJECTIVE: This study aimed to assess the level of nonpersistence (NP) and nonadherence (NA) to methotrexate (MTX) therapy in German patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Based on German claims data, RA patients who received a MTX therapy (subgroup: treatment-naive patients) were analyzed. NP was defined as treatment gap >12 weeks. Regarding NA, it is the overall medication possession ratio (MPR) during an observational period of 12 or 24 months after therapy, and the MPR is calculated only for the periods of therapy continuation; NA was defined as MPR <80%. RESULTS: A total of 7,146 RA patients who received at least one MTX prescription (subgroup: 1,211 treatment-naive patients) could be observed (mean age: 64.4 years, 73.6% female). Percentage of NP patients among MTX-naive patients after 6, 12 and 18 months was 16.7%, 34.0% and 36.7%, respectively. After MTX therapy discontinuation, 39.9% had restarted their MTX therapy, 13.8% had received another non-MTX synthetic disease-modifying antirheumatic drug (sDMARD), 8.1% had biological DMARD (bDMARD) and 49.2% had not received any DMARD prescription at all. Overall, 12- and 24-month MPRs for MTX therapy were 83.0% and 76.5% with a percentage of NA patients of 25.8% and 33.8%, respectively. During periods of general treatment continuation, the percentage of patients with an MPR <80% was 6.5%. CONCLUSION: NP to MTX treatment seems to be common in one-fourth of German patients with RA. An additional number of patients, at least 6.5%, are also affected by NA. A considerable percentage of RA patients who discontinued MTX therapy do not receive any follow-up DMARD therapy.

6.
Biochim Biophys Acta ; 1842(12 Pt B): 2656-63, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25257405

RESUMO

Pharmacological modulation of tumor radiosensitivity is a promising strategy for enhancing the outcome of radiotherapy. cAMP signaling plays an essential role in modulating the proliferation and apoptosis of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In the present study, the role of an alternative source of cAMP, the intracellular localized soluble adenylyl cyclase (sAC), in the radiosensitivity of prostate cancer cells was investigated. Pharmacological inhibition of sAC activity led to marked suppression of proliferation, lactate dehydrogenase release, and induction of apoptosis. The combination of ionizing radiation with partial suppression of sAC activity (~50%) immediately after irradiation synergistically inhibited proliferation and induced apoptosis. Overexpression of sAC in normal prostate epithelial PNT2 cells increased the cAMP content and accelerated cell proliferation under control conditions. The effects of radiation were significantly reduced in transformed PNT2 cells compared with control cells. Analysis of the underlying cellular mechanisms of sAC-induced radioresistance revealed the sAC-dependent activation of B-Raf/ERK1/2 signaling. In agreement with this finding, inhibition of ERK1/2 in prostate cancer cells enhanced the cytotoxic effect of irradiation. In conclusion, the present study suggests that sAC-dependent signaling plays an important role in the radioresistance of prostate cancer cells. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.


Assuntos
Inibidores de Adenilil Ciclases , Neoplasias da Próstata/radioterapia , Tolerância a Radiação , Adenilil Ciclases , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
7.
J Biol Chem ; 288(5): 3126-35, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23255611

RESUMO

cAMP signaling plays an essential role in modulating the proliferation of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In this study, significant overexpression of soluble adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma, and therefore, the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3. Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells, led to lactate dehydrogenase release, and induced apoptosis. Cell cycle analysis revealed a significant rise in the G(2) phase population 12 h after sAC inhibition, which was accompanied by the down-regulation of cyclin B(1) and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap1/B-Raf signaling pathway. In contrast, protein kinase A does not play a role. In conclusion, this study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells.


Assuntos
Adenilil Ciclases/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Inibidores de Adenilil Ciclases , Proteínas de Ciclo Celular/metabolismo , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular , Técnicas de Silenciamento de Genes , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Mitose , Transporte Proteico , Solubilidade , Frações Subcelulares/enzimologia
8.
Cardiovasc Res ; 93(2): 340-9, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22106416

RESUMO

AIMS: Apoptosis of cardiomyocytes significantly contributes to the development of post-ischaemic cardiomyopathy. Although mitochondria have been suggested to play a crucial role in this process, the precise mechanisms controlling the mitochondria-dependent apoptosis in cardiomyocytes under ischaemia/reperfusion are still poorly understood. Here we aimed to analyse the role of the soluble adenylyl cyclase (sAC). METHODS AND RESULTS: Adult rat cardiomyocytes were subjected to simulated in vitro ischaemia (SI) consisting of glucose-free anoxia at pH 6.4. Apoptosis was detected by DNA laddering, chromatin condensation, and caspases cleavage. SI led to the translocation of sAC to the mitochondria and mitochondrial depolarization followed by cytochrome c release, caspase-9/-3 cleavage and apoptosis during simulated reperfusion (SR). Pharmacological inhibition of sAC during SI, but not during SR, significantly reduced the SI/SR-induced mitochondrial injury and apoptosis. Similarly, sAC knock-down mediated by an adenovirus coding for shRNA targeting sAC prevented the activation of the mitochondrial pathway of apoptosis. Analysis of the link between sAC and apoptosis revealed a sAC and protein kinase A-dependent Bax phosphorylation at Thr(167) and its translocation to mitochondria during SI, which subsequently caused mitochondrial oxygen radical formation followed by cytochrome c release and caspase-9 cleavage during SR. CONCLUSION: These results suggest a key role of sAC in SI-induced mitochondrial Bax translocation and activation of the mitochondrial pathway of apoptosis in adult cardiomyocytes.


Assuntos
Adenilil Ciclases/fisiologia , Apoptose , Mitocôndrias Cardíacas/metabolismo , Reperfusão Miocárdica , Miócitos Cardíacos/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Células Cultivadas , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Masculino , Miócitos Cardíacos/citologia , Transporte Proteico , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
9.
Cardiovasc Res ; 89(2): 392-400, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20962104

RESUMO

AIMS: Bicarbonate transport has been shown to participate in apoptosis under ischaemic stress. However, the precise transporting mechanisms involved in ischaemic apoptosis are unknown and were thus the aim of the present study. METHODS AND RESULTS: Rat coronary endothelial cells (EC) were exposed to simulated in vitro ischaemia for 2 h, and apoptosis was subsequently determined by chromatin staining and caspase-3 activity analysis. By examining the expression of bicarbonate transporters (BT) in EC by reverse transcriptase polymerase chain reaction and western blotting, a marked expression of the electroneutral sodium bicarbonate co-transporter (SLC4A7) was defined. To analyse the potential role of this transporter during apoptosis, a selective inhibitor (S0859, Sanofi-Aventis) was applied. Treatment with S0859 significantly increased caspase-3 activity and elevated the number of apoptotic EC. These results were comparable with an unselective inhibition of all BT due to withdrawal of bicarbonate in the anoxic medium. Knockdown of SLC4A7 in EC by transfecting appropriate siRNA similarly increased apoptosis of EC under simulated ischaemia. The initial characterization of the participating mechanisms of SLC4A7-dependent apoptosis revealed an activation of the mitochondrial pathway of apoptosis, i.e. cleavage of caspase-9 and binding of Bax to mitochondria. In contrast, no activation of the endoplasmic reticulum-dependent pathway (caspase-12 cleavage) or the extrinsic apoptotic pathway (caspase-8 cleavage) was found. Finally, a mitochondrial localization of SLC4A7 was demonstrated. CONCLUSION: The electroneutral sodium bicarbonate co-transporter SLC4A7 localizes in mitochondria and suppresses the ischaemia-induced activation of the mitochondrial pathway of apoptosis in coronary EC.


Assuntos
Apoptose , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Mitocôndrias/metabolismo , Isquemia Miocárdica/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Western Blotting , Caspase 3/metabolismo , Caspase 9/metabolismo , Hipóxia Celular , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Glucose/deficiência , Concentração de Íons de Hidrogênio , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Isquemia Miocárdica/patologia , Interferência de RNA , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simportadores de Sódio-Bicarbonato/antagonistas & inibidores , Simportadores de Sódio-Bicarbonato/genética , Sulfonamidas/farmacologia , Transfecção , Proteína X Associada a bcl-2/metabolismo
10.
J Biol Chem ; 284(22): 14760-8, 2009 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-19336406

RESUMO

The cAMP signaling pathway plays an essential role in modulating the apoptotic response to various stress stimuli. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase. In addition to transmembrane AC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). However, the role of this cyclase in apoptosis was unknown. A mitochondrial localization of this cyclase has recently been demonstrated, which led us to the hypothesis that sAC may play a role in apoptosis through modulation of mitochondria-dependent apoptosis. To prove this hypothesis, apoptosis was induced by simulated in vitro ischemia or by acidosis, which is an important component of ischemia. Suppression of sAC activity with the selective inhibitor KH7 or sAC knockdown by small interfering RNA transfection abolished endothelial apoptosis. Furthermore, pharmacological inhibition or knockdown of protein kinase A, an important cAMP target, demonstrated a significant anti-apoptotic effect. Analysis of the underlying mechanisms revealed (i) the translocation of sAC to mitochondria under acidic stress and (ii) activation of the mitochondrial pathway of apoptosis, i.e. cytochrome c release and caspase-9 cleavage. sAC inhibition or knockdown abolished the activation of the mitochondrial pathway of apoptosis. Analysis of mitochondrial co-localization of Bcl-2 family proteins demonstrated sAC- and protein kinase A-dependent translocation of Bax to mitochondria. Taken together, these results suggest the important role of sAC in modulating the mitochondria-dependent pathway of apoptosis in endothelial cells.


Assuntos
Adenilil Ciclases/metabolismo , Apoptose , Vasos Coronários/citologia , Células Endoteliais/citologia , Células Endoteliais/enzimologia , Mitocôndrias/enzimologia , Acidose/induzido quimicamente , Acidose/enzimologia , Animais , Western Blotting , Membrana Celular/enzimologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Técnicas de Silenciamento de Genes , Isquemia/induzido quimicamente , Isquemia/enzimologia , Masculino , Ratos , Ratos Wistar , Análise de Regressão , Solubilidade , Proteína X Associada a bcl-2/metabolismo
11.
Apoptosis ; 14(1): 90-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19082728

RESUMO

To analyze the underlying cellular mechanisms of adaptation to ischemia-induced apoptosis through short acidic pretreatment, i.e. acidic preconditioning (APC), Wistar rat coronary endothelial cells (EC) were exposed for 40 min to acidosis (pH 6.4) followed by a 14 h recovery period (pH 7.4) and finally treated for 2 h with simulated in vitro ischemia (glucose-free anoxia at pH 6.4). APC led to a transient activation of p38 and Akt kinases, but not of JNK and ERK1/2 kinases, which was accompanied by significant reduction of the apoptotic cell number, caspase-12/-3 cleavage and Bcl-xL overexpression. These effects of APC were completely abolished by prevention of Akt- or p38-phosphorylation during APC. Furthermore, knock-down of Bcl-xL by siRNA-transfection also abolished the anti-apoptotic effect of APC. Therefore, APC leads to protection of EC against ischemic apoptosis by activation of Akt and p38 followed by overexpression of Bcl-xL, which is a key anti-apoptotic mechanism of APC.


Assuntos
Apoptose , Células Endoteliais/enzimologia , Regulação Enzimológica da Expressão Gênica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína bcl-X/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Caspase 12/metabolismo , Concentração de Íons de Hidrogênio , Precondicionamento Isquêmico , Masculino , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo
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