RESUMO
OBJECTIVES: To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). METHODS: This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240â mg) at week 0 and followed by 120â mg every 2â weeks (120 Q2W), 120â mg every 4â weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. RESULTS: Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. CONCLUSION: SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. TRIAL REGISTRATION NUMBER: NCT01205438.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Fator Ativador de Células B/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais Humanizados , Autoanticorpos/sangue , Fator Ativador de Células B/administração & dosagem , Linfócitos B/metabolismo , Biomarcadores/sangue , População Negra , Complemento C3/metabolismo , Complemento C4/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Ixekizumab, an anti-IL-17A monoclonal antibody, demonstrated a high level of efficacy in moderate-to-severe plaque psoriasis (PP) patients. OBJECTIVE: To evaluate the efficacy and safety of open-label ixekizumab in Japanese patients with moderate-to-severe PP, erythrodermic psoriasis (EP) and generalized pustular psoriasis (GPP). METHODS: Patients received 160-mg subcutaneous ixekizumab injection at Week 0, 80-mg every 2 weeks through Week 12 and 80-mg every 4 weeks through Week 24. Efficacy and safety are reported through 24 weeks; additional safety data are available for some patients. RESULTS: A total of 78 patients with PP, 8 with EP and 5 with GPP enrolled. In PP patients, PASI75 and PASI90 response rates were 98.7% (77/78) and 83.3% (65/78) at Week 12 respectively. In EP patients, PASI75 and PASI90 were 100.0% (8/8) and 62.5% (5/8) and in GPP patients were 80.0% (4/5) and 60.0% (3/5). Overall, 84.0% (76/91) had a treatment-emergent AE through ≥24 weeks. There were no serious AEs, deaths, cases of tuberculosis or invasive fungal infections. LIMITATIONS: No control group and small sample sizes, especially for EP and GPP. CONCLUSION: By Week 12, nearly all patients with PP, EP and GPP achieved PASI75. The safety profile was consistent with reported results and no unexpected safety signals were observed.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Imunossupressores/efeitos adversos , Interleucina-17/antagonistas & inibidores , Japão , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
High inter- and intra-laboratory variability exists for the single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) test. To detect small changes in diffusing capacity in multicentre clinical trials, accurate measurements are essential. The present study assessed whether regular D(L,CO) simulator testing maintained or improved instrument accuracy and reduced variability in multicentre trials. The 125 pulmonary function testing laboratories that participated in clinical trials for AIR(R) Inhaled Insulin validated and monitored the accuracy of their D(L,CO) measuring devices using a D(L,CO) simulator, which creates known target values for any device. Devices measuring a simulated D(L,CO) different from target by >3 mL.min-1.mmHg(-1) failed testing and were serviced. Device accuracy was assessed over time and with respect to differences in several variables. Initially, 31 (25%) laboratories had a D(L,CO) device that failed simulator testing. After fixing or replacing devices, 124 (99%) laboratories had passing devices. The percentage of failed tests significantly decreased over time. Differences in geographical region, device type, breath-hold time, temperature and pressure were not associated with meaningful differences in D(L,CO) device accuracy. Regular diffusing capacity of the lung for carbon monoxide simulator testing allows pulmonary function testing laboratories to maintain the accuracy of their diffusing capacity measurements, leading to reduced variability across laboratories in multicentre clinical trials.
Assuntos
Monóxido de Carbono/análise , Testes de Função Respiratória/instrumentação , Ensaios Clínicos como Assunto , Humanos , Estudos Multicêntricos como Assunto , Reprodutibilidade dos Testes , Testes de Função Respiratória/normasRESUMO
GM-CSF gene targeted (GM(-/-)) mice are susceptible to respiratory infections and develop alveolar proteinosis due to defects in innate immune function and surfactant catabolism in alveolar macrophages (AMs), respectively. Reduced cell adhesion, phagocytosis, pathogen killing, mannose- and Toll-like receptor expression, and LPS- or peptidoglycan-stimulated TNFalpha release were observed in AMs from GM(-/-) mice. The transcription factor PU.1 was markedly reduced in AMs of GM(-/-) mice in vivo and was restored by selective expression of GM-CSF in the lungs of SPC-GM/GM(-/-) transgenic mice. Retrovirus-mediated expression of PU.1 in AMs from GM(-/-) mice rescued host defense functions and surfactant catabolism by AMs. We conclude that PU.1 mediates GM-CSF-dependent effects on terminal differentiation of AMs regulating innate immune functions and surfactant catabolism by AMs.
Assuntos
Proteínas de Drosophila , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Animais , Adesão Celular , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Pulmão/citologia , Macrófagos Alveolares/citologia , Macrófagos Alveolares/microbiologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Fagocitose , Proteínas Proto-Oncogênicas/genética , Surfactantes Pulmonares/metabolismo , RNA Mensageiro/biossíntese , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Receptores Toll-Like , Transativadores/genética , TransfecçãoRESUMO
Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.
Assuntos
Brônquios/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Fibrose Cística/fisiopatologia , Citocinas/farmacologia , Junções Comunicantes/efeitos dos fármacos , Brônquios/citologia , Brônquios/metabolismo , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Conexinas/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Corantes Fluorescentes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoquinolinas/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Adenovirus is a common respiratory pathogen which causes a broad range of distinct clinical syndromes and has recently received attention for its potential for in vivo gene delivery. Although adenovirus respiratory tract infection (ARTI) results in dose-dependent, local inflammation, the pathogenesis of this remains unclear. We hypothesized that alveolar macrophages (AMphi) rapidly internalize adenovirus following in vivo pulmonary administration and then initiate inflammatory signaling within the lung. To evaluate the role of AMphi in the induction of lung inflammation during ARTI in vivo, we directly assessed adenovirus uptake by murine AMphi and correlated uptake with the initiation of proinflammatory gene expression. Stimulation of cytokine (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and MIP-1alpha) expression in the lung was evaluated at the level of mRNA (by reverse transcription-PCR [RT-PCR]) and protein (by enzyme-linked immunosorbent assay) and by identification of cells expressing TNF-alpha and IL-6 mRNA in lung tissues (by in situ hybridization) and isolated lung lavage cells (by RT-PCR). Adenovirus, labeled with the fluorescent dye (Cy3), was rapidly and widely distributed on epithelial surfaces of airways and alveoli and was very rapidly ( approximately 1 min) localized within AMphi. At 30 min after infection AMphi but not airway epithelial or vascular endothelial cells expressed mRNA for TNF-alpha and IL-6, thus identifying AMphi as the cell source of initial cytokine signaling. IL-6, TNF-alpha, MIP-2, and MIP-1alpha levels progressively increased in bronchoalveolar lavage fluid after pulmonary adenovirus infection, and all were significantly elevated at 6 h (P < 0.05). To begin to define the molecular mechanism(s) by which adenovirus initiates the inflammatory signaling in macrophages, TNF-alpha expression from adenovirus-infected RAW264.7 macrophages was evaluated in vitro. TNF-alpha expression was readily detected in adenovirus-infected RAW cell supernatant with kinetics similar to AMphi during in vivo infection. Blockage of virus uptake at specific cellular sites, including internalization (by wortmannin), endosome acidification and/or lysis (by chloroquine) or by Ca(2+) chelation (by BAPTA) completely blocked TNF-alpha expression. In conclusion, results showed that during ARTI, (i) AMphi rapidly internalized adenovirus, (ii) expression of inflammatory mediators was initiated within AMphi and not airway epithelial or other cells, and (iii) the initiation of inflammatory signaling was linked to virion uptake by macrophages occurring at a point after vesicle acidification. These results have implications for our understanding of the role of the AMphi in the initiation of inflammation following adenovirus infection and adenovirus-mediated gene transfer to the lung.
Assuntos
Infecções por Adenoviridae/virologia , Adenoviridae/fisiologia , Inflamação/etiologia , Macrófagos Alveolares/virologia , Infecções Respiratórias/virologia , Doença Aguda , Animais , Cálcio/fisiologia , Linhagem Celular , Citocinas/genética , Técnicas de Transferência de Genes , Vetores Genéticos , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/fisiologia , Vírion/isolamento & purificaçãoRESUMO
A polymerase chain reaction kit (AMPLICOR EV) for the detection of enteroviruses (EV-PCR) in the cerebrospinal fluid (CSF) was evaluated in clinical conditions in a prospective blinded-intention study. Forty-three children (mean age 2.7 years) hospitalized for suspected meningitis or fever of unclear etiology were enrolled. EV-PCR was performed on a daily basis. Results were available in less than 2 days in 72% of cases. EV-PCR was positive in nine (21%) children, including three infants without CSF pleocytosis. Knowing their EV-PCR result would have allowed a saving of 18 hospital days and 12 days of antibiotic therapy. The EV-PCR in the CSF can thus be practically useful for children hospitalized for meningitis or fever if available on-site on a daily basis.
Assuntos
Infecções por Enterovirus/líquido cefalorraquidiano , Reação em Cadeia da Polimerase/métodos , Adolescente , Líquido Cefalorraquidiano/virologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Estudos de Avaliação como Assunto , Feminino , Febre de Causa Desconhecida/líquido cefalorraquidiano , Febre de Causa Desconhecida/microbiologia , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Meningite Viral/líquido cefalorraquidiano , Meningite Viral/microbiologia , Estudos ProspectivosRESUMO
Measurement of transepithelial potential difference (PD) on the nasal mucosa has been proposed to test for defective ion transport in cystic fibrosis (CF), and its possible correction after gene therapy or other treatments. The "classical" method records nasal PD under the inferior turbinate, with the disadvantage that the tip of the electrode is not seen by the operator. We have developed a purpose-designed perfusion electrode for PD recording on the visible, medial/posterior aspect of the turbinate. We wanted to determine whether such PD recordings adequately discriminate between CF patients and normal subjects. Measurements of baseline PD and response to a standardized perfusion protocol were performed in 20 normal subjects and 12 CF patients. Solutions of amiloride, with or without low chloride buffer were applied for 3 min. Increased baseline PD and depolarization after amiloride discriminated CF patients from normal subjects. Only one CF patient overlapped with the normal range. Superfusion of low chloride buffer with amiloride and terbutaline caused repolarization in 18 out of 20 normal subjects (90%), consistent with physiological Cl- secretion process, but in none of the CF patients. We conclude that measurements of potential difference on the medial/posterior aspect of the turbinate can discriminate between cystic fibrosis patients and normal subjects. At this site, visual control of the measurement is possible, and the mucosa is easily accessible for subsequent cytological sampling or biopsy.
Assuntos
Fibrose Cística/diagnóstico , Mucosa Nasal/fisiologia , Adulto , Amilorida , Estudos de Casos e Controles , Fibrose Cística/fisiopatologia , Condutividade Elétrica , Eletrodos , Endoscopia , Desenho de Equipamento , Feminino , Humanos , Transporte de Íons/fisiologia , Masculino , Perfusão , Terbutalina , Conchas NasaisRESUMO
To explore the changes in resting energy expenditure (REE) and whole body protein turnover induced by malaria, 23 children aged 6 to 14 y (23.9 +/- 1.0 kg, 1.3 +/- 0.02 m) were studied on three separate days after treatment (d 1, d 2, and 15 d later). REE was assessed by indirect calorimetry (hood), whereas whole body protein turnover was estimated using a single dose of [15N]glycine administered p.o. by measuring the isotopic enrichment of [15N]ammonia in urine over 12 h. Within the first 3.5 h after treatment, the body temperature dropped from 39.8 +/- 0.1 to 37.8 +/- 0.1 degrees C (p < 0.0001), and REE followed the same pattern, decreasing rapidly from 223 +/- 6 to 187 +/- 4 kJ/kg/d (p < 0.0001). Whole body protein synthesis and breakdown were significantly higher during the 1st day (5.65 +/- 0.38 and 6.21 +/- 0.43 g/kg/d, respectively) than at d 15 (2.95 +/- 0.17 and 2.77 +/- 0.2 g/kg/d). It is concluded that Gambian children suffering from an acute episode of malaria have an increased REE averaging 37% of the control value (d 15) and that this was associated with a substantial increase (by a factor of 2) in whole body protein turnover. A rapid normalization of the hypermetabolism and protein hypercatabolism states after treatment was observed.
Assuntos
Acetaminofen/farmacologia , Cloroquina/análogos & derivados , Malária Falciparum/tratamento farmacológico , Proteínas/metabolismo , Adolescente , Índice de Massa Corporal , Temperatura Corporal , Peso Corporal , Criança , Cloroquina/farmacologia , Metabolismo Energético , Gâmbia , Frequência Cardíaca , Humanos , Malária Falciparum/metabolismo , Malária Falciparum/fisiopatologia , Resultado do TratamentoRESUMO
Body composition, resting energy expenditure (REE), and whole body protein metabolism were studied in 26 young and 28 elderly Gambian men matched for body mass index during the dry season in a rural village in The Gambia. REE was measured by indirect calorimetry (hood system) in the fasting state and after five successive meals. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotopic enrichment of urinary ammonia over a period of 12 h after a single oral dose of [15N]glycine. Expressed in absolute value, REE was significantly lower in the elderly compared with the young group (3.21 +/- 0.07 vs. 4.04 +/- 0.07 kJ/min, P < 0.001) and when adjusted to body weight (3.29 +/- 0.05 vs. 3.96 +/- 0.05 kJ/min, P < 0.0001) and fat-free mass (FFM; 3.38 +/- 0.01 vs. 3.87 +/- 0.01 kJ/min, P < 0.0001). The rate of protein synthesis averaged 207 +/- 13 g protein/day in the elderly and 230 +/- 13 g protein/day in the young group, whereas protein breakdown averaged 184 +/- 13 g protein/day in the elderly and 203 +/- 13 g protein/day in the young group (nonsignificant). When values were adjusted for body weight or FFM, they did not reveal any difference between the two groups. It is concluded that the reduced REE adjusted for body composition observed in elderly Gambian men is not explained by a decrease in protein turnover.