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1.
Circ Res ; 135(7): 739-754, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39140440

RESUMO

BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca2+. METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca2+, and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca2+ release in the cell interior. Systolic Ca2+, ICa-L, sarcoplasmic reticulum Ca2+ content, and sarcoendoplasmic reticulum Ca2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca2+ transient, the rate of Ca2+ removal, and the peak L-type Ca2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L, sarcoplasmic reticulum Ca2+ content, and systolic Ca2+. We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.


Assuntos
Átrios do Coração , Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Ovinos , Cálcio/metabolismo , Sinalização do Cálcio , Ratos , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/ultraestrutura , Retículo Sarcoplasmático/patologia , Recuperação de Função Fisiológica , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Mitocôndrias Cardíacas/patologia , Células Cultivadas , Sístole , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Ratos Sprague-Dawley , Feminino
2.
Br J Clin Pharmacol ; 86(4): 801-811, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31770451

RESUMO

AIMS: Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. METHODS: Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data. RESULTS: Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL-1 ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] µg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL-1 and median C.E.R.A. dose was 100 µg). CONCLUSIONS: These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.


Assuntos
Anemia , Eritropoetina , Hematínicos , Insuficiência Renal Crônica , Adulto , Anemia/tratamento farmacológico , Anemia/etiologia , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Hemoglobinas , Humanos , Polietilenoglicóis , Proteínas Recombinantes , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
3.
Br J Dermatol ; 191(4): 646, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-38912786

Assuntos
Dermatoglifia , Humanos
4.
J Allergy Clin Immunol ; 139(5): 1489-1495.e5, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27639934

RESUMO

BACKGROUND: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies. OBJECTIVE: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. METHODS: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. RESULTS: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). CONCLUSION: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.


Assuntos
Antiasmáticos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Omalizumab/efeitos adversos , Adulto , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Omalizumab/uso terapêutico , Vigilância de Produtos Comercializados , Estudos Prospectivos
5.
Thorax ; 71: 411-420, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26962015

RESUMO

BACKGROUND: Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD. METHODS: Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity. RESULTS: Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, ß 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (ß 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (ß 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, ß 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes. CONCLUSION: Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS. TRIAL REGISTRATION NUMBER: NCT01969344 (clinicaltrials.gov).

6.
Am J Respir Crit Care Med ; 191(5): 557-65, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25562375

RESUMO

RATIONALE: Links between occupational exposures and morbidity in individuals with established chronic obstructive pulmonary disease (COPD) remain unclear. OBJECTIVES: To determine the impact of occupational exposures on COPD morbidity. METHODS: A job exposure matrix (JEM) determined occupational exposure likelihood based on longest job in current/former smokers (n = 1,075) recruited as part of the Subpopulations and Intermediate Outcomes in COPD Study, of whom 721 had established COPD. Bivariate and multivariate linear regression models estimated the association of occupational exposure with COPD, and among those with established disease, the occupational exposure associations with 6-minute-walk distance (6MWD), the Modified Medical Research Council Dyspnea Scale (mMRC), the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), 12-item Short-Form Physical Component (SF-12), and COPD exacerbations requiring health care utilization, adjusting for demographics, current smoking status, and cumulative pack-years. MEASUREMENTS AND MAIN RESULTS: An intermediate/high risk of occupational exposure by JEM was found in 38% of participants. In multivariate analysis, those with job exposures had higher odds of COPD (odds ratio, 1.44; 95% confidence interval, 1.04-1.97). Among those with COPD, job exposures were associated with shorter 6MWDs (-26.0 m; P = 0.006); worse scores for mMRC (0.23; P = 0.004), CAT (1.8; P = 0.003), SGRQ (4.5; P = 0.003), and SF-12 Physical (-3.3; P < 0.0001); and greater odds of exacerbation requiring health care utilization (odds ratio, 1.55; P = 0.03). CONCLUSIONS: Accounting for smoking, occupational exposure was associated with COPD risk and, for those with established disease, shorter walk distance, greater breathlessness, worse quality of life, and increased exacerbation risk. Clinicians should obtain occupational histories from patients with COPD because work-related exposures may influence disease burden.


Assuntos
Exposição Ocupacional , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Idoso , Progressão da Doença , Modificador do Efeito Epidemiológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Qualidade de Vida , Fumar/epidemiologia
7.
J Allergy Clin Immunol ; 134(3): 560-567.e4, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24679845

RESUMO

BACKGROUND: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. OBJECTIVE: We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. METHODS: EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. RESULTS: The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. CONCLUSION: Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.


Assuntos
Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Asma/tratamento farmacológico , Asma/epidemiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/epidemiologia , Adulto , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Asma/mortalidade , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Prospectivos , Risco , Neoplasias Cutâneas/mortalidade , Fatores de Tempo , Resultado do Tratamento
8.
N Engl J Med ; 365(12): 1088-98, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21812663

RESUMO

BACKGROUND: Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. METHODS: We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. RESULTS: At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 µg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). CONCLUSIONS: Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Interleucina-13/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Asma/imunologia , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Moléculas de Adesão Celular/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Humanos , Interleucina-13/imunologia , Masculino
9.
J Clin Oncol ; : JCO2302742, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353163

RESUMO

PURPOSE: We evaluated the efficacy and safety of roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, for chemotherapy-induced anemia (CIA) in patients with nonmyeloid malignancies receiving multicycle treatments of chemotherapy. PATIENTS AND METHODS: In this open-label, noninferiority phase III study conducted at 44 sites in China, 159 participants age ≥18 years with CIA nonmyeloid malignancy and CIA were randomly assigned (1:1) to oral roxadustat or subcutaneous recombinant human erythropoietin-α (rHuEPO-α) three times a week for 12 weeks. Roxadustat starting dosages were 100, 120, and 150 mg three times a week for participants weighing 40-<50, 50-60, and >60 kg, respectively. rHuEPO-α starting dosage for all participants was 150 IU/kg three times a week. Both roxadustat and rHuEPO-α dosages could be modified. The primary end point was least-squares mean (LSM) change in hemoglobin (Hb) concentration from baseline to the concentration averaged over weeks 9-13. RESULTS: Of the 159 participants randomly assigned, 140 were included in the per-protocol set (roxadustat, n = 78; rHuEPO-α, n = 62). The LSM (95% two-sided CI) change from baseline to weeks 9-13 in Hb concentration was 17.1 (13.58 to 20.71) g/L with roxadustat and 15.4 (11.34 to 19.50) g/L with rHuEPO-α (mean difference [95% CI], 1.7 [-3.39 to 6.84]). The lower bound of the one-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined noninferiority margin of ‒6.6 g/L, establishing noninferiority. Noninferiority was supported by five of six key secondary end points. Rates of adverse events were generally comparable between treatments and consistent with previous findings. CONCLUSION: Roxadustat was noninferior to rHuEPO-α in treating CIA in participants with nonmyeloid malignancies receiving multicycle treatments of myelosuppressive chemotherapy. The oral formulation of roxadustat may potentially increase compliance.

10.
Med Care ; 51(8): 740-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23703646

RESUMO

BACKGROUND: Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). METHODS: Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures-forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)-improved predictions. Separately, we examined household income as a cost predictor. RESULTS: Mean costs were $12,334/y. Controlling for Relative Risk Score, each ½ SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576-$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. CONCLUSIONS: Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.


Assuntos
Gastos em Saúde/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/economia , Risco Ajustado/métodos , Índice de Gravidade de Doença , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Doença Crônica , Teste de Esforço , Feminino , Volume Expiratório Forçado , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Estudos Prospectivos , Fatores Sexuais , Estados Unidos
12.
J Allergy Clin Immunol ; 129(4): 983-9.e6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22365654

RESUMO

BACKGROUND: Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation. OBJECTIVE: We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients. METHODS: This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials. RESULTS: There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified. CONCLUSIONS: In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely.


Assuntos
Antiasmáticos/efeitos adversos , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Neoplasias/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Omalizumab , Risco , Adulto Jovem
13.
J Neuromuscul Dis ; 10(4): 685-699, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37248912

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was -4.2 (0.7) (95% CI -5.5, -2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/genética , Distrofina , Anticorpos Monoclonais/uso terapêutico , Fator de Crescimento do Tecido Conjuntivo
14.
Am J Epidemiol ; 176(11): 1014-24, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23139248

RESUMO

Asthma has been associated with increased cardiovascular disease (CVD) risk. The authors ascertained the association of asthma with CVD and the roles that sex, concurrent allergy, and asthma medications may play in this association. They assembled a cohort of 203,595 Northern California adults with asthma and a parallel asthma-free referent cohort (matched 1:1 on age, sex, and race/ethnicity); both cohorts were followed for incident nonfatal or fatal CVD and all-cause mortality from January 1, 1996, through December 31, 2008. Each cohort was 66% female and 47% white. After adjustment for age, sex, race/ethnicity, cardiac risk factors, and comorbid allergy, asthma was associated with a 1.40-fold (95% confidence interval (CI): 1.35, 1.45) increased hazard of coronary heart disease, a 1.20-fold (95% CI: 1.15, 1.25) hazard of cerebrovascular disease, a 2.14-fold (95% CI: 2.06, 2.22) hazard of heart failure, and a 3.28-fold (95% CI: 3.15, 3.41) hazard of all-cause mortality. Stronger associations were noted among women. Comorbid allergy predicted CVD but did not synergistically increase the CVD risk associated with asthma. Only asthma patients using asthma medications (particularly those on oral corticosteroids alone or in combination) were at enhanced risk of CVD. In conclusion, asthma was prospectively associated with increased risk of major CVD. Modifying effects were noted for sex and asthma medication use but not for comorbid allergy.


Assuntos
Asma/tratamento farmacológico , Asma/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Doença das Coronárias/epidemiologia , Insuficiência Cardíaca/epidemiologia , Adulto , Algoritmos , Asma/etnologia , California/epidemiologia , Estudos de Casos e Controles , Transtornos Cerebrovasculares/classificação , Transtornos Cerebrovasculares/etnologia , Comorbidade , Intervalos de Confiança , Doença das Coronárias/classificação , Doença das Coronárias/etnologia , Feminino , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/etnologia , Humanos , Incidência , Masculino , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Risco , Fatores Sexuais
15.
Crit Care Med ; 40(5): 1532-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22511134

RESUMO

OBJECTIVE: We sought to examine trends in the race-specific incidence of acute respiratory failure in the United States. DESIGN: Retrospective cohort study. SETTING: We used the National Hospital Discharge Survey database (1992-2007), an annual survey of approximately 500 hospitals weighted to provide national hospitalization estimates. PATIENTS: All incident cases of noncardiogenic acute respiratory failure hospitalized in the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified noncardiogenic acute respiratory failure by the presence of International Classification of Diseases, Ninth Revision, codes for respiratory failure or pulmonary edema (518.4, 518.5, 518.81, and 518.82) and mechanical ventilation (96.7×), excluding congestive heart failure. Incidence rates were calculated using yearly census estimates standardized to the age and sex distribution of the 2000 census population. Annual cases of noncardiogenic acute respiratory failure increased from 86,755 in 1992 to 323,474 in 2007. Noncardiogenic acute respiratory failure among black Americans increased from 56.4 (95% confidence interval 39.7-73.1) to 143.8 (95% confidence interval 123.8-163.8) cases per 100,000 in 1992 and 2007, respectively. Among white Americans, the incidence of noncardiogenic acute respiratory failure increased from 31.2 (95% confidence interval 26.2-36.5) to 94.0 (95% confidence interval 86.7-101.2) cases per 100,000 in 1992 and 2007, respectively. The average annual incidence of noncardiogenic acute respiratory failure over the entire study period was 95.1 (95% confidence interval 93.9-96.4) cases per 100,000 for black Americans compared to 66.5 (95% confidence interval 65.8-67.2) cases per 100,000 for white Americans (rate ratio 1.43, 95% confidence interval 1.42-1.44). Overall in-hospital mortality was greater for other-race Americans, but only among patients with two or more organ failures (57% [95% confidence interval 56%-59%] for other race, 51% [95% confidence interval 50%-52%] for white, 50% [95% confidence interval 49%-51%] for black). CONCLUSIONS: The incidence of noncardiogenic acute respiratory failure in the United States increased between 1992 and 2007. Black and other-race Americans are at greater risk of developing noncardiogenic acute respiratory failure compared to white Americans.


Assuntos
Grupos Raciais/estatística & dados numéricos , Insuficiência Respiratória/epidemiologia , Doença Aguda , Fatores Etários , População Negra/estatística & dados numéricos , Feminino , Disparidades nos Níveis de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos
16.
J Asthma ; 49(6): 642-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22793527

RESUMO

BACKGROUND: Asthma guidelines emphasize the importance of achieving and maintaining asthma control; however, many patients with moderate to severe asthma fail to achieve adequate control. OBJECTIVE: This 2-year interim analysis evaluated the longitudinal effects of omalizumab on asthma control in patients treated in real-world clinical practice settings. METHODS: EXCELS is an ongoing observational cohort study of approximately 5000 omalizumab-treated and 2500 non-omalizumab-treated patients aged ≥12 years with moderate to severe asthma. Asthma control was measured using the Asthma Control Test (ACT) every 6 months. RESULTS: Subgroups of the omalizumab cohort included those who initiated omalizumab at baseline (new starts, n = 549) and those treated with omalizumab >7 days before baseline (established users, n = 4421). For reference, data are also presented for patients who were not receiving omalizumab prior to or at the time of enrolment (non-omalizumab, n = 2867). Over half of the new starts (54%) achieved improvement in ACT consistent with the minimally important difference (MID, defined as ≥3-point improvement) by Month 6 and this proportion increased throughout the follow-up period, reaching 62% at Month 24. Similar results were observed in patients stratified by moderate and severe asthma. Established users of omalizumab maintained asthma control throughout the observation period. CONCLUSION: Over a 2-year period, patients initiating omalizumab therapy experienced clinically relevant improvements in asthma control, which were maintained during 2 years of longitudinal follow-up. Established users of omalizumab maintained asthma control over the 2-year period with a small improvement similar to that seen in non-omalizumab users.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Adulto , Asma/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Omalizumab , Resultado do Tratamento
17.
Am J Respir Crit Care Med ; 183(12): 1660-5, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21471091

RESUMO

RATIONALE: Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied. OBJECTIVES: We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma. METHODS: We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI. MEASUREMENTS AND MAIN RESULTS: Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22-8.68; P = 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15-8.04; OR for active smoking, 2.77; 95% CI, 1.28-5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse. CONCLUSIONS: Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar/complicações , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Ferimentos não Penetrantes/complicações , Adulto , Cotinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome do Desconforto Respiratório/etiologia
18.
Am J Respir Crit Care Med ; 184(5): 561-8, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21562125

RESUMO

RATIONALE: ß2-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies. OBJECTIVES: This clinical trial was designed to test the hypothesis that an aerosolized ß2-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI). METHODS: We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. MEASUREMENTS AND MAIN RESULTS: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P = 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95%confidence interval for the difference,-4.0 to 14.7%;P = 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. CONCLUSIONS: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of ß2-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).


Assuntos
Lesão Pulmonar Aguda/terapia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Albuterol/administração & dosagem , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/mortalidade , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Albuterol/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia
19.
Ann Intern Med ; 154(9): 573-82, 2011 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-21536936

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) and long-acting ß(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN: Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING: 193 investigational sites in the United States and 4 sites in Canada. PATIENTS: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE: Genentech and Novartis Pharmaceuticals.


Assuntos
Antialérgicos/uso terapêutico , Antiasmáticos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Administração por Inalação , Adolescente , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Antialérgicos/efeitos adversos , Antiasmáticos/efeitos adversos , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Prospectivos , Qualidade de Vida , Adulto Jovem
20.
Prim Care Respir J ; 21(2): 194-201, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22453663

RESUMO

BACKGROUND: Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. AIMS: To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD). METHODS: We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30 kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO. RESULTS: Of 371 subjects (aged 40-65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67 ± 9 m; 95% CI 50 to 84 m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO. CONCLUSIONS: Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.


Assuntos
Pneumopatias Obstrutivas/complicações , Obesidade/complicações , Atividades Cotidianas , Índice de Massa Corporal , Feminino , Humanos , Entrevistas como Assunto , Pneumopatias Obstrutivas/epidemiologia , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/epidemiologia , Obesidade/fisiopatologia , Razão de Chances , Aptidão Física , Estudos Prospectivos , Análise de Regressão , Fumar/efeitos adversos , Espirometria
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