RESUMO
Adenosine A2A receptor (A2AR) agonists reduce invariant natural killer T (iNKT) cell activation and decrease inflammation in sickle cell disease (SCD) mice. We conducted a phase 1 trial of the A2AR agonist regadenoson in adults with SCD. The target dose was 1.44 µg/kg/h. iNKT cell activation was evaluated using antibodies targeting the p65 subunit of nuclear factor-κB (phospho-NF-κB p65), interferon-γ (IFN-γ), and A2AR. Regadenoson was administered to 27 adults with SCD. We examined 21 patients at steady state and 6 during painful vaso-occlusive crises (pVOC). iNKT cell activation was also measured in 14 African-American controls. During pVOC, the fraction of iNKT cells demonstrating increased phospho-NF-κB p65 and A2AR expression was significantly higher compared with controls (P < .01) and steady-state patients (P < .05). IFN-γ expression was also significantly higher compared with controls (P = .02). After a 24-hour infusion of regadenoson during pVOC, phospho-NF-κB p65 activation in iNKT cells decreased compared to baseline by a median of 48% (P = .03) to levels similar to controls and steady-state SCD. No toxicities were identified. Infusional regadenoson administered to adults with SCD at 1.44 µg/kg/h during pVOC decreases activation of iNKT cells without toxicity.
Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Células T Matadoras Naturais/metabolismo , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Receptor A2A de Adenosina/química , Doenças Vasculares/tratamento farmacológico , Agonistas do Receptor A2 de Adenosina/farmacocinética , Adulto , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Infusões Intravenosas , Interferon gama/metabolismo , Masculino , Fosforilação , Prognóstico , Purinas/farmacocinética , Pirazóis/farmacocinética , Receptor A2A de Adenosina/metabolismo , Distribuição Tecidual , Fator de Transcrição RelA/metabolismo , Doenças Vasculares/metabolismo , Doenças Vasculares/patologiaRESUMO
BACKGROUND: Patients with sickle cell disease (SCD) can suffer frequent hospital admissions for painful vasoocclusive crises. Hydroxyurea was approved by the FDA in 1998 to decrease the morbidity of SCD, but nationwide hospitalizations for SCD in the United States since 1998 have not been evaluated. We hypothesized that the availability of hydroxyurea for SCD would be associated with a decrease in hospitalizations for SCD over time. OBJECTIVE: To assess trends in hospitalization and length-of-stay in hospital for SCD in the United States, 1998 through 2008. RESEARCH DESIGN: Retrospective cohort study of SCD-related hospital discharges in the Nationwide Inpatient Sample of US hospital discharges. SUBJECTS: All discharges in the Nationwide Inpatient Sample associated with a principal diagnosis of SCD in blacks, 1998 through 2008. MEASURES: Trends in hospitalization rates and average length-of-stay in hospital for SCD. RESULTS: We found 216 (95% confidence interval, 173.3-258.7) SCD-related hospitalizations per 100,000 US blacks in 1998 and 178.4 (95% confidence interval, 144.2-212.5) in 2008, but no consistent yearly decrease, 1998 through 2008 (P=0.30). Conversely, the length-of-stay in hospital in 1998 was 5.38 days and in 2008 was 5.18 days, an absolute change of 0.2 days and a downward trend that was statistically significant. CONCLUSIONS: Between 1998 and 2008, there was not a steady decrease in hospitalization rates for the population of SCD in the United States. On the contrary, there was a decline in length-of-stay in hospital over this time. Hydroxyurea underuse is well documented. Efforts to increase hydroxyurea use may help to reduce hospitalization rates.
Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Aprovação de Drogas , Hospitalização/estatística & dados numéricos , Hidroxiureia/uso terapêutico , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologia , United States Food and Drug Administration , Adulto JovemRESUMO
Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.
Assuntos
Síndrome Torácica Aguda/diagnóstico , Síndrome Torácica Aguda/etiologia , Anemia Falciforme/complicações , Fosfolipases A2 Secretórias/sangue , Síndrome Torácica Aguda/sangue , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Prognóstico , Adulto JovemAssuntos
Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Adulto , Antidrepanocíticos/administração & dosagem , Antidrepanocíticos/efeitos adversos , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Masculino , VorinostatRESUMO
Oral iron replacement is the standard therapy in iron-deficiency anemia (IDA). However, 59% of patients have gastrointestinal toxicity. With impaired iron uptake from the gastrointestinal tract (in anemia of chronic disease (ACD) or after bariatric surgery), suboptimal responsiveness to exogenous erythropoietin (in chronic renal failure), in patients with cancer receiving chemotherapy, or when oral iron is poorly tolerated, IV iron therapy is the preferred mode of repletion. Although effective in increasing hemoglobin, the relative safety of the available IV iron preparations is not well documented. We examined the comparative safety of IV iron formulations used at hospitals associated with our institution. Among 619 unique patients who received IV iron over a 2-year period, we found 32 adverse events (AEs), ranging from urticaria to chest pain. There were no serious AEs or anaphylactic-type reactions. In a multivariate model, there was no difference in AE rates between low-molecular-weight iron dextran (LMWD) and ferric gluconate; however, iron sucrose had significantly higher odds ratio of AEs (OR = 5.7; 95% CI = 1.621.3). Our data suggest that AE rates with IV iron are acceptable. More widespread use of LMWD, in particular, which can be given safely as a total dose infusion (TDI), should be considered.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/efeitos adversos , Ácido Glucárico/efeitos adversos , Hematínicos/efeitos adversos , Complexo Ferro-Dextran/efeitos adversos , Anemia Ferropriva/sangue , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/uso terapêutico , Óxido de Ferro Sacarado , Ácido Glucárico/administração & dosagem , Ácido Glucárico/uso terapêutico , Hematínicos/administração & dosagem , Hematínicos/uso terapêutico , Hemoglobinas/análise , Humanos , Injeções Intravenosas , Complexo Ferro-Dextran/administração & dosagem , Complexo Ferro-Dextran/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos RetrospectivosRESUMO
A humanized murine sickle cell-disease (SCD) model (NY1DD) has been used to study ischemia/reperfusion injury (IRI) in sickle cell anemia, and iNKT cells (a very small subset of murine and human T cells) have been found to instigate such injury in this model. Furthermore, levels of activated iNKT cells are generally elevated in the circulation of patients with SCD. Because activated iNKT cells are rich in adenosine A2A receptors which, when agonized, down-regulate the inflammatory cytokine expression that characterizes the cells, we have conducted a phase 1 trial of a constant infusion of low-dose regadenoson (an adenosine analogue with high A2A receptor specificity) to determine its safety and the capacity of a safe dose to down-regulate circulating iNKT cells in patients with SCD. We have found two dose rates that are both safe and effective and now plan a controlled Phase 2B clinical trial to determine whether our highest dose, administered as a 48-hour constant infusion, will induce faster remission in both painful vaso-occlusive crisis (pVOC) and acute chest syndrome (ACS).
Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/patologia , Células T Matadoras Naturais/patologia , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Agonistas do Receptor A2 de Adenosina/administração & dosagem , Contagem de Células , Relação Dose-Resposta a Droga , Humanos , Infusões Intravenosas , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
CONTEXT: Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE: To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES: The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. RESULTS: There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION: Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094887.
Assuntos
Anemia Falciforme/complicações , Fatores Relaxantes Dependentes do Endotélio/administração & dosagem , Óxido Nítrico/administração & dosagem , Dor/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Medição da Dor , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Linfócitos B , Deficiência de IgA , Fator de Transcrição Ikaros/genética , Células Matadoras Naturais , Imunodeficiência Combinada Severa , Hiperplasia do Timo , Adolescente , Animais , Feminino , Humanos , Camundongos , Camundongos Knockout , Mutação , Receptores de Antígenos de Linfócitos T/fisiologia , Imunodeficiência Combinada Severa/genética , Transdução de Sinais , Timoma/imunologia , Neoplasias do Timo/imunologiaRESUMO
BACKGROUND: Oral iron-replacement therapy is the mainstay of treatment for iron-deficiency anemia, but it is often poorly tolerated or ineffective. Hemoglobin response at day 14 of oral iron may be useful in assessing whether and when to transition patients from oral to intravenous (IV) iron. METHODS: Pooled data from 5 randomized trials were analyzed to compare oral and IV iron-replacement therapy for iron-deficiency anemia. Treatment criteria and assignment to oral versus IV iron were defined per protocol; this analysis included only subjects receiving oral iron. Responders were subjects with ≥1.0-g/dL increases in hemoglobin at day 14, and nonresponders were those with smaller increases. Demographic and clinical characteristics were evaluated for association with hemoglobin response at multiple timepoints. RESULTS: Most subjects (72.8%) were classified as responders. The proportion of subjects with hemoglobin increases ≥1.0, ≥2.0, and ≥3.0 g/dL was greatest among those with postpartum anemia, intermediate among those with heavy uterine bleeding or gastrointestinal-related causes of anemia, and lowest among those with other causes; this proportion was also significantly greater among responders than nonresponders. A ≥1.0-g/dL increase in hemoglobin on day 14 most accurately predicted satisfactory overall hemoglobin response to oral iron on day 42/56 (sensitivity 90.1%; specificity 79.3%; positive and negative predictive values of 92.9% and 72.7%, respectively). Iron-replacement therapy improved quality of life and reduced fatigue. CONCLUSION: Hemoglobin responses <1.0 g/dL at day 14 of oral iron identify subjects with iron-deficiency anemia who should be transitioned to IV iron supplementation.
Assuntos
Administração Intravenosa , Administração Oral , Anemia Ferropriva/tratamento farmacológico , Ferritinas/efeitos dos fármacos , Compostos Ferrosos/administração & dosagem , Hemoglobinas/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Ferropriva/complicações , Suplementos Nutricionais , Fadiga/etiologia , Feminino , Ferritinas/sangue , Compostos Ferrosos/uso terapêutico , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Resultado do Tratamento , Adulto JovemRESUMO
Sickle cell disease (SCD) is a severe genetic disorder of hemoglobin causing vaso-occlusion. Patients suffer severe anemia, strokes, renal failure, pulmonary compromise and shortened life expectancy. Over 90,000 people in the USA have SCD, and the options for therapy are limited and only partially effective. With the available therapies - hydroxyurea, blood transfusion, hydration and pain medicines - patients continue to suffer the long-term complications of the disease. This review focuses on the pathogenesis of SCD and the role of fetal hemoglobin in disrupting the polymerization of sickle hemoglobin. The authors review the compounds that induce fetal hemoglobin: hydroxyurea, which is currently US FDA approved, and the histone deacetylase inhibitors and discuss their role in the treatment of SCD and other ß-hemoglobinopathies.
Assuntos
Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Antidrepanocíticos/uso terapêutico , Hemoglobina Fetal/metabolismo , Hemoglobina Falciforme/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Hidroxiureia/uso terapêutico , Anemia Falciforme/patologia , Animais , Antidrepanocíticos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Hidroxiureia/farmacologiaRESUMO
Anemia in pregnancy is a global health problem affecting nearly half of all pregnant women worldwide. High fetal demands for iron render iron deficiency the most common cause of anemia of pregnancy, with other micronutrient deficiencies contributing less frequently. In certain geographical populations, human pathogens such as hookworm, malarial parasite and human immunodeficiency virus are important factors in anemia of pregnancy. The hemoglobinopathies, sickle cell disease and thalassemia, represent diverse causes of anemia of pregnancy, requiring specialized care. Aplastic anemia is a rare, morbid cause of anemia of pregnancy and is managed with transfusions until the completion of pregnancy.