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2.
N Engl J Med ; 383(23): 2242-2254, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33264546

RESUMO

BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).


Assuntos
Anemia/tratamento farmacológico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária/prevenção & controle , Quinolinas/uso terapêutico , Assistência ao Convalescente , Pré-Escolar , Combinação de Medicamentos , Doenças Endêmicas , Feminino , Humanos , Lactente , Quênia/epidemiologia , Malária/epidemiologia , Masculino , Readmissão do Paciente/estatística & dados numéricos , Uganda/epidemiologia
3.
PLoS One ; 15(11): e0242068, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33170905

RESUMO

INTRODUCTION: Infection with Human Immunodeficiency Virus (HIV) is highly prevalent worldwide, especially in Sub-Saharan Africa, where anaemia is also widespread. HIV infection is known to be associated with anaemia and various other haematologic alterations, but little data on correlation with immunological and virologic conditions in treatment-naïve patients and impact on mortality are available. Our study aims to investigate hematologic features in HIV-infected individuals in Malawi and Mozambique and assesses possible correlations with early morality. MATERIAL AND METHODS: We conducted a retrospective analysis of baseline data (general details, nutritional status, full blood count and HIV infection progress data) and 12 months follow-up status for HIV+ adult patients in 22 health facilities in Malawi (11 sites) and Mozambique (11 sites) run by DREAM program. Anagraphic details, anthropometric characteristics, full blood count, CD4+ count and Viral Load data were collected from electronical medical records (EMR) for all the HIV-positive, treatment-naïve patients starting care in the sites in the period January 2007 -December 2016. Follow-up status after one year since enrolment in care was also considered. All the data extracted from the EMR were included in a dataset and then analysed. Univariate and multivariate analysis were conducted through logistical regression to investigate associations, and survival analysis analysed in a Cox regression model. RESULTS: On the whole, 22.657 patients were included; severe and moderate anaemia were observed in 1.174 (8,2%) and 4.703 (21,9%) patients respectively. Gender, nutritional status, CD4+ count, and viral load (VL) were associated with anaemia, leukopenia, and thrombocytopenia. Among 21.166 fully evaluable patients, 8.494 (40,1%) had at least one cytopenia. Any cytopenia was present in 1/3 of patients with normal nutritional status and less advanced HIV infection, and it wouldn't be diagnosed in a basic HIV care setting. During the first year of treatment, 1.725 subjects (7,6% of the entire sample) died. Anaemia, lower Red blood cells and platelets counts correlated with mortality in the first year of care, independently by body mass index, haemoglobin, CD4+ count and VL. CONCLUSIONS: Notwithstanding anaemia is known to be associated with HIV infection at diagnosis, full blood count is not routinely performed in many African countries. Our results emphasize that including the study of a broader set of parameters in the routine HIV care services in Sub-Saharan Africa would provide significant clinical information able to predict other alterations and poor outcomes.


Assuntos
Anemia/epidemiologia , Infecções por HIV/epidemiologia , Infecções por HIV/mortalidade , Adulto , África ao Sul do Saara/epidemiologia , Anemia/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade/métodos , Índice de Massa Corporal , Contagem de Linfócito CD4/métodos , Contagem de Linfócito CD4/tendências , Estudos de Coortes , Comorbidade , Feminino , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Malaui/epidemiologia , Masculino , Moçambique/epidemiologia , Estado Nutricional , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carga Viral/fisiologia
4.
Sci Rep ; 10(1): 20202, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214633

RESUMO

Alterations in hemodialysis patients' serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients' chromium and antimony levels exceeded established accepted upper limits of normal.


Assuntos
Anemia/sangue , Hematínicos/administração & dosagem , Falência Renal Crônica/sangue , Diálise Renal , Insuficiência Renal Crônica/sangue , Oligoelementos/sangue , Anemia/tratamento farmacológico , Anemia/etiologia , Feminino , Ferritinas/sangue , Hemoglobina A Glicada/análise , Hematínicos/uso terapêutico , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia
5.
Lancet Diabetes Endocrinol ; 8(11): 903-914, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33065060

RESUMO

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors might enhance erythropoiesis and increase red blood cell mass. We assessed the long-term effects of canagliflozin on anaemia-related outcomes. METHODS: In a post-hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we included patients with type 2 diabetes and chronic kidney disease who were randomly assigned to treatment with canagliflozin or placebo at 690 sites in 34 countries. We assessed the effects of canagliflozin versus matched placebo on haemoglobin and haematocrit using linear mixed-effects models. The primary outcome of this post-hoc analysis was a composite outcome of investigator-reported anaemia or treatment for anaemia, which was assessed using Kaplan-Meier analysis and Cox regression models. All analyses were done by intention to treat. FINDINGS: Between March 24, 2014, and May 5, 2017, 4401 participants were randomly assigned to receive canagliflozin (100 mg; n=2202) or placebo (n=2199). At baseline, mean haemoglobin concentration was 132·0 g/L (SD 17·7), 1599 (36%) of 4401 participants had anaemia (defined as haemoglobin <130 g/L in men or <120 g/L in women), and 33 (<1%) of 4401 participants used erythropoiesis-stimulating agents. During a median follow-up period of 2·6 years (IQR 2·1-3·1), mean haemoglobin concentration was 7·1 g/L (95% CI 6·4-7·8) higher and haematocrit was 2·4% (2·2-2·6) higher in the canagliflozin group than the placebo group. Overall, 573 of 4401 participants had either an investigator-reported anaemia event or initiation of treatment for anaemia: 358 (8%) of 4401 participants reported anaemia events, 343 (8%) initiated iron preparations, 141 (3%) initiated erythropoiesis-stimulating agents, and 114 (2%) received blood transfusion. The risk of the composite outcome of anaemia events or initiation of treatment for anaemia was lower in the canagliflozin group than the placebo group (hazard ratio 0·65, 95% CI 0·55-0·77; p<0·0001). Compared with the placebo group, participants in the canagliflozin group also had lower risks of anaemia events alone (0·58, 0·47-0·72; p<0·0001), initiation of iron preparations (0·64, 0·52-0·80; p<0·0001), and need for erythropoiesis-stimulating agents (0·65, 0·46-0·91; p=0·012). INTERPRETATION: These data suggest that canagliflozin reduces the risk of anaemia-associated outcomes, including the need for erythropoiesis-stimulating agents, among patients with type 2 diabetes and chronic kidney disease. FUNDING: Janssen Research and Development.


Assuntos
Anemia/tratamento farmacológico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Anemia/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Resultado do Tratamento
6.
J Pharmacol Sci ; 144(4): 229-236, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070842

RESUMO

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/complicações , Adenina/efeitos adversos , Anemia/tratamento farmacológico , Anemia/etiologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Inibidores de Prolil-Hidrolase , Pirazóis/uso terapêutico , Triazóis/uso terapêutico , Lesão Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Eritropoetina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Triazóis/administração & dosagem , Triazóis/farmacologia
7.
Medicine (Baltimore) ; 99(44): e22799, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126317

RESUMO

BACKGROUND: As far as we know, several systematic review and meta-analysis have assessed the safety and efficacy of erythropoiesis-stimulating agents (ESAs) in the patients with chemotherapy-induced anemia (CIA). But no study assesses the safety and efficacy of ESAs combined with traditional Chinese medicine (TCM). The aim of our study is to assess the efficacy and safety of ESAs combination with TCM for patients with CIA and will provide a higher level of evidence for clinical applications. METHODS: This protocol adheres to the preferred reporting items for systematic reviews and meta-analysis protocol statement. The source of literature will be a structured search of the following 7 electronic databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Database. Records will be independently evaluated by 2 reviewers. Disagreements will be resolved through consensus or third-party adjudication. Review Manager 5.3 software (Cochrane Collaboration, Copenhagen Denmark) will be used to perform meta-analysis. For dichotomous variables, odds ratio with 95% confidence intervals will be obtained by the Mantel-Haenszel method. For continuous data, mean difference with 95% confidence intervals will be used. P < 0.05 will be considered to be statistically significant. RESULTS: This study will be performed to test the efficacy and safety of ESAs combined with TCM for CIA in patients with cancer. CONCLUSIONS: The result of this study will be promoted mainly in 2 ways: publish in peer-reviewed journals in the fastest way; and promotion in domestic and foreign conferences. INPLASY REGISTRATION NUMBER: INPLASY202080041.


Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Medicina Tradicional Chinesa/normas , Metanálise como Assunto , Anemia/etiologia , Protocolos Clínicos , Tratamento Farmacológico/métodos , Eritropoetina/normas , Humanos , Medicina Tradicional Chinesa/métodos , Revisões Sistemáticas como Assunto
8.
Rev. Hosp. Ital. B. Aires (2004) ; 40(3): 105-116, sept. 2020. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1129064

RESUMO

Este trabajo tiene como objetivo revisar las contribuciones de la biotecnología, en relación con el tratamiento, diagnóstico y la monitorización de la enfermedad renal crónica (ERC) y sus comorbilidades más frecuentes, especialmente la anemia. En relación con los tratamientos, enfocamos el desarrollo de productos biofarmacéuticos como los agentes estimulantes de la eritropoyesis (ESA), que fueron los primeros biofármacos utilizados para el tratamiento de la anemia asociada a la ERC; analizamos sus características y utilización actual después de varios años de experiencia clínica, así como también otras alternativas en desarrollo. Revisamos distintos tipos de bioterapias, la utilización de las células estromales mesenquimales de médula ósea (MSC) y tratamientos alternativos con modificaciones dietarias, que se basan en la asociación entre la microbiota intestinal de los pacientes renales crónicos y sus condiciones fisiopatológicas. Finalmente, en relación con el diagnóstico y monitorización, nos referimos al estudio y validación de biomarcadores diagnósticos, predictivos y terapéuticos que han permitido optimizar los resultados clínicos en este tipo de pacientes. (AU)


The aim of this work is to review the contributions of biotechnology, in relation to the treatment, diagnosis and monitoring of chronic kidney disease (CKD) and its most frequent comorbidities, especially anemia. Regarding the treatment, we focus on the development of biopharmaceutical products such as erythropoiesis stimulating agents (ESA), which were the first biopharmaceuticals used to treat anemia associated with chronic kidney disease (CKD). We analyzed their characteristics and their current use after several years of clinical experience, as well as other alternatives in development. We also review different types of biotherapies, the use of bone marrow mesenchymal stromal cells (MSC) and alternative treatments with dietary modifications, which are based on the association between the intestinal microbiota of chronic kidney patients and their pathophysiological conditions. Finally, in relation to diagnosis and monitoring, we refer to the study and validation of diagnostic, predictive and therapeutic biomarkers that have made clinical results possible to be optimized in this type of patient. (AU)


Assuntos
Humanos , Terapia Biológica/tendências , Insuficiência Renal Crônica/terapia , Qualidade de Vida , Biotecnologia , Biomarcadores , Eritropoetina/deficiência , Probióticos/uso terapêutico , Transplante de Células-Tronco Mesenquimais/tendências , Eritropoese/efeitos dos fármacos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/reabilitação , Prebióticos/classificação , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Microbioma Gastrointestinal , Hematínicos/administração & dosagem , Hematínicos/farmacologia , Hematínicos/farmacocinética , Anemia/diagnóstico , Anemia/etiologia , Anemia/tratamento farmacológico
10.
Sci Rep ; 10(1): 16029, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994444

RESUMO

A large proportion of end-stage renal disease (ESRD) patients under long-term haemodialysis, have persistent anaemia and require high doses of recombinant human erythropoietin (rhEPO). However, the underlying mechanisms of renal anaemia have not been fully elucidated in these patients. In this study, we will be focusing on anaemia and plasma proteins in ESRD patients on high-flux haemodialysis (HF) and on-line haemodiafiltration (HDF), to investigate using two proteomic approaches if patients undergoing these treatments develop differences in their plasma protein composition and how this could be related to their anaemia. The demographic and biochemical data revealed that HDF patients had lower anaemia and much lower rhEPO requirements than HF patients. Regarding their plasma proteomes, HDF patients had increased levels of a protein highly similar to serotransferrin, trypsin-1 and immunoglobulin heavy constant chain alpha-1, and lower levels of alpha-1 antitrypsin, transthyretin, apolipoproteins E and C-III, and haptoglobin-related protein. Lower transthyretin levels in HDF patients were further confirmed by transthyretin-peptide quantification and western blot detection. Since ESRD patients have increased transthyretin, a protein that can aggregate and inhibit transferrin endocytosis and erythropoiesis, our finding that HDF patients have lower transthyretin and lower anaemia suggests that the decrease in transthyretin plasma levels would allow an increase in transferrin endocytosis, contributing to erythropoiesis. Thus, transthyretin could be a critical actor for anaemia in ESRD patients and a novel player for haemodialysis adequacy.


Assuntos
Anemia/tratamento farmacológico , Eritropoetina/administração & dosagem , Falência Renal Crônica/terapia , Pré-Albumina/metabolismo , Proteômica/métodos , Diálise Renal/classificação , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/etiologia , Proteínas Sanguíneas/análise , Cromatografia Líquida , Regulação para Baixo , Eritropoetina/uso terapêutico , Feminino , Hemodiafiltração/métodos , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Diálise Renal/métodos , Espectrometria de Massas em Tandem
11.
Leuk Res ; 97: 106430, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32763582

RESUMO

Myelodysplastic syndromes (MDS) encompass a clinically heterogenous group of diseases defined by a clonal bone marrow failure state. Patients with lower-risk MDS primarily suffer from the consequences of anemia, with a subset having increased risks of bleeding and infection. There are few good therapeutic options for this patient population, as patients are dependent on cytokine support to improve hematopoiesis. Our review will discuss luspatercept, a transforming growth factor (TGF)-Beta ligand trap, the first new Food & Drug Administration (FDA)-approved treatment in MDS in over a decade. We will explore the different TGF-Beta ligand traps that have been developed for a number of diseases, with a focus on myeloid malignancies.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Anemia/tratamento farmacológico , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Anemia/patologia , Animais , Humanos , Síndromes Mielodisplásicas/patologia
12.
J Med Chem ; 63(17): 10045-10060, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787144

RESUMO

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Glicina/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Inibidores de Prolil-Hidrolase/uso terapêutico , Anemia/induzido quimicamente , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cisplatino , Cães , Desenho de Fármacos , Eritropoetina/metabolismo , Feminino , Glicina/farmacocinética , Glicina/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/toxicidade , Inibidores de Prolil-Hidrolase/síntese química , Inibidores de Prolil-Hidrolase/farmacocinética , Inibidores de Prolil-Hidrolase/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Med. clín (Ed. impr.) ; 155(4): 152-158, ago. 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-195761

RESUMO

ANTECEDENTES Y OBJETIVO: La mielofibrosis es una neoplasia mieloproliferativa crónica infrecuente. Nuestro objetivo fue describir las características clínico-biológicas, el tratamiento y el curso evolutivo de los pacientes con mielofibrosis en España. MATERIAL Y MÉTODOS: Se analizaron 1.000 pacientes del Registro Español de Mielofibrosis diagnosticados de mielofibrosis primaria (n=641) o secundaria (n=359). RESULTADOS: La mediana de edad era de 68 años. La frecuencia de sintomatología constitucional, anemia moderada o severa (Hb<10g/dl) y esplenomegalia sintomática fue del 35, 36 y 17%, respectivamente. La incidencia de trombosis y hemorragia fue de 1,96 y 1,6 eventos por 100 años-paciente, respectivamente. La incidencia acumulada de leucemia fue del 15% a los 10 años. Para la anemia se emplearon principalmente agentes eritropoyéticos y danazol. A partir del 2010 se observó un incremento significativo del uso de ruxolitinib. Un 7,5% de los pacientes fue trasplantado. El 42% de los enfermos falleció, debido principalmente al deterioro clínico provocado por la mielofibrosis y a la transformación leucémica. La supervivencia mediana de la serie fue de 5,7 años. El IPSS identificó 4 grupos de riesgo: la supervivencia mediana no se alcanzó en el de bajo riesgo, mientras que fue de 8,8 años, 5,3 años y 2,8 años en los de riesgo intermedio-1, intermedio-2 y alto, respectivamente. CONCLUSIONES: la mielofibrosis es una enfermedad invalidante que afecta sobre todo a personas de edad avanzada y cuyo tratamiento es fundamentalmente sintomático. A pesar de su heterogeneidad clínica se dispone de modelos pronósticos útiles para la selección de candidatos a trasplante


Background and objective Myelofibrosis: is an infrequent chronic myeloproliferative neoplasm. We aimed to describe the clinico-biological characteristics, treatment, and evolutive course of myelofibrosis patients in Spain. MATERIAL AND METHODS: A total of 1,000 patients from the Spanish Registry of Myelofibrosis diagnosed with primary (n=641) or secondary (n=359) myelofibrosis were analysed. RESULTS: Median age was 68 years. The frequency of constitutional symptoms, moderate to severe anaemia (Hb<10g/dL), and symptomatic splenomegaly was 35%, 36%, and 17%, respectively. The rate of thrombosis and haemorrhage was 1.96 and 1.6 events per 100 patient-years, respectively. The cumulative incidence of leukaemia at 10 years was 15%. The most frequent therapies for the anaemia were the erythropoiesis stimulating agents and danazol. From 2010, a progressive increase in the use of ruxolitinib was noticed. A total of 7.5% of patients were transplanted. During the observation period, 42% of patients died mainly due to the clinical deterioration caused by myelofibrosis or leukaemic transformation. The median survival of the series was 5.7 years. Four different risk categories were identified by the IPSS: median survival was not reached in the low risk group and was 8.8 years, 5.3 years, and 2.8 years in the intermediate-1, intermediate-2, and high-risk groups, respectively. CONCLUSIONS: Myelofibrosis is a disabling condition mainly affecting elderly people. Its treatment is mostly driven by symptom control. Despite its clinical heterogeneity, several prognostic models are useful to select candidates for transplantation


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/patologia , Espanha/epidemiologia , Registros , Trombose/epidemiologia , Hemorragia/epidemiologia , Leucemia/epidemiologia , Anemia/tratamento farmacológico , Anemia/epidemiologia , Prognóstico , Grupos de Risco , Taxa de Sobrevida
14.
Cochrane Database Syst Rev ; 8: CD012451, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32790892

RESUMO

BACKGROUND: Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion. OBJECTIVES: To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery. SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery. We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight. DATA COLLECTION AND ANALYSIS: Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation). MAIN RESULTS: Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively. We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens. Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I2 = 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group. Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I2 = 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI -0.46 to 0.69; participants = 334; studies = 4; I2 = 69%; low-quality evidence due to inconsistency and risk of bias). There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD -0.09, 95% CI -0.23 to 0.05; participants = 1420; studies = 6; I2 = 2%; moderate-quality evidence due to imprecision).  There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I2 = 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I2 = 0%; moderate-quality evidence due to imprecision). The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD -1.07, 95% CI -4.12 to 1.98; participants = 293; studies = 3; I2 = 87%; low-quality evidence due to inconsistency and imprecision). AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient. There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.


Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Ferro/uso terapêutico , Cuidados Pré-Operatórios/métodos , Procedimentos Cirúrgicos Operatórios , Adulto , Anemia/sangue , Procedimentos Cirúrgicos do Sistema Digestório , Transfusão de Eritrócitos/estatística & dados numéricos , Feminino , Procedimentos Cirúrgicos em Ginecologia , Hemoglobina A/metabolismo , Humanos , Tempo de Internação , Masculino , Procedimentos Ortopédicos , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/uso terapêutico , Procedimentos Cirúrgicos Operatórios/mortalidade
15.
PLoS Med ; 17(6): e1003091, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511251

RESUMO

BACKGROUND: Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. METHODS AND FINDINGS: We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. CONCLUSIONS: Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02599012.


Assuntos
Anemia/tratamento farmacológico , Compostos Férricos/uso terapêutico , Maltose/análogos & derivados , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Biomarcadores/sangue , Eritropoetina/sangue , Feminino , Compostos Férricos/administração & dosagem , Hemoglobinas/análise , Hepcidinas/sangue , Humanos , Infusões Intravenosas , Masculino , Maltose/administração & dosagem , Maltose/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Projetos Piloto , República da Coreia , Transferrina/análise , Resultado do Tratamento
16.
J Pharmacol Exp Ther ; 374(2): 342-353, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32487538

RESUMO

Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1α and HIF-2α proteins, leading to an increase in EPO production, even in the presence of EPO-suppressing inflammatory cytokines. Roxadustat administered intermittently to healthy rats and cynomolgus monkeys increased circulating EPO levels, reticulocytes, blood Hb, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after five-sixth nephrectomy and in a rat model of anemia of inflammation with impaired iron metabolism induced by peptidoglycan-polysaccharide (PG-PS). In the PG-PS model, roxadustat significantly decreased hepatic expression of hepcidin, a hormone responsible for iron sequestration and functional iron deficiency, and increased expression of two genes involved in duodenal iron absorption: divalent metal transporter 1 and duodenal cytochrome b. In conclusion, by activating the HIF pathway, roxadustat increased EPO production, elevated Hb, corrected anemia, and improved iron homeostasis. The coordinated erythropoietic response stimulated by roxadustat, involving both EPO production and mobilization of iron stores, makes this compound a promising treatment of anemia of CKD and anemia associated with functional iron deficiency. SIGNIFICANCE STATEMENT: Roxadustat is a novel orally available small-molecule inhibitor of HIF prolyl hydroxylase enzymes that reversibly stabilizes HIF-α, thus activating transcription of HIF-dependent genes, including EPO and regulators of iron homeostasis. Activation of the HIF pathway by roxadustat induces erythropoiesis in healthy rats and monkeys and corrects experimentally induced anemia in rats. The coordinated erythropoietic response that increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of chronic kidney disease and anemia associated with functional iron deficiency.


Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Glicina/análogos & derivados , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/farmacologia , Insuficiência Renal Crônica/complicações , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Eritropoese/efeitos dos fármacos , Eritropoetina/metabolismo , Glicina/farmacocinética , Glicina/farmacologia , Glicina/uso terapêutico , Haplorrinos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoquinolinas/farmacocinética , Isoquinolinas/uso terapêutico , Masculino , Ratos
19.
Transfusion ; 60(5): 932-939, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32358832

RESUMO

BACKGROUND: Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time. STUDY DESIGN AND METHODS: Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records. RESULTS: Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived. CONCLUSIONS: Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC.


Assuntos
Anemia/tratamento farmacológico , Transfusão de Sangue , Contraindicações , Hemoglobinas/administração & dosagem , Adulto , Idoso , Anemia/diagnóstico , Anemia/patologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hemoglobinas/efeitos adversos , Humanos , Assistência de Longa Duração/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Reação Transfusional/prevenção & controle , Resultado do Tratamento , Adulto Jovem
20.
Clin Nephrol ; 94(1): 36-42, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32352372

RESUMO

INTRODUCTION: Hemodialysis patients frequently suffer from anemia. Proper utilization of therapies such as iron and erythropoiesis-stimulating agents (ESAs) is crucial to attain symptom management and established hemoglobin targets. The purpose of this study was to evaluate the clinical and financial impact of nephrology-trained pharmacists on anemia management in these patients. MATERIALS AND METHODS: A retrospective study of outpatient hemodialysis patients observed between January 2010 and December 2011. In December 2010, pharmacists were tasked to manage anemia under a medical directive. Primary endpoints were compared across years using a mixed-effects model strategy. An unstructured random effects correlation matrix was utilized to capture patient-level variation in 2010 and 2011, separately. RESULTS: Of 202 patients identified, 163 contributed in both years, 57% were males, aged 65.18 ± 16.3 years. Hemoglobin levels were 10.95 ± 0.95 and 10.83 ± 0.94 g/dL in 2010 vs. 2011, respectively (p = 0.158), while the transfusion rate was 1.3% and 1.8%, respectively (p = 0.196). Ferritin levels of 273.5 ± 22 and 317.1 ± 12 ng/mL (p = 0.0019), iron saturation 0.30 ± 0.11 and 0.30 ± 0.05 (p = 0.838), and parenteral iron dose of 215.4 ± 100.2 and 317.1 ± 123.7 mg, respectively (p = 0.996), were identified. Finally, the average weekly ESA dose in 2010 was higher and trending up as compared to 2011 where it significantly trended down. The amount of intravenous erythropoietin alfa was 12,315.6 ± 76 vs. 11,364.1 ± 52 units/week, respectively (p = 0.0556) with expenditure of 2.8 million Canadian dollars in 2010 vs. 2.3 million Canadian dollars in 2011. CONCLUSION: The participation of a nephrology pharmacist resulted in favorable outcomes in dose optimization, decreased expenditure, and positive trends in therapeutic goal achievement.


Assuntos
Anemia/tratamento farmacológico , Farmacêuticos , Diálise Renal/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Anemia/etiologia , Canadá , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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