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1.
N Engl J Med ; 381(6): 509-519, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199090

RESUMO

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Benzaldeídos/administração & dosagem , Hemoglobina Falciforme/efeitos dos fármacos , Hemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina Falciforme/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Polimerização/efeitos dos fármacos , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Adulto Jovem
2.
Ann Hematol ; 98(8): 1805-1812, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31030250

RESUMO

Sickle cell disease (SCD) is a relatively common inherited hemolytic anemia among individuals of African descent. Genetic factors might clarify clinical diversity of the disease and variations in treatment response. Some researchers investigated heme oxygenase-1 (HMOX1) or chemokine receptor 5 (CCR5Δ32) genotypes among SCD patients and their correlation with fetal hemoglobin (HbF) and disease severity. However, there are no such records among Arab nations. We aimed to estimate the prevalence of the HMOX1-413 A>T (rs2071746) and CCR5Δ32 (rs333) polymorphisms, and to assess their effect on SCD phenotype and HbF level among Egyptian patients. Polymerase chain reaction assay was used to determine these polymorphisms among 100 SCD patients and 100 healthy controls. Though not statistically significant, the frequency of individual carrying HMOX-1 polymorphic AT and TT genotypes in both patient and control groups was 92% and 85% respectively. Regarding CCR5Δ32 polymorphisms, all SCD patients harbored the wild genotype (100%), while the heteromutant genotype was encountered in 2% of our controls. Patients harboring mutant HMOX-1 had a less frequent vaso-occlusive crisis (VOC)/lifetime, less VOC in the last year, less incidence of stroke, less frequency of hospitalization, and responded more frequently to hydroxyurea with statistically significant differences (p = 0.028, 0.007, 0.046, 0.007, and 0.011 respectively). No significant associations with HbF level or other hematologic parameters were encountered among our cohort. Our study results suggest a protective effect of mutant HMOX-1 genotypes in ameliorating the phenotypic severity of the disease. HMOX1-413 A>T (rs2071746) polymorphisms might prove to be a prognostic marker among Egyptian SCD, but not CCR5Δ32 (rs333) polymorphisms.


Assuntos
Anemia Falciforme/genética , Heme Oxigenase-1/genética , Polimorfismo Genético , Receptores CCR5/genética , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/etnologia , Anemia Falciforme/patologia , Antidrepanocíticos/uso terapêutico , Árabes , Estudos de Casos e Controles , Criança , Pré-Escolar , Egito , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Expressão Gênica , Genótipo , Heme Oxigenase-1/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Hidroxiureia/uso terapêutico , Masculino , Fenótipo , Receptores CCR5/metabolismo , Índice de Gravidade de Doença
4.
N Engl J Med ; 379(3): 226-235, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30021096

RESUMO

BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Glutamina/uso terapêutico , Hidroxiureia/uso terapêutico , Manejo da Dor , Administração Oral , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glutamina/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Dor/prevenção & controle , Adulto Jovem , Talassemia beta/tratamento farmacológico
5.
Pediatr Clin North Am ; 65(3): 427-443, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29803275

RESUMO

Sickle cell disease (SCD) complications begin with the polymerization of sickle hemoglobin (HbS). Thus, SCD therapies are focused on preventing HbS production or reducing the circulating amount of HbS. Hydroxyurea treatment has become more widespread, whereas the number of evidence-based indications for erythrocyte transfusion is small. Hematopoietic stem cell transplant is a curative option for SCD but less than 25% of patients have a suitable donor. This article focuses on supportive and preventive care improvements and the benefits of hydroxyurea. Indications for erythrocyte transfusion, hematopoietic stem cell transplant, and gene therapy trials are also summarized.


Assuntos
Anemia Falciforme/terapia , Anemia Falciforme/complicações , Anemia Falciforme/mortalidade , Antidrepanocíticos/uso terapêutico , Transfusão de Eritrócitos , Transplante de Células-Tronco Hematopoéticas , Humanos , Hidroxiureia/uso terapêutico
6.
Pediatr Clin North Am ; 65(3): 445-464, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29803276

RESUMO

We have entered an era of exploding interest in therapeutics for sickle cell disease. The expansion in our understanding of sickle cell disease pathophysiology has enhanced the range of potential therapeutic targets. From induction of fetal hemoglobin to antiadhesion molecules, we are potentially on the cusp of making life-altering modifications for individuals with sickle cell disease. This disease population cannot afford to let the current momentum wane. Studies exploring combinations of therapies affecting multiple steps in the pathophysiology and exploring novel and clinically relevant outcomes are incumbent.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Drogas em Investigação/uso terapêutico , Hemoglobina Fetal/efeitos dos fármacos , Humanos
7.
Dis Markers ; 2018: 6105691, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619129

RESUMO

This study investigated associations between SNPs in genes encoding metabolizing drug enzymes and laboratory parameters in sickle cell anemia patients under hydroxyurea (SCA-HU+). We evaluated hematologic and biochemical parameters by electronic methods and SNPs by PCR-RFLP and multiplex PCR in 35 SCA-HU+ patients and 67 SCA-HU- patients. The HbS, total cholesterol, lactate dehydrogenase, aspartate aminotransferase, total bilirubin and fractions levels, and leukocyte, eosinophil, monocyte, and erythroblast counts were reduced in SCA-HU+ patients (p < 0.05). Moreover, they presented higher HbF, C-reactive protein, and ferritin levels and elevated MCH and MCV values (p < 0.05). Genotype frequencies of variants GA + AA of MPO -463G>A and c1c2 + c2c2 of CYP2E1 -1293G>C/-1053C>T were higher in SCA-HU+ patients (p < 0.05). Independent associations were found between the variant A allele and lower total cholesterol, between c2 allele and low alpha-1 antitrypsin and between the null GSTT1 variant and high indirect and total bilirubin in SCA-HU+ patients. In SCA-HU- patients, independent associations were found between the variant A allele and high uric acid and between c2 allele and high urea. Our results suggest that SNPs MPO -463G>A, CYP2E1 -1293G>C/-1053C>T, and GSTT1 can be associated with alterations in lipid, inflammatory, renal, hemolytic, and hepatic profiles. However, further studies are needed to elucidate these associations.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Hidroxiureia/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Anemia Falciforme/genética , Biomarcadores/análise , Criança , Pré-Escolar , Citocromo P-450 CYP2E1/genética , Feminino , Glutationa Transferase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Peroxidase/genética , Adulto Jovem
9.
Int J Mol Sci ; 19(3)2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29495591

RESUMO

In sickle cell disease (SCD), hydroxyurea (HU) treatment decreases the number of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) by increasing fetal hemoglobin (HbF). Data are lacking regarding the frequency of HU dose modification or whether sub-therapeutic doses (<15 mg/kg/day) are beneficial. We reviewed the medical records of 140 patients from 2010 to 2014. The laboratory parameters and SCD complications were compared between the first and last visits based on HU use. Fifty patients (36%) never took HU or suspended HU ("no HU" group). Among patients taking <15 mg/kg/day HU on their first visit, half remained at the same dose, and the other half increased to ≥15 mg/kg/day. Among patients taking ≥15 mg/kg/day, 17% decreased to <15 mg/kg/day, and 83% stayed at ≥15 mg/kg/day. The "no HU" group had fewer episodes of VOC and ACS. Both HU treatment groups had a reduction in both complications (p < 0.0001). This improvement was observed in all SCD phenotypes. The white blood cell (WBC) counts were found to be lower, and HbF increased in both HU groups (p = 0.004, 0.001). The maximal HbF response to HU in HbS/ß⁺-thalassemia was 20%, similar to those observed for HbSS (19%) and HbS/ß°-thalassemia (22%). HbS/ß⁺-thalassemia could have a similar disease severity as HbSS or HbS/ß°-thalassemia. Patients with HbS/ß°-thalassemia or HbS/ß⁺-thalassemia phenotypes responded to HU.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Anemia Falciforme/mortalidade , Antidrepanocíticos/administração & dosagem , Criança , Pré-Escolar , Índices de Eritrócitos , Feminino , Seguimentos , Testes de Função Cardíaca , Humanos , Hidroxiureia/administração & dosagem , Lactente , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/diagnóstico , Talassemia beta/mortalidade
10.
Am J Dermatopathol ; 40(9): 682-685, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29533274

RESUMO

We report a case in which a 43-year-old African American male with medical history of sickle cell disease (SCD) presented with a nonhealing ulcer. Biopsy revealed features of livedoid vasculopathy. Previously, livedoid vasculopathy had only been described in a patient with sickle cell trait, but never in a patient with SCD. Livedoid vasculopathy most commonly affects the distal lower extremities and is characterized by irregular, punched-out, painful ulcers that heal with stellate white scars of atrophie blanche. Histologically, it reveals segmental hyalinizing vessels, focal thrombosis, and endothelial proliferation. The etiology is currently unclear, but it has been shown to be related to procoagulant states and a diagnosis of livedoid vasculopathy should prompt a thorough hypercoagulable workup, including testing for SCD in high-risk patients.


Assuntos
Anemia Falciforme/complicações , Úlcera da Perna/patologia , Livedo Reticular/patologia , Pele/irrigação sanguínea , Adulto , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Biópsia , Inibidores do Fator Xa/uso terapêutico , Humanos , Úlcera da Perna/etiologia , Úlcera da Perna/terapia , Livedo Reticular/etiologia , Livedo Reticular/terapia , Masculino , Inibidores da Agregação de Plaquetas/uso terapêutico , Fatores de Risco , Transplante de Pele , Resultado do Tratamento
11.
Cochrane Database Syst Rev ; 2: CD004448, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29446825

RESUMO

BACKGROUND: Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an update of a Cochrane Review first published in 2004, and updated in 2010, 2013, and 2015. OBJECTIVES: To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 10 April 2017; ISRCTN: 26 July 2017; AMED: 24 August 2017; ClinicalTrials.gov: 02 August 2017; and the WHO ICTRP: 27 July 2017. SELECTION CRITERIA: Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. MAIN RESULTS: Two trials (182 participants) and two phytomedicines Niprisan® (also known as Nicosan®) and Ciklavit® were included. The Phase IIB (pivotal) trial suggests that Niprisan® was effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not affect the risk of severe complications or the level of anaemia (low-quality evidence). No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises (low-quality evidence), and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). AUTHORS' CONCLUSIONS: While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with sickle cell disease and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit®. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in sickle cell disease. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing sickle cell disease.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Anemia/induzido quimicamente , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Humanos , Extratos Vegetais/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Br J Haematol ; 180(2): 189-200, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29143315

RESUMO

Fetal haemoglobin (HbF, α2γ2) induction has long been an area of investigation, as it is known to ameliorate the clinical complications of sickle cell disease (SCD). Progress in identifying novel HbF-inducing strategies has been stymied by limited understanding of gamma (γ)-globin regulation. Genome-wide association studies (GWAS) have identified variants in BCL11A and HBS1L-MYB that are associated with HbF levels. Functional studies have established the roles of BCL11A, MYB, and KLF1 in γ-globin regulation, but this information has not yielded new pharmacological agents. Several drugs are under investigation in clinical trials as HbF-inducing agents, but hydroxycarbamide remains the only widely used pharmacologic therapy for SCD. Autologous transplant of edited haematopoietic stem cells holds promise as a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, and pharmacological therapies are still needed.


Assuntos
Anemia Falciforme/terapia , Hemoglobina Fetal/biossíntese , Anemia Falciforme/etiologia , Anemia Falciforme/metabolismo , Animais , Antidrepanocíticos/farmacologia , Antidrepanocíticos/uso terapêutico , Ensaios Clínicos como Assunto , Hemoglobina Fetal/química , Hemoglobina Fetal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Terapia Genética , Humanos , Resultado do Tratamento
15.
J Stroke Cerebrovasc Dis ; 27(2): 425-431, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29056404

RESUMO

BACKGROUND AND OBJECTIVES: Hydroxyurea (HU) was recently described as a substitute for chronic transfusion for children with sickle cell disease (SCD) and abnormal transcranial Doppler (TCD) velocities who have received at least 1 year of transfusions. However, the role of HU in reverting elevated TCD velocities in patients not treated with transfusion is still debatable. The objective of the study was to examine whether HU influences the progression of TCD velocities in children with SCD. PATIENTS AND METHODS: Children with SCD with at least 2 TCDs not less than 6 months apart were evaluated over 51 months. Time-averaged maximum mean (TAMM) velocities for the initial and the last transcranial Doppler examinations were noted and differences compared between HU and HU-naive groups. RESULTS: Overall, 68.8% of the HU-group with elevated TCD velocities compared with 40.0% of the HU-naive experienced TCD reversal (P = .047). A higher proportion of the HU-naive group, 7 (14.3%) versus 9.8% of the HU group experienced TCD conversion. Those with initial conditional velocities in the HU-group experienced a significant reduction in TAMM velocities (from 176.8 ± 5.3 to 162.7 ± 13.9 cm/s, difference of 14.1 cm/s; P = .001) unlike those in the HU-naive group (176.3 ± 5.3 to 170.0 ± 18.6 cm/s, difference of 6.3 cm/s; P = .148). The change in the TAMM velocities was also significantly higher among the HU-group (14.1 ± 12.4 cm/s versus 6.3 ± 18.5 cm/s, P = .015). CONCLUSION: Our data suggest a beneficial role of HU in TCD velocity reduction in patients not treated with chronic transfusions, particularly among those with initial conditional TCD velocities.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Hidroxiureia/uso terapêutico , Ultrassonografia Doppler Transcraniana , Adolescente , Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
16.
Semin Hematol ; 55(2): 68-75, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30616808

RESUMO

Sickle cell disease is an inherited hemoglobinopathy characterized by hemolytic anemia, frequent painful episodes, poor quality of life, end organ damage and a shortened lifespan. Although the seminal event is the polymerization of the abnormal hemoglobin, the downstream pathophysiology of vaso-occlusion results from heterotypic interactions between the altered, adhesive sickle cell RBCs, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These downstream targets are the focus of emerging treatments with considerable potential to ameliorate disease manifestations. This review summarizes the progress on development of these agents.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Terapia de Alvo Molecular/métodos , Anemia Falciforme/complicações , Anemia Falciforme/fisiopatologia , Anti-Infecciosos/uso terapêutico , Anticoagulantes/uso terapêutico , Adesão Celular/efeitos dos fármacos , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Eritrócitos/fisiologia , Hemólise , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Qualidade de Vida
17.
Semin Hematol ; 55(2): 53-59, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30616807

RESUMO

The mutation of ß6 from glu to val in hemoglobin is responsible for the polymer formation that leads to vaso-occlusion, and a range of severe consequences in sickle cell disease. The treatment of the disease can be addressed in many ways, but the prevention of polymer formation is one of the most fundamental approaches one can take. Such prevention includes affecting the polymer structure, or dilution of the fraction of polymerizable hemoglobin. The latter approach includes (1) induction of HbF, which does not itself, nor in hybrid form, join sickle polymers, or (2) restricting the allosteric change in hemoglobin that occurs in oxygen delivery, and which is required for polymer formation. These approaches will be critically reviewed, as well as the most recent developments that show the benefits of simply swelling the volume of the red cell.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/farmacologia , Hemoglobina Falciforme/química , Hemoglobinas/química , Regulação Alostérica/efeitos dos fármacos , Antidrepanocíticos/uso terapêutico , Humanos , Terapia de Alvo Molecular/métodos , Consumo de Oxigênio/efeitos dos fármacos , Polimerização/efeitos dos fármacos
18.
Adv Exp Med Biol ; 1013: 1-26, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29127675

RESUMO

Sickle cell disease (SCD) and ß-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5-7% of the world's population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and ß-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for ß-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.


Assuntos
Anemia Falciforme/terapia , Talassemia beta/terapia , Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , Antidrepanocíticos/uso terapêutico , Transfusão de Eritrócitos/métodos , Terapia Genética/métodos , Humanos , Hidroxiureia/uso terapêutico , Talassemia beta/genética , Talassemia beta/fisiopatologia
19.
Blood ; 130(24): 2585-2593, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29051184

RESUMO

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.


Assuntos
Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , Hidroxiureia/uso terapêutico , Malária/epidemiologia , Anemia Falciforme/sangue , Antidrepanocíticos/uso terapêutico , Contagem de Células Sanguíneas , Pré-Escolar , Método Duplo-Cego , Doenças Endêmicas , Feminino , Hemoglobina Fetal/metabolismo , Humanos , Incidência , Lactente , Masculino , Estudos Prospectivos , Resultado do Tratamento , Uganda/epidemiologia
20.
PLoS One ; 12(9): e0184076, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28863145

RESUMO

BACKGROUND: Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA). An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA. METHODS: This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6-18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP), glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU) and those who were not. RESULTS: Flow-mediated vasodilation (FMD) values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS) episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not. CONCLUSIONS: Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/complicações , Endotélio Vascular/fisiopatologia , Doenças Vasculares/sangue , Doenças Vasculares/complicações , Adolescente , Antidrepanocíticos/uso terapêutico , Bilirrubina/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Criança , Células Endoteliais/patologia , Feminino , Glucose/análise , Humanos , Hidroxiureia/uso terapêutico , Contagem de Leucócitos , Lipoproteínas/sangue , Masculino , Oxiemoglobinas/análise , Reticulócitos/citologia , Ultrassonografia Doppler , Doenças Vasculares/diagnóstico por imagem
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