Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.731
Filtrar
1.
Einstein (Sao Paulo) ; 17(4): eAO4742, 2019 Sep 09.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31508660

RESUMO

OBJECTIVE: To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea. METHODS: The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted. RESULTS: Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups. CONCLUSION: In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.


Assuntos
Anemia Falciforme/genética , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Criança , Pré-Escolar , Citocinese , Dano ao DNA/genética , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/efeitos adversos , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Adulto Jovem
2.
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
3.
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.
Vox Sang ; 114(4): 325-329, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30937917

RESUMO

BACKGROUND: Normal saline has been the fluid of choice for resuscitation, rehydration and fluid replacement during plasma or red cell exchange/cytapheresis. There are increased concerns about its clinical effects and data showing it causes more haemolysis in vitro than buffered solutions such as Plasma-Lyte A. METHODS: We investigated whether normal saline or Plasma-Lyte A was associated with greater haemolysis during hours of in vitro incubation with both normal red cells and samples from patients with sickle cell anaemia. RESULTS: Sickle red cells haemolysed more than normal red cells did in both crystalloid solutions. The results of 24-hour exposure to saline were particularly striking (median of 163 mg/dl (IQ range 105-247) for sickle red cells vs. 53 (48-92) for normal red cells (P < 0·0001). In patient samples containing variable quantities of haemoglobin S red cells, increased haemoglobin S was associated with increased haemolysis. This effect was greater for normal saline than Plasma-Lyte A (P = 0·12). CONCLUSIONS: These in vitro models demonstrate that short-term ex vivo exposure of sickle red cells to normal saline leads to greater haemolysis than short-term exposure of normal red cells, and this effect is exacerbated by normal saline. Whether use of normal saline causes increased haemolysis in vivo is unknown. Given recent evidence that normal saline increases renal failure and mortality in critically ill patients, further studies are urgently needed.


Assuntos
Eletrólitos/química , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Solução Salina/química , Anemia Falciforme/tratamento farmacológico , Anticoagulantes , Transfusão de Sangue , Estado Terminal , Contagem de Eritrócitos , Hidratação , Testes Hematológicos , Hemoglobina Falciforme/análise , Humanos , Segurança do Paciente , Plasma , Ressuscitação , Cloreto de Sódio/química
5.
Cutis ; 103(2): 93-94, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30893386

RESUMO

Plaque psoriasis is a chronic inflammatory disease driven by the proliferation of T cells and the production of several immunomodulators such as tumor necrosis factor (TNF) α. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. We present a patient with plaque psoriasis and sickle cell disease who began treatment with the TNF-α inhibitor adalimumab. With this treatment, the patient had improvement in both psoriasis and sickle cell disease symptoms. Tumor necrosis factor α inhibitors may be the drug of choice in patients with both psoriasis and sickle cell disease.


Assuntos
Adalimumab/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Psoríase/tratamento farmacológico , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Antirreumáticos/uso terapêutico , Feminino , Humanos , Psoríase/complicações , Psoríase/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
6.
Ann Hematol ; 98(4): 841-849, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30783732

RESUMO

Inhaled mometasone was shown to improve pain scores and decrease soluble vascular cell adhesion molecule (sVCAM) concentration in a randomized controlled trial of nonasthmatic patients with sickle cell disease. We sought to explore potential changes in systemic inflammation as a mechanism underlying this effect. Serum samples from 41 trial participants (15 placebo- and 26 mometasone-treated) were analyzed using a 92 inflammatory marker panel at baseline and after 8 weeks of mometasone therapy. Individual marker analysis and correlation analysis were conducted. Adjusted for age, the mometasone-treated group decreased the concentration of CXCL9, CXCL11, CD40, IL-10, and IL-18 relative to placebo-treated participants. Hierarchical clustering and correlation analysis identified additional evidence for a decrease in cytokines linking to macrophage signaling and migration. There was no statistically significant change in markers of asthma and allergy, indicating that the improvement was unlikely mediated by modulation of occult reactive airway disease. This analysis of inflammatory markers suggests that decrease in macrophage activity may be involved in the mediation of the clinical benefit seen with use of inhaled mometasone in nonasthmatic patients with sickle cell disease.Trial registration: clinicaltrials.gov identifier: NCT02061202.


Assuntos
Anemia Falciforme/tratamento farmacológico , Macrófagos/metabolismo , Furoato de Mometasona/administração & dosagem , Dor/tratamento farmacológico , Administração por Inalação , Adulto , Anemia Falciforme/sangue , Asma/sangue , Biomarcadores/sangue , Antígenos CD40/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Feminino , Humanos , Interleucina-10/sangue , Interleucina-18/sangue , Masculino , Pessoa de Meia-Idade , Dor/sangue
7.
Artif Cells Nanomed Biotechnol ; 47(1): 95-103, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30739524

RESUMO

Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and deform red blood cells (RBC) into the sickle shape. A novel carboxyhaemoglobin-based oxygen carrier (PEG-COHb; PP-007) promotes unsickling in vitro by relieving RBC hypoxia. An in vivo rat model of vaso-occlusive crisis (VOC) capable of accommodating a suite of physiological and microcirculatory measurements was used to compare treatment with PEG-COHb to a non-oxygen carrying control solution (lactated ringer's [LRS]). Male Sprague-Dawley rats were anesthetized and surgically prepared to monitor microvascular interstitial oxygenation (PISFO2), cardiovascular parameters and blood chemistry. Human homozygous SCD RBCs were isolated and exchange transfused into the rats until the distal microcirculation of the exteriorized spinotrapezius muscle was hypoxic and RBC aggregates were visualized. VOC was left untreated (Sham) or treated 15 min later with PEG-COHb or LRS and observed for up to 4 h. Treatment with PEG-COHb showed better improvement of PISFO2, end-point lactate, mean arterial pressure and survival duration compared to Sham and LRS. Restoring PISFO2 was associated with relieving the RBC aggregates driving VOC, which then affected other study metrics. Compared to LRS, PEG-COHb's oxygen-carrying properties were key to improved outcomes.


Assuntos
Anemia Falciforme , Substitutos Sanguíneos , Carboxihemoglobina , Microcirculação/efeitos dos fármacos , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Animais , Substitutos Sanguíneos/química , Substitutos Sanguíneos/farmacologia , Carboxihemoglobina/química , Carboxihemoglobina/farmacologia , Humanos , Masculino , Oxigênio/sangue , Ratos , Ratos Sprague-Dawley
8.
Vox Sang ; 114(2): 178-181, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30695814

RESUMO

Disturbances in the physiological regulation of erythropoietin (EPO) in patients with sickle cell disease (SCD) may contribute to worsening anaemia and increased transfusion requirements, but the use of recombinant EPO in this group of patients is controversial. The objective of this study was to evaluate the use of this drug in adult patients with SCD and its effects on haemoglobin levels and transfusion requirements. We conducted a retrospective analysis at the University of Campinas, with nineteen adults with a diagnosis of SCD (HbSS and HbS/ß+ thalassaemia), who had received at least 1 year of EPO therapy between 2007 and 2014. Haemoglobin concentrations and trends of variation in transfused RBC volumes were compared before and after EPO administration. We observed that seven patients had a good response to treatment (Hb increment higher than 1·5 g/dl) and nine had a partial response (0·5-1·5 g/dl increment) and there was a significant decrease in the need for transfusion amongst those who usually required regular transfusions. There were no increases in the rates of vaso-occlusive crisis or venous thromboembolism in comparison to the year before the onset of the therapy. Erythropoietin therapy led to a marked increase in haemoglobin concentration with a concomitant decrease in the demand for transfusion. Considering all complications related to allogeneic transfusion, we believe that EPO therapy represents an important therapeutic tool in sickle cell anaemia.


Assuntos
Anemia Falciforme/tratamento farmacológico , Eritropoetina/uso terapêutico , Adulto , Anemia Falciforme/terapia , Transfusão de Eritrócitos/efeitos adversos , Eritropoetina/administração & dosagem , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
11.
BMC Infect Dis ; 18(1): 650, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541465

RESUMO

BACKGROUND: About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients. METHODS: We searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square. RESULTS: Six qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total, seven different interventions (Chloroquine, Mefloquine, Mefloquine artesunate, Proguanil, Pyrimethamine, Sulfadoxine-pyrimethamine, Sulfadoxine-pyrimethamine amodiaquine) were evaluated in 912 children with SCD. Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267-1.959; I2 = 0.0%), blood transfusion (OR = 0.83, 95% CI = 0.542-1.280; I2 = 29.733%), vaso-occlusive crisis (OR = 19, 95% CI = 1.713-2.792; I2 = 93.637%), and mortality (OR = 0.511, 95% CI = 0.189-1.384; I2 = 0.0%) did not differ between the intervention and placebo groups. CONCLUSION: The data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42016052514).


Assuntos
Anemia Falciforme/tratamento farmacológico , Antimaláricos/uso terapêutico , Quimioprevenção/métodos , Malária/prevenção & controle , África/epidemiologia , Anemia Falciforme/epidemiologia , Quimioprevenção/estatística & dados numéricos , Criança , Humanos , Malária/epidemiologia , Meta-Análise em Rede , Parasitemia/epidemiologia , Parasitemia/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Resultado do Tratamento
13.
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
14.
Science ; 361(6399): 285-290, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30026227

RESUMO

Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of ß-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain-focused CRISPR-Cas9-based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.


Assuntos
Anemia Falciforme/genética , Proteínas de Transporte/genética , Células Eritroides/metabolismo , Hemoglobina Fetal/genética , Regulação da Expressão Gênica , Proteínas Nucleares/genética , eIF-2 Quinase/genética , Anemia Falciforme/tratamento farmacológico , Sistemas CRISPR-Cas , Proteínas de Transporte/metabolismo , Linhagem Celular , Testes Genéticos , Humanos , Terapia de Alvo Molecular , Proteínas Nucleares/metabolismo , RNA Guia , eIF-2 Quinase/metabolismo
15.
Hematology ; 23(10): 856-863, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29848208

RESUMO

OBJECTIVES: In adults with sickle cell disease (SCD), pain often necessitates opioid use. Few studies have examined the relationship between opioid use and health-related quality of life (HRQOL) in adults with SCD. We tested the hypothesis that higher doses of opioids are associated with worse HRQOL. METHODS: A cross-sectional cohort study was performed in adults with SCD who completed standardized and validated HRQOL questionnaires: Patient Health Questionnaire-15 (PHQ-15), Patient Health Questionnaire-9 (PHQ-9), Medical Outcome Study 36 Item Short Form (SF-36), and Generalized Anxiety Disorder questionnaire (GAD-7). Daily outpatient opioid dose was converted into morphine milligram equivalents (MME) and categorized as < 90 mg/day or ≥ 90 mg/day. Subject's questionnaire scores were compared by opioid dose. RESULTS: Ninety-nine adults completed questionnaires. The majority had HbSS and median age was 30 years. The median MME was 80 mg/day. When the association between HRQOL and opioid dose was compared, those prescribed ≥ 90 MME had significantly lower SF-36 subscale scores in 7 of 8 domains, and significantly higher severity scores in the PHQ-15, GAD-7, and the PHQ-9 in comparison those prescribed < 90 MME. Using a multivariable regression tree analysis, in addition to the presence of chronic pain, mental health, physical health, and somatic burden were key predictors of ≥ 90 MME opioid use. CONCLUSION: Higher daily opioid dose is associated with chronic pain. Among those with chronic pain, opioid dose ≥ 90 MME is associated with worse HRQOL.


Assuntos
Anemia Falciforme , Transtornos de Ansiedade , Dor Crônica , Morfina/administração & dosagem , Qualidade de Vida , Inquéritos e Questionários , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/etiologia , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Estudos Transversais , Feminino , Humanos , Masculino
16.
Eur J Med Chem ; 154: 341-353, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29852459

RESUMO

N-oxide derivatives 5(a-b), 8(a-b), and 11(a-c) were designed, synthesized and evaluated in vitro and in vivo as potential drugs that are able to ameliorate sickle cell disease (SCD) symptoms. All of the compounds demonstrated the capacity to releasing nitric oxide at different levels ranging from 0.8 to 30.1%, in vivo analgesic activity and ability to reduce TNF-α levels in the supernatants of monocyte cultures. The most active compound (8b) protected 50.1% against acetic acid-induced abdominal constrictions, while dipyrone, which was used as a control only protected 35%. Compounds 8a and 8b inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Both compounds increased γ-globin in K562 cells at 100 µM. The mechanisms involved in the γ-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds. In vitro, the most promising compound (8b) was not cytotoxic, mutagenic and genotoxic.


Assuntos
Anemia Falciforme/tratamento farmacológico , Descoberta de Drogas , Histonas/metabolismo , Oxidiazóis/farmacologia , gama-Globinas/biossíntese , Ácido Acético/antagonistas & inibidores , Ácido Acético/farmacologia , Acetilação , Anemia Falciforme/metabolismo , Relação Dose-Resposta a Droga , Humanos , Células K562 , Estrutura Molecular , Óxido Nítrico/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
17.
Transfus ; 58(6): 1555-1566, June 2018.
Artigo em Inglês | BIGG | ID: biblio-987782

RESUMO

BACKGROUND Red blood cell (RBC) transfusions remain essential in the treatment of patients with sickle cell disease (SCD) and ß­thalassemia. Alloimmunization, a well­documented complication of transfusion, increases the risk of delayed hemolytic transfusion reactions, complicates crossmatching and identifying compatible units, and delays provision of transfusions. Guidance is required to optimize the RBC product administered to these patients. STUDY DESIGN AND METHODS An international, multidisciplinary team conducted a systematic review and developed, following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, recommendations to assist treating physicians and transfusion specialists in their decision to select RBCs for these patients. RESULTS Eighteen studies (17 clinical studies and one cost­effectiveness study) were included in the systematic review. The overall quality of the studies was very low. In total, 3696 patients were included: 1680 with ß­thalassemia and 2016 with SCD. CONCLUSION The panel recommends that ABO D CcEe K­matched RBCs are selected for individuals with SCD and ß­thalassemia, even in the absence of alloantibodies, to reduce the risk of alloimmunization. In patients with SCD and ß­thalassemia who have developed clinically significant alloantibodies, selection of RBCs antigen negative to the alloantibody is recommended, if feasible. In these patients, selection of more extended phenotype­matched RBCs will likely reduce the risk of further alloimmunization. However, given the limited availability of extended phenotype­matched units, attention should be given to ensure that a delay in transfusion does not adversely affect patient care.


Assuntos
Humanos , Transfusão de Eritrócitos , Hemoglobinopatias/terapia , Anemia Falciforme , Talassemia beta/terapia , Transfusão de Eritrócitos/estatística & dados numéricos , Eritrócitos/metabolismo , Reação Transfusional , Reação Transfusional/prevenção & controle , Isoanticorpos/uso terapêutico , Isoantígenos/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/terapia
18.
Expert Rev Clin Pharmacol ; 11(6): 641-650, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29727586

RESUMO

BACKGROUND: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis. METHODS: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy. RESULTS: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons. CONCLUSION: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials.


Assuntos
Anemia Falciforme/tratamento farmacológico , Quelantes de Ferro/uso terapêutico , Talassemia/tratamento farmacológico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Deferasirox , Deferiprona , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Desferroxamina/uso terapêutico , Quimioterapia Combinada , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro , Meta-Análise em Rede , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Silimarina/administração & dosagem , Silimarina/efeitos adversos , Silimarina/uso terapêutico , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/uso terapêutico
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA