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1.
Acta Biomed ; 92(4): e2021386, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34487059

RESUMO

Sickle cell disease (SCD) is traditionally associated with growth failure and delayed puberty. Wasting and stunting are still prevalent in children and adolescents with SCD, especially in developing countries. In addition, sperm abnormalities are frequent in males with SCD, with high rates of low sperm density, low sperm counts, poor motility, and increased abnormal morphology.  Severe anemia, vaso-occlusive attacks with ischemic injury to different organs including the pituitary gland and testis, and nutritional factors are incriminated in the pathogenesis of defective growth, puberty, and spermatogenesis. There is great phenotypic variability among patients with SCD. The variability in the clinical severity of SCA can partly be explained by genetic modifiers, including HbF level and co-inheritance of α-thalassemia. In the past, severe disease led to early mortality. Advancements in treatment have allowed patients with SCD to have a longer and better quality of life. For most patients, the mainstays of treatment are preventive and supportive. For those with severe SCD, three major therapeutic options are currently available: erythrocyte transfusion or exchange, hydroxyurea, and hematopoietic stem cell transplantation. In this mini-review, the authors tried to recognize, delineate, and update knowledge on abnormalities due to SCD from those created by the use of different treatment modalities.


Assuntos
Anemia Falciforme , Hidroxiureia , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos , Transfusão de Sangue , Humanos , Hidroxiureia/uso terapêutico , Quelantes de Ferro , Masculino , Puberdade , Qualidade de Vida , Espermatogênese
2.
J Opioid Manag ; 17(4): 301-310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34533824

RESUMO

INTRODUCTION: Sickle cell disease (SCD) is associated with recurrent complications and healthcare burden. Although SCD management guidelines differ based on age groups, little is known regarding actual utilization of preventative (hydroxyurea) and palliative therapies (opioid and nonopioid analgesics) to manage complications. This study assessed whether there were agerelated differences in SCD index therapy type and SCD-related medication utilization. DESIGN AND PATIENTS: Texas Medicaid prescription claims from September 1, 2011 to August 31, 2016 were retrospectively analyzed for SCD patients aged 2-63 years who received one or more SCD-related medications (hydroxyurea, opioid, or nonopioid analgesics). OUTCOME MEASURES: The primary outcomes were SCD index drug type and medication utilization: hydroxyurea adherence, and days' supply of opioid, and nonopioid analgesics. Chi-square, analysis of variance, and Kruskal-Wallis tests were used. RESULTS: Index therapy percentages for included patients (N = 2,339) were the following: opioids (45.7 percent), nonopioids (36.6 percent), dual therapy-opioids and nonopioids (11.2 percent), and hydroxyurea (6.5 percent), and they differed by age-groups (χ2 = 243.0, p < 0.0001). Hydroxyurea as index therapy was higher among children (2-12:9.1 percent) compared to adults (26-40:3.7 percent; 41-63:2.9 percent). Opioids as index therapy were higher among adults (18-25:48.0 percent; 26-40:54.9 percent; 41-63:65.2 percent) compared to children (2-12:36.6 percent). Mean hydroxyurea adherence was higher (p < 0.0001) for younger ages, and opioid days' supply was higher for older ages. CONCLUSIONS: Texas Medicaid SCD patients had low hydroxyurea utilization and adherence across all age groups. Interventions to increase the use of hydroxyurea and newer preventative therapies could result in better management of SCD-related complications and reduce the frequency of pain crises, which may reduce the need for opioid use.


Assuntos
Anemia Falciforme , Medicaid , Idoso , Analgésicos Opioides/efeitos adversos , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , Humanos , Hidroxiureia/uso terapêutico , Pessoa de Meia-Idade , Prescrições , Estudos Retrospectivos , Texas/epidemiologia , Estados Unidos/epidemiologia
3.
BMJ Open ; 11(8): e047949, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389570

RESUMO

INTRODUCTION: Pregnancy in sickle cell disease is fraught with many complications including pre-eclampsia (PE) and intrauterine growth restriction (IUGR). Previously, we found an abnormality in prostacyclin-thromboxane ratio in sickle cell pregnant women, a situation that is also found in non-sickle pregnancies with PE and unexplained IUGR. Low-dose aspirin (LDA) has been shown to reduce the incidence of PE and IUGR in high-risk women by reducing the vasoconstrictor thromboxane while sparing prostacyclin, in effect 'correcting' the ratio. It has been found to be safe for use in pregnancy but has not been tested in sickle cell pregnancy. We hypothesise that LDA will reduce the incidence of IUGR and PE in pregnant haemoglobin SS (HbSS) and haemoglobin SC (HbSC) women. METHODS AND ANALYSIS: This is a multisite, double blind, randomised controlled trial, comparing a daily dose of 100 mg aspirin to placebo, from 12 to 16 weeks' gestation until 36 weeks, in Lagos state, Nigeria. Four hundred and seventy-six eligible pregnant HbSS and HbSC women will be recruited consecutively, randomly assigned to either group and followed from recruitment until delivery. The primary outcome will be the incidence of birth weight below 10th centile for gestational age on INTERGROWTH 21 birth weight charts, or incidence of miscarriage or perinatal death. Secondary outcomes will include PE, maternal death, preterm delivery, perinatal death, number of crises, need for blood transfusion and complications such as infections and placental abruption. Analysis will be by intention to treat and the main treatment effects will be quantified by relative risk with 95% CI, at a 5% significance level. ETHICAL APPROVAL: Ethical approval has been granted by the Health Research and Ethics committees of the recruiting hospitals and the National Health Research and Ethics Committee. Study findings will be presented at conferences and published appropriately. TRAIL REGISTRATION NUMBER: PACTR202001787519553; Pre-results.


Assuntos
Anemia Falciforme , Pré-Eclâmpsia , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Aspirina , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/prevenção & controle , Humanos , Nigéria , Placenta , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/prevenção & controle , Gravidez , Resultado da Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Biophys J ; 120(12): 2543-2551, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33932439

RESUMO

An oxygen-affinity-modifying drug, voxelotor, has very recently been approved by the FDA for treatment of sickle cell disease. The proposed mechanism of action is by preferential binding of the drug to the R quaternary conformation, which cannot copolymerize with the T conformation to form sickle fibers. Here, we report widely different oxygen dissociation and oxygen association curves for normal blood in the presence of voxelotor and interpret the results in terms of the allosteric model of Monod, Wyman, and Changeux with the addition of drug binding. The model does remarkably well in quantitatively explaining a complex data set with just the addition of drug binding and dissociation rates for the R and T conformations. Whereas slow dissociation of the drug from R results in time-independent dissociation curves, the changing association curves result from slow dissociation of the drug from T, as well as extremely slow binding of the drug to T. By calculating true equilibrium curves from the model parameters, we show that there would be a smaller decrease in oxygen delivery from the left shift in the dissociation curve caused by drug binding if drug binding and dissociation for both R and T were rapid. Our application of the Monod, Wyman, and Changeux model demonstrates once more its enormous power in explaining many different kinds of experimental results for hemoglobin. It should also be helpful in analyzing oxygen binding and in vivo delivery in future investigations of oxygen-affinity-modifying drugs for sickle cell disease.


Assuntos
Anemia Falciforme , Preparações Farmacêuticas , Regulação Alostérica , Anemia Falciforme/tratamento farmacológico , Hemoglobinas/metabolismo , Humanos , Cinética , Oxigênio , Ligação Proteica
7.
Blood Adv ; 5(9): 2385-2390, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33944896

RESUMO

Sickle cell anemia (SCA) results from an abnormal sickle hemoglobin (HbS). HbS polymerizes upon deoxygenation, resulting in red blood cell (RBC) sickling and membrane damage that cause vaso-occlusions and hemolysis. Sickle RBCs contain less adenosine triphosphate and more 2,3-diphosphoglycerate than normal RBCs, which allosterically reduces hemoglobin (Hb) oxygen (O2) affinity (ie, increases the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen [P50]), potentiating HbS polymerization. Herein, we tested the effect of investigational agent FT-4202, an RBC pyruvate kinase (PKR) activator, on RBC sickling and membrane damage by administering it to Berkeley SCA mice. Two-week oral FT-4202 administration was well tolerated, decreasing HbS P50 to levels similar to HbA and demonstrating beneficial biological effects. In FT-4202-treated animals, there was reduced sickling in vivo, demonstrated by fewer irreversibly sickled cells, and improved RBC deformability, assessed at varying shear stress. Controlled deoxygenation followed by reoxygenation of RBCs obtained from the blood of FT-4202-treated mice showed a shift in the point of sickling to a lower partial pressure of oxygen (pO2). This led to a nearly 30% increase in RBC survival and a 1.7g/dL increase in Hb level in the FT-4202-treated SCA mice. Overall, our results in SCA mice suggest that FT-4202 might be a potentially useful oral antisickling agent that warrants investigation in patients with SCA.


Assuntos
Anemia Falciforme , Hemoglobina Falciforme , Anemia Falciforme/tratamento farmacológico , Animais , Antidrepanocíticos , Eritrócitos Anormais , Humanos , Camundongos , Piruvato Quinase
8.
Biophys J ; 120(11): 2138-2147, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861996

RESUMO

We have characterized the imbibed horizontal flow of sickle blood into 100-µm-diameter glass capillaries. We find that blood containing sickled cells typically traverses the capillaries between three and four times as slowly as oxygenated cells from the same patient for all genotypes tested, including SS, AS, SC and Sß+ thalassemia blood. Blood from SS patients treated with hydroxyurea has a viscosity intermediate between the SS and AA values. Blood containing cells that are not rigidified, such as normal red cells or oxygenated sickle cells, follows a simple Lucas-Washburn flow throughout the length of the 3-cm capillary. By fitting the flexible-cell data to the Lucas-Washburn model, a viscosity can be derived that is in good agreement with previous measurements over a range of volume fractions and is obtained using an apparatus that is far more complex. Deoxygenation sickles and thus rigidifies the cells, and their flow begins as Lucas-Washburn, albeit with higher viscosity than flexible cells. However, the flow further slows as a dense mass of cells forms behind the meniscus and increases in length as flow progresses. By assuming that the dense mass of cells exerts a frictional force proportional to its length, we derive an equation that is formally equivalent to vertical imbibition, even though the flow is horizontal, and this equation reproduces the observed behavior well. We present a simple theory using activity coefficients that accounts for this viscosity and its variation without adjustable parameters. In the course of control experiments, we have found that deoxygenation increases the flexibility of normal human red cells, an observation only recently published for mouse cells and previously unreported for human erythrocytes. Together, these studies form the foundation for an inexpensive and rapid point-of-care device to diagnose sickle cell disease or to determine blood viscosity in resource-challenged settings.


Assuntos
Anemia Falciforme , Capilares , Anemia Falciforme/tratamento farmacológico , Animais , Viscosidade Sanguínea , Eritrócitos , Eritrócitos Anormais , Humanos , Camundongos , Oxigênio
9.
Br J Pharmacol ; 178(17): 3463-3475, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33864386

RESUMO

BACKGROUND AND PURPOSE: Reduced bioavailability of NO, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vaso-occlusion and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP-amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNFα-induced inflammation in wild-type C57BL/6 mice and in 'humanised' mouse models of SCD. EXPERIMENTAL APPROACH: Effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. KEY RESULTS: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte-endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic agent, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFα-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte-endothelial cell interactions, improved blood flow and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat- than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-h urine excretion, plasma levels of cystatin C and urinary excretion of N-acetyl-ß-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. CONCLUSION AND IMPLICATIONS: Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion and kidney injury in mouse models of SCD and systemic inflammation.


Assuntos
Anemia Falciforme , Doenças Vasculares , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Animais , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Guanilil Ciclase Solúvel
10.
JAMA ; 325(15): 1513-1523, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877274

RESUMO

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.


Assuntos
Anemia Falciforme/tratamento farmacológico , Dor/tratamento farmacológico , Poloxâmero/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/complicações , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Dor/etiologia , Placebos/efeitos adversos , Placebos/uso terapêutico , Poloxâmero/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto Jovem
11.
Biochem Biophys Res Commun ; 554: 222-228, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33823382

RESUMO

Optical folding and rotation behavior of red blood cells (RBCs) in polarized laser tweezers are considerably important for understanding the biophysical and biomechanical properties using the fast probing method. Here, a dual-mode polarized single-laser tweezers technique with distinct principal axes exhibiting different polarization states is presented and designed to investigate the deformation, optical folding, and rotation of single living cells with one measurement. RBC optical folding and rotation speed are measured in patients with sickle cell disease (SCD), including follow up of patients after hydroxyurea (HU) treatment for at least three months. Folding angle and rotation speed are significantly lower in patients with SCD and do not significantly differ in patients treated by HU compared with the healthy control group. The RBC folding angle and rotation speed in patients treated with HU drug increase linearly at lower laser powers and rapidly at higher powers, and increase much slowly in patients not treated with HU. The difference in the folding angle and rotation speed of RBCs could be useful for drug response in SCD or predicting pain crisis in SCD.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Eritrócitos/fisiologia , Hidroxiureia/administração & dosagem , Anemia Falciforme/metabolismo , Antidrepanocíticos/administração & dosagem , Biomarcadores/análise , Estudos de Casos e Controles , Contagem de Eritrócitos , Eritrócitos/efeitos da radiação , Feminino , Humanos , Lasers , Masculino , Pinças Ópticas , Rotação , Resultado do Tratamento
12.
Pan Afr Med J ; 38: 41, 2021.
Artigo em Francês | MEDLINE | ID: mdl-33854670

RESUMO

Introduction: hydroxyurea is the unique medication that has been proven to prevent complications in patients with sickle cell disease and is approved by the Food and Drug Administration. This medication requires a prescription to be dispensed, it must be available and at an affordable price. The purpose of this study was to determine the availability and market price of hydroxyurea in the Democratic Republic of the Congo and to make a comparison between these two aspects in a small city, such as Mbujimayi, and in a big city, such as Lubumbashi. Methods: we conducted a cross-sectional study in the context of a face-to-face survey involving 188 Congolese pharmacies from 1st April to 1st September 2017. Results: hydroxyurea was available at 41/188 (22%) participating pharmacies, but more frequently at those of a big city than at those of a small city (34/96 versus 7/92). Most patients got a prescription (36/41; 88%). The average price of hydroxyurea was $15 (from $10 to $35 a blister packs of 25 capsules), which was higher than the purchasing power of the majority of sickle cell patients. Hydroxyurea is still an imported product from Europe, the United States or Asia. Conclusions: hydroxyurea is one of the main treatments to slow down disease progression in sickle cell patients. Nevertheless, in the Democratic Republic of the Congo, its availability could be improved, in particular in small cities, and its price is still too high.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/provisão & distribuição , Hidroxiureia/provisão & distribuição , Assistência Farmacêutica/estatística & dados numéricos , Anemia Falciforme/economia , Antidrepanocíticos/economia , Estudos Transversais , República Democrática do Congo , Custos de Medicamentos/estatística & dados numéricos , Humanos , Hidroxiureia/economia , Assistência Farmacêutica/economia , Inquéritos e Questionários
13.
JAMA ; 325(15): 1524, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877286
15.
Lancet Haematol ; 8(5): e323-e333, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33838113

RESUMO

BACKGROUND: For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. METHODS: HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. FINDINGS: Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. INTERPRETATION: Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. FUNDING: Global Blood Therapeutics.


Assuntos
Anemia Falciforme/tratamento farmacológico , Benzaldeídos/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Benzaldeídos/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Genótipo , Cefaleia/etiologia , Hemoglobina Falciforme/genética , Hemoglobina Falciforme/metabolismo , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Resultado do Tratamento , Adulto Jovem
16.
JMIR Mhealth Uhealth ; 9(4): e25496, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33847598

RESUMO

Sickle cell disease (SCD) is a chronic genetic disease that requires lifelong therapy and monitoring. Low drug adherence and poor monitoring may lead to an increase in morbidities and low quality of life. In the era of digital technology, various mobile health (mHealth) apps are being tested for their potential in increasing drug adherence in patients with SCD. We herewith discuss the applicability and feasibility of these mHealth apps for the management of SCD in India.


Assuntos
Anemia Falciforme , Aplicativos Móveis , Telemedicina , Anemia Falciforme/tratamento farmacológico , Humanos , Índia/epidemiologia , Qualidade de Vida
17.
Indian Pediatr ; 58(3): 229-232, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33713057

RESUMO

OBJECTIVE: To compare the efficacy of intravenous acetaminophen and intravenous diclofenac sodium in the management of skeletal vaso-occlusive crisis among children with sickle cell disease. DESIGN: Single blind randomized controlled trial. SETTING: Tertiary care hospital. PARTICIPANTS: 104 children with sickle cell disease and skeletal vaso-occlusive crisis. INTERVENTION: Intravenous acetaminophen at 10mg/kg/dose 8 hourly and intravenous diclofenac sodium at 1mg/kg/dose 8 hourly in 1:1 ratio. MAIN OUTCOME MEASURES: Reduction in pain score (50%), number of doses needed to relieve pain after 24 hours of drug administration and decrease in pain score at 1 hour. RESULTS: A 50% reduction in pain score was seen in 35 (77.3%) and 10 (21.7%) children among acetaminophen and diclofenac sodium groups respectively (RR, 95% CI 3.6; 2.02-6.33, P< 0.001). The mean (SD) fall in pain score at 1 hour was significantly higher among intervention arm as compared to control arm [1.51 (0.5) and 1.06 (0.5); P<0.001]. Eight (17.4%) patients developed local phlebitis at the site of infusion among diclofenac group. CONCLUSIONS: Intravenous acetaminophen is a better alternative to intravenous diclofenac in children with skeletal vaso-occlusive crisis.


Assuntos
Anemia Falciforme , Diclofenaco , Acetaminofen/uso terapêutico , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Criança , Diclofenaco/uso terapêutico , Método Duplo-Cego , Humanos , Medição da Dor , Método Simples-Cego
18.
Blood Cells Mol Dis ; 89: 102561, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744514

RESUMO

Increased expression of developmentally silenced fetal globin (HBG) reduces the clinical severity of ß-hemoglobinopathies. Benserazide has a relatively benign safety profile having been approved for 50 years in Europe and Canada for Parkinson's disease treatment. Benserazide was shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed fetal hemoglobin (HbF) induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice containing the entire human ß-globin gene (ß-YAC) and anemic baboons. The goal of this study is to evaluate efficacies and plasma exposure profiles of benserazide racemate and its enantiomers to select the chemical form for clinical development. Intermittent treatment with all forms of benserazide in ß-YAC mice significantly increased proportions of red blood cells expressing HbF and HbF protein per cell with similar pharmacokinetic profiles and with no cytopenia. These data contribute to the regulatory justification for development of the benserazide racemate. Additionally, dose ranges and frequencies required for HbF induction using racemic benserazide were explored. Orally administered escalating doses of benserazide in an anemic baboon induced γ-globin mRNA up to 13-fold and establish an intermittent dose regimen for clinical studies as a therapeutic candidate for potential treatment of ß-hemoglobinopathies.


Assuntos
Anemia Falciforme/tratamento farmacológico , Benserazida/farmacologia , Dopaminérgicos/farmacologia , Hemoglobina Fetal/genética , Regulação para Cima/efeitos dos fármacos , Talassemia beta/tratamento farmacológico , Anemia Falciforme/genética , Animais , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papio , Talassemia beta/genética , gama-Globinas/genética
19.
Front Immunol ; 12: 627944, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763072

RESUMO

Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the ß-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.


Assuntos
Anemia Falciforme/complicações , Anticorpos/toxicidade , Antígenos CD40/agonistas , Inflamação/etiologia , Hepatopatias/etiologia , Anemia Falciforme/sangue , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/imunologia , Animais , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Etanercepte/farmacologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/imunologia , Hemólise , Hemopexina/farmacologia , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/prevenção & controle , Mediadores da Inflamação/sangue , Hepatopatias/sangue , Hepatopatias/imunologia , Hepatopatias/prevenção & controle , Camundongos Transgênicos , Inibidores do Fator de Necrose Tumoral/farmacologia , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/imunologia
20.
Transl Res ; 234: 141-158, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33711512

RESUMO

Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop nonopioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.


Assuntos
Anemia Falciforme/complicações , Manejo da Dor/métodos , Dor/etiologia , Dor Aguda/etiologia , Dor Aguda/fisiopatologia , Dor Aguda/terapia , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/fisiopatologia , Animais , Dor Crônica/etiologia , Dor Crônica/fisiopatologia , Dor Crônica/terapia , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Humanos , Hiperalgesia/etiologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Dor/fisiopatologia , Manejo da Dor/tendências , Pesquisa Médica Translacional
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