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In a trial evaluating two daily-dose levels of voxelotor, which binds to sickle hemoglobin and prevents polymerization under hypoxic conditions, hemoglobin levels increased by more than 1 g per deciliter in approximately half the patients who received the drug, and markers of hemolysis decreased. Toxic effects were mainly low grade and not different from those with placebo.

A year-long, phase 3, randomized trial involving patients with sickle cell disease showed that the median number of pain crises was 25% lower and the median number of hospitalizations was 33% lower with l -glutamine supplementation than with placebo.

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB , which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings. Sickle cell disease includes genetic conditions that are caused by mutations in one of the genes encoding haemoglobin. Mutant haemoglobin molecules can polymerize, causing the red blood cells to acquire a characteristic crescent shape that gives the disease its name.

Patients with non-transfusion-dependent thalassaemia (NTDT), although they do not require regular blood transfusions for survival, can still accrue a heavy burden of comorbidities. No approved disease-modifying therapies exist for these patients. We aimed to investigate the safety and efficacy of mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD β-thalassaemia. In this open-label, multicentre, phase 2 study, patients were recruited from four academic clinical study sites in Oakland, CA, and Boston, MA, USA; Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18 years or older, with NTDT (including β-thalassaemia with or without α-globin gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period, mitapivat was administered orally at 50 mg twice daily for the first 6 weeks followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin concentration from baseline at one or more assessments between weeks 4 and 12). Efficacy and safety were assessed in the full analysis set (ie, all patients who received at least one dose of study drug). This study is registered with ClinicalTrials.gov, NCT03692052, and is closed to accrual. Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with α-thalassaemia) and received mitapivat. The median age of patients was 44 years (IQR 35–56), 15 (75%) of 20 patients were female, five (25%) were male, and ten (50%) identified as Asian. 16 (80% [90% CI 60–93]) of 20 patients had a haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11 (73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent adverse event, and 13 had a treatment-emergent event that was considered to be treatment related. One serious treatment-emergent adverse event occurred (grade 3 renal impairment), which was considered unrelated to study drug, resulting in discontinuation of treatment. The most commonly reported treatment-emergent adverse events were initial insomnia (ten [50%] patients), dizziness (six [30%]), and headache (five [25%]). No patients died during the 24-week core period. These efficacy and safety results support the continued investigation of mitapivat for the treatment of both α-thalassaemia and β-thalassaemia. Agios Pharmaceuticals.

Hemoglobin H disease can result from deletion of three α-globin genes or deletion of two such genes with a point mutation in the third, as is seen in patients with hemoglobin H Constant Spring. Nearly all the clinical manifestations occur in patients with hemoglobin H Constant Spring. Hemoglobin H disease is prevalent in parts of Asia and around the Mediterranean, as well as in countries with migration from these regions. 1 In this disease, patients have compound heterozygosity for α + -thalassemia, which is caused by the deletion of one α-globin gene and is widely distributed, with carrier rates approaching 70% in some areas of the world, 2 and for α 0 –thalassemia, which is caused by the deletion of two α-globin genes in cis and was formerly restricted to populations from certain regions 2 but is now being observed in other ethnic groups. 1 Point mutations in the gene encoding α-globin that . . .

Background Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. Methods STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. Discussion Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. Trial registration The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).

L-Glutamine is FDA-approved for sickle cell disease (SCD), yet the mechanism(s)-of-action are poorly understood. We performed a pharmacokinetics (pK) study to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD. A pK study was performed where patients with SCD fasting for > 8 h received oral L-glutamine (10 g). Blood was analyzed at baseline, 30/60/90 min/2/3/4/8 hrs. A standardized diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had pK studies performed without glutamine supplementation to follow normal diurnal fluctuations in amino acids. Comprehensive SCD Center in Oakland, California Five patients with SCD were included, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 ± 5.6 years, 60% were female, 40% SS, 60% SC. Plasma glutamine levels increased significantly after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30-min of ingestion (p = 0.01) before decreasing to a plateau by 2-h that remained higher than baseline by 8 h. Oral glutamine also increased plasma arginine concentration, which peaked by 4-h (p = 0.03) and remained elevated through 8-h. Erythrocyte glutamine levels began to increase by 8-h, while erythrocyte arginine concentration peaked at 4-h. Oral glutamine supplementation acutely improved glutamine and arginine bioavailability in both plasma and erythrocytes. This is the first study to demonstrate that glutamine therapy increases arginine bioavailability and may provide insight into shared mechanisms-of-action between these conditionally-essential amino acids. •Mechanism(s)-of-action for FDA-approved oral L-glutamine to treat SCD are unknown.•Oral glutamine rapidly increases plasma glutamine concentration within 30 min of supplementation in patients with SCD.•A 10-gram dose of oral glutamine increases both glutamine and arginine bioavailability.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0–21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

[...]patients develop both haemolytic anaemia and vasculopathy. 2 Organ damage is also an ongoing problem. Clinical advances in treatment of sickle cell disease Screening of newborn infants Screening of newborn infants Family education Counselling Comprehensive care Infection Prophylactic penicillin Pneumococcal vaccine Prevention Brain injury Screening Transcranial Doppler ultrasonography (now recommended for detection of brain injury and subsequent transfusion of high risk patients) Magnetic resonance imaging Neurocognitive testing Lung injury Incentive spirometry Antibiotics, including macrolides Transfusion Prevention with prophylactic hydroxyurea Screening for pulmonary hypertension Transfusion safety and prevention of iron overload Phenotypically matched red cells (routine transfusion with C, E, and Kell red cells minimises alloimmunisation) Red cell pheresis (minimises iron overload) Safety during surgery and anaesthesia Preoperative transfusion Avascular necrosis of hip Decompression coring procedures (may prevent progression of disease; randomised controlled trial in process) Priapism Adrenergic agonist Antiandrogen therapy Pain Multidisciplinary management (decreases number of admissions to hospital) Prevention with prophylactic hydroxyurea Patient controlled analgesic devices New non-steroidal anti-inflammatory drugs Day unit Renal system Angiotensin converting enzyme inhibitors for proteinuria (may prevent renal disease) Improved renal transplantation Gallbladder disease Laparoscopic cholecystectomy (decreases perioperative morbidity) Severe disease Allogenic bone marrow transplantation (patients aged < 16 years) Chronic transfusions or hydroxyurea Recurrent acute chest syndrome, pain crises, or central nervous system disease indicate eligibility for transplantation Adolescent patients Adolescents with sickle cell disease present with unique needs, including delayed sexual development, avascular necrosis of the hip, gallstones, priapism, proteinuria, pulmonary hypertension, and the onset of retinopathy.

The acute chest syndrome is the leading cause of death and hospitalization among patients with sickle cell disease. 1 – 3 The optimal treatment has not been established because the cause remains largely unknown. Both infectious and noninfectious causes have been described, but their frequency and clinical course are unknown. 4 – 12 Pulmonary fat embolism has been identified during autopsies and in studies examining fat-laden pulmonary macrophages from bronchoalveolar fluid. 4 , 11 – 13 However, the number of patients included in these reports is too small for general recommendations to be made. 11 Appropriate therapy remains controversial. The antibiotics used are based on organisms identified decades . . .