Hydroxyurea Research Articles

Successful quality improvement project to increase hydroxyurea prescriptions for children with sickle cell anaemia

Hydroxyurea (HU) is an effective but underused disease-modifying therapy for patients with sickle cell anaemia (SCA). EMBRACE SCD, a sickle cell disease treatment demonstration project, aimed to improve access to...

Unraveling Binding Mechanism and Stability of Urease Inhibitors: A QM/MM MD Study

Soil bacteria can produce urease, which catalyzes the hydrolysis of urea to ammonia (NH3) and carbamate. A variety of urease inhibitors have been proposed to reduce NH3 volatilization by interfering with the urease activity. We report a quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) study on the mechanism employed for the inhibition of urease by three representative competitive inhibitors; namely, acetohydroxamic acid (AHA), hydroxyurea (HU), and N-(n-butyl)phosphorictriamide (NBPTO). The possible connections between the structural and thermodynamical properties and the experimentally observed inhibition efficiency were evaluated and characterized. We demonstrate that the binding affinity decreases in the order NBPTO >> AHA > HU in terms of the computed activation and reaction free energies. This trend also indicates that NBPTO shows the highest inhibitory activity and the lowest IC50 value of 2.1 nM, followed by AHA (42 μM) and HU (100 μM). It was also found that the X=O moiety (X = carbon or phosphorous) plays a crucial role in the inhibitor binding process. These findings not only elucidate why the potent urease inhibitors are effective but also have implications for the design of new inhibitors.

Heteroatom (B, N, P, and S)-Doped Cyclodextrin as a Hydroxyurea (HU) Drug Nanocarrier: A Computational Approach.

Theoretical examination of hydroxyurea adsorption capabilities toward the cyclodextrin surface for proper drug delivery systems was carried out utilizing DFT simulations. The study aims to assess the efficacy of doped cyclodextrin (doped with boron, nitrogen, phosphorus, and sulfur atoms) in increasing its stability and efficiency in intermolecular interactions, hence facilitating optimal drug delivery. The adsorption energies were found to follow a decreasing order of B@ACD-HU>N@ACD-HU>P@ACD-HU>S@ACD-HU with energies of -0.046, -0.0326, -0.015, and 0.944 kcal/mol, respectively. The S@ACD-HU complex, unlike previous systems, had a physical adsorption energy. The N@ACD-HU and B@ACD-HU complexes had the shortest bond lengths of 1.42 Å (N122-C15) and 1.54 Å (B126-C15), respectively. The HOMO and LUMO values were also high in identical systems, -6.367 and -2.918 eV (B@ACD-HU) and -6.278 and -1.736 eV (N@ACD-HU), respectively, confirming no chemical interaction. The N@ACD-HU has the largest energy gap of 4.54 eV. For the QTAIM analysis and plots, the maximum electron density and ellipticity index were detected in B@ACD-HU, 0.600 au (H70-N129) and 0.8685 au (H70-N129), respectively, but N@ACD-HU exhibited a high Laplacian energy of 0.7524 a.u (H133-N122). The fragments' TDOS, OPDOS, and PDOS exhibited a strong bond interaction of greater than 1, and they had different Fermi levels, with the highest value of -8.16 eV in the N@ACD-HU complex. Finally, the NCI analysis revealed that the complexes were noncovalent. According to the literature, the van der Waals form of interactions is used in the intermolecular forces of cyclodextrin cavities. The B@ACD-HU and N@ACD-HU systems were more greenish in color with no spatial interaction. These two systems have outperformed other complexes in intermolecular interactions, resulting in more efficient drug delivery. They had the highest negative adsorption energies, the shortest bond length, the highest HOMO/LUMO energies, the highest energy gap, the highest stabilization energy, the strongest bonding effect, the highest electron density, the highest ellipticity index, and a strong van der Waals interaction that binds the drug and the surface together.

Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea.

Patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary and secondary myelofibrosis (MF), are known to have an increased risk of second malignancies (SMs). Hydroxyurea (HU) is a guideline-recommended cytoreductive therapy for patients at high risk for MPNs. Controversy exists as to whether HU use is associated with a higher risk of SMs, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We conducted a retrospective cohort study of older patients diagnosed with MPN (age ≥66 years) between 2010 and 2017 and included the data in the Surveillance, Epidemiology, and End Results Medicare-linked database. Multivariable competing risk analyses adjusting for patient characteristics were used to assess the impact of HU on the development of SM. We identified 4023 patients (1688 with PV, 1976 with ET, and 359 with MF) with a median age of 77 (interquartile range [IQR], 71-83) years at the time of MPN diagnosis. After a median follow-up of 3.25 (IQR, 2.10-5.00) years, 489 patients developed an SM (346 solid, 73 lymphoid, and 70 myeloid malignancies). The cumulative incidence probability of SM was 19.88% (95% confidence interval [CI], 17.16%-22.75%) among 2683 HU users and 22.31% (95% CI, 17.51%-27.47%) among 1340 nonusers, respectively (Gray's test, P< .01). We did not identify significant differences in the incidence of solid or hematologic SMs, including AML/MDS (hazard ratio, 1.33; 95% CI, 0.77-2.29; P= .30), between HU users and nonusers. Our results suggest that the use of HU does not increase the risk of SM in older patients with MPN.

Outcomes of Pregnancy in Sickle Cell Disease Patients: Results from the Prospective ESCORT-HU Cohort Study.

Sickle cell disease (SCD) refers to a group of inherited hemoglobin disorders in which sickle red blood cells display altered deformability, leading to a significant burden of acute and chronic complications, such as vaso-occlusive pain crises (VOCs). Hydroxyurea is a major therapeutic agent in adult and pediatric sickle cell patients. This treatment is an alternative to transfusion in some complications. Indeed, it increases hemoglobin F and has an action on the endothelial adhesion of red blood cells, leukocytes, and platelets. Although the safety profile of hydroxyurea (HU) in patients with sickle cell disease has been well established, the existing literature on HU exposure during pregnancy is limited and incomplete. Pregnancy in women with SCD has been identified as a high risk for the mother and fetus due to the increased incidence of maternal and non-fetal complications in various studies and reports. For women on hydroxyurea at the time of pregnancy, transfusion therapy should probably be initiated after pregnancy. In addition, there is still a significant lack of knowledge about the incidence of pregnancy, fetal and maternal outcomes, and management of pregnant women with SCD, making it difficult to advise women or clinicians on outcomes and best practices. Therefore, the objective of this study was to describe pregnancy outcomes (n = 128) reported in the noninterventional European Sickle Cell Disease COhoRT-HydroxyUrea (ES-CORT-HU) study. We believe that our results are important and relevant enough to be shared with the scientific community.

Early detection of glomerular dysfunction and renal tubulopathy in children with sickle cell disease in India

Sickle cell disease causes microvascular occlusion in different vascular beds. In kidneys, it leads to occult glomerular dysfunction causing asymptomatic microalbuminuria, proximal tubulopathy causing hyposthenuria and increased free water loss and distal tubulopathy causing poor urine acidification. We studied the prevalence of various types of renal dysfunction, the ability of different tests to detect it at an early stage and the correlation of these parameters in children receiving hydroxyurea (HU). Fifty-six children (sample size calculated using SAS9.2 package) attending paediatric clinical services in a tertiary care hospital between 2 and 12 years of age diagnosed by high-performance liquid chromatography (HPLC) were enrolled. Their demographic and laboratory data including renal and urine parameters were collected. Parameters like fractional excretion of sodium (FeNa), trans tubular potassium gradient (TtKg) and free water clearance (TcH2O) were derived by calculations. Data were analysed using IBM SPSS Version 21.0 and Microsoft Office Excel 2007. We found a significant number of children to have microalbuminuria (17.8%), hyposthenuria (30.4%) and impaired renal tubular potassium excretion (TtKg) (81.3%). A significant correlation was found between the dose of HU with urine osmolality (p < 0.0005) and free water clearance (p = 0.002), while all parameters showed a significant correlation with compliance with HU. Derangement in urine microalbumin and TcH2O correlated significantly with low mean haemoglobin levels (<9 g/dl). Renal dysfunction is common in children with SCD and can be detected early using simple urine parameters and can be prevented with an early and appropriate dosage of HU with good compliance.

Health Equity in Sickle Cell Research and Access to Therapy

Health Equity in Sickle Cell Research and Access to Therapy

SOHO State of the Art Updates and Next Questions | Polycythemia Vera: Is It Time to Rethink Treatment?

Polycythemia vera (PV) is a Philadelphia-negative myeloproliferative neoplasm characterized by excessive myeloid cells production, mostly secondary to mutations in the Janus kinase 2 (JAK2) gene. PV natural history might be burdened by thrombotic events (TEs) and evolution into post-PV myelofibrosis (PPV-MF) or blast phase (BP). To date, no treatment strategies have been shown to have disease modifying effects, so therapy is directed at preventing TEs. All patients require phlebotomies (PHLs) to keep hematocrit below 45% and once-daily low dose aspirin (if not contraindicated). Apart from patients at "high risk" because of age over 60 years or a thrombosis history, cytoreductive therapies (CT) should be given to patients with relevant signs of myeloproliferation or intolerance to PHLs. Approved choices both for first and second line CT are hydroxyurea (HU) and pegylated forms of interferon (peg-IFN), the latter probably being better for young patients, and subjects without critical and recent vascular events or massive splenomegaly. The JAK1/2 inhibitor ruxolitinib is the treatment of choice in case of resistance/intolerance to HU, with proved efficacy in terms of thrombotic prevention. Data are too preliminary to consider CT for "low risk" PV cases, but ropeg-IFN is being studied in this setting with a short follow-up. A careful monitoring for signs of evolution into PPV-MF is fundamental for optimizing patient management.

Polymorphisms and gene expression of metalloproteinases and their inhibitors associated with cerebral ischemic stroke in young patients with sickle cell anemia.

Sickle cell anemia (SCA) is a genetic disease with great clinical heterogeneity and few viable strategies for treatment; hydroxyurea (HU) is the only widely used drug. Thus, the study of single nucleotide polymorphisms (SNPs) and the gene expression of MMPs 1, 2, 9, 7 and TIMPs 1 and 2, which are involved in the regulation of extracellular matrix, inflammation, and neuropathies, may provide further insights into the pathophysiology of the disease and elucidate biomarkers and molecules as potential therapeutic targets for patients with SCA. We evaluated 251 young individuals with SCA from northeastern Brazil. The groups were divided according to vaso-occlusive crisis (VOC) and cerebrovascular disease (CVD), compared to control individuals. SNP detection and gene expression assays were performed by real-time PCR, TaqMan system®. Both the expression levels of MMP1 gene, and the SNP MMP1-1607 1G/2G were associated with the risk of cerebral ischemic stroke (IS), and the expression of MMP1 was also associated with a higher frequency of VOC/year. Expression levels of MMP7, TIMP1, and TIMP2 were increased in patients conditioned to IS. The SNP 372T>C (rs4898) TIMP1 T alleles were more frequent in patients with > 5 VOC events/year. The SNP rs17576 of MMP9 showed differences in gene expression levels; it was increased in the genotypes AG, and AG+GG. The findings of this study, the SNPs, and expression provide initial support for understanding the role of MMPs-TIMPs in the pathophysiology of SCA in young patients.

Hydroxyurea as a promising ADAM17 inhibitor

A disintegrin and metalloproteinase-17 (ADAM17) is a multi-domain, type 1 trans-membrane protein with a zinc-binding catalytic domain and a rich history of research scrutinizing its cellular activation and presentation, shedding activity, and prominent physiological and pathological roles. Presently, despite the advancement in the inhibitory approaches focusing on ADAM17, clinically approved therapies targeting its inhibition are not available. A principal approach to inhibit ADAM17 involves ligating the catalytic zinc atom using a zinc binding group (ZBG), with the hydroxamate functionality being the principal ZBG directing the synthesis of a vast number of zinc-binders as ADAM17 inhibitors. In addition, multiple biological and pathophysiological pathways are involved in the activation and upregulation of ADAM17 with a capacity for pharmacological interventions to modulate these pathways and hence indirectly inhibit the activity of ADAM17. Thus, we hypothesize that hydroxyurea (HU), as the simplest hydroxamate, has the intrinsic ability to chelate the zinc atom of the active site region of ADAM17, which shares similarity with matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs) as zinc-confining enzymes. Furthermore, our hypothetical argument sheds light on the structural characteristics, the nitric oxide (NO) donation properties, and the iron-chelating attributes of HU in addition to its immunomodulatory and anti-angiogenic activities; hence, a multi-faceted strategic targeting of ADAM17 is proposed that can be employed to put forward an approved hydroxamate-bearing compound as an inhibitor of ADAM17. Finally, a novel mechanism of action of HU is hypothesized that mandates further research within the field of therapeutics.

Application of zinc oxide nano-tube as drug-delivery vehicles of anticancer drug

Zinc oxide nano-tube (ZnONT) nano-structures, which possess chemical stability and non-toxicity in the human body, are considered promising for delivering different drugs. Within this work, we scrutinized the drug delivery capability of the ZnONT and its adsorptional properties as a drug delivery vehicle (DDV) for hydroxyurea (HU) as an anti-cancer drug through density functional theory along with the solvent impacts. Based on the optimized structures, it can be suggested that Zn atoms of ZnONT are the ideal sites on this nano-tube for the adsorption of HU. HU had a strong physical adsorption through the O atom of carbonyl groups onto the local pyramidal site of the ZnONT. At 1.96 Å and Ead of -39.28 kcal/mol, in the configuration which was favorable in terms of energy, there was an interaction between the O atoms of -C=O group of the drug and a Zn atom of the ZnONT. In order to scrutinize the excited state properties of the HU-ZnONT complex, we also examined the UV/Vis data of the HU/ZnONT interaction system. Following the adsorption of HU onto the surface of the ZnONT, there was a significant red-shift based on the maximum absorption wavelength, showing that the ZnONT is an ideal candidate for optic sensors in order to detect and monitor the drug molecule. HU could be released in the cancer tissues where pH was low based on the drug release mechanism. The current work thoroughly investigated the mechanism of interaction between the ZnONT and HU, showing that ZnONT can be used for the smart drug delivery of HU. Overall, the findings suggest that ZnONT could be used as an efficient drug-delivery system for the HU drug to treat various types of cancer. In this work we used B3LYP-gCP-D3 functional and the basis set LANL2DZ on the transition metal (Zn) and the basis set cc-pVDZ on the others. GAMESS software program was employed for performing the calculations. we performed analyses, including charge transport, molecular electrostatic potential surface (MEP), energetic, electronic, natural bond orbitals (NBOs), and structural optimizations.

Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients

Hydroxyurea (HU) is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated. In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71+ erythroid cells and the expression was determined using Taqman probes. The mean HbF level increased 7.54 ± 2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression negatively correlate with HbF and γ-globin gene while increased expression of miR-210, miR-16-1 and miR-29a post HU therapy positively corelate with HbF and γ-globin gene. Thus, suggest that miR-210, miR-16-1 and miR-29a are positive regulator of γ-globin gene and miR-96 is negative regulator of γ-globin gene. The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in γ-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction.

Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model.

Hydroxyurea (HU) is commonly used as a treatment for patients with sickle cell disease (SCD) to enhance fetal hemoglobin production. This increased production is expected to reduce anemia (which depresses oxygen transport) and abnormal Hb content alleviating clinical symptoms such as vaso-occlusive crisis and acute chest syndrome. The effects of HU on skeletal muscle bioenergetics in vivo are still unknown. Due to the beneficial effects of HU upon oxygen delivery, improved skeletal muscle energetics and function in response to a HU treatment have been hypothesized. Muscle energetics and function were analyzed during a standardized rest-exercise-recovery protocol, using 31P-magnetic resonance spectroscopy in Townes SCD mice. Measurements were performed in three groups of mice: one group of 2-mo-old mice (SCD2m, n = 8), another one of 4-mo-old mice (SCD4m, n = 8), and a last group of 4-mo-old mice that have been treated from 2 mo of age with HU at 50 mg/kg/day (SCD4m-HU, n = 8). As compared with SCD2m mice, SCD4m mice were heavier and displayed a lower acidosis. As lower specific forces were developed by SCD4m compared with SCD2m, greater force-normalized phosphocreatine consumption and oxidative and nonoxidative costs of contraction were also reported. HU-treated mice (SCD4m-HU) displayed a significantly higher specific force production as compared with untreated mice (SCD4m), whereas muscle energetics was unchanged. Overall, our results support a beneficial effect of HU on muscle function.NEW & NOTEWORTHY Our results highlighted that force production decreases between 2 and 4 mo of age in SCD mice thereby indicating a decrease of muscle function during this period. Of interest, HU treatment seemed to blunt the observed age effect given that SCD4m-HU mice displayed a higher specific force production as compared with SCD4m mice. In that respect, HU treatment would help to maintain a higher capacity of force production during aging in SCD.

Investigation of the adsorption behavior of the anti-cancer drug hydroxyurea on the graphene, BN, AlN, and GaN nanosheets and their doped structures via DFT and COSMO calculations.

To reduce the direct side effects of chemotherapy, researchers are trying to establish a new approach of a drug-delivery system using nanomaterials. In this study, we investigated graphene and its derivative nanomaterials for their favorable adsorption behavior with the anti-cancer drug hydroxyurea (HU) using DFT calculations. Initially, different pristine and doped graphene and its derivatives were taken into consideration as HU drug carriers. Among them, AlN, GaN, GaN-doped AlN, and AlN-doped GaN nanosheets exhibited favorable adsorption behavior with HU. The HU adsorbed on these four nanosheets with adsorption energies of -0.92, -0.75, -0.83, and -0.69 eV, transferring 0.16, 0.032, 0.108, and 0.230 e charges to the nanosheets, respectively, in air medium. In water solvent media, these four nanosheets interacted with HU by -0.56, -0.45, -0.58, and -0.56 eV by accepting a significant amount of charge of about 0.125, 0.128, 0.192, and 0.126 e from HU. The dipole moment and COSMO analysis also indicated that these nanosheets, except for GaN-doped AlN, show high asymmetricity and solubility in water solvent media due to the increased values of the dipole moment by two or three times after the adsorption of the HU drug. Quantum molecular descriptors also suggest that the sensitivity and reactivity of the nanosheets are enhanced during the interaction with HU. Therefore, these nanosheets can be used as anti-cancer drug carriers.

Impact of hydroxyurea on psychological health of beta thalassemia patients with moderating role of healthcare professionals’ performance

Background: Beta –thalassemia (β- thalassemia) has more than 300 different mutations of beta globin gene. The complexity of its physical composition is caused by the imbalance ratio of β-globin which classified into blood transfusion- dependent (TDT) and non-transfusion dependent (NTDT). Modern treatment approaches considered for TDT patients is monthly transfusions to maintain hemoglobin (Hb) levels ranges between 9-10 g/dL. The objectives of this study are to seek out the impact of hydroxyurea (HU) on improving psychological health problems of Quality of Life (QoL), patients’ satisfaction with the use of HU and moderating role of healthcare professionals in satisfying the gap between the use of medicine in managing β- thalassemia disease in a tertiary care hospital. Methods: A cross-sectional, non-probability study and purposive- judgment sampling was conducted after ethical approval. The World Health Organization (WHO) sample size calculator 2.0 was used to recruit TDT patients on HU therapy while visiting the outpatient (OPD) and daycare department of National Institute of Blood Diseases &amp; Bone Marrow Transplantation (NIBD &amp; BMT) hospital in Karachi. A well -structured electronic questionnaire as web form was used for data collection by using Likert scale, with a range of 1-5 and 1-7. The data was analyzed using IBM Statistical Package for Social Sciences (SPSS) version 23.0 and moderation process done by using Process Hayes for SPSS version 3.5.2. Results: We enrolled 290 patients. This study revealed that the impact of HU on improving the psychological health problems of β- thalassemia patients are not evident (r=0.078; p=0.185). Similarly, by inducing moderating role of healthcare professional performance, the impact of HU on psychological health problems were a weak positive non- significant with (r=0.050; p=0.397) correlation observed. Moreover, no significant improvement was observed in psychological health problems of QoL by moderating role of healthcare professional performance (p=0.0835 and 0.6764, respectively). Conclusion: The psychological health problems in β- thalassemia patients are not dependent on HU therapy to have better QoL. In addition, the introduction of healthcare professionals' performance as a moderator does not improve the correlation between HU and psychological domain of QoL.

Enhanced brain delivery of hypoxia-sensitive liposomes by hydroxyurea for rescue therapy of hyperacute ischemic stroke.

Ischemic stroke is characterized by high morbidity, disability, and mortality. Unfortunately, the only FDA-approved pharmacological thrombolytic, alteplase, has a narrow therapeutic window of only 4.5 h. Other drugs like neuroprotective agents have not been clinically used because of their low efficacy. To improve the efficacy of neuroprotective agents and the effectiveness of rescue therapies for hyperacute ischemic stroke, we investigated and verified the variation trends of the blood-brain barrier (BBB) permeability and regional cerebral blood flow over 24 h in rats that had ischemic strokes. Hypoperfusion and the biphasic increase of BBB permeability are still the main limiting factors for lesion-specific drug distribution and drugbrain penetration. Herein, the nitric oxide donor hydroxyurea (HYD) was reported to downregulate the expression of tight junction proteins and upregulate intracellular nitric oxide content in the brain microvascular endothelial cells subjected to oxygen-glucose deprivation, which was shown to facilitate the transport of liposomes across brain endothelialmonolayer in an in vitro model. HYD also increased the BBB permeability and promoted microcirculation in the hyperacute phase of stroke. The neutrophil-like cell-membrane-fusogenic hypoxia-sensitive liposomes exhibited excellent performance in targeting the inflamed brain microvascular endothelial cells, enhancing cell association, and promoting rapid hypoxic-responsive release in the hypoxic microenvironment. Overall, the combined HYD and hypoxia-sensitive liposome dosing regimen effectively decreased the cerebral infarction volume and relieved neurological dysfunction in rats that had ischemic strokes; these therapies were involved in the anti-oxidative stress effect and the neurotrophic effect mediated by macrophage migration inhibitory factor.

The rs368698783 (G>A) Polymorphism Affecting LYAR Binding to the Aγ-Globin Gene Is Associated with High Fetal Hemoglobin (HbF) in β-Thalassemia Erythroid Precursor Cells Treated with HbF Inducers

The human homologue of mouse Ly-1 antibody reactive clone protein (LYAR) is a putative novel regulator of γ-globin gene transcription. The LYAR DNA-binding motif (5′-GGTTAT-3′) is located within the 5′-UTR of the Aγ-globin gene. The LYAR rs368698783 (G>A) polymorphism is present in β-thalassemia patients and decreases the LYAR binding efficiency to the Aγ-globin gene. The objective of this study was to stratify β-thalassemia patients with respect to the rs368698783 (G>A) polymorphism and to verify whether their erythroid precursor cells (ErPCs) differentially respond in vitro to selected fetal hemoglobin (HbF) inducers. The rs368698783 (G>A) polymorphism was detected by DNA sequencing, hemoglobin production by HPLC, and accumulation of globin mRNAs by RT-qPCR. We found that the LYAR rs368698783 (G>A) polymorphism is associated with high basal and induced production of fetal hemoglobin in β-thalassemia patients. The most striking association was found using rapamycin as an HbF inducer. The results presented here could be considered important not only for basic biomedicine but also in applied translational research for precision medicine in personalized therapy of β-thalassemia. Accordingly, our data suggest that the rs368698783 polymorphism might be considered among the parameters useful to recruit patients with the highest probability of responding to in vivo hydroxyurea (HU) treatment.

Polymorph II of hydroxyurea 150 years after its first synthesis

Form II of hydroxyurea (HU) has been crystallized in the presence of urea in methanol solvent. The isoenergetic novel form II is isolated 150 years after its first synthesis (form I).

Gallbladder status among children with chronic hemolytic anemia attending Assiut University Children's Hospital

BackgroundOne among the numerous comorbidities of chronic hemolytic anemia (CHA) is bladder stones. The extensive use of abdominal ultrasound in kids documented raised detection rate of gallstones.Aim and objectivesTo see the frequency of gallbladder diseases among kids with CHA and to see the risk factors of gallbladder diseases among patients with CHA attending Assiut University Children's hospital.Patients and methodsThis cross-sectional study included 50 kids with CHA aged from 1 to 18 years, who were admitted to the Hematology Unit at Assiut University Children's Hospital (from the start of December 2018 to the end of November 2019). All patients were evaluated by full history, general and abdominal examination, laboratory assessment, and ultrasound findings to find the probable risk factors for gallstones.ResultsThe age of patients ranged from 1 year up to 18 years. The commonest age of bladder diseases detection was at 6 years. Twenty-one (42%) cases had gallbladder diseases. Bladder diseases were symptomatic in –81 with abdominal pain in affected kids. Thalassemia major was recorded more frequently (72%) in the studied group with 20 and 8% reporting sickle cell anemia and spherocytosis, respectively. The frequency of blood transfusion had statistical significance with gallbladder affection.ConclusionFrom this study, it can be concluded that the type of hemolytic disease, frequency of blood transfusion, history of hydroxy urea intake, and splenomegaly were risk factors for gallbladder affection in children with chronic hemolytic disease.

Clinical and laboratory characterization of adult sickle cell anemia patients in Kinshasa.

Sickle cell anemia (SCA) is a monogenic hemoglobinopathy associated with severe acute and chronic complications, with the highest incidence worldwide in Sub-Saharan Africa. The wide variability in clinical manifestations suggest that a uniform response to hydroxurea may not be attained. In view of a potential treatment with hydroxyurea (HU), we assessed the variability of clinical and hematological manifestations in a cohort of adults with SCA in Kinshasa, capital of the DR Congo in Central Africa. A cross-sectional study was conducted in a hospital dedicated to SCA management in Kinshasa. Clinical history of patients was recorded, a complete physical examination performed. The diagnosis was confirmed by means of DNA analysis. A full blood count and hemolysis markers were measured. The severity of the disease was evaluated by means of a previously reported score. The study group consisted of 166 genetically confirmed SCA patients. The SCA severity was mild in 28.9%, moderate in 64.5% and severe in 6.6%. The disease severity score increased with patient's age (p ≤ 0.001). The severity was higher in males compared to females (p = 0.012). In males, the severity score was correlated with the presence of priapism (p = 0.045), a manifestation not previously incorporated in the severity score. The severity score was inversely correlated with the fetal hemoglobin (HbF) rate (p = 0.005). Malnutrition (BMI <18.5 kg/m2) was present in 47% of patients and was related to the male sex, hip disease (aOR 3.11; p = 0.019) and severe phenotype (aOR 3.53; p = 0.012). Leg ulcers were more frequent in males than in females (p = 0.001; OR 24.3) and were correlated with the number of days of hospitalization (p = 0.029). Hip disease was related to the increasing age (p = 0.008). In this selected, hospital-based populations of adults with SCA, severe disease was rare, which may be due to survival bias. However, two thirds had moderate severity of the disease, mostly with a low HbF, and they may benefit from HU treatment. In the Central-African setting the separation between vaso-occlusive and hyperhemolytic sub-phenotypes was not applicable.