RÉSUMÉ
BACKGROUND: Suboptimal medication adherence is common across youth with chronic health conditions and may contribute to health disparities and adverse health outcomes, especially in underserved communities. METHODS: Using pharmacy prescription records and guided by the World Health Organization Multidimensional Adherence Model, we examined patient-, treatment-, and health system-related factors that may affect hydroxyurea adherence in 72 youth with sickle cell disease (SCD), 10-18 years who had participated in the multisite "Hydroxyurea Adherence for Personal Best in SCD" (HABIT) feasibility (6 months) and efficacy (12 months) trials. Pharmacy data were collected from the year prior to study entry through the duration of each trial. We also examined hydroxyurea dose at baseline, prescribing patterns (hydroxyurea formulation and dose prescribed), quantity of hydroxyurea dispensed, and number of daily capsules/tablets prescribed. Data were analyzed using descriptive statistics. RESULTS: On average, youth were prescribed 1095 ± 402 mg hydroxyurea per day, requiring ingestion of 3 or more capsules for 39.4% of youth. Frequently identified potential barriers were complex medication regimens in which dose of hydroxyurea differed by day of week (47.2%); receipt of an inadequate (< 30 days) supply of hydroxyurea from the pharmacy ≥ 3 times during record collection period (29.2%); and prescription of hydroxyurea suspension suggesting problems swallowing capsules (22.2%). In this sample, most youth were exclusively prescribed 500 mg capsules (62.5%), which was associated with complex medication regimens (RR 3.0, 95% CI 1.4-6.7). Potential barriers were common, occurred at all levels and are potentially modifiable with targeted interventions at the treatment- and health system-related levels.
Sujet(s)
Drépanocytose , Antidrépanocytaires , Hydroxy-urée , Adhésion au traitement médicamenteux , Humains , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Drépanocytose/traitement médicamenteux , Adolescent , Mâle , Enfant , Femelle , Adhésion au traitement médicamenteux/statistiques et données numériques , Antidrépanocytaires/usage thérapeutique , Ordonnances médicamenteuses/statistiques et données numériquesRÉSUMÉ
Methemoglobinemia secondary to administration of hydroxyurea is only reported in veterinary medicine as a result of accidental ingestion of high doses, and once at therapeutic dose in human medicine. A 2.5-year-old female spayed mixed breed dog was presented for acute signs of neurologic disease and diagnosed with severe erythrocytosis without an identified underlying cause, leading to suspicion of polycythemia vera. The dog was managed with phlebotomies, supportive care, and administration of hydroxyurea. Within 2 h of administration of hydroxyurea (37 mg/kg) administration, respiratory distress with cyanosis, and methemoglobinemia developed. Signs resolved within 24 h but recurred after a second administration of lower dosage of hydroxyurea (17 mg/kg) 20 days later. The dog remained asymptomatic except for mild cyanosis but was humanely euthanized for lack of relevant improvement of signs of neurologic disease. This case report documents the repeated occurrence of methemoglobinemia in a dog after administration of hydroxyurea at therapeutic doses.
Sujet(s)
Maladies des chiens , Hydroxy-urée , Méthémoglobinémie , Chiens , Animaux , Hydroxy-urée/effets indésirables , Hydroxy-urée/administration et posologie , Hydroxy-urée/usage thérapeutique , Méthémoglobinémie/médecine vétérinaire , Méthémoglobinémie/induit chimiquement , Femelle , Maladies des chiens/induit chimiquement , Maladies des chiens/traitement médicamenteuxRÉSUMÉ
Sickle cell disease (SCD) is an inherited blood disorder that affects approximately 100,000 Americans, primarily from underrepresented racial minority populations, and results in costly, multi-organ complications. Hydroxyurea, the primary disease-modifying therapy for SCD, is effective at reducing most complications; however, adherence to hydroxyurea remains suboptimal and is the primary barrier to clinical effectiveness. Video directly observed therapy (VDOT) has shown promise as an adherence-promoting intervention for hydroxyurea, yet previous VDOT trials were limited by high attrition from gaps in technology access, use of unvalidated adherence measures, and healthcare system limitations of delivering VDOT to patients. As such, we fostered a small business partnership to compare VDOT for hydroxyurea to attention control to address previous shortcomings, promote equitable trial participation, and maximize scalability. VDOT will be administered by Scene Health (formerly emocha Health) and adherence monitoring will be performed using a novel electronic adherence monitor developed to meet the unique needs of the target population. Adolescent and young adult patients as well as caregivers of younger patients (<11 years of age) will be recruited. In addition to visit incentives, all participants will be offered a smartphone with a data plan to ensure all participants have equal opportunity to complete study activities. The primary objectives of this pilot, multi-center, randomized controlled trial (RCT) are to assess retention and sustained engagement and to explore needs and preferences for longer-term adherence monitoring and interventions. This RCT is registered with the National Institutes of Health (NCT06264700). Findings will inform a future efficacy RCT applying VDOT to hydroxyurea to address adherence gaps and improve outcomes within this vulnerable population.
Sujet(s)
Drépanocytose , Hydroxy-urée , Humains , Drépanocytose/traitement médicamenteux , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Adolescent , Enfant , Adhésion au traitement médicamenteux , Jeune adulte , Antidrépanocytaires/usage thérapeutique , Mâle , Femelle , AdulteRÉSUMÉ
Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.
Sujet(s)
Drépanocytose , Azathioprine , Transplantation de cellules souches hématopoïétiques , Hydroxy-urée , Fratrie , Conditionnement pour greffe , Humains , Adulte , Transplantation de cellules souches hématopoïétiques/méthodes , Femelle , Mâle , Conditionnement pour greffe/méthodes , Études prospectives , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Adulte d'âge moyen , Drépanocytose/thérapie , Azathioprine/usage thérapeutique , Azathioprine/administration et posologie , Jeune adulte , Chimère obtenue par transplantation , Alemtuzumab/usage thérapeutique , Alemtuzumab/administration et posologie , Rejet du greffon/prévention et contrôle , Maladie du greffon contre l'hôte/prévention et contrôle , Maladie du greffon contre l'hôte/étiologieRÉSUMÉ
Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.
Sujet(s)
Interféron alpha-2 , Interféron alpha , Polyglobulie primitive essentielle , Polyéthylène glycols , Protéines recombinantes , Humains , Polyglobulie primitive essentielle/traitement médicamenteux , Interféron alpha/usage thérapeutique , Interféron alpha/administration et posologie , Polyéthylène glycols/usage thérapeutique , Polyéthylène glycols/administration et posologie , Protéines recombinantes/usage thérapeutique , Interféron alpha-2/usage thérapeutique , Mâle , Adulte d'âge moyen , Études rétrospectives , Femelle , Sujet âgé , Sélection de patients , Résultat thérapeutique , Adulte , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologieRÉSUMÉ
BACKGROUND: Realizing Effectiveness Across Continents with Hydroxyurea (REACH) is an open-label non-randomised trial of hydroxyurea (hydroxycarbamide) in children with sickle cell anaemia in sub-Saharan Africa. The short-term results of REACH on safety, feasibility, and effectiveness of hydroxyurea were published previously. In this paper we report results from extended hydroxyurea treatment in the REACH cohort up to 8 years. METHODS: In this open-label, non-randomised, phase 1/2 trial, participants were recruited from four clinical sites in Kilifi, Kenya; Mbale, Uganda; Luanda, Angola; and Kinshasa, Democratic Republic of Congo. Eligible children were 1-10 years old with documented haemoglobin SS or haemoglobin Sß zero thalassaemia, weighing at least 10 kg. Participants received fixed-dose hydroxyurea of 17.5 (±2.5) mg/kg per day for 6 months (fixed-dose phase), followed by 6 months of dose escalation (2·5-5·0 mg/kg increments every 8 weeks) as tolerated, up to 20-35 mg/kg per day (maximum tolerated dose; MTD), defined as mild myelosuppression. After the MTD was reached, hydroxyurea dosing was optimised for each participant on the basis of changes in bodyweight and laboratory values over time (MTD with optimisation phase). After completion of the first 12 months, children with an acceptable toxicity profile and favourable responses were given the opportunity to continue hydroxyurea until the age of 18 years. The safety and feasibility results after 3 years has been reported previously. Here, haematological responses, clinical events, and toxicity rates were compared across the dosing phases (fixed-dose hydroxyurea vs MTD with optimisation phase) as protocol-specified outcomes. REACH is registered on ClinicalTrials.gov (NCT01966731) and is ongoing. FINDINGS: We enrolled 635 children between July 4, 2014, and Nov 11, 2016. 606 children were given hydroxyurea and 522 (86%; 266 [51%] boys and 256 [49%] girls) received treatment for a median of 93 months (IQR 84-97) with 4340 patient-years of treatment. The current (Oct 5, 2023) mean dose is 28·2 (SD 5·2) mg/kg per day with an increased mean haemoglobin concentration (7·3 [SD 1·1] g/dL at baseline to 8·5 [1·5] g/dL) and mean fetal haemoglobin level (10·9% [SD 6·8] to 23·3% [9·5]) and decreased absolute neutrophil count (6·8 [3·0] × 109 cells per L to 3·6 [2·2] × 109 cells per L). Incidence rate ratios (IRR) comparing MTD with fixed-dose hydroxyurea indicate decreased vaso-occlusive episodes (0·60; 95% CI 0·52-0·70; p<0·0001), acute chest syndrome events (0·21; 0·13-0·33; p<0·0001), recurrent stroke events (0·27; 0·07-1·06; p=0·061), malaria infections (0·58; 0·46-0·72; p<0·0001), non-malarial infections (0·52; 0·46-0·58; p<0·0001), serious adverse events (0·42; 0·27-0·67; p<0·0001), and death (0·70; 0·25-1·97; p=0·50). Dose-limiting toxicity rates were similar between the fixed-dose (24·1 per 100 patient-years) and MTD phases (23·2 per 100 patient-years; 0·97; 0·70-1·35; p=0·86). Grade 3 and 4 adverse events were infrequent (18·5 per 100 patient-years) and included malaria infection, non-malarial infections, vaso-occlusive pain, and acute chest syndrome. Serious adverse events were uncommon (3·6 per 100 patient-years) and included malaria infections, parvovirus-associated anaemia, sepsis, and stroke, with no treatment-related deaths. INTERPRETATION: Hydroxyurea dose escalation to MTD with dose optimisation significantly improved clinical responses and treatment outcomes, without increasing toxicities in children with sickle cell anaemia in sub-Saharan Africa. FUNDING: US National Heart, Lung, and Blood Institute and Cincinnati Children's Research Foundation.
Sujet(s)
Drépanocytose , Antidrépanocytaires , Hydroxy-urée , Humains , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Hydroxy-urée/effets indésirables , Drépanocytose/traitement médicamenteux , Drépanocytose/complications , Drépanocytose/sang , Enfant d'âge préscolaire , Enfant , Mâle , Femelle , Afrique subsaharienne , Études de suivi , Nourrisson , Antidrépanocytaires/usage thérapeutique , Antidrépanocytaires/effets indésirables , Antidrépanocytaires/administration et posologie , Résultat thérapeutique , Relation dose-effet des médicamentsRÉSUMÉ
BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.
Sujet(s)
Prise de décision clinique , Tests de criblage à haut débit , Leucémie aigüe myéloïde , Humains , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/diagnostic , Leucémie aigüe myéloïde/thérapie , Prise de décision clinique/méthodes , Tests de criblage à haut débit/méthodes , Pyrazoles/usage thérapeutique , Nitriles/usage thérapeutique , Pyrimidines/usage thérapeutique , Mâle , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Adulte d'âge moyen , Protéines de fusion oncogènes/génétiqueRÉSUMÉ
Consistent with studies showing a high prevalence of the Duffy null phenotype among healthy Black Americans, this retrospective study found that Duffy null was present in >75% of a young and contemporary cohort of children with sickle cell disease (SCD) in the United States. Despite the potential for this phenotype to impact absolute neutrophil counts, hydroxyurea (HU) dosing, and outcomes, it was not associated with being prescribed a lower HU dose or having increased acute SCD visits early in the HU treatment course. Future studies are needed to confirm these findings in older children with SCD.
Sujet(s)
Drépanocytose , Antidrépanocytaires , Système Duffy , Hydroxy-urée , Humains , Hydroxy-urée/usage thérapeutique , Hydroxy-urée/administration et posologie , Drépanocytose/traitement médicamenteux , Drépanocytose/épidémiologie , Mâle , Femelle , Études rétrospectives , Enfant d'âge préscolaire , États-Unis/épidémiologie , Enfant , Système Duffy/génétique , Prévalence , Antidrépanocytaires/usage thérapeutique , Nourrisson , Récepteurs de surface cellulaire/génétique , AdolescentRÉSUMÉ
INTRODUÇÃO: Atualmente, a hidroxiureia é disponibilizada no SUS como cápsula de 500 mg, entretanto, foram submetidas para a análise do Comitê de Medicamentos da Conitec duas demandas para a incorporação desse medicamento nas formas farmacêuticas de comprimidos de 100 e 100 mg, o que motivou a elaboração desse relatório técnico. A primeira demanda partiu do grupo de especialistas que participam do processo de atualização do Protocolo Clínico e Diretrizes Terapêuticas de Doença Falciforme (PCDTDF). Para essa primeira demanda, o objetivo foi analisar somente o impacto orçamentário de uma possível incorporação da hidroxiureia nas concentrações de 100 e 1000 mg para o tratamento de indivíduos com pelo menos 9 meses de idade. A análise apenas do impacto orçamentário foi realizada porque o referido grupo elaborador do PCDTDF também solicitou a avaliação da ampliação de uso da hidroxiureia para todas as crianças entre 9 meses e 2 anos de idade independentemente de critérios de inclusão, que hoje é a regra para o fornecimento de hidroxiureia nesta
Sujet(s)
Humains , Nourrisson , Hydroxy-urée/administration et posologie , Drépanocytose/traitement médicamenteux , Système de Santé Unifié , Brésil , Efficacité en Santé Publique , Analyse coût-bénéfice/économieRÉSUMÉ
Excessive reactive oxygen species (ROS) contribute to damage of retinal cells and the development of retinal diseases including age-related macular degeneration (AMD). ROS result in increased metabolites of lipoxygenases (LOXs), which react with ROS to induce lipid peroxidation and may lead to ferroptosis. In this study, the effect of 5-LOX inhibition on alleviating ROS-induced cell death was evaluated using sodium iodate (NaIO3) in the retinal pigment epithelium (RPE) cell line ARPE-19 and a mouse model investigating oxidative stress in AMD. We demonstrated that NaIO3 induced cell death in the RPE cells through mechanisms including ferroptosis. Inhibition of 5-LOX with specific inhibitor, Zileuton, or siRNA knockdown of ALXO5 mitigated NaIO3-induced lipid peroxidation, mitochondrial damage, DNA impairment, and cell death in ARPE-19 cells. Additionally, in the mouse model, pretreatment with Zileuton reduced the NaIO3-induced lipid peroxidation of RPE cells, cell death in the photoreceptor layer of the retina, inflammatory responses, and degeneration of both the neuroretina and RPE monolayer cells. Our results suggest that 5-LOX plays a crucial role in ROS-induced cell death in the RPE and that regulating 5-LOX activity could be a useful approach to control ROS and ferroptosis-induced damage, which promote degeneration in retinal diseases.
Sujet(s)
Arachidonate 5-lipoxygenase/métabolisme , Ferroptose/effets des médicaments et des substances chimiques , Ferroptose/génétique , Iodates/effets indésirables , Dégénérescence maculaire/induit chimiquement , Dégénérescence maculaire/métabolisme , Épithélium pigmentaire de la rétine/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/génétique , Animaux , Arachidonate 5-lipoxygenase/génétique , Lignée cellulaire , Modèles animaux de maladie humaine , Techniques de knock-down de gènes/méthodes , Humains , Hydroxy-urée/administration et posologie , Hydroxy-urée/analogues et dérivés , Inhibiteurs de la lipoxygénase/administration et posologie , Mâle , Souris , Souris de lignée C57BL , Stress oxydatif/effets des médicaments et des substances chimiques , Stress oxydatif/génétique , Agents protecteurs/administration et posologie , Espèces réactives de l'oxygène/métabolisme , Épithélium pigmentaire de la rétine/effets des médicaments et des substances chimiques , Transfection/méthodesRÉSUMÉ
Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-ß1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-ß1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion: ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.
Sujet(s)
Dégradation associée au réticulum endoplasmique/génétique , Rein/anatomopathologie , Protéines Klotho/déficit , Néphrite interstitielle/enzymologie , Obstruction urétérale/enzymologie , Animaux , Modèles animaux de maladie humaine , Fibrose , Humains , Hydrazones/administration et posologie , Hydroxy-urée/administration et posologie , Hydroxy-urée/analogues et dérivés , Injections péritoneales , Tubules rénaux/cytologie , Protéines Klotho/effets des médicaments et des substances chimiques , SourisRÉSUMÉ
Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in ß-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent ß-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE ß-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent ß-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE ß-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.
Sujet(s)
Hydroxy-urée/administration et posologie , bêta-Thalassémie/traitement médicamenteux , Administration par voie orale , Adolescent , Adulte , Transfusion sanguine , Méthode en double aveugle , Femelle , Hémoglobine foetale/génétique , Hémoglobine foetale/métabolisme , Humains , Mâle , Polymorphisme génétique , bêta-Thalassémie/sang , bêta-Thalassémie/génétiqueRÉSUMÉ
Little is known about cognitive impairment in patients with sickle cell disease in Africa. This study aimed to assess cognitive impairment and identify possible risk factors in patients with sickle cell disease in Egypt. This study was conducted at Cairo University Children Hospital. Patients with sickle cell disease, between ages of 6-20 years were enrolled. Cognitive ability was tested using the Stanford Binet intelligence quotient (IQ) test, fourth edition. Transcranial Doppler, magnetic resonance imaging and magnetic resonance angiography of the brain were performed within a week of the IQ test. Among the 40 enrolled patients, 55% had a Full Scale IQ at least 1 standard deviation below the mean, and 27.5% had an IQ 2 standard deviations below the mean. High lactate dehydrogenase was significantly associated with low IQ (p = 0.004). In univariate analyses, IQ was significantly correlated with older age (p = 0.025), high lactate dehydrogenase (p = 0.008) and older age at the start of hydroxyurea (p = 0.025). Impaired cognition is prevalent among sickle cell disease patients. Early initiation of hydroxyurea therapy, which should also reduce hemolysis and lactate dehydrogenase, may be a simple measure to preserve mental abilities in these patients.
Sujet(s)
Drépanocytose/complications , Drépanocytose/épidémiologie , Cognition , Dysfonctionnement cognitif/épidémiologie , Dysfonctionnement cognitif/étiologie , Adolescent , Adulte , Facteurs âges , Drépanocytose/diagnostic , Marqueurs biologiques/sang , Encéphale/imagerie diagnostique , Encéphale/physiopathologie , Enfant , Dysfonctionnement cognitif/diagnostic , Dysfonctionnement cognitif/prévention et contrôle , Imagerie diagnostique , Égypte/épidémiologie , Femelle , Humains , Hydroxy-urée/administration et posologie , Hydroxy-urée/usage thérapeutique , Tests d'intelligence , L-Lactate dehydrogenase/sang , Mâle , Prévalence , Facteurs de risque , Jeune adulteRÉSUMÉ
Hydroxyurea (hydroxycarbamide) (HU) for sickle cell anaemia (SCA) is underutilised. Case management is an evidence-based health management strategy and in this regard patient navigators (PNs) may provide case management for SCA. We hypothesised that HU-eligible patients exposed to PNs would have improved indicators of starting HU and HU adherence. We randomised 224 HU-eligible SCA adults into the Start Healing in Patients with Hydroxyurea (SHIP-HU) Trial. All patients received care from trained physicians using standardised HU prescribing protocols. Patients in the Experimental arm received case management and education from PNs through multiple contacts. All other patients were regarded as the Control arm and received specialty care alone. Study physicians were blinded to the study arms and did not interact with PNs. At baseline, 6 and 12 months we assessed and compared laboratory parameters and HU adherence indicators. Experimental patients had higher 6-month mean fetal haemoglobin (HbF) levels than controls. But at 12 months, mean HbF was similar, as were white blood cell count, absolute neutrophil count, total haemoglobin, platelet count and mean corpuscular volume. At 12 months there were fewer experimental patients missing HU doses than controls (mean 1·8 vs. 4·5, P = 0·0098), and more recent HU prescriptions filled than for controls (mean 53·8 vs. 92 days, median 27·5 vs. 62 days, P = 0·0082). Mean HU doses were largely similar. We detected behavioural improvements in HU adherence but no haematological improvements by adding PNs to specialty care.
Sujet(s)
Drépanocytose/épidémiologie , Agents de santé communautaire , Adhésion au traitement médicamenteux , Adulte , Drépanocytose/sang , Drépanocytose/diagnostic , Drépanocytose/thérapie , Index érythrocytaires , Femelle , Humains , Hydroxy-urée/administration et posologie , Hydroxy-urée/effets indésirables , Hydroxy-urée/usage thérapeutique , Analyse en intention de traitement , Mâle , Adulte d'âge moyen , Soins aux patients , Amélioration de la qualité , Qualité de vie , Résultat thérapeutique , Jeune adulteRÉSUMÉ
Alpha haemoglobin-stabilising protein (AHSP) is a key chaperone synthesised in red blood cell (RBC) precursors. Many studies have reported AHSP as a potential biomarker of various diseases. AHSP gene expression has been studied in detail, but little is known about AHSP protein levels in RBCs. We investigated the AHSP concentration of RBC lysates from control subjects (n = 10) and patients with sickle cell anaemia (SCA) with (n = 10) and without (n = 12) hydroxycarbamide (HC) treatment, to evaluate the clinical relevance of AHSP in SCA. We developed a sandwich enzyme-linked immunosorbent assay method, with which we were able, for the first time, to determine the mean AHSP concentration in control RBC lysates (0·82 µg/ml). The AHSP concentration (2·23 µg/ml) was significantly higher in untreated patients with the SS genotype than in controls. The AHSP concentration decreased significantly on HC treatment (1·50 µg/ml) but remained significantly higher than that in controls. A strong positive correlation was observed between the AHSP concentration and the α-haemoglobin pool with the three groups of subjects pooled into a single group. Our present findings indicate that AHSP concentration can be considered a candidate biomarker for monitoring HC responses in patients with SCA and suggest a role for AHSP in various RBC diseases.
Sujet(s)
Drépanocytose/métabolisme , Marqueurs biologiques , Protéines du sang/métabolisme , Érythrocytes/métabolisme , Chaperons moléculaires/métabolisme , Adulte , Drépanocytose/diagnostic , Drépanocytose/traitement médicamenteux , Drépanocytose/génétique , Études cas-témoins , Test ELISA , Index érythrocytaires , Femelle , Hémoglobines/métabolisme , Humains , Hydroxy-urée/administration et posologie , Hydroxy-urée/effets indésirables , Hydroxy-urée/usage thérapeutique , Mâle , Adulte d'âge moyen , Fragments peptidiques/métabolisme , PronosticRÉSUMÉ
Carbohydrate polymers were widely used in pharmaceuticals and drug delivery systems due to their biodegradability and biocompatibility. Among them, chitosan (Cs) has been considered in many new drug delivery systems. Poly(ethylene glycol) as a hydrophilic polymer can increase the solubility and stealth functions of nanocarriers. The Fe3O4 nanoparticles functionalized with polymers act as non-toxic drug vehicles for tumor targeting under external magnetic fields. In present study, the Fe3O4/SiO2-NH2 nanoparticles were prepared and then functionalized with methoxy-PEGylated chitosan (Cs-g-mPEG2000) and the hydroxyurea (HU) was loaded on this nanoparticles. The structure, crystallinity, and morphology of HU/Fe3O4/SiO2/Cs-g-mPEG2000 were determined using spectroscopic and electron microscopy analysis. Encapsulation efficiency of HU and the percentage of loading and release rate at different pH values at 37 °C were examined. Maximum drug release was observed at pH = 7.4. According to TEM results, the nanoparticle sizes were between 18 and 157 nm. The cytotoxicity effect of HU-loaded nanoparticles against MCF-7 human breast cancer cell was evaluated using MTT assay and cell cycle arrest analysis. The inhibitory concentration (IC50) values were 249 and 85 µg/mL on the MCF-7 cell line compared to the control group in 24 h and 96 h, respectively. In addition, the expression of p53 and lincRNA-P21 genes in treated cells and control group was assessed using real-time PCR, and the results showed that the ratio of p53 expression to lincRNA-P21 in MCF-7 cells was significantly increased (P < 0.05). The cell cycle arrested in the S-phase and the population of cells increased 1.3-fold compared to the control group.
Sujet(s)
Antinéoplasiques/pharmacologie , Systèmes de délivrance de médicaments , Hydroxy-urée/pharmacologie , Nanoparticules , Antinéoplasiques/administration et posologie , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Chitosane/composition chimique , Vecteurs de médicaments/composition chimique , Libération de médicament , Femelle , Composés du fer III/composition chimique , Humains , Concentration en ions d'hydrogène , Hydroxy-urée/administration et posologie , Concentration inhibitrice 50 , Cellules MCF-7 , Taille de particule , Polyéthylène glycols/composition chimique , ARN long non codant/génétique , Silice/composition chimique , Protéine p53 suppresseur de tumeur/génétiqueRÉSUMÉ
We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability.
Sujet(s)
Drépanocytose , Antidrépanocytaires/administration et posologie , Hydroxy-urée/administration et posologie , Accident vasculaire cérébral , Drépanocytose/complications , Drépanocytose/traitement médicamenteux , Drépanocytose/épidémiologie , Enfant , Enfant d'âge préscolaire , Femelle , Humains , Mâle , Nigeria/épidémiologie , Évaluation de programme , Accident vasculaire cérébral/épidémiologie , Accident vasculaire cérébral/étiologie , Accident vasculaire cérébral/prévention et contrôleRÉSUMÉ
Despite high prevalence and incidence of ß-thalassemia in Pakistan, there is very limited work on the use of hydroxyurea (HU) in thalassemia patients in the country. This is the first insight regarding genetic profiling of BCL11A and HU responses in Pakistani ß-thalassemia. It correlates single-nucleotide polymorphisms on BCL11A (rs4671393, rs766432) and HBG2 (XmnI), age at first transfusion, and ß-globin mutations with HU response in ß-thalassemia major (BTM). Of 272 patients treated with HU, 98 were complete responders, 55 partial responders, and 119 nonresponders. Our analysis shows that HU response was significantly associated with patients having IVSI-1 or CD 30 mutation (P<0.001), age at first transfusion >1 year (P<0.001), and with the presence of XmnI polymorphism (P<0.001). The single-nucleotide polymorphisms of BCL11A were more prevalent among responders, but could not show significant association with HU response (P>0.05). Cumulative effect of all 5 predicting factors through simple binary scoring indicates that the likelihood of HU response increases with the number of primary and secondary genetic modifiers (P<0.001). Predictors scoring is a pragmatic tool to foresee HU response in patients with BTM. The authors recommend a score of ≥2 for starting HU therapy in Pakistani patients with BTM.
Sujet(s)
Hydroxy-urée/administration et posologie , Polymorphisme de nucléotide simple , Protéines de répression/génétique , bêta-Thalassémie , Enfant , Enfant d'âge préscolaire , Études transversales , Femelle , Humains , Mâle , Pakistan , bêta-Thalassémie/traitement médicamenteux , bêta-Thalassémie/génétiqueRÉSUMÉ
Sickle cell anemia or sickle cell disease is an autosomal recessive disease, caused by a mutation in the hemoglobin gene, where glutamic acid is substituted for valine at position 6 of the beta chain of hemoglobin, resulting in hemoglobin S The diagnosis is made with electrophoresis. The clinical manifestations are varied, the most frequent being the vaso-occlusive crisis, which can increase in pregnancy, during which sickle cell disease also increases the risk of maternal-fetal complications, caused by pre-eclampsia infections, intrauterine growth restriction, and premature delivery. and miscarriage. The usual treatment for the management of seizures is hydroxyurea, a drug that is teratogenic, so its use is contraindicated during pregnancy. Other treatment alternatives are red blood cell transfusion and red blood cell exchange. Next, the first case of red blood cell exchange or exchange transfusion in a pregnant patient with sickle cell anemia at the Hospital Regional de Talca is presented.