Menopause in Brazilian women with sickle cell anemia with and without hydroxyurea therapy.
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ABSTRACT:
SUBMITTER: Queiroz AM
PROVIDER: S-EPMC8446238 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons.In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA.In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.
| S-EPMC5868345 | biostudies-literature
Project description:Background and objectiveSusceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses.MethodsT-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG).ResultsCompared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use.ConclusionsHydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.
| S-EPMC4179098 | biostudies-literature
Project description:Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBCs) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71(+)) and micronucleated mature erythrocytes (MN-RBC) was then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71(+) and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71(+) was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71(+) and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow.
| S-EPMC5831106 | biostudies-literature
Project description:The Multicenter Study of Hydroxyurea (HU) in Sickle Cell Anemia (MSH) previously showed that daily oral HU reduces painful sickle cell (SS) crises by 50% in patients with moderate to severe disease. The morbidity associated with this disease is known to have serious negative impact on the overall quality of life(QOL) of affected individuals.The data in this report were collected from the 299 patients enrolled in the MSH. Health quality of llife (HQOL) measures were assessed in the MSH as a secondary endpoint to determine if the clinical benefit of HU could translate into a measurable benefit perceptible to the patients. HQOL was assessed with the Profile of Mood States, the Health Status Short Form 36 (SF-36), including 4-week pain recall, and the Ladder of Life, self-administered twice 2-weeks apart pre-treatment and every 6 months during the two-year, randomized, double-blind, treatment phase. The effects of factors including randomized treatment, age, gender, pre-treatment crises frequency, Hb-F level mean, daily pain from 4-week pre-treatment diaries, and 2-year Hb-F response level (low or high) were investigated.Over two years of treatment, the benefit of HU treatment on QOL, other than pain scales, was limited to those patients taking HU who maintained a high HbF response, compared to those with low HbF response or on placebo. These restricted benefits occurred in social function, pain recall and general health perception. Stratification according to average daily pain prior to treatment showed that responders to HU whose average daily pain score was 5-9 (substantial pain) achieved significant reduction in the tension scale compared to the placebo group and to non-responders. HU had no apparent effect on other QOL measures.Treatment of SS with HU improves some aspects of QOL in adult patients who already suffer from moderate-to-severe SS.
| S-EPMC1569824 | biostudies-other
Project description:Background: Despite a high incidence of sickle cell anemia, hydroxyurea (HU) treatment is rarely used in the DR Congo. This study aims to assess the efficacy of HU, the incidence of side effects that may limit its use in adults and to determine the dose needed for clinical improvement in patients. Methods: In a prospective study, patients received an initial dose of 15 mg/kg/day which was increased by 5 mg/kg every 6 months, up to a maximum of 30 mg/kg/day. The response and side effects to HU were evaluated biologically and clinically every 3 months during a 2-year period. Results: Seventy adult patients with a moderate or severe clinical phenotype initiated treatment. Only minor side effects were reported. At the end of the 2-year treatment phase, 45 (64.3%) had dropped out, of whom 33 were without a clear reason. Clinical and biological improvement was more marked during the first year. There was a reduction in severe vaso-occlusive crises (p < 0.001), need for transfusion (p < 0.001), and hospitalization days (p = 0.038). Fetal hemoglobin (HbF) levels increased on average 2.9 times after 12 months (p < 0.001). The increase in mean corpuscular volume was greater in the first year (p < 0.001) than in the second year (p = 0.041). The decrease in leukocytes (p < 0.001) was significant during the first year. In 70% of patients, the 20 mg/kg/day dose was needed to reach the 20% HbF threshold. Conclusion: HU is effective and well tolerated. The magnitude of the response varies from one patient to another. Improvement of clinical manifestations is achieved in most patients with a relatively low dose. Effective implementation of HU treatment will require improved adherence to treatment.
| S-EPMC10435708 | biostudies-literature
Project description:Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 106 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.
| S-EPMC5675769 | biostudies-literature
Project description: Not available
| S-EPMC5389903 | biostudies-literature
Project description:BackgroundHydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.MethodsWe enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell-related events, transfusions, and survival).ResultsA total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).ConclusionsHydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731 .).
| S-EPMC6454575 | biostudies-literature
Project description:Purpose of reviewOver the past several decades, hydroxyurea has emerged as a well tolerated and potent disease-modifying therapy for children and adults with sickle cell anemia (SCA). Strong, evidence-based recommendations from the National Institutes of Health, American Society of Hematology, and British Society of Haematology document that hydroxyurea is now standard of care treatment for SCA. In low-resource settings, however, hydroxyurea is rarely utilized due to lack of availability, inadequate treatment guidance, and excessive costs.Recent findingsResearch trials conducted within the Caribbean and sub-Saharan Africa confirm the efficacy of hydroxyurea as a well tolerated, feasible, and beneficial treatment in low-resource countries. Hydroxyurea is therefore vital to reaching the targets for control of SCA outlined by the WHO. To maximize its utilization toward real-world effectiveness, specific attention must be given to healthcare provider education and training, public and institutional awareness, and medication access and affordability.SummaryEfforts to introduce hydroxyurea effectively into low-resource countries should urgently address the lack of treatment guidelines, gaps in knowledge and clinical infrastructure, and medication inaccessibility. Partnerships among governmental, academic, pharmaceutical, and charitable organizations must tackle these barriers so that all individuals living with SCA worldwide can benefit from hydroxyurea.
| S-EPMC9364839 | biostudies-literature
Project description:Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute-sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment.
| S-EPMC2902131 | biostudies-literature