Higher hydroxyurea adherence among young adults with sickle cell disease compared to children and adolescents

BackgroundSickle cell disease (SCD) results in severe complications, such as anaemia and pain episodes. Hydroxyurea (HU) is efficacious in SCD, yet adherence remains low.ObjectiveTo assess the relationship of HU adherence to health care utilization and patients’ characteristics.MethodsThis is a 5-year retrospective chart review. Patients’ demographics and medical history were collected from the electronic medical record (EMR). HU adherence was evaluated using foetal haemoglobin “HbF%”, mean corpuscular volume “MCV”, and absolute neutrophil count “ANC”. Age groups included children (<12 years), adolescents (12–17 years), and young adults (≥18 years).ResultsA total of 113 SCD patients on HU were included (median age 14 years, IQR 10–20; 50% female; 88% HbSS). Young adults had significantly higher HU adherence compared to adolescents and children, including higher median HbF% (24.2 vs. 12.4 vs. 8.6, p = .003), MCV (fl) (106.4 vs. 96.2 vs. 95.4, p = .01) and lower ANC (10³/ml) (3.25 vs. 4.9 vs. 4.2, p = .01), respectively. Patients with chronic pain had lower HU adherence (HbF% 15.3 vs. 10.7, p = .04; ANC 3.6 vs. 6.3, p = .002; MCV 102.3 vs. 93.1, p = .1). Patients with higher HbF or MCV and lower ANC had significantly less frequent emergency room visits (r_s=–0.26, p = .01; r_s=–0.23, p = .01; r_s=0.24, p = .01) and hospitalizations (r_s=–0.27, p = .01; r_s=–0.31, p = .01; r_s=0.21, p = .02) as well as shorter length of stays (r_s=–0.27, p = .0045; r_s=–.34, p = 0.004; r_s=0.23, p = .02), respectively. Similar trends in HU adherence and health care utilization were seen in subgroup analysis of only HbSS patients. There was no significant association of HU adherence to patients’ sex, socio-economic status, distance from hospital, and HU duration.ConclusionsYoung adults with SCD had significantly higher HU adherence compared to children and adolescents. Patients with lower HU adherence and/or chronic pain had increased health care utilization. Future studies examining barriers to adherence and evaluating interventions to optimize HU adherence in SCD are warranted.

KEY MESSAGES

1. Young adults with SCD had significantly higher HU adherence, as reflected in their laboratory markers, compared to children and adolescents.
2. Patients with higher HU adherence and/or those without chronic pain had lower or less frequent health care utilization.
3. No significant association of HU adherence to patients’ sex, socio-economic status and distance from hospital.

     

The use of metabolic inhibitors to compare the excision repair of pyrimidine dimers and nondimer dna damages in human skin fibroblasts exposed to 254-NM and sunlamp-produced >310-NM ultraviolet radiation

Normal human skin fibroblasts were exposed to either 0–5 J/m² of 254-nm ultraviolet (UV) radiation or 0–50 kJ/m² of the Mylar-filtered UV (>310 nm) produced by a fluorescent sunlamp. These cells were then incubated for 0–20 min in medium containing 10 mM hydroxyurea (HU) and 0.1 mM 1-β-D-arabinofuranosyl cytosine (ara C), and the yield of DNA strand breaks was measured by means of the alkaline elution technique. For cells irradiated with 254-nm UV, which results primarily in the formation of cyclobutane pyrimidine dimers, a rapid increase in DNA strand breaks was detected following incubation with these metabolic inhibitors. In contrast, only a low level of strand breaks formed in cells incubated with HU and ara C after irradiation with approximately equitoxic fluences of sunlamp UV >310 nm, which mainly causes the induction of nondimer DNA lesions. Hence, these results are consistent with the conclusion that the pathways involved in the repair of nondimer DNA damages induced by UV wavelengths >310 nm differ from the repair of pyrimidine dimers.     

Phase I trial of high-dose infusional hydroxyurea,high-dose infusional 5-fluorouracil and recombinant interferon-α-2a in patients with advanced malignancies

The ribonucleotide reductase inhibitor, hydroxyurea (HU), augments the cytotoxic effects of 5-fluorouracil (5FU)in vitro; both drugs are synergistic with interferon- (IFN)in vitro. The aim of this phase I study was to determine the maximal duration of HU, 4.3 g/m², administered as a parenteral infusion in combination with 5FU, 2.6 g/m² administered over 24 hrs each week, + IFN, 9 MU, subcutaneously three times per week. There were 26 patients enrolled and evaluable. This included 14 patients with colorectal cancer of whom 13 had been previously treated, and 12 patients with other refractory malignancies (pancreas, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and others), of whom 10 were previously untreated. The dose-limiting toxicity of this regimen was myelosuppression. This prohibited dose escalation of HU above the starting dose (24 hrs) on a 6-weeks-on, 2-weeks-off therapy schedule. When filgrastim, 480 g, was administered subcutaneously on days 3–6, the duration of HU could be extended to 48 hrs on a 2-weeks-on, 1 -week-off therapy schedule. There were two instances of fatal infection, one in a patient with a rectovaginal fistula with neutropenic sepsis and the second in a patient with non-neutropenicClostridium septicum sepsis. All therapy was administered in the ambulatory setting. There were three responders, all among previously untreated patients. High-dose parenteral hydroxyurea, 4.3 g/m² administered over 24 hrs, can be safely combined with high-dose weekly 5FU, 2.6 g/m² over 24 hrs + IFN, 9 MU subcutaneously three times per week, without filgrastim in the ambulatory setting. Parenteral hydroxyurea, 4.3 g/m² over 24 hrs daily × 2 can also be combined with high-dose 5FU + IFN, but requires the addition of filgrastim to avoid severe myelosuppression.     

Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia

In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso‐occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities.     

Hydroxyurea use among children with sickle cell anemia

This study describes hydroxyurea use among children ages 1 to 17 with sickle cell anemia (SCA) enrolled in at least one year of Medicaid in six states from 2005 to 2012. Administrative claims were used to summarize the number of days’ supply of hydroxyurea dispensed by state and year. A total of 7963 children with SCA contributed 22 424 person‐years. Among person‐years with greater than 30 days of hydroxyurea, only 18% received at least 300 days of hydroxyurea, which varied by state. Following updated recommendations for all children with SCA to be offered hydroxyurea, strategies to increase hydroxyurea adherence among this population are needed.     

复方补骨脂对羟基脲家兔激素水平的影响

目的观察复方补骨脂对羟基脲家兔激素水平的影响。方法将白兔21只随机分成3组:正常组每日按10 mL/kg体质量喂饲生理盐水;模型组每日以10 mL/kg体质量喂饲50 g/L羟基脲悬浊液;中药组每日按5 mL/kg体质量喂饲100 g/L羟基脲悬浊液,另加补肾阳中药煎剂5 mL/kg体质量。3组共饲喂7~10 d。放免方法测定血清雌二醇(E2)、睾酮(T)水平。结果模型组家兔造模后血中E2含量从造模前(2.10±0.84)μg/L降低至(0.25±0.09)μg/L,两者比较有显著性差异(P<0.01);T含量由造模前(10.5±0.38)ng/L降低至(0.36±0.18)ng/L,两者比较有显著性差异(P<0.05);E2/T比值造模前后变化无显著性差异。中药组造模加中药治疗后E2含量为(1.92±0.92)μg/L,与治疗前比较无显著性差异(P>0.05);血中T水平为(1.28±1.24)ng/L,与治疗前比较无显著性差异(P>0.05)。结论复方补骨脂对羟基脲家兔激素水平有明显的保护作用。     

Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study

Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate fetal hemoglobin (Hb F) levels in patients with β type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type hemoglobinopathies.