A Population Pharmacokinetic Analysis of L-Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects.

BACKGROUND AND OBJECTIVE: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants. METHODS: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed. RESULTS: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food. CONCLUSIONS: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits. CLINICAL TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT04684381).

Early hydroxyurea use is neuroprotective in children with sickle cell anemia.

Children with sickle cell disease (SCD) who began hydroyxurea before age five years scored no differently on a measure of cognitive funciton than age, sex, and race-matched unaffected peers.

Urinary 11-dehydrothromboxane B2 aspirin efficacy testing is sensitive to perioperative inflammation in pediatric solid-organ transplant patients.

BACKGROUND: Evidence for aspirin efficacy testing in pediatrics is limited, especially outside of cardiology, yet thrombotic events have high morbidity in other areas such as pediatric transplant surgery. Debates about whether thromboembolic events while on aspirin represent "aspirin resistance" or "high on-treatment platelet reactivity" persist, given the poor intertest agreement between testing platforms. PROCEDURE: This prospective observational study involved measuring aspirin efficacy using ex vivo testing of platelet aggregation (VerifyNow-Aspirin, VN) and urine 11-dehydrothromboxane B2 (AsprinWorks, UTxB2) contemporaneously at up to three time points after major noncardiac organ transplant surgery. The collection days (CD) were the second and seventh days after stable aspirin dosing and then a convalescent time point 2-9 months later. RESULTS: Fifty-five participants (age range, 0-21 years) were enrolled, having undergone total pancreatectomy with islet autotransplantation (N = 36), orthotopic liver transplantation (N = 18), and combined liver-kidney transplantation (N = 1). Platelet reactivity measured by VN remained unchanged, whereas UTxB2, which was elevated postoperatively, decreased significantly from CD1 to CD2 and CD3. Discordance in therapeutic efficacy was noted per manufacturer cutoffs, with therapeutic VN results in 86% of tests, whereas 12% of UTxB2 were therapeutic. Age-based stratification of UTxB2 results using previously published pediatric median levels increased overall UTxB2 therapeutic rates (80%) and intertest concordance (67% vs 27% if using adult range). No thrombotic events were observed. CONCLUSIONS: Our data suggest that urine thromboxane production may be an underappreciated reflection of postoperative inflammation. Validation of pediatric normal ranges for UTxB2 is a critical next step.

Low-frequency exercise training improves cardiovascular fitness and strength during treatment for breast cancer: a single-arm intervention study.

Aerobic and resistance exercise during and after cancer treatment are important for health-related outcomes, however treatment-specific barriers may inhibit adherence. We explored the effect of lower-frequency exercise training on fitness, body composition, and metabolic markers (i.e. glucose and lipids) in a group of recently diagnosed breast cancer patients. Fifty-two females ≥ 18 years with stage I-IIIB breast cancer were instructed to attend 2 cardiovascular and strength training sessions/week over 12 weeks, but program length was expanded as needed to accommodate missed sessions. Pre- and post-intervention, we measured: (1) cardiovascular fitness, (2) isometric strength, (3) body composition (dual-energy X-ray absorptiometry), and (4) fasting glucose, insulin, c-peptide, and lipids. Pre-intervention, participants were 53 ± 10 years old (mean ± SD) and overweight (BMI: 27.5 ± 5.4 kg m-2, 40.1 ± 6.5% body fat). Forty participants completed the program over a median 20 weeks (range: 13-32 weeks, median frequency: 1.2 sessions/week), over which predicted VO2peak improved by 7% (2.2[0.1-4.4] mL/kg/min) (delta[95% CI]), and strength increased by 7-9% (right arm: 2.3[0.1-4.5] N m; right leg: 7.9[2.1-13.7] N m; left leg: 7.8[1.9-13.7] N m). Body composition and metabolic markers were unchanged. An exercise frequency of 1.2 sessions/week stimulated significant improvements in fitness, and may represent a practical target for patients during active treatment.

Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics-guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia.

Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (near-pancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

Hydroyxurea improves cerebral oxygen saturation in children with sickle cell anemia.

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.

AnemoCheck-LRS: an optimized, color-based point-of-care test to identify severe anemia in limited-resource settings.

BACKGROUND: Severe anemia is common and frequently fatal for hospitalized patients in limited-resource settings. Lack of access to low-cost, accurate, and rapid diagnosis of anemia impedes the delivery of life-saving care and appropriate use of the limited blood supply. The WHO Haemoglobin Colour Scale (HCS) is a simple low-cost test but frequently inaccurate. AnemoCheck-LRS (limited-resource settings) is a rapid, inexpensive, color-based point-of-care (POC) test optimized to diagnose severe anemia. METHODS: Deidentified whole blood samples were diluted with plasma to create variable hemoglobin (Hb) concentrations, with most in the severe (≤ 7 g/dL) or profound (≤ 5 g/dL) anemia range. Each sample was tested with AnemoCheck-LRS and WHO HCS independently by three readers and compared to Hb measured by an electronic POC test (HemoCue 201+) and commercial hematology analyzer. RESULTS: For 570 evaluations within the limits of detection of AnemoCheck-LRS (Hb ≤ 8 g/dL), the average difference between AnemoCheck-LRS and measured Hb was 0.5 ± 0.4 g/dL. In contrast, the WHO HCS overestimated Hb with an absolute difference of 4.9 ± 1.3 g/dL for samples within its detection range (Hb 4-14 g/dL, n = 405). AnemoCheck-LRS was much more sensitive (92%) for the diagnosis of profound anemia than WHO HCS (22%). CONCLUSIONS: AnemoCheck-LRS is a rapid, inexpensive, and accurate POC test for anemia. AnemoCheck-LRS is more accurate than WHO HCS for detection of low Hb levels, severe anemia that may require blood transfusion. AnemoCheck-LRS should be tested prospectively in limited-resource settings where severe anemia is common, to determine its utility as a screening tool to identify patients who may require transfusion.

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia.

BACKGROUND: Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. METHODS: HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 µL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. DISCUSSION: HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.

Bioelectrical Impedance Analysis Overestimates Fat-Free Mass in Breast Cancer Patients Undergoing Treatment.

BACKGROUND: Bioelectrical impedance analysis (BIA) is commonly used to assess fat-free mass (FFM) and fat mass (FM) in breast cancer patients. However, because of the prevalence of overweight, obesity and variable hydration status in these patients, assumptions for existing prediction equations developed in healthy adults may be violated, resulting in inaccurate body composition assessment. METHODS: We measured whole-body FFM using single-frequency BIA (50 kHz) and dual-energy x-ray absorptiometry (DXA) in 48 patients undergoing treatment for breast cancer. We applied raw BIA data to 18 previously published FFM prediction equations (FFMBIA ) and compared these estimates to DXA (FFMDXA ; reference method). RESULTS: On average, patients were 52 ± 10 (mean ± SD) years of age and overweight (body mass index: 27.5 ± 5.5 kg/m2 ; body fat by DXA: 40.1% ± 6.6%). Relative to DXA, BIA overestimated FFM by 4.1 ± 3.4 kg (FFMDXA : 42.0 ± 5.9 kg; FFMBIA : 46.1 ± 3.4 kg). Individual equation-generated predictions of FFMBIA ranged from 39.6 ± 6.7 to 52.2 ± 5.6 kg, with 16 equations overestimating and 2 equations underestimating FFMBIA compared with FFMDXA . Based on equivalence testing, no equation-generated estimates were equivalent to DXA. CONCLUSION: Compared with DXA, BIA overestimated FFM in breast cancer patients during treatment. Although several equations performed better than others, none produced values that aligned closely with DXA. Caution should be used when interpreting BIA measurements in this clinical population, and future studies should develop prediction equations specific to breast cancer patients.

Utilization trends and safety of intravenous iron replacement in pediatric specialty care: A large retrospective cohort study.

BACKGROUND: Iron deficiency is a common and clinically diverse hematologic disorder in childhood for which oral iron is often an infeasible or ineffective treatment option. Intravenous (IV) iron can be an efficient and highly successful means of iron replacement but its use has not been well-characterized on a large scale in pediatrics. PROCEDURE: All IV iron doses administered to patients for iron replacement therapy at a tertiary pediatric hospital from January 2010 through October 2016 were evaluated. Analyses included patient demographics, underlying medical conditions, and detailed information for each dose. Individual chart review was performed to identify infusion-related reactions. Nephrology patients as well as those patients 21 years or older at the time of the first infusion were excluded. RESULTS: A total of 1,088 doses of IV iron administered to 194 patients met inclusion criteria. A wide variety of specialties prescribed IV iron, with gastroenterology, hematology, and hospital medicine being the highest users in this cohort. A majority of patients (68%) required multiple infusions and dosing was highly variable, ranging from 1.3-1,030 mg per infusion. Premedication use was infrequent (10.3% of doses) and no severe infusion-associated reactions occurred. CONCLUSIONS: IV iron is commonly prescribed by certain pediatric specialties but there is little standardization in the indications, formulations, or dosing. These data suggest that IV iron should be considered a safe alternative for iron deficiency treatment in pediatrics when oral iron is either unsuccessful or contraindicated.

Long-term outcomes of drug-eluting stents versus bare-metal stents in saphenous vein graft disease: results from the Prairie "Real World" Stent Registry.

OBJECTIVES: This study was designed to compare long-term clinical outcomes of drug-eluting stents (DES) versus bare metal stents (BMS) in patients with saphenous vein graft (SVG) disease in the "real world." BACKGROUND: The safety and efficacy of DES versus BMS in SVG remains uncertain due to contradictory reports of either lower revascularization rates with DES; or clinical equivalence to BMS; or even an excess of clinical events associated with DES use. METHODS: We identified consecutive patients who underwent stent placement within a de novo SVG lesion between May 1, 2003 and July 31, 2007. Follow-up was obtained at regular intervals. The Kaplan-Meier method was used to produce actuarial survival estimates. Cox regression analysis was used to predict the risk associated with stent type, and propensity scores were generated to risk-adjust the results. RESULTS: The study group included 379 stent recipients (284 DES; 95 BMS) with 410 stented lesions. BMS were placed more frequently in current smokers, acute myocardial infarctions, larger vessels, and longer lesions. In-hospital mortality was higher in BMS recipients than in their DES counterparts (3.2% vs. 0, respectively; P = 0.015). At 3 years, there was no significant difference in clinical adverse event rates between DES and BMS recipients, even after risk adjustment. CONCLUSIONS: Three-year adverse event rates are similar among patients treated with DES or BMS in SVG lesions. Therefore, while DES are safe, they do not appear to offer an advantage in terms of long-term graft patency.