Hydroxyurea Pharmacokinetics in Pediatric Patients After Total Pancreatectomy With Islet Autotransplantation.

Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which pediatric hydroxyurea pharmacokinetics have primarily been studied. Plasma hydroxyurea levels were quantified in 14 participants aged 4-19 years using high-performance liquid chromatography. Blood collections were scheduled 20 minutes, 1 hour, and 4 hours after the first dose, on pharmacokinetic day 1 (PK1), and again 2-3 months later if still on hydroxyurea (PK2). Six participants had PK1 and PK2 data at all 3 postdose timed collections, 5 only had PK1 samples, and 3 only had PK2 samples. Total pancreatectomy with islet autotransplantation participants had reduced and delayed absorption compared with sickle cell anemia participant data from the Hydroxyurea Study of Long-Term Effects, regardless of timing or dosing methodology. Total pancreatectomy with islet autotransplantation participants had different pharmacokinetic profiles at PK1 versus PK2, with lower dose-normalized exposures than previously reported in sickle cell anemia. These results suggest variability exists in hydroxyurea absorption and bioavailability in total pancreatectomy with islet autotransplantation patients, suspected to be primarily because of Roux-en-Y reconstruction, and suggest that more pharmacokinetic data are needed for scenarios when hydroxyurea is prescribed to children without sickle cell anemia.

A highly sensitive UPLC-MS/MS method for hydroxyurea to assess pharmacokinetic intervention by phytotherapeutics in rats.

Hydroxyurea (HU) is the first-ever approved drug by the United States Food and Drug Administration (USFDA) for the management of sickle cell anemia (SCA). However, its treatment is associated with severe liabilities like myelosuppression. Therefore, the aim of the present investigation was to identify phytotherapeutics through assessment of the pharmacokinetic interaction of HU with dietary bioflavonoids followed by elucidation of the same phytoconstituents for their ability to protect HU-induced toxicity in hematological profile. In this direction, we developed a sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to estimate HU in rat plasma at first and then validated as per USFDA guidelines as there is no such precedent in the literature. A simple plasma protein precipitation method was employed for plasma sample processing. The separation was achieved in gradient mode using Syncronis HILIC column (100 × 4.6 mm, 3 µm) with a mobile phase composition of water containing 0.1% (v/v) formic acid and acetonitrile. Ionization was carried out in positive heated-electrospray ionization (H-ESI) mode. Detection was done in selected reaction monitoring (SRM) mode with m/z 77.1 > 44.4 and m/z 75.1 > 58.2 for HU and methylurea (internal standard), respectively. All the validation parameters were within the acceptable criteria. This bioanalytical method was found to be useful in assessing the preclinical pharmacokinetic interaction of HU. Concomitant administration of chrysin or quercetin with HU in rats significantly enhanced the oral exposure of HU. Lowering of total red blood cells (RBC) and hemoglobin (Hb) level by HU in rats was significantly improved in the presence of chrysin, quercetin, and naringenin. Overall, both chrysin and quercetin showed potential to be a promising phytotherapeutics for concomitant therapy with HU to combat its dose-dependent side effects.

Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia.

Hydroxyurea is FDA-approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight-based dosing with step-wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center study designed to prospectively validate a novel personalized PK-guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9-26 months), and PK-guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3-9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK-guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK-guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight-based dosing.

Functionalized nitrogen doped graphene quantum dots and bimetallic Au/Ag core-shell decorated imprinted polymer for electrochemical sensing of anticancerous hydroxyurea.

A novel molecularly imprinted polymer-capped acrylated nitrogen doped graphene quantum dots and bimetallic Au/Ag core-shell was synthesized to serve as a sensing nano-hybrid film for the detection of an anticancerous drug, hydroxyurea. This exploited the use of a functionalized nitrogen doped graphene quantum dots iniferter. This initiated the polymerization, following "surface grafting-from" approach, over the surface of a screen-printed carbon electrode to obtain requisite stability and selectivity of the measurement. Herein, nitrogen doped graphene quantum dots were prepared utilizing the degree of dehydration/carbonization of citric acid (carbon skeleton) and urea (nitrogen dopant) as source materials. This provided an efficient sensor platform anchoring bimetallic Au/Ag core-shell on its surface. The nano-assembly of acrylated nitrogen doped graphene quantum dots and bimetallic Au/Ag core-shell@imprinted polymer actually amplified the electrode kinetics by improving the diffusion coefficient (~20-fold) and electron-transfer kinetics (~5-fold), in comparison to the simple bimetallic Au/Ag core-shell decorated imprinted sensor. Under optimized conditions of differential pulse anodic stripping voltammetric transduction, a linear relationship between the current and the concentration was obtained in the range of 0.62-102.33 ng mL-1 for hydroxyurea. The detection limit was observed to be 0.07 ng mL-1 in blood plasma, without having any matrix effect, cross-reactivity, and false-positives. The proposed sensor assures its clinical applicability for the treatment of cancer.

Determination of hydroxyurea in human plasma by HPLC-UV using derivatization with xanthydrol.

A simple and rapid high performance liquid chromatography (HPLC) method using ultraviolet (UV) detection was developed to determine hydroxyurea (HU) concentration in plasma sample after derivatization with xanthydrol. Two hundred microliters samples were spiked with methylurea (MeU) as internal standard and proteins were precipitated by adding methanol. Derivatization of HU and MeU was immediately performed by adding 0.02M xanthydrol and 1.5M HCl in order to obtain xanthyl-derivatives of HU and MeU that can be further separated using HPLC and quantified using UV detection at 240nm. Separation was achieved using a C18 column with a mobile phase composed of 20mM ammonium acetate and acetonitrile in gradient elution mode at a flow rate of 1mL/min. The total analysis time did not exceed 18min. The method was found linear from 5 to 400µM and all validation parameters fulfilled the international requirements. Between- and within-run accuracy error ranged from -4.7% to 3.2% and precision was lower than 12.8%. This simple method requires small volume samples and can be easily implemented in most clinical laboratories to develop pharmacokinetics studies of HU and to promote its therapeutic monitoring.

Hydroxyurea-Lactose Interaction Study: In Silico and In Vitro Evaluation.

The Maillard reaction between hydroxyurea (a primary amine-containing drug) and lactose (used as an excipient) was explored. The adduct of these compounds was synthesized by heating hydroxyurea with lactose monohydrate at 60 °C in borate buffer (pH 9.2) for 12 h. Synthesis of the adduct was confirmed using UV-visible spectroscopy and Fourier transform infrared, differential scanning calorimetry, high-pressure liquid chromatography, and liquid chromatography-mass spectrometry studies. An in silico investigation of how the adduct formation affected the interactions of hydroxyurea with its biological target oxyhemoglobin, to which it binds to generate nitric oxide and regulates fetal hemoglobin synthesis, was carried out. The in silico evaluations were complemented by an in vitro assay of the anti-sickling activity. Co-incubation of hydroxyurea with deoxygenated blood samples reduced the percentage of sickled cells from 38% to 12 ± 1.6%, whereas the percentage of sickled cells in samples treated with the adduct was 17 ± 1.2%. This indicated loss of anti-sickling activity in the case of the adduct. This study confirmed that hydroxyurea can participate in a Maillard reaction if lactose is used as a diluent. Although an extended study at environmentally feasible temperatures was not carried out in the present investigation, the partial loss of the anti-sickling activity of hydroxyurea was investigated along with the in silico drug-target interactions. The results indicated that the use of lactose in hydroxyurea formulations needs urgent reconsideration and that lactose must be replaced by other diluents that do not form Maillard adducts.

Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU-13C1,15N2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200µg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring.

Stable-Isotope Dilution HPLC-Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples.

BACKGROUND: Sickle cell anemia (SCA) is a life-threatening blood disorder characterized by the presence of sickle-shaped erythrocytes. Hydroxyurea is currently the only US Food and Drug Administration-approved treatment and there is a need for a convenient method to monitor compliance and hydroxyurea concentrations, especially in pediatric SCA patients. METHODS: We describe a novel approach to the determination of hydroxyurea concentrations in dried whole blood collected on DMPK-C cards or volumetric absorptive microsampling (VAMS) devices. Hydroxyurea was quantified by electrospray ionization LC-MS/MS using [13C15N2]hydroxyurea as the internal standard. Calibrators were prepared in whole blood applied to DMPK-C cards or VAMS devices. RESULTS: Calibration curves for blood hydroxyurea measured from DMPK-C cards and VAMS devices were linear over the range 0.5-60 µg/mL. Interassay and intraassay CVs were <15% for blood collected by both methods, and the limit of detection was 5 ng/mL. Whole blood hydroxyurea was stable for up to 60 days on DMPK-C cards and VAMS devices when frozen at -20 °C or -80 °C. Whole blood hydroxyurea concentrations in samples collected on DMPK-C cards or VAMS devices from SCA patients were in close agreement. CONCLUSIONS: This tandem mass spectrometry method permits measurement of hydroxyurea concentrations in small volumes of dried blood applied to either DMPK-C cards or VAMS devices with comparable performance. This method for measuring hydroxyurea from dried blood permits the evaluation of therapeutic drug monitoring, individual pharmacokinetics, and medication adherence using heel/finger-prick samples from pediatric patients with SCA treated with hydroxyurea.

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSßspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

Isotope-dilution gas chromatography-mass spectrometry method for the analysis of hydroxyurea.

BACKGROUND: Hydroxyurea is used in the treatment of various malignancies and sickle cell disease. There are limited studies on the pharmacokinetics of hydroxyurea, particularly in pediatric patients. An accurate, precise, and sensitive method is needed to support such studies and to monitor therapeutic adherence. We describe a novel gas chromatography-mass spectrometry (GC-MS) method for the determination of hydroxyurea concentration in plasma using stable labeled hydroxyurea C N2 as an internal standard. METHODS: The method involved an organic extraction followed by the preparation of trimethylsilyl (TMS) derivatives of hydroxyurea for GC-MS selected ion-monitoring analysis. The following mass-to-charge (m/z) ratio ions for silated hydroxyurea and hydroxyurea C N2 were monitored: hydroxyurea-quantitative ion 277, qualifier ions 292 and 249; hydroxyurea C N2-quantitative ion 280, qualifier ion 295. This method was evaluated for reportable range, accuracy, within-run and between-run imprecisions, and limits of quantification. RESULTS: The reportable range for the method was 0.1-100 mcg/mL. All results were accurate within an allowable error of 15%. Within-run and between-run imprecisions were <15%. Samples were stable for at least 4 hours at room temperature, 2 months at -20°C, and 6 months at -70°C, and after 3 freeze/thaw cycles. Extraction efficiency for 1-, 5-, 10-, and 50-mcg/mL samples averaged 2.2%, 1.8%, 1.6%, and 1.4%, respectively. CONCLUSIONS: The isotope-dilution GC-MS method for analysis of hydroxyurea described here is accurate, sensitive, precise, and robust. Its characteristics make the method suitable for supporting pharmacokinetic studies and/or clinical therapeutic monitoring.

Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2) = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure.

Quantification of the 5-lipoxygenase inhibitor zileuton in human plasma using high performance liquid chromatography-tandem mass spectrometry.

Zileuton is an orally active, selective inhibitor of 5-lipoxygenase, which catalyzes the first step in the conversion of arachadonic acid into leukotrienes. Given the important role of leukotrienes in inflammation and cell signaling, multiple studies have investigated the efficacy of zileuton in the treatment of human disease. Examples of disease targets include asthma, ulcerative colitis, rheumatoid arthritis, and more recently, acne, ischemic/reperfusion injury, inflammatory pain, and sickle cell anemia. Zileuton is currently approved for the prophylaxis and chronic treatment of asthma. We report the development and validation of a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of zileuton in human EDTA plasma. The range of reliable response was 3.05-20,000ng/mL in human plasma. The calibration curves had a correlation coefficient of r(2)>0.99. The intra-day precision was 3.4-5.3%. The inter-day precision ranged from 4.5% to 7.3% and inter-day accuracy from 100% to 107%. No matrix interferences, ion suppression/enhancement, or carry-over was observed. The assay met all predefined acceptance criteria and was subsequently employed to measure plasma zileuton concentrations in a clinical trial.

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen.

BACKGROUND: Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. METHODS: The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. RESULTS: The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. CONCLUSIONS: The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU. TRIAL REGISTRATION: The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient.

Determination of hydroxyurea in serum or plasma using gas chromatography-mass spectrometry (GC-MS).

Hydroxyurea is an antineoplastic drug, which is also widely used in the treatment of sickle cell disease. Various methods including colorimetry, high performance liquid chromatography, and gas chromatography-mass spectrometry (GC-MS) are available for the assay of hydroxyurea. In the gas chromatography method described, the drug is extracted from serum, plasma, or urine using ethyl acetate and phosphate buffer (pH 6). The organic phase containing drug is separated and dried under a stream of nitrogen. After trimethylsilyl derivatization, samples are analyzed using GC-MS. Quantitation of the drug in a sample is achieved by comparing responses of the unknown sample to the responses of the calibrators using selected ion monitoring. Tropic acid is used as an internal standard.

Plasma hydroxyurea determined by gas chromatography-mass spectrometry.

Hydroxyurea treatment is efficiently used to ameliorate the clinical course of patients affected with sickle cell disease. To understand the patient's wide variation in the clinical response to that drug and monitor its plasma levels, a new method was developed and validated. Fifty microL plasmatic samples containing hydroxyurea are added with internal standard, deproteinized, evaporated to dryness, silanized, and analyzed by gas chromatography-mass spectrometry, which operates in the selected ion mode after electron impact fragmentation. Linearity was found to extend to at least 100mg/L. Over a 1-25mg/L concentration range, coefficients of variation for intra-day and inter-day precision are 5.3% and 7.7%, respectively. Plasma blank-samples reveal endogenous hydroxyurea at a level

Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients.

BACKGROUND: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine--as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine--are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). METHODS: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). RESULTS: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). CONCLUSION: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.

Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void.

Pain due to vaso-occlusive crisis is the major cause of hospital use in sickle cell disease. Although available guidelines provide recommendations for opioid administration in this setting, only 4 (21%) of 19 medical textbooks present treatment regimens that are consistent with them. Moreover, only 7 texts (37%) note that addiction is infrequent in this population, while 11 (92%) of 12 texts provide such reassurance for cancer-related pain (P < .005). Finally, hydroxyurea use to decrease the frequency of vaso-occlusive crises is completely defined only in 2 textbooks. Thus, most medical texts provide neither adequate information for the treatment or prevention of pain due to vaso-occlusive crisis in sickle cell disease nor reassurance of the unlikelihood of addiction in this population. In contrast, treatment recommendations for less common hematologic disorders are consistent with current standards in 53% to 84% of appropriate texts (P < .05). Limited knowledge regarding the principles and appropriateness of opioid therapy; a lack of evidence-based research on pain control; and misconceptions and prejudices about drug abuse and addiction contribute to this educational void. Thus, research and training on pain control in sickle cell disease are needed to parallel studies of environmental and genetic factors contributing to the known clinical heterogeneity of this disorder.

Plasma and urine hydroxyurea levels might be useful in the management of adult sickle cell disease.

Hydroxyurea (HU) is useful for treating sickle cell anemia because of its ability to reduce some of the severe clinical events such as painful crises and acute chest syndrome. It may also reduce the need for blood transfusions and frequent hospitalizations and reduce mortality. Nevertheless, no consistent recommendations regarding its therapeutic schedule are defined. Our aim was to improve and validate a high performance liquid chromatography (HPLC) technique to measure HU and to study HU levels in serum and urine of sickle cell anemia patients and relate this to treatment efficacy and compliance. Thirty-seven patients received 1,128 +/- 333 mg of HU per day (8.0 to 28.0 mg/kg/day). Plasma and/or urine were sampled and HU was measured using an HPLC method coupled with UV detection. We validated a specific, sensitive assay with good reproducibility and linearity, and showed a positive relationship between plasma HU concentrations and time elapsed between oral HU intake and sampling. We observed plasma HU concentrations were positively correlated with change in mean corpuscular volume (MCV) before and during the treatment. No correlation was obtained between HU concentration and Hb F level.

Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease.

Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted.

Quantitative analysis of trimethylsilyl derivative of hydroxyurea in plasma by gas chromatography-mass spectrometry.

Hydroxyurea is an antitumor drug widely used in the treatment of sickle cell disease. The drug has been analyzed in biological fluids by a number of high-performance liquid chromatography (HPLC) methods. This paper describes a fast and highly reliable capillary gas chromatography-mass spectrometry (GC-MS) procedure that was developed for the detection and quantitation of hydroxyurea in plasma. The compound and its labeled internal standard were liquid extracted from plasma and derivatized with BSTFA before analysis. The detection limit of the assay was 0.078 microg/ml and the limit of quantitation was 0.313 microg/ml with linearity up to 500 microg/ml. Intra-day variation, as coefficient of variation (C.V., %) over the selected concentration range, was 0.3-8.7% and inter-day variation was 0.4-9.6%.