An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites.

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Biopharmaceutical characterization of a novel sustained-release formulation of allopurinol with reduced nephrotoxicity.

The present study was aimed to develop a novel sustained-release formulation for allopurinol (ALP/SR) with the use of a pH-sensitive polymer, hydroxypropyl methylcellulose acetate succinate, to reduce nephrotoxicity. ALP/SR was evaluated in terms of crystallinity, the dissolution profile, pharmacokinetic behavior, and nephrotoxicity in a rat model of nephropathy. Under acidic conditions (pH1.2), sustained release behavior was seen for ALP/SR, although both crystalline ALP and ALP/SR exhibited rapid dissolution at neutral condition. After multiple oral administrations of ALP samples (10 mg-ALP/kg) for 4 days in a rat model of nephropathy, ALP/SR led to a low and sustained plasma concentration of ALP, as evidenced by half the maximum concentration of ALP and a 2.5-fold increase in the half-life of ALP compared with crystalline ALP, possibly due to suppressed dissolution behavior under acidic conditions. Repeated-dosing of ALP/SR resulted in significant reductions in plasma creatinine and blood urea nitrogen levels by 73% and 69%, respectively, in comparison with crystalline ALP, suggesting the low nephrotoxic risk of ALP/SR. From these findings, a strategic SR formulation approach might be an efficacious dosage option for ALP to avoid severe nephrotoxicity in patients with nephropathy.

Electrochemical sensor based on magnetite graphene oxide/ordered mesoporous carbon hybrid to detection of allopurinol in clinical samples.

Allopurinol (ALO) is a radical scavenging clinical drug, a drug in the treatment of gout, an inhibitor of xanthine oxidase and an effective agent for anti-cancer purposes. The xanthine oxidase is thus essential, and the amount of ALO needs to be controlled more strictly. In this study, a new electrochemical sensor based on magnetite graphene oxide/ordered mesoporous carbon (Fe3O4@GO/OMC) hybrid was prepared and characterized. The results showed sphere shape Fe3O4 nanoparticles with a diameter in the range 17-22 nm on composite. Modification of carbon paste electrode (CPE) with Fe3O4@GO/OMC (Fe3O4@GO/OMC-CPE) allowed the ultrasensitive and selective detection of ALO at oxidation potential of 1.05 V with linear range of 0.05-7 µmol L-1, limit of detection of 47 nmol L-1 and sensitivity of 708 µA mmol-1 L. Also, the results demonstrate that charge transfer at the interface of Fe3O4@GO/OMC hybrid can provide a synergistic effect in comparison with Fe3O4@GO and OMC. The unique surface chemistry of Fe3O4@GO/OMC interface allows π-π stacking and electrostatic interactions with ALO. The advantages are the possibility to regenerate the surface of the sensor, its rapid and easy of production, as well as its applicability for detection of ALO in Tablets and human serum samples, making Fe3O4@GO/OMC-CPE promising interface for bio-electrochemical applications.

Ultra-performance hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma: Application to pharmacokinetic study in rats.

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7µm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats.

Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model.

Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h after each PZA dose, and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC0-8) (18.32 h · µg/ml versus 24.63 h · µg/ml for PZA alone versus PZA plus allopurinol) (P < 0.001) and its peak plasma concentration (Cmax) (2.81 µg/ml versus 4.00 µg/ml) (P < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) (P = 0.49). Higher systemic POA levels were associated with greater WBA levels (P < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.).

Fabrication of nitrogen-doped carbon dots for screening the purine metabolic disorder in human fluids.

Fabrication of nitrogen-doped carbon dots (N-CDs) electrode for the screening of purine metabolic disorder was described in this paper. Peroxynitrite is a short-lived oxidant species that is a potent inducer of cell death. Uric acid (UA) can scavenge the peroxynitrite to avoid the formation of nitrotyrosine, which is formed from the reaction between peroxynitrite and tyrosine (Try). Scavenging the peroxynitrite avoids the inactivation of cellular enzymes and modification of the cytoskeleton. Reduced level of UA decreases the ability of the body from preventing the peroxynitrite toxicity. On the other hand, the abnormal level of UA leads to gout and hyperuricemia. Allopurinol (AP) is administered in UA lowering therapy. Thus, the simultaneous determination of UA, Try and AP using N-CDs modified glassy carbon (GC) electrode was demonstrated for the first time. Initially, N-CDs were prepared from L-asparagine by pyrolysis and characterized by different spectroscopic and microscopic techniques. The HR-TEM image shows that the average size of the prepared N-CDs was 1.8±0.03nm. Further, the N-CDs were directly attached on GC electrode by simple immersion, follows Micheal's nucleophilic addition. XPS of N-CDs shows a peak at 285.3eV corresponds to the formation of C-N bond. The GC/N-CDs electrode shows higher electrocatalytic activity towards UA, Tyr and AP by not only shifting their oxidation potentials toward less positive potential but also enhanced their oxidation currents in contrast to bare GC electrode. The GC/N-CDs electrode shows the limit of detection of 13×10-10M (S/N=3) and the sensitivity of 924µAmM-1cm-2 towards the determination of UA. Finally, the N-CDs modified electrode was utilized for the determination of UA, Tyr and AP in human blood serum and urine samples.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis.

PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days). RESULTS: The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC7days of 279 µmol/L h in dialysis patients, a value 50-75 % lower than the AUC7days predicted for patients with normal renal function taking 200 to 400 mg daily (427-855 µmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis. CONCLUSIONS: Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.

Outcome of Treatment in Gouty Arthritis Patients: A Retrospective Study.

BACKGROUND: Effective treatment in gouty arthritis can prevent joint and renal damage. Target serum uric acid levels of < 6 mg/dl and < 5 mg/dl are recommended in gouty arthritis and those with tophi, respectively. OBJECTIVE: To evaluate: (i) whether patients achieved recommended serum uric acid target and assess influencing factors and (ii) renal function between patients who achieved and not achieved the goal. MATERIAL AND METHOD: The medical records of gouty arthritis patients treated in outpatient department at Thammasat University Hospital between January 2013 and December 2013 were reviewed. Patients were divided into adequately (ATG) and inadequately treated groups (ITG) based on the ACR uric acid criteria after six months of treatment. Factors associated with inadequate treatment were explored and post treatment renal function compared between A and ITGs. RESULTS: Of 139 patients, 46 (33%) achieved target serum uric acid concentrations. Alcoholic consumption was the significant factor influencing the outcome. 75.5% of patients were followed-up > 1 month for second evaluation of uric acid and most of them not receiving dosage up-titration even though not achieving the target. Both groups had similar alterations of renal function after treatment (p = 0.68). CONCLUSION: Most patients failed to achieve recommended uric acid targets. Alcohol consumption was identified as a key risk factorfor a suboptimal outcome. The treat-to-target approach should be underlined. Other risk factors should be explored prospectively.

Pharmacogenetic considerations in the treatment of gout.

Gout is one of the most common forms of arthritis and the prevalence is increasing. Management comprises rapid and effective control of the inflammation in acute gout and sustained urate lowering in the long term. Improving the outcomes for cheaper old drugs and for the increasing number of new, more expensive agents is an important clinical goal. The role of pharmacogenetics in predicting response and adverse events to gout therapies is of considerable interest. Currently, prospective screening is employed to detect HLA-B*5801 carriage and glucose-6-phosphate dehydrogenase deficiency, to minimize occurrence of allopurinol hypersensitivity and pegloticase-related hemolytic anemia. In the future it is likely that other genetic markers of drug response will make the transition to clinical practice to further improve the efficacy and safety of gout therapies. In this review, we will examine the potential clinical relevance of specific genetic variants in the management of gout.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Therapeutic drug monitoring in rheumatic diseases: utile or futile?

Rapid and effective suppression of inflammation is a primary goal in the treatment of rheumatic diseases. However, the therapeutic effect of most medications may be slow to manifest, in the order of weeks or months in the case of DMARDs. Monitoring of drug concentrations allows the possibility of appropriate dose adjustment or changes in medication to achieve more rapid or better outcomes. We review the evidence for drug concentration monitoring. Despite the theoretical utility for monitoring of MTX polyglutamate concentrations in red blood cells in patients with RA, studies have not shown a clear association between concentrations and either efficacy or toxicity and routine measurement is not yet recommended. Small studies associating disease control with concentrations of anti-TNF therapies and anti-drug antibodies suggest that routine monitoring may be useful in the future. However, the data are not yet sufficient for this recommendation. With the use of allopurinol in gout, there is a putative therapeutic range for the active metabolite oxypurinol; however, adjusting the allopurinol dose to achieve a target urate concentration is likely to be most effective, and measuring oxypurinol may be best suited to assessing drug adherence. Although measuring thiopurine metabolite concentrations with AZA therapy has been shown to be useful in IBD, studies in rheumatic diseases have so far failed to confirm a useful association between concentrations and disease control or drug toxicity. Whole blood concentrations of HCQ have been associated with disease control in SLE and future studies may be able to determine a therapeutic range.

Pharmacokinetics and comparative bioavailability of allopurinol formulations in healthy subjects.

Allopurinol is the most commonly used urate-lowering therapy in gout. This study was undertaken to evaluate the pharmacokinetics and relative bioavailability of two brands of allopurinol tablets. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, Two Way, Cross-Over Study with a washout period of 1 week. Under fasting conditions, 24 healthy male volunteers were randomly allocated to receive a single oral dose (200 mg) of either test and reference formulations. Plasma samples were obtained over a 6-hour interval and analyzed for allopurinol by reversed phase liquid chromatography with ultraviolet detection. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUCt-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two allopurinol formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 200-mg allopurinol and both formulations were well tolerated.

Determination of allopurinol and oxypurinol in human plasma and urine by liquid chromatography-tandem mass spectrometry.

Allopurinol is used widely for the treatment of gout, but its pharmacokinetics is complex and some patients show hypersensitivity, necessitating careful monitoring and improved detection methods. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed to determine the concentrations of allopurinol and its active metabolite oxypurinol in human plasma and urine using 2,6-dichloropurine as the internal standard (IS). Analytes and the IS were extracted from 0.5ml aliquots of plasma or urine using ethyl acetate and separated on an Agilent Eclipse Plus C18 column using methanol and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (95:5, v/v) as the mobile phase (A) for allopurinol or methanol plus 5mM ammonium formate aqueous solution (95:5, v/v) as the mobile phase (B) for oxypurinol. Allopurinol was detected in positive ion mode and the analysis time was about 7min. The calibration curve was linear from 0.05 to 5µg/mL allopurinol in plasma and 0.5-30µg/mL in urine. The lower limit of quantification (LLOQ) was 0.05µg/mL in plasma and 0.5µg/mL in urine. The intra- and inter-day precision and relative errors of quality control (QC) samples were ≤11.1% for plasma and ≤ 8.7% for urine. Oxypurinol was detected in negative mode with an analysis time of about 4min. The calibration curve was linear from 0.05 to 5µg/mL in plasma (LLOQ, 0.05µg/mL) and from 1 to 50µg/mL in urine (LLOQ, 1µg/mL). The intra- and inter-day precision and relative errors were ≤7.0% for plasma and ≤9.6% for urine. This method was then successfully applied to investigate the pharmacokinetics of allopurinol and oxypurinol in humans.

The population pharmacokinetics of allopurinol and oxypurinol in patients with gout.

PURPOSE: The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics. METHODS: Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent-metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling. RESULTS: Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively. CONCLUSIONS: The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.

Computational design and synthesis of molecular imprinted polymers for selective extraction of allopurinol from human plasma.

The present study was focused on the rational development of polymers for selective extraction of allopurinol (ALP) from human plasma. Therefore, a computational modeling approach was combined with the molecular imprinting technology to obtain the polymers. The computational approach was used in order to screen the functional monomers as well as the polymerization solvents for rational design of molecular imprinted polymers (MIPs). It was based on the comparison of the binding energy (ΔE) of the formed complexes between the template molecule and different functional monomers. In the design, the effect of the polymerization solvent was also included using the polarizable continuum model. The theoretical calculation results showed that among virtual solvents tested, acrylamide (AAM) gave the largest ΔE while acrylonitrile (ACN) gave the smallest ΔE in acetone. Therefore, the MIP prepared using AAM as functional monomer in acetone was desired. To examine the validity of this approach, three MIPs were synthesized with different functional monomers i.e. AAM, acrylic acid (AA), and ACN, and then evaluated using Langmuir-Freundlich (LF) isotherm. The results obtained from this experiment confirmed the computational results that the MIP prepared by AAM was the most appropriate adsorbent. Subsequently, the MIP was used to develop a molecular imprinted solid-phase extraction (MISPE) procedure. Finally, the MISPE procedure followed by HPLC was developed for selective extraction and determination of allopurinol in human plasma. For the proposed MISPE method, the linearity between peak area and concentration was found in the range of 0.100-25.000 µM with a linear regression coefficient (R²) of 0.995. The limit of detection (LOD) and quantification (LOQ) in plasma were 0.028 and 0.093 µM, respectively. The results of this study indicated the possibility of using computer aided design for rational selection of functional monomers and solvents for preparation of the MIPs capable of extracting allopurinol from human plasma.

Allopurinol reduces oxidative stress in the ovine fetal cardiovascular system after repeated episodes of ischemia-reperfusion.

In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical cord. This study tested the hypothesis that maternal treatment with clinical doses of the antioxidant allopurinol in the setting of fetal asphyxia would reduce oxidative stress in the fetal cardiovascular system. The hypothesis was tested in chronically instrumented fetal sheep in late gestation by investigating the effects of maternal treatment with therapeutic doses of allopurinol or vehicle on the fetal cardiovascular system during and after episodes of I/R. The latter were produced by repeated, measured compressions of the umbilical cord. The data show that maternal treatment with allopurinol helped maintain umbilical blood flow and it reduced fetal cardiac oxidative stress after I/R of the type associated with clinically relevant acidemia and repetitive fetal heart rate decelerations. The data support the hypothesis tested and suggest that maternal treatment with allopurinol may offer plausible clinical intervention in the management of perinatal asphyxia in complicated labor.

Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B.

BACKGROUND: Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role. HYPOTHESIS: Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (primary outcome) and reduce S-100B and free radical formation (secondary outcome). METHODS: In a randomized, double-blind feasibility study, 53 pregnant women in labor (54 fetuses) with a gestational age of >36 weeks and fetal hypoxia, as indicated by abnormal/nonreassuring fetal heart rate tracing or fetal scalp pH of <7.20, received 500 mg of allopurinol or placebo intravenously. Severity of fetal hypoxia, brain damage and free radical formation were assessed by arterial cord blood lactate, S-100B and non-protein-bound-iron concentrations, respectively. At birth, maternal and cord blood concentrations of allopurinol and its active metabolite oxypurinol were determined. RESULTS: Allopurinol and oxypurinol concentrations were within the therapeutic range in the mother (allopurinol > 2 mg/L and/or oxypurinol > 4 mg/L) but not always in arterial cord blood. We therefore created 3 groups: a placebo (n = 27), therapeutic allopurinol (n = 15), and subtherapeutic allopurinol group (n = 12). Cord lactate concentration did not differ, but S-100B was significantly lower in the therapeutic allopurinol group compared with the placebo and subtherapeutic allopurinol groups (P < .01). Fewer therapeutic allopurinol cord samples had measurable non-protein-bound iron concentrations compared with placebo (P < .01). CONCLUSIONS: Maternal allopurinol/oxypurinol crosses the placenta during fetal hypoxia. In fetuses/newborns with therapeutic allopurinol/oxypurinol concentrations in cord blood, lower plasma levels of the brain injury marker protein S-100B were detected. A larger allopurinol trial in compromised fetuses at term seems warranted. The allopurinol dosage must be adjusted to achieve therapeutic fetal allopurinol/oxypurinol concentrations.