Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study.

BACKGROUND: An increasing number of pediatric patients suffer from thrombotic events necessitating anticoagulation therapy including heparins. Some such patients develop heparin-induced thrombocytopenia (HIT) and thus require alternative anticoagulation. As such, studies evaluating the safety, efficacy, and dosing of alternative anticoagulants are required. PROCEDURE: In this multicenter, single arm, open-label study, 18 patients ≤ 16 years old received argatroban for either a suspicion of or being at risk for HIT, or other conditions requiring nonheparin anticoagulation. Endpoints included thrombosis, thromboembolic complications, and bleeding. RESULTS: Patients (ages, 1.6 weeks to 16 years) received argatroban usually for continuous anticoagulation (n = 13) or cardiac catheterization (n = 4). One catheterization patient received a 250 µg/kg bolus only; 17 patients received argatroban continuous infusion (median (range)) 1.1 (0.3-12) µg/kg/min (of whom four received a bolus) for 3.0 (0.1-13.8) days. In patients without bolus dosing, typically argatroban 1 µg/kg/min was initiated, with therapeutic activated partial thromboplastin times (aPTTs) (1.5-3× baseline) achieved within 7 hr. Within 30 days, thrombosis occurred in five patients (two during therapy). No one required amputation or died due to thrombosis during therapy. Two patients had major bleeding. Pharmacometric analyses demonstrated the optimal initial argatroban dose to be 0.75 µg/kg/min (if normal hepatic function), with dose reduction necessary in hepatic impairment. CONCLUSIONS: In pediatric patients requiring nonheparin anticoagulation, argatroban rapidly provides adequate levels of anticoagulation and is generally well tolerated. For continuous anticoagulation, argatroban 0.75 µg/kg/min (0.2 µg/kg/min in hepatic impairment), adjusted to achieve therapeutic aPTTs, is recommended.

Population pharmacokinetics of fluconazole in young infants.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Augmented immunity in cancer patients treated with alpha-interferon.

Thirty patients with metastatic colon or breast cancer were treated with recombinant alpha-interferon, clone A, 9 to 50 X 10(6) units/sq m, i.m., 3 times weekly for up to 4 months. Immunological parameters including natural killer activity, antibody-dependent cellular cytotoxicity, an assay of inhibition of tumor cell growth in culture, and quantification of leukocyte subsets were monitored serially. Statistically significant increases in the inhibition of tumor growth and in the proportion of peripheral blood mononuclear cells bearing the T10 marker were observed both early and late in the treatment course in the population as a whole (p less than 0.03 and p less than 0.0001, respectively). The true maximum effect in the assay of inhibition of tumor growth was probably higher, since the monitoring was not performed at peak activity for this assay. Other immune parameters, including natural killing, could not be shown to change consistently in the population as a whole, although interferon effects could be discerned easily in the activity profiles of some individual patients. The two patients with tumor response showed increased putative tumor immunity by these measures. These data confirm results previously published supporting the responsiveness of these parameters to interferon as administered clinically and may provide the basis for optimization of interferon dose and scheduling.

Continuous Video Electroencephalographic (EEG) Monitoring for Electrographic Seizure Diagnosis in Neonates: A Single-Center Study.

The objective of this study was to determine the diagnostic yield of continuous video electroencephalographic (EEG) monitoring in critically ill neonates in the setting of a novel, university-based Neonatal Neurocritical Care Service. Patient demographic characteristics, indication for seizure monitoring, and presence of electrographic seizures were obtained by chart review. Among 595 patients cared for by the Neonatal Neurocritical Care Service, 400 (67%) received continuous video EEG. The median duration of continuous video EEG monitoring was 49 (interquartile range = 22-87) hours. Electrographic seizures were captured in 105 of 400 (26% of monitored patients) and of those, 25 of 105 (24%) had no clinical correlate. In addition, 52 of 400 subjects (13%) were monitored due to paroxysmal events concerning for seizures, but never had electrographic seizures. Continuous video EEG monitoring helped confirm or rule out ongoing seizures in more than one-third of the cases. This finding helps to support the use of continuous video EEG in critically ill neonates.

Analysis of the variability in the pharmacokinetics and pharmacodynamics of bumetanide in critically ill infants.

OBJECTIVES: Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants. METHODS: This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide. RESULTS: Total clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect. CONCLUSIONS: The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.

Pharmacokinetics of bumetanide in critically ill infants.

OBJECTIVE: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques. RESULTS: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose. CONCLUSIONS: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.

Dose-ranging evaluation of bumetanide pharmacodynamics in critically ill infants.

OBJECTIVES: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug. RESULTS: Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses. CONCLUSIONS: Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.

BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase.

In vivo, hormone-sensitive lipase (HSL) is known to be phosphorylated on two sites termed the regulatory and basal sites. However, the intracellular role of the basal site or the identity of the protein kinase phosphorylating this site has not been established. We show that 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR) markedly activates cellular AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. As expected for an agent that activates AMPK intracellularly, AICAR had no effect on the basal activity of HSL. However, preincubation of adipocytes with AICAR led to a reduced response of these cells to the lipolytic agent isoprenaline. AICAR was also shown to profoundly inhibit lipogenesis through increased phosphorylation of acetyl-CoA carboxylase (ACC). Thus it appears that in addition to regulating lipogenesis, AMPK also plays an important antilipolytic role by regulating HSL in rat adipocytes.

The cloning expression and tissue distribution of human PP2Cbeta.

We have cloned a novel PP2Cbeta isoform from a human liver cDNA library which codes for a protein homologous to other mammalian PP2Cbetas at the N-terminus but with an extended C-terminus that is unique amongst the PP2Cs. The protein expressed in E. coli is indistinguishable from human recombinant PP2Calpha in its cation dependence and insensitivity to okadaic acid. Northern blot analysis of PP2Cbeta along with that of PP2Calpha shows that human PP2Cs are widely expressed and are most abundant in heart and skeletal muscle.

Heart transplantation as a treatment option for end-stage heart disease in patients older than 65 years of age.

Because of the critical donor organ shortage for heart transplantation, selection of recipients should be based on the potential for maximum benefit. To evaluate the effects of advancing age on outcome after heart transplantation, we compared the clinical variables of 12 recipients aged 65 years or older (66.1 +/- 0.9 years [x +/- standard deviation]; range, 65 to 67 years) with those of 57 patients aged 55 to 64 years (59.3 +/- 2.7 years) at the time of the procedure. The two study groups were similar in sex, race, pretransplantation heart disease, immunocompatibility, maintenance immunosuppression, and length of first hospitalization at the time of the procedure. Groups were also similar regarding the incidence of malignancies, fractures, diabetes, neurologic complications, and renal dysfunction occurring over the follow-up period. Patients 65 years of age or older had a significantly higher number of hospital days (36 +/- 29 versus 15 +/- 18 days; p < 0.02) and increased frequency of infections/month (0.7 +/- 0.3 versus 0.3 +/- 0.4 infections/month; p < 0.03) during the first postoperative year. Older patients had a higher incidence of cytomegalovirus infections (50% versus 19%; p < 0.06), lower rates of rejection at 1 and 6 months after operation (p < 0.03), and more severe functional limitation (p < 0.002) than patients aged 55 to 64 years. One-year actuarial survival was not significantly different in the two groups. The results of our study suggest that, because of lower rejection and higher infection rates, heart transplantation recipients older than 65 years of age should receive less intense immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluating IAIMS at Yale: information access.

OBJECTIVE: To evaluate use of information resources during the first year of IAIMS implementation at the Yale-New Haven Medical Center. The evaluation asked: (1) Which information resources are being used? (2) Who uses information resources? (3) Where are information resources used? (4) Are multiple sources of information being integrated? DESIGN: Measures included monthly usage data for resources delivered network-wide, in the Medical Library, and in the Hospital; online surveys of library workstation users; an annual survey of a random, stratified sample of Medical Center faculty, postdoctoral trainees, students, nurses, residents, and managerial and professional staff; and user comments. RESULTS: Eighty-three percent of the Medical Center community use networked information resources, and use of resources is increasing. Both status (faculty, student, nurse, etc.) and mission (teaching, research, patient care) affect use of individual resources. Eighty-eight percent of people use computers in more than one location, and increases in usage of traditional library resources such as MEDLINE are due to increased access from outside the Library. Both survey and usage data suggest that people are using multiple resources during the same information seeking session. CONCLUSIONS: Almost all of the Medical Center community is using networked information resources in more settings. It is necessary to support increased demand for information access from remote locations and to specific populations, such as nurses. People are integrating information from multiple sources, but true integration within information systems is just beginning. Other institutions are advised to incorporate pragmatic evaluation into their IAIMS activities and to share evaluation results with decision-makers.

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Radiovisiography in the detection of periapical lesions.

The periapical areas of 16 teeth from 6 human mandibular jaw specimens were randomly examined by 3 observers using conventional radiography with Kodak E-speed film and radiovisiography (with variable contrast and with fixed contrast). Each periapical area was examined preoperatively and after #2, #4, #6, and #8 sized bur periapical lesions were created in the cortical bone. The three radiographic methods were compared by repeated-measures ANOVA of the accuracy scores for the 16 periapical lesions. Accuracy increased with size of lesion, but did not vary by method. Repeated-measures ANOVA of the accuracy scores of only the smallest and no lesion condition showed that conventional radiography and radiovisiography (variable contrast) have opposite strengths. Conventional radiography tended to be more accurate in the no lesion condition, whereas radiovisiography using variable contrast was somewhat more accurate in the smallest lesion condition. The accuracy of radiovisiography with fixed contrast was not significantly different from the other two methods.

Super-EBA as an endodontic apical plug.

Forty extracted human single-rooted teeth were sequentially instrumented with nickel-titanium rotary files to a size 0.36 mm at the working length. Ten teeth were randomly assigned to the two control groups. The other 30 teeth were randomly divided into three groups and were obturated by a 5-mm apical plug of either Super-EBA, IRM, or laterally condensed gutta-percha and Roth's sealer. After 2 days, and at 1 month, the samples were tested for microleakage by the fluid filtration system under 15 psi. The negative controls were used to consider the time that it took the fluid filtration system to stabilize. A one-way analysis of variance showed that, at 1 month post obturation, there was no statistical difference in the ability of the three materials to seal the apex from coronal microleakage. However, at 2 days, Super-EBA gave a significantly better seal than IRM or laterally condensed gutta-percha and sealer.

Reliability of a new device used to measure shoulder subluxation.

The purposes of the study were to determine the reliability of a new device used to quantify shoulder subluxation and to estimate its standard error of measurement. The device is an L-shaped thermoplastic jig with a metric tape measure embedded in it. A sliding beak-like marker, which can be anchored with a thumbscrew, is used to identify landmarks and to measure the amount of subluxation. Eight male and two female hemiplegic subjects, 40 to 80 years old, consented to be measured for subluxation. Three standardized subluxation measurements were taken by one investigator to determine the reliability with a single rater. One measurement was taken by a second investigator and compared with the first measurement obtained by the first investigator to determine the reliability using more than one rater. Both investigators were experienced physical therapists. Each measurement was read by the other investigator, who disassembled the jig and cleaned the marks from the patient between measurements. For both analyses, an analysis of variance for repeated measurements reflected no differences between measurements attributable to raters. The unbiased intraclass correlation coefficient for a single measurement by a single rater was .89 (p less than .01) and for more than one rater was .74 (p less than .01). The standard error of measurement was +/- 0.77 mm for a single rater and +/- 1.20 mm for more than one rater. We recommend the jig as a tool to measure shoulder subluxation in patients.

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. OBJECTIVE: To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. METHODS: A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming. RESULTS: EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14). CONCLUSIONS: Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.

Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.