Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose.

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.

Potential pharmacokinetic basis for zolpidem dosing in children with sleep difficulties.

The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.

Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux.

BACKGROUND: The use of over-the-counter antacids has increased in children under the age of 12 years, and has been followed by an apparent increase in the use of over-the-counter histamine-2 receptor antagonists. However, the pharmacokinetic and pharmacodynamic effects of over-the-counter histamine-2 receptor antagonists in the paediatric population are largely unknown. AIM: To evaluate the pharmacokinetics and pharmacodynamics of a single dose of the over-the-counter histamine-2 receptor antagonist, ranitidine, 75 mg, in children with symptoms of gastro-oesophageal reflux disease. METHODS: Children aged between 4 and 11 years with symptoms of heartburn suspected to be due to gastro-oesophageal reflux disease were recruited at six clinical centres. Following a single dose of either oral ranitidine, 75 mg (n=19), or placebo (n=10), recording of intragastric pH and serial blood sampling were carried out for 6 h. RESULTS: The estimated pharmacokinetic parameters of ranitidine, 75 mg, were as follows: the median Cmax value of 477 ng/mL occurred within a median of 2.5 h after dosing, and the median half-life was 2.0 h. The intragastric pH began to rise approximately 30 min after dosing with ranitidine to a peak of pH; 4. The pH in the ranitidine group remained higher than that in the placebo group throughout the 6-h evaluation period. Adverse events were generally mild. CONCLUSIONS: Ranitidine, 75 mg, significantly increased the intragastric pH in children aged 4-11 years. The pharmacokinetic and pharmacodynamic profiles were similar to those in adults. Ranitidine, 75 mg, appears to be effective for the control of intragastric acidity for 5-6 h in children aged 4-11 years.

The pharmacokinetics of colistin in patients with cystic fibrosis.

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group.

OBJECTIVE: To determine the safety, tolerance, pharmacokinetics and efficacy of linezolid, a new oxazolidinone antibiotic in the treatment of community-acquired pneumonia in hospitalized children. DESIGN: A Phase II, open label multicenter study of intravenous linezolid followed by oral linezolid suspension, both at a dose of 10 mg/kg every 12 h. Efficacy was assessed at 7 to 14 days after the last dose of linezolid. PATIENTS: Children 12 months to 17 years old with community-acquired pneumonia admitted to the hospital of 14 participating centers. RESULTS: From July 21, 1998, through May 14, 1999, 79 children were enrolled and 78 received linezolid. Sixty-six children completed treatment and follow-up and were evaluable for clinical outcome. The median age of the evaluable patients was 3 years (range, 1 to 12 years); 47 were 2 to 6 years old. Pathogens were isolated from blood or pleural fluid cultures in 8 children: Streptococcus pneumoniae, 6 (2 penicillin-resistant); Group A Streptococcus, 1; methicillin-resistant Staphylococcus aureus, 1. Chest tubes were placed in 9 patients. The mean total duration of intravenous and oral administration was 12.2 +/- 6.2 days (range, 6 to 41 days). The mean peak and trough plasma concentrations of linezolid were 9.5 +/- 4.8 and 0.8 +/- 1.2 microg/ml, respectively. At the follow-up visit 7 to 14 days after the last dose of linezolid, 61 patients (92.4%) were considered cured including all the patients with proven pneumococcal pneumonia, one failed (methicillin-resistant Staphylococcus aureus) and 4 were considered indeterminate. The most common adverse effects in the intent to treat group were diarrhea (10.3%), neutropenia (6.4%) and elevation in alanine aminotransferase (6.4%). CONCLUSIONS: Linezolid was well-tolerated and could be considered an alternative to vancomycin for treating serious infections caused by antibiotic-resistant Gram-positive cocci in children pending results of additional studies.

Review of the pharmacokinetics of cefepime in children.

BACKGROUND: Because determining the pharmacokinetics of drugs used in pediatric patients allows for appropriate dosing and optimal clinical response, we have reviewed the pharmacokinetic data on the use of cefepime in the pediatric population. METHODS: Three studies encompassing 88 patients ages 2 months to 16 years examined the pharmacokinetics of cefepime given as a single iv dose, as multiple iv doses and by im administration. In all studies serial blood and urine or cerebrospinal fluid (CSF) samples were collected after a single dose and/or at steady state, defined as after at least 2 days of dosing. Pharmacokinetic parameters were generated from concentration-vs.-time curves and were analyzed using noncompartmental methods. RESULTS: In all studies cefepime exhibited a linear pharmacokinetic profile and concentrations declined proportionally over time. Minimal accumulation was observed after multiple dosing. Pharmacokinetic parameters were similar in all studies and appeared to be dose-independent. Mean (range) parameters observed in this review were: t 1/2 = 1.7 h (1.26 to 1.93); volume of distribution at steady state, 0.37 liter/kg (0.33 to 0.40); total body clearance, 3.1 ml/min/kg (1.43 to 4.01); renal total body clearance, 2.3 ml/min/kg (1.86 to 3.05); absolute bioavailability of cefepime after the im dose, 82.3%; and urinary recovery, 72% (57 to 85%). Penetration into CSF appeared to be good, with CSF concentrations averaging 3.3 to 5.7 microg/ml 0.5 and 8 h after administration of the dose, respectively. CONCLUSION: Cefepime displayed a linear pharmacokinetic profile, was well-absorbed via im injection and had adequate penetration into the CSF of patients with bacterial meningitis, compared with other beta-lactams.

Safety of antihistamines in children.

The histamine H1 receptor antagonists (antihistamines) are an important class of medications used for the relief of common symptoms associated with hyperhistaminic conditions occurring in children and adults. This group of drugs may be subdivided into 3 classes, or generations, based upon their propensity to induce sedation and cardiotoxicity. The first generation (classical) antihistamines are highly effective in treating hyperhistaminic conditions. However, they frequently induce sedation and may adversely affect a child's learning ability. First generation antihistamine-induced sedation has been described to occur in more than 50% of patients receiving therapeutic dosages. Serious adverse events are unusual following overdoses of first generation antihistamines although life-threatening adverse events have been described. When the so-called 'second generation' antihistamines terfenadine and astemizole were introduced they were widely embraced and quickly used by clinicians of all specialities, including paediatricians, as nonsedating alternatives to the first generation compounds. These new agents were found to be equally or more effective than first generation antihistamines in relieving symptoms associated with hyperhistaminic conditions without the soporific effects of the first generation agents. Unfortunately, after approximately 10 years of widespread clinical use, disturbing reports of potentially life-threatening dysrhythmias, specifically torsades de pointes, were described. Both terfenadine and astemizole have been shown in vitro to inhibit several ion channels, and in particular the delayed outward rectifier potassium channel in the myocardium, predisposing the heart to dysrhythmias. The potential life-threatening cardiotoxicities of the second generation antihistamines led to the search for noncardiotoxic and nonsedating agents. Loratadine, fexofenadine, mizolastine, ebastine, azelastine and cetirizine are the first of the new third generation antihistamines. These drugs have been shown to be efficacious with few adverse events including no clinically relevant cytochrome P450 mediated metabolic-based drug-drug interactions or QT interval prolongation/cardiac dysrhythmias. Appropriate treatment of an antihistamine overdose depends upon which class of compound has been ingested. There is no specific antidote for antihistamine overdose and treatment is supportive particularly for ingestions of first generation compounds. Ingestion of excessive doses of terfenadine or astemizole requires immediate medical attention. Children who accidentally ingest excessive doses of a third generation compound may usually be adequately managed at home. However, patients ingesting large amounts (approximately >3 to 4 times the normal therapeutic daily dose) should receive medical attention. These patients should be monitored for 2 to 3 hours after the ingestion and patients ingesting cetirizine should be advised about the potential for sedation. The availability of newer generation antihistamine compounds has clearly added to the clinical effectiveness and patient tolerance of a widely prescribed class of drugs. These advances have also been accompanied by improved safety profiles, particularly in the case of third generation antihistamine overdose.

Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.

The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.

Exercise-dependent growth hormone release is linked to markers of heightened central adrenergic outflow.

To test the hypothesis that heightened sympathetic outflow precedes and predicts the magnitude of the growth hormone (GH) response to acute exercise (Ex), we studied 10 men [age 26.1 +/- 1.7 (SE) yr] six times in randomly assigned order (control and 5 Ex intensities). During exercise, subjects exercised for 30 min (0900-0930) on each occasion at a single intensity: 25 and 75% of the difference between lactate threshold (LT) and rest (0.25LT, 0.75LT), at LT, and at 25 and 75% of the difference between LT and peak (1.25LT, 1.75LT). Mean values for peak plasma epinephrine (Epi), plasma norepinephrine (NE), and serum GH concentrations were determined [Epi: 328 +/- 93 (SE), 513 +/- 76, 584 +/- 109, 660 +/- 72, and 2,614 +/- 579 pmol/l; NE: 2. 3 +/- 0.2, 3.9 +/- 0.4, 6.9 +/- 1.0, 10.7 +/- 1.6, and 23.9 +/- 3.9 nmol/l; GH: 3.6 +/- 1.5, 6.6 +/- 2.0, 7.0 +/- 2.0, 10.7 +/- 2.4, and 13.7 +/- 2.2 microg/l for 0.25, 0.75, 1.0, 1.25, and 1.75LT, respectively]. In all instances, the time of peak plasma Epi and NE preceded peak GH release. Plasma concentrations of Epi and NE always peaked at 20 min after the onset of Ex, whereas times to peak for GH were 54 +/- 6 (SE), 44 +/- 5, 38 +/- 4, 38 +/- 4, and 37 +/- 2 min after the onset of Ex for 0.25-1.75LT, respectively. ANOVA revealed that intensity of exercise did not affect the foregoing time delay between peak NE or Epi and peak GH (range 17-24 min), with the exception of 0.25LT (P < 0.05). Within-subject linear regression analysis disclosed that, with increasing exercise intensity, change in (Delta) GH was proportionate to both DeltaNE (P = 0.002) and DeltaEpi (P = 0.014). Furthermore, within-subject multiple-regression analysis indicated that the significant GH increment associated with an antecedent rise in NE (P = 0.02) could not be explained by changes in Epi alone (P = 0.77). Our results suggest that exercise intensity and GH release in the human may be coupled mechanistically by central adrenergic activation.

A double-blind pilot study of risperidone in the treatment of conduct disorder.

OBJECTIVE: To examine whether risperidone is superior to placebo in the treatment of youths with conduct disorder. METHOD: This was a 10-week, randomized, double-blind, placebo-controlled study with 2 parallel arms. Ten youths were randomly assigned to receive placebo and 10 youths were randomly assigned to receive risperidone. Patients were seen weekly throughout the trial. Medications could be increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg. Patients weighing 50 kg or greater had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. RESULTS: Risperidone was superior to placebo in ameliorating aggression on most measures. Risperidone was reasonably well tolerated, with none of the risperidone-treated patients developing extrapyramidal side effects. CONCLUSIONS: These data provide preliminary evidence that risperidone may have efficacy in the treatment of youths with conduct disorder. Because of the small sample size and the brief length of this study, further research is necessary to confirm these findings.

Acute encephalopathy due to aluminum toxicity successfully treated by combined intravenous deferoxamine and hemodialysis.

Acute aluminum intoxication is uncommon in clinical practice but can be fatal. This limited experience is reflected in the paucity of data assessing a viable approach to the treatment of these patients. In this report, the authors describe the clinical course and successful, pharmacokinetic-based deferoxamine-hemodialysis treatment regimen of a patient with severe aluminum encephalopathy following alum bladder irrigation. The combined use of deferoxamine and appropriately timed hemodialysis appears to be a very reasonable means of treating patients with severe acute aluminum intoxication.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.