Although the metabolism and pharmacokinetics of chloral hydrate (CH) have been studied in healthy adults, no comprehensive studies have been done in neonates and young infants. Major physiological differences between these groups could greatly affect drug disposition. In this study the patient population (22 patients) was divided into three groups according to postconceptual age: group 1 = preterm infants (31-37 weeks), group 2 = fullterm infants (38-42 weeks) and group 3 = toddler-child patients (57-708 weeks). After receiving one 50 mg/kg oral dose of CH, the parent drug and its metabolites were determined by gas chromatography utilizing an electron capture detector. CH, contrary to what has been reported in the adult, was detectable for several hours after oral administration to patients in all three groups. A highly significant negative correlation was observed amongst the three groups for the half-life (t(1/2)) and area-under-the-curve for 0 to ∞ values for trichloroethanol (TCE), the active metabolite responsible for the sedation effect. The t(1/2) value for TCE in group 3 (9.67 h) was similar to that reported for the adult population, but in the less mature subjects it was approximately three (group 2: 27.8 h) to four times (group 1: 39.8 h) greater. Trichloroacetic acid had a remarkably long residence time in the study population after a single dose of CH. The concentration of this metabolite failed to decline even 6 days after dose. These issues should be carefully considered when CH administration is contemplated for clinical use in neonates, infants and children.

This investigation was designed to investigate the effects of ingestion of multiple therapeutic doses of acetaminophen on the disposition of the drug and on the cosubstrate, sulfate. Nine healthy volunteers and nine outpatients receiving acetaminophen for chronic pain were involved in the study. Volunteers were given a single 650 mg oral dose of acetaminophen. One week later they were given 650 mg of acetaminophen every six hours for five doses. Patients were maintained on their normal treatment and dosage schedules (600 mg every 3 to 8 h) for the study. In healthy volunteers the half-life of acetaminophen after single and multiple dosing was not significantly different. However, the fraction of acetaminophen recovered in the urine as the sulfate conjugate was less and the glucuronide conjugate greater after multiple dosing than after a single of the drug. There was no difference in the percentage recovered as the parent compound between single and multiple dosing. Serum sulfate levels fluctuated over the 6-h period following administration of single and multiple doses of acetaminophen to volunteers. The mean serum sulfate concentration was less after administration of five sequential 650 mg doses of acetaminophen than after a single dose. The renal clearance of inorganic sulfate showed a corresponding decrease. Unexpectedly, patients on chronic acetaminophen therapy exhibited elevated serum sulfate levels (levels higher than the maximum sulfate concentration seen in volunteers).

Solid-phase extraction (SPE) is becoming a commonly used extraction technique. Most existing SPE methods extract a single drug from a relatively clean biological matrix (e.g., plasma, serum, or urine) using a silica-based column. These methods, however, are generally not satisfactory for forensic applications because the majority of biological samples are not as clean (e.g., whole blood, bile, tissues). Silica-based columns also may have reproducibility and stability problems. Polymer-based columns have been developed to overcome some of these limitations. In this study, sequential extraction of acidic, neutral, and basic drugs from whole blood using a polymer-based column, Oasis MCX, was undertaken. The extraction procedure developed involved a conditioning step using methanol followed by water; a three-step wash sequence using water, 0.1 M hydrochloric acid, then water/methanol (95:5); and two elution steps. One elution step was for acidic and neutral drugs utilizing acetone/chloroform (1:1), and a second used ethyl acetate/ammonium hydroxide (98:2) for basic drugs. Of the drugs tested, 75% were extractable from whole blood and detectable at therapeutic concentrations. Good recoveries and clean extracts were achieved for the basic drugs; however, the extracts were not as clean for acidic drugs. Unfortunately, the Oasis MCX procedure was not suitable for extracting all drugs (e.g., benzodiazepines).

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Plasma ß-endorphin concentrations were measured in two groups of neonates. The control group (group 1) consisted of 20 infants with a mean gestational age of 31.5 ± 0.6 weeks and a mean birth weight of 1,720 ± 135 g. Blood samples were collected at a mean postnatal age of 1.0 ± 0.3 days. Group 2 consisted of 23 infants with clinical evidence of acute illness and associated significant stress who had a mean gestational age of 33.2 ± 1.1 weeks and a mean birth weight of 2,075 ± 225 g. Their blood samples were collected at a mean postnatal age of 3.4 ± 1.3 days. The mean ß-endorphin concentration in group 1 was 27.8 ± 6 pg/ml and 63.9 ± 4.2 pg/ml in group 2 (p < 0.05). No correlation was observed for gestation or birth weight and ß-endorphin concentrations in group 1 ; however, in group 2 a positive correlation was seen for gestational age and plasma ß-endorphin concentrations (r = 0.4411) suggesting an increased release of plasma ß-endorphin with increasing gestation when faced with significant clinical stress.

Low birth weight preterm infants with suspected infection were administered gentamicin intramuscularly every 18 h (2.5 mg/kg) or 24 h (3.0 mg/kg). For both dosage regimens plasma gentamicin levels were monitored during a dosage interval on three separate occasions over a 10 day period. Both regimens gave satisfactory plasma concentrations and there was no important statistically significant difference between the two. The body clearance of gentamicin correlated with gestational age (r = 0.76, p less than 0.01). The results indicate either regimen may be useful in the clinical situation but from a practical standpoint administration every 24 h may be easier to comply with then every 18 h.

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Chloral hydrate has been used clinically for over 100 years. There is significant paucity of information regarding chloral hydrate metabolism in neonates and infants. Chloral hydrate and its various metabolites were quantitated in 12 neonates and 2 infants at prescribed time intevals. The analysis of the data indicates accumulation of trichloroacetic acid and trichloroethanol in tissue of compromised infants. There is indirect evidence of competition for hepatic glucuronidation for bilirubin with trichloroethanol in ill preterm infants. Multiple dosing of chloral hydrate in preterm infants should be used with caution and frequent monitoring of serum bilirubin concentrations is indicated in such cases. The mechanism of chloral hydrate metabolism is discussed in detail.