Plasma concentrations of clonazepam after single rectal administration.

Clonazepam was administered rectally to six children aged 1.4 to 4.7 years in a dose of 0.05 mg/kg and to five children aged 1.4 to 4.1 years in a dose of 0.1 mg/kg. Plasma concentrations indicate that it is rapidly absorbed, and it may therefore be an alternative to rectal administration of diazepam in continuing convulsions.     

Variability of serum indomethacin concentrations after oral and intravenous administration to preterm infants

Fifteen preterm infants with patent ductus arteriosus and respiratory distress syndrome were given indomethacin (0.2 mg/kg) at 12 h intervals up to three times, either orally or intravenously, in an uncontrolled, non-randomized study. Serum indomethacin concentrations were determined in blood samples taken 12 h after dosing. There was considerable variability in the serum indomethacin concentrations, especially after oral administration, although the mean concentrations after each of the three doses were similar after both oral and intravenous administration. The frequency of closures and transient closures of the ductus arteriosus was also similar for both routes of administration. There was, however, no relation between concentration and effect in individual patients. The sustained exposure to indomethacin which appears to be necessary for ductal closure can sometimes be attained by oral administration.     

Plasma concentrations after oral or intramuscular vitamin K1 in neonates.

One hundred and seven healthy, breast fed infants received 1 mg vitamin K1 either at birth (orally or intramuscularly) or with the first feed (orally). Venous blood samples collected in the next 24 hours were assayed for plasma vitamin K1. In babies given the vitamin orally at birth, the peak median concentration (73 ng/ml) occurred at four hours. By 24 hours median plasma concentrations had fallen to 23 ng/ml and 35 ng/ml in the groups fed vitamin K1 at birth or with the first feed, respectively; this difference was not, however, significant. Plasma concentrations after intramuscular injection exceeded those in the oral groups at all comparable times, with a peak median concentration of 1781 ng/ml at 12 hours falling to 444 ng/ml at 24 hours. Since median plasma vitamin K1 concentrations 24 hours after oral administration were some 100 times and 1000 times greater than previously estimated adult and newborn values respectively, this study supports giving vitamin K1 orally at birth to well, mature babies to protect against early haemorrhagic disease of the newborn. Further studies are needed to determine the optimum dose for protection over subsequent weeks.     

Plasma 17OH-progesterone concentrations in newborn infants.

Plasma concentrations of 17OH-progesterone were determined in 60 normal newborn infants aged between 3 and 36 hours. Mean levels decreased rapidly during this time after removal of the placental contribution of this steroid. A further 70 normal infants, studied between ages 2 and 7 days, showed a mean plasma 17OH-progesterone concentration of 3.5 nmol/1 (1.2 ng/ml). By comparison, plasma concentrations in untreated infants with congenital adrenal hyperplasia were markedly raised. At 36 hours of age, there was an obvious difference between plasma levels of this steroid in normal and affected infants. Determination of plasma 17OH-progesterone concentrations are valuable in the evaluation of disorders of sexual differentiation and electrolyte balance in newborn infants, provided due care is given to the timing of sample collections.     

Methotrexate bioavailability after oral and intramuscular administration in children

Although methotrexate is one of the most commonly used drugs for maintenance therapy in childhood acute lymphocytic leukemia (ALL), its oral absorption is highly variable and its intramuscular bioavailability at dosages used for ALL therapy has not been assessed in children. We therefore determined the absolute bioavailability of orally and intramuscularly administered methotrexate in 12 pediatric patients receiving 13 to 120 mg/m2 methotrexate every week as maintenance therapy for ALL. Mean bioavailability, as determined by comparing the area under the concentration-time curve after oral or intramuscular administration with that produced by the same dosage given intravenously, was 33% (range 13% to 76%) for oral (n = 11) and 76% (54% to 112%) for intramuscular (n = 7) administration (P less than 0.01). Median bioavailability (with orally administered dosages less than or equal to 40 mg/m2 (range 13 to 40 mg/m2) was 42% (19% to 76%); at dosages greater than 40 mg/m2 (43 to 76 mg/m2), bioavailability was significantly lower, 17.5% (12.7% to 22.3%, p less than 0.02). Conversely, there was no significant relationship between dosage and bioavailability with intramuscularly administered drug. The substantially higher bioavailability for intramuscularly injected methotrexate may warrant its consideration as an alternative to oral administration, especially for dosages greater than 40 mg/m2.     

Intestinal excretion of nystatin during and after oral administration to newborn infants at risk

The concentrations of nystatin excreted with faeces during and after oral application of 3 x 150,000 IU/d, either continuously for 14-21 days or every second day were determined in 42 newborns at risk by means of a bioassay (agar diffusion test). Results indicate that nystatin is distributed heterogeneously in the gastrointestinal tract. The excretion occurs discontinuously. 24 to 48 h after beginning of therapy there were effective concentrations of nystatin in the faeces. The daily application of 3 x 150,000 IU nystatin is recommended.     

Plasma amino acid concentrations in newborn infants breast-fed ad libitum

Plasma amino acid concentrations were measured in peripheral venous blood of 40 newborn infants breast-fed ad libitum. When these data are compared with amino acid concentrations of umbilical cord artery plasma, only lysine and threonine show a striking decrease after birth: the concentrations of hydroxyproline, asparagine, glutamine, proline, cystine, leucine, tyrosine, and ornithine significantly increase during the first days of life. The high-protein concentration of colostrum and transitional milk may explain this observation.     

Absorption of phenobarbital after the intramuscular administration of single doses in infants.

Blood concentrations of phenobarbital, following an intramuscular administration of a single large dose of approximately 10 mg/kg, were studied in 39 infants. A rapid rise was obtained with a mean concentration of 9.30 mug/ml at 30 minutes, 12.76 mug/ml at 90 minutes, and a mean peak concentration of 13.28 mug/ml, which was reached in most cases within 2 hours of injection or less. Cerebrospinal fluid values in 13 patients averaged half the blood phenobarbital concentrations.     

Comparison of intraosseous, intramuscular, and intravenous administration of succinylcholine

The intraosseous route of vascular access has been popularized recently for resuscitation of children. Intraosseous succinylcholine use has been anecdotally reported for airway management. This drug could be utilized for control of the airway in pediatric burns, status epilepticus, or combative head-injured patients. No series quantifying the efficacy of the intraosseous route has been reported for succinylcholine. To accomplish this goal, six sheep serving as their own controls were anesthetized with halothane and subsequently intubated. Succinylcholine (1 mg/kg) was given. The time to respiratory arrest and 100% loss of the forefoot twitch upon stimulation of the anterior tibial nerve were noted. Each animal was successively studied using the intravenous (IV), intraosseous (IO), and intramuscular (IM) routes of administration, with a minimum of seven days separating trials. The average time from administration to respiratory arrest in seconds was 30.8 +/- 7.3 (IV), 57.5 +/- 10.3 (IO), and 230 +/- 106 (IM). The average time from administration to 100% loss of forefoot twitch in seconds was 93.3 +/- 34.0 (IV), 100.8 +/- 24.2 (IO), and 291 +/- 109 (IM). All groups were statistically significantly different using the t-test for the difference of means, with a p value less than 0.0015. We conclude that the intraosseous route of administration of succinylcholine in this series of sheep is comparable to the intravenous route and superior to the intramuscular route.     

13C]Acetate oxidation in infants after oral versus rectal administration: a kinetic model

To study the fate of volatile fatty acids (VFA) in the large bowel, we compared the rate of oxidation of 13C-labeled VFA administered rectally with that of the orally administered substrate. On two different days, 1-[13C]acetate was administered rectally or orally to five infants recovering from diarrhea. Breath samples were collected over 4 h and analyzed for 13C enrichment of breath CO2 by gas isotope ratio mass spectrometry. The percent dose recoveries of 13C in breath were fitted to multicompartmental models using the SAAM-27 program. Following model development procedures, the oral acetate breath test curves could be accounted for only by a compartmental model in which labeled acetate underwent absorption into and mixed with a systemic pool before oxidation took place. The rectal acetate breath test curves could be accounted for by a simpler model in which oxidation occurred directly in the compartment in which the rectal acetate was administered, and required no rate-limiting absorptive process. Our results indicate that the labeled acetate was oxidized more rapidly when the substrate was administered rectally than orally. This observation points to the direct utilization of volatile fatty acids within the colon.     

High density lipoprotein concentrations in newborn infants.

The lipoprotein pattern was analyzed by agarose gel electrophoresis in 19 new born infants of varying gestational age. The HDL concentration was determined by rocket immunoelectrophoresis in another 41 newborn infants. Infants with a gestational age of less than 33 weeks had very low HDL concentrations compared to preterm infants with a gestational age of less than or equal to 33 weeks and term ihfants. In the first 5-10 days after birth the HDL concentration increased markedly in preterm infants (gestational age less than 37 weeks) whereas it remained unchanged in term infants.     

Plasma homocysteine concentrations of preterm infants.

Mild hyperhomocysteinemia in adults is associated with an increased risk of vascular disease. Although information is available about plasma homocysteine concentrations in childhood, data are entirely lacking for preterm infants despite their known abnormalities of sulfur amino acid metabolism. We measured plasma total homocysteine concentrations of 9 preterm infants (gestational age 23-31 weeks) within 48 h of birth and over the subsequent 14 days of life, and 4 term infants (gestational age 36-39 weeks) on a single occasion within 72 h of birth. As measured within 48 h of birth, average plasma homocysteine and cysteine concentrations of the preterm infants were 3.8 +/- 0.3 and 122 +/- 8 microM, both significantly less than those of the term infants (6.1 +/- 1.3 and 187 +/- 39) and of normal adults (8.2 +/- 0.5 and 232 +/- 6). Plasma homocysteine (but not cysteine) appeared to gradually increase during the first 2 weeks of life (p = 0.053). Our results indicate that hyperhomocysteinemia does not normally occur in preterm infants.     

Pharmacokinetics of intravenous clindamycin in newborn infants

We studied 12 newborn infants (gestational ages 26-39 wk [mean +/- SD, 30.6 +/- 4.7]; birth weight 640-2700 g, [mean, 1,322 +/- 688]; postnatal age 1-24 days [mean, 9.6 +/- 8.5]) who received clindamycin phosphate for suspected or proven necrotizing enterocolitis (ten patients) or suspected anaerobic septicemia (two patients) in doses of 3.2-11 mg/kg every six hours. Range of mean serum concentration of clindamycin at steady state was between 12.7 and 40 micrograms/ml (therapeutic range = 2-10 micrograms/ml). High concentrations could be attributed to elimination T1/2 (6.3 +/- 2.1 hr) 100% longer than in older children or adults. Clindamycin clearance (61.6 +/- 31.6 hr ml/kg/hr) was lower than in older children or adults. Because of the observed prolongation in T1/2 and correspondingly lower clearance, the IV dose of clindamycin in newborn infants should be reduced to 15-20 mg/kg/day given in four daily doses.