Reba M. Hill

Detection of 5-(3, 4-Dihydroxy-1, 5-Cyclohexadien-1-Yl) -5-Phenylsydantoin as a Major Metabolite of 5, 5-Diphenylhydantoin (Dilantin) in the Newborn Human

Abstract The metabolism of 5, 5-diphenylhydantoin was studied in the newborn human in two instances; one involved direct administration of the drug, and the other was by placental transfer of the drug from the mother. 5-(3,4-Dihydroxy-1, 5-cyclohexadien-1-yl)-5-phenylhydantoin was found to be a major metabolite. The GC and GC-MS methods employed here are well suited to the problem of studying drug metabolism in the newborn.

O-benzyloximes: Derivatives for the study of ketosteroids by gas chromatography. Application to urinary steroids of the newborn human

Abstract Benzyloxime-trimethylsilyl (BO-TMSi) derivatives of infant urinary steroids have been prepared and studied by GC and GC-MS techniques. These derivatives were used in a “metabolic profile” procedure which provides a urinary steroid profile in which the hydroxy (H-series) steroids and those containing a reactive ketone group (K-series) are well separated. Distinctive profiles may be obtained in this way. Comparisons may be made for normal infants, for the same infant with increasing age, and for pathologic circumstances.

Individual growth curve standards in twins: Prediction of third-trimester growth and birth characteristics

The ability of Rossavik growth models, determined from measurements obtained before 24 weeks, to predict third-trimester growth and birth characteristics in normally growing twins has been investigated. Third-trimester values for head circumference, abdominal circumference, and femur diaphysis length were predicted with an accuracy of +/- 6% to 9% (95% to 98% of percent deviations). For thigh circumference and estimated weight, the comparable values were +/- 15% and +/- 16%, respectively. The head circumference at birth was predicted without bias; the random error was approximately +/- 5% (94% of percent differences). Weight, abdominal circumference, and thigh circumference were systematically overestimated (3.1%, 14.9%, and 11.3%, respectively) as a result of differences in prenatal and postnatal measurement procedures. After correction for systematic errors, these parameters could be predicted with random errors of -11.5% to 7.2% (weight), -12.8% to 5.4% (abdominal circumference), and -15.3% to 10.0% (thigh circumference). Growth Potential Realization Index values were found to have means of approximately 100% and ranges from 91% to 118%. These results are similar to those for singletons and indicate that individual assessment of growth in twins can be carried out with the same methods used for singletons.

The use of stable isotopes in gas chromatography-mass spectrometric studies of drug metabolism.

Abstract Internal reference compounds labeled with stable isotopes have been used to quantify drugs and drug metabolites in urine, plasma and breast milk. [2,4,5-13C3]Diphenylhydantoin, [2,4,5-13C3]phenobarbital and [1-C2H3]valium have been used to quantify diphenylhydantoin, phenobarbital and valium, respectively; [2,4,5-13C3]pentobarbital has been used to quantify amobarbital, secobarbital, butabarbital and pentobarbital. Analyses have been carried out in the picogram to nanogram range by selective ion detection with two gas chromatograph—mass spectrometer—computer systems. Instrumental measurements with picogram samples have also been made using an atmospheric pressure ionization mass spectrometer.

Variations in urinary steroid profiles after birth.

Abstract Quantitative steroid profiles were obtained in fifty-three newborn infants. The excretion of steroids (mg/24 h) did not correlate with birth weight, sex or gestational age. The steroid profiles of individual infants were followed for four months. During this period the profiles changed completely from a profile in which neonatal steroids predominate to a profile composed of metabolites of adrenocortical steroids.

An investigation of recurrent pine oil poisoning in an infant by the use of gas chromatographic-mass spectrometric methods

An 18-month-old infant required six hospital admissions in a period of six months for episodes consisting of coughing, respiratory depression, hematemesis, coma, dehydration, and lesions about the mouth. A negative history of ingestion of toxins was repeatedly obtained from the family and two home inspection by the local Health Department failed to identify potential toxins. Metabolic work-up was entirely negative. Utilizing methods of GC-MS, metabolites of a-terpineol were isolated from infant urine on two admissions to the hospital. These metabolites were confirmed by mass spectrometry to be the same metabolites excreted by Sprague-Dawley rats injected with a-terpineol or pine oil. The child had no additional episodes after physical separation from the home environment.

The use of gas chromatographic-mass spectrometric-computer systems in pharmacokinetic studies

Pharmacokinetic studies involving plasma, urine, breast milk, saliva and liver homogenates have been carried out by selective ion detection with a gas chromatographic-mass spectrometric-computer system operated in the chemical ionization mode. Stable isotope labeled drugs were used as internal standards for quantification. The half-lives, the concentration at zero time, the slope (regression coefficient), the maximum velocity of the reaction and the apparent Michaelis constant of the reaction were determined by regression analysis, and also by graphic means.

DRUG UTILIZATION DURING THE PERINATAL PERIOD

In a progressive study, 231 gravid females and their progeny were monitored to assess drug utilization during the perinatal period. The patients came from a middle to high socioeconomic population and delivered in a university hospital. Gravid patients were found to take a mean (M) of 9.6 drug preparations (DP) during the prenatal course with a range of 1-37; 6.4 DP (R=0-28) were prescription drugs; 3.2 DP (R=0-12) were over the counter drugs; and .03 drugs (R=0-3) were not identified. Twenty-five percent of patients received a drug chronically throughout pregnancy. Ninety percent were prescribed. The mother received a M = 6.0 (R=0-14) drugs during labor and delivery. Single drugs were administered during L&D, whereas DP containing multiple agents were ingested during the prenatal course. During the post partum course the mother received a M = 8.7 drug preparations (R=1-25). Thirty-nine percent of the mothers were discharged home on medications. Fifty-nine percent of the mothers who were breast feeding were sent home on medications. During the nursery stay the progeny received a M = 3.1 drugs (R=1-15) with 23% of the infants receiving 4-15. In infants who received >6 drugs, 40% were treated because of a direct or indirect effect of maternal drugs. Within the first natal days the average newborn infant had been exposed to a M = 18.7 drugs by intrauterine or extrauterine exposure. Breast fed infants may be exposed to an additional 7.7 (R=2-15) drugs.

A SCORING SYSTEM TO ASSESS NUTRITION AT BIRTH

357 infants delivered consecutively from a high socioeconomic population were given a clinical score of 0-2 if well nourished (WN) or 3-4 if intrauterine malnourished (IM). 46 infants (14%) were identified as IM. To confirm the clinical impression of IM, the amount of subcutaneous tissue (SCT) at the face, neck, chest, lateral abdominal contour, anterior biceps, anterior thigh, back, buttocks & Whartons jelly was scored 0-3, ie 3 representing abundance and 0 a decrease.Infants with a clinical score of 3-4 had lower scores for SCT, weight, length, weight/length2 × 100, FOC, chest, abdominal girth, & Whartons jelly (p<.01) than infants with scores 0-2.The SCT score differed between the 5 categories (0-4) of infants (p<.01). Length, FOC & Whartons jelly were least helpful in identifying an IM infant. Different patterns of SCT deposition were seen with scores of ≤ 2 & 3 or 4. The Kappa score to measure agreement between examiners was significant (p <.02)

48 A 14 STUDY OF THE MENTAL DEVELOPMENT OF INFANTS MANIFESTING INTRAUTERINE MALNUTRITION (IM) AT BIRTH

The mental achievement of 32 infants manifesting IM at birth without evidence of chromosome abnormalities or intrauterine infection have been compared to 13 well nourished (WN) infants. All infants came from a middle to a high socioeconomic background. Selection of patients was made in 1963 so the Colorado Intrauterine Growth Grid was not available. Retrospective plotting of infant weights showed that 41% of the IM infants fell above the 10th percentile. Knobloch-Pasamanick modification of the Gesell test demonstrated statistically lower scores in fine motor ability in the IM infant at 9 months of age. By 3 years of age all subtest scores were statistically lower in the IM infant except gross motor skills. The WPPSI, WISC, & WISC-R phychometric tests were used at older ages. The following findings were observed in the IM infant compared to the WN infant. Full scale IQ <90 19%/0; full scale IQ >120 7%/38%; educatable mental retardate 19%/0; learning disabilities 34%/15%; non-compensated learning disability 18%/0; specific learning disability 28%/15%; special education 19%/0; seizures beyond the newborn period 13%/8%; language problems 16%/0; significant visual problems 3%/0; medical Rx for hyperactivity 9%/0. Evidence of IM in infants at birth may serve as an important clinical marker for potential learning disability in the infant at an older age.- Work supported by the MacDonald & the Doris Hebbard Knapp Fund