Charles E. Pippenger

Phenobarbital and diphenylhydantoin levels inneonates with seizures

Little information is available regarding appropriate plasma levels of anticonvulsant drugs in neonates. We determined the plasma levels of phenobarbital and diphenylhydantoin following initial administration and during maintenance therapy in 59 neonates with seizures. Following intravenous administration of 15 to 20 mg/kg, levels of 20.7 +/- 4.4 microgram/ml were achieved for phenobarbital and levels of 14.5 +/- 3 microgram/ml for DPH. Maintenance doses of 5 mg/kg of phenobarbital resulted in initial drug accumulation followed by more rapid elimination of the drug with increasing duration of exposure. Therapeutic plasma levels of DPH could not be achieved by oral administration in the neonate.

Salivary levels of anticonvulsants: A practical approach to drug monitoring

Phenobarbital, phenytoin, carbamazepine, primidone, and ethosuximide were measured in saliva and plasma obtained simultaneously from 115 patients. A method to correct for the effect of salivary pH on phenobarbital concentration of saliva was developed. Salivary concentrations of these drugs were found to be equivalent to the plasma free drug and to correlate closely with the total plasma levels. Expressed as percent of total plasma drug, the salivary (S) and plasma free (P) concentrations were: phenytoin, S 11.1 ± 2.0 percent (mean ± SD), P 10.1 ± 2.4 percent (r = 0.97); carbamazepine, S 26.0 ± 2.4 percent, P 25.9 t 3.4 percent (r = 0.97); phenobarbital, S 43.1 ± 5.2 percent, P 40.8 ± 7.9 percent (r = 0.91); primidone, S 75.4 ± 24.9 percent, P 66.4 ± 8.8 percent (r = 0.76). Ethosuximide was not bound by plasma proteins, and its plasma and salivary levels were equal.

Pharmacologic observations on the neonatal withdrawal syndrome

The relationship between a maternal dose of methadone and the incidence and severity of neonatal signs of withdrawal, placental transfer of drug, and the relationship between maternal and neonatal plasma levels of methadone were studied in 30 mothers and their infants. Plasma levels of methadone were analyzed using a gas chromatographic method. Our studies demonstrate that the relationship between maternal dose of methadone and the incidence of neonatal withrawal symptoms was closely related to the last maternal dose of methadone. The ratio of neonatal to maternal plasma concentrations of methadone was 2.2:1. Neonatal withdrawal symptoms appear to be related to individual variation in maternal metabolism of the drug, placental transfer of methadone, and most importantly, to the individual variations in the rate of excretion of methadone as reflected in the neonatal plasma t 1/2. At plasma levels of methadone greater than or equal to 0.06 mug/ml, the symptomatic patients appeared to be protected from withdrawal. When the plasma concentration fell below this level, withdrawal symptoms began within 24 hours.

Sodium valproate in the treatment of intractable seizure disorders: a clinical and electroencephalographic study

A 12-week study of clinical response, EEG changes and serum antiepileptic drug (AED) levels using sodium valproate (VAL) was undertaken. The study showed that VAL is a powerful adjunct in the treatment of intractable epilepsy. It was most effective in patients with generalized seizures, but no seizure type was totally resistant. No serious adverse effects were encountered; nausea was easily overcome by readjusting the drug dosage. In most cases the only EEG change was decrease of epileptiform activity, and this correlated well with decreased frequency of clinical seizures. These two features in turn were most often seen with a serum VAL level of 40 μg per milliliter or greater. Intoxication with VAL was accompanied by marked slowing of the background rhythms, but no increase in beta activity. Other modifications of the EEG were probably due to changes in the plasma levels of other drugs. Interactions between VAL and conventional antiepileptic drugs occur, so that serum concentrations of all drugs must be monitored in patients receiving VAL.

Quantitative evaluation of anticonvulsant effects on penicillin‐induced spike foci in cats

We evaluated the effects of phenytoin, carbamazepine, phenobarbital, sodium valproate, and ethosuximide on penicillin-induced spike foci. Phenytoin, carbamazepine, and phenobarbital at blood levels within or slightly above the human therapeutic range in humans increased spike frequency, decreased spike duration, and abolished afterdischarges. Ethosuximide and sodium valproate had no statistically significant effect even at blood levels considered toxic in humans. The experimental spike focus and the method of analysis appear useful for: (1) detection of new potentially anticonvulsant drugs, (2) classifying new potentially anticonvulsant drugs according to the type of clinical seizure for which benefit is most likely, and (3) comparing different anticonvulsant drugs.

NEONATAL METHADONE WITHDRAWAL SYNDROME: CORRELATION WITH PLASMA METHADONE CONCENTRATION AND MATERNAL METHADONE DOSAGE

The relationships between maternal dose of methadone and neonatal withdrawal, and between neonatal plasma levels of methadone ([M]) and symptomatology have been investigated. Methadone was analyzed by gas chromatography; recovery was 88-94 % in the 0.1-1.0 ug/ml range. Ten mothers and their neonates were studied: 3 mothers were taking methadone 10 mg/day and 5, 40-60 mg/day; 2 mothers were detoxified during the 3rd trimester of pregnancy. All 8 infants of mothers on methadone exhibited withdrawal; 3 had no detectable [M] in the 1st 24 hours of life; 2 of these began withdrawal in the 1st few hours of life and the 3rd after 24 hours. In the other 5 symptomatic infants [M] at birth = 0.07-.14 ug/ml; in 4,[M] = 0-.06 uq/ml after 24 hours, at which time withdrawal began, and the 5th had [M] = 0.12 ug/ml at 24 hours with no detectable [W] at 48 hours. Withdrawal commenced in this infant shortly thereafter. Neither infant of the detoxified mothers developed withdrawal nor had they any detectable [M] at birth. Thus there appears to be no relationship between maternal dosages of methadone (10-60 mg/day) and the time of onset of neonatal withdrawal. Infants born to mothers who are drug-free in the 3rd trimester do not withdraw. Newborns with [M] = .07-.14 uq/ml do not withdraw: withdrawal begins when [M] falls to 0-.06 ug/ml.

1653 PHARMACOKINETICS OF SALIVARY THEOPHYLLINE IN ASTHMATIC CHILDREN

Although salivary theophylline concentrations have been used to monitor therapy and compliance, considerable variation has been noted. To determine whether the factor of time-dependency can account for this variability, we have measured simultaneous saliva (S) and plasma (P) samples between 2 and 6 hours post oral drug administration in a group of 7 asthmatic children aged 10-14 years. Comparison of the S/P ratios of theophylline revealed higher values during the absorption phase (mean 0.72) and lower values during the elimination phase (mean 0.49) (p<0.01). A comparison of free drug fractions in S and P indicated consistently higher levels in S compartment (mean Free S/Free P ratio of 1.79 with range of 1.0 - 2.85), indicating an active transport mechanism. Our data demonstrate a clear time-dependent relationship for theophylline in S corresponding with drug absorption and elimination. We conclude that: 1) salivary levels of theophylline may in part depend on an active transport mechanism; 2) salivary levels should be obtained at fixed time intervals when evaluating their usefulness in monitoring theophylline therapy.

247 DIETARY INFLUENCES ON THEOPHYLLINE PHARMACOKINETICS IN CHILDREN

We have examined the influence of diet on theophylline (T) pharmacokinetics in 14 asthmatic children, receiving chronic oral T. Doses from 4.2-8.8 mg/kg were given in an amount determined to yield therapeutic serum levels. Each patient was placed on 3 separate diets with different proportions of protein and carbohydrate and with constant fat and calories. Sequential serum T levels were obtained following a single oral dose on day 12 of each test diet. T half-life (t½) decreased on high protein (P) diet to a mean of 4.75 hr. compared to 6.76 on normal (N) diet and increased to 18.10 on high carbohydrate (C) diet (both p < .001). The metabolic clearance rate rose from a mean of .045 L/kg/hr on N to .055 on P and decreased to .037 during C (both p < .001). The apparent volume of distribution remained unchanged, except for an increase from .423 L/kg to .988 on C (p < .01). Multiple linear regression function demonstrated t½ differences to correlate significantly only with dietary changes. No abnormal blood chemistries were detected during any test periods. These results clearly show the effect of diet on T pharmacokinetics in children.