John Alvin

Phenobarbital compared with phenytoin for the treatment of neonatal seizures.

BACKGROUND Seizures occur in 1 to 2 percent of neonates admitted to an intensive care unit. The treatment is usually with either phenobarbital or phenytoin, but the efficacy of the two drugs has not been compared directly. METHODS From 1990 to 1995, we studied 59 neonates with seizures that were confirmed by electroencephalography. The neonates were randomly assigned to receive either phenobarbital or phenytoin intravenously, at doses sufficient to achieve free plasma concentrations of 25 microg per milliliter for phenobarbital and 3 microg per milliliter for phenytoin. Neonates whose seizures were not controlled by the assigned drug were then treated with both drugs. Seizure control was assessed by electroencephalographic criteria. RESULTS Seizures were controlled in 13 of the 30 neonates assigned to receive phenobarbital (43 percent) and 13 of the 29 neonates assigned to receive phenytoin (45 percent; P=1.00). When combined treatment is considered, seizure control was achieved in 17 (57 percent) of the neonates assigned to receive phenobarbital first and 18 (62 percent) of those assigned to receive phenytoin first (P=0.67). The severity of the seizures was a stronger predictor of the success of treatment than was the assigned agent. Neonates with mild seizures or with seizures that were decreasing in severity before treatment were more likely to have their seizures end, regardless of the treatment assignment. CONCLUSIONS Phenobarbital and phenytoin are equally but incompletely effective as anticonvulsants in neonates. With either drug given alone, the seizures were controlled in fewer than half of the neonates.

Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use

A prospective study of the efficacy of seizure cessation by phenobarbital versus phenytoin administration utilized both clinical and electroencephalographic expressions of seizure behaviors. The phenomenon of uncoupling was defined as the persistence of electrographic seizures despite the suppression of >or=50% clinical seizures after either one or both antiepileptic drugs use. Fifty-nine neonates (25 to 43 weeks estimated gestational age) with electrically-confirmed seizures were assigned to either of two drugs and continuously monitored over a 24-hour period. Nine of the fifty-nine patients had only electrographic seizure expression both before and after drug administration. Of the remaining 50 patients who had both electrical and clinical seizure expression before treatment, 24 infants responded to the first choice of an antiepileptic drug with no further seizures. Fifteen of the remaining 26 infants (58%) with persistent seizures after treatment had uncoupling of electrical and clinical expressions of seizures; no difference in the uncoupling effect was noted for neonates who were treated with either antiepileptic drug or based on prematurity or gender. Serial electroencephalographic monitoring helps document continued electrographic seizure expression after antiepileptic drug use, following complete or partial suppression of clinical seizure behaviors.

Neonatal Phenobarbital and Phenytoin Binding Profiles

Phenobarbital and phenytoin binding profiles were determined in 27 neonates. Binding of both drugs decreased compared with that in older subjects. In vitro binding of both agents correlated significantly with total protein and albumin concentrations. In vivo binding at 0.5 hours correlated significantly with birthweight and gestational age. Phenobarbital, but not phenytoin, binding decreased when three other therapeutic agents were concomitantly administered. Bilirubin concentrations, free fatty‐acid concentrations, and pH values encountered in this population did not significantly influence binding. An in vitro binding profile accurately predicted in vivo free fractions (percent drug unbound) and plasma concentrations of both drugs.

Determination of plasma mexiletine levels with gas chromatography—mass spectrometry and selected-ion monitoring

Mexiletine, 1-(2,6-dimethylphenoxy)-2-aminopropane (Mexitil), is an orally effective agent useful in the treatment of serious ventricular arrhythmias. This paper describes a gas chromatographic-mass spectrophotometric assay with selected-ion monitoring for the measurement of plasma or serum mexiletine levels. The drug and internal standard (p-chlorophenylalanine methyl ester) were extracted from plasma into ethyl acetate-hexane-methanol (60:40:1, v/v). After separation and evaporation of the organic phase, the drug and internal standard were derivatized to their pentafluoropropyl derivatives prior to analysis. The reproducibility of the daily standard curve yielded mean inter- and intra-day coefficients of variability from 0.7 to 11.0%. The coefficients of variability for control plasma samples (0.5 and 1.0 micrograms/ml) ranged from 2.6 to 5.0% and the accuracy of the assay was 106 +/- 6 and 100 +/- 5% for the low and high level controls respectively. The limit of quantitation for the assay was 0.1 micrograms/ml. No interfering peaks were detected in any patient samples. This method can be used as a primary analytical method to measure mexiletine plasma levels or can serve as a convenient back-up method to HPLC procedures when contaminating peaks coelute with mexiletine.

Neonates With Seizures What Predicts Development

Animal and human studies indicate that neonatal seizures are detrimental to the developing nervous system. This study addressed whether parameters of seizure severity and treatment were predictive of outcome and influenced the incidence of epilepsy. The outcome of babies with neonatal seizures was assessed based on follow-up examination, record review, and school performance. Epilepsy was assessed relative to developmental outcome and imaging abnormalities. There was no association between response to therapy and outcome. Neonates with mild or moderate seizure severity and decreasing severity over time, prior to anticonvulsant treatment, were more likely to have normal or moderately abnormal development than a severe outcome or death. Babies who had the highest seizure severity following treatment were more likely to have adverse outcomes. Those with normal imaging studies were more likely to have better outcome than those with diffuse severe abnormalities. Children with epilepsy were more likely to have abnormal development and imaging.

Pharmacologic implications of alterations in the metabolism of chloramphenicol

Abstract In the present study, it was shown that in rats the glucuronide conjugation of chloramphenicol was reduced by 18- to 24-hr fasting and by pretreatment with o - and p -toluic acids. This was reflected in the increased availability of chloramphenicol to produce liver microsomal enzyme inhibition. Eighteen- to 24-hr fasting and administration of o - and p -toluic acids delayed the disappearance of chloramphenicol from the plasma and from the liver and reduced the levels of chloramphenicol glucuronide in the plasma and in the liver tissue. These changes in the inactivation profile were accompanied by potentiation of chloramphenicol-induced prolongation of hexobarbital sleeping time. In fasted rats, glucose administration antagonized the changes observed in chloramphenicol metabolism and its effect on hexobarbital sleeping time. Pretreatment with o -toluamide, which is not conjugated with glucuronic acid, did not have a significant effect on glucuronide conjugation of chloramphenicol. It was also shown that thiamphenicol-induced inhibition of liver microsomal enzymes in vivo , measured in terms of its effect on the prolongation of hexobarbital sleeping time, was not affected either by fasting or by administration of o - and p -toluic acids. Thiamphenicol, an analog of chloramphenicol, is not metabolized by glucuronide conjugation, but is excreted unchanged. These observations indicate that the potentiation of chloramphenicol-induced prolongation of hexobarbital sleeping time in fasted and in o - or p -toluic acid-treated rats was due to the availability of higher amounts of chloramphenicol producing a greater degree of microsomal inhibition.

Discriminative, disinhibitory, and depressant effects of several anticonvulsants

The discriminative attributes of drugs were used to assess the degree to which several anticonvulsants have behavioral effects resembling those of pentobarbital. Rats were trained to make alternative responses to obtain water, depending on whether they had been injected IP with pentobarbital (10 mg/kg) or saline 10 min before the session. The pentobarbital response was chosen in tests with phenobarbital, dimethylphenobarbital, or methsuximide in the anticonvulsant dosage range. Increasing doses increased the percentage pentobarbital choice. Response rate was generally increased by doses that increased percentage of pentobarbital choice. The rats predominantly chose the saline response when administered phenytoin, primidone, or phenylethylmalondiamide, even at doses that were sufficiently high to reduce the response rate. The results suggest that different types of depressant effects are associated with the anticonvulsants tested.

A reliability study of a neonatal seizure scoring system

Abstract Two measures of reliability assessed inter-rater agreement regarding neonatal seizure scoring: coefficient of variation and intraclass correlation coefficient. Ten neonates with electrographic seizures recorded during each of 2 h of an EEG-sleep study were submitted for visual analysis. The onset, spread, and termination of seizures were coded. The number of anatomical sites with electrographic seizures as well as the durations for each of three phases of the seizure were calculated. Seven EEG scores for these 10 patients were coded independently by three different raters. The number of sites at the onset of each seizure and the duration of seizures, both at the onset and for the entire duration of the seizure, had moderate-to-excellent reliability. Lower reliability, however, was noted for the number of seizures during the phases of spread and termination. Before the development of computerized programs to detect and document the evolution of neonatal seizures, particularly in the context of treatment with different medications, practical strategies based on visual analysis need to be developed. Although the onset and total duration of seizures can be reliably scored among raters, the more variable description of spread and termination of the seizure is more problematic and requires greater attention and experience. This technique may be useful in evaluating the medication efficacy.

Phenytoin and phenobarbital stable isotope studies in neonates.

A pharmacokinetic study of phenytoin and phenobarbital with nonradioactive isotopes was performed in nine neonates in an intensive care unit setting. A single-pulse dose of either labeled phenobarbital (1,3-(15)N, 2-(13)C) or labeled phenytoin (2-(13)C, 1, 3-(15)N) was administered to neonates who manifested gestation between 25 and 40 weeks and were receiving maintenance medication. Blood samples were collected at fixed intervals, and with a computerized gas chromatography mass spectrometry system, plasma concentrations of the labeled and unlabeled drug in relation to time administered were obtained. According to the calculations obtained from labeled analogue, several kinetic characteristics related to drug absorption, clearance, and elimination were determined. The use of a nonradioactive labeled isotope overcomes the limitations of conventional pharmacokinetic methodology and can be specifically useful in neonates and infants in whom volumes of distribution are rapidly changing and steady state is not achieved.

Barbiturate N-demethylase activity in isolated rat hepatocytes

The isolated hepatocyte preparation has become an increasingly popular system for studying xenobiotic metabolism, and there is a need for methods of determining metabolic activity. Described here is a simple and sensitive radiometric assay for barbiturate N-demethylase activity in the isolated hepatocyte suspension. The demethylation of 1,3-dimethylphenobarbital is determined by measuring the formation of its only significant metabolite, N-methylphenobarbital. The reaction is a typical P-450-mediated dealkylation.