The relation between the serum levels and the oral dose of phenobarbital and carbamazepine was studied in children with chronic anticonvulsant treatment, and also the therapeutic levels of phenobarbital to prevent recurrence of the febrile and afebrile general convulisions were studied.The ratio of the serum level (μg/ml) to the dose (mg/kg) of phenobarbital was 3.1-3.4 in children under 3 years of age, 3.88 in children of 4-5 years of age and 5.48 in children over 6 years of age.There was no relationship between the serum levels and the oral dose of carbamazepine.Serum levels of carbamzepine in a day showed a marked fluctuation which was assumed due to rapid plasma half life of this drug, and seemed to explain the lack of relationship between the levels and doses.
Of 35 children with febrile convulsion whose serum lvels of phenobarbital were examine shortly before or after febrile episodes, only one of 14 children whose serum levels of phenobarbital were 16μg/ml or more had convulsion.On the other hand, 5 of 21 children whose serum levels of phenobarbital were 15 u g/ml or less had convulsions.Therapeutic levels of phenobarbital to prevent recurrence of febrile convulsion were suggested to be more than 16μg/ml. We could not find a clear-cut therapeutic range of phnobarbital to control afebrile generalized convulsion.

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Two diphenylhydantoin (PHT) preparations with different particle sizes and shapes, of“large”spherical crystals of100-300pin in diameter and of“small”rod-like crystals of10-50μm in width and50-150μm in length, were compared with regard to blood levels and clinical effects on 20epileptic children as a crossover experiment.
The small particle PHT preparation caused2-3fold higher blood levels than the large particle preparation.Five patients on the small size preparation showed definite clinical improvements with a decrease in frequency of seizures. It was concluded that the PHT blood levels should be monitored whenever the preparations of this anti convulsant are to be changed.

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Steady state plasma levels of carbamazepine (CBZ), diphenylhydantoin (PHT) and phenobarbi tal (PB) in171adult patients with epilepsy were determined by gaschromatography using the method of Nishina et al in a total number of221 samples.
The171patients were divided into7groups according to the type of comedication.
51patients treated with PHT alone41patients treated with PHT+PB 13patients treated with PHT +CBZ 23patients treated with PHT+PB+CBZ 24patients treated with PB alone 4patients treated with PB+CBZ15patients treated with CBZ alone The following conclusions were obtained.
1) The plasma levels of carbamazepine were decreased when the drug was combined with phenobarbital or diphenylhydantoin or both drugs, although the difference failed to show a statistical significance in the combination of CBZ and PHT.
2) No significant difference was found in the plasma PB or PHT concentration between the patients receiving the other antiepileptic drugs and those not receiving, although a tendency to elevation of PB plasma levels was observed in the case of simultaneous administration of CBZ, PHT and PB.

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Carbamazepine (CBZ) serum levels in steady state were measured in 17 epileptic children given CBZ only.Their ages ranged from 6 months to 15 years (6 years in average).The determination was carried out by enzyme immunoassay (EMIT). The relationship between serum level-dose ratio (S/D; ug/ml/mg/kg/day) and body weight (wkg) was shown as the regression line:
S/D=0.01 w+ 0.47
with the correlation coefficient:
r=0.66 (p<0.05)
Many previous reports, mostly analyzed in adult patients, have pointed out that on continu ous administration, the serum CBZ level has little or no correlation to the dose and it tends to fall when the treatment is continued for a long period.Recently, however, it has become clear that the duration of CBZ administration and polypharmacy have an unnegligible effect upon CBZ serum level-dose relationship.
In 9 children from 1 year to 5 years of age and administered CBZ only for 1 month up to 5 months, the serum level correlated significantly with the dose:
S=0.35 D+2.6,
r=0.83 (p<0.001)
In another group of children the serum levels were determined more than twice on different days, but there were no significant changes in serum level-dose ratio during 1 month to 2 years after initiation of CBZ treatment.The serum level-dose ratio in some cases seemed to decre ase, but in other cases seemed to show no change or slight increase when the duration became long.
These results seem to indicate that the phar macokinetics of CBZ in small children may have some characteristics different from those of other age groups.

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In order to evaluate the data of serum levels of the antiepileptic drugs (AED), the investigators should be in mind to grasp the whole conditions around the patients.
We followed the AED serum levels by repeated determinations in the subjects of 23 institutiona lized patients with epilepsy who were checked strictly about their conditions. The dosage for each patient was not changed throughout the whole period of this study.We kept punctually the time of ingestion at 7 a.m., and drew the blood at 10 a.m.The determinations of serum levels of AED were done 5 times on the succeed ing days and once after one month and once after two months, i.e.7 times in all in each patient. This study was done by the method of EMIT AEDImmunoassay for 4 drugs;diphenylhydan toin (PHT), phenobarbital (PB), primidone (PRM), carbamazepine (CBZ).
Results were as follows:
1.The relationship between the dosage (mg/kg/day) and serum levels showed a slightly significant correlation.The coefficient of correla tion for each drug was shown in Table.
2. The AED serum levels in the same subjects fluctuated considerably more than expected.In order to evaluate the range of the fluctuations, we calculated the ratio of standard deviation (S. D.) /mean value of 7 determinations in each patient.The distribution of this ratio was shown in Figure.Among 4 drugs, PHT showed a remarka ble wide range than PB (P<0.005).
3. During this investigation, we could get 7 samples immediatly after the clinical seizure in 3 patients.In 5 of 7 samples, the serum levels at this point showed a remarkable fall in one or two drugs in the prescriptions.

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Ninety-eight epileptic patients treated with antiepileptic drugs (AED), 54 males and 44 females, between 2 and 68 years of age were included in this study.In all these patints, liver functions (GOT, GPT, LDH, ALP, γ-GTP, LAP and ch-E) and serum AED Ievels by enzyme immunoassay (EMIT) or by gas liquid chromatography were tested.In this paper, particularly, the serum levels of phenobarbital (PB) and phenytoin (PHT) and the serum activities of γ-GTP and LAP are compared. (Normal range of γ-GTP is below 40 mU/m l and LAP, 100 to 180 GR-U.).
1.A higher incidence of abnormality was seen in γ-GTP (39.8%), ALP (18.8%), and LAP (16.3 %).Abnormalities in GOT and GPT were less frequent (8.2% and 4.1%).
2.The number of patients with high level of γ-GTP was increased by depending on the duration of AED medication.While 14% of the patients within one year of AED medication showed increased γ-GTP, further increases in γ-GTP were shown as follows: 43% of them with AED medication over a period of one to 5 years, 50% of them over 6 to 10 years, 50% of them over 11 to 15 years and 67% over 15 years.
3.The high value of LAP was mainly seen in cases with high γ-GTP.Correlation between high γ-GTP and high LAP was as follows: r=0.825 (P<0.001).
4.Relation to AED medication: high value of γ-GTP was seen in 16% of cases treated only with PB and in over 50% of cases treated with various combinations of medication including PHT.The high value of LAP was only seen in cases treated with medication including PHT and none in cases treated with PB.
5.Relation to serum concentration of AED: The high value of γ-GTP was noted in 86% of cases in which serum PHT levels were over 5μg/ml and in 39% of cases in which serum PHT levels were below 5μg/ml.The incidence of high γ-GTP was increased with the increase of the serum concentration of PB, but the mean value of γ-GTP in cases treated with only PB was slightly higher than the normal range (44.5mU/ml at the level of over 25μg/m/ of PB).By addition of PHT to PB, the mean value of γ-GTP was increased in comparison with the same PB level.

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Serum concentrations of anticonvulsants were determined in 89 cases of epileptic patients, 78 phenobarbital specimen, 19 phenytoin specimen, 21 carbamazepine specimen. Sixty percent of the cases on phenobarbital and 14% of those on carbamazepine had therapeutic concentration.No cases receiving phenytoin achieved the therapeutic concentration of 10-20μg/ml.Furthermore, we found that serum concentrations of phenytoin were influenced by drug preparations.-especially by the particle size.Determination of serum concentration must be done in every patient with epilepsy because of differences in individual physiological factors as well as in the particle of drugs.

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The application of centrifugal analyzer to EMIT is worth-while to assay quickly many specimens and to minimize the expenses of the reagents for each specimen.An attempt to apply centrifugal analyzer to five drugs (phenytoin, phenobarbital, primidone, carbamazepine and ethosuximide) and to obtain directly the computerized data of concentration was performed for the practical use of centrifugal analyzer.
The temperature differences between cells in the disc of the analyzers (Gemsaec N III and Rotochem II) were eramind by cresol red method, and were found to be within±0.015°C.
In using centrifugal analyzer the EMIT reagents were diluted based on the method of Finley et al., while both delay-time and reaction-time were chosen to be 100 seconds for all five drugs.The standard curves for phenytoin, primidone and carbamazepine on bilogarithmic diagram were straight lines, while those of phenobarbital and ethosuximide revealed nonlinear curves.Therefore, in order to obtain computerized data of concentratic equadratic equation and logit transformation were found to be acceptable for all five drugs. The precision of the EMIT assay using the procedure described here was at the level from 2.7 to 5.3% (between disc) and from 2.1 to 4.5% (within disc), expressed as coefficient of variation.
With this analytical system for the patient sera, the correlation coefficient of EMIT manual vs centrifugal procedures wes at the level from 0.962 to 0.990 for five drugs.This was similar to the previously reported values of the correlationship between GC and EMIT manual procedures, that is from 0.940 to 0.991.As a matter of fact the centrifugal procedure described hese seems to be as dependable as GC, and is more rapid and less expensive than EMIT manual procedure.

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A quality control scheme for determination of antiepileptic drugs was conducted as the second attempt on a nationwide scale in June, 1978, in which 43 laboratories participated.
The freeze-dried control serum containing a series of known amounts of six drugs was usedfor the study.The drugs used were phenytoin, phenobarbital, primidone, carbamazepine, etho suximide and sodium valproate.The methods employed were GC (16 laboratories), EMIT (31), heterogeneous enzyme immunoassay (1), ultra violet method (3) and radioimmunoassay (1). Some of the participating laboratories performed more than two methods.
The mean values of each drug were found to be in good agreement with the spiked values, regar dless of the different levels of concentration and the methods used in this study.All the values of coefficient of variation (CV) fell in the range from 9.4 to 18.9%.There was no significant difference in CV between EMIT and GC. Most of the mean values by both methods agreed with the spiked concentrations.However, high level speci mens of phenobarbital and ethosuximide measu red by EMIT indicated a slightly higher levels than the spiked concentrations.
It is proposed that all laboratories that analyze antiepileptic drugs should check their procedures by themselves and participate in the quality control scheme which is to be regularly con tinued.

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A clinical pharmacological study was conduct ed to disclose a pertinent correlation between oral dosage of valproate sodium (VPA) and the serum concentration of dipropyl acetate in steady state determined by gasliguid chromatography.The following two conditions were deliberately distinguished;firstly, the comparison of the dose-level correlations in reference to the age of the patients especially of children, and secondly, the distinction between the patients receiving VPA along with other antiepileptic drugs (poly pharmacy) and those taking VPA as the sole drug (monopharmacy).
One hundred and twenty-five assays from 116 patients in monopharmacy and 92 assays from 91 patients in polypharmacy were studied.All thepatients were“compliant”and their blood speci-mens were taken 2 to 3 hours after the first mor-ning dose.
Almost linear relationship was demonstrated between the dosage and the concentration.The level-dose ratios were apparently high in adult patients over 15 years of age, compared to those of younger children under 6 years.Regardless of the age of the patients, dipropyl acetate concen-trations attained significantly to a higher level in monpharmacy than those on polypharmacy, that is, 111.3±18.0μg/ml and 86.5+14.9μg/ml re spectively (40 assays each), when adult patients were receiving a comparable dose of VPA at 15±2.5 mg/kg/day.
In an attempt to elucidate possible interaction effects of phenytoin (PHT) exerting on dipropyl acetate concentration, a prospective study was carried out.To eliminate the influnce of daily fluctuation of dipropyl acetate concentration, blood specimens were taken immediately before the first morning dose in this study.In 3 patients, after VPA levels reached a certain steady state (12.3 to 16.5 mg/kg/day), PHT (3.8 to 4.6mg/kg/day) was added.In each case, as the PHT concentration increased toward the steady state, the dipropyl acetate concentration decreased inver sely with the rate of 30 to 45%.
In another timecourse study done on a healthy volunteer, the decreasing effect by PHT upon dipropyl acetate concentration (one-ffect) was exemplified by the fact that the dipropyl acetate concentration increaded again when concomitat ly used PHT was withdrawn (off-effect).
Since the accuracy of the measurements shown by coefficients of variation using spiked sera were as low as 2.3 to 3.3%, the result on both these on-and-off effects was convinced to be highly dependable.
As far as dipropyl acetate serum concentra tions are concerned, the following three condi tions have to be taken into consideration: 1. sampling time of blood specimens, 2.age of the patients especially of children, 3.presence of other concomitant antiepileptic drug (s), at least of PHT.
All these results suppors a view that VPA monopharmacy appeared to be rather rational so far as VPA was chosen as a primarily adequate antiepileptic drug.

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The interactions between VPA (valproate sodi um) and PB (phenobarbital) or PHT (phenytoin) were studied in 84 patients aged from 1 month to 19 years (average: 6 years) old.
The doses of those anticonvulsant drugs were as follows.VPA: 30mg/kg/day, PB: 4mg/kg/day (age: 0 to 3 years) or 3mg/kg/day (age: over 4 years),
PHT: 10mg/kg/day (body weight: under 10kg), 8mg/kg/day (body weight: 10 to 25kg), or 5 mg/kg/day (body weight: over 25kg).
In 54 patients, VPA was administered for 1 to 2 weeks, and then PB was added for the following 2 to 3 weeks.Decreased serum VPA concentra-tions were obtained in 38 of 54 patients during the additional PB therapy.The mean serum VPA levels were lowered from 99.1+33.7μg/ml to 79.5+24.0μg/ml.
In 17 patients, PB was administered for 2 to 3 weeks, and then VPA was added for the follow ing 1 to 2 weeks.Increased serum PB concent rations were obtained in 12 of 16 patients during the additional VPA therapy.The mean serum PB levels raised from 13.6+5.8μg/ml to 17.3+6.0μg/ml.In 9 patients, VPA was administered for 1 to 2 weeks, and then PHT was added for the following 2 to 3 weeks.Decreased serum DPA concentrations were obtained in 7 of 9 patients during the additional PHT therapy.The mean serum VPA levels were lowered from 85.9+22.0μg/ml to 64.3±25.1μg/ml. These results suggest to us:
1) Serum VPA levels might decrease when ei ther PB or PHT was given concomitantly.
2) Serum PB levels might increase when VPA was given concomitantly.

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Serum concentrations of valproate sodium (VPA, Depakene (R)) after a single dose were determined in 25 Japanese previously untreated epileptic patients (Ep group) and eight Japanese healthy volunteers (N group).All cases but three were given no medication at least for one month prior to the study.Three epileptic patients were given monosodium trichlorethyl phosphate (Trichloryl (R)) or pentobarbital calcium (Ravona (R)) at the time of EEG examination for sleep activation.Six healthy volunteers were given either a single dose of 200mg or 400mg VPA for crossover test.
1) Plots of peak level (Pl, μg/ml) versus dose (d, mg/kg) were linear in Ep group and N group (calculated by the method of least squares).
Ep group: P1=9.41d-7.71 (n=25, r=0.90, p<0.001) N group: P1=7.02d+1.82 (n =14, r=0.94, p<0.001)
2) Plots of log (level (1, μg/ml) /dose (d, mg/kg) ratio after peak level) versus time after single dose administration in the following four groups were linear (calcualted by the method of least squares).Differences between these four groups were not statistically significant.
Ep 200mg group (epileptic patients who were given a single dose of 200mg VPA)
log (1/d) =-0.0304t+0.9420 (n=12, r=-0.9979, p<0.001) Ep 400mg group
log (1/d) =-0.0178t+0.9029 (n=13, r=-0.9948, p<0.001)
N 200mg group log (1/d) =-0.0256t+0.9111 (n=7, r=-0.9961, p<0.001)
N 400mg group log (1/d) =-0.0230t+0.9058 (n=7, r=-0.9842, p<0.001)
3) Peak level time for Ep 200 mg group was 1.99+0.76 hr;for Ep 400mg group, 2.32+1.26 hr;for N 200mg group, 1.87±0.52 hr;and for N 400 mg group, 2.22±0.51 hr.Differences between these four groups were not statistically significant.
4) Biological half-life for Ep 200mg group was 14.32+3.08 hr;for Ep 400mg group, 17.18±7.71 hr;for N 200mg group, 14.06+3.51 hr;and for N 400 mg group, 17.28±6.12 hr.Differences between these four groups were not statistically significant.
No differences of pharmacokinetics of valproate sodium between Japanese previouly untrated epileptic patients and healthy volunteers were found.

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The necessity and effectiveness of anticonvulsant therapy for the prevention of febrile convulsions are the controversial matters.
The present study aimed to assess the effect of daily sodium valprote (VPA) for the prevention of febrile convulsions in relation to its plasma levels.One hundred children aged 7 months to 6 years were studied, who had febrile convulsions more than twice.VPA, 20-25mg/kg daily, was given to [I] 61 children (group A: 32 cases with“simple”febrile convulsions, and group B: 29 cases with“epilepsy triggered by fever”) in two divided doses, and to [II] 39 children (group A: 22 cases, and group B: 17 cases) in three divided doses.They were followed closely for 6-22 months.
The plasma concentrations of VPA were determined by gasliquid chromatography every 6 months.All blood samples were drawn 2-4 hours after the morning dose.During the follow-up period, all of these 100 children had febrile episodes.
Recurrence rate was 21.3% (13/61) in group C I C, but only 1 (3.4%) of the 29 children whose plasma concentrations were above 80 ug/ml, had a new convulsion.On the other hand, recurrence rate was 12.8% (5/39) in group [II], and 4 of the 5 children who had a recurrence, showed the lower plasma concentrations below 50, ug/ml.
This study suggests that the continuous therapy with VPA is effective for the prevention of febrile convulsion recurrences when plasma levels are maintained above 80, ug/ml in the group with two daily divided doses and above 50μg/ml in the group with three daily divided doses.
In an additional trial, the daily fluctuations in steady state plasma concentration of VPA were examined in other 10 children;5 receiving two daily divided doses and 5 receiving three daily divided doses.
The peak levels were higher in the former group due to the large single dosage (mg/kg) than in the latter, while the minimum levels stayed in almost the same range in both groups.
Owing to the rapid absorption and the short biological half-life of VPA, and therefore to the considerable daily fluctuation of its plasma levels, it is necessary to standardize the time when doses are given and when blood samples are drawn, in evaluating the therapeutic plasma level of VPA.

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Relationship among plasma total (Ct), plasma free (Cf) and mixed salivary (Cs) concentrations of phenobarbital (PB) was studied in an epileptic patient.A highly significant correlation was ob-served between Ct and Cf, and Ct/Cf ratio was 1.88.Although a significant correlation was observed between Cf and Cs, Cs/Cf ratio was only 0.59.When Cs was corrected by using pKa of PB and pH of saliva with Matin's equation of estimate free PB concentration (Cest·f), a highly significant correlation was obtained between Cf and Cest·f, and Cest·f/Cf ratio was 1.00.
The temporal curves of Cest·f after single oral doses of 50 mg and 100 mg PB in a healthy adult volunteer were approximated as triexponential equations respectively.The rate constants for both equations were found to be almost the same, and the apparent half-lives were 66 and 68 hours, respectively.The predicted values of minimum concentrations at steady state on the basis of these parameters corresponded well with the actually obtained Cest·f following repetitive administration of 50 mg PB every 12 hours.The pharmacokinetic analysis of PB and dosage regimen designs for individual patients can be made accurately by using concentrations of PB in mixed saliva, especially by employing a single dose study.

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Saliva and plasma levels of phenytoin (PHT) and phenobarbital (PB) in epileptic inpatients who were on chronic anticonvulsant medication were determined by homogenous enzyme immunoassay technique (Emit) and ultraviolet spectrophotometric method (UV).
1.There was a good linear correlation between the concentrations of both PHT and PB in saliva and plasma.The saliva concentration of PHT was approximately 10% of the plasma level, and the saliva concentration of PB varied according to the salivary pH, ranging from 30% to 40% of the plasma level.
2. For PHT which is present in lower concentrations in saliva, a modified single dilution technique was developed in EMIT assay instead of the stadard double dilution procedure.The modified EMIT precedure and the UV spectrophotometric method showed a good correlation in determining the saliva levels of PHT and PB.

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DeMyer described the detailed EEG findings in the patients with holoprosencephaly. Otherwise only a few brief reports are available in the lite-rature.In this study EEGs of 2 cases of alobar type and 4 cases of semilobar type holoprosence-phaly were investigated.
I.EEG findings of the alobar and the semilo bar types:
(1) an occipital plane wave onsistent with dorsal sac
(2) a burst of non specific slow waves with high amplitude repeatedly appearing periodically or irregularly or a group of sharp waves and slow waves with high amplitude
(3) shifting of the phase
(4) alternate appearance of abnormal waves
II.EEG findings of the lobar and analogous types The findings were not specific;only abnormal rhythm of slow waves was seen, and EEG was varied depending on the size of single ventricle and brain damage.
The periodic synchronous discharges (PSD) which were seen particularly (non specificly) in the alobar type had the interval shorter than in SSPE.The shapes of the waves in these dischar-ges were similar to these in SSPE.
It seems that the appearance of periodic syn-chronosus discharges were caused by disconnec tion of subcortico-cortical pathways due to non differentiation of holotelencephalon and persis-tent brain stem dominancy.

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