Valproic Acid in Epilepsy:

Clinical and Pharmacological Effects

Richard H. Mattson, MD, Joyce A. Cramer, BS, Peter D. Williamson, MD, and Robert A. Novelly, PhD

The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with
uncontrolled seizures of a g e o e M or partial type. Two-thirds of the patients experienced reduction in seizure
frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the
drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient.
Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 &ml) and maximum (42.5
c18/ml)serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in
divided daily doses.
During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5
to 10.2 pg/ml;p < 0.001)while the percentage of free pbenytoin increased (10.9to 20%). The quantity of unbound
phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid
competed with phenytoin for access to plasma protein binding sites.
Manson RH,Cramer JA, Williamson PD, et al: Valproic acid in epilepsy: clinical and pharmacologicaleffects.
Ann Neurol3:20-25.1978

Valproic acid (dipropylacetic acid) is a promising an-
tiepileptic drug only recently introduced into this
country for clinical trial. Meunier and associates [ 141
first reported the anticonvulsant properties of the
drug in animals in 1963. Clinical trials by Carraz and
co-workers [31 in France and later by investigators in
other countries suggested both efficacy and freedom
from serious side-effects [2, 8, 12, 21, 221. Valproic
acid seems to be most effective in the treatment of
generalized seizures of absence type but is of some
value for all seizure types [91.
Valproic acid has a chemical formula unlike that of
other antiepileptic drugs. It is a short-chain, branched
fatty acid containing no nitrogen (Fig 1). The exact
mechanism of action is unknown, but studies with
animals suggest that the drug increases brain levels of
y-aminobutyric acid with a corresponding inhibition
of seizures [ 5 ] .
Although the present clinical study was undertaken
to obtain further data concerning the efficacy and
toxicity of valproate, it was particularly designed
to delineate pharmacological features including
bioavailability, half-life, and interaction with other an-
tiepileptic drugs.
Materials a n d Methods
Twenty-three adult patients participated in an open,
three-month clinical study; each gave informed consent.
The 20 men and 3 women were subject to uncontrolled
seizures despite therapeutic serum concentrations of two or
three antiepileptic drugs, and had no evidence of progres-
sive medical or neurological disorder. As documented by
case history, clinical observations, and, in many cases, elec-
troencephalogram and videotape recordings, the primary
seizure types were: 1 1 partial complex; 5 partial elementary;
2 partial with secondary generalization; 2 generalized
tonic-clonic; and 3 generalized absence. Each patient served
as his own control based on documentation of seizure
frequency for three months prior to the addition of val-
proate to the medication regimen.
In 2 patients absence attacks were quantitated by 24-hour
EEG and videotape monitoring before and during valproate
therapy. All patients were hospitalized for one week during
initiation of valproate therapy for observation of clinical
efficacy, toxicity, and pharmacokinetics. Laboratory tests
administered prior to and during valproate therapy included
blood measurements of the following:alkaline phosphatase,
serum glutamic-oxaloacetic transaminase, lactic dehydro-
genase, blood urea nitrogen, glucose, calcium, phophorus,
sodium, potassium, chloride, bilirubin, total protein, albu-
min, uric acid, creatinine, cholesterol, white blood cell and
red blood cell count, differential, hemoglobin, hematocrit,
platelet and reticulocyte counts, and bleeding time.
Urinalysis plus 24-hour urine creatinine analysis were done.
Each patient also received audiological, ophthalmologic,
electrocardiographic, and electroencephalographic exam-
inations and a battery of neuropsychological tests [ 161 at
baseline and at three- or six-month intervals. After the initial
three-month trial, 14 of 17 patients who benefited from
valproic acid agreed to participate in a long-term study.
The drug, supplied as Depakene by Abbott Laboratories

From the Epilepsy Center, Veterans AdministrationHospital, West Accepred for publication June 28, 1977.
Haven* Yale-New Haven Hospital* and the Of
Address reprint requests to Dr Manson, Epilepsy Center, Vererans
Neurology, Yale University School of Medicine, New Haven, CT. Administration Hospital, Haven, CT 065 16,

20 0364-513417810003-0103$01.25@ 1978 by the American Neurological Association


Fig I . Valproic acid.
(North Chicago, IL)was administered as sodium valproate
in a syrup form. After we had a year's experience with this
formulation, the drug was given to long-term patients in a
capsule as valproic acid. Bioavailabiiity and dosage equiva-
lence were studied. The syrup formulation of sodium val-
proate (300 mg/5 mi dose) was initially administered three
times daily to each patient; the dosage was increased to 900
to 2,400 mg per day as tolerared. The capsules contain 250
mg of valproic acid, which is equivalent to 288 mg of sodium
salt. The total daily dosage in capsules ranged from 750 to
2,000 mg per day.
Blood concentration of valproic acid was analyzed by the
method of Kupferberg (personal communication, 1975).
Internal-standard cyclohexanecarboxylicacid was added to
0.5 ml of serum or plasma, followed by acidification with 0.2
ml of 10% perchloric acid. After extraction with 5 ml of
chloroform,the samplewas concentrated in isoamyl-acetate.
A Varian 2100 gas chromatograph with a column of 10%
diethylene glycol succinate o n 80-100 Supelcoport was
used for analysis. The injector temperature was 175"C, the
detector 200°C. and the column oven was isothermal at
150°C.
Since serum phenytoin concentrations fell in many pa-
tients after initiation of valproate therapy, changes in pro-
tein binding were measured. Protein binding of phenytoin
was estimated by plasma ultrafiltration (at 34°C) with Cen-
triflo CF-50 membrane cones (Amicon, Lexington, MA);
this method for separation of unbound phenytoin from
plasma proteins is comparable to equilibrium dialysis 171.
The coefficientof variation for ultrafiltration with the cones
of 10 aliquots of a plasma sample from a patient receiving
phenytoin was 3.8% Phenytoin concentrations were de-
termined by EMIT enzyme immunoassay (SYVA Corp,
Palo Alto, CA) and validated by gas chromatography using
a modification of the method of Chang and Glazko
[4]. Concentration of the phenytoin metabolite 5-(p-
hydroxyphenyl)-5-phenyihydantoin(HPPH) was measured
in urine by gas chromatography [4].
Results
The number of seizures during the initial three
months of valproate therapy was compared with the
previous three-month period for the 23 patients. The
mean monthly seizure frequency was reduced by more
than 75% in 8 patients, by 50 to 74% in 5 patients, and
by 25 to 49% in 4 patients. Six patients had minimal or
no (0 to 24%) decrease in seizure occurrence. Nine
out of 16 patients having partial seizures with elemen-
tary or complex symptomatology experienced 50% or
more reduction in seizure frequency. For those pa-
tients with multiple seizure types, tonic-clonic attacks
had been well controlled prior to valproate therapy.
Optimal benefit was observed in those with absence
attacks documented by 24-hour videotape and EEG
monitoring. Paroxysmal spike-wave discharges de-
creased 79 and 96%.
Side-effects occurred in 7 patients but were not
serious. Only 2 patients had to withdraw during the
first month of the trial because of side-effects. Both
experienced sedation, ataxia, and nausea. Sedation
and gastrointestinal upset were noted most commonly
at the initiation of therapy and were usually transient.
Ataxia, nystagmus, diplopia, and changes in psy-
chological tests for drug toxicity usually cleared im-
mediately when the valproate dosage was reduced.
The side-effects appeared to be direct effects of the
valproate and were not due to interaction with other
antiepileptic drugs since no increase in the serum
levels of other medications was observed. Repeated
observations for nearly two years in some patients
revealed no hematological, hepatotoxic, or neph-
rotoxic effects of the drug.
Electroencephalographic recordings revealed a de-
crease in interictal abnormalities, primarily in patients
with absence attacks. A decrease of several hertz in
background alpha rhythm accompanied the transient
clinical complaints of hypnotic toxicity. There was loss
of alpha background in 1 patient after the administra-
tion of 300 mg and 600 rng doses, at which time
increasing side-effects were noted. Toxicity abated as
soon as the drug was stopped, and the EEG returned
to its pre-treatment pattern.
Bioavaika bility
The valproate sodium (Vp-Na) was given as syrup in
maintenance doses of 900 to 2,400 mg per day (range,
8 to 39 mg/kg). In patients doing well, the dose was
not further increased, and the maximal tolerable dose
was not fully tested. When 1 1 long-term patients were
changed to the valproic acid (Vpa) capsule formula-
tion, doses were approximated one-for-one using the
following equivalence: 300 mg V p N A = 260 mg
V p a Maintenance doses of Vpa ranged from 750 to
2,000 mg per day (10 to 33 mg/kg). The mean Vpa
dose of 18.4 mg per kilogram was little changed from
the mean V p N a dose of 20.9 mg per kilogram.
Absorption of the drug differed between the two
formulations (Table 1). The syrup was rapidly ab-
sorbed and often gave peak serum levels within 15 min-
utes of ingestion. Similar peak levels were achieved
somewhat more slowly in nonfasting patients, but
within 60 minutes. The rapid elevation of serum con-
centration was followed by a steady decline, resulting
in wide fluctuations in valproic acid serum concen-
trations throughout the day. The use of gelatin cap-
sules resulted in slower absorption of Vpa; it took 1 to
2 hours to reach a maximum. The serum level occa-
sionally reached a plateau 2 to 4 hours before declin-
Mattson et al: Valproic Acid in Epilepsy 2 1
Table 1 . AbJorptiori a d HaU-Lge of Sodium
Vatproale and Vulproii Acid
Sodium Valproic
Valproace Acid
Time Syrup Capsules
TIll,XU 15-60 rnin 60-120 min
T,r21'.c 8.73 hr 8.67 hr
Range ' 6-10.5 hr 6-10.5 hr
N 13 6 VALPROIC
"Interval between administration of the oral dose and point of
maximum serum concentration.
hSerum half-life.
'Serum half-life and range show no significant difference between
the two formulations.
ing. The range of the half-life of valproic acid in blood
was found to be 6 to 10.5 hours (average, 8.7 hours) in
these patients receiving two or three other antiepilep-
tic drugs. When the first dose of 600 mg Vp-Na, given
on the fifth day, was compared with a dose given
after six months of valproate therapy, no change in
half-life was observed, as shown in Figure 2. The
unaltered rate of elimination indicates no self-
induction of metabolism by valproate.
T h e variation in valproic acid serum levels was de-
fined for both formulations by obtaining blood sam-
ples serially to determine the maximum level achieved
by each patient as well as the lowest level prior to the
next dose (approximately one half-life). Table 2 sum-
marizes the mean low and high valproic acid serum
concentrations with multiple daily dosing. The mean
valproic acid serum concentrations for all doses, both
syrup and capsule formulation, were 23.3 ? 8.0 pg
per milliliter 8 hours after the previous dose, with a
maximum of 42.5 k 11.2 pg per milliliter.
Drug Interactioti
During the first week of valproate therapy, many
patients exhibited a significant reduction in the serum
phenytoin level. For 2 1 patients, mean serum concen-
tration of phenytoin before valproate was begun was
19.4 p g per milliliter, representing an average of three
o r four previous clinic visits each. The mean serum
concentration declined to 14.6 pg per milliliter during
the fourth to seventh day after valproate was begun in
the hospital (p < 0.001). An average of two or three
phenytoin serum levels at the lowest point during four
months showed a decline from 19.4 to 11.1 pg per
milliliter during valproate therapy ( p < 0.001).
T h e rapid fall of the phenytoin level in many pa-
tients reflected displacement of phenytoin from
plasma protein by valproic acid (Table 3). When val-
proate was stopped, phenytoin returned to approxi-
mately 10% free, considered to be within the normal
range [ 101. The reciprocal relationship between total
plasma phenytoin and the percentage of free pheny-
2 2 Annals of Neurology Vol 3 No 1 January 1978
601
50-
40-
I
30 -
I
I
I
I
ACID
I
ugh1 1
01 -600mq 6mos
I .--.600mQ day 5
20. I
1
lo-
0 I 2 3 4 5 6
hours
Fig 2 . Elimination of valproir ucid from serum. Vafproate
u'as started on duy I at 300 mg per dose ( 3 doses per da.y),
increusing to 450 nig per dore o n day 3 and to 600 mfi per
dose o n day 5 . Serial bloodsamples were obtained ufter the
first dose of 600 rng of Vp-Na on day S and ufter six
mnnths of therapy. There is n o apparent difference in the
rate of elimination of the drug between initiation of
therapy or aber long-term therapy.
toin is illustrated in Figure 3. When Patient 6 was
started on valproate treatment at a low dosage, the
total phenytoin level was 17.5 pg per milliliter with
8% free. After six months of Vp-Na treatment (2,400
mg/day), the patient was rehospitalized and the val-
proate was stopped. Mean total phenytoin levels were
14.6 f 1.4 p g p e r milliliter (N = 7) with 11.3 f 2.0%
free when the patient was not taking valproate and was
receiving 400 mg of phenytoin and 160 mg of
phenobarbital daily. When valproate was restarted,
total phenytoin immediately declined to a mean of 8.5
2 1.0 pg per milliliter (N = 5) with a concurrent and
sustained increase of free phenytoin to 18.5 t 2.7%
(both,p < 0.001). The absolute concentration of free
phenytoin in plasma remained essentially unchanged
whether the patient was on or off valproate therapy.
The quantity of unbound phenytoin prior to and dur-
ing initiation of valproate (Fig 3) was 1.42 f 0.3 1 pg
per milliliter (N = 6). When the valproate was
stopped, free phenytoin was 1.63 k 0.19 p g per
milliliter (N = 7). It remained in a similar range, 1.55
2 0.20 pg per milliliter (N = 5), when the adminis-
tration of valproate was resumed.
Studies were done to see if the decrease in total
phenytoin was secondary to altered metabolism re-
Table 2 . Coniparison of Mean Serum Concentrations of Valproic Acid in Syrup and Capsule Forma

Dose of Dose of
Sodium Valproate Valproic Acid
Syrup (me) Capsule (mg)
Determination 300 450 600 250 500 All Doses
8 hr
pglml Vpa 16.3 22.2 26.5 21.1 28.5 23.3
SD 2.0 7.0 8.9 4.7 7.4 8.0
N 10 6 17 5 6 44
Max
pglrnl Vpa 33.0 43.9 48.7 30.9 47.7 42.5
SD 4.3 8.6 11.0 8.7 7.2 11.2
N 11 6 18 3 4 42
Mdkg 11.2 20.8 24.9 10.9 21.0 19.2
aSamples were obtained approximately 8 hours after the dose was administered and serially thereafter to determine the maximum level for
each patient. Some patients were tested on more than one dose.

lated to increased absolute phenytoin in serum when
displaced by valproic acid. While Patient 6 was under
observation, 24-hour urine samples were collected for
quantification of the principal phenytoin metabolite
H P P H (Fig 4). The samples showed normal H P P H
output from 400 mg per day of phenytoin both prior
to and during valproate therapy (mean, 244.7 19.5
mg per day; N = 7) except when valproate was being
started and stopped. Initiation of valproate therapy
brought an immediate, transient increase in H P P H
production, which was repeated subsequently when
valproate was restarted. The mean H P P H output rose
to 342.6 t 25.7 mg per day (N = 4) on these two
occasions. Each time, urinary H P P H levels returned
Table 3. Protein Binding of Phenytoin
following Valproate Administration a
to normal (61.2% of dose) after two days of excess
production (85.7% of dose). When valproate therapy
was stopped, mean H P P H levels in urine declined to
182.5? 28.3mgperday(N = 2)fortwodays(45.6%
of dose) (p < 0.001).
The interaction of valproic acid and phenytoin is
* well demonstrated in Patient 6 (see Figs 3, 4). While
the total plasma phenytoin levels declined, the plasma
protein binding of phenytoin also decreased and the
metabolism of phenytoin (as reflected in urinary
H P P H quantity) transiently increased. At the same
time, bioavailable free phenytoin remained constant.
In Patient 6, phenobarbital serum concentration was
unchanged throughout, ranging from 22 to 26 p g per
milliliter whether the patient was on or off valproate.
In the whole group of patients no significant changes
in serum phenobarbital were seen.

Valproare Dose (mg/day) Discussion

The results of this uncontrolled open trial of valproate
Determination 0 900 1,350 therapy confirm the clinical effectiveness of the drug.
Mean phenytoin Its optimal benefit is that it decreases absence attacks,
level (pg/ml) but it also relieves partial seizures. The reduction in
Total 16.5 13.3 10.2 seizure frequency closely approximates that reported
Free 1.74 1.94 2.08 in a review by Simon and Penry [20]. They tabulated
5% free phenytoin that 130 (68%) of 192 patients with partial seizures
Mean 10.9 16.1 20.0 showed 33 to 100% benefit. In our group, 13 of 18
SD 1.8 5.0 1.7 patients (72%) reported 25 to 100% fewer partial
seizures. A more precise definition of efficacy requires
N 25 11 9
controlled clinical trials.
P < 0.001 < 0.001
T h e side-effects of valproate were annoying but not
L<0 . 0 2 1
serious. Most symptoms were transient or were re-
aProtein binding of phenytoin is altered when sodium valproate is versed by reducing the dose. Gastrointestinal upset
administered. The increase in percentage of free phenytoin is dose
dependent, as shown by the significant effects of administering900 (e.g., stomachache, nausea, and vomiting) was most
or 1,350 mg per day of Vp-Na. Some patients were tested o n both common when the drug was administered to fasting
doses or were tested before and after therapy. The concentration of patients. The syrup formulation was unpleasantly
free phenytoin was higher when 1,350 mg per day was given than
when no valproate was adminisrered ( p < 0.05).The decline in total sweet and occasionally produced transient nausea or
phenytoin was significant at each dose. vomiting. When the formulation was changed from

Mattson er al: Valproic Acid in Epilepsy 2 3


20.
PHENYTOIN
rglm I
[plasma1
15.
.-.'.--.
IO-
5.
2 1
t START
VALP ROATE
syrup to capsule, the rate of absorption slowed while
associated gastrointestinal upset diminished. W e
found that allowing only one week to build to the
maintenance dose was too rapid for some patients; a
gradual increase in dose over two to three weeks is
suggested if patients begin to show toxicity. When
patients appeared drug toxic but levels of drugs other
than valproate.were normal, the dose of valproate was
reduced. This usually relieved the symptoms, indicat-
ing that valproate can cause side-effects which are not
attributable to other medications.
Previous investigiuions of valproate [6, 81 have re-
ported alopecia. O n e patient in our group commented
on hair loss during the initial month-long trial, but this
could not be objectively verified.
Extensive testing of hepatic, renal, and hernatopoi-
etic functions gave no evidence of any biochemical or
hematological abnormality. A decade of clinical use of
valproate indicates that it is an exceptionally safe an-
tiepileptic drug [181.
Because of the relatively short half-life of the drug,
ranging from 6 to 10.5 hours, multiple dosing is advis-
able to maintain relatively constant serum/brain val-
proic acid levels. Since the variation between the
Fig 4. Changes in urinaq HPPH concentration (in
24-hour aliquots) associated with valproate therapy.
Patient 6 received 400 mgper day ofphenytoin
throughout. Mean normal H P P H level is 244.7 t 19.5
nrg (in 24 hours) for this patient.
24 Annals of Neurology Vol 3 No 1 January 1978
-
.---a
A
TOTAL
%FREE
FREE
.=-.
I .20
;4 X FREE
PHENYTOIN
11 5
I
b
I -10
--"
5
t
2 3 4 5 6-0s ~ ' 1 2 3 4 5 6 1 E 9 1 01 2 1 4 5 6
R:% f 0 AT E
RESTART
VALPROATE
F i g 3. Phenytoin concentration was monitored daily
during initiation of therapy and when ualproate treatment
uJaJstopped after six months to observe changes in
pbenytoin bindin# in plasma. For Patient 6 (asfar the
other patient.f),valproate u i a ~administered slowly oz!erone
week, the dose increasing from 900 to 2,400 mg per day.
When aalproate was started again after a period of ten
d a y ujithout i t , tQtalphenytOinconcentration declined
significantly while the percentage of free phenytoin increased
(both.p < 0,0011. The concentration of unbound.free
phenytoin showed no statistically sigriijcant alteration
throughout.
mean low premedication level and the mean
maximum serum concentration was wide (23.3 to 42.5
pg/ml) for both formulations, we found it valuable to
determine the kinetic profile of drug absorption for
each patient in order to be able to interpret blood
levels obtained at varying times on clinic days. The
serum levels that usually produce benefit without tox-
icity (i.e., therapeutic level) reportedly range from
67 to 82 pg per milliliter [ 131, 40 to 70 pg per millili-
ter [ I l l , 25 to 150 p g p e r milliliter [18], and 34 to 68
pg per milliliter [171. Schobben et a1 [191 have
suggested a therapeutic range of 50 to 100 kg per
milliliter, which is higher than our experience.
Even at highest doses, peak valproic acid concentra-
tion infrequently approached this range in our pa-
tients. Since the serum concentration varies depend-
ing on the interval between doses, the disparity may
result from lack of uniformity in sample collection.
Results indicate good absorption with either syrup or
capsule administration of the drug. The capsule has
the advantages of slower absorption, gradual peaking
of plasma concentration, and greater acceptance by
patients.
In a previous report, Richens and Ahmad [17]
documented an average 27% elevation of phenobar-
bital in 7 patients receiving valproate, with n o consis-
tent rise in phenytoin concentration or half-life. Win-
dorfer, Sauer, and Gadeke [23] described elevation of
blood levels of phenytoin in 5 patients and elevation
of primidone in 7 when valproate therapy was started.
Several other investigators have mentioned elevated
levels of phenobarbital [2, 8, 221, primidone [2, 221,
phenytoin [6, 81, benzodiazepines [8, 10, 221, and
ethosuximide [9].
In the present investigation of 23 patients, all
receiving multiple antiepileptic drug therapy, we
obtained n o evidence of phenobarbital or phenytoin
elevation attributable to valproate. We did, however,
confirm a previously noted [ 11valproic-phenytoin in-
teraction, reflected by a decline in total serum pheny-
toin concentration and alteration in the proportion of
protein-bound to free phenytoin. There appears to be
a rapid, significant increase in the percentage of free
phenytoin when valproate is administered. The ratio
of unbound to bound phenytoin in plasma increased
directly as a function of increasing valproate dose.
Assuming that 1.5 to 2.0 pg per milliliter of free
phenytoin is an appropriate therapeutic blood concen-
tration, this level is normally maintained by a total
phenytoin concentration of 15 to 20 pg per milliliter
with approximately 10% free. It follows that when
valproate is present and phenytoin is altered to 20%
free, only 7.5 to 10 pg per milliIiter of total phenytoin
is required to maintain 1.5 to 2.0 pg per milliliter of
free phenytoin.
Valproic acid competes with phenytoin for access to
the limited binding sites on plasma proteins. The pro-
portional displacement of phenytoin by valproic acid
has been confirmed in in vitro studies [15] and in
unpublished studies from this laboratory. No evi-
dence suggests that enzyme induction accelerates
phenytoin metabolism since the fall in total serum
phenytoin is immediate and reverts to pretreatment
level when valproate is removed. If para-hydroxylase
enzymes were saturated, there would be no visible
change in HPPH production. Increased or decreased
elimination of the HPPH metabolite may be seen only
during the period of reequilibration of body stores of
phenytoin.
Evidence of the stability of unbound phenytoin (see
Fig 2, Table 3) suggests that the dosage of phenytoin
may not need to be increased despite a decline of total
phenytoin and an increase in the percentage of the
unbound drug. It is generally assumed that plasma
concentration of free phenytoin represents the
therapeutically significant measure of the active drug
[7, 101. Therefore, the decline in total plasma concen-
tration of phenytoin due to displacement by valproic
acid is compensated by a proportionate increase in the
ratio of the free drug: unless the total phenytoin is
low, the clinical effect should be insignificant.
Supported by the Veterans Administration, by National Institutes
of Health Grant USPHS 5 P01NS06208-12, and by Abbom
Laboratories.
Presented in part ar the Annual Meeting of the American Epilepsy
Society, Dearborn, MI, October 1-2, 1976.
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