February, 1952 SCIENTIFIC

EDITION 05
REFERENCES
( I ? Hurtner, R. P,arid Ciisic. J. W., J . Am. Clzcm. Soc., (9) Knorr, I,,, Ber., 22, 2092(188Y).
6 5 , 262(1!)43); ibid , 65, IS%?( 194.7). (10) Gardner, J. H., and Stevens, J . R . . .I. ,4777. l’hrm.
(21 Tilford. C €1.. Van Camoen.. M. C . . and Shelton. R .
I ~I ~~ ~ Soc.. 71.1859119491.
S..;bid.. 69,2Y62~1!447). ~ (11) krit. pat. GOF,181, August 10, 1948; through Chem.
(3) Scholz, C. R . , Ahstr. First Nat. Med. Chem. Sym- Abstr.,43,3472c(1949).
posiuni of the A m . Chetn. Soc.. Ann Arbor, Mich., June, (12) Schulemann, W., Schonhofer, F.. and Wingler, A.,
1948, pp. 10, 1I . 1J. S. pat. 1,752,617,April 1.1930.
(4) Roherts, R . C . , and Johnson, ’l‘. B . , J . A m . Chem. (13) I.eonard, F., and Solmssen, IT. V., J. A m . Chem. Soc.,
So(., 47,1396(1925) 70,2064(1948).
( 5 ) Case. H. F.. and Koft, E . , ibid., 63, 508(1941): (14) Tilford, C. H.. Shelton, R. S., and Van Campen.
(6) Atkinson, E. R . , and Lawler, H. J . , “Organic Syn- M . G . , Jr.,ibrd.,70,4001(1048).
theses,” Coll. Vul. I , John Wiley 8- Sons, Inc., New York, (15) Wegerhoff, P . ,Ann.,
1941, p. 222. (16) Huttrer, C. P . , Dje
(7) Underwood, H . W.,and Kochmann, E. I,., J. A m . R. L., aiidScholz, C. R., J.
Chcm. Sol., 46,2072(1924). (17) Slotta, K. H . , and Behnisch, K.,Ber., 68,768(1936).
(8) Cortene, F.. “Organic Syntheses.” COIL Val. 11, (18) Dlicke, F. P.. and Zienty. F. B..J. A m . Chem. Soc.,
John Wiley & Sous, Inc., N e w York, 1943, p. 91. 61,776(1939).

The Central Depressive Effect of Carbrital

(Pentobarbital and Carbromal)*
By GRAHAM CHEN and CHAKLES R. ENSOK
T h e central nervous depressive effects of pentobarbital sodium and carbromal,
both individually and jointly, were determined by their anti-Metrazol activity i n rats.
At two times their minimal hypnotic dose levels, a maximal anti-Metrazol effect was
reached with pentobarbital about fifteen minutes after ingestion; about one hour with
carbromal. T h e duration of effect was five hours for pentobarbital; approximately
ten hours for carbromal. Carbrital (1.5 parts of pentobarbital plus 4 parts of car-
bromal) was shown to produce a rapid and prolonged central depression. T h e
early hypnotic effect is primarily due to pentobarbital while the prolonged sedation is
maintained by carbromal. T h e two also produce their sedative effect synergistically.

ARBRITAL~ is an oral hypnotic and sedative MATERIALS AND METHODS

preparation consisting of pentobarbital so-
dium, 1.5 gr., and carbromal, 4 gr. in Kapseals,’
or 2 and 6 gr. respectively in each fluidounce of
elixir. It is employed for producing rapid hyp-
nosis and prolonged sedation. The rationale is
based upon the laboratory and clinical observa-
tions that pentobarbital sodium is essentially
hypnotic and sedative, while carbromal is primar-
ily sedative and mildly hypnotic in its central ef-
fects.
Recently, a method has been devised by us
for the quantitative titration of central depres-
$on (1). The anticonvulsant activity of a com-
pound is taken as a measure of its central depres-
sive effect. By such a procedure, the central
nervous effects of pentobarbital sodium and car-
bromal, both individually and jointly, were in-
vestigated. The study includes their sedative
and hypnotic potencies, the rate of onset, and the
duration of action. The results are given in this
report.
*Received July 1 1 1961, from the Research Labora-
tories, Parke, DavisanJ Co., Detroit, Mich.
1 Parke, Davis and Company registered trade mark.
Female Sprague-Dawley rats weighing between
100 and 130 Gm., without food for sixteen hours,
were used. Pentobarbital sodium and carbromal
suspended in 7y0 gum acacia were administered
orally in a volume of 10 ml./Kg. One-half hour
later a pentatnethylene tetrazol (Metrazol) solution
(the convulsant) h a s injected intramuscularly. The
animals were then observed for thirty minutes for
convulsions. Three groups of ten rats each were
given a dose of the depressant and three graded
doses of Metrazol. The doses of Metrazol were so
adjusted as to produce convulsions in 20 t o 8070
of the animals. From the prohit log-dose regression
line, the CD50 (convulsive dose for 50% of the arii-
mals) was interpolated (2).
RESULTS AND DISCUSSION
The data obtained in experiments with pentohar-
hital sodium and carbromal alone are presented
graphically in Fig. 1 in which the CDbavalues ol
Metrazol and the corresponding doses of the depres-
sant are plotted on the ordinate and on the abscissa,
respectively. The three lines for pentobarbital so-
dium represent with increasing dosage the stage
of sedation, hypnosis, and general anesthesia. The
intersects of the lines give on the abscissa the mini-
mal hypnotic and anesthetic doses. The slope of
 JOURKAL OF THE AMERICANPHARMACEUTICAL
ASSOCIATIOX Vol. XLI, No. 2

250

400 200

6
-
Y

I
. ?L
\
I

300 P 150

2
n
d
n
u U

J A
0
2 200 :
0

n
100
LL +
I-W W
5: I

100 50

' 0
L .L-- L- -
20 40 610 sb Id0 IhO
DOSE OF DEPRESSANT, MGM/KG.
Pig. l.-Thc anti-Metrazol effects of pentobarbital
and carbron~al.
The intersects of the lines shown by arrows give
on the abscissa the minimal hypnotic and anesthc-
tic doses. Slope of line A represents the scdative
potency of each drug. The distance on the ordi-
nate between solid line B and the dotted line A ' shows
the depth of hypnosis.
the first lowcr line signifies a sedative potency while
the ordinate a t the minimal hypnotic level repre-
sents the extent of prehypnotic sedation. The dif-
ference in values on the ordinate between the sccond
solid line B and the dotted line A' shows the depth
of hypnosis and this divided by the amount of the
deprcssant required above the minimal hypnotic
dose in producing such a stage of hypnosis gives the
hypnotic potency. For example, the slope of line
A for pentobarbital is the ratio of 17 mg./Kg. of
Metrazol 011 the ordinatc to 15 mg./Kg. of pentobar-
I tencies are nearly equal, a greater degree of sedation
1 I - - - -1
1 2 3 4 5 6 7
TIME POURS
Fig. 2 -The ouset and duration of central ner-
vous depression induccd by pentobarbital-Na and
carbrotnal as indicated by their anti-Metrazol ac-
tivity.
In equivalent hypnotic doses, the effect of pen-
tobarbital is quicker, while that of carbromal is more
prolonged.
ld0 1$0 1 2 3 4 5 6 7 8
TIME, H O U R S
Fig. 3.-The joint central dcprcssive effect of pen-
tobarbital and carbromal (Carbrital).
(1) 0 Pentobarbital alone; (2) x carbrotnal alone;
( 3 ) 0 pentobarbital plus carbrotnal; ( 4 ) +
summa-
tion of (1) and ( 2 ) as experimentally determined;
(5) A calculated from the values on the individual
curves for an additive effect of pentobarbital and
carbromal, including a joint hypnotic action [see
reference 3 for details in calculation).
bits1 on the abscissa, a value of 1.2, which indicates
the sedative potency of pentobarbital. The differ-
ence on the ordinates between the solid line B and
thc dotted line A' a t 30 rng./Kg. of pentobarbital
is 48 mg./Kg. of Metrazol, and this divided by the
difference between 30 mg./Kg. and its minimal
hypnotic dosc (1.5 mg./Kg.), viz., a ratio of 48/15
or 3.2, is taken as its hypnotic potency. The seda-
tive and hypnotic potencies of pentobarbital and
carbromal so calculated, expressed in terms of their
anticonvulsant activities, are thus 1.2 and 3.2 mg.
of Metrazol per mg. of pentobarbital, 1.3 and 0.6
trig. of Mctrazol per mg. of carbrornal. The mini-
mal hypnotic doses for pentobarbital and carbrotnal
arc 15 and 40 mg./Kg., respectively. Thc maximal
prehypnotic sedation is shown by their anticon-
vulsant action (at their minimal hypnotic dose levels)
equivalent to 18mg.jKg. of Metrazol for pentoharbi-
tal and 70 mg./Kg. for carbrornal. As calculated
from the slopes of the lines for hypnosis, pentobdr-
bital is about five times more potent than carbromal
as a hypnotic agent. Although their sedative po-
may he induced with larger doses of carbromal
8 9 10 than with pentobarbital without producing hyp-
nosis. Generlil anesthesia occurs with 30 mg./Kg.
of pentobarbital. It was JlOt possible t o produce
general anesthesia with carbromal at 2.0 Gni./Kg..
a minimal lethal dose.
The rate of onset and the duration of central dc-
pressive action of pentobarbital and carbrornal are
shown in Figs. 2 and 3. I n Fig. 2. two times their

tic
I hypnotic action ( 3 ) . This is evident a t the fourth
L
15
- 11.25 7.5 3 75 O
PENTOBARBITAL, MGM/KG
0 10 20 30 40
CARBROMAL, MGM/KG.
Pig. 4.-The synergistic effect of pentobarbital and
carbromal,
The synergistic effect is shown by the experimen-
tal curve; an additive effect is indicated by the
dotted straight line.
niinirnal hypnotic doses were used. I t is seen that a
maximal aiiti-Metrazol effect was reached with
pentobarbital about fiftcen minutes after ingestion;
about one hour with carbromal. Since carbromal
is given in a suspension, the difference in onset may
be due to a difference in the rate of absorption of thc
two drugs from the gastrointestinal tract. After
having reached a maximum, the effect of carbromal
receded at a much slower rate than that of pento-
harbital. The duration of effect was five hours for
pentobarbital; approximately ten hours for car-
hromsl.
Similar results are shown in Fig. 3, obtained froin
an experiment in which the joint effect of pentobar-
bital and carbrornal was also determined with oue
minimal hypnotic dose of each. Their joint anti-
Metrazol effect is seen to be grentcr than that due to
a summation of their individual effects, either hy
adding the values on the indiviclual curves or as
calculated from thcse values for an additive effect
of pentobarbital and carbrornal, including a joint
hour after ingestion when the effect of pentobarbital
had vanished when it IVIS given alone. At that time
the effect of thc combindtiorl was approximately
three times greater than the individual effect of
carbromal. The eriharicecl anti-Metrazol activity
of the combhlation may be explained by a synergism
of the two in central nervous depression.
The synergistic effect of pentobarbital and car-
broinal is further shown in Fig. 4 by data which were
obtained with equivalent sedative doses of the com-
bination of the two in various proportions. Thc
experimcntal curve shows their synergistic effect; its
curvature represents the intensity of synergism (4).
The dottcd straight line is for an additive joint ac-
tion.
CONCLUSION
As determined b y t h e anti-Metrazol activity in
rats, Carbrital (1.5 parts of pentobarbital plus 4
parts of carbromal) was shown t o produce a
rapid and prolonged ccntral depression. The
early hypnotic effect is primarily due t o pentobar-
bital, while the prolonged sedation is maintained
by carbrornal. T h e two also produce their seda-
tive etTert synergistically.
REFERENCES
(1) Chen, G., and Portman, R., “The Determination of
Central Nervous Uepression, to he puhlished.
(2) Miller, L. C., aud Tainter, M. I,., P m r . SOC.E x p f l .
B i d . M e d . . 57,261 (1944).
(3) Chcn, G., and Portman, R., “The Joint Effect of
Central Nervous Depressants,” t o be published.
(4) Loewe, S., and Muisechnek, F.. Arch. exgil. Path.
Phavmakol.. 114,313(1926).

WHO MAKES IT?

The National Registry of Rare Chemicals. Arrnour Research Foundation, 33rd, Federal, and
Dearborti Streets, Chicago, Ill., seehs information on sources of supply for the following chemicals:
3-Methylquinoline 3 Ioclothyronine
4,4’-Dipiperidine 3,5’-I)iiodothyronine
2.6-Dinitrotoluene puaru-Hydroxyphenyl serine
1,8-Dichloronaphthalerle 2-Hydroxynaphthalcne-8-sulfonic acid
Uvitonic acid Fcrrous albuminate
Triisopropyl phosphate Beryllium phthalwyanine
1,3,6-Trihydroxynaphthaletie Avidin
Thymine-2-dcsoxyriboide Coprost anon e
2-Methyloxazole 3-F,thyl-2-aminophenylbcuzthiazolinc
Phenyldihydroquinazoline one
1,4-Dihydroxy-~,8-clichloroari~hraqui.