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COMPARATIVE DEPRESSION OF SEVERAL SHORT ACTING BARBITURATES AND SPIRO-BARBITURATES
Jap. J. Pharmacol.2, 123-126(1958)
COMPARATIVE
DEPRESSION
BARBITURATES
OF
AND
SEVERAL
SHORT
ACTING
SPIRO-BARBITURATES
WOO CHOO LEE* Department of Pharmacology,SeveranceUnion MedicalCollege, Seoul,Korea Received for publication October 8, 1952
In an effort to develop new and possibly better types of barbiturates, suitable for intravenous use, a large number of spiro-barbiturates have been prepared by a ring closure on the 5-carbon atom of the barbituric acid and afforded for pharmacologic study. Spiro(2'-ethyl-3',5'-dimethyl cyclopentane) thio-barbituric acid appears to be the most promising product of a series of 50 analogues. Stoelting et al.(1) reported the anesthetic and hypnotic proper ties of this compound in laboratory animals and the satisfactory clinical appli cation for anesthesia in fifty patients. The present report (2) deals with the study of the duration of depression of this new spiro-thiobarbituric acid and its non-thioanalogue**. For the purpose of brevity, spiro-thiobarbiturate and spiro-barbiturate will be used in this report instead of the long chemical name. The comparative results of depression of these new compounds and a well known short acting barbiturate seemed necessary and of interest. Pentobarbital and its thio-analogue, thiopental, are well known barbiturates, thus should serve admirably as a standard by which to judge the new barbiturates. Secobarbital and its thio-analogue, surital (thioamytal), are also included in this comparative study because of their similar depressive potency in the pentobarbital series. METHOD AND RESULTS The experimental barbiturates, constant
volume
drug
would
sary
to compare
as those chosen
work
dissolved
at a constant
give a longer
Introduced of Tokyo, Supplied
these
through
the
For
courtesy
Professor
rabbits.
sixty
seconds. than
purpose,
Research
salts
As a large
Faculty Laboratories,
in a
dose of one
dose, it is neces
by using doses
of the
intravenously
a smaller
and thiopental
of Pharmacology,
of Eli Lilly
Sodium
injected
as determined this
of pentobarbital
by Y. Kobayashi, Tokyo, Japan.
and were
of depression
of action
drug.
doses
on rats water,
rate within
period
the periods
of the standard because
was done
in distilled
same
doses
of 20-30 mg/kg
the
were
are usually
of Medicine, Indianapolis,
employed
University U.S.A.
124
WOO CHOO LEE
in experiments with a fair degree of safety. In addition, they produce a pro found sleep which permits accurate determination of the duration of action. Following a single administration, both species of animals remained satis factorily anesthetized for a considerable period and recovered fairly promptly and completely. The duration of anesthesia, corresponding to the duration of action in the experiment of Fitch and Tatum(3), has been measured in minutes from the end of injection until the animals resumed their normal posture. I. Experiment; on rats Rats were divided into two groups, growing and mature. The growing rats had initial weights of between 80 and 115 gm with an average of 99 gm and final weights during the twenty day experimental period of between 95 and 170 gm, average 120 gm. The mature rats weighed between 250 and 390 gm, average 325 gm. Table1 shows the mean duration of anesthesia in growing and mature rats receiving 20, 25 and 30 mg/kg of the six drugs into tail vein. The duration of anesthesia of spiro-thiobarbiturate in both groups is clearly shorter than that
of thiopental
of the former
or
has
surital
almost
the
of the latter.
Spiro-barbiturate
pentobarbital barbiturate,
or secobarbital. however, is still
on
the basis
same
duration
has similarly
of the same of action a shorter
dosage.
Thirty
mg/kg
as twenty
mg/kg
of each
duration
of anesthesia
The duration of action of thirty mg/kg of spiro shorter than that of twenty mg/kg of pentobarbital
TABLE 1. Mean duration of anesthesia .in rats. Twenty days experimental period. Anesthetized every 2-3 days
4:
Initial Weights
weights
80-115; final weights
250-390 grams
than
95-110 grams
COMPARATIVE
DEPRESSION
OF BARBITURATES
125
or secobarbital. In general, secobarbital and its thio-analogue are respectively shorter acting as compared to the pentobarbital and its thio-analogue. It is interesting to note that in growing rats at the specific dosage of 30 mg/kg, the relative activity (and for most drugs the absolute duration of action) of the thio-derivative is larger than the non-thioanalogue and in mature rats much like other mammals, thio-barbiturates are. shorter acting than their non thioanalogue. As shown in Table 2, in growing rats, thiopental has a longer action than spiro-barbiturate; surital for the immature rats has almost the same duration of action as secobarbital. Chen and his coworkers (4) reported that thio-barbiturates have a longer action than non-thiobarbiturates in rats and apparently the rat does not metabolize thio-barbiturates as readily as do the dog and man. The above experimental data, however, shows that the thio barbiturate is longer acting only in growing rats at a specific dosage of thirty mg per kg of body weight and is still shorter acting in mature rats, the same, as it is in higher mammals. Furthermore, Table 2 shows that growing and mature rats have a different sensitivity to thio-barbiturates and non-thiobarbi turates. In other words, thio-barbiturates have a longer action in growing rats than in mature rats; on the contrary, non-thiobarbiturates have a longer action in mature rats than growing rats. TABLE 2. Mean duration of anesthesia in rats at a dosage of 30 mg/kg Twenty days experimental period. Anesthetized every 2-3 days
** :
2.
Experiment
Mature Table
final
weights
95-170
grams
on rabbits
rabbits
3 shows
Initial weights 80-115; Weights 250-390 grams
that
weighing
between
2.1 and 3.0 kg, average
on the basis of the same
dosage,
2.5 kg, were
the mean duration
of spiro-thiobarbiturate
is clearly
shorter
than that of thiopental
or surital
the basis
an equal
degree
of
mg/kg
of producing
thiobarbiturate er action than
corresponds thiopental.
to twenty Similarly
pared to pentobarbital or secobarbital. spiro-barbiturate is required to produce
depression,
mg/kg of surital spiro-barbiturate
thirty
used.
of action of
and on spiro
which has slightly short is shorter acting com
This indicates that an equivalent degree
a larger dose of depression.
of
126
WOO
CHOO
LEE
TABLE 3. Mean duration of anesthesia in rabbits
Spiro-thiobarbiturate ration
and spiro-barbiturate
of depression
ing compared
in the same
to their
dosage,
have
while
almost
the
same
other barbiturates
mean
du
are longer act
thio-analogues. SUMMARY
1. Spiro thioanalogue able
period
(2'-ethyl-3',5'-dimethyl
cyclopentane)
produce
hypnotic
in rats
satisfactory and
3.
and anesthetic
acid action
and
its non
for a consider
rabbits.
2. Spiro-thiobarbiturate of depression in the same surital
thio-barbituric
and spiro-barbiturate have almost the same dose in the above species of animals.
Spiro-thiobarbiturate ; spiro-barbiturate
has has
a shorter
a shorter
action action
than
than
that
that
duration
of thiopental
of pentobarbital
and and
secobarbital. 4. logues
In general, but they
thio-barbiturates are
longer
are
acting
shorter
in growing
acting
rats
than
their
non-thioana
on the basis of the same dosage
of 30 mg/kg. Acknowledgement. Orth
of the
It is a great
Department
School for his suggestion
pleasure
to record
of Pharmacology, and help
throughout
my indebtedness
University
to Prof. O.S.
of Wisconsin
Medical
this work.
REFERENCES 1) STOELTING,V. K., GRAF, J. P. AND THEYE, R. A.: J. Indiana State Med. Assoc. 43, 477 (1950) 2) A preliminary report of this investigation was made at third fall meeting of the Ameri can Soc. for Pharmacol. and Exper. Therap., Omaha, Nebraska, October 15-17, 1951 -3) FITCH , R. H. AND TATUM, A. L.: J. Pharmacol. & Expe: Therap. 44, 325 (1932) 4) SWANSON,E. E., MUELLER,L. B., HENDERSON,F. G. AND CHEN, K. K.: Current Re searches in Anesth. and Analgesia 29, 89 (1950)
COMPARATIVE
DEPRESSION
BARBITURATES
OF
AND
SEVERAL
SHORT
ACTING
SPIRO-BARBITURATES
WOO CHOO LEE* Department of Pharmacology,SeveranceUnion MedicalCollege, Seoul,Korea Received for publication October 8, 1952
In an effort to develop new and possibly better types of barbiturates, suitable for intravenous use, a large number of spiro-barbiturates have been prepared by a ring closure on the 5-carbon atom of the barbituric acid and afforded for pharmacologic study. Spiro(2'-ethyl-3',5'-dimethyl cyclopentane) thio-barbituric acid appears to be the most promising product of a series of 50 analogues. Stoelting et al.(1) reported the anesthetic and hypnotic proper ties of this compound in laboratory animals and the satisfactory clinical appli cation for anesthesia in fifty patients. The present report (2) deals with the study of the duration of depression of this new spiro-thiobarbituric acid and its non-thioanalogue**. For the purpose of brevity, spiro-thiobarbiturate and spiro-barbiturate will be used in this report instead of the long chemical name. The comparative results of depression of these new compounds and a well known short acting barbiturate seemed necessary and of interest. Pentobarbital and its thio-analogue, thiopental, are well known barbiturates, thus should serve admirably as a standard by which to judge the new barbiturates. Secobarbital and its thio-analogue, surital (thioamytal), are also included in this comparative study because of their similar depressive potency in the pentobarbital series. METHOD AND RESULTS The experimental barbiturates, constant
volume
drug
would
sary
to compare
as those chosen
work
dissolved
at a constant
give a longer
Introduced of Tokyo, Supplied
these
through
the
For
courtesy
Professor
rabbits.
sixty
seconds. than
purpose,
Research
salts
As a large
Faculty Laboratories,
in a
dose of one
dose, it is neces
by using doses
of the
intravenously
a smaller
and thiopental
of Pharmacology,
of Eli Lilly
Sodium
injected
as determined this
of pentobarbital
by Y. Kobayashi, Tokyo, Japan.
and were
of depression
of action
drug.
doses
on rats water,
rate within
period
the periods
of the standard because
was done
in distilled
same
doses
of 20-30 mg/kg
the
were
are usually
of Medicine, Indianapolis,
employed
University U.S.A.
124
WOO CHOO LEE
in experiments with a fair degree of safety. In addition, they produce a pro found sleep which permits accurate determination of the duration of action. Following a single administration, both species of animals remained satis factorily anesthetized for a considerable period and recovered fairly promptly and completely. The duration of anesthesia, corresponding to the duration of action in the experiment of Fitch and Tatum(3), has been measured in minutes from the end of injection until the animals resumed their normal posture. I. Experiment; on rats Rats were divided into two groups, growing and mature. The growing rats had initial weights of between 80 and 115 gm with an average of 99 gm and final weights during the twenty day experimental period of between 95 and 170 gm, average 120 gm. The mature rats weighed between 250 and 390 gm, average 325 gm. Table1 shows the mean duration of anesthesia in growing and mature rats receiving 20, 25 and 30 mg/kg of the six drugs into tail vein. The duration of anesthesia of spiro-thiobarbiturate in both groups is clearly shorter than that
of thiopental
of the former
or
has
surital
almost
the
of the latter.
Spiro-barbiturate
pentobarbital barbiturate,
or secobarbital. however, is still
on
the basis
same
duration
has similarly
of the same of action a shorter
dosage.
Thirty
mg/kg
as twenty
mg/kg
of each
duration
of anesthesia
The duration of action of thirty mg/kg of spiro shorter than that of twenty mg/kg of pentobarbital
TABLE 1. Mean duration of anesthesia .in rats. Twenty days experimental period. Anesthetized every 2-3 days
4:
Initial Weights
weights
80-115; final weights
250-390 grams
than
95-110 grams
COMPARATIVE
DEPRESSION
OF BARBITURATES
125
or secobarbital. In general, secobarbital and its thio-analogue are respectively shorter acting as compared to the pentobarbital and its thio-analogue. It is interesting to note that in growing rats at the specific dosage of 30 mg/kg, the relative activity (and for most drugs the absolute duration of action) of the thio-derivative is larger than the non-thioanalogue and in mature rats much like other mammals, thio-barbiturates are. shorter acting than their non thioanalogue. As shown in Table 2, in growing rats, thiopental has a longer action than spiro-barbiturate; surital for the immature rats has almost the same duration of action as secobarbital. Chen and his coworkers (4) reported that thio-barbiturates have a longer action than non-thiobarbiturates in rats and apparently the rat does not metabolize thio-barbiturates as readily as do the dog and man. The above experimental data, however, shows that the thio barbiturate is longer acting only in growing rats at a specific dosage of thirty mg per kg of body weight and is still shorter acting in mature rats, the same, as it is in higher mammals. Furthermore, Table 2 shows that growing and mature rats have a different sensitivity to thio-barbiturates and non-thiobarbi turates. In other words, thio-barbiturates have a longer action in growing rats than in mature rats; on the contrary, non-thiobarbiturates have a longer action in mature rats than growing rats. TABLE 2. Mean duration of anesthesia in rats at a dosage of 30 mg/kg Twenty days experimental period. Anesthetized every 2-3 days
** :
2.
Experiment
Mature Table
final
weights
95-170
grams
on rabbits
rabbits
3 shows
Initial weights 80-115; Weights 250-390 grams
that
weighing
between
2.1 and 3.0 kg, average
on the basis of the same
dosage,
2.5 kg, were
the mean duration
of spiro-thiobarbiturate
is clearly
shorter
than that of thiopental
or surital
the basis
an equal
degree
of
mg/kg
of producing
thiobarbiturate er action than
corresponds thiopental.
to twenty Similarly
pared to pentobarbital or secobarbital. spiro-barbiturate is required to produce
depression,
mg/kg of surital spiro-barbiturate
thirty
used.
of action of
and on spiro
which has slightly short is shorter acting com
This indicates that an equivalent degree
a larger dose of depression.
of
126
WOO
CHOO
LEE
TABLE 3. Mean duration of anesthesia in rabbits
Spiro-thiobarbiturate ration
and spiro-barbiturate
of depression
ing compared
in the same
to their
dosage,
have
while
almost
the
same
other barbiturates
mean
du
are longer act
thio-analogues. SUMMARY
1. Spiro thioanalogue able
period
(2'-ethyl-3',5'-dimethyl
cyclopentane)
produce
hypnotic
in rats
satisfactory and
3.
and anesthetic
acid action
and
its non
for a consider
rabbits.
2. Spiro-thiobarbiturate of depression in the same surital
thio-barbituric
and spiro-barbiturate have almost the same dose in the above species of animals.
Spiro-thiobarbiturate ; spiro-barbiturate
has has
a shorter
a shorter
action action
than
than
that
that
duration
of thiopental
of pentobarbital
and and
secobarbital. 4. logues
In general, but they
thio-barbiturates are
longer
are
acting
shorter
in growing
acting
rats
than
their
non-thioana
on the basis of the same dosage
of 30 mg/kg. Acknowledgement. Orth
of the
It is a great
Department
School for his suggestion
pleasure
to record
of Pharmacology, and help
throughout
my indebtedness
University
to Prof. O.S.
of Wisconsin
Medical
this work.
REFERENCES 1) STOELTING,V. K., GRAF, J. P. AND THEYE, R. A.: J. Indiana State Med. Assoc. 43, 477 (1950) 2) A preliminary report of this investigation was made at third fall meeting of the Ameri can Soc. for Pharmacol. and Exper. Therap., Omaha, Nebraska, October 15-17, 1951 -3) FITCH , R. H. AND TATUM, A. L.: J. Pharmacol. & Expe: Therap. 44, 325 (1932) 4) SWANSON,E. E., MUELLER,L. B., HENDERSON,F. G. AND CHEN, K. K.: Current Re searches in Anesth. and Analgesia 29, 89 (1950)