Tilt Table Test: A general vasodilating effect
of the drug was not only observed during the
exercise but also in the supine as well as in the
tilted position on the tilt table. In one of the
subjects tilting caused syncope although the con-
trol tests before and 30 hours after drug admin-
istration had shown “normal” response pattern
{see Figure 3).

Subjectively, the drug made the subjects feel
“keyed up” for about 12 hours after ingestion.
Approximately 24 hours later both individuals
experienced faint anginal sensations of short
duration.

EQUANIL

Work Capacity Test: The cardiovascular
responses to the treadmill test work was prac-
tically unaffected by doses of up to 800 mg.
The slight variations observed were similar to

those seen in repeatedly performed contro} tests.
However, with dosages above 1200 mg, either in
single or accumulated doses, a typical response
pattern appeared to become evident in all sub-
jects: at each given work load the systolic blood
pressure was 10-20 mm Hg lower than in the
controls while the diastolic blood pressure as
well as the heart rate remained essentially un-
changed. These responses are illustrated in Fig-
ure 4 which shows the relative changes of sys-
tolic pressure and heart rate from the control
resting values (systolic Bl. Pr. = 112, Heart
Rate = 42 beats/min.) for the course of the
work capacity test. The product of these relative
systolic pressure and pulse rate changes, serv-
ing as an indicator of relative changes in cardi-
ac output during exercise (*), appears to dis-
close a depressing effect of the drug on the
cardiac output. Equanil also caused a slight re-
duction of the systolic blood pressure during

RG BB
SYNCOPE
20 ‘ SYSTOLIC PR.
wy oO > Lo
85 ;
Of 90
aw
ag —
o —
80 —~- CONTROL
80 DIASTOLIC PR. ssseaee RECORDIL
Ew
ee
we
= 40
wee
Los Libtriipiisy CL LL LiLittiisrij 11
13579 1 8 13 5790 BIS
TIME IN MINUTES
Ficure 3: Effects of Recordil on cardiovascular response to passive changes of body position

(tilting footwards to 60°).

~—4—


to use this drug with cardiac patients and found
an attenuation of symptoms in four out of five
eases of recent myocardial infarct. Strausak,
Cuttier and Schmid('°) used Recordil in twenty
anginal patients to determine their tolerance to
walking on level ground and ascending steps.
60 to 90 mg were given daily for periods ap to
16 months with considerable success. Star-
cich('’) prescribed Recordi! for more than 25
cardiac patients and emphasized the lack of sig-
nificant changes in blood pressure and pulse
frequency. Epstein(’*) administered Recordil to
medical students and faculty members for peri-
ods up to 30 days with dosages ranging from
30 - 660 mg daily. He noted slight lowering of
hemoglobin levels with large dosages.

The results of this investigation, using a
rather large dose of Recordil, indicates that the
systolic and diastolic blood pressure were sig-
nificantly altered during moderate to strenuous
physical exercise. Ischemic pains, usually ex-
perienced during the later stages of the tread-
mill test, were less conspicuous in both subjects.
The syncope of subject R.G. during tilting points
to a marked peripheral vasodilation at rest as
well as during work. Mild anginal pain was ob-
served by both subjects about 24 hours after
completion of the exercise test. One might specu-
late that the syndrome arose as an over-compen-
satory reaction of the coronary vessels after the
drug effect had worn off.

The meprobamate drugs, whose general ef-
fects have been extensively discussed in the
literature(**), are known to be excellent muscle
relaxants, create drowsiness, result in some
ataxia, depress certain portions of the EEG re-
cords (particularly those nuclei associated with
the thalamus). In very tense patients with mark-
ed muscle spasms, the drugs have proven quite
useful.

The marked drop in the blood pressure after
administration of Equanil may only have been
the consequence of general muscular relaxation

in the resting state, but the persistency of lower
blood pressures during work of identical inten-
sity on the treadmill suggests an involvement of
the central nervous system. It is not improbable,
in light of the generally observed effects of the
meprobamate drugs, that the stimuli or lack of
stimuli, which became evident in the blood pres-

sure disturbances, had a thalamic-medullary
component of interest. The atypical cardiody-
namic response was the result of some obscure
effect on the vasomotor center. This could con-
ceivably have arisen at some higher level in the
central nervous system. There also seemed to be
a lack of coordination in the response to sensory
input stimuli arising in the muscles under
identical working conditions. All subjects re-
ported some motor instability during the early
stages of the treadmill test and were, at the out-
set, disinclined to work. The extent of the vaso-
motor system depression is perhaps best empha-
sized by the fact that the “activity”, even at the
most strenuous level, did not alter the blood
pressure response to work. Relatively low blood
pressure during work was persistent.

Summary and Conclusioas

Using standardized tests on the treadmill and
on the tilt table the effects of the following
analeptie and tranquilizing drugs on physica!
working capacity and on orthostatic tolerance
were investigated: Caffeine-Metrazol: A
combination of ‘this drug (in combined dosages
of .1g or .2g each) appeared to have potency
as antifatiguing medication and ergogenic aid,
accomplishing an improvement in cardiac eco-
nomy by increasing the stroke volume at a low-
ered heart rate and augmenting maximum car-
diac output as well as maximum oxygen intake.
Further investigations of this drug are war-
ranted.

Recordil: _(Flavon-7-ethyl-oxyacetate): The
physical working capacity of the subjects was
materially benefited by a dose of 200 mg of
this drug taken 4 hours before the exercise test.
The absence of localized fatigue and leg pain
supports the thesis that peripheral vasodilation
is present and effective. The psychic-excitatory
effect of Recordil could not be explained except
on the basis of some conceivable increased cere-
bral blood flow mechanism for which there is
no evidence at this time.

Equanil: One must not associate disinclina-
tion to exertion (a common effect of meproba-
mates) with potential working capacity of the
individual. Although the latter was actually not
altered even under massive doses of Equanil,
disturbances of the vasomotor system became
evident. A real hazard seemed to exist with the

—7T—



\

\
beats per minute lower than
the systoli¢ pressure about 6 - 10 mm Hg higher.
Work capacity, under the effect of the drug,
was improved: the oxygen intake at the crest
load was 57.7 ml/kg/min against 54.4 ml/kg
in the control test. In both cases the maximum
pulse rate was 188 beats per minule, the maxi-
mum systolic pressure, however, was 235 mm
Hg in the drug experiment compared to 225 mm
Hg in the control test.

the contro] test,

RECORDIL

Work Capacity Test: Four hours after in-
gestion of a single dose of 200 mg Recordil the

BLUOD PRESSURE mmHg

HEART RATE

two participants in this study reached a higher
peak load with an unusual subjective ease and
with an uncommon lack of straining symptoms.
Both subjects exceeded their maximum pulse
rate of 162 beats per minute attained in the
control tests, one reaching a final rate of 172,
the other 2 rate of 174 beats per minute. In con-
trast to the previously reported experiment
(caffeine-meirazol), in which pulse rate was
lower and systolic pressure higher throughout
the drug-test, in this series the heart rate was
slightly higher most of the time, but both the
systolic and diastolic pressure were substanti-
ally lower than in the control test (see Figure
2).

% TREADMILL SLOPE

15
MINUTES ON TREADMILL, SPEED = 91.5m/min

Ficure 2: Effects of Recordil (flavon-7-ethyl-oxyacetate) or cardio-vascular response to the

standard treadmill test.



HEART RATE

350:
J
i x
30 /
or x
/
A
8 250
2
z
oot
Y
5 200:
z 3 CONTROLS AVERAGE CONTROLS =F Equany x 4x400ma
ry w--equani © 1x1200mg
i
: |
© 150: i xt
i x let
1 ae
is ' “
: at
iooy 4 LaF PR
a
o 4 8@ 2@ 6 0 4 8 2 6 0 4 8 2 6
TEST TIME iN MINUTES
Ficune 4: Relative changes of heart rate and systolic blood pressure as functional response to

gradually increasing energy demands during three control tests and two work capacity
tests affected hy Equanil. Values are expressed as per cent changes from the resting
pulse rate of 40 beats per minute and systolic blood pressure of 112 mm Hg.

relaxed resting conditions accompanied by a
slight rise in heari rate while diastolic pressure,
on the average, did not change ‘(Table 1). The
effect of tilting on blood pressure and heart
rate was similar in both the control experiments
and when different doses of the drug were in-
gesied. As schematically indicated in Table 2,

Systolic Bl. Pr.

mm Hg

Subjects BG PR
Control 1 122 110 120 135
Control 2 120 116 122 125
Average: 121 113 121 130
Equanil:

2 x400 mg 110 108 115 114
4-5x400 mg 110 107 115 124
1 x1200 mg — 111 102 121

Taste 1:

tilting did not result in a uniform change of the
systolic blood pressure, but in almost all cases
a rise of the diastolic pressure and pulse rate
did occur. Only after administration of a large
single dose of 1200 mg the already lowered
resting systolic pressure dropped furthermore
upon tilling in the three subjects tested; ino syn-
cope was observed.

Diastolic BI. Pr. Heart Rate
mm Hg per minute
BGPR BGPR
74 77 75 71 56 54 48 62
80 73 75 75 54 58 40 66
TT 15 75 73 55 56 44 64
84 86 60 75 58 61 48 66
72 72 72 80 57 60 40 60
— 75 70 80 — 60 48 62

The effect of Equanil on blood pressure and heart rate in the supine resting state.

~5—


tendency of blood pressures to be depressed,
particularly with subjects who naturally pos-
sessed low blood pressure. These vasomotor dis-
turbances suggested central nervous system de-
pression, especially of thalamic origin.

The psychic energizing effects of benzedrine
and amphetamine compounds are well known
but the improvements in working capacity with
these substances are more often the result of
motivational factors than physiological improve-
ment. Substances which enhance capacity with-
out noticeable psychological side effects are of
great value. One must be concerned, however,
with the question of “real” improvements in
efficacy since these artificial means of unlock-
ing the individual’s reserve energy stores may
not be subject to the will.

One strongly questions the safety of people
engaged in the operation of aircraft or motor
vehicies when “sedated” by such drugs as the
meprobamates. Blood pressure depressions, as
observed, would be. aggravated by sudden
changes in posture and increased “g” forces
during aircraft maneuvers. Serious * ncidents
and fata! accidents may be precipitated by the
emotional indifference to suddenly arisi:z
problems or as a consequence of delayed cir-
culatory responses during flight maneuvers.

REFERENCES

L. Balke, 3.: Circulatory-respiratory response to physical
work. Department of the Army Quartermaster Corps:
A Symposium on Performance Capacity. February 1961.
Washington, D.C.

2. Charlier. R.: Coronary vasodilators. Permagoz Press.
1963, New York.

3. Balke, B., G. Sevelius and E. E. Phillips: Changes in
blood flow from rest to maximum exercise. The Physio
logist Vol. 4, 3:8, 1961. .

4. Hartwich, A.: Cardiazol in der aerztlichen Praxis. Wien.
med. Wschr, 87:622, 1937.

5. Graf, O.: Increase of efficiency by means of pharmaceu-
tics (stimulants) German Aviation Medicine W.W. MI,
Vo}. 11-1080, U.S. Government Printing Office. Washing-
ton 25, D. C., 1950.

6. Atzler, E., G. Lehmann and A. Szakall: Ueher die Wirk
ung des ‘Coffeins auf den Koblehydrat-und Eiweiss-Stoff-
wechsel. Arbeits-physiol. 10:30, 1939.

. Hedman, R.: The available glycogen in man. Acta Phy-
siol. Scand. 40:305, 1957.

8 Setnikar, I. and Zanolini, T.: Proprieta farmacologiche
di alcuni nuovi coronarodilatator ed in_particolare def
flavon-7-ossiacetato di-etile I] Farmaco. Ed. Sci. 14:855,
1956.

9. Tartara, A. and F. Corbetta: Prime osservazioni svllazi-
one terapeutica de un nuova coronarodilatatore di sin-
tesi: I] flavon-7-ossiacetato di-etile. Folia Cardiologica
15:539, 1956.

16. Strausak, Ay P. Cuttier and A. Schmid: Aethyl-7-oxy-
aceto-flavon ”(Recordil) in der Behandlung der Angina
pectoris and seine Wirkung auf Haemodynamik und Nie-
renfunktion. Cardiologia 34:138, 1959.

11. Starcich, R.: On the clinical action of 2 new synthetic
coronary vascdilator: Fiaven-7-ethyl oxyucetate. Minerva
Medica II: 887, 1956.

12. Epstein. Wm. L.: University of California Medical Cen-
ter, San Francisco, Personal Communication to A.
Robins and Co. Dec. 22, 1960.

13. Miller. J. G.. Frank M. Berger et. al.: Meprobamate and
other agents used in mental disturbances. Annals of the
New York Academy of Sciences. Vol. 67. pp. 671-294.
May 1957.

U.S, GOVERNMENT PRINTING OFFICE. 1964 0—732-428


4

AD Ges Fae

EFFECTS OF SOME TRANQUILIZING,
ANALEPTIC AND VASODILATING DRUGS
ON PHYSICAL WORK CAPACITY
AND ORTHOSTATIC TOLERANCE

R. V. GANSLEN
B. BALKE
F, J. NAGLE
E. E. PHILLIPS
Biodynamics Branch

63-34.

FEDERAL AVIATION AGENCY
CIVIL AEROMEDICAL RESEARCH INSTITUTE
AERONAUTICAL CENTER
OKLAHOMA CITY, OKLAHOMA
DECEMBER 1963


Systolic BL Pr.
Subjects BGPR
Control 1 -_=
Control 2 -+t-—t+

Equanil:
2 x 400 mg -_= _
5 x 400 mg -—==—+

i x 1200 mg --

i+

Tasre 2:

Duast. Bi. Pr. Heart Rate
BGPR BGPR
=+ et t++a+4+
++ tt ttt
te +t t+ 44
=+t t+ +++
+ +4 +++

Effects of Equanil on orthostatic tolerance. The direction of changes in blood pressure

and heart rate from supine to the tilted position is indicated by — (drop), + (in

crease), = (no change).

DISCUSSION

Hartwich (*) reported beneficial effects from
the ingestion of metrazol (cardiazol, pentame-
thylene tetrazol) on the work capacity of man
during the German Himalayan Expedition
(1931). According to Graf (*), this drug stimu-
lates circulation in states of severe physica!
fatigue but has no effect on performance under
normal conditions. In other experiments in
which psychomotor performance was tested, im-
provement resulted in both cases when a com-
bination of metrazol and caffeine (dose: .2g
+ .1g) was given. This combination of drugs
also had the advantage of not producing the
“sagging” after-effects frequently observed after
administration of caffeine only.

The increase of aerobic work capacity in the
experiment described in Figure 1 must have
been the result of improved cardiac dynamics.
Since oxygen intakes had remained the same at
given work loads, cardiac output was assumed
to have remained unchanged too. Therefore, the
lowering in heart rate had to be compensated
for by an increase in stroke volume. The in-
crease in systolic blood pressure — relatively
in the same order of magnitude as the decrease
in heart rate — appeared to substantiate such
postulation. The increase of the maximum oxy-
gen intake capacity (about 6 per cent above the
control test) was a consequence of the greater
maximum cardiac output derived from a larger
systolic blood volume at the maximum heart
rate.

Atzler, Lehmann and Szakall(*) have report-
ed on the role of caffeine in carbohydrate and
protein metabolism. Undoubtedly, the caffeine-

metrazol combination assists in mobilizing ener-
gy from the body stores as was also observed in
a field experiment simulating an emergency
situation: one of the author’s covered in 13
hours a distance of approximately 55 miles in
the mountains with a vertical ascent totaling
10,000 feet. This performance required an ener-
gy expenditure of about 9,000 kilocalories, of
which only 1,000 kcal were supplied by exter-
nal food intake after 3 hours of work. Since in
a well-trained athlete about 400 g of glycogen
(~ 1,600 keal) are available as energy
source(") 7,400 keal of energy must have been
supplied from mobilized {.t and/or protein
stores. Normally, even the trained organism is
not capable of working at a very high rate of
energy expenditure for a period much longer
than 2-3 hours without brief “refueling.” In
this case, caffeine-metrazol (.2g + .2g) was ad-
ministered sublingually whenever symptoms of
approaching exhaustion called for a slowing
down. Then, after awhile the pace picked up
again and the improved work capacity lasted
from 120 to 60 minutes, decreasing in duration
with the accumulation of working time. In re-
peat dosages a total of 1.0 g caffeine and 1.0 g
metrazol was consumed. Despite the deficit in
caloric balances and general fatigue recovery

was excellent and mountaineering was resumed
after an eight-hour rest period.

Flavon-7-Ethyl-oxyacetate (Recordil), when

used for the perfusion of the isolated rabbit
heart by Semikar and Zanolini (*), caused a

“marked dilatation of the coronary vessels with-

out changes in amplitude or frequency of the
beats. Tartara and Corbetta (*) were the first

—6—


EFFECTS OF SOME TRANQUILIZING, ANALEPTIC
AND VASODILATING DRUGS ON PHYSICAL WORK
CAPACITY AND ORTHOSTATIC TOLERANCE

*R. V. GANSLEN, Ph.D.
B. BALKE, M. D.
**, E. PHILLIPS, Ph.D.
F. J. NAGLE, Ed.D.

For ages, man has attempted to induce
changes of psychosomatic behavior by utilizing
plants or plant products with stimulating or se-
dating properties. Some of these products have
become such normal ingredients of daily life
that most people are no Jonger aware of their
addiction to the specific biological effects of
such chemicals as caffeine, nicotine or alcohol.
During the most recent years, drugs which had
been developed for controlling psychosomatic
disturbances of various types and origins have
become almost as popular as coffee, tobacco, or
alcohol. There can be no doubt, however, that
uncer certain conditions the individual’s sensory
and functional capacity might become affected
by such pharmaca in a way interfering with, or
being detrimental to, an important working task.

This investigation was predicated on the ba-
sis: (a) that drugs used for general therapeutic
purposes, such as the tranquilizers of the me-
probamate group, may affect the work, capacity
or efficiency of normal subjects; (b) that cer-
tain drugs, vaguely or specifically referred to
as aids to heart function in persons evidencing
cardiac insufficiency, may materially alter the
maximal working capacity of normal healthy
subjects; (c) that the biological effects of the
drugs under investigation were of such a nature
that their ingestion should be indicated or con-
tra-indicated for persons in certain occupations

such as pilots, motor vehicle operators, or for
individuals who might be subjected to extensive
physical demands.

Methods and Procedure

Five healthy male subjects in the range from
29 to 54 years participated in one or the other
phase of the experimental investigations. Two
different testing procedures were empleyed for
studying the effects of various drugs on hemo-
dynamic adjustments to stress: (a) a tilt table
test, for the assessment of orthostatic tolerance,
and (b) a treadmill test for the determination
of the aerobic work capacity and of the quality
of the functional adjustments.

Tilt Table Test

The subject assumed a supine position on a
horizontal tilt table, with the feet firmly planted
against a footboard. Straps were pulled across
the hips and across the forelegs, the head was
slightly raised on a cushion. After a state of
complete relaxation was attained, measurements
of blood pressure and heart rate were made twice
during each of 5 minutes in the supine position,
likewise during a period of 10 minutes (unless
syncope intervened) tilted footwards to a 60-
degree angle, and during 4 minutes of supine
recovery. The pulse rate count was obtained
electronically, the blood pressure by the con-
ventional auscultatory method.

From she Biodynamics Branch. Civil Aeromedical Research Institute. Oxlahoma City, Oklahoma.

Present Address: *R. V. Ganslen, McDonnell Aircraft Corp..
**E. E. Phillips, Univ. of Florida, Gainesvii

ais, Mo.

Research Supported in part by National Institute of Health, Cran “6364

—l—


Treadmill Test

The treadmill test consisted of walking at a
speed of 91.5 m/min (3.4 m-p.h.) at a grade
of 1 per cent during the first minute, at 2, 3, 4,
etc., per cent during each of the following
minutes. The cardio-vascular response to the in-
creasing metabolic demands was monitored reg-
ularly by measuring heart rate and blood pres-
sure by the conventional Korotkoff method dur-
ing the second half cf each minute.(*)

The subjects taking part in this study were
accustomed to the walking on the treadmill and
to all the laboratory procedures. They were in
such a state of training condition that repeated
but sufficiently spaced control tests elicited the
same functional responses. In order to study
the effects of a particular drug when taken rou-
tinely in several single doses during a 1 - 2
day period, the work capacity tests were ter-
minated at submaximal efforts, at pulse rates
of 160 beats per minute. In that way, two or
three tests per day were possible without ill ef-
fects on the physiological responses due to fa-
tigue.

240:
200:

160:

120.

BLOOD PRESSURE mm Hg

DIAST. BL. PR.

80:

After satisfactory control patterns had been
established, the drug of particular interest was
administered orally. The re-test then, was per-
formed after elapse of the time necessary for
the drug to become effective. The following
drugs were studied: (1) Caffeine and Metrazol
(Pentamethylenctretrasol) separately, and com-
bined in a tablet containing .2g Caffeine and .4g
Metrazol; (2) Recordil (flavon-7-ethyl oxyace-
tate), an Italian vasodilator substance,(*) in a
single dose of 200 mg; (3) Equanil (Meproba-
mate), in the clinical dose of 5 x 400 mg/day,
or in single dosages of varying amounts.

RESULTS

Caffeine-Metrazol: Preliminary experimen-
tation with either ome of the substances taken
by a well-trained subject did not reveal any
change in work capacity or in the cardiovascular
response pattern to the test work. The combina-
tion of both drugs in a single tablet, when ab-
sorbed sublingually, had the effect as shown in
Figure 1: for any given Joad during the gradu-
ally increasing test work the heart rate was 4 - 8

SUBS. 8. (57)
— conTROL

0 CAFFEINE METRAZOL
(24.49)

180

HEART RATE

Ficure 1:
expenditure.

MINUTES

Effects of caffeine-metrazol on cardiovascular response to gradually increased energy

—2—