ings were slightly higher. Brendle’* reports a
lower T, at altitude. He attributed this effect,
however, to a colder temperature at altitude and
the fact that the subjects were well-insulated by
protective clothing which prevented stimuli from
skin receptors to increase heat production, while
cooling was increased via the respiratory tract.
However, Weihe** reports that body heat regu-
latory mechanisms are undisturbed at high alti-
tudes. T, with placebo remained fairly constant
throughout the experiments (Fig. 6). Both drug
groups, however, showed an increase in T,
through time which might be indicative of an
increase in vasoconstriction, thereby conserving
heat. Antihistamines have the ability to block
the dilating action of histamine on vascular
smooth muscle. Initial T, readings for drug A
subjects were higher, and for the drug B group
were lower, than with the placebo, although
compound B responses compared with placebo
responses showed no significant effects. The
cause for the higher readings for compound A
could be due to increased metabolism or periph-
eral vasoconstriction greater than with placebo
or compound B. The phenylephrine in com-
pound A is an effective vasoconstrictor although
its effects are transient unless the drug is repeat-
edly administered.* Phenindamine is known to
increase metabolic rate in rats and to increase
adrenaline responses in humans. Although
these measurements were not made, it appears
to be consistent with the stimulatory effects of
other parameters determined for compound A.
Phenindamine in contradistinction to other anti-
histamines, which are sedatives, is an excitant to
humans.’*

On the performance test the total response
with drug A was somewhat poorer than with
the placebo, but not significantly so. Drug B,
however, when compared with placebo produced
significantly longer response-time scores (Fig. 7).
The performance of subjects at higher altitudes
was poorer than those at ground level, and the

performance of those individuals using drug B
was significantly poorer than the performance
of those receiving the placebo. However, the
decrement for the combined effects was greater
than the sum of the decrement of the two (Fig.
7). There was, then, a synergistic effect, so that
performance under both drug B and 14,000 foot
altitude conditions was poorer than the sum of
the two separate influences. Wagner,” in a
study of the effects of 28 different antihistamines
on performance, recommended that individuals
taking pheniramine (a chemical compound closely
related to chlorpheniramine found in drug B)
should not drive a vehicle because of the impair-
ment of performance caused by the drug. How-
ever, there were no objections to the use of
phenindamine (found in drug A) in small doses
since it did not show an impairment in perform-
ance. Although our study revealed no significant
decrement of performance by those individuals
who received the compound containing pheninda-
mine, it did produce some undesirable side-effects.
Three of the subjects who received compound A
experienced a short-term loss of consciousness,
and several others reported symptoms such as
feeling “uneasy,” “jumpy,” or “jittery.”

Vv. Summary.

In a study of 45 human subjects it was deter-
mined that a compound drug containing the
antihistamine phenindamine did not statistically
impair performance on a modified Mashburn
coordinator. Another compound, containing the
antihistamine chlorpheniramine, did impair per-
formance. Performance also was impaired by
increasing altitudes. The combined effects of
chlorpheniramine compound and increased alti-
tude proved more detrimental to performance
than the sum of the decrements that each influ-
ence caused when encountered separately. Al-
though no performance change was demonstrated
as a result of administering the phenindamine
compound, undesirable side-effects were noted.



Op SATURATION

98r

rs

& 96

5

& 94F

n

5 92b

3)

ii 907 5
oe oe

GROUND 10,000 14,000
LEVEL FT. FT.

Frauen 3, Oxygen saturation expressed as percentage saturation for three altitudes. Reported as means plus or
minus standard error.

O2 SATURATION

100
o—* DRUG A
o--° PLACEBO
98F
-— =e f= —J GROUND
o6b poste ate <Je== = § ==} LEVEL
7] a 10,000
94bt ~~] FEET

—

oe a
L -L-4LL

o2h
XS I I
90F ~~ tot feer

88F

PERCENT SATURATION

1 1 L nN

4 4
te) 10 20 30 40 50 60
TIME (MIN.)

Ficure 4. Oxygen saturation for drug A and placebo expressed as percentage saturation for three altitudes.
Reported as means plus oF minus standard error.

7



Figure 1. Modified Mashburn Coordinator.

5



e

Po

i

a

@

10.

BIBLIOGRAPHY

DrParma, J. R., Ed.: Drill’s Pharmacology in Medi-
cine, pp. 763-782, McGraw-Hill, New York, 1965.
MovELL, W., Ed.: Drugs of Choice, pp. 487-491, C. V.
Mosley Co., St. Louis, 1966.

. GamBINo, S. R. and H. Scuremer: A Two Minute

Assay Technique for pH and Pco, Utilizing an
Ultramicro pH/Pco, Electrode. Am. J. Clin. Path.
45 (6) : 772-774, 1966.

. Frorica, V.: An Improved Semi-Automated Proce-

dure for Fluorometric Determination of Plasma
Catecholamines. Clin. Chem. Act., 12: 191-197, 1965.

. MeLton, A. W.: The Selection of Pilots by Means

of Psychomotor Tests,
1944,
O'Connor,
Hypoxia and Performance Decrement,
No. AM 66-15, 1966.

Winer, B. J.: Statistical Principles in Experimental
Design. McGraw-Hill, New York, 1962, ,
CunnincuaM, W. L., E. J, Becker, and F. Kreuzer:
Catecholamines in Plasma and Urine at High Alti-
tude. J. Appl. Physiol., 20: 607-610, 1965,

Aviation Med., 15: 116-123,

W. F., J. Scow and G. PENnperckass:
OAM Report

. Moncroa, F., M. Gomez and A. Hurrapo: Plasma

Catecholamines at High Altitude. J. Appl. Physiol.,
20: 1329-1331, 1965.

Unvenat, F., W. R. SmirH and B. E. WeELcH: Ste-
roid and Catecholamine Studies on Pilots During

11.

12,

13,

14,

15.

16.

17.

Prolonged Experiments in a Space Cabin Simulator.
J. Appl. Physiol., 18 : 1257-1263, 1963.

Von Muratr, A.: “Introduction” in The Physiologi-
cal Effects of High Altitude, Edited by W. H. Weihe,
p. xix, The MacMillan Co., New York, 1964,

Brenvet, W.: Ampassung von Atmung, Himoglobin,
Kérpertemperatur und Kreislauf bei langfristigem
Aufenthalt in grossen Hthen (Himalaya). Pfiligers
Archiv., 263 : 227-252, 1956,

Werne, W. H.: “Some Examples of Endocrine and
Metabolic Functions in Rats During Acclimatization
to High Altitude” in The Physiological Effects of
High Altitude, Edited by W. H. Weihe, p. 35, The
MacMillan Co., New York, 1964,

Gottman, A., Ed.: Pharmacology and Therapeutics,
p. 425, Lea and Febiger, Philadelphia, 1962.

Kassiza, O. J. and M. Paarsoren: Chlorprophen-
pyridamine and Phenindamine—Effect on Increased
Oxygen Consumption Produced by Adrenaline. Ann.
Med. Hzper. et Biol. Fenniae., 32: 230-234, 1954.

Conen, M. B., H. B. Davies and W. A. Mowsry:
Thephorin in Allergy—-A Study of 292 Cases. Am.
J. Med., 5: 44-47, 1948,

Wacner, H. J.: Review of Performance Under the
Effects of Various Antihistamines. Arzneimittel-
forschung, 12: 1065-1070, 1962.


p
7.387

H
7.365
7.345
7.325
O 60

4 a
te) 3
TIME (MIN.)

po

pCO2

44.0-
o 42.0F
a
i=
E 40.0+
38.0 l
_d 6 ft

0 30 60
TIME (MIN.)

Figure 2, pH and Poo, expressed as a function of time. Reported as means plus or minus standard error.

6


AM 68-15

EFFECTS OF TWO ANTIHISTAMINE-CONTAINING
COMPOUNDS
UPON PERFORMANCE AT THREE ALTITUDES

E. Arnold Higgins, Ph.D.
Audie W. Davis, Jr., M.D.
Vincent Fiorica, Ph.D.

P. F. Iampietro, Ph.D.
John A. Vaughan, B.S.
and
Gordon E. Funkhouser, B.A.

Approved by Released by
J. Rozerr Ditiz, M.D. P. V. Srzcer, M.D.
Cuter, Crvrm AEROMEDICAL Fevers, Air SurGEON
INstIruT
June 1968

DEPARTMENT OF TRANSPORTATION

FEDERAL AVIATION ADMINISTRATION
Office of Aviation Medicine



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O2 SATURATION

{titted g

O 10 20 30 40 50 60
TIME (MIN.)

Fioure 5. Oxygen saturation expressed as percentage saturation as a function of time. Reported as means plus
or minus standard error.

94,

92

90

x

PERCENT SATURATION

RECTAL TEMPERATURE °C
37.30

37.20 p IJ] DRUG A

_---%) DRUG B
x xo

37.10 | ° aol — Jo — | pLaceso
prev

37.00

—

T

36.90

DEGREES CENTIGRADE

{ 1 1 1 it it it J

fe) 10 20 30 40 50 60
TIME (MIN.)

Fieure 6. Rectal temperature in degrees Centigrade expressed as a function of time for the two drugs and
placebo. Reported as means plus or minus standard error.

8


Fiaure 1, Modified Mashburn Coordinator.

5



of variance for repeated measures." The main
effects were drug, altitude, and time. Student
multiple-range tests were also employed to fur-
ther test for differences.

Respiratory Rate and Plasma Catecholamines—
These parameters showed no significant differ-
ences for main effects or interactions.

Pco,—This parameter showed a significant
time effect (<.001 level) with Pco, values de-
creasing through time. There was also a signifi-
cant altitude-time interaction (<.001 level); the
higher the altitude, the greater the decrease of
Pco, as a function of time.

pH—pH showed a significant increase with
time (<.001 level). The altitude-time interac-
tion was also significant (<.001 level); the
higher the altitude, the greater the increase in
pH with time.

Heart Rate—HR was significantly higher
(<.05 level) at 14,000 feet than at the two lower
altitudes. There was also a significant time
effect (<.001 level) with HR increasing from
the initial measurement through the successive
measurement periods. Although the heart rates
for drug A were higher than for drug B and
placebo, statistical significance was not obtained.

Oxygen Saturation—This parameter was sig-
nificantly different (<.001 level) for altitude
effect; the lower the altitude the higher the O,
saturation readings. There was also a significant
time effect (<.01 level), the readings being low-
est at 30 minutes and highest at the beginning
and at the end of the experimental period. There
was also a significant altitude-time interaction
(<.001 level), The decline in oxygen saturation
with time was greatest at 14,000 feet.

Internal Temperature—A significant altitude-
time interaction (<.01 level) was obtained, with
little change at ground level and an increase
through time at the higher altitudes. Further,
there was a significant drug-altitude interaction
(<.05 level). Groups taking drugs A and B
demonstrated an increase in T, with time, but
the placebo groups demonstrated little change.

Motor Coordination—There was a significant
time effect (<.001 level) with an improvement
in performance scores through time. There was
also a significant drug effect (<.10 level), when
comparing drug B responses with placebo re-
sponses. Performance under drug B was poorer
than under the placebo. Scores for those receiv-

ing drug A were also poorer than for those re-
ceiving the placebo, but not statistically so.
Also, there was a significant altitude effect
(<.05 level) with the performance scores lower
for those at 14,000 feet than for those at ground
level.

IV. Discussion.

Where changes in catecholamines have been
described with exposure to altitude,s*?° the
studies examined longer altitude exposures than
those used here or involved acclimatization.
There were no significant catecholamine responses
seen for any effects in the short-term exposure
used in this study.

Both blood pH and Pco, showed significant
changes with time (Fig. 2). These gave a con-
sistent picture, indicating an increased hyper-
ventilation; Pco, decreased and pH increased
with time. Although RR did not reflect hyper-
ventilation, no assessments of minute-volume
changes were made. The changes in pH and
Pco, were quite marked at 10,000 feet, and were
even more produced at 14,000 feet. The data
suggest that the effects would be even greater
for higher altitudes. Von MuraltTM states that
one of the well-established facts of high altitude
physiology is the development of acapnia leading
to a respiratory alkalosis. This alkalosis, how-
ever, disappears with acclimatization.

There was a significant altitude effect for the
O, saturation measurements (Fig. 3). This ex-
pected effect showed declines in oxygen satura-
tion for each higher altitude. Oxygen saturation
measurements with drug A compared to those
with placebo demonstrated a drug effect (Fig. 4).
Although no significant differences appeared at
ground level, drug A responses declined less with
exposure to the higher altitudes than did the
responses with the placebo. Apparently drug A
enhanced the oxygen saturation ability at these
higher altitudes. It is possible that there was
an increased cardiac output with drug A. The
heart rate for drug A conditions was higher than
the placebo conditions, although the differences
were not statistically significant. There was also
a significant change through time, with time
period “30 minutes” showing the lowest O,
saturation (Fig. 5). Satisfactory explanations
for this finding are not presently apparent.

Our study shows no significant difference in
T, due to altitude, although ground level read-


RC toy4S
UsA4
Agiars

BIOLOGY ©
UBRARY

EFFECTS OF TWO ANTIHISTAMINE-CONTAINING COMPOUNDS
UPON PERFORMANCE AT THREE ALTITUDES

I. Introduction.

A number of antihistaminic compounds are
available today for symptomatic treatment of
common colds, hay fever, and allergies. Many
of these can be obtained without prescription.
Some of the antihistamines found in these com-
pounds are known to have side-effects which
might modify both psychomotor performance
and physiological function.1? Although these
drugs may not impair performance while the
individual .using them is under no stress, the
imposition of adverse environments may place
the individual in a condition where decrements
in both physiological function and psychomotor
performance occur. It is the purpose of this
study to test for synergistic effects of antihista-
mine-containing compounds and lowered at-
mospheric oxygen on psychomotor performance
and physiological response.

II. Methodology.

Forty-five healthy human male subjects (18
to 85 years old) were tested under nine experi-
mental conditions (five subjects per condition),
in combinations of three altitudes (ground level
[1,274 ft.], 10,000 ft. and 14,000 ft.) and three
drug compounds. Experiments were conducted
with conditions presented in a random sequence.

Fasted subjects were examined by a medical
monitor. Each subject was then trained on a
modified Mashburn coordination task (Fig. 1).
This task required repeated matchings of four
banks of lights with four adjacent banks of
lights. The controls for lighting the adjacent
banks were manipulated by moving hand levers
and foot pedals, with one bank each under the
control of the right hand, the left hand, the
right foot, and the left foot. Nine practice runs,
each consisting of 28 sets of matchings, were
completed to reduce learning effects. After train-
ing, each subject ingested two capsules of one of
the compounds or the placebo. Compound A

contained phenylephrine (5 mg.), phenindamine
(10 mg.), aspirin (320 mg.), and caffeine (16
mg.). Compound B contained chlorpheniramine
maleate (2 mg.), aspirin (390 mg.), and caffeine
(30 mg.). Capsule C, the placebo, was filled
with sucrose. The experimental phase was begun
1 hour after drug ingestion when the orally ad-
ministered antihistamines reach peak blood levels.
Neither the drug administered nor the chamber
altitude was revealed to the subjects.

The experimental period consisted of 1 hour
in an altitude chamber. After the prescribed
altitude was attained, respiratory rate (RR) was
measured with an impedance pneumograph across
the chest connected to a low-level DC pre-ampli-
fier; heart rate (HR) was measured with EKG
leads to the EKG pre-amplifier; and rectal tem-
perature (T,) was measured by means of a
thermistor probe inserted 10 centimeters beyond
the anal sphincter with signals transferred
through an appropriate bridge to a low-level DC
pre-amplifier. All these responses were displayed
on a Grass (Model 5C) polygraph. The oxygen
saturation measurements were assessed with a
Waters ear oximeter (Model XP-350) using the
Waters earpiece (Model XE-350). All the above
measurements were obtained each 10 minutes over
the 1-hour period.

Venous blood samples were drawn immediately
prior to ascent, at 25 to 28 minutes after ascent,
and at the end of the experimental period prior
to descent. From these samples determinations
were made of blood pH and Pco,* and plasma
catecholamines.* Performance tests were con-
ducted using the complex coordination task**
immediately after each set of physiological
measurements. Performance scores were the total
time (in seconds) required to match pre-
programmed 28 sets of lights.

IIL. Results.
The data were treated by a three-way analysis

&87



ACKNOWLEDGMENTS

The authors wish to thank Miss Mary Jo Burr, Miss Elinore Galerston,
and Mr. Russell Moses for their technical assistance in conducting this study.
We are grateful to Drs. H. L. Gibbons and R. H. Delafield for medical
coverage. We also wish to express appreciation to the Physiological Opera-
tions Section for operating the altitude chamber for this study. We also
thank Mr. Paul Costiloe of the University of Oklahoma Medical Center
Biostatistical Unit for statistical assistance.

Qualified requesters may obtain Aviation Medical Reports from Defense Documentation
Center. The general public may purchase from Clearinghouse for Federal Scientific
and Technical Information, U.S. Dept. of Commerce, Springfield, Va. 22151