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Figure 1. = This

adjustments to increasingly demanding physical
work under normal conditions and ae
states of fatigue.

PROCEDYRE

1

The experimental plan called for the evalua-
tion of work capacity under normal conditions
und at two different stages of induced phyzical
fatigue, This was accomplished by determin-
ing. the biodynamic potential. of four subjects
on a treadmill by means of ¢ Work Capacity
Test (WCT) ‘described else ” The sub-
fects were thoroughly rested and in a post
absorptive state,

Immediately following .he first test (WCT I)
the subjects ran for 60-minutes on # country
roa, attempting to cover the greatest possible
digtance during that time period, This activity
caused a certain emount of physical fatigue
which was made evident in WCT 1 adminis:
tered inimeuiately after returning from the 60-
minute nm. After another best-effort nun of
40 minutes duration the fatiguing consequences

CO, © WH 6 ATP 6 tag’*
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of the overall effort were evaluated in a final
WCT UL.

ro orld 8
years of age partici the study, Subject
A (81) was Mcollege student trained for com-
Polowed a regular inning regimen ranalng

a ir tral men,

from one to four miles three ‘ie cach week,

Subject C (32) played occasional tennis but
had not participated in physical exercises of
any signi for weeks to the

expefiments, Subject D (53), out of regular
training foe several months, ran distances of
For Subjet Ge thy two periods of coud
‘or Sul the two
munning were replaced by equivalent but more
teadily controllable work-outs on the treadmill.
During the treadmill tests pulse rate, blood
Pressure pulmonary ventilation were meas:
ured at regular intervals and the oxygen intake
and carbon dioxide output were determined at
the crest load, The total energy expenditures
during the ninning periods were estimated from
the oxygen requirements for given ninning


ExCRTISE

yt PRE soe ~ POST-
9) fo
uy ow mmm conten, \ 1 =
100)
gel fm ee ~ my a!”
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wo) due
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400
Pa — gooey — aaa
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sae reeres teereeres
wovies

3 ~ ECG obtained uri rk ta Contd ant
Pigs Kon tec during work capacity tots Spactane

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Figure 2. = Physiological date swewred ch
“ iho atime isis

Of cach successive test was lower than In the

Hous test, For this experimental subject
the values were 104, 4, and 76 U/min (BTPS)
for WCT I, If and HI, respectively.

Figure 2 also shows the test results alter
the administration of Spaftase, The subject's
functional response pattern as well as the pore
formance capacity In all throe tests were
nearly Kentical,s However, in case of Subject D
(Figuro 3) Spattaso appeared to have altered
the, pattern armen iratoy adjustment in
tesponse tu the same energy Hemo-

conditions were a tly more eco-
nomical (lower pulse’rate and pulse pressure)
and the ventilatory efficiency was certainly
improved in WCT II and IIL (less vohime of air
moved at same pevgen tequirentent). tte
subject was not only a tu perform more worl
during the 40-minute run, but also demon.
stfatcd a considerable improvement of work
capacity in the last test,

The essential performance data of all four
subjects are shown in Table 2% Because body
weights changed consiterably during tho ex:
perimental procedure, the minute values for

wok cepecity teste im Control and Spartese
object,

maximum arygen intake (in the work capacity
tests) and for the average oxygen requirements
during the running periods were presented in
milliliters per kilogram of body weight. Since
maximum oxygen intake served as the main
performance criterion, the various work levels

attained were ex In per cent of the
oxygen intake in the first “control”
teat,

Consklering the decline of performance from

WCT Ito wrt itl as rat Soto for the
assessment fatigue,” the results
obtained in the ena tests revealed for all
four subjects, a decrease to 64-72 per cent of
the original work capacity as a consequence of
the preceding r*ysical efforts, In the Spartase
experiments the two well-trained individuals
e essentially the same

deterioration as in the “control” experiments,
The two physically bess active subjects, how.
ever, demonstrated an increase of functional
and metabolic reserves in the final test, their
tia drum oxygen intake being 33.3 for Subject
C ord 363 ml/kg for Subject D compared to
AS and 27.9 mi/ky, tespectively, in “control”

“4-


velocities.” In the treadmill experiments, the
speed and slope of the belt served as factors
for the estimation of oxygen intake and total
energy out-put.”

Considering the possibility of changes in
orthostatic tolerance due to physical fatigue,
tilt table tests were carried ont on cach subject
before the first and following the last WCT
of each experimental series, During 5 minutes
in the supine position, for 7 minutes tilted foot-
ward to 60 degrees and for 3 minutes following
the retum to the horizontal, pulse rate and
blood pressure were measured in half-minute
intervals. In addition, one-lead ECG tracings
from chest electrodes were obtained during the
tilt and exercise experiments.

After the “control” responses to this com-
plete test procedure had established, the

- .. Spartase regimen was begun, Four tablets of

250 mg potassium aspartate and 250 mg mag-
nesiim aspartate cach were taken daily for
a period of one week by Subject D and for
two weeks hy the other three subjects, Then,
the entire testing procedure was repeated in
@ second series, under extemal environmental
conditions nearly identical to those of the first
series as shown in Table 1.

RESULTS

The ‘course of the entire exercise procedure
and the functional adjustments observed during
its various phases are shown by the data of
Subject B in Figure 2. The subject's cardio-
respiratory responses to the gradually incteas-
ing energy demands, the latter expressed in
amounts of oxygen required per unit of body
weight, provide a proper accounting of his
functional reserves and limitations during cach
of the Work Capacity Tests. In this partic-
ular case, the subject attained a maximum oxy-
gen intake of 44.2 ml/kg/min in the first “con-
trol” test and then worked at an estimated 86
per cent of this potential capacity during the
60-minute rin, The physical fatigue resulting
from this effort caused a considerable reduction
of work capacity in WCT II. Accordingly, the
average performance during the second steady
state period of work, running 40 minutes, was
lower than during the first peciod, The maxt-
mum oxygen intake at the end of the third
WCT was only 72 per cent of that attained
in WCT I. Although, for any given workload,
the pulmonary ventilation Increased with sccu-
mulating fatigue, the peak volume at the end

TABLE |

Y
i

‘

.

Ain YOIPERATURE BNO K..ATIVE WAQMOITY OURO THEE OUT-DOOR muNe t

ASE CXPERWENTS
dvevect c MMOITY & teu *c HUMNOITY ®
+ .
a 30 Ty ge a
. wa, a o
0 32 a) rT) re
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WCT III. The improved work capacities of
Subjects Cand D were also expressed in
greater total energy expenditures (See Table 3).
Thus, while the untrained subjects undoubtedly
benefited from the drug, the application of
Spartase in the two subjects who were trained
for peak performance in ninning appeared tu
tipset slightly the adequate adjustments for
severe physical efforts, These differences in

response were certainly not the result of train
ing or motivating factors nor, apparently, the
result of climatological factors (See Table 1)
In the case of Subject C, all experimental worb
was dene in the laboratory under controlled
environmental conditions, and in the other ex
periments temperature, humidity and solar ra-
diation were nearly the same.

TABLE 3

ESTIMATED TOTAL ENERGY EXPEMOITURE

CONTROL EXPEAMENTS

SPARTASE DPERENTS

Crew Eo, Seretion Gow Co. Ovreten
suencr teat, om, test, ta,
ay wee, toe 170 wre 10
0) rRamen 1900 to ter 190
wena t008 10.8 we we
c) Ltss— (208 10 104 “r
ob TRameo tre ur tors we
avenaes : m0 “ os 11.8
TILT TABLE TEST circulatory responses to the postural chan;

<The orthostatic tolerance tests revealed sim-
ilar reaction, patterns In all four subjects. The
group averages of blood pressure and pulse
tate, presentefl in Figure 4, show that, In the
“control” experiments, the pre-exercise tilting
from the supine osition to a 6Odegree incline
caused a slight fall of blood pressure from an
average of 124/82 to 120/83 mm Hg accom-
e by a se in pu rate from SO to, 67
ts per minute, “Alter the fatiguing exercise,
during a period of recovery, the changes were
more impressive, the blood pressure declining
from 113/83 to 93/76 mm Hg while the pulse
rate increased from 103 beats per minute to
126 as an average for the Z-minute period of
tile,
‘Thus, orthostatic tolerance appeared defin-
itely affected by physical fatigue, In the
“Spartase” experiments the peripheral netiro-

vere nearly identical, This might indicate

in both experimental situations physical fatig
had developed to an identical extent, or that
the tilt table tests were not specific enough for
detecting more subtle differences in accumu:
lated fatigue.

EGG.

Figure 5 shows a representative recordin
of the ECG taken at rest and during exercise
‘bwiore and after Spartase, There was no indi.
cation uf changes in the ECG that might be
attributable to Spartuse. :

The fatigue effect occurring with work in
cach series of tests-is apparent in r
the Oth minute tracings for WCT I and IIL
The WCT HI tracing made at a metabolic rate
of 8 times the resting level closely resembles
the peak minute tracings of WCT I made at 12
times the resting metabolic level,


63-la

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g THE MITIGATION
. OF
SH PHYSICAL FATIGUE
WITH “SPARTASE”

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AEROMEDICAL RESEARCH DIVISION

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Laborit’s work. - Respiratory center activity
during work might have been diminished be-
cause of ‘lower blood CO, content. Greater
eoonomy in the respiratory effort did occur in
the cases of Subjects -C and D, following Spar-
tase, Both subjects showed sizeable reductions
in ventilation at identical workloads, indicating
greater ventilatory efficlency since the oxygen
requirements remained the same,

The limitations of this study preclude any
‘generalizations about the anti-fatigue effects
of Spartase. However, the results, showing a
fatigue mitigating effect in some individuals,
are of sufficient interest to justify a more de
tailed study of its role in affecting respiratory
gas exchange and intermediary metabolism dur-
ing prolonged severe stress,

‘The authors gratefully acknowledge the tech-
nical assistance of Wilbur L, Smith and Kamal
Shanbour.

SUMMARY

Some experimental and clinical investigations
have shown that Spartase — the potassium and
Magnesium salts of aspartic acid — has a
inltigating effect on physical fatigue,

Tt was the of this sturdy to evaluate
the effects of the drug on the work capacity of
four men before and “Wak con of ysleally
fatiguing exercises, Work capacity was
termined on the treadimilli using the standard.
ized procedure pf gradual minute-by-minute
increases of slopo at constant walking speed.
‘The test was repeated after the subject had
been running cross-country for a period of 60
mimites, again after another such
of 40 minutes, In this way effects of fatigue
upon functional adaptability to stress became
apparent. After control data had been estab-
lished, Spartase was taken orally in recom:
mended dosages for two weeks, whereupon the
same complex testing procedure was repeated.

The performances of two well-trained in-
dividuals appeared to be unaffected by the
drug. Two other individuals, who did not train
regularly appeared to benefit from the Spartase
medication,” After Spartase these subjects ex:
pended 100-300 kilocalories of actditional cn-
ey under conditions of nearexhaustion, and
still scored considerably better on the crucial

last performance tests.

The sesults indicated that Spartase. was
effective in’ mitigating physical fatigue in un-
trained individuals engaging in stenuons work,
Tt appeared to have no effect on trained
individuals,

BIBLIOCRAPHY

1. Ratner, Sarah, Mechanium of Urea Syn-
thevs, Fed, Proc., 8:603-609, 1949,

2 Knue, C, A, Treatment of Fatigue with
Aspartic Acid Salts, Northwest Medicine
60;508, 1961.

& Vial, C, A Contribution ta the Study of
Neuromuscular Fatigue and Its Treatment
in Athletes, Paris, Imprimerie des Tour-
nelles, 1959,

4, Laborit, H., RB, Colrault, G, Gulot, Physin-
logical and Clinical Significance of Neuro-
muscular Excitability, Presse Med, 63:571-
573, 1957,

5 Thichault, M., Studies on Sports Fatigue
and Its Therapy, Bull. Mens, Soc, Med.
Mil. Franc, 52-139-149, 1958,

6. Shaw, D. L, Jr, M. A, Chesney, 1. F.
Tells, WP. * ania I Management
‘atigue:
read before Annual Meeting, noe
ian Therapeutic Society, N, Y., 1961.

7. Batke, BR. W. Ware, An Experimental
Study of “Physical Fitness” of Alr Force
Personnel, U.S, Armed Forces Medical
Journal, 10;673-688, "1939,

& ‘Henry, F. M., The Oxygen Requirement of
Walking and Running, Research Quarterly
24:169, 1953,

 Astrand, P.O. Experimental Studies of

* Physical Working Capacit in Relation to
Sex and Age, Einar Munkagaard Forlag,
Copenhagen, 1952.

-9-~


DISCUSSIONS

Improved swimming performances of rats
tseated with Spartase wer feported by Laborit,
et al, and Rosen et al." ‘The latter group
of investigators made the following ubserva-
tions: Thé performances observed in 36 con-
trol rats appeared to divide them lito two major
groups, one of lower and one of higher survival
tapabitity in endurance swimming. In another
experimentul series with 36 rats treated with
Spartase, this differentiation did not occur and
the mean swimming time of this group ex-
ceeded that of the control rats, The investi-

tors concluded that the animals of initiall

performance capacity were favorably af-
fected by this drug.

A similar response pattern seems apparcat In
this study with humans, A fatigue mitigating
effect of, Spartase was observed in the two
untrained subjects when thelr cardioresptratory
and metabolic functions were severely taxed
in extended physical efforts, After the admin-
istration of Spartase, Subjects C and D ex-
pended 100 to 300 kilocalories of additional
energy tinder conditions of near-exhaustion and
still scored considerably better in the final
performance tests, The two-trained subjects,

on the other hand, showed only slight quantit
tive changes in performance and no qualitath
changes in the fatigue pattern of function
fesponse to the test work, Whatever ro
Spartase may play in intermediary metabolist
it contributes nothing to the metabolic capabi
ity of the trained individual, Evidently, tt
trained organism has attained a point of opt
mum coordination of functional and metabo

adjustments that cannot advantageously £
affected by this drug,

We can only speculate on the mechanisir
Involved in mitigating the fatigue of the ur
trained Individuals, A Hints economical hay
tory action is a ibility suggested t
work of Laborit and others." They found
reduction of CO, in plasma and expired al
of hypercapnic dogs treated with magnesiun
and potassium aspartates, This reduction sup
posedly ocettrred as CO, and NH, were utilize:
in the ornithine cycle, In the case of Subject C
on whom lic measurements of CO,
expired alr were made, there was an indication
of reduced CO, production after the admin.
istration of Spartase. This fs shown in the dati
of Table 4. While these data are not con:
clusive, they are in the direction expected fron

TABLE 4

(EXPIRED VOLUME OF CARBON DIOXIDE

- mi/hg/min — .Sedject C
, s
wer wer n ~ wera
Min, Pre-Sp,_/ Post-Sp,Pre-Sp, 5... PosteSp, Pre-Sp, — Pos-Sp,
95 out ae 13.4 12.0 10.8
10.8 10.4 I7.6 TA] (7.2 16.4
to 24.2 24.0 26.0 23.8
4 31.2 2a9
rT) 426 40.1
~8—


fo 8 7009 —— Cone Bon,
wan Sete foe

wen
ss 3 8

VeNTiLation (oTPs?

;

WEAnT Rate
eee oe

ES)
sor avs, oes,
jet
i"
oF Wes oust, pets,
wr ‘
>

a .on he

Figure 2 ~ Physltoicl date wcured ding wrk, capeity tela In Control ond Sparta

tories of euperiments on unt
TABLE 2
we Putemesee Wig Prrtermence
. « eure .
‘} We__peet wre bet pro oeet re pest pre out oped

i

wre 040 |earlore [een |o | s04] ot.7 [eas ieas | eas loo we |

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wera 42.0 | e2.e]ene/ sen] 00 | 00]|/ ra] re0/sa0| s00] 02 | 90

Oona re oy | -+[ses}sar] or | eal] | Jane] mal oo | 00

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r ,

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were TU | 9} 400] 447 [000 | tet] ree] rey fens | 440] 200 | 108
C-om re as] [306 [906] ‘78 Tel] + | ++ jsee[sest oe | ee
wer Mas] Ms) abe MP] 0d | O6]] rae] ras] ore] moles | te
Care so] so[ ee leet ot Gi wt fara] sel est oe
¥ wim ha | ear] cee saa] 6s © i] r28} rae] are | ses] ee | Oe

DeOvideat veteen ter ely wvight, oxygen btnbe (nen, iy be Werk Copecity Tet ond
rerege Vy tng rraniog) ond purtermanee relative 10 the wart mgesity tonbmied
WET T of ie cagerencntel contest terime igen ond geet Spertecel.

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‘THE MITIGATION OF PHYSICAL FATIGUE
WITH “SPARTASE”

i i
if
i
rfl

z. i
hi
i
i

andl shee) wok wad sopertathy aa paced
physical worl apparently an essent

factor in the establishment of the rhythmic
cycle of wakefulness and sleep. It is accom-
panied by biological properties eaten good
performance capacity, igh these prop
Pies are reverie andedconlitone of ates
quate sest, man jhas long sought for physical
or chemical tgans to prevent or te

5 J

One of the drugs reputed 4o moderate phy-
sical fatigue is Spartaso® trade name for
tho potassium and magnesium salts of aspartic
acid. Aspartic actd is a non-essential glycogenic
amino acid, playing some role in protein metab-
olism where urea is the end product. It is,
acconiing to Ratner,” the speciffe nitrogen
enor in the conversion of citrulline to arginine
which occurs anaerohically in the
of magnesium tons and adencsine triphosphate
in the omithine cycle, Of possible significance

*Ntacdhun and axpartates used in thie shedy
were provided by Wyeth Laboratories as Spartass.

ter
2
Feel
38
HE
£
if
rit

Is the fact that the omithing cycle is related
to the energy producing Krebs cycle as sche-
matically shown in Figure 1,

Clinical and laboratory investigations have
indicated that potassium and magnesium aspar-
tates can te physical fatigue. KruseTM
and Vial have reported reductions in the
subjective symptoms fatigue, former
treating patients with Spertase, the latter ad-
ministering it to trained athletes.

Extensive work has been ‘reported in which
the theotome was used as a tool for

ance evaluation, The rheotome permits
muscle excitation by electric stimulation of
the proper motor nerves in designated cutan-
cous areas, or by stimulation of underlying
miscles directly. The relationship of intensi
duration curves for nerve and muscle, ‘which,
according to the investigators ts characteristic
of the fatigue state, has been shown to revert
back to normal following treatment with
“The A aves of this investigation was to
study objectively the effect of the drug on
work capacity by measuring the physiological


THE MITIGATION OF PHYSICAL FATIGUE

WITH “SPARTASE”

FRANCIS J. NAGLE, Ed.D.
BRUNO BALKE, MD.
RICHARD V. GANSLEN, Ph.D.
AUDIE W. DAVIS, JR. M.D.

Biodynamics Branch

63-12

/ Sage

FEDERAL AVIATION AGENCY
2 Aviation MEDICAL SERVICE
ROMBDICAL RESEARCH DIVISION
wit ABROMEDICAL ARSKARCIE INSTITUTE
ORLATON | oY toe OKLAHOMA


ny

i
rma

sl ysiology .
hurmavolo,

1. Stresay Phy
2. Stress Ph
3. Physical Fitness

Institute, Federal Aviation
63-12.
With

Oklahoma, CARI Re;

HE MITICATION OF PHYSICAL FATIC'

‘Civil Aeromedical Research 11
Oklahoma Ci

rman

1. Strom Physiol
3. Physical Fitness

indicated that
gnesium —
63 ply

un and maj
rate

si le lus

jabol

sal
lity to
pertae was taken orally in a

GE
Ed.D., Bruno Balke,
weeks whereu
ts

5
t
Upon funictianal

and Audie W. Davis,

s

Francis J. Nagle,
Galea, PhD.
aspartic acid salts of

lary inet
e
jects of igor

aor two

dow

in the tatermed!
in

a the
way of

Richard V.

Phanaacological and clinical observations have
efi tr
Col Aeromedical Hesearch Institute, Federal Aviation

“SPARTASE”
Jr, M.D.

si
ar
i

MD.

2. Strona Phe

wt 63-12,
WITll

UE
Francis J, Nagle, Ed.D., Bruno Balke,
Canale, PhD. and Audie W. Davis

Oblahoma City, Oklahoma. CAN Ke]
ITIGATION OF PHYSICAL FATIC!

tae

Cod Acsomedical Research Inetitute, Vederal Aviation

Ageucy, Oblabenmas

3
ze
3.
3
2?
3s
#
2
ria

were mate to evs
before and alte

wtudy attempts
capaci
ctercises Work

d treadmill test.
ey

‘worl
bor:
wy elle
nt.

6
on
fatiguing

standardize.

M.D. Richard V.
=

Jr, M.D.

“SPARTASE”



“10, Laborit, H., A. Moynier, A. Trzebski, C.

iM.

Cuiot, C. Baron, Effect of the Ionic Com-
position of the Extra ‘Cellular Medium and
the Comparable Influence of Aspartic Acid,
Aspartate of Potawium and of Glucose on
the Swimming Test of the White Rat.
Compt. Rend. Soc, Biol, 151:1383-1386,
1957.

‘Rosen, H., A, Blumenthal, 11. P, K, Agery
borg, Effects of the Potassium and Mag-

12

nesium Salts of Aspartic Acid on Metaboli.
Exhaustion, Journal of Pharmacologica
Sciences, 51:392-593, 1962,

Laborit, H., P. Niaussat, J, Jouany, 8
Weber, J. Martin, C, Baron, Action o
Potassium and Magnesium Salts of DL
Aspartic Acid on the Total Plasma CO, i
Induced Hypercapnia in the Dog. Compt
Rend. Soc, Biol, 152:1094-1097, 1958,

A COVERAMENT PRINTING OF ICE: 13 0+ TE-108