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Acknowledgments

The authors wish to thank Audie W. Davis, M.D., for conductingthe preselection physical examinations and for providing sedi-cal monitoring for the study. We also thank Mr. Russell MNsesof the Stress Analysis Research Unit for the epinephrine andnorepinephrine analyses. We acknowledge the valuable assistanceof Ms. Rebecca B. Brooks of the Human Performance Research Unitfor her conduct of the Multiple Task Performance Battery. Weare also grateful to the Physiological Cperations and TrainingSection for their excellent support in operating the CAMI ResearchAltitude Chamber for this study. Additional chamber operatorswere provided by the Air Training Cc'mand, U.S. Air Force.

4S., .

Technical kepert Dcumentetien Page

2. Goeronment Accession No. 3. Recipient's Catalog No.

4- Til an •wt~l S. Report Date

FECTS OFALTITUDI. AND ]OJCONGESTANTx'Work6. Perfwrming orgrniTation Clde

•* CTIONS AND F OMNE tM

S• . " we 10, w.,•-•

FAA Civil oeroeedical Institute tP.O. Box 25082 f 1. Contfh•pton s rant Noe

Oklahoma City, Oklahoma 73125 B ia

re. ponsrted lgeast su je tie at en i en s withes Ayp and Rre tesowth lactose . Sig ifi

Office of Aviation Medicine i r n ce g t aFederal Aviation Adminostratsio f a r or t o va e800 Independence Avenue, S.W. 14. firnsoe seg A.. odJU 9 19711Washinrtonb D.C. 20591

Work was performed under Tasks AM-A-77-PHY-100 and AMpAb77-PSY 65a

Fogive n were studied to determine the combined effects of two altitudes(ground level (1,274 ft) and 12,500 wit, and three preparations dactose placebo,SCompound A (ActL-ed ® ,and Compound B (Drist~an 0 )}.

Physologsical dath a sho that A was a stimulant and B a depressanth . Subjectsreported least subjectil e attlentveness with A and greatest with lactose. Signifn-ctnt time effects were evident in subjective ratings (increasing fat.gue anddecreasing energy, interest, and attentiveness). The Multiple Task PerformanceBatt~ery (MTPB) showed no effects of altitude, drugs, or time on overall performance;

however, performance declined from the first to the second hour in several tasks,while problem solving improved. The data are compatible with reported decreasingintDerest and attentiveness; subjects enjoyed the problem-solving tasks and may havegiven those tasks preference as their levels of interest declined.

Though performance on the MTPB, with the drug doses evaluated, did not produce anychanges in the overall composite scores earned by these healthy subjects, the

results from physiological parameters and some subjective evaluations indicate thattime after ingestion and type of compound ingested are important. Declines in

A 0 energy and attentiveness 2 1/2 h after ingestion could result: in neglect ofimportant ait~hough routine tasks. Hypoxia might enhance this effect and con-sequences might be worse in subjects whose medical conditions require these drugs.

17. Key words 18. Distribution Statemen~t

Decongestants, Antihistamines, Document is available to the public throughComplex Performance, Altitude, the National Technical Information Service,Physiological Functions, and Springfield, Virginia 22161.

Biochemical Responses

19. Security Clessil. (of this report) 20. Security Clossif. (of this page) 21. No. of Page7 22. Price

Unclassified Unclassified 1

Form DOT F 1700.7 (8-72) Reproductlon of completed page authorized

L __ lo

THE EFFECTS OF ALTITUDE AND TWO DECONGESTANT-ANTIHISTAWINEPREPARATIONS ON PHYSIOLOGICAL FUNCTIONS AND PERFORMANCE

A

I. Introduction.

A number of decongestant-antihistamine preparations areavailable for symptomatic treatment of common colds, hayfever, and allergies. Many of these can be obtained withoutprescription. Some of the decongestants and antihistaminesfound in such preparations are known to have effects on bothphysiolo~ical function and performance (1,2,3). In anearlier study (5), we found that the combination of a simu-lated high altitude and a drug containing the antihistaminechlorpheniramine produced a synergistic detrimental effecton a psychomotor task.

To provide data useful for aeromedical standardsdevelopment and medical certification, this study wasdesigned to measure the combined effect of altitude andeach of two decongestant-antihistamine preparations on com-plex performance and physiological functions. The drugsevaluated were: Compound A (Actifed@ ), one of the mostfrequently prescribed medications of this type (9), con-taining 60 mg pseudoephedrine hydrochloride and 2.5 mgtriprolidine hydrochloricle; and Compound B (DristanS ),a common over-the-counter medication, containing 10 mgphenylephrine hydrochloride, 20 mg phenindamune tartrate,aspirin, caffeine, and aluminum hydroxide/magnesium car-bonate co-dried gel.

II. Methods.

Fourteen healtry male paid subjects (aged 18 to 33years) were tested in random sequence under six experi-mental conditions, vith combinations of two altitudes(ground level { 1,274 ft} and 12,500 ft) with the two drugsand a placebo of lactose. All subjects were interviewedand given physical examinations prior to selection.During the interviews subjects received a thorough explana-tion of the test procedures end purposes of the study.After selection, subjects were trained for 10 h on theCivil Aeromedical Institute (CAMI) Multiplo. Task Per-formance Battery kMTPB). After training, su'bjects reportedindividually to the laboratory twice a week (either Monday

I- . . ' ' "• •r ;- --

and Thursday or Tuesday and rriday) for 3 consecutiveweeks for the experimental sessions described in Table 1.

TABLE 1. Experiment Schedule

Mornina AfternoonTime Time Scheduled Activity

0900 1230 Report to laboratoryVoid urine, record timeExecute subjective formsInsert rectal probePlace electrodes for heart rate recording

0930 1300 Take capsules

0950- 1320- Begin ascent to preselected altitude1000 1330 Complete ascent

1000- 1330- Experiment period in altitude chamber1200 1530

1200- 1530- Begin descent to ground level,Execute subjective forms

1210 1540 Complete descent

1210 1540 Return to laboratoryCollect urine, record timeRemove probe and electrodesRelease subjects from experiment

The preexperiment and postexperiment subjective formscompleted by the subjects were the Subjective Fatigue Index(8) and a subjective nine-point rating scale for attention,energy, strain, interest, and irritability. During theexperiments heart rate (HR) was recorded continuously via

Oe chest electrodes connected to an electromagnetic taperecorder. Measurements of internal body temperature (Tre)

and blood pressure (BP) were obtained at the beginning ofthe experiment and dliring the last minute of each 15-minsegment of the experimental period. Complex performancewas measured throughout the 2-h experiment by using tha

CAMI one-man MTPB (4). The three monitoring tasks of the

2

I

NrB (red lights, green lights, and meters) were pre-sented continuously during the testing session. The other

iTPB tasks were presented in different combinations foreach 15-sin interval of the session. These tasks were:(i) tracking and arithmetic; (11) problem solving andarithmetic; (iii) problem solving and pattern identifi-catinu; (iv) tracking and pattern identification. Thesame schedule was repeated during the second hour of thetesting. The postexperimental urine collections were pre-served and later analyzed for their epinephrine (I),norepinephrine (NI,, and 17-ketogenic steroid (17-KGS)content (7).

I11. Results.

All data were subjected to analysis of variance tech-niques (6). The level considered to be statisticallysignificant was < .05.

A. Physiological Parameters.

Heart rate. Mean HR data are presented in Table 2.There were several statistically significant effects onHR: An altitude effect, with mean HR higher at 12,500 ft thanat ground level; a drug effect, with mean HR greatest withCompound A and lowest with Compound B; and an a]titude-druginteraction with the difference in HR between Compound Asessions and Compound B sessions being greater at 12,500 ft(about 8 heats per min) than at ground level (about 4beats per min). There was also a time effect; HR decreasedover the 2-h experimental period.

Internal body temperature. The mean T data arere

presented in Table 3. The mean I was significantlyre

higher at ground level than at 12,500 ft. There was alsoa drug effect with subjects having the highest mean Tre

during Compound A sessions and the lowest mean T duringre

the Compound B sessions.

Blood pressure. Blood pressure data are presentedin Table 4. The anticipated altitude effects were evidentwith systolic blood pressure (SBP) and diastolic bloodpressure (DBP) significantly greater at ground level than

3

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at 12,500 ft and pulse pressure (PIP) greater at 12,500ft. There mea a drug affect for UP only,, with Compound

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-ld Les ieattueItrcin wt envle

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level.

TANA 3. Internal lody Temperature

(in 0C)

AltatudeLGround 12,500Le"e Feet meanp

Compound A 37.29 37.22 37.26

Compound 3 37.08 37.06 37.07

Placebo 37.22 37.07 37.15

mean 37.20 37.12 37.16

&trnary hormone excretion. There were nosignificant findings fur the urinary excretion of 1. The17-KGS and ME data are proseanted in Tasles 5 and 6. Theonly drug effect was for 17-ErM with the highest meanvalues occurring when subjects took Comvund A and thelowest matn values occurring when subjects took Compound B.

B. _Colex Performance.

Performance ou the MTPB was assessed by computing twocomposite scores, one representing all tasks and onerepresevting only the wtonitoriug tasks. These scores werecalculated so that each measure froa the Individu*al tasksmade an equal contribution to the variance of the coa-posite score. Recip?3cals of the respon*e time and trackingscores were used. The composite scores were then analysedin a treatmet-by-subjects analysis of variance; altitude,drugs, and hours (first and second) within sessions were

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the three sources of variance. The mean scores associatedwith these analyses are reported in Table 7. No significantdifferences were found in the overall composite scores. Theanalysis of the monitoring composite shv*ed no significanteffects of altitude or drugs, but there was a significant(,• < .05) effect of hours, with the second hour of per-foruauce being poorer than the first.

TABUL 5. 17-Ketogenic Steroid Excretion(in Kicrograsm8 per hour)

Altitt-weGround 12,500Level Feet mom

Compound A 622 718 670

Compoud 3 436 569 503

Placebo 546 688 617

n 535 659 597

TABLZ 6. Norepinephrine Excretion(in ?denogrms per hour)

AltitudeGround 12,500Level Feet Mean

Compound A 2,100 2,005 2,053

Compound 1 2,262 1,984 2,123

Placebo 2,68A 1,944 2,314

heen 2,349 1,978 2,163

Similar analyses performed on the individual perform-ance measures ravealed only a significant effect of hours

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within sessioý 4. Red lights, meter monitoring, and tracking

were significantly poorer in the secord hour; problem-

solving solution time and problem-solving confirmationtime were significantly better during the tecond hour.

C. Subjective EValuations.

Fatigue. The only statistically significant findingfor the Subjective Fatigue Index was a time effect with allsubjects reporting greater fatigue at the ed of the experi-ment than at the beginning (p_< .01) (Table 8).

TABLE 8. Subjective Fatigue*

Pretest PosttestScore Score

Ground Level

Compound A 7.5 9.8Compound B 8.1 9.3Placebo 7.6 9.7

12,500 Feet

Compound A 8.6 10.9Compound B 7.6 9.4Placebo 7.2 10.4

Mean 7.7 9.9

* On a 20-point scale, 0 - fully refreshed, 20 =completelyexhausted.

Energy. Complementing the fatigue data, subjectsreported having less energy (p_ .01) at the end of theexperiment than at the beginning. However, there was also

a. a drug effect (kp.< .01) on reported energy levels (Table 9).Subjects reported highest energy levels after the placebosession and lowest levels sfter the session that involvedCompound A.

Strain, irritation, and interest. Table 10 pre-aents the data for strain, irritation, and interest. The

9

only statistically significcut findings were for time;subjects reported more strain, more irritation, and lessinterest from beginning to end of experiment (P. .01).

TABLE 9. Energy*

•,•Pretest PosttestScore Score

Ground Level

Compound A 4.2 3.1Compound B 4.j, 3.6Placebo 4.8 4.1

12,500 Feet

Compound A 4.0 2.5[ Compound B 4.1 3.4

Placebo 4.8 3.4

Mean

Compound A 4.1 2.8Compound B 4.1 3.5Placebo 4.8 3.8Overall 4.3 3.4

* On a 9-point scale, 0 - lowest, 9 = highest

TABLE 10. Strain, Irritation, and Interest*

Pretest PosttestScore Score

Strain 2.7 3.3

Irritation 0.6 1.4IAInterest 6.5 4.8* On a 9-point scale, 0 - lowest, 9 - highest

10

I

&xtentisene~a.. The subjects were less attentiveS.01) after the axperiment than before (Table 11). There

was also a drug effect (jp' ..05) on attentiveness, reportedattentiveness being least following Compound A sessions andgreatest following the placebo sessions.

TABLE 11. Attentiveness*

freteat Posttest

Score Score

Compound A 4.6 3.4

Compound B 4.7 4.1

Placebo 5.2 4.2

Mean 4.,8 3.9

* On a 9-point scale, 0 - lowest, 9 - highest

IV. Discussion.

The drugs used in this study caused statisticallysignificant changes in several of the parameters measured.Altitude also produced an effect. In only one parameter,HR, was there a significant drug-altitude interaccion. TheHR increase when 12,500 ft and Compound A were combinedwas greater than the sum of the HR increases for the twofactors independently.

The physiological and biochemical data, averaged over

the 2-h period, indicate that Compound A acted as astimulant and Compound B as a depressant. Heart rate, Treand the 17-KGS were highest values when subjects weretaking Compound A and lowest when they were taking Compound B.This time period covers from 1/2 to 2 1/2 h after ingestion.

The subjective evaluations were made before and afterthe test but cannot be interpreted as reflecting the averagefeelings of the subjects during the 2-h period. Subjects

: 11

iL.

reported the least energy and attentiveness when takingCompound A and the greatest when taking the placebo. Oneof the reported effects of the antihistamine components ofthese compounds is "drowsiness"; this could account for thedecline in feelings of energy and alertness.

The overall composite MTPB scores showed no effects ofaltitude, drugs, or time. However, the significant declinein performance from the first to the second hour in themonitoring composite, red light monitoring, and trackingscores and the improvement from the first to the secondhour in problem-solving solution time and problem-solvingconfirmation time may both be directly compatible with thesubjects' self-reports of increasing fatigue as well asdecreasing energy, interest, and attentiveness. Thesubjects generally reported enjoying the problem-solvingtasks more than the ceher MTPB tasks; they may thereforehave devoted more attention to problem solving as theirgeneral levels of interest and attention declined, whileallocating less attention to the more ambiguous and lessenjoyable tracking and monitoring tasks. Thus, the declinein performance on the "less enjoyable" tasks was offset byimproved performance on the "more enjoyable" tasks,resulting in no significant change in the composite score.

1For performance on the MTPB, the drugs and dosagesev&luated fn this study did not produce any significantchanges in the overall composite scores earned by otherwisehealthy subjects, although with time there were changes inthe levels of effort and attention devoted to differenttasks. However, the results from some of the physiologicalparameters and some of the subjective evaluations indicatethat the time after ingestion and the type of compound!ngeeted are important considerations. The decline inself-reported energy and. attentiveness reported 2 1/2 h Allafter ingestion could result in the neglect of importantalthough routine taskc that require some degree of concen-tration. This drug effect could be enhanced by hypoxiaand consequences might be less favorable in subjects whoseI medical condition requires the use of these drugs.

12

References

1. American Pharmaceutical Association: Handbook of Non-

prescription Drugs, Sh Ed., p. 88, Americal PharmaceuticalAssociation, Washington, 1977.

2. Di Palma, J. R., Ed.: Drill's Pharmacology f n Medicine,4th Ed., pp. 1006-1007, McGraw-Hill, New York, 1971.

3. Dukes, M. N. G., Ed.: Meylt's Side Effects of Drugs,Vol. 8, pp. 305, 407, Excerpta Medica, Amsterdam, 1975.

4. Higgins, E. A., W. D. Chiles, J. M. McKenzie, A. W. Davis;Jr., G. E. Funkhouser, A. E. Jennings, S. R. Mullen, andP. R. Fowler: Effects of Lithium Carbonate on Performanceand Biochemical Functions. FAA Office of Aviation MedicineReport No. FAA-AM-77-17, 1977.

5. Higgins, E. A., A. W. Davis, Jr., V. Fiorica, P. F. lampietro,J. A. Vaughan, and G. E. Funkhouser: Effects of TwoAntihistamine-containing Compounds Upon Performance at ThreeAltitudes. FAA Office of Aviation Medicine Report No.

6. Kirk, Roger E.: Experimental Design: frocedures for theBehavioral Sciences, pp. 237-244, Brooks/Cole PublishingCompauy, Belmont, California, 1968.

7. Melton, C. E., J. M. McKenzie, B. D. rolls, S. M. Hoffmann,and J. T. Saldivar, Jr.: Physiological Responses in AirTraffic Control Personnel: Houston Intercontinental Tower.FAA Office of Aviation Medicine Report No. FAA-AM-73-21, 1973.

8. Pearson, R. G., and G. E. Byars, Jr.: The Development andValidation of a CheLklist for Measuring Subjective Fatigue.USAF School of Aviation Medicine Report No. TR-56-115, 1956.

9. Pharmacy Times: 1976: The Top 200 Drugs. PHARMACY TIMES,43(4) :37-44, 1977.

13