134 THE CANADIAN MEDiCAL ASSocIATION JouI.Ai. [Aug. 1937

ASCORBIC ACID (VITAMIN C) TREATMENT OF WHOOPING COUGH*

BY M. J. ORMEROD, M.B. AND BYRON M. UNKAUF, M.D., B.Sc.(MED.)Winnipeg

WHOOPING cough is an almost universalinfectious disease, with its greatest infec-

tivity in pre-school and school children. Whilesome protection has been afforded against it byvaccination. treatment of the active diseasehas not progressed as has treatment of otherinfectious diseases such as scarlet fever anddiphtheria. Madsen' reports that, of 1,842vaccinated children, about 25 per cent escapedinfection, while of 446 non-vaccinated childrenless than 2 per cent escaped. This decidedimprovement warrants the use of vaccines, butstill leaves the infected child confronted withsome weeks of unpleasantness and a not incon-siderable mortality rate. According to Tice,2 inthe registration area of the United States therewere 7,518 deaths in 1934. In the years 1932-34there were 45,755 cases of whooping coughreported to the Dominion Bureau of VitalStatistics, with 1,982 deaths. Of the fatalcases over 50 per cent occur in the first yearof life. The non-fatal cases undergo a mostdisagreeable experience and lose considerabletime from studies, in the case of the school-child. The disease is characterized by spas-modic coughing and vomiting, and thisspasmodic or paroxysmal stage persists forweeks. How this paroxysmal stage originates,and why it should be so prolonged, has alwaysintrigued investigators, and various hypotheseshave been put forward. Among them is onesuggested by Brown,3 that a neurotropic toxinelaborated by the bacillus in the early catarrhalstage affects the vagus and respiratory centresand possibly the sensory nerve-endings in theupper respiratory mucosa. Fixation of thistoxin in nervous tissue would explain the com-parative failure of vaccines or convalescentserum to influence the course of the diseaseunless given in the incubation period -or earlyin the catarrhal stage. Both exo- and endo-toxins have been obtained from the Bordet-Gengou bacillus.

Ascorbic acid has been investigated by* From the Department of Physiology and Pharma-

cology, University of Manitoba, Winnipeg.

several workers from the standpoint of itsdetoxicating action. Grootton and Bezsonoff4record the results of mixing diphtheria toxinand ascorbic acid, incubating very briefly, andinjecting the mixture into guinea-pigs. Un-neutralized ascorbic acid completely destroyedthe toxic action, but this effect was one of pHand not a specific effect. Ascorbic acid neutral-ized with soda and mixed with the toxin soaltered its potency that, of four guinea-pigsreceiving 4 M.L.D. of toxin each, one survivedand the others died respectively on the 4th,6th, and 9th day. Controls injected with 4M.L.D. each of unaltered toxin all died on the2nd day. These workers, in the same paper,tested the actual bactericidal action of ascorbicacid against various bacteria by adding varyingamounts of the acid to the culture medium,bringing the mixture to a pH of. 7.0, and in-oculating with such organisms as staphylo-coccus, streptococcus, gonococcus, typhosus,Bordet-Gengou, etc. With 0.5 per cent ascorbicacid mixtures only the gonococcus and Bordet-Gengou bacillus were inhibited, as comparedwith controls. The gonococcus grew readilyin a 0.2 per cent mixture. In a percentage of0.008, ascorbic acid inhibited the growth ofthe Bordet-Gengou bacillus. Glacial acetic acidadded to the culture medium in correspondingamounts, and then neutralized, failed to affectthe growth of this bacillus.Woringer and Sala5 reported 4 cases of

whooping cough complicated by scurvy occur-ring among a series of infants treated in theirclinic. No scurvy appeared among the otherchildren, although all were on exactly the samedietary regimen. They suggest that vitamin Cis an essential part of the body's defenceagainst the Bordet-Gengou bacillus, and thatexcessive demands made in the presence ofsuch an infection may so deplete the vitaminstores of the tissues as to lead to the clinicalcondition of seurvy.Gander and Niederberger6 and Hochwald7

report the use of ascorbic acid in the treatmentof pneumonias. Pneumonia cases showed con-

.134 THE CANADIAN AhDlCALASSOCIATION JOURNAL [Aug. 1937

Aug. 19.7] ORMEROD AND OTHERS: ASCORBIC ACID 135

sistently a. deficit in vitamin C. Administrationof the vitamin produced an effect comparablewith that of specific serum. The pulse andtemperature subsided by crisis when the avita-minosis was completely relieved, as shown bybeginning urinary excretion of the ascorbicacid. When small doses of ascorbic acid weregiven, the saturation point for the vitamin was

reached slowly, and no clinical improvementwas shown until this point was reached.

Various investigators8' 9,10 have shown thatthe tissues of normal children and younganimals contain more vitamin C than those ofnormal older subjects, and that the saturationpoint, as judged by beginning urinary excre-

tion, is attained in young subjects only bymuch larger doses than relative weights wouldindicate. This suggests a greater need of vita-min C by young animals, and so a greaterstorage of it in the presence of an amplesupply.From this evidence, ascorbic acid seemed to

have possibilities in the treatment of whoopingcough, and one of us (B.M.U.) has been using

it in practice for the last two months or so.To date, we can report 9 cases, and 1 fromanother practitioner.* In each case, diagnosiswas made from a history of contact with knowncases together with personal observation of thetypical cough, vomiting and nocturnal parox-ysms. Cough plates or serological tests were

not used in this preliminary investigation.Condensed case reports follow.

DISCUSSIONThe short series of cases presented is too

small to draw any statistical conclusions, butone fact stands out. Ascorbic acid has a

definite efTect in shortening the period ofparoxysms from a matter of weeks to a matterof days. We have not checked by cough platesor otherwise in this preliminary work to seewhether the infectivity subsides simultaneouslywith the spasmodic symptoms, but are con-

tinuing with a larger series of cases in whichthese and other tests will be employed.

* Case 4. We are indebted to Dr. C. H. A. Waltonfor details of this case.

TABLE

Age Duration ofCase (years) Sex Contact Symptoms Treatment Results

1 7 days-cough reduced markedlyR.T. 6 M School 6 weeks-typical 150 mg. per day 10 days-cough disappeared

Unknown inhalations No effect2 Temperature 102 F. 3 weeks-typical sinapisms 3 days 7 days-temperature normal,

C.H. 1 ½2 M Bronchopneumonia 10 days "fever" expectorants cough reducedwhen seen at home 175 mg. daily-11 dys. 14 days-cough disappeared

3 6 days-cough reducedM.C. 12 M School 10 days-typical 200 mg. daily 13 days-only occasional night coughs

15 days-all cough absent4 over 4 weeks- 3 days-cough less, no vomiting

J.P. 6 F School typical 200 mg. daily 7 days-occasional cough5

B.O. 2½4 M Known case 2 weeks-typical 250 mg. daily 5 days-cough disappeared6 4 days-cough less

H.F. 7 M School 2 weeks-typical 375 mg. daily 9 days-night cough only11 days-all cough absent

7 Maid 4 dys., paroxysmal 500 mg. daily-3 days 4 days-cough less, no vomitingE.H. 22 Child in house had cough, vomited 125 mg. daily 6 days-coughed only once in 2 days

whooping cough once, no whooping 11 days-cough absent

8 500 mg. daily-4 daysB.P. 4 M Known case 10 days-typical 250 mg. daily-4 days 5 days-cough disappeared9 500 mg. daily-4 days 4 days-cough reduced

M.W. 6½ F School 2 weeks-typical 250 mg. daily-5 days 7 days-coughed once in 24 hours9 days-cough disappeared

10 500 mg. daily-4 daysW. 4½2 F Sister (Case 9) 1 week-typical 250 mg. daily- 5,days Same as for Case 9C. . ._._.

ORMEROD AND OTHIMS: AscoRBic ACID 135AUg. 1937 1

136 THE CANADIAN MEDICAL ASSOCIATION JOURNAL [Aug. 1937

The dosages used have been empirical, witha tendency to use larger doses early in thedisease as our experience of its effects pro-gressed. The acid is available at reasonableprices, and the danger of overdosage seemsnegligible. Animals have received 2,000 timestheir estimated requirements without any dele-terious effects. Any excess is excreted by thekidneys.

CONCLUSIONS1. A method has been described for the treat-

ment of whooping cough by ascorbic acid(vitamin C).

2. Ascorbic acid definitely shortens the par-oxysmal stage of the disease, particularly ifrelatively large doses are used early in thedisease.

The ascorbic acid used by us was the Hoffmann-LaRoche product sold under the trade name of "Red-

oxon". Grootton and Bezsonoff4 have shown that thisproduct is identical chemically, physically and biologicallywith the original product prepared by Szent-Gyorgi.

REFERENCES1. MADSEN, T.: Vaccination against whooping cough, J.

Am. M. Ass., 1933, 101: 187.2. TICE, F.: Internat. Med. Digest, 1936, 29: 121.3. BROWN, H. H.: Whooping cough, Clin. J., 1936, 65:

246.4. GROOTTON, 0. AND BEZSONOFF, N.: Action de la vita-

mine C sur la toxine dipht6rique, et sensibilitM dubacille de la coqueluche vis-a-vis de lPhydroquinolet de le vitamine C, Ann. de l'Inst. Pasteur, 1936,56: 413.

5. WORINGER, P. AND SALA, T.: Rev. frang. de Pdd., 1928,4: 809. (Quoted by Grootton and Bezsonoff).

6. GANDER, J. AND NIEDERBERGER, W.: Vitamin C In derPneumonie-Behandlung., Miinch. med. Wchschr.,1936, 83: 2074.

7. HOCHWALD, A.: Beobachtungen tiber Ascorbinsaure-wirkung bei der krupposen Pneumonie, Wien. Arch.f. inn. Med., (in press). (Quoted by Gander andNiederberger).

8. EVERSON, G. J. AND DANIELS, A. L.: Vitamin C studieswith children of pre-school age, J. Nutrit., 1936,12: 15.

9. BESSEY, 0. A. AND KING, C. G.: The distribution ofvitamin C in plant and animal tissues and Itsdetermination, J. Biol. Chem., 1933, 103: 687.

10. YAVORSKY, M., ALMADEN, P. AND KING, C. G.: Vitamincontent of human tissues, J. Biol. Chem., 1934, 106:525.

CHANGES IN CONDITIONED RESPONSES BROUGHT ABOUT BYANA.STHETICS AND SEDATIVES*

BY SIMON DWORKIN, WESLEY BOURNE AND BERNARD B. RAGINSKYMontreal

pAVLOV7 (1927) and his co-workers first ob-served that conditioned salivary reflexes

could be modified by drugs like alcohol, caffeine,chloral hydrate and bromide. Recently Wolffand Gantt8 (1935) studied the effects of amytalupon conditioned salivary secretion. The objectof the present research was to extend the workto conditioned alimentary-motor responses ofdogs and cats. From this viewpoint we havere-investigated the influence of alcohol and ofamytal, and tested several new drugs, namelynembutal, avertin, paraldehyde, bulbocapnine,carbon dioxide, ethylene, nitrous oxide, morphia,and hyoscine.Two dogs and two cats served as subjects.

The dogs received sodium amytal and nembutalintravenously, avertin per rectum, alcohol andparaldehyde by stomach tube, and morphia,hyoscine and bulbocapnine subcutaneously. Thegaseous anaesthetics were administered to thecats under a bell jar. We naturally waited forfull recovery from one drug before we adminis-tered a new drug or even a different dose of thesame drug.

* From the Department of Physiology, McGill Uni-versitv.

The general procedure for establishing conditionedreflexes is by now well known. The measured and re-corded response may be salivary secretion or any othereasily observed reaction (cf. Liddell, 1934).

In our work a lid-lifting response was used. Thisparticular training procedure was described by Dworkin2(1935). The stimuli selected comprised auditory, visualand tactile signals. The successive tests were made atintervals of 2 to 6 minutes. During these intervals theanimals had been trained not to touch the lid of thefood container. Consistent absence of response betweenstimuli, eventually developed by training, may be called"interval inhibition" (Fig. 1A). The animals werealso trained to make two discriminations, (1) betweentwo different buzzers-"coarse" discrimination, (2) be-tween a loud and a quiet musical tone of fixed frequency--"fine" discrimination. The time of incidence of thesignals, as well as that of the animals' response, wasrecorded graphically. Thus we had information as tothe latent period, presence or absence of conditionedresponse, duration of conditioned and unconditionedphases, and finally the amount of interval inhibition.

The latent period of the positive responses variedbetween 1 and 3 seconds. Often it was just as shortfor a visual as for a tactile or auditory stimulus.Nevertheless, a loud sound usually evoked a responsesooner than a quiet sound; similarly, the latent periodfor a strong light was often shorter than for a weaklight. When a negative stimulus was turned on fordifferentiation there was at times a slight turning of thehead away from the food container, and other signs ofgeneral irritation, but no attempt to raise the lid (seeFig. 1B).

RESULTSOur observations indicate that the eleven

drugs tested may be classed into three main