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220
THE CANADUN MEDIcAL ASSOCIATION JOURNAL
THE CANADIAN MEDICAL ASSOCIATION JOURNAL
ON THE EXPECTORANT ACTION OF RESYL AND OTHER GUAIACOLS*
By W. FORD CONNELL, GRANT M. JOHNSTON AND ELDON M. BOYD
Kingston, Ont.
FEIV drugs are more empirically used and less
scientifically understood than expectorants.
There is no uniformly accepted definition of an
expectorant. Presumably, it is generally re-
garded as a drug which increases the production,
or the disposal, or both, of liquid secretions in
the respiratory airway. Practically nothing is
known, however, about the normal production,
composition, control, or functions of liquid secre-
tions in the respiratory airway. It is a field of
medical research which has been neglected. A
review of the common textbooks of pharmacology
and therapeutics reveals a picture of confusion,
contradiction, neglect and, in a few instances,
a candid admission of the lack of information.
Knowledge of any subject becomes concrete
and substantial only as reliable methods of in-
vestigation become available. There are few
methods, used in the study of expectorants which
cannot be criticized from one point of view or
another. Methods have been devised for the
study of disposal of pulmonary secretions, and
experiments have been reported on the effect of
drugs on ciliary movements, ".bronchial peri-
stalsis", cough, respiratory movements, and re-
absorption from the lung.6
A number of methods have been used to study
the production of pulmonary secretions.3 Rosse-
bach viewed mucus production in the exposed
tracheal mucosa. Henderson and Taylor col-
lected secretions in a calcium chloride tube from
the trachea of an anTsthetized cat held upside
down. Shilf put a calcium chloride tube into
the trachea. Vollman compared the dry weight
of the lungs with that of the liver after ad-
ministering expectorants. Since the lining of
the respiratory airway is exceedingly sensitive,
it appeared that methods involving prolonged
exposure, anesthesia, foreign bodies, and exten-
sive mutilating experiments would probably not
yield results analogous to those which obtain in
the intact body. We sought a method which
would be free of these objections.
*
From the Departments of Medicine and of Phar-
macology, Queen 's University, Kingston.
[Mar. 1940
[Mar.
1940~~~~~
METHOD
It was considered that if a drug increased
the production of secretions in the respiratory
airway it should be possible to demonstrate at
certain intervals the presence of more water in
different parts of the respiratory system. By
quickly killing an animal at a given interval
after administering a drug, quickly dissecting
out its lung and finding the water content of
the different parts, values should be yielded
which would be similar to those in the intact
animal. The finding of an increased water con-
tent would signify under these circumstances
an increased production of liquid secretions
containing more water than the tissues from
which they came and produced more rapidly
than removed. If the drug produced a patho-
logical aedema or congestion this would also
register as an increased water content. The
finding of a decreased water content would
signify the removal of watery secretions more
rapidly than formerly produced, or an inhibi-
tion of the production of secretions or a vaso-
constriction.
When cells begin to secrete more actively
-they may also receive an increased blood
supply which might of itself increase their
water content. If this physiological vaso-
dilation remained the same or decreased on
ascending through the alveolar, bronchial and
tracheal parts of the respiratory tract one
might expect to encounter an increased water
content on ascending through the same parts,
due to an increasing accumulation of secretion
within the airway. Such a finding would in-
dicate increased production and excretion of
pulmonary secretions. Increased water in the
upper respiratory tract with no change or a
decrease in the lower tract would indicate, in
the absence of vascular changes, an increased
excretion of pulmonary secretions only. No
change or a decrease in the water of the upper
tract with a diminishing water content of the
lower tract would indicate decreased produc-
Mar. 1940]
Mar. 1940] CONNELL
CONNELL
AND OTHERS:
AND OTHERS: GUAIACOLS
GUAIACOLS
221
221

tion of secretions. Increased water in the pital. These included patients with cough as-
lower tract with no cedema or congestion and sociated with acute bronchitis, bronchitis with
no change or a decrease in the water of the asthma and chronic pulmonary fibrosis. Through
upper tract would indicate decreased excretion the courtesy of Dr. Bruce Hopkins, the drug
of pulmonary secretions. was also administered to a dozen patients suf-
The method used consisted in measuring the fering from chronic pulmonary tuberculosis in
water content of three parts of the respiratory the tuberculosis section of the isolation hospital.
tract, namely the trachea, the proximal part of Without exception the drug was shown to be
the lung which consisted of or contained most free of any unpleasant side-effects. A few pa-
of the bronchial tissue, and the distal part of tients reported no subjective improvement, but
the lung which contained mostly alveolar the great majority of both tuberculous and non-
tissue. After examining several species, albino tuberculous patients noted that expectoration
rats were found most suitable for this work and was easier and freer, and that useless, irritating
a more detailed account of the technique will cough was greatly diminished. These results
be published elsewhere." When any change in were most striking, as would be expected, in
water content was encountered the data were conditions of acute bronchitis with dry, irritat-
supplemented by further histological studies to ing cough. In a number of patients with tuber-
ascertain the vascular picture. Fortunately, culosis receiving the drug the beneficial effect
the water content of the normal respiratory obtained with the dose noted above appeared to
tract was found to remain remarkably constant last only about one week. Further work is being
in a given season,1 and this facilitated detection done in these latter cases with increasing doses.
of relatively slight changes in water content Laboratory data.-Guaiacol and glycerol guai-
brought about by expectorants. acolate were dissolved in saline to 0.2 per cent
In this paper we wish to report the effect on or less and injected intraperitoneally into albino
pulmonary secretions of guaiacol and several rats in doses of from 0.066 to 6.6 mg. per kilo
guaiacol derivatives with some clinical data on (i.e., up to the minimal oral dose of guaiacol
resyl. Information on the expectorant action of the British Pharmacopoeia, 1932, per equiva-
of guaiacols is limited. According to Professor lent weight). All of the doses of both guaiacol
Gordonoff, of Berne, Switzerland, who has done and glycerol guaiacolate had the same effect on
most of the recent work on them,3' 4' 5 guaiacols lung water. Hence a summation curve repre-
stimulate excretion of pulmonary secretions. senting the changes in the water content of the
entire respiratory tract produced by the injec-
RESULTS tion of guaiacol and glycerol guaiacolate into a
total of 141 white rats was prepared and is
Most of the experiments were performed on shown in Fig. 1. It will be seen that the injec-
guaiacol and glycerol guaiacolate (Resyl-Ciba) tions produced an immediate increase in lung
which have the following structure: water during the first hour and that this in-
OCHS OCHS
crease was more or less sustained for 3 days and
returned to normal on the 4th day. In a control
--O--CH2
I group of 72 rats similarly injected, but no
CHOH guaiacol or glycerol guaiacolate given, there
\/ ~~~~~~~~~~~~I
CH20H were no appreciable variations from the initial
GUAJACOL GLYCEROL GUAIACOLATE water content.
Statistical signijicance.-It will be noted in
Guaiacol is a liquid soluble 1-80 in water, and Fig. 1 that the absolute increase in lung water
usually irritant to the stomach; glycerol guaiaco- was not marked. This fact became obvious
late is a crystalline powder, soluble 1-20 in early in these researches, and it emphasized that
water, and reported to be almost non-irritant to if the difference were to be proved significant
the stomach. large numbers of both drug-treated and control
Clinical data on resyl-0.1 g. of resyl was rats would be necessary, and that the distribu-
dissolved in sweetened water and administered tion of results in both groups must be within
by mouth 4 times a day to 20 patients on the narrow limits. For statistical purposes the
medical service of the Kingston General Hos- changes in lung water between 1 hour and 3
222
22
T-HE
TH
CANADIAN MEDICAL AssociATioN JOURNAL
CAAINMDCLASCAINJUNL[a.14 [Mar. 1940

days after injection may be considered together were also recorded with none of them statisti-
and the entire group compared with the controls cally significant.
using the statistical formulhe of Davenport and Both guaiacol and glycerol guaiacolate thus
Ekas.2 A summary of this analysis is presented increased the water content of the trachea with
either no change or small increases in the water
content of the lower respiratory tract. The
lung parenchyma of these rats appeared pinker
than normal, and histological sections revealed
an increased blood supply. The trachea was,
however, of normal colour and of an unaltered
appearance, histologically. These changes agree
with the conclusion that these drugs act as
785 " exeretotropic " expectorants, a term which we
use to designate increased excretion of pul-
10 20 30 40 50 60 70 JO W
monary secretions. The marked increase in
HOUR AER INJECTION lung water within the first hour after injection
Fig. 1.- The effect of guaiacol and glycerol also agrees with this conclusion. A curve for
guaiacolate (resyl) on the water content in grams per the tracheal water, similar to that in Fig. 1 for
100 g,. of Tat respiratory tract. The line is drawn
through means of 10 to 34 rats each. whole respiratory tract water, revealed-an even
in Table I in which it is seen that the co-efficient more marked increase in the first few hours
of reliability of the mean increases in lung water after injection. However both the trachea and
produced by these drugs is in both cases greater the whole respiratory tract contained increased
than 2, which is the minimal value indicative amounts of water for three days after injection
of a reliable mean difference. of the drugs. This long duration of the re-
action would suggest that in addition to acting
TABLE I. as exeretotropic expectorants, guaiacol and
THE STATISTICAL SIGNIFICANCE OF THE INCREASE IN glycerol' guaiacolate also act as what we may
RESPIRATORY TRACT WATER PRODUCED BY INJECTION
OF GuIACOL AND GLYCEROL GuIACOLATE. call "secretotropic" expectorants, stimulating
the production of pulmonary secretions which
Coefficien of are removed as quickly as produced. Gor-
Drug administered Mean increase reliability of
in water mean increase donoff's observations were presumably made
(g./100 g.) only within the first few hours after giving the
Guaacol. .... 1.1 3.4 drugs3' 5 in which case he may have missed
Glycerol guaiacolate. . 1.4 4.5
the evidence upon which we base our conclu-
The effect on lung fractions.-The -mean in- sion that these drugs may also be secretotropic
crease in water, in g. per 100 g. of each expectorants. Our evidence suggests, there-
fraction of the respiratory tract has been given fore, that guaiacol and glycerol guaiacolate act
in Table II. Both drugs increased most both as secretotropic and exeretotropic ex-
pectorants.
TABLE II.
THE MEAN INCREASE IN WATER CONTENT OF FRACTIONS
(uaiwcol corbonate, N.F.-Guaiacol carbonate
OF THE RESPIRATORY TRACT AFTER INJECTION OF is not a pharmaeopoeial drug but has been
GUAIACOL AND GLYCEROL GUAIACOLATE. recommended as a substitute for guaiacol be-
Increase in water cause it is tasteless. It is almost insoluble in
(g./1lOOg.) water. To investigate its expectorant action, it
Drug administered Trachea Alveolar part Bronchial part was dissolved in olive oil and injected in the
same maner as guaiacol with controls injected
Guaiacol .... 3.3 0.7 0.0
Glycerol guaiacolate 3.5 0.0 0.7 with an equivalent volume of olive oil alone.
Equivalent doses of guaiacol carbonate were
markedly the water content of the trachea and found to have the same effect on the water
both of the increases in tracheal water were content of the trachea and lungs as had guaia-
calculated.to be statistically significant. Vari- col and glycerol guaiacolate. It may be con-
able and smaller changes in; the water content cluded that guaiacol carbonate is also a
of the bronchial and alveolar parts of the lung secretotropic-exeretotropic expectorant.
Mar-. 1940]
Mar; 1940] CONNELL
CONNELL
AND OTHERS:
AND OTHERS:
Potassium gusiacolsulphonate, N.1F. - Potas-
sium guaiacolsulphonate is also recommended
as a tasteless expectorant, soluble in water.
Chemically it is different from the carbonate of
guaiacol and glycerol guaiacolate which may be
regarded as phenolic ethers; potassium guaia-
colsulphonate contains a sulphonic group sub-
stituted for one of the hydrogens in the ben-
zene ring. It also appears to differ pharmaco-
logically from the other two guaiacols. As
long ago as 1903, Knapp and Sutere and others
pointed out that this compound in moderate
doses was inactive pharmacologically. It ap-
pears to be quickly excreted unchanged in the
urine and not to be converted into guaiacol in
the body since it does not lead to an increased
urinary output of ethylsulphonates and gly-
curonates, the usual excretory combinations of
guaiacol. More recently, Gordonoff and Wyss7
have shown that guaiacol does not appear in
the lungs after giving potassium guaiaeolsul-
phonate, while it does after guaiacol, guaiacol
carbonate and guaiacol glycerol ether; they
concluded that it had no expectorant action
like that of the other three compounds.
Our conclusions correspond with those of the
European investigators, as we have been unable
to demonstrate any change in the water content
of the respiratory tract of rats following the
injection of potassiut guaiacolsulphonate. From
evidence at present available, it would appear
that this compound has no place in the thera-
peutic armamentarium.
SUMMARY
By measuring the water content of different
parts of the respiratory tract, supplemented
BRONCHIAL CANCER MIMI6S MANY DISEASES.-
Cancer of bronchial origin "like the devil, can appear
in any shape or form", that is, it mimics many dis-
eases. Because of the danger that such cancer may
go unrecognized the respiratory passages of every
patient with obscure chest s)mptoms should be ex-
amined by means of the bronchoscope and x-ray.
Some of the disorders or symptoms complained of by
their twenty-three patients diagnosed as having bron-
chial cancer were: hemorrhage, pain on swallowing,
difficult and laboured breathing, pain in the chest,
productive cough, fever, hoarseness, and pain in some
remote part (hip, groin or spine) because of spread
GUAIACOLS
GUAIACOLS 223
223
where necessary by histological studies, a method
has been offered for the study of expectorant
action.
Clinically, Resyl-Ciba has been found to be' a
guaiacol which does not disturb digestion and
which effectively aids expectoration and amelio-
rates cough.
Experimentally, guaiacol, guaiacol carbonlate
and glycerol guaiacolate (resyl) were found in
white rats to increase signifieantly the water cou.
tent of the trachea and this increase lasted over
a period of 3 days from the time of administra-
tion. In conjunction with the absence of his-
tological changes in the trachea, this evidence is
offered as indicative of both an exeretotropic
and seeretotropic expectorant action by these
compounds.
On the other hand, potassium guaiacolsul-
phonate was found to be inactive.
REFERENCES
1. BOYD, E. M. AND JOHNSTON, G. M.: Seasonal variation
in the water content of the respiratory tract, Am.
J. M. Sc. (in 'pressi.
2. DAVENPORT, C. B. AND EKAS, M. P.: Statistical
Methods in Biology, Medicine and Psychology, New
York, 1936.
3. GORDONOFF, T.: Die Expektoration, ihre Physiologie
und pharmakologische Beeinflussung, Wien. kim.
Wchnschr., 1934, 47: 137.
4. Idem: Physiologie et pharmacologie de l'expectoration,
An'nh et Bull. de la Soc. Roy. des Sc. Nat. et Med.
de Bruxelles, 1937, 7-8: 173.
5. Idem: Die Expectorationsvorgang und seine pharma-
kologische Beeinflussung, Wien. klin. Wchnschr.,
1938, 51: 289.
6. GORDONOFF, T. AND LEHMANN, J.: Ueber die Beein-
flussung der Resorptionsfahigheit der Lunge durch
Expektorantien, Zeit. f. d. ges. exp. Med., 1936, 99:
731.
7. GORDONOFF, T. AND WYSS, W. J.: Ueber das Kalium-
sulfoguaiacolicum, Zeit. f. d. ges. exp. Med., 1934,
9g: 169.
8. KNAPP, T. AND SUTER, F.: Experimentelle Unter-
suchungen tiber die Resorptions- und Ausscheid-
ungsverhaltnisse einiger Guaiacolderivate, Arch. f.
exp. Path. u. Pharmakol., 1903, 50: 332.
of the cancer. All of these are symptoms frequently
attributed to ailments far removed from cancer.
,Nine of the twenty-three patients also had a history
of a complicating infectious disease. The mimicking
symptoms of these cancers are dependent on the loca-
tion of the growth, which nmay either displace or
create pressure oni al} internal organ, thus producing
the symptoms which are so misleading. The possible
contributing causes of bronchial cancer ate chronic
inflammatory conditions, the inhalation of irritating
substances, and a hereditary susceptibility.-E. L.
Jenkinson and A. F. Hunter, in J. Am. M. Ase., 1939,
113: 2392.