boyd 1946

Prévia do material em texto

Acta Pharrnacol., 1946, 2, 235-246. 
From the Dcpartmcnt of Pharmacology, 
Quoen's University, Kingston, Canada. 
(Professor Eldon M. Boyd). 
The Effect of Qiiillaia, Seiiega, Squill, Grindelia, San- 
guinaria, Cliionanthiis arid Dioscorea upoii 
the Output of Respiratory Tract Fluid. 
BY 
Eldon M. Boyd and Mary E. Palmer. 
(lteceived 26. May 1946). 
Comparatively little is known about the pharmacology of 
expectorant drugs. This is due to a lack of interest on the part 
of the majority of those undertaking modern pharmacological 
research which, in turn, is a result of three factors. I n the first 
place, expectorants are in about the same situation as were 
chloroform and ether as anaesthetics in the latter half of the 
last century and the beginning of the present, i. e. they do 
the job they are supposed to do fairly well so why bother in- 
vestigating them or look for better ones. I n the second place, 
while physicians, pharniacologists, etc., readily agree as to 
what is meant by an expectorant, few are able to give an exact 
definition and what definitions one may obtain, either in the 
literature or verbally, are obviously tnscieatific, dogmatic, 
empirical and often one definition is the opposite of another. 
To list such definitions is not an object of this report; suffice 
it to say that from our experimental and clinical observations, 
we define an expectorant in this laboratory as a drug which 
increases the production and/or excretion of respiratory tract 
fluid (B, T. F.) and is useful in the treatment of cough; this 
is a working definition and may or may not have to be changed 
8s time goes on and further data are available. 
A third and serious obstruction to advance in the knowledge 
k t : i i l i i ~ i r i i i ~ c ~ l i ) ~ i ~ : ~ vol. 2 f'iibc. 3 3 
ANA_JULIA
Nota
ós definimos um expectorante neste laboratório como uma droga quenullAumenta a produção e / ou a excreção do trato respiratórionullFluido (B, T. F.) e é útil no tratamento da tosse; estanullÉ uma definição de trabalho e pode ou não ter que ser alteradanullO tempo de 8 horas continua e outros dados estão disponíveis.
ANA_JULIA
Nota
Uma terceira e séria obstrução para avançar no conhecimento da farmacologia de medicamentos expectorantes tem sido a falta de um método que poderia ser aplicado a animais e medida de ação expectorante com precisão razoável. Embora subjamos que elaboramos neste departamento um método que é satisfatório para os animais, reconhecemos que até agora não temos nenhum método, nenhum método cientificamente preciso, que pode ser aplicado ao homem. Há cerca de oito a dez anos, foi decidido investigar o problema anterior de forma sistemática. Métodos que foram utilizados para estudar a ação expectorante no meio século passado foram revistos e cada um descartou por uma razão ou outra. O primeiro método real experimentado foi descrito por BOYDa nd JOHNSTO (1N9 40) e consistiu em medir mudanças no conteúdo de água da traquéia e nas áreas brônquica e alveolar do pulmão. Foi aplicado a um estudo da ação expectorante de guaiacols (19), mas foi posteriormente abandonado como insatisfatório. Finalmente, um método foi concebido por PERRY e BOYD (1941), que, com as nodificações descritas posteriormente (5), consiste essencialmente na coleta de RTF através de uma cânula na traqueia de um animal decerebrado ou uretanizado, sendo o ar inalatório condicionado à temperatura corporal e saturado Com vapor de água. Para mais detalhes da técnica, pode-se fazer referência aos artigos citados e também a outros (4, 9, 11)nullnullUtilizando esta técnica, foram realizados estudos sobre a ação expectorante de creosotes e guaiacols (7), aminas simpaticomiméticas (5), éter (6), amônia (I l), cloreto de amônio e carbonato (32), ipecacuanha (32), Tymol (32), tintura de cânfora de opiuni, BP 1932 (9), iodetos inorgânicos e orgânicos (12), teofilina etilenodiamina (15), citrato de potássio (15), cloroforni (15), parasympathomimetic drugs (14, 31), volátil Óleos e bálsamos (16), sulfonamidas (13) e outros estudos estão em andamento.nullnullA presente comunicação é um relatório da aplicação da mesma técnica a um grupo de drogas que foram denominadas "saponinas expectorantes" (33) e a medicamentos relacionados conforme listado no título deste artigo. Uma vez que nem todos, de fato muito poucos, os autores concordam com a classificação dos expectorantes, ele decidiu listar, no título deste artigo, cada uma das drogas estudadas. Estes incluíram quillaia, senega, squill, grindelia, sanguinaria, chionanthus e dioscorea, utilizados na forma de tinturas ou extratos líquidos conforme indicado abaixo
236 E. M. UOYI) AND MARY E. PALMER 
of the pharmacology of expectorant drugs has been the lack 
of a method which could be applied to animals and measure 
expectorant action with reasonable accuracy. While we submit 
that we have devised in this department a method which is 
satisfactory for animals, we acknowledge that as yet we have 
no method, no scientifically accurate method, which may be 
applied to man. Some eight to ten years ago, it was decided to 
investigate the former problem systematically. Methods which 
had been used to study expectorant action in the previous 
half century or so were reviewed and each discarded for one 
reason or another. The first actual method tried was described 
by BOYD and JOHNSTON (1940) and consisted in measuring 
changes in the water content of the trachea and of the bron- 
chial and alveolar areas of the lung. It was applied to a study 
of the expectorant action of guaiacols (19), but was subsequently 
abandoned as unsatisfactory. Finally a method was devised by 
PERRY and BOYD (1941) which, with niodifications described 
subsequently (5), consists essentially in collecting R. T. F. 
through a cannula in the trachea of a decerebrate or urethanized 
animal, the inhaled air being conditioned to body temperature 
and saturated with water vapour. For further details of tech- 
nique, reference may be made to the papers cited and also to 
others (4, 9, 11). 
Using this technique, studies haqve been made upon the ex- 
pectorant action of creosotes and guaiacols ( 7 ) , sympathomi- 
metic amines (5), ether (6), ammonia ( I l ) , ammonium chloride 
and carbonate (32), ipecacuanha (32), thymol (32), camphorated 
tincture of opiuni, B. P. 1932 (9), inorganic and organic iodides 
(12), theophylline ethylenediamine (15), potassium citrate (15), 
chloroforni (15), parasympathomimetic drugs (14, 31), volatile 
oils and balsams (16), sulphonamides (13) and further studies 
are in progress. 
The present communication is a report of the application of 
the same technique to a group of drugs which have been termed 
“expectorant saponins” (33) and to related drugs as listed in 
the title of this article. Since not all, in fact very few, authors 
agree upon the classification of expectorants, it v as decided 
ANA_JULIA
Nota
A presente comunicação é um relatório da aplicação denullA mesma técnica para um grupo de drogas que foi denominadonull"Saponinas expectorantes" (33) e medicamentos relacionados, conforme listado emnullO título deste artigo. Como nem todos, de fato muito poucos, autoresnullConcordar com a classificação dos expectorantes, ele decidiu listar, no título deste artigo, cada uma das drogas estudadas.nullEstes incluíram quillaia, senega, squill, grindelia, sanguinaria,nullChionanthus e dioscorea, utilizados na forma de tinturas ounullExtratos líquidos como indicado abaixo
ANA_JULIA
Realce
ANA_JULIA
Realce
EXPECTORANT SAPONINS 237 
to list, in the title of this article, each of the drugs studied. 
These included quillaia, senega, squill, grindelia, sanguinaria, 
chionanthus and dioscorea, used in the form of tinctures or 
liquid extracts as indicated below. 
Method . 
Over 500 animals were employed, including approximately 
equal numbers of urethanized cats, decerebratecats, uretha- 
nized rabbits and urethanized guinea-pigs. About 200 of these 
animals were used in preliminary experiments to determine the 
effective dosage range, some died before sufficient data had 
been obtained and only results obtained upon the remainder 
will be described below. 
Tlw g c n c d procedure was to arrange the animals for collection of 
R. T. F. and at the end of 3 hours, when the volume output had reached 
a steady level, tlie drugs were given by stomach tube in doses of from 
0.1 to 10 ml. per kilo body weight of the respective pharmaceutical 
form, and washed down with water to a total volume of 10 ml. per kilo 
body wcight. Controls were given 5 mnl. of 60 per cent (v-v) alcohol plus 
5 ml. of water per kilo body weight. The volume output of R. T. F. 
was measured each hour for the thrctt hours before giving the drug 
and for four hours after giving the drug. To allow for differences in body 
Wright, tlie volume output was calculated as ml. of R. T. F. per kilo 
body weight per 24 hours. To simplify presentation of results and at 
the same time reduce all data to R coinmon denominator, the volume 
output of R. T. F. was averaged during the 2 hours just before giving 
the chug and then any increased output each hour after giving the 
respective drug was expressed as a percentage of this mean. Percentage 
changes in the output of R. T. F. during the last 4 hours of the experi- 
ment were averaged for rach hour and these means have been assembled 
in Tablc I. 
The composition of R. T. F. has been described in previous reports 
(8, 10, 32). An extensive chemical and physical analysis of R. T. F. was 
not feasible in the present investigation, but as an index of the effect 
of tho various drugs upon the composition of R. T. F., samples taken 
3 hours before giving a drug and 4 hours after giving a drug were sepa- 
rately pooled and, when a sufficient aliquot was available, analysed for 
their chloride content after the method of VAN SLYKE (1923). The mearis 
of all such values for R. T. F. chloride were determined and are listed 
in Table I1 for each drug in each species. 
3a, 
ANA_JULIA
Nota
Mais de 500 animais foram empregados, incluindo aproximadamentenullNúmeros iguais de gatos uretanizados, gatos decerebrados, uretanizadosnullCoelhos e cobaias urethanizadas. Cerca de 200 dessesnullOs animais foram utilizados em experimentos preliminares para determinar onullFaixa de dosagem efetiva, alguns morreram antes de dados suficientes teremnullFoi obtido e apenas resultados obtidos sobre o restantenullSerá descrito abaixo.nullO procedimento GCncd de Tlw foi organizar os animais para a coleta denullR. T. F. e no final de 3 horas, quando o volume de saída havia chegadonullUm nível constante, os medicamentos foram administrados pelo tubo de estômago em doses denull0,1 a 10 ml. Por peso corporal do respectivo produto farmacêuticonullFormar e lavar com água até um volume total de 10 ml. Por quilonullCorpo seguro. Os controles foram dados 5 mnl. De 60 por cento (v-v) álcool maisnull5 ml. De água por quilo de peso corporal. O volume de saída de R. T. F.nullFoi medido a cada hora durante as três primeiras horas antes de administrar o medicamentonullE por quatro horas depois de dar a droga. Para permitir diferenças no corponullWright, a produção de volume foi calculada como ml. De R. T. F. por quilonullPeso corporal por 24 horas. Para simplificar a apresentação dos resultados e emnullAo mesmo tempo, reduzir todos os dados para R denominador denominador, o volumenullA saída de R. T. F. foi calculada em média durante as 2 horas imediatamente antes de darnullO chug e, em seguida, qualquer aumento de saída a cada hora após dar onullO respectivo fármaco foi expresso como uma porcentagem desse significado. PercentagemnullMudanças na saída de R. T. F. durante as últimas 4 horas do experimentonullForam calculados em média para horas de piquetes e esses meios foram montadosnullEm Tablc I.
ANA_JULIA
Nota
A composição de R. T. F. foi descrita em relatórios anterioresnull(8, 10, 32). Uma extensa análise química e física de R. T. F. foinullNão é viável na presente investigação, mas como um índice do efeitonullDos vários medicamentos sobre a composição de R. T. F., amostras colhidasnull3 horas antes de administrar um medicamento e 4 horas após a administração de um medicamento foram separadasnullCombinado e, quando uma alíquota suficiente estava disponível, analisounullSeu teor de cloreto após o método de VAN SLYKE (1923). Os mearisnullDe todos esses valores para o cloreto de R. T. F. foram determinados e estão listadosnullNa Tabela I1 para cada droga em cada espécie.
238 E. M. BOYD AND MAHY E. PALMER 
Table 1 . 
The effect of expectorant saponins and related drugs upon the output 
of respiratory tract fluid. 
~ ~~ ~~ 
Number Percent increase in out- 
Animals 1stHr. 2ndHr. 3rdHr. 4thHr. 
Drug Species of put of R. T. P. 
Quillaia 
Senega 
Squill 
Grindelia 
Sanguinaria 
Chionanthus 
Dioscorea 
None (Control) Urethanized Cats 15 -29 -17 -23 -17 
None (Control) Decerebrate Cats 9 -6 -26 -22 4 
None (Control) Urethanized Rabbits 8 19 -12 22 7 
None (Control) Urethanized Guinea-pigs 12 0 21 22 -28 
Urethanized Cats 11 0 26 45 T i 
Decerebrate Cats 26 
Urethanized Rabbits 16 
Urethanized Guinea-pigs 21 
Urethanized Cats 18 
Decerebrate Cats 9 
Urethanized Rabbits 24 
Urethanized Guinea-pigs 9 
Urothanized Cats 8 
Decerebrate Cats 6 
Urethanized Rabbits 8 
Urethanized Guinea-pigs 10 
Urethanized Cats 7 
Urethanized Rabbits 10 
Urethanized Guinea-pigs 9 
Urethanized Cats 9 
Urethanized Cats 10 
Decerebrate Cats c 
3 
5 
140 
-2 
14 
-8 
21 
61 
-9 
16 
-5 
10 
31 
-5 1 
82 
22 
38 
22 
69 
40 
44 
30 
0 
63 
56 
21 
-39 
98 
79 
-3 
-31 
110 
38 
49 
39 
43 
66 
41 
173 
-4 
186 
86 
33 
-32 
146 
15 
-26 
-29 
89 
39 
146 
66 
-10 
22 
127 
93 
-4 
51 
-9 
13 
-16 
38 
1 
-3 1 
-2 1 
24 
49 
41 
R c s u I t s. 
I . Quillaia. 
Quillnia was given in the form of Tinctura Quillsiae, B. P. 
(36), of which the average dose for man is about 0.05 ml. per 
Idlo body weight. There have been several reports upon the 
expectorant action of quillnia, of which mention niay be made 
of the fo1,'owing. VOLLMER (1932) presented evidence that 
quillaia augments the output of secretions in the respiratory 
tract of guineb-pigs. GORDONOFF (1934, 1935, 1937, 1938 a, 
1938 b) conilrmed this conclusion in experiments upon man 
and further gave evidence, with LEHMAN (1936), that there is 
also increased resorption of R. T. F. in the lymphatics of the 
EXPECTORANT SAPONINS 239 
Table 2. 
Tlic cffect of expcctorant saponins and related drugs upon the chloride 
contrnt of respiratory tract fluid. 
Chloride Content (mgm per 100 ml) 
3 Hrs. before drug 4 Hrs.after drug Drug Species 
Nonc (Control) Urethanized Cats 
None (Control) Decercbrate Cats 
None (Control) Urethanized Rabbits 
None (Control) IJrethanized Guinea-pigs 
Quillaia Urethanized Cats 
Decerebrate Cats 
Urethanized Rabbits 
Urrthanized Guinea-pigs 
Scnega Urethanized Cats 
Decerebrate Cats 
Urethanized Rabbits 
Urethanized Guinea-pigs 
Squill Urethanized Cats 
Decerebrate Cats 
Urethanized Rabbits 
Urethanized Guinea-pigs 
Urethanized Rabbits 
Urethanized Guinea-pigs 
Grindelia Urethanized Cats 
Sanguinaria Urethanized Cats 
Chionanthus Urethanized Cats 
Dioscorca Decerebrate Cats 
64 73 
65 73 
52 58 
61 76 
50 25 
48 36 
52 120 
69 63 
61 36 
63 71 
57 57 
73 72 
49 41 
68 56 
52 93 
54 48 
64 163 
66 63 
79 39 
58 95 
61 33 
75 66 
lung following the drug. ALSTEAD (1940) has criticized Gor- 
donoff’s deductions from his experimental data. YOUNG (1940) 
states that quillaia is a nauseant expectorant, increasing the 
volurre of secretions inthe lung by a reflex from the stomach, 
when the drug is given by mouth. 
As shown by the data summarized in Table 1, tincture of 
quillaia was found to augment the output of R. T. F. in cats, 
rabbits and guinea-pigs to what might be classified as a mode- 
rate extent when compared with the effect of other expecto- 
rants (14). The greatest increase in the output of R.T.F. was ob- 
tained with the larger doses of the tincture-and the least in- 
creases with the smaller doses. Since the range of doses used 
240 E. M. BOYD AND MARY E. PALMER 
was a good deal higher than the recommended human dose, 
on a body weight basis, the data do not substantiate the con- 
clusion that quillaia is a useful expectorant in man. Of course, 
caution must be exercised in extrapolating to man data ob- 
tained upon animals. Quillaia had no consistent effect upon 
the chloride content of R. T. F. As shown in Table 11, in cats 
the drug produced a lowering of the chloride concentration, in 
rabbits it rose, while there was little change in guinea-pig 
R. T. F. chloride. 
Il'. Senega. 
Senega was administered by stomach tube in the forin of 
Fluidextractum Senegae, N. F. (36). The average reconmended 
dose of this preparation for man is about 0.02 ml. per kilo 
body weight. Senega is native to the United States of America 
and to Canada where it is known under various names. The 
early Europeans in North America found the plant being used 
by the Seneca Indians against the bite of the rattle-snake. 
A Scotch physician, Ur. TENNANT, suggested about 1735 the 
use of senega in pleurisy and pneumonia and from his writings 
it became popular in Europe; for example, LINNAEUS wrote 
at length upon its virtues about 1749 (21). 
The expectorant properties of Senega have been studied arid 
reported upon by several investigators. In 1896, CALVERT 
stated that senega diminished the rate of output of tracheal 
fluids from observations upon 2 cats. Fourteen years later in 
Canada, the late Professor V. E. HENDERSON and his assistant 
A. H. TAYLOR (1910) concluded that senega increased the 
output of bronchial fluids in cats, acting by way of a reflex 
from the stomach. GUNN (1927) also stated that senega was 
a reflex expectorant. YOUNG (1940) reported that senega in- 
creased the output of R. T. F. BASOH et a1 (1941) collected 
samples of fluid by bronchoscopic drainage in man and found 
in 3 subjects that senega lowered the viscosity, increased the 
total nitrogen and dry residue and had no effect upon the pH 
of this fluid. 
In the experiments, the results of which have been listed in 
ANA_JULIA
Nota
O Senega foi administrado por tubo de estômago no forin denullFluidextractum Senegae, N. F. (36). A média foi confirmadanullA dose desta preparação para o homem é de cerca de 0,02 ml. Por quilonullpeso corporal. Senega é nativa dos Estados Unidos da AméricanullE para o Canadá, onde é conhecido sob vários nomes. onullPrimeiros europeus na América do Norte descobriram que a planta estava sendo usadanullPelos índios Seneca contra a mordida da serpente de chocalho.nullUm médico escocês, Ur. TENNANT, sugeriu cerca de 1735 onullUso de senega em pleuresia e pneumonia e de seus escritosnullTornou-se popular na Europa; Por exemplo, LINNAEUS escreveunullPor fim, sobre suas virtudes em 1749 (21)
ANA_JULIA
Nota
As propriedades expectorantes do Senega foram estudadas e áridasnullRelatado por vários pesquisadores. Em 1896, CALVERTnullAfirmou que a Senega diminuiu a taxa de produção de traquealnullFluidos de observações sobre 2 gatos. Quatorze anos depois, emnullCanadá, o falecido Professor V. E. HENDERSON e seu assistentenullA. H. TAYLOR (1910) concluiu que a Senega aumentou anullSaída de fluidos brônquicos em gatos, atuando por meio de reflexonullDo estômago. GUNN (1927) também declarou que a Senega eranullUm expectorante reflexo. JOVENS (1940) relataram que Senega aumentounullA saída de R. T. F. BASOH et a1 (1941) coletadanullAmostras de fluido por drenagem broncoscópica no homem e encontradasnullEm 3 assuntos que a senega abaixou a viscosidade, aumentou anullNitrogênio total e resíduo seco e não teve efeito sobre o pHnullDeste fluido.
ANA_JULIA
Nota
Nas experiências, cujos resultados foram listados na Tabela I, a senega foi considerada moderadamente efetiva nas doses relativamente grandes usadas no aumento da produção de R. T. 3. '. Em gatos e cobaias, mas não em coelhos. Deve-se notar que, embora fossem utilizadas grandes doses, conforme descrito abaixo, esses fármacos atuam, se atuem, como expectorantes reflexos. Nessas condições, a anestesia pode ser esperta para aborrecer o reflexo gástrico, embora o grau de anestesia utilizado seja leve e em relação ao nível inferior do plano 1 da anestesia cirúrgica, de acordo com os critérios da GUEDEL (1937). Em experimentos não publicados deste laboratório, foi demonstrado que esse grau de anestesia aborrece ligeiramente, mas não evita a agitação gástrica dos expectorantes reflexos - pelo menos no caso da ipecacuanha que foi utilizada neste trabalho. No que diz respeito ao efeito, de senega com o teor de cloreto de R. T. F., houve uma diminuição na ocorrência de gatos uretanizados, mas nenhuma alteração significativa nos outros grupos de animais. Estes estudos indicariam que a senega não é uma droga expectorante particularmente eficaz.
Table I, senega was found to be moderately effective in the 
relative large doses used in increasing the output of R. T. 3.’. 
in cats and guinea-pigs but not in rabbits. It should be noted 
that while large doses were used, as will be described below, 
these drugs act, if they act at all, as reflex expectorants. Under 
these conditions anaesthesia might be expected to dull the 
gastric reflex, although the degree of anaesthesia used was 
liglit and about the lower level of plane 1 of surgical anaesthesia, 
according to GUEDEL’S criteria (1937). I n unpublished experi- 
ments from this laboratory, it has been shown that this degree 
of anaesthesia dulls slightly, but does not prevent gastric 
stirnulation from reflex expectorants - at least in the case of 
ipecacuanha which was used in this work. As regards the effect, 
of senega upon the chloride content of R. T. F., there was a 
decrease in the instance of urethanized cats but no significant 
change in the other groups of animals. These studies would 
indicate that senega is not a particularly effective expectorant 
drug. 
I I I . Squill. 
Squill is one of the most ancient of drugs, having been used 
at least as early as the 30th Olympiad by the Greek physician 
Epimenides (21). Previous conclusions drawn from experiments 
upon the expectorant effect of squill are at variance. BROWE; 
(1939) stated that squill was a “stimulant expectorant” which 
tended to “diminish excessive secretion.’’ On the other hand, 
YOUNG (1940) described squill as a nauseant expectorant 
which increased the output of R. T.F. and he ascribed the 
mechanism of action to a reflex from the stomach, a mechanism 
also postulated by GUNN (1927). I n contrast with these para- 
doxical conclusions, it has further been stated (20) that squill 
is not an expectorant at all. 
In the investigation herein reported, squill was given by 
stomach tube in the form of Tinctura Scillae, B. P. (35) in the 
same doses as used with the other drugs, namely 0.1 to 10 ml. 
per kilo body weight. The average recommended human dose 
242 E. M. BOYD AND MARY E. PALMER 
of the tincture is about 0.02 ml. per kilo body weight. As shown 
by the results cited in Table I, squill did not augment the out- 
put of R. T. F. in rabbits, it had practically no effect in decere- 
brate cats, a slight expectorant action in urethanized cats 
and a moderate effect in guinea-pigs. In view of the relatively 
large doses used, the conclusion seems justified that squill 
is not a particularly effective expectorant. From the data, listed 
in Table11, it is evident that while squill increased the chloride 
concentration in rabbit R. T. F., it had little effect upon the 
concentration of chloride in the other species. 
I V . GrincEe&a. 
YOUNG (1940) classified grindelia as a nauseant expectorant, 
increasing the output of R. T. F. through a gastric reflex. The 
drug was administered as the Fluidextracturn Grindeliae, N. F. 
(36) in the same range of doses as previously described. The 
average recommended human dose of the preparation is in the 
neighborhood of 0.04 ml. per kilo body weight. Grindelia had 
a moderate expectorant action in cats but no effect in rabbits 
and guinea-pigs (Table I). It increased the concentration of 
R. T. F. chloride in cats, decreased it in guinea-pigs and had 
no effect in rabbits. These results do not substantiate the con- 
clusion that Grindelia is a useful expectorant. 
V . Sanguiruaria;. 
SOLIS-COREN and GITHENS (1928) devote considerable space 
to a discussion of the pharmacology and therapeutics of san- 
guinaria and state that it stimulates the production of bronchial 
secretions. The drug was given as the Fluidextractum Sangui- 
nariae, N. F. (36) in doses of 0.1 to 10 ml. per kilo body weight 
to urethanized cats. The average recommended human dose 
of this extract is of the order of 0.0025 ml. per kilo body weight. 
In the considerably larger doses herein used, it produced only 
a moderate increase in the output of R. T. F. and an increase 
in the concentration of cat R. T. F. chloride (Tables I and 11). 
EXPECTORANT SAPONINS 243 
V I . C'hionntnthus. 
Chionanthus has been classified as a nauseant, expectorant 
saponin, increasing the output of R. T. F. (33). Given to uretha- 
nized cats in the usual doses as the Fluidextractum Chionanthi, 
N. F. (36), it had little effect upon the volume or chloride 
content of urethanized cat R. T. F. (Tables I and 11), in spite 
of the fact that the doses used were a good deal higher than 
the recommended human dose which is about 0.04 ml. per 
kilo body weight. 
VII . Dioscorea;. 
Dioscorea has been described as allied to chionanthus in its 
expectorant properties (33). It was given in the form of Fluid- 
extractum Dioscoreae, N. F. (36) to urethtanized cats in the 
usual range of doses, the average recommended human dose 
being somewhere near 0.1 nil. per kilo body weight. The drug, 
however, produced only a moderate increase in the output 
of R. T. F. and little change in cat R. T. I?. chloride (Tables I 
and 1 1 ) . 
Mechanism of Action. 
The drugs described above produced vomiting in cats, and 
occasionally in rabbits, when used in doses sufficient to elicit 
an expectorant effect. This evidence may be taken to indicate 
froni the irritated gastric mucosa. When studying the mecha- 
nism of action of drugs with a definite expectorant action, it 
is the practice in this department to prove that the increased 
output of R .T .F . was by way of a reflex from the stomach 
by showing that no augmented outflow of R. T. F. occurs after 
section of the afferent gastric nerves. In view of the indifferent 
effect of the drugs investigated in the work herein reported, 
and in view of the occurrence of vomiting when any appreci- 
able expectorant action was obtained, it did not seem neces- 
sary to perform these additional experiments in order to con- 
clude that the drugs ,studied acted as reflex expectorants when 
they acted at all. 
244 E. M. BOYD AND MARY E. PALMER 
I) i s c u s s i on. 
SOLLMANN (1942) makes the statement that “the great 
number of expectorants is not generally needed,” and proceeds 
t , list five or six drugs which, he concludes, “suffice to meet 
the conditions in the most effective manner.” Few will contest 
the Statement that there are too niany drugs in the expectorant 
group - and in many other groups of drugs, for that matter. 
While modern pharmacological research is directed mainly 
to a study of new drugs, pharmacologists should at the same 
time scientifically reassess the virtues of older drugs, in order 
t8hat useless or less useful drugs may be eliminated as obsolete. 
Ordinarily, this work is not as interesting, may be even more 
difficult but is just as necessary as the study of new drugs. 
-4lthough there have been few new expectorants, and no out- 
standing ones, proposed in later years, this group of drugs 
undoubtedly is too voluminous. Is it possible at this time to 
scientifically state which expectorants are useless, which are 
c,f little value and which are most effective? I n spite of many 
years of research upon animals and man on the part of inve- 
stigators in this department, it has been possible to conclude 
t,liat only a few expectorants have little or no therapeutic 
value. To dogmatically state that only a half dozen or so ex- 
pectorants are all that need be considered is not consistent 
with the spirit of scientific truth. However, the evidence obtained 
in the present investigation, while not entirely conclusive, in- 
dicates that the drugs herein studied could well be deleted 
from the list of effective expectorants on the grounds that 
they have only slight or moderate expectorant action and 
then only when used in large, nauseant doses. 
S u mm ar y. 
Some 500 animals, including cats, rabbits and guinea-pigs, 
were arranged for the collection of R. T. 3’. (respiratory tract 
fuid). At the end of three hours, the animals were separately 
given, by stomach tube, a range of doses of quillaia, senega, 
quil l , grindelia,, sanguinaria, chionanthus and dioscorea in 
EXPECTORANT SAPONINS 245 
appropriate pharmaceutical forms, either as tinctures or liquid 
extracts, control groups receiving the vehicle alone. 
Practically all of these drugs produced a mild to moderate 
increase in the rate of output of R. T. F. but only in doses con- 
siderably above the recommended human dose per kilo body 
weight. 
There was no consistent change in the chloride content of 
R. T. F. 
As vomiting occurred in most of the cats and some rabbits, 
it was concluded that these drugs act, when they act, as ex- 
pectorants by way of a reflex from the stomach. 
In view of the indifferent expectorant action and of the 
gastric irritation, it was concluded that these drugs might 
well be deleted from the list of useful expectorants. 
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