The Expectorant Effect of Glyceryl

Guaiacolate in Patients with Chronic Bronchitis

A Controlled in Vitro and in Vivo Study
S . R. Hirsch, M.D., F.C.C.P.,' P. F. Viernes, M.D." R . C. Koy, M.D., F.C.C.P.t and

Glyceryl guaiacolate (GG) is one of the most common expectorants given to patients with chronic bronchitis. I n an in vitro study, G G was found to be no more effective than water in lowering the consistency (viscosity) of 27 sputum specimens obtained from various patients with chronic bronchitis. I n a clinical study of 11 patients with chronic bronchitis, GG at dosage levels of 800 mg and 1,600 mg daily was no more effective than the placebo in lowering sputum consistency, increasing sputum volume, or improving ventilatory function. Finally, in a double-blind evaluation of ten patients over a 20-day period, the ease of expectoration with GG was no different than with a placebo. O n the basis of these studies, G G appears to be ineffective as an expectorant in patients with chronic bronchitis.

lthough glyceryl guaiacolate ( GG ) has steadily in popularity as an expectorant since the animal studies of Eldon Boyd and his associate^,^ there continues to be a question as to its effectiveness in humans. The early clinical evaluations of GG used preparations which also contained the bronchodilator desoxyephedrinees and these studies, for the most part, were based on subjective responses without a double blind design. More recent objective studies with GG have suggested that this drug was slightly effective in reducing wheezing, primarily in patients with bronC h o d ~ s h , ' in a brief note, de~ chial scribed a double blind crossover study of 26 patients with chronic bronchitis in which he found no

A increased

'Associate in Research, Wood Veterans Administration Hospital; Clinical Assistant Professor of Medicine, Medical College of Wisconsin, hlilwaukee. Presently at Wauwatosa,
Wi.

change in sputum volume resulting from GG administration but some subjective improvement in ease of raising sputum as well as a decrease in measured "stickiness." We have developed an instrument, the fluid consisto-viscosimeter, which measures the viscoelastic properties (consistency) and volume of sputum. Our previous studies using this instrument11-15 have shown that certain agents used in expectorant procedures are effective in reducing the consistency of sputum (making it "thinner"). It is, therefore, appropriate to apply these techniques to measure the effectiveness of GG as an expectorant. We have chosen a group of patients with relatively stable chronic bronchitis for this evaluation.

''Fellow in Pulmonary Diseases, Wood Veterans Administration Hospital; Assistant Inehuctor in kledicine, Medical College of Wisconsin, Milwaukee. Presently at Wauwatosa,
Wic

.. ....

t ~ s s o c i a t eChief of Staff and Chief, Pulmonary Function Laboratory Wood Veterans Administration Hospital; ProResearch, Medical College of Wisconsin. fessor of ~ i i n i c a l Presently at Veterans Administration Hospital, Tampa. Reprint requests: Dr. Hirsch, W o o d V A Hospital, Milwaukee 53193

This study is divided into three phases: Phase 1 is an i n citro study of the direct effect of GC, on spuhlrn consistency. Phase 2 is a single blind crossover clinical and physiologic study of the effect of CC on the clinical status, the pulmonary function, and the volume and consistency of s p u h ~ m of patients with chronic bronchitis. Phase 3 is a dor~bleblind crossover evaluation of the effect of CG o n the ease of expectoration in patients with chronic bronchitis.

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10

HIRSCH, VIERNES, KORY

APLUNGER CONNECTING

0 RING

pressure is recorded on a potentiometric strip chart recorder. This pressure is directly proportional to the sputum consistency, which is expressed in "consistency units" ( C U ) . The thicker the spntum, the greater is the number of consistency units. When the instrument is calibrated with homogeneous silicones, one CU is equivalent to 1,500 centistokes. The instrument and its calibration have been previously described in greater detail.1331" The direct effect of GG on spuh~mconsistency was evaluated by the application of the "repeated passage" method, as described by us previously.l* Because the shearing force of the fluid consisto-viscosimeter is low, the fourth and fifth passages of the plunger through the sputum cause only minimal changes in the consistency values and continued passages of the plunger will not appreciably change the consistency value (Table 1 ) . This permits us to add liquifying agents to the sample following the third passage of the plunger and, after two more passages, observe the decrease in consistency resulting from the agents. The consistency value of the third passage thus serves as a control value for each specimen with which the fifth value can be compared. The difference between the third and the fifth passage, taken as the percent of the consistency value of the third passage, is the percent decrease in consistency due to the agent tested. As a matter of convenience and for ease of comparison with the work of others,lW.O ml of the agent to be tested is added to 5.0 ml of sputum.

Phase 2
FIGURE 1. Basic components of the fluid consisto-viscosimeter showing the plunger with the perforated disc, barrel and transducer.
Eleven patients with stable chronic bronchitis and considerable sputum production were selected from the medical wards or the domiciliary section of Wood Veterans Adrninistration Hospital. The patients were hospitalized for the entire period of study in order that a controlled environmental status col~ld maintained. be The patients were maintained on their routine medications including bronchodilators, antibiotics, and intennittent positive pressure breathing treatments consisting of saline and isoproterenol. One patient (No. 1 ) received N-acetylcysteine plus isoproterenol during the entire study. Other expectorant drugs were discontinued at least three days prior to the study. The design of this phase was a single blind crossover which allowed each patient to rotate through the plan shown in Table 2. The medication was given at 7 AM, 11 AM, 3 phi, and 7 PM. The placebo was made according to the following formula: ethyl alcohol 95 percent, 35 ml; glycerine, 35 ml; and wild cherry syrup, qsad, 1,000 ml. To simulate the bitter aftertaste

Phase 1
The fluid consisto-viscosimeter was designed in our laboratory to measure the consistency of heterogeneous semiplastic materials such as sputum. We use the word "consistency" as equivalent to "apparent viscosity" since the term "viscosity" per se is properly reserved for homogeneous fluids. Figure 1 is a diagram of the basic components of the fluid consi~to-viscosimeter.' A hollow stainless steel plunger with a perforated disk at its lower end is driven by a constant infusion pump through a close fitting barrel Bled with sputum. The bottom of the cylinder is fitted with a transducer which reflects the pressure generated as the sputum is forced through the perforated disk. A tracing of the 'Available from Quin-Tron Instrument Co., Inc., Brookfield, Wiscu)nsin.

Table 1-In
l'irssiigr No I 2 3 .\tltlition of:

Vitro Sputum Studies b y the Repeated Pasrage Technique*

A
N=U) 130 CI' 85 CIT 76 C1J Nothing

B
N ==20
126 CU 95 CU 82 CI' 1 ml water

D
N =20 125 CIT 81 CIi 68 CU

N =27
209 CU 88 C172 CIT 1 m l 2 % GG

. 1 ml20r/;, X-ac
85 $',

Pcr~cant decrease in c~onsistcncy** '1':issagc~ numher (see text). S-LL(~ = S-nc.etyl(.yste~ne. G ( ; = Glgcrryl guaiacolate.

8%

35%

38%

**Computed for each specimen; then averaged. N =Number of sputum specimens. CU =Consistency units.

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EXPECTORANT EFFECT OF GLYCERYL GUAIACOLATE

Table
Week
1
2-Plan of Study for Phaw

Drug Placebo

Dose 10 ml qid 10 ml (200 mg) qid . 20 ml qid

GG
Placebo

3
1
5

GG
Placebo

20 ml (100 mg) qid

20 ml qid

of GG, 650 mg of quinine HC1 was added. ~h~ taste of the placebo was indi-tinguishable from that of CG. ~~~h patient.s spuhlm was collected during the entire study. Each 24-hour sputum-collection period was divided into a morning specimen ( 8 ahf-12 noon), a n afternoon specimen ( 12 noon-4 PM ), and an overnight specimen ( 4 PM8 A M ) . Each specimen was frozen upon collection and just ~ r i o r measurement. Previous s h ~ d i e s to allowed to thaw . in our laboratory have shown that a single freezing and thawing of a spuhlm specimen does not significantly alter the consistency of the specimen when measured by the fluid consisto-viscosimeter. Spirometric testing, before and after nebulization of racemic epinephrine, was performed on the last day of each testing period two to four hours after a dose of CG or placebo. The measurements included: the forced vital capacity, the one-second forced expiratory volume, the 200-1,200 n ~ forced expiratory flow, and the 25 percent to 75 l percent forced expiratory flow. Lung volume studies, including the vital capacity, residual volume, and total lung capacity as well as the helium mixing time, were performed on the same days as the spirometic tests. Daily clinical observations included evaluation by a physician of the ease of expectoration and side-effects of CC. Changes in rales, breath sounds, and wheezing were noted daily. The major features of the evaluation were the results of y the sputum volume and ~ o n s i ~ t e n cmeasurements together with the pulmonary function evaluation. The technician performing these studies had no knowledge of the patient's regimen. The tabulation of results and their statistical evaluation were performed as detailed previously.'"

hospitalized for the entire study and maintained on their routine medication other than mucolytic agents or expectorants. In this phase, we utilized a double blind doublecrossover technique of study. The patients were divided into two groups of five patients each. Each group was given 20 ml of GG or placebo four times daily throughoi~t two alternating five-day periods. Both groups were on schedr~lesopposite of each other. Each patient was asked to place a check mark at the end of each day in the correct column on a sheet, the format of which is shown in Table 3. The check mark was in response to the question printed on top of the sheet, "How e a y or hard was it for you to bring u p sputum today?" Evaluation of results was performed by tramforming each response to a numerical score, which is listed above each column in Table 2.

Phase
In order to appreciate the direct effect of drugs On Sputum consistency as measured by the repeated passage technique, it is necessary to compare the results from several different aeents. Table 1 shows of the effects of water, ~ - ~ a 'ysteine? and GG On the 'puturn consistency of Samples collected at random from 35 patients. Column A shows the mean consistency values for 20 sputum samples to which nothing was added. The decrease in consistency from passage 3 to passage 5 was only six consistency units, or 8 percent. We consider this 8 percent change minimal and within the range of reproducibility of the method. In colun~n of Table 1 are listed the results of adding B 1.0 ml of demineralized water to 5.0 ml of each of 20 sputum specimens after the third passage. The mean decrease in sputum consistency between passage 3 and passage 5 was 30 CU, or 35 percent. In column C are the results of adding 1.0 ml of 2 percent GG ( the concentration used clinically ) to 5.0 ml of each of 27 sputum specimens. The mean

Phase 3
Ten patients with chronic bronchitis in a stable phase were

Table
Patient's Name

3--Format

of a Completed Questionnaire

U d

in Phase 3

How easy or hard was it for you to bring up sputum today? (please check)
(1)

(2)

(3)

(4)
Harder than usual

(5)

Day of Study

En: ier
Date Much easier than usual than usual Usual

Murh harder than usual

'The scorc for rarh rrsponne i.i shown almvc rach rolumn.

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HIRSCH, VIERNES, KORY

1001
MORNING

FICUIIE. A comparison of the 2 mean spuh~mconsistency values in consistency units for all of the patients for each period of shldy (luring tlw ~norning, afternoon, ;lntl overnight collections. Glycer>,l gr~aiacu)latedoes not significantly lower the s p ~ ~ hcon~m sistrncy as compared to the ~ ~ l a c e ltlr~rinrr , of the collec> o . . anv tion periods.

2 s; i 5 m
0

fv,
OVERNIGHT

I-

10072 74

78
d

50 0

PLACEBO 8 0 0 MG GG / DAY PLACEBO

1 6 0 0 MG GG/ DAY

PLACEBO

WEEK

decrease in consistency was 27 CU, or 38 percent, which does not differ appreciably from the effect of water. Column D shows the effect of adding 1.0 ml of 20 percent N-acetylcysteine to 5.0 ml of each of 20 sputum specimens. The decrease in consistency is ,Sf3 CU, or 85 percent, which is an obviously significant decrease in consistency as compared to GG.
Phase 2

The it1 oivo effect of GG on sputum consistency is shown in Figure 2. Each bar represents the mean sputum consistency value of all the patients for each period of study during the morning, afternoon, and overnight collections. The placebo was given during periods 1, 3 and 5 ( represented by the white hars). The daily dose of 800 mg GG was given during the second week (shown by the hatched bars ) and 1,600 mg daily (black bars) during the
MORNING

fourth week. It is obvious that there was no appreciable lowering of sputum consistency in either the morning, afternoon or overnight specimens resulting from either dose of GG as compared with the placebo. The results are in sharp contrast to our previous of the effect of nebulized 20 percent Nacetylcysteine (N-ac) and racemic epinephrine ( R E ) on the sputum consistency of similarly collected specimens from 12 patients with chronic bronchitis. Figure 3 shows the results of that study. For each collection period (morning, afternoon and overnight) there was a striking reduction in sputum consistency during the weeks when N-acetylcysteine plus racemic epinephrine were nebulized. This was in sharp contrast to the nebulization of saline plus racemic epinephrine, which failed to reduce the sputum consistency. It is evident that the nebulization of N-acetylcysteine resulted in a marked lowering of sputum consistency, particular-

100

AFTERNOON
86

*.

-FIGURE Demonskation of the 3. lowering of the weekly mean sputum consistency, which can be achieved with nebulization of N-acctylcysteine. During the control weeks there was no nebulization. S RE = nebulization of 3.5 ml saline 2.0 mg racemic epinephrine, three times daily. N-ac RE = nebulization of 3.5 ml 20 percent Nacetylcysteine 2.0 mg of racemic epinephrine, three times daily.

100 7

OVERNIGHT
90 89

CONTROL

N-ac

+
R. E.

CONTROL

+
R. E.

N-ac

CONTROL

R. E.

R.E.

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EXPECTORANT EFFECT OF GLYCERYL GUAIACOLATE

ly as compared to the oral administration of GG. The sputum volume values, the spirometric and lung volume measurements, as well as the helium mixing time, failed to show any change resulting from either dose of GG in comparison with the placebo. There was no consistent change in the auscultatory findings during the periods of GG administration as compared with the periods of placebo administration. Side-effects were surprisingly absent despite the high doses of GG used. Each patient was questioned daily as to whether the raising of his sputum was easier, unchanged or more difficult. Because the results of this questioning were inconclusive, the third phase of the study was initiated. Phase 3 Table 4 shows the effect of GG, as compared to the placebo, on the ease of expectoration. The scoring possibilities are noted at the bottom of the table. Since each ~ a t i e n twas tested for ten davs with GG and ten days with placebo, the lowest score which would represent the easiest possible expectoration would be ten; the score for the most difficult expectoration would be 50. If there was no change from the patient's usual effort of expectoration, the score would be 30. The mean value for C G was 28.3 and for the placebo 27.7, are obviously not different.

Table P

A Contparison of the Eflect of Glyceryl

Guaiacolate u Placebo on the Ease of Expectoration s (Phase 3 ) (Total Ten-Day Score).

1':. ' ir,r? t

GIycbervI Guni:tcoli~ te
21 26 25 37 24 26
20

I'lac-elm
18

SO. 2

so. 3 So. 4 SO. 5 No. 6 So. 7 S O .8 NO. !I S o . 10 So. I I blean 'Scores

30 38 36 28.3 35 31 27.7

For easiest possibIe expectoration = 10 For hardest ~ & s i bexwrtoration-50 l~ -30 For usual ease of expertoration

found that excessively large doses of GG adminis-

. tered via gastric tube to cats and rabbits increased

r e ~ ~ i r a t o r ~ 'uid during the ha'' the output a u t ~ m nmonths. In a later ~ u b l i c a however. , ~~~~ emphatically stated that Boyd and "there is no ~ h a r m a ~ ~ l o g i c a l proof. . . . that therapeutic doses (of G G ) have any consistent expectorant effect whatsoever on respiratory tract fluid." Following these animal studies a number of cli~ical evaluations of GG were reported. In several of these studies the GG was combined with deso x y e ~ h e d r i n e and it seems likely that the bron,~~ chodilating effect of the desoxyephedrine contributed materially to the subjective improvement reported. Townley and Bronstein,' however, did conduct a double blind crossover study comparing 200 mg of choline theophyllinate (CTh) with identical appearing tablets containing the same dose of CTh combined with 100 mg GG in a group of 27 patients with chronic obstructive pulmonary disease. A high percentage of these patients had asthma. These investigators concluded that GG plus CTh resulted in less wheezing than CTh alone, although there was no significant difference in vital capacity or in the ease of expectoration. Pulse also conducted a double blind crossover study of the same GG-CTh combination compared with CTh alone in 20 patients with asthma, bronchitis, and emphysema. The only significant difference observed in these patients was a slightly greater improvement in vital capacity with the GG-CTh combination.

Glycer~lguaiacolate is a derivative of guaiacol which is the chief constituent of creosote and takes its name from guaiac resin from which it was first isolated. Because of the small quantities of guaiacol in guaiac resin it probably did not contribute to the therapeutic effect claimed for the resin.3 After being used for most of the common ills of man during the 1800s, creosote gradually became limited in use to chronic lung disease, particularly tuberculosis in which it was thought by some to have an antiseptic action. As clinical experience gradually failed to support its effectiveness as a tuberculocide, many observers continued to use the drug as an antitussive. In the early 1900's, guaiacol compounds were used in place of creosote because it was thought they were better absorbed and less irritating to the gastrointestinal tract. Although guaiacol derivatives are absorbed from the gastrointestinal tract and conjugated as sulfates in the urine," it is not known whether they are excreted in respiratory tract fluid. The current popularity of GG is based largely on the animal work of Boyd and his associate^,'-^ who
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HIRSCH, VIERNES, KORY

Miller9 studied 23 patients with acute bronchospasm and reported improvement in his subjective evaluation with the GG-CTh combination as compared with theophylline elixir, but observed no appreciable differences in ventilatory function. most In all of these previous s t u d i e ~ , ~ - ~ of the patients exhibited varying degrees of bronchospasm. Careful review of the results in these studies suggests that GG may have potentiated slightly the effect of the bronchodilator with which it was administered. In the present study, the patients were chosen because of their relatively stable chronic bronchitis ( therefore allowing adequate control periods ) , their persistent sputum production, and the similar nature of their disease. The study was designed to evaluate the expectorant effect of GG and not its effect on bronchospasm. Although careful spirometric studies were performed on the last day of each testing period, they were usually done three or four hours after the prior dose of GG or placebo. Thus, these tests would be unlikely to demonstrate any bronchodilating effect resulting from the drug. The differences in our findings from those of the previous investigator^^-^ suggest that reversible processes such as acute bronchitis, acute laryngitis and bronchial asthma are more likely to benefit from GG than chronic bronchitis, emphysema, bronchiectasis, or pulmonary fibrosis. Since we have previously demonstrated that effective expectorant procedures such as inhalation of N-acetylcysteine are associated with a decrease in sputum c o n s i s t e n ~ y , ~ ~ it~ ~is ' ~ reasonable to . . judge the effect of GG by the same criterion. However, in the present study we have not only shown that GG did not change sputum consistency or volume but also that GG did not affect the ventilatory function or the ease of expectoration in these patients. We must conclude that GG has no expectorant action in patients with chronic bronchitis.
ACKNOWLEDGhlENTS: We would like to express our appreciation to Mrs. Joyce E. Zastrow for her invaluable technical assistance and to Mrs. Catherine A. Walther for her aid in preparing the manuscript.

ASSOC 42:220-223, 1940 J 2 Perry WF, Boyd EM: A method for studying expectorant

1 Connell WF, Johnston GM, Boyd Ehl: On the expectorant action of resyl and other guaiacolates. Canad Med

action in animals by direct measurement of the or~tpr~t of respiratory tract fluids. J Pharmacol Exp Ther 72:65-77, 1941 3 Stevens MET, Ronan AK, Sourkes TS, et al: On the expectorant action of creasote and guaiacols. Canad kled ASSOCJ 48: 124-127, 1943 4 Cass LJ, Frederick WS: Comparative clinical effectiveness of cough medication. Am Practit Dig Treat 2:844851, 1951 5 Hayes EW, Jacobs LS: A clinical evaluation of the effectiveness of Robitussin@ in chronic cough. Dis Chest 30:441-448, 1956 6 Schwartz E, Levin L, Leibowitz H, et al: The use of Am antitussives in the management of bronchial a~thma. Practit Dig Treat 7:585-588, 1956 7 Townley RG, Bronstein SB: A double blind clinical evaluation of glyceryl guaiacolate. Ann Allergy 21:683-691, 1963 8 Puls RJ: Clinical s h ~ d y oxtriphylline-glyceryl gnaiacoof late tablets in chronic pulmonary disease. A double blind crossover study. Curr Ther Res 6:353-356, 1964 9 hliller J : Objective and clinical evaluation of oxtriphyllineglyceryl guaiacolate. Clin hled 71 : 1929-1932, 1964 10 Chodosh S: Glyceryl guaiacolate. A controlled laboratory and clinical study. Am Rev Resp Dis 90:285, 1964 11 Hirsch SR, Kory RC, Hamilton LH: Evaluation of changes in sputum consistency with a new instrument. Am Rev Resp Dis 94:784-789, 1966 12 Hirsch SR, Kory RC: An evaluation of the effect of nebulized N-acetylcysteine on sputum consistency. J Allerg 39:265-273, 1967 13 Kory RC, Hirsch SR, Giraldo A: Neublization of Nacetylcysteine combined with a bronchodilator in patients with chronic bronchitis. A controlled study. Dis Chest 54: 18-23, 1968 14 Hirsch SR, Zastrow J, Kory RC: Sputum liquefying agents. A comparative in vitro evaluation. J Lab Clin hled 743345353, 1969 15 Hirsch SR, Viernes PF, Kory RC: Clinical and physiological evaluation of mucolytic agents nebulized with isoproterenol: 1011: N-acetylcysteine versus 10%mercaptoethane sulfonate. Thorax 25:737-743, 1970 16 Lieberman J : Measurement of sputum viscosity in a coneplate viscosimeter, 11. Am Rev Resp Dis 97:662-672, 1968 17 Knapp T, Suter F: Experimentelle Untersuchungen iiber die Resorptions und Ausscheidungsverhiiltnisse einiger Guajakolderivate (Guajakolkarbonat, Guatakolzimmtsaureather, Guajakolsulfos#ure, G~ajakolgl~zeriniither ). Arch Exp Path Pharmack 50:332-352. 1903 18 Boyd Ehl, Sheppard EP, Boyd CE: The pharmacological basis of the expectorant action of glyceryl guaiacolate. Appl Ther 9:55-59, 1967

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