GG (dari orang lain).pdf

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." and R . C. Koy, M.D., F.C.C.P.t

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. On 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 A increased 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 con- tained 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 sug- gested that this drug was slightly effective in reducing wheezing, primarily in patients with bronchial C h o d ~ s h , ' ~ in a brief note, described a double blind crossover study of 26 patients with chronic bronchitis in which he found no

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

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

t~ssoc ia te Chief of Staff and Chief, Pulmonary Function Laboratory Wood Veterans Administration Hospital; Pro- fessor of ~ i in ica l Research, Medical College of Wisconsin. Presently at Veterans Administration Hospital, Tampa.

Reprint requests: Dr. Hirsch, Wood V A Hospital, Milwaukee 53193

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 visco- elastic properties (consistency) and volume of sputum. Our previous studies using this instru- ment11-15 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 tech- niques to measure the effectiveness of GG as an expectorant. We have chosen a group of patients with relatively stable chronic bronchitis for this evaluation.

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 spuh~m of patients with chronic bronchitis. Phase 3 is a dor~ble blind crossover evaluation of the effect of CG o n the ease of expectoration in patients with chronic bronchitis.

CHEST, VOL. 63, NO. 1, JANUARY, 1973

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10 HIRSCH, VIERNES, KORY

APLUNGER CONNECTING

0 RING

FIGURE 1. Basic components of the fluid consisto-viscosimeter showing the plunger with the perforated disc, barrel and transducer.

Phase 1

The fluid consisto-viscosimeter was designed in our laboratory to measure the consistency of heterogeneous semi- plastic 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.

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~m consistency was eval- uated 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 liquify- ing 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 Eleven patients with stable chronic bronchitis and consid-

erable sputum production were selected from the medical wards or the domiciliary section of Wood Veterans Adrninis- tration Hospital. The patients were hospitalized for the entire period of study in order that a controlled environmental status col~ld be maintained.

The patients were maintained on their routine medications including bronchodilators, antibiotics, and intennittent posi- tive 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

Table 1-In Vitro Sputum Studies b y the Repeated Pasrage Technique*

A B C D l'irssiigr No N=U) N ==20 N =27 N =20

I 130 CI' 126 CU 209 CU 125 CIT 2 85 CIT 95 CU 88 C1- 81 CIi 3 76 C1J 82 CI' 72 CIT 68 CU

.\tltlition of: Nothing 1 ml water 1 ml2% GG . 1 ml20r/;, X-ac

Pcr~cant decrease in c~onsistcncy** 8% 35 % 38% 85 $', '1':issagc~ numher (see text). **Computed for each specimen; then averaged. S-LL(~ = S-nc.etyl(.yste~ne. N =Number of sputum specimens. G(; = Glgcrryl guaiacolate. CU =Consistency units.



EXPECTORANT EFFECT OF GLYCERYL GUAIACOLATE

Table 2-Plan of Study for Phaw 2 hospitalized for the entire study and maintained on their routine medication other than mucolytic agents or expec-

Week Drug Dose torants. In this phase, we utilized a double blind double-

1 Placebo 10 ml qid crossover technique of study. The patients were divided into two groups of five patients each. Each group was given 20 ml

2 GG 10 ml (200 mg) qid of GG or placebo four times daily throughoi~t two alternating - .

five-day periods. Both groups were on schedr~les opposite of 3 Placebo 20 ml qid each other. Each patient was asked to place a check mark at 1 GG 20 ml (100 mg) qid 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 5 Placebo 20 ml qid response to the question printed on top of the sheet, "How

of GG, 650 mg of quinine HC1 was added. ~h~ taste of the e a y or hard was it for you to bring up sputum today?" placebo was indi-tinguishable from that of CG. Evaluation of results was performed by tramforming each

~~~h patient.s spuhlm was collected during the entire response to a numerical score, which is listed above each study. Each 24-hour sputum-collection period was divided column in Table 2. into a morning specimen ( 8 ahf-12 noon), an afternoon specimen ( 12 noon-4 PM ), and an overnight specimen ( 4 PM- 8 A M ) . Each specimen was frozen upon collection and allowed to thaw just ~ r i o r to measurement. Previous sh~dies Phase

. -

in our laboratory have shown that a single freezing and thawing of a spuhlm specimen does not significantly alter the In order to appreciate the direct effect of drugs consistency of the specimen when measured by the fluid On Sputum consistency as measured by the repeated consisto-viscosimeter. Spirometric testing, before and after passage technique, it is necessary to compare the nebulization of racemic epinephrine, was performed on the results from several different aeents. Table 1 shows - last day of each testing period two to four hours after a dose a of the effects of water, ~ - ~ ~ ~ ~ l - of CG or placebo. The measurements included: the forced vital capacity, the one-second forced expiratory volume, the 'ysteine? and GG On the 'puturn consistency of 200-1,200 n ~ l forced expiratory flow, and the 25 percent to 75 Samples collected at random from 35 patients. percent forced expiratory flow. Lung volume studies, includ- Column A shows the mean consistency values for 20 ing 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 the sputum volume and ~ o n s i ~ t e n c y measurements together with the pulmonary function evaluation. The technician per- forming these studies had no knowledge of the patient's regimen. The tabulation of results and their statistical evaluation were performed as detailed previously.'"

Phase 3

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 B of Table 1 are listed the results of adding 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

Ten patients with chronic bronchitis in a stable phase were 5.0 ml of each of 27 sputum specimens. The mean

Table 3--Format of a Completed Questionnaire U d in Phase 3

Patient's Name

How easy or hard was it for you to bring up sputum today? (please check) ( 1 ) (2) (3) (4) ( 5 )

Day En: ier Harder of Much easier than than Murh harder

Study Date than usual usual Usual usual than usual

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



HIRSCH, VIERNES, KORY MORNING

1001

FICUIIE 2. A comparison of the mean spuh~m consistency values in consistency units for all of the patients for each period of shldy (luring tlw ~norning, afternoon, ;lntl overnight collections. Gly- cer>,l gr~aiacu)late does not significantly lower the s p ~ ~ h ~ m con- sistrncy as compared to the ~~lacel>o tlr~rinrr anv of the collec-

I- fv, 2 s; i5

m 0 OVERNIGHT

GG / DAY GG/ DAY

100-

. . ,

tion periods. W E E K 1 2 3 4 5

5 0 -

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.

72 7 4 78 d

Phase 2

0 PLACEBO 8 0 0 MG PLACEBO 1 6 0 0 MG PLACEBO

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

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 N-

acetylcysteine (N-ac) and racemic epinephrine (RE) 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-

MORNING

AFTERNOON *. 100 8 6 - -

OVERNIGHT 100 7 9 0 8 9

FIGURE 3. Demonskation of the 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 N-

CONTROL N-ac S CONTROL S N - a c CONTROL acetylcysteine + 2.0 mg of race- + + + + mic epinephrine, three times

R. E. R. E. R. E. R .E . daily.



EXPECTORANT EFFECT OF GLYCERYL GUAIACOLATE

ly as compared to the oral administration of GG. Table P A Contparison of the Eflect of Glyceryl The sputum volume values, the spirometric and Guaiacolate us Placebo on the Ease of Expectoration (Phase 3 ) (Total Ten-Day Score). lung volume measurements, as well as the helium

mixing time, failed to show any change resulting GIycbervI from either dose of GG in comparison with the 1':. ' ir,r? t Guni:tcoli~ te I'lac-elm placebo. S O . 2 21 18

There was no consistent change in the ausculta- s o . 3 26 tory findings during the periods of GG administration as compared with the periods of placebo S o . 4 25 administration. Side-effects were surprisingly absent SO. 5 37 despite the high doses of GG used. Each patient No. 6 24 was questioned daily as to whether the raising of his sputum was easier, unchanged or more difficult. S o . 7 26 Because the results of this questioning were incon- S O . 8 20 clusive, the third phase of the study was initiated. NO. !I 30

Phase 3 S o . 10 38 35 S o . I I 36 31 Table 4 shows the effect of GG, as compared to

the placebo, on the ease of expectoration. The blean 28.3 27.7 scoring possibilities are noted at the bottom of the For easiest possibIe expectoration = 10 table. Since each ~ a t i e n t was tested for ten davs 'Scores For hardest ~ & s i b l ~ exwrtoration-50 with GG and ten days with placebo, the lowest For usual ease of expertoration -30 score which would represent the easiest possible found that excessively large doses of GG adminis- expectoration would be ten; the score for the most . tered via gastric tube to cats and rabbits increased difficult expectoration would be 50. If there was no the output r e ~ ~ i r a t o r ~ ha'' 'uid during the change from the patient's usual effort of expectora- a u t ~ m n months. In a later ~ u b l i c a ~ ~ ~ ~ , however. tion, the score would be 30. The mean value for CG Boyd and emphatically stated that was 28.3 and for the placebo 27.7, are "there is no ~ h a r m a ~ ~ l o g i c a l proof. . . . that obviously not different. therapeutic doses (of GG) have any consistent

expectorant effect whatsoever on respiratory tract

Glycer~l guaiacolate 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 lim- ited 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

fluid." Following these animal studies a number of

cl i~ical evaluations of GG were reported. In several of these studies the GG was combined with des- o x y e ~ h e d r i n e , ~ ~ and it seems likely that the bronchodilating effect of the desoxyephedrine con- tributed 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 ap- pearing 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.



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.

In all of these previous s t u d i e ~ , ~ - ~ most 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 na- ture 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.

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

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

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 ASSOC J 48: 124-127, 1943

4 Cass LJ, Frederick WS: Comparative clinical effectiveness of cough medication. Am Practit Dig Treat 2:844- 851, 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 antitussives in the management of bronchial a~thma. Am 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 sh~dy of oxtriphylline-glyceryl gnaiaco- 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 oxtriphylline- glyceryl 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 N- acetylcysteine 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 physiolog- ical 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 cone- plate 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, Guatakolzimmts- aureather, 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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