Current Medical Research and Opinion Vol. 1 , No. 4, 1973

A between-patient, double-blind comparison of S-carboxymethylcysteine and bromhexine in chronic obstructive bronchitis

Curr. med. Res. Opin., (1973), 1,219.

Summary

Mansel AyIward,* M.D., M.B.,B.Sc.,

St. Tydfil's Hospital, Merthyr Tydfil, Wales

Received: 5th January 1973

S-carboxymethylcysteine was compared with bromhexine in a double-blind between- patient clinical trial in bronchitic patients with mucoid sputum. Oral S-carboxymethyl- cysteine, administered as a 5 % wlv syrup was given in a dosage of 750 mg. three times daily for I0 days and compared with oral bromhexine syrup (4 mg./5ml.) in a dosage of 16 mg. three times daily. Treatment with both drugs resulted in a signiJicant increase in sputum volumes and a signifcant increase in the 'pourability' of sputum. An improvement was also noted with both drugs in the subjective measures of ease of expectoration, severity of coughing, and sputum consistency. However, there was no improvement in ventilatory capacity or peak expiratory pow rates. S-carboxymethyl- cysteine was preferred signifcantly more by the patients' and the clinician's assess- ment. Bromhexine was not considered to improve the overall respiratory state as assessed by clinician or patients themselves. Whereas both drugs demonstrated valuable therapeutic responses, and were equally efective in their action on improving expectoration, sputum volumes and sputum pourability, S-carboxymethylcysteine produced a beneficial response in complementary parameters at least 4 da.ys before a notable respome to bromhexine treatment. Side-effects only occurred in 2 patients. One patient was withdrawn because of severe nausea and vomiting whilst receiving bromhexine and another patient experienced transient abdominal disconfort whilst receiving S-carboxymethylcysteine.

Key words: Bronchitis - S-carboxymethylcysteine - bromhexine - mucolytic agent

Introduction Several derivatives of cysteine exert a mucolytic action in vitro or in the lumen of the bronchi when administered as an aerosol spray. S-carboxymethylcysteine has been shown to clear viscous-secretions from the bronchi of laboratory animals when given by mouth,l,* and there is evidence that it has an intracellular effect upon mucus synthesis.3 Bromhexine, a synthetic derivative of the plant alkaloid vasicine, has also shown similar properties in animaIs4.5 and appears to alter the fibrillary structure of mucus.6

*Clinical Research Consultant, Research Division

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A between-patient, double-blind comparison of Scarboxynethylcysteine and brornhexine in chronic obstructive bronchitis

Double-blind trials of bromhexine in the United Kingdom are difficult to interpret. Whereas Gent et al. reported’ that significantly more patients improved on bromhexine, 8 mg. three times daily by mouth, than with placebo, Langlands* using a similar technique and the same dosage was unable to discover any significant change in sputum volume, viscosity or ventilatory capacity. However, Hamilton et u I . ~ using a higher dose, 16 mg. three times daily, found a significant increase in sputum volume and a significant decrease in sputum viscosity, but no improvement in ventilatory capacity or in the overall respiratory state of the patient.

Similarly, the clinical experiences with S-carboxymethylcysteine have been conflicting. Sadoul et a1.10, and Edwards et a].” have reported a significant reduction in sputum viscosity occurring about the 3rd to 6th day following the administration of a 5 7; w/v S-carboxymethylcysteine syrup, at a dosage of 15 ml. three times daily, Increased sputum volume and reduction of viscosity has also been observed at this time, together with significant objective clinical benefit and subjective improvement in the greater ease of expectoration ; the beneficial effect of S-carboxymethylcysteine continuing throughout the period of study. However, Edwards el al. discovered no significant effect of S-carboxymethylcysteine on changes in ventilatory volumes. On the other hand, Lemercier et a/.’ have noted an increase in ventilatory function, a decrease in dyspnoea. and a decrease of sputum viscosity in patients receiving S-carboxymethylcysteine.

In a preliminary evaluation of oral S-carboxymethylcysteine syrup in patients with chronic bronchitis, expectorant properties of the drug were observed during the administration of 3 x 5 ml. three times daily for 6 weeks. A statistically significant increase in sputum volumes and peak expiratory flow rates were observed after the first few days of administration, and were maintained throughout the period of study.13

The present study reports the results of a double-blind between-patient com- parison of the effects of S-carboxymethylcysteine, 750 mg. three times daily, with those of bromhexine, 16 mg. three times daily, in patients with chronic bronchitis.

Materials and methods Thirty patients attending as out-patients, following an acute exacerbation of chronic bronchitis, and expectorating macroscopically mucoid sputum were ad- mitted to the trial. Patients with a past history of peptic ulceration, intestinal or colonic disease, and those with severe renal, hepatic or myocardial disease were excluded.

There were 20 men and 10 women, whose age ranged from 39 years to 72 years, (mean 56.2 9.7 years). Twenty-five percent of the men were classified as non- smokers for 4 years or more. All the other patients were smokers and all had been heavy smokers. Furthermore, 14 of the 20 men had worked in the coal-mining industry and each exhibited minimal radiological pneumoconiosis.

Both drugs were administered in the form of a syrup, bromhexine 16 mg. three times daily or S-carboxymethylcysteine 750 mg. three times daily being taken for

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Manse1 Aylward

10 days, according to a double-blind randomization scheme. Neither the patients nor the clinician were aware of which drug was being administered. Bronchodilator therapy was continued, but the dosage was maintained constant throughout the 10 day period. Cough suppressants and expectorants were discontinued for the 4 days prior to and throughout the trial.

Forced expiratory volumes and Peak Expiratory Flow Rates (P.E.F.R.) were obtained at the beginning and end of the trial using a Wright Peak Flow Meter and a Vitalograph. The Forced Vital Capacity (F.V.C.), the Forced Expiratory Volume in 1 second (F.E.V.,) and the F.E.V., as a percentage of the F.V.C. (F.E.V., %) were calculated. All these indices are shown as a percentage of predicted normal values so that any differences in age, sex, and body build are allowed for.

The total daily volumes of sputum were recorded for each patient 3 days and 1 day prior to entry, and thereafter on Day 1 of trial and each alternate day during the period when the drugs were being administered. The sputum volumes on the third day following cessation of treatment were also recorded.

Figure 1. A simple apparatus for the objective assessment of sputum ‘pourabdity’

.25“ dia. orifice /-----

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A between-patient, double-blind comparison of S-carboxynethylcysteine and bromhexine in chronic obstructive bronchitis

A special proforma was completed daily by the patient. The frequency and severity of diurnal and nocturnal cough, and the ease of expectoration were assessed subjectively by the patient. On alternate days of the study, the patients were also asked to grade the consistency of sputum on a 4-point scale (0 =jellylike, no watery content, to 3 =runs like water). On days during which the total volumes of sputum were not measured, a sample of the sputum expectorated during the first hour after rising was assessed in the following objective manner for ‘pourability’ - the time taken for 1 ml. of freshly expectorated sputum to travel 20 cm. in a tube angled at 45” to the horizontal was compared with the time taken for the same volume of pure glycerol.

The diagram in Figure 1 shows the apparatus used. Two half-inch constant bore glass tubes graduated in cm. from 0 to 30 cm. are placed horizontally adjacent to each other. At the ‘closed end’ of both tubes there is a hole measuring 0.25 inches in diameter, directly above the zero mark. One ml. of sputum is placed in one tube at the same time as the introduction of 1 ml. of glycerol into the other tube. Each tube rests on a modified hydraulic reference arm which, when released, smoothly lowers both tubes simultaneously to an angle of 45”.

The observer watches from a position vertically above the 20 cm. mark. Two stop watches, one for the glycerol and one for the sputum, are used to time the flow. The watches are stopped when the head of the column of glycerol or sputum crosses the 20 cm. mark. Pourability is expressed as a percentage of the ‘glycerol time’.

Pourability assessments were made in duplicate on specimens of sputum by the same observer.

Each patient was graded for dyspnoea’ before and immediately after the treat- ment periods. All side-effects were noted, direct questions being avoided.

Overall assessments of ‘respiratory disability’ were made by clinician and patient at the end of the trial, and recorded as unchanged, improved, or deteriorated.

Estimations of haemoglobin, mean corpuscular haemoglobin concentration, white cell count, and alkaline phosphatase (serum) were carried out at the beginning and end of the trial.

Results Twenty-eight patients completed the trial - 15 received S-carboxymethylcysteine, and 13 received bromhexine. Analysis of disease characteristics in all patients revealed that the two groups were comparable, in respect of severity of disease.

Two patients were withdrawn, one because of pronounced nausea and vomiting whilst receiving bromhexine, and the other because of failure to attend for assess- ments.

Sputum volume The mean daily volumes on alternate days are shown in Table I.

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Table I. Mean sputum volumes (ml.) f standard error of mean

Group Base- Day Two days line 1 3 5 7 9 M7 MT aftertrial

S-carboxymethyl- cys teine 21.5 24.5 32.5 36.8 36.2 31.0 32.75 32.2 25.6

rt2.3 1 1 . 9 1 2 . 8 h3.0 1 2 . 3 1 1 . 9 1 2 . 3 1 2 . 4 1.3.1

Bromhexine 23.0 23.6 25.6 24.4 37.3 32.4 27.72 28.7 20.8 1 2 . 5 *2.1 1 2 . 3 12.1 rt3.1 12.0 1 2 . 4 1 1 . 9 k2.7

M7 = Mean sputum volumes to Day 7 MT = Mean sputum volumes during total actual treatment period

The volumes are seen to increase during the administration of both drugs. How- ever, sputum volume increased earlier during treatment with S-carboxymethyl- cysteine, being noticeably higher on the third day of treatment. Sputum volumes did not increase to any extent until the 7th day of bromhexine administration. During the actual periods of treatment the mean daily volumes were 32.2 ml. for those on S-carboxymethylcysteine, and 28.7 ml. for those on bromhexine. This difference of 3.5 ml. is not significant, (p > 0.05). However, if the mean alternate daily volumes for the first 7 days of treatment are compared, i.e., 32.8 ml. on S-carboxymethyl- cysteine, and 27.7 ml. on bromhexine, this difference of 5.1 ml. is significant (p < 0.05). Since the patients were randomly allocated to each treatment group, the observed increase at this time seems most likely due to S-carboxymethylcysteine.

Respiratory volumes The results obtained with the Vitalograph and Wright’s Peak Flow Meter at the beginning and end of the treatment period are given in Table 11.

Table II. Mean F.V.C., F.E.V, (% predicted) and F.E.V,% and P.E.F.R% before and at the end of treatments

Measurement S-carboxymethylcysteine Bromhexine

F.V.C. 43.7 i 4.9 49.9 & 5.1 +6.2 53.1 1 4.3 58.7 rt 6.2 +5.6 F.E.V., 34.7 f 5.2 41.8 f 3.8 +7.1 32.0 i 3.6 37.3 1 3.2 $5.3 F.E.V.,s 43.8 f 3.6 45.9 1 4 . 1 +2.1 46.3 1 4.9 47.5 1 5.0 + 1.2 P.E.F.R. 56.7 f 4.1 62.8 f 5.6 +6.1 51.2 rt 7.3 56.4 1 6.1 +5.2

Note: None of the measurements exhibit a statistically significant difference between treatment groups. + = Standard error of mean.

Baseline Terminal Change Baseline Terminal Change

Both treatments were followed by moderate improvement in all indices, treat- ment with Scarboxymethylcysteine showing slightly more improvement compared with bromhexine. However, the differences between the treatment groups is not statistically significant for any of these measurements.

Table I11 shows the changes in assessment scores at the 5th and 10th days of treatment, expressed as percentages of baseline values. Sputum consistency, ease of expectoration and severity of cough show statistically significant improvement (p < 0.05) by Day 10 in both groups, and by Day 5 in the S-carboxymethylcysteine

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A between-patient, double-blind comparison of S-carboxymethylcysteine and brornhexine in chronic obstructive bronchitis

group alone. Improvement in frequency of cough and dyspnoea did not reach statistical significance in either group.

Table III. Mean assessment scores at Day 5 and Day 10 of treatment, expressed as a percentage of baseline values

\ ~ ? R Sputum Ease o f Severity of Frequency of' Dyspnoea consistency expectoration cough cough

Days Base 5 10 Base 5 10 Base 5 10 Base 5 10 Base 5 10

S-carhoxymethyl- cysteine group IOO",, 7.5. 66" IOO",, 50' 45' lOOu0 50' 49' IOOo,, 70 68 IOO", 75 70

Hrornhexine group loo",, 96 72' IOO", 69 56' IOO",. 68 52' loo0,, 80 69 IOO", 84 76

*Differences from baseline value staristically significant. p<O.O5

The final assessments by both clinician and patient are shown in Table IV. Both assessments of response to S-carboxymethylcysteine show a statistically significant improvement during therapy and both show response to be significantly better to S-carboxymethylcysteine than to bromhexine (p < 0.05).

Table IV. Patient and clinician assessment

Assessment S-carboxyrnethylcysteine Bromhexine Patient Clinician Patient Clinician

improved 1 1 10 5 6 Unchanged 3 4 6 7 Deteriorated 1 1 2 1

Side-eflects No significant changes were observed in haemoglobin values, MCHC, or serum alkaline phosphatase. In both groups there was a moderate reduction in total white cell count. One patient receiving bromhexine had to be withdrawn on the third day of the trial because of severe nausea and vomiting. One patient receiving S-carboxy- rnethylcysteine reported epigastric discomfort during the first 2 days of the treat- ment. No other side-effects were reported.

Pourability measurements The mean values of 'pourability time' are given in Table V. Estimations were carried out on the day before the trial, the 2nd, 4th, 6th, Sth, 10th day of the trial and 2 days after stopping treatment. The values shown in Table V are the means of the time for specimens of sputum to flow to a standard mark in the apparatus described above, expressed as a percentage of the time taken by pure glycerol under the same conditions. A decrease in sputum flow times is observed in both groups. However, there is a significant reduction at 4 days in the group receiving S-carboxymethyl- cysteine (p<O.O5) becoming highly sigmficant at 8 and 10 days (p<O.OI). The group receiving brornhexine did not exhibit a significant reduction in mean per- centage glycerol time until the 8th day estimation (p =0.05). On the 10th day the difference from baseline was highly significant (p < 0.01).

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Table V. Means of glycerol time (%) of sputum: assessment of apparent ‘pourability’ of sputum

Group Baseline Day Two days 2 4 6 8 10 after trial

S-carboxymet hyl- cysteine 646.2 682.4 322.8 240.2 119.6 120.0 480.6

540.6 550.1 129.6 &25.2 120.1 k18.6 k32.1

Brornhexine 651.4 678.6 568.7 490.6 210.4 168.6 499.9 f39.2 147.0 530.0 *27.3 h21.0 *21.6 k34.6

Means standard error of percentage glycerol time of expectorated sputum in both groups.

Discussion This double-blind controlled clinical trial shows that both S-carboxymethyl- cysteine and bromhexine increase sputum volume, reduce the viscidity, i.e., increase fluidity, of sputum and significantly improve the subjective assessments of ease of expectoration, severity of cough, and sputum consistency. However, S-carboxy- methylcysteine consistently produced an amelioration in all these indices at least 4 days before an improvement was observed with bromhexine. Furthermore, an overall clinical improvement in the respiratory state was found only in the group receiving S-carboxymethylcysteine.

No attempt was made to establish exact rheological indices for sputum before or after treatment. The method of measuring ‘pourability’ by comparison with pure glycerol in the apparatus described, however, is considered sufficiently sensitive to show a marked comparability of sputum-flow in both groups before and after treatment, and to demonstrate reduction in sputum viscosity during both treat- ments, as has been reported by other authors. It seems likely, therefore, that the greater increase in sputum flow rate under treatment with S-carboxymethylcysteine detected by this method is a valid observation.

The absence of significant improvement in ventilatory volumes and peak expiratory flow rates, although apparently paradoxical in the face of significant increases in sputum volume and ‘pourability’, is in line with some previous reports on both S-carboxymethylcysteine and bromhexine. Hamilton and his colleaguesg suggest that this lack of response may be due to severe and largely irreversible obstruction of airways by chronic inflammatory damage. However, other studies have shown measureable improvement in ventilation. Gent et ~ 1 . ~ used a smaller dose of bromhexine than administered in the present trial, and reported improve- ment in ventilatory function in patients with chronic bronchitis and asthma. Edwards’ 4 and Aylwardl3 have found that the dosage of S-carboxymethylcysteine used in this trial produced a significant effect upon F.E.V., and upon P.E.F.R., respectively.

In clinical terms, both Sadoul’O and Edwards et al.” agree in finding that the general state of the patient, as assessed subjectively and by the physician, improved during treatment with S-carboxymethylcysteine. There is less agreement on clinical improvement during bromhexine therapy, the findings of Gent et ~ 1 . ~ and Lang- lands8 being contradictory. This present study confirms a significant improvement

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A between-patient. double-blind comparison of Scarboxymethylcysteinc and bromhexine in chronic obstructive bronchitis

following S-carboxymethylcysteine, but found no significant improvement in the bromhexine group, considering patients’ and clinicians’ overall assessments.

It is arguable that these clinical changes are related to the observed mucolytic action of the two drugs. Bromhexine, which in this study was found to decrease sputum viscosity rather less, has been shown by Burgi et aZ.6 to alter the fibrillary structure of viscous mucus, probably by reducing the ionic forces which cause the macromolecules of polymucosaccharides to aggregate.3 S-carboxymethylcysteine exerts a similar action but also has been shown to disrupt the stronger disulphide bonding which cross-links the peptide chains of mucins.

There is also evidence of an effect upon the intracellular synthesis of mucins, possibly by reactivation of the enzyme sialyl transferase. These mechanisms may explain the greater clinical effect which S-carboxymethylcysteine appears to have.

No abnormalities were discovered in laboratory investigations, apart from a moderate fall in white cell count in both groups, consistent with recuperation from the acute exacerbation of their disease. Only two patients exhibited adverse reactions. One had to be withdrawn from the trial because of severe nausea and vomiting whilst receiving bromhexine, the other complained of epigastric dis- comfort which lasted 2 days during the administration of S-carboxymethylcysteine.

The results of former trials carried out with both these agents at this centre, and the results of the present study, support the findings of others that bromhexine and S-carboxymethylcysteine are valuable therapeutic agents in the treatment of patients with respiratory disease, where bronchial secretions are retained or difficult to expectorate.

Acknowledgements My thanks are due to Berk Pharmaceuticals Ltd. for supplying the drug as S-carboxymethyl- cysteine syrup (‘Mucodyne’)? 5% w/v, and to Mrs. Valerie Vale for clerical assistance.

References 1 , Vu-Ngoc-Huyen, Garcet, S., and Lakah, L., (1966). Methodes d‘ttude experimentale des modifications des secretions bronchiques. Sdonc. SOC. belge Biol., 160, 1849.

2. Quevauviller, A., Vu-Ngoc-Huyen, Garcet, S., and Lakah, L., (1967). Experimental hyper- secretion of bronchial mucus in the rat - application to the study of a mucolytic agent. Thdropie, 22,485.

3. Havez, R., Degand, P., Roussel, P., and Randoux, A.. (1970). Mode daction biochemique des derives de la cysttine sur le mucus bronchique. Poumon Coeur, 26,Sl . 4. Englehorn, R., and Pucchmann, S., (1963). Pharmacological studies on a substance with secretory activity. Arzneim.-forsch., 13,474.

5 . Boyd, E. M., and Sheppard, P., (1966). The expectorant activity of Bisolvon. A r c h . int. Phormocodyn. Thdr., 163,284.

6 . Burgi, H., (1965). Erste klinische-experimentelle erfahrungen mit dem mucolyticum Bisolvon. Sckweiz med. Wschr., 95,274.

+trade mark Berk Pharmaceuticals Ltd.

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7. Gent, M., Knowlson, P. A., and Prime, F. J., (1969). Effect of bromhexine on ventilatory capacity in patients with a variety of chest diseases. Lancet, 2, 1094. 8. Langlands, Jean H. M., (1970). Double-blind clinical trial of bromhexine as a mucolytic drug in chronic bronchitis. Lancet, 1,448. 9. Hamilton, W. F. D., Palmer, K. N.V.,and Gent, M., (1970). Expectorantactionofbromhexine in chronic obstructive bronchitis. Brit. rned. J . , 3,260. 10. Sadoul, P., (1970). Clinical utilisation of S-carboxymethylcysteine and its fluidifying effect on bronchial secretions. Unpublished, on files of Berk Pharmaceuticals Limited. 11. Edwards, G. F., Steel, A. E., and Leszczynski, S. 0.. (1970). The rheological effects of S-carboxymethylcysteine on sputum in chronic asthma and bronchitis. Communication at 3rd International Congress of Allergology, Florence. 12. Lemercier, J. P., Langlois, A., Michel, M. J., Laumonier, R., and Metayer, J., (1970). Clinical test on a new mucolytic agent, S-carboxymethylcysteine. Ouest rnPd., 23,411. 13. Aylward, M., (1972). An assessment of S-carboxymethylcysteine in the treatment of chronic bronchitis. Personal findings to be published. 14. Edwards, G. F., (1972). Clinical trials with fluidifying agents. Communication at Entretiens de Physio-pathologie respiratoire, 9eme serie, Nancy-Vittel. 15. Medical Research Council, (1965). Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet, 1,775.

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