an assessment of s-carboxymethylcysteine in the treatment of chronic bronchitis

Current Medical Research and Opinion Vol. 2, No. 7, 1974

An assessment of S-car box ymeth ylc ysteine in the treatment of chronic bronchitis

Mansel Aylward,* M.D., B.Sc.. M.R.C.S.

Research Division, Merthyr General Hospital, Merthyr Tydfil, Wales

Curr. med. Res. Opin., (1974), 2, 387.

Summary A single-blind study is reported of S-carboxymethylcysteine, administered as a 5 % wlv syrup at a dosage of 3 x 5 ml. three times daily, compared with placebo therapy in the treatment of 30 patients with chronic bronchitis.

The great majority of patients reported greater ease of expectoration, decrease in severity and frequency of coughing, and an increase in the volumes of sputum e.upectorated, A statistically signijicant increase in PEFR, accompanied by an improvement in the severity of dyspnoea and functional grade was recorded; these indices deteriorated follo wing the withdrawal of S-carboxymethylcysteine.

Overall clinical assessment at the end of a period of 8 weeks (bweeks baseline therapy on placebo followed by 6-weeks treatment with S-carboxymethylcysteine syrup) indicated that 23 patients had improved and none had deteriorated. Deteri- oration in all parameters occurred after withdrawal of the drug.

Received: 10th August, 1974

Key words: Bronchitis - S-carboxymethylcysteine - mucolytic agents

Introduction Clinical experience with S-carboxymethylcysteine has shown that oral administration of this drug significantly reduces sputum viscosity, this reduction occurring about the third to sixth day following administration of the 5 % w/v syrupt at a dosage of 15 ml. 3-times Increase in sputum volume has also been observed at this time, together with significant objective clinical benefit, and subjective improvement in the greater ease of expectoration. However, Edwards et a1.2 and Aylwardl discovered no significant effect of S-carboxymethylcysteine on changes in ventilatory volumes, when administered to chronic bronchitis in the short term. On the other hand, Lemercier et al.4 have reported an improvement in ventilatory function, a decrease in dyspnoea, and a decrease in sputum viscosity in patients receiving S-carboxymethylcysteine orally.

Since it is essential in the management of a disease process to obtain improvement in patient disability as a response to therapeutic procedures, it seemed desirable to assess the effects of prolonged treatment with S-carboxymethylcysteine

*Clinical Research Consultant YMucodyne’ Syrup, trade mark Berk Pharmaceuticals Limited

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An assessment of Starboxymethylcysteine in the treatment of chronic bronchitis

in patients with chronic bronchitis and to study the changes in the symptomatology of the patient during treatment.

Material and method Scope of investigation Patients were drawn from a predominantly working class urban district set in a coal-mining area. Many of the middle-aged and elderly patients had been occupied in the mining industry and pneumoconiosis was quite common in the sample of patients studied in this trial. No age group was studied specifically, but only those were included who had chronic bronchitis (M.R.C. criteria5) and who expectorated mucoid viscid sputum. Since the aim was to gain a preliminary evaluation of the therapeutic efficacy of S-carboxymethylcysteine before embarking upon more controlled trials, it was decided to adopt a single-blind technique. To this end, a number of complementary parameters were incorporated in the trial, improvement in which would be considered as showing evidence of drug activity.

Patients Thirty patients were admitted to the study during the winter months, October to December, and following initial assessment, further assessments were carried out by the same clinician at fortnightly intervals for a total study period of 12 weeks.

Each patient received a ‘placebo’ syrup, identical in appearance and taste with the ‘active ’syrup, for the 2iweek period following initial assessment. After the second assessment, S-carboxymethylcysteine syrup (5 percent w/v) was substituted for the placebo syrup, and patients continued to receive the active treatment for 6 consecutive weeks, before being crossed over, once again, to the placebo syrup for a further 4 weeks. Patients were instructed to take 3 x 5 ml. spoonfuls of syrup provided, 3 times per day.

No changes were made in the treatments of patients during the study period of 12 weeks.

Assessments A special proforma was completed by each patient for each day of the study, in which the following parameters of response were scored according to a simple 5-point scale, (i.e. much improved =4, better = 3, no change =2, worse = 1 , much worse = 0) : (i) the frequency and character of cough, (ii) the frequency and seventy of nocturnal cough, and (iii) the ease of expectoration.

In addition, the volume of sputum produced in the first hour after rising was measured by the patient on alternate days of the study, a graduated test tube being provided for this procedure. Certain characteristics of the sputum were also analysed in a simple manner: on alternate days during the trial the patients were asked to grade the colour and consistency of the sputum produced in the first hour,

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Mansel Aylward

on a 4-point scale (from 0 =jellylike, no watery content to 3 =runs like water). These parameters of volume and consistency were also checked by the clinician on the assessment days.

Patients were also graded for dyspnoea (M.R.C. Criteria5) and placed in severity classes based upon their incapacity as an indication of their ability to perform everyday activities. Peak expiratory flow rate (PEFR) was also measured at each assessment with a Wright’s Peakfl ow Meter. Any episodes of infection were recorded. Side-effects were noted, direct questions being avoided.

A global assessment was recorded at each assessment denoting change in general health and scored on a 3-point scale (improved + 1 ; unchanged 0; deteriorated -1).

Results Thirty patients were admitted to the study. None was withdrawn, although 1 patient could not be followed after the ninth week of the study as he was admitted to hospital for re-assessment of his pneumoconiosis. Analysis of the patients by clinical diagnosis is shown in Table I. Table 1. Patient characteristics in the diagnostic groups included in the study

Diagnosis No. patients ~~~ ~ ~

Chronic bronchitis 10 Chronic bronchitis with emphysema 9 Asthma with chronic bronchitis 2 Chronic bronchitis, pneumoconiosis 9 and emphysema

Total 30

Malelfemale ratio 4:l *Mean length of history (years) f S.E. Non-smokers/smokers ratio 8 :22

*The length of patients’ histories ranged from 4) to 43 years

There were 26 men and 4 women, aged 25 to 72 years (average age, 53.2) all of whom had tenancious, viscid, mucoid sputum. No patient had received any mucolytic agent or expectorant during the 2 weeks they were monitored prior to admission to the study. However, 7 patients received oxytetracycline (1.0 g./day) for periods varying from 5 to 7 days during the fortnight prior to inclusion.

Table I1 shows the percentage change in the mean of the assessments made by the clinician, and Table I11 the mean changes in PEFR recordings. Analysis of each patient’s completed proforma was made at the end of the 12 weeks of treatment and the results of the various measurements were plotted against time (Figure I).

The results indicate that there was a tendency for all parameters of response to improve during the 6 weeks of treatment as compared with baseline values and those obtained during the 2-weeks prior to the administration of S-carboxymethylcysteine. It is notable that the various measures of response changed in a

27 f 2

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An assessment of S-carboxymethylcysteine in the treatment of chronic bronchitis

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Table II. Mean values of clinician’s assessment at each attendance (expressed as % initial values)

Assessment Placebo S-carboxymethylcysteine Placebo

20 -

Week 0

Dyspnoea (M.R.C.) 100 Sputum volume 100 Sputum consistency 100 Sputum colour 100 Frequency of cough 100 Severity of cough 100 Incapacity 100 Ease of expectoration 100

I I S- carboxymethylcysteine

t , , , , , , , , , , , , , . , , , , , , , , , , , , , , ~

2

85 81

100 89

100 88 96

104

4

72 168* 54’ 72* 70 * 50* 84 49 *

6

52* 156* 45* 76* 55* 48* 68* 50*

8

36* 136* 29* 73* 59* 42* 58* 40 *

10

110 112 59* 88 71 64* 83 69

12

140 98 89 86 79 74 82 71

-

*Statistically significant change (p < 0.05) from Week 0 and Week 2

Figure 1. Percentage change in means of indices monitored by the patients on alternate days. S-carboxymethylcysteine administered in a dosage of 3 x 5 ml. t.d.s. (5% syrup) from Day 14 to Day 56. (N=30)

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Sputuni volume D-a. Difficulty of expectoration &

Cough frequency M

Sputum thickness M

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Manse1 Aylward

PEFR during the administration of the drug, such that at the second week of the administration there was a statistically significant increase in PEFR (p< 0.05), which increase was maintained throughout the remainder of the study. The grades of dyspnoea, obtained with the ‘M.R.C. Short Questionnaire’, showed an improvement throughout the period of treatment with S-carboxymethylcysteine. At the end of the 6-week treatment period the dyspnoeic index, expressed as the percentage change in the means, was -36 percent.

Table 111 also shows the overall assessment by the clinician of the patients at each attendance. After 2-weeks treatment with S-carboxymethylcysteine, 60 % were considered improved and 40% unchanged; at the end of the period on S-carboxymethylcysteine 77.3 % were assessed as improved and 22.6 % unchanged. None were considered to have deteriorated. Following withdrawal of S-carboxymethylcysteine there was a deterioration in all parameters recorded at the tenth week and twelfth week assessments. Table III. Changes in mean PEFR at each attendance, and cumulative percentages of patients classihed as improved, no change, or deteriorated

Assessment Placebo S-carboxymethylcysteine Placebo

Week 0 2 4 6 8 10 12

PEFR (l/min.) 148 135 192* 189* 210* 130 146 Mean f S.E. &23 1t26 &29 &31 &33 . &29 &32 Percentage of initial mean 100 91 130 128 142 93 98

Cumulative percentage of patients: Improved 3.3% 60.0% 66.7% 71.3% 33.3% 22.7% No change 20.1% 40.0% 33.3% 22.7% 66.7% 77.3% Deteriorated 76.6%

*Statistically significant change (p <0.05) from Week 0 and Week 2

Side-eflects Three patients complained of side-effects during the study, none of which were serious. One patient reported headache and insomnia during the first 2 weeks of the administration of S-carboxymethykysteine, and 2 patients reported heartburn (1 case) and nausea (2 cases), again during the first 2 weeks of the trial. No other possible adverse effect was reported.

Concomitant drug therapy Twenty-two patients had required no antibiotic therapy throughout the whole study. Three patients during the first 2 weeks prior to S-carboxymethylcysteine were given antibiotics for 4 days because of mucopurulent sputum and 5 patients required antibiotics for the same reasons during the second and third week of S-carboxymethylcysteine treatment. Diprophylline tablets 200 mg., 1 or 2 tablets 3-times daily, had been taken by 4 patients for at least 3 months prior to the study, and they were allowed to continue with these. No bronchodilators or expectorant

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therapy were prescribed to any of the other patients participating. A check on the containers at each assessment period indicated that the medication had been taken.

Discussion This study is open to criticism since a double-blind technique was not employed and, therefore, the improvement noted might be explained as due to time, or the operation of known or unknown factors in the environment. Since it was decided to admit only those patients with chronic bronchitis who had mainly mucoid sputum, it was foreseen that the number of patients would be limited. Thus a ‘between-patient study’ was rejected because the adoption of such a technique might have reduced the number of patients on the active treatment, and the possibility of an influenza epidemic might further have reduced the number of patients fulfilling the requirements of the study. Since it was a further intention to administer S-carboxymethylcysteine over a reasonably long period during the winter months, a crossover technique was not considered practicable. The admission of suitable patients in time to allow all to receive 12-weeks treatment before the end of the winter was thought impracticable.

It was considered that any improvement maintained throughout the study and reflected in several complementary parameters was most probably due to a beneficial effect of the drug S-carboxymethylcysteine, since the assessments at 2 weeks and at 4 weeks after withdrawal of S-carboxymethylcysteine indicated a deterioration in all of the parameters recorded.

The decrease in tenacity and consistency of the sputum supports the observa- tions of Sadoul et u I . , ~ Edwards et a1.,2 and Ay1ward.l Furthermore, it was noted that in the present study the increase in sputum volumes accompanied by ease of expectoration and the subjective assessments of decrease in tenancity and viscidity, occurred after the fourth day of administration of S-carboxymethylcysteine and were maintained throughout the period of the study. Reduction in the objective, quantitative measurements of viscosity of sputum produced by oral S-carboxymethylcysteine was found to occur at this time by Sadoul et al.7

Although sputum volumes decreased during the final fortnight of treatment with S-carboxymethylcysteine, the mean values remained 36 % above initial mean values. This decrease in volume was accompanied by maintained ease of, and reduced frequency of, coughing, and might be explained by an increasing tendency to swallow the less viscid sputum rather than to expectorate it.

It would seem that the results achieved showed a significant effect of S-carboxymethylcysteine. The decrease in sputum consistency is in agreement with the results from the controlled studies by Sadoul7 using a Haake rotating cylinder viscometer and by Aylwardl using an objective estimation of sputum ‘pourability’. This decrease in the viscidity of the sputum was reflected in greater ease of expectoration plus decreased frequency and severity of cough. Also, as reported by Sadou17 and Aylward,’ sputum volumes increased during S-carboxymethylcysteine therapy. In clinical terms, these authors agree in finding that the general state of the patient,

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as assessed subjectively and by the physician, improved during treatment with this drug.

The recorded improvement in PEFR in the present study supports the results obtained by Lemercier et al.4 in their patients who had received an average of 30 days S-carboxymethylcysteine therapy. This increase in ventilatory function was accompanied by a decrease in dyspnoea and an improvement in the patients’ clinical state.

It is highly likely that the clinical changes reported here are related to the observed mucolytic effect of the drug. Biochemical studies in man have shown that S-carboxymethylcysteine disrupts the disulphide bonds which cross-link the peptide chains of mucins, which network is responsible for increasing the viscosity of bronchial secretion^.^

It is not possible with such a preliminary trial to establish the reasons for the observed increase in PEFR in the population studied. However, 14 of the patients included were known cases of minimal or non-reversible obstructive airways disease; thus is it quite possible that the favourable effect upon PEFR may have been a direct consequence of an action upon sputum.

The beneficial effects are unlikely to be an artifact due to the patients’ learning to use the Wright’s Peakflow Meter, since they were well versed in its use prior to the study. The negligible incidence of side-effects confirms the low toxicity reported in other studies.

Conclusions The results of a single-blind, placebo incorporated, study of S-carboxymethylcysteine in the treatment of chronic bronchitis indicate that this new mucolytic agent effectively changed the consistency of sputum, with resultant ease of expectoration and the expectoration of increased volumes of such sputum. There was notable improvement in symptomatic indices monitored and peak expiratory flow rates. No side-effects of clinical significance were reported.

Acknowledgements I wish to express my thanks to Berk Pharmaceuticals Limited for supplying the drug as S-carboxymethylcysteine syrup (‘Mucodyne’) 5% w/v and to Mrs. Sandra Thomas for her invaluable secretarial assistance.

References 1 . Aylward, M., (1973). A between-patient, double-blind comparison of S-carboxymethylcysteine and bromhexine in chronic obstructive bronchitis. Curr. med. Res. Opin., 1,219. 2. Edwards, G. F., Steel, A. E., and Leszczynski, S. O., (1970). The rheological effects of S-carboxymethylcysteine on sputum in chronic asthma and bronchitis. Communication at 3rd International Congress of Allergology, Florence. 3. Havez, R., Degand, P., Roussel, P., and Randoux, A., (1970). Mode d’action biochemique des derives de la cystkine sur le mucus bronchique. Poumon Coeur, 26,81.

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4. Lemercier, J. P., Langlois, A., Michel, M. J., Laumonier, R., and Metayer, J., (1970). Clinical tests on a new mucolytic agent, S-carboxymethylcysteine. Ouest mid., 23,411.

5. Medical Research Council, (1965). Definition and classification of chronic bronchitis for clinical and epidemiological purposes. Lancet, 1,775.

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

7. Sadoul, P., (1970). Clinical utilization of S-carboxymethylcysteine and its fluidifying effect on bronchial secretions. In press.

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an assessment of s-carboxymethylcysteine in the treatment of chronic bronchitis

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