THE CLINICAL EFFECT OF ERDOSTEINE ON ACUTE RESPIRATORY TRACT DISEASES IN CHILDREN
Balli F(1); Bergamini B(1); Calistru P(2); Ciofu EP(3), Domenici R(4); Doros G(5); Dragomir
D(6); Gherghina I(7); Iordachescu F(8); Murgoci G(9); Orasanu D(3), Plesca D(6); Vaccaro
A(4); Assereto R(10)
1. Department of Ginecology, Obstetrics and Paediatry, University of Modena, Italy 2. Infectious and tropical diseases Hospital “Prof. Dr. Victor Babes”, Bucharest,
Romania
3. Clinical Emergency Hospital for Children “Grigore Alexandrescu”, Bucharest, Romania
4. Paediatric Unit, Hospital “Campo di Marte”, Lucca, Italy
5. III Paediatric Clinic, Faculty of Medicine, University of Medicine and Pharmacy Timisoara, Romania
6. Clinical Hospital for children “Prof. Dr. Victor Gomoiu”, Bucharest, Romania 7. II Paediatric Clinic, Institute of Mother and Child Protection “Alfred Rusescu”,
Bucharest, Romania
8. Clinical Emergency Hospital for children “Marie Sklodowska Curie”, Bucharest, Romania
9. National Institute of Pneumology “Marius Nasta”, Bucharest, Romania 10. Edmond Pharma Research Department, Milano, Italy
Address for correspondence: Dr. Roberto Assereto MD, Edmond Pharma Srl, Via G.B. Grassi 15, 20157 Milano (Italy). Tel: +39.02.332078601 – Fax: +39.02.3570027 – E-mail: [email protected]
INTRODUCTION
Erdosteine is a mucoactive molecule discovered and developed by Edmond Pharma (Milan, Italy) and available on the market in about 30 Countries worldwide for the treatment of acute and chronic diseases of the lung.
The drug contains two blocked thiol groups (one of them in a thiolactone ring) that are stable in the gastric acidic environment. When the drug is exposed to an alkaline pH (e.g. in the intestine), the thiolactone ring opens giving a metabolite called Metabolite 1 (Met1) that has a free thiol group available; the pharmacological and clinical effects of erdosteine are mainly due to the activity of Met1. Thanks to the presence of the free SH-group in Met1, erdosteine is able to improve the rheology of sputum (1) and to increase the mucociliary clearance (2). Besides these “classic” activities, Met1 was demonstrated to significantly inhibit bacterial adhesion to mucosal cells (3); this activity is extremely important because bacterial adhesion to the mucosal cells of the respiratory tract is the first step of bacterial infections. The inhibition of the adhesion is due to the presence of the free SH-group that breaks the disulphide bonds of pilin, the major structural component of the bacterial fimbriae that allows the infective microorganisms to adhere to the bronchial mucosa. It is of interest to note that Met1 is active at concentrations that are easily attained in humans (3). Both “in vitro“ (4) and clinical studies (5-6) have demonstrated a synergistic activity of erdosteine with different antibiotics such as penicillines, quinolones and macrolides.
Another very important activity of Met1 is its potent antioxidant effect, again due to the presence of the SH-group. The importance of the so called Reactive Oxygen Species (ROS) in the initiation and maintenance of the inflammatory processes that are at the basis of both acute and chronic pulmonary diseases is now widely recognized by the
scientific community (7, 8). The active Met1 of erdosteine demonstrated a potent antioxidant activity “in vitro” (9, 10), in animal models (11, 12, 13, 14) and very recently in patients with COPD (15) and in healthy smokers (16).
Due to the described multiple mechanisms of action, erdosteine has shown in a great number of clinical trials a significant therapeutic activity in both acute and chronic diseases of the bronchopulmonary tract (17, 18, 19, 20). In the paediatric field Titti et al (21) showed in a randomised, double-blind, placebo-controlled trial that ampicillin in association with erdosteine was significantly more active than ampicillin plus placebo in the therapy of acute lower respiratory tract diseases. The tolerability of erdosteine in that paediatric population was excellent.
Aim of our study was to confirm and enlarge the results of the previous experiences with erdosteine in paediatric patients and to test the activity of erdosteine in association with a different antibiotic, amoxycillin. Amoxycillin was seleted for two reasons; first, it is an antibiotic widely used in the acute pathologies of the respiratory tract; secondly it has been shown that erdosteine is able to increase the concentration of amoxycillin in sputum of patients with acute infective exacerbations of chronic bronchitis (22).
MATERIALS AND METHODS
Study design. The study was a multinational (Italy and Romania), multicenter, fully randomised, double-blind, placebo-controlled trial in children with age between 2 and 12 years males and females, both in- and out-patients with a diagnosis of acute lower respiratory tract infective diseases for which an antibiotic therapy was envisaged.
Ethics. The study was GCP-driven according to the ICH E6 GCP Consolidated Guidance.
The trial was approved by the appropriate Ethical Committees in both Countries and it was performed in accordance with the principles of the Declaration of Helsinki and subsequent revisions (till Edinburgh 2000). Before initiation of any activity related to the trial a written informed consent in the presence of a witness was obtained from the parents. An insurance policy was issued to cover the risks arising from the participation to the trial.
Sealed envelopes with the indication of the treatment assigned were supplied for each patient; they had to be open only in the case of serious adverse events under the exclusive judgement of the attending Physician.
Sample size calculation
The sample size was calculated according to the algorithm of Snedecor on the basis of the following assumptions: (i) two-tailed test; (ii) % (estimated % size of the difference between the effects of the treatments derived from Ref. 21): 25%; (iii) d (variability measured on cough from the available data on erdosteine): 15; (iiii) Type I error: 0.05; (iiiii) Type II error 0.20.
On the basis of these assumptions the number of patients to be included was estimated to be around 80/group corresponding to a total of 160 subjects.
Inclusion/exclusion criteria.
Patients with age 2-12 years (in-and out-patients) of both genders with a diagnosis of acute lower respiratory tract diseases to be treated with antibiotics were eligible for the study provided that written informed consent was obtained.
Patients were excluded if they had a rapidly progressing disease, serious concomitant diseases (liver, blood, CNS, gastrointestinal, cancer etc.), drug hypersensitivity history,
or treatment with mucolytics, anti-cough, antibiotics, bronchodilators, steroids or oral non-steroidal antinflammatory agents in the last two weeks before admission to the study
Treatments
After enrollment patients were randomly allocated to the following treatment groups : Group 1: erdosteine dry syrup* (dosage according to age and weight from 5 to 15 ml/day
corresponding to 175 to 525 mg/day) plus amoxycillin syrup (dosage recommended by the producer according to weight and age) for 7 ± 1 days. Group 2: placebo dry syrup* (at the same doses in ml and indistinguishable from the
active) plus amoxycillin syrup at the same doses as for Group 1 for 7 ± 1 days. Concomitant therapies, including different antibiotics (in the case of suspected failure of amoxycillin according to the judgement of the attending physician) but excluding antitussive and mucoactive drugs, were allowed if needed provided that they were recorded in the Case Report Forms supplied for each patient.
Evaluation of efficacy
The primary efficacy parameter was cough that was evaluated by mean of a Visual Analogue Scale (VAS) of 100 mm were 0 = absent and 100 = maximal severity. The symptom was evaluated at baseline, at Day 3 and at the end of the treatment period. Secondary efficacy parameters were polypnoea, ronchi, rales (measured on a 100 mm VAS were 0 = absent and 100 = severe) and body temperature measured in C°. These parameters were evaluated at baseline and thereafter at the same time intervals as for cough.
Evaluation of safety
The occurrence of Adverse Events (AE’s) was strictly monitored throughout the study. AE’s definitions according to the actual international standards were provided in the Study Protocol.
If an AE occurred the eventual correlation with the study medications was to be assessed according to the usual criteria. AE’s were to be reported to the competent Health Authorities according to local legislations.
Heart rate and blood pressure were evaluated at baseline and at days 3 and 7.
The usual panel of laboratory tests plus C-reactive protein and mucoproteins were evaluated at baseline and at the end of the treatment period.
Statistical analysis
The statistical analysis was performed by mean of the SAS/PC package Release 8.2. The intention-to-treat analysis was performed.
The between-treatments comparison for the efficacy variables was performed by General Linear Model (GLM procedure). The comparison was performed with an ANOVA two-sided test. The following sources of variation were taken into account: time, treatments, the interaction time*treatment, centers, the interactions center* treatment and center*time. Moreover, with the GLM procedure the Bonferroni T-test was performed to test the differences between treatments and between times. Also, a T-test was performed to compare the treatments at every observation time
The laboratory parameters were analysed by a T-test comparing basal and final values. The significance level was set at 0.05.
Results
Nine Paediatric Centers ( 2 in Italy and 7 in Romania) took part in the study.
A total of 158 patients were enrolled: 78 in the erdosteine group and 80 in the placebo group.
The characteristics of the study population are shown in Table 1. There were no significant differences between the groups with regard to demographic or clinical characteristics.
3 patients, 1 in the erdosteine and 2 in the placebo group, were included in violation of the protocol for age >12 years; 2 patients in the erdosteine group were lost for follow-up at the Day 3 and at the final visit respectively. All these patients were included in the intention-to-treat analysis.
The two groups were comparable at baseline for age, sex, diagnosis and severity of signs and symptoms.
The mean duration of treatment was 7.28 days (range 3-9) and the mean dosage was 435.28 mg/day ( range 175-525).
The tolerability of erdosteine was excellent: no AE’s were reported and the statistical analysis did not reveal any significant modification of the laboratory data except for WBC, ESR, C-reactive protein and mucoproteins, all significantly decreased at the final control compared to baseline; these changes are clinically positive and reflect the progressive healing of the patients.
The primary efficacy parameter, cough severity (Table 2), at Day 3 decreased by 46.83% in the erdosteine group and by 33.36% in the placebo group compared to baseline; the difference is statistically significant (p<0.0001). At the final visit the
decrease compared to baseline was 89.66% and 73.94% in the erdosteine and placebo groups respectively; the difference is statistically significant (p<0.0001).
Table 3 reports the results for the secondary efficacy parameters. Polypnoea showed a similar decrease at Day 3 in both groups compared to baseline (57.79% and 54.79% respectively for erdosteine and placebo); the difference is not significant. At the final visit polypnoea was practically absent in both groups.
The intensity of the ronchi at Day 3 showed a decrease of 50.92% in the erdosteine group and of 43.93% in the placebo group; the difference is not significant. The decrease at the final visit was 91.82% for erdosteine and 82.95% for placebo (all compared to baseline). The difference is statistically significant (p<0.02) in favour of erdosteine.
The severity of rales at Day 3 decreased by 52.05% in the erdosteine group and by 43.10% in the placebo group and the difference is statistically significant in favour of erdosteine (p<0.05). At the final visit rales were practically absent in both groups, being the decrease vs.baseline 95.55% and 91.87% for erdosteine and placebo respectively with no significant differences.
Body temperature decreased similarly in the two groups with no significant differences at any observation time (data not shown).
The statistical analysis did not put in evidence any significant center effect nor time*center and center*treatment interactions.
DISCUSSION
The results of our study confirm those observed in the previous randomised trial by Titti et al. We can make this assertion because the design of the two studies was very similar (apart the different antibiotic that was ampicillin in the Titti study and amoxycillin in our trial), allowing for the data to be compared.
First of all, erdosteine proved to be well tolerated by the paediatric patients: no adverse events have been reported and no negative modifications were detected as far as the laboratory parameters are concerned. The formulation was also well accepted as far as the taste is concerned, as it is indicated also by the good compliance observed.
A good tolerability is always important for a drug treatment (“safety first”) but it is a key factor when we have to treat a paediatric population.
The comparison between the two treatment groups for the primary efficacy parameter cough, showed clearly better results of the combination erdosteine-amoxycillin against the combination of the antibiotic with placebo: the difference between the two treatment groups is not only statistically but also clinically significant; cough, in fact, is a very disturbing symptom, especially at night, and affects negatively the quality of life of the patient and of his/her parents: the rapid and consistent relief observed already at Day 3 in the erdosteine group with a decrease in the severity of around 48% is, therefore, to be considered clinically relevant.
As for the other parameters, polypnoea showed a good and similar decrease in both groups, mainly reflecting the action of the antibiotic therapy as one could expect.
It is of interest to note that the rales, indicators of mucus excessive production and stagnation in the airways, were improved by erdosteine more rapidly than placebo, as indicated by the significant difference at Day 3.
Again it is not surprising that the difference at the end of the treatment period was not significant: the patients were practically healed as expected after 7 days of antibiotic therapy.
The ronchi showed a similar trend in both groups: even if at Day 7 there was a statistically significant difference between the two groups in favour of erdosteine, this difference, in our opinion, is to be considered not clinically relevant.
The excellent results obtained in our trial are possibly explained by the multiple mechanisms of action of erdosteine that we have described above, that lead to a good synergistic action with antibiotics without any additional toxicity, as reported in the previous clinical experiences with the drug in both adults and children.
According to our results, however, it seems that in the acute conditions that we have treated the prevalent activity is that on mucus, as it is suggested by the significant improvements of cough and rales.
On the basis of the results of our controlled study we can conclude that erdosteine in combination with amoxycillin allows for a more rapid improvement of the clinical conditions of paediatric patients affected by acute diseases of the lower respiratory tract and that this effect is associated with an excellent tolerability that is of a paramount importance especially in children.
Aknowledgments
The Authors wish to thank Edmond Pharma (Milan, Italy) for financial support and for providing the blinded study medications and amoxycillin. The contribution of Dr. C. Montoro (Milan, Italy) to the statistical analysis of the data is also greatly aknowledged.
REFERENCES
1. Busin S., Clerici R. et al. Erdosteine: evaluation of mucorheological and immunosecretory parameters in patients with bronchial phlogistic pathology. Med. Praxis, 12, 197, 1991.
2. Olivieri D., Del Donno M. et al. Activity of erdosteine on mucociliary transport in patients affected by chronic bronchitis. Respiration, 58, 91, 1991.
3. Braga P.C., Dal Sasso M. et al. Effects of erdosteine and its metabolite on bacterial adhesiveness. Arzneim.-Forsch./Drug Res., 49, 344, 1999.
4. Braga P.C., Zuccotti T. et al. Bacterial adhesiveness: effects of the SH metabolite of erdosteine (mucoactive drug) plus clarithromycin versus clarithromycin alone. Chemotherapy, 47, 208, 2001.
5. Marchioni C.F., Polu J.M. et al. Evaluation of efficacy and tolerability of erdosteine in patients affected by chronic bronchitis during an infective exacerbation phase and receiving amoxicillin as a basic treatment. Int. J. Clin. Pharmacol. Therap., 33,162, 1995.
6. Mohanty K.C. Thiappanna G. et al. Evaluation of efficacy and safety of erdosteine in patients affected by exacerbation of chronic bronchitis and receiving ciprofloxacin as basic treatment. J.Clin.Res., 4, 35, 2001.
7. MacNee W., Rahman I. et al. Oxidants and antioxidants as therapeutic targets in COPD. Am. J. Respir. Crit. Care Med., 160, S58, 1999.
8. Repine J.E., Bast A. et al. Oxidative stress in COPD. Am. J. Respir. Crit. Care Med., 156, 341, 1997.
9. Hosoe H., Kaise T. et al.Effects on the reactive oxygen species of erdosteine and its metabolite in vitro. Arzneim.-Forsch./Drug Res., 52, 435, 2002.
10. Myiake K., Kaise T. et al. The effect of erdosteine and its active metabolite on reactive oxygen species production by inflammatory cells. Inflamm.Res., 48, 205, 1999.
11. Yildirim Z., Turkoz Y. et al. Effects of aminoguanidine and antioxidant erdosteine on bleomycin-induced fibrosis in rats. Nitric Oxide, 11(2), 156, 2004.
12. Terzi A., Iraz M. et al. Protective effect of erdosteine on rotenone-induced oxidant injury in liver tissue. Toxicol. Ind. Health., 20(6-10), 141, 2004.
13. Gurel A., Armuctu F. et al. Erdosteine improves oxidative damage in a rat model of renal ischemia-reperfusion injury. Eur. Surg. Res., 36(4), 206, 2004.
14. Koc A., Duru M. et al. Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats. Mol. Cell. Biochem., 278(1-2), 79, 2005.
15. Dal Negro R.W., Visconti M. et al. Erdosteine 900 mg/day affects substantially blood ROS, e-NO and some chemotactic cytokines from bronchial secretions of current smokers. A pilot study. Am. J. Respir. Crit. Care Med., Suppl. Issue 2, A89, 2005
16. Basyigit I., Yildiz F. et al. Effects of erdosteine on smoking-induced lipid peroxidation in healthy smokers. Drugs RD, 6(2), 53, 2005.
17. Sulsenti G. Erdosteine in acute, subacute and chronic exacerbated rhinopharyngitis and pharyngo-laryngotrachitis: study of efficacy and tolerability. Med. Praxis, 13, 155, 1992.
18. Bisetti A., Mancini C. Mucolytic activity of erdosteine: double blind clinical trial vs.placebo. Arch. Med. Int., 47(4), 1995.
19. Aubier M., Berdah L., Etude multicentrique un double aveugle de l’efficacité et de la tolerance de Vectrine (erdosteine) versus placebo dans le traitement de la bronchite chronique hypersecrétante stabilisée. Rev. Mal. Respir., 16, 521, 1999 20. Moretti M., Bottrighi P. et al., The effect of long-term treatement with erdosteine on
COPD: the EQUALIFE study. Drugs.Exptl. Clin.Res. XXX(4), 143, 2004
21. Titti G., Lizzio A. et al. A controlled multicenter paediatric study in the treatment of acute respiratory tract diseases with the aid of a new specific compound,erdosteine. (IPSE, Italian Paediatric Study Erdosteine). Int. J. Clin. Pharmacol. Ther., 38, 402, 2000
22. Ricevuti G., Mazzone A. et al. Influence of erdosteine, a mucolytic agent, on amoxycillin penetration in patients with an infective exacerbation of chronic bronchitis. Thorax, 43, 585, 1988
SUMMARY
Erdosteine has positive effects on mucus rheology and transport; thanks to its active Metabolite I containing a free thiol group erdosteine inhibits bacterial adhesiveness and has antioxidant properties. A synergistic effect of erdosteine with different antibiotics was demonstrated in pharmacological and clinical studies.
The present study was a multicenter, randomised, double blind, placebo-controlled study aimed at comparing the combination of erdosteine with amoxycillin with the antibiotic associated with placebo in paediatric patients with acute lower respiratory tract diseases. 158 patients (78 in the erdosteine and 80 in the placebo group) were treated for 7±1 days. The efficacy parameters were cough (primary), polypnoea, ronchi, rales and body temperature (all measured at baseline, at Day 3 and at the end of treatment).Safety was assessed by strictly monitoring the occurrence of adverse events and by the usual laboratory parameters. The results of the intention-to-treat analysis showed that cough severity was decreased by 47% at Day 3 in the erdosteine group with a statistically significant difference compared to placebo; the difference was still significant at the final visit. Also the rales severity showed a significant greater decrease at Day 3 in the erdosteine group compared to placebo. Polypnoea and ronchi showed similar decreases in both groups, mainly reflecting the healing of the patients due to the antibiotic. No adverse events occurred and no negative modifications of laboratory parameters were observed.
It is concluded that the combination of erdosteine with amoxycillin is clinically superior to that of the antibiotic with placebo especially on the most disturbing symptom cough. The safety of erdosteine was excellent.
Table 1: Characteristics of the patients ITEMS ERDOSTEINE GROUP PLACEBO GROUP ALL CASES No. of cases 78 80 158
Sex (no.) Male Female 36 42 49 31 85 73 Age (years) Min
Max Mean 2 13 6.94 2 15 6.90 2 15 6.92 Height (cm) Min Max Mean 86 155 120.27 81 175 120.68 81 175 120.72 Weight (kg) Min Max Mean 11.7 57 24.38 10.5 65 24.81 10.5 65 24.60 Diagnosis (no. of cases)
Bronchitis Pneumonia Tracheobronchitis 36 22 20 30 28 22 66 50 42 Treatment duration (days) Min Max Mean 3 8 7.26 5 9 7.28 3 9 7.28 Posology (mg/day) Min Max Mean 175 525 448.71 175 525 422.19 175 525 435.28
Table 2: Primary end-point: cough severity values on VAS (*) (Mean ± SD)
ERDOSTEINE
GROUP PLACEBOGROUP P
Basal 63.27±15.15 67.08±12.85 ns
Day 3 33.64±13.31 44.70±13.94 <0.0001
Final 6.54±527 17.48±11.26 <0.0001
Table 3: Secondary end-points values on VAS (*) (Mean ± SD) ERDOSTEINE
GROUP PLACEBOGROUP P
Polypnea Basal 21.96±18.32 28.00±19.43 ns Day 3 9.27±12.66 12.66±13.73 ns Final 0 0.50±3.52 ns Rhonchi Basal 45.86±24.56 45.39±23.04 ns Day 3 22.51±15.89 25.45±18.25 ns Final 3.75±5.42 7.74±9.73 <0.002 Rales Basal 41.38±25.10 44.43±22,04 ns Day 3 19.84±15.51 25.28±17.78 <0.05 Final 1.84±4.08 3.61±8.99 ns
