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Erdosteine: a New Therapeutic Weapon Beyond the PEACE

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Erdosteine: a New Therapeutic Weapon Beyond the PEACE Review Erdosteine: a new therapeutic weapon beyond the PEACE Summary Due to its multiple mechanism of actions, Erdosteine can be considered one of the most interesting thiol in the long term treatment of COPD and its exacerbations. New findings confirm the potential of this molecule to exceed the PEACE study results, as expected after the RESTORE study conclusion, and they open an additional space for clinical research to treat patients with resistant infections or comorbidity associated to COPD. Cogo R. Erdosteine: a new therapeutic weapon beyond the PEACE. Trends Med 2012; 12(3):133-142. ©2012 Pharma Project Group srl. ISSN: 1594-2848 Key words: he growth of mortality re- is therefore an ongoing commit- erdosteine Tlated to COPD is being well ment for the scientific commu- PEACE confirmed by the World Health nity. It has been following two COPD Organization in its most recent major paths: the discovering of RESTORE studies. The table below shows new drugs and the best admini- the evolution of the importan- stration of already known drugs. ce of COPD and its relative For years the major efforts have importance among the other been focused on the first path major causes of mortality. but, given the very few new Ageing population and increa- drugs developed in the last ye- sing pollution are among the ars, the importance of the se- major factors for the COPD cond path is growing. evolution (Table 1). The pneumologist community The research of more and more had always considered mucolyti- effective therapeutic approaches cs necessary for the treatment Table 1. Change in rank order of deaths for the 10 leading causes worldwide2. 2002 2030 1. Ischaemic heart disease 1. Ischaemic heart disease 2. Cerebrovascular disease 2. Cerebrovascular disease 3. Lower respiratiory infections 3. HIV/AIDS 4. HIV/AIDS 4. Chronic obstructive pulmonary disease 5. Chronic obstructive 5. Lower respiratory infections pulmonary disease 6. Perinatal conditions 6. Diabetes mellitus 7. Diarrhoeal disease 7. Trachea, bronchus, lung cancer 8. Tuberculosis 8. Road traffic accidents Roberto Cogo Riab. Respiratory 9. Trachea, bronchus, lung cancer 9. Tuberculosis Hospital A. Zappatoni Cassano d’Adda (MI), Italy 10. Road traffic accidents 10. Perinatal conditions July 2012 Volume 12 Number 3 Trends in Medicine 133 R. Cogo Figure 1. Probability of exacerbation1. of COPD, but the “evidence of 600 mg a day associated with the related mortality of this pa- based medicine” had rightly topical steroid therapy is “inef- thology we need a step further. asked for clear results on life fective” in slowing the progres- The RESTORE study is still on expectancy and quality of life. sion of the disease1. going in 10 countries, with re- In this scenario three large in- The PEACE study, gave signi- sults expected in 2014. After the ternational studies have been ficant results which allowed Car- PEACE study and waiting for planned and developed with si- boxymethylcysteine to be inclu- the RESTORE conclusion it is milar objectives on the most ded in the recent update of the important to reconsider and re- known thiols with a solid clini- GOLD guidelines among the evaluate the old and the new cal experience on the mucus treatment options for COPD2. scientific data on Erdosteine. rheological changes, the N-Ace- Carbocisteine demonstrated a Erdosteine, N-(carboxymethyl- tilcysteine (NAC) (BRONCUS significant effect on exacerba- thioacetyl) homocysteine thio- study1), the Carboxy-methylcy- tions and improvement in he- lactone, is the most recent drug steine (PEACE study2), and the alth-related quality of life (Fi- developed in its class. Erdosteine (RESTORE study). gure 1). The molecule of Erdosteine is Besides to their clinical expe- Despite this promising results, characterized by the presence of rience, the choice of these sub- that confirm the role that thiols a carboxylic acid group and of stances is based on their meta- could play in the treatment of two sulphur atoms (Figure 2). bolic role rather than their ac- COPD, due to the severity and Erdosteine is quickly absorbed tions on mucus. Indeed, in or- der to achieve significant resul- ts in the prevention of relapses Figure 2. Chemical structure of erdosteine. and reducing the progression of COPD is necessary to rely on effective antioxidant activity, bacteria anti-adhesion and an- tinflammatory effect. The addi- tional organ protection is a very desirable therapeutical target. The BRONCUS and the PEA- CE study have been completed and published1,2. The BRONCUS, perhaps be- cause of an inadequate thera- peutic dose of NAC has not met the expected results and its con- clusions are that the NAC dose 134 Trends in Medicine July 2012 Volume 12 Number 3 Erdosteine: a new therapeutic weapon beyond the PEACE after oral administration and ra- tum viscosity at day 3 (-15.8%; pidly transformed through a p<0.001) and at the end of tre- This active metabolite of first-pass metabolism to a bio- atment (-39.6%; p<0.001) (Fi- Erdosteine - Met I - is for- logically active metabolite – N- gure 3)3. med by the opening of the thiodiglycolyl-homocysteine A second placebo-controlled thiolactone ring with for- (Met I). The chemical structu- study in patients with stable mation of a free thiol (SH) re of Erdosteine results in a chronic obstructive bronchitis group. compound with a unique multi- (COB) concluded that Erdoste- factorial mechanism: Muco- ine provides a statistically signi- ched a rate comparable to that modulatory, Anti-oxidant activi- ficant decrease in the glycopro- of healthy non-smokers in ty, Bronchial anti-infammatory tein content of mucus (reduc- 37.5% of patients in the Er- and Bacterial anti-adhesion (Fi- tion in the macromolecular dry dosteine group5 (Figure 4). gure 2). weight of mucus)4. Erdosteine improves the muco- Anti-oxidant activity Muco-modulatory ciliary clearance indirectly through its effect on mucus The direct free-radical scaven- activity rheological properties, and by ging activity of Erdosteine, Met The muco-modulatory activity directly acting on ciliary move- I, NAC, S-carboxymethylcistei- of Erdosteine improves the ment. ne (S-CMC), and Ambroxol has mucus rheological characteristi- The effect of Erdosteine on been examined in vitro by de- cs in terms of viscosity, elastici- mucociliary transport has been termining their effects on the ty and biochemical composition: specifically demonstrated in a luminol-dependent chemilumi- this is due to the active metabo- double blind, placebo-control- nescence (LDCL) 6,7. (Figure 5). lite I that contains the SH group led study. Patients were treated The LDCL of human neu- that cleaves the disulphide bon- for eight days with either pla- trophils was statistically signifi- ds in mucin glycoproteins. cebo or Erdosteine and the mu- cantly inhibited by Met I, from The effect of Erdosteine on cociliary transport (MCT) as- a concentration of 100 µmol/ rheological characteristics of the sessed using a modified bron- L (p<0.05). This value was mucus was evaluated in patien- cho-fiberoscopic technique5. found to be similar to that obtai- ts with an exacerbation of chro- Erdosteine induced a statistical- ned by reduced glutathione nic obstructive bronchitis3. ly significant mean MCT chan- (GSH) under the same test con- Comparison with each study ge of +60.4% versus -3.0% re- ditions. All other tested mole- group, revealed that patients re- ported for placebo-treated pa- cules were found to be inactive ceiving Erdosteine experienced tients (p<0.01). Moreover, mu- at this concentration. a significant reduction in spu- cus transport progression rea- Erdosteine confirmed to affect Figure 3. Mean sputum viscosity before and after treatment with Erdosteine or placebo (p<0.001 vs baseline)3. July 2012 Volume 12 Number 3 Trends in Medicine 135 R. Cogo Figure 4. Mean values (±SD) of mucociliary transport (MCT) before and after treatment with Erdosteine or placebo (p<0.01)5. substantially ROS in peripheral Polymorphonuclear neutrophi- sonide and Met I on the pro- blood: the effect confirmed ra- ls (PMNs) can generate supero- duction of harmful oxidants pid in onset and proved of ma- xide anions and nitric oxide such as peroxynitrites. Chemi- ximal extent following a 4-day (NO), which reacting can pro- luminescence generation during treatment, while the effect of duce peroxynitrite anions stimulated respiratory bursts of placebo was absolutely negligi- (ONOO-), a potent and poten- human neutrophils was measu- ble at any time7. tially toxic oxidant. Also in this red as a marker of ROS produc- Furthermore, the reduction in case, Met I showed a marked tion9. When the two drugs were ROS levels observed in the Er- inhibition of the ROS peroxy- combined, there was a greater dosteine-treated patients is si- nitrite anions8. significant decrease in luminol- gnificantly higher at the end of A study investigated the possi- amplified chemiluminescence the study (Figure 5)7. ble synergistic effect of Bude- (LACL), indicating a synergistic Figure 5. Free radical scavenging measured in vitro and vivo6,7. Mean integral of luminal-dependent chemiluminescence (LDCL ± SD) of human neutrophils, induced by PMA, associated with Met 1 (*p<0.05 vs control) (A). ROS changes measured in Erdosteine and the placebo group of subjects at the different experimental times (*p<0.01 vs placebo) (B). 136 Trends in Medicine July 2012 Volume 12 Number 3 Erdosteine: a new therapeutic weapon beyond the PEACE Figure 6. Change in various biochemical properties of sputum after treatment with Erdosteine and placebo (p≤0.05)4. anti-oxidant effect of the two In a study with NAC and Er- chial inflammatory markers4. combined drugs, this is of inte- dosteine in chronic bronchitis A subsequent double-blind, pla- rest for counteracting the ai- patients comparing their effect cebo-controlled, study con- rways phlogosis involved in on plasma levels and BAL Fluid ducted in 20 current smokers many respiratory diseases.
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