INTERNA VALORTERAPÉUTICODELOS MEDICINA · · 2012-05-21valorterapÉuticodelos mucolÍticos...
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VALOR TERAPÉUTICO DE LOS MUCOLÍTICOS SESIONES BIBLIOGRÁFICAS DE RESIDENTES HOSPITAL MONTE SAN ISIDRO MARI CRUZ PÉREZ PANIZO MIR2 MEDICINA INTERNA COMPLEJO ASISTENCIAL UNIVERSITÁRIO DE LEÓN 1552012 SERVICIO DE MEDICINA INTERNA HOSPITAL DE LEÓN
Transcript of INTERNA VALORTERAPÉUTICODELOS MEDICINA · · 2012-05-21valorterapÉuticodelos mucolÍticos...
VALOR TERAPÉUTICO DE LOS MUCOLÍTICOS
SESIONES BIBLIOGRÁFICAS DE RESIDENTES HOSPITAL MONTE SAN ISIDRO MARI CRUZ PÉREZ PANIZO MIR2 MEDICINA INTERNA
COMPLEJO ASISTENCIAL UNIVERSITÁRIO DE LEÓN 15-‐5-‐2012
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Lo que sabemos es una gota de agua; lo que ignoramos es el océano.
Isaac Newton (1642-1727) Matemático y físico británico. SERVIC
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INTRODUCCIÓN PUBLICACIONES CONCLUSIONES BIBLIOGRAFÍA
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INTRODUCCIÓN
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Se denominan mucolíKcos aquellas sustancias que Kenen la capacidad de destruir las disKntas estructuras quimicoQsicas de la secreción bronquial anormal, consiguiendo una disminución de la viscosidad y, de esta forma, una más fácil y pronta eliminación. La fluidificación del moco reduce la retención de las secreciones y aumenta el aclarado mucociliar, disminuyendo con ello la frecuencia e intensidad de la tos.
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Los mucolíKcos actúan por: -‐-‐ Disminución de la tensión superficial. -‐-‐ Alteración de las fuerzas de asociación intermolecular. -‐-‐ Ruptura de las fuerzas de cohesión intramolecular.
Mucolí8cos: modifica las propiedades ;sico-‐químicas de la secreción traqueobronquial, para que la expectoración sea más eficaz y cómoda • Expectorantes: es8mulan mecanismos de expulsión del moco, porque aumenta el movimiento ciliar o el reflejo tusígeno o el volumen hídrico
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Los agentes mucolíKcos se pueden clasificar en los siguientes grupos: -‐-‐ Enzimas: tripsina, dornasa. -‐-‐ Productos azufrados: N-‐aceKlcisteína, S-‐carboximeKlcisteína, MESNA (mercaptoetan-‐sulfonato sódico), letosteína, ciKolona. -‐-‐ Compuestos sinté8cos derivados de la vasicina: bromhexina y ambroxol. -‐-‐ Agentes tensioac8vos: propilenglicol, Kloxapol. Con algunos de estos medicamentos se ha puesto de manifiesto una acKvidad in vitro que no se ha podido demostrar in vivo. Junto a estudios que han mostrado mejorías clínicas y de los parámetros de la viscoelas8cidad, existen otros que no han demostrado beneficio alguno. Bromhexina, ambroxol y N-‐ace8lcisteína son los mucolíKcos que presentan mayor eficacia, así como el MESNA cuando es aplicado in situ SERVIC
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N-‐ace8lcisteína: Rompen puentes disulfuros de cis8na en mucoproteínas, Ig. A y seroalbúmina, reduciendo la viscosidad del moco • Impide la acKvación de factores de transcripción (NF-‐kB) inflamatorios, por lo que tendría acción an8inflamatoria • Deprime la acKvidad ciliar por acción directa • Precursor en la síntesis del gluta8ón por lo que es ú8l como anPdoto en las intoxicaciones por paracetamol y en la prevención de la nefropaPa inducida por contraste en cateterismos, Radiologia con contraste… (carbocisteina no) Se uKliza vía oral: mayores de 7 años y adultos
200 mg. c/8 hs o 600 mg./d.; en niños de 2-‐7 dar mitad de dosis. También en nebulización y vía insKlación traqueal en solución al 10-‐20 % • Efecto mucolíKco es mayor a pH alcalino • Tienen buena tolerancia • R.A.M.: naúseas, vómitos, cefaleas, rinorrea, hipersensibilidad, broncoespasmo, olor sulfúreo, reacción con goma o metal de aparatos de nebulización
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BROMHEXINA Y AMBROXOL: Actúan in vitro por despolimerización de sialomucinas, con reducción de la viscosidad • Ambroxol es el metabolito de bromhexina • Absorción oral, inhalatoria, difunden a los tejidos, incluído el epitelio bronquial • Pueden producir molesKas gastrointesKnales • Dosis oral: ambroxol 30 mg. c /8 hs, acción retardada 75 mg./día y bromhexina 15 mg. c/8 hs • Adamexina y brovahexina son derivados de bromhexina con acKvidad similar • CiKolona:400mg.c/8 h
• Letosteína: 50mg.c/8-‐12 hs (azufrado) • MercaptoeKlsulfonato • Sobrerol • Tiloxapol (expectorante y tensioacKvo) • Dornasa: hidroliza y rompe las cadenas de ADN; úKl en la fibrosis quísKca SERVIC
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-‐ Mucolí8cos (mucociné8cos, mucorreguladores): Ambroxol, erdosteína, carbocisteína, glicerol yodado. El uso regular de mucolí8cos há sido evaluado en estudios a largo plazo, con resultados controver8dos. Aunque algunos pacientes con esputo viscoso pueden beneficiarse del Tratamiento con mucolíKcos, los beneficios globales parecen ser muy escasos. Existe alguna evidencia
en pacientes que no han sido tratados con cor8coides inhalados, en los que la carbocisteína reduce el número de exacerbaciones. -‐ Sustancias an8oxidantes. Los anKoxidantes, en parKcular N-‐ace8lcisteína, han demostrado reducir el número de exacerbaciones y podrían desempeñar un papel en el tratamiento de pacientes con EPOC que presentan Exacerbaciones recurrentes.
TIEMPOS MEDICOS/N.° 660 -‐ SepKembre2009, ENFERMEDAD PULMONAR OBSTRUCTIVA CRÓNICA, C. Marlín-‐Carbajo, P. Cano, R. Me. Girón Moreno, Servicio de Neumología, Hospital Universitario de la Princesa. Madrid
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FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormaliKes despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./
N-‐ACETYLCYSTEINE
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PUBLICACIONES: CONTROVERSIA
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1.EN CONTRA
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Flu8casone and N-‐acetylcysteine in primary care pa8ents with COPD or chronic bronchi8s. Respir Med 2009 Apr;103(4):542-‐51. Epub 2009 Jan 9.Radboud University Nijmegen Medical Centre, Department of General PracKce, Nijmegen, The Netherlands. -‐ Increased oxida8ve stress and bronchial inflamma8on are important mechanisms in the pathophysiology of COPD. -‐ To invesKgate : if are effec8ve in primary care paKents: 286(ex-‐)smokers COPD/CB (44 GP): oral an8-‐oxida8ve agent N-‐acetylcysteine N-‐ 600mg/24h or inhaled Flu8casone propionate 500microg/12h or placebo -‐ primary outcomes: ExacerbaKon rate and quality of life measured with the Chronic Respiratory QuesKonnaire (CRQ) -‐ secondary outcomes: FEV(1) decline and respiratory symptoms -‐ RESULTS: ExacerbaKon rate was 1.35 Kmes higher for NAC (p=0.054) and 1.30 Kmes higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo.
-‐ CONCLUSION: No beneficial treatment effects for either high-‐dosed inhaled fluKcasone propionate or oral N-‐acetylcysteine were observed in our study populaKon of paKents with COPD or chronic bronchiKs.
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. The evidence for the use of oral mucolytic agents in chronic obstructive pulmonary disease (COPD). Davies L, Calverley PM. Br Med Bull 2010;93:217-27. Epub 2009 Dec 22 Source Aintree Chest Centre, University Hospital Aintree, Lower Lane, Liverpool, UK. Abstract INTRODUCTION: Oral mucolytics are now recommended in some treatment guidelines for the management of chronic obstructive pulmonary disease (COPD). This article reviews the evidence for their use and their possible benefits. SOURCES OF DATA: The review is based upon peer reviewed publications relating to the use of mucolytics in COPD cited in PubMed. AREAS OF AGREEMENT: Much of the published evidence is of somewhat poor quality and many studies include patients with both chronic bronchitis and COPD. Mucolytics reduce exacerbations by up to 0.8 exacerbations per year, but have little additional benefit in those on standard maximum therapy. AREAS OF CONTROVERSY: Data that mucolytics improve symptoms, alter mucus or impact health-related quality of life in COPD patients receiving other standard therapy are unconvincing. In those on little or no other treatment, they may reduce exacerbation rate. PMID: 20031934 [PubMed - indexed for MEDLINE]
GROWING POINTS: The use of mucolytics to treat acute exacerbations is promising. AREAS TIMELY FOR DEVELOPING RESEARCH: Head-to-head trials of mucolytics versus long-acting bronchodilators and/or inhaled corticosteroids are lacking. Even in patients with severe COPD who remain symptomatic despite maximal inhaled therapy the role of mucolytics remains unproven.
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2.A FAVOR:
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Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Poole PJ, Black PN. University of Auckland, Private Bag 92019, Auckland, New Zealand. [email protected] Update in Cochrane Database Syst Rev. 2010;(2):CD001287. 2006 Jul 19;(3):CD001287 BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume and/or purulence of sputum. Because of the personal and healthcare costs associated with exacerbations, any therapy that reduces the number of exacerbations is useful. There is a marked difference between countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective. OBJECTIVES: To assess the effects of oral mucolytics in adults with stable chronic bronchitis or COPD. SEARCH STRATEGY: We have searched the Cochrane Airways Group Specialised Register and reference lists of articles on four separate occasions, the most recent being in June 2005. This is the third major update. SELECTION CRITERIA: Randomised trials that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. Studies of people with asthma and cystic fibrosis were excluded. DATA COLLECTION AND ANALYSIS: One reviewer extracted data. Study authors and drug companies were contacted for missing information. MAIN RESULTS: Twenty six trials were included (7335 participants). Compared with placebo, there was a significant reduction in the number of exacerbations per patient with oral mucolytics (weighted mean difference (WMD) -0.05 per month, 95% confidence interval -0.05, -0.04). Using the annualised rate of exacerbations in the control patients of 2.6 per year, this is a 20% reduction. The number of days of disability also fell (WMD -0.56, 95% confidence interval -0.77, -0.35). A recent study has shown that the benefit may apply only to those patients not already receiving inhaled corticosteroids. The number of patients who remained exacerbation-free was greater in the mucolytic group (OR 2.13 (95% CI 1.86 to 2.42)). There was no difference in lung function or in adverse effects reported between the treatments.
AUTHORS' CONCLUSIONS: -In subjects with CB or COPD, treatment with mucolytics was associated with a small reduction in acute exacerbations and a reduction in total number of days of disability. -Benefit may be greater in individuals who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations with COPD. -They should be considered for use, through the winter months at least, in patients with moderate or severe COPD in whom inhaled corticosteroids are not prescribed.
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[The effect of inhaled ambroxol treatment on clinical symptoms and chosen parameters of ventilation in patients with exacerbation of chronic obstructive pulmonary disease patients]. [Article in Polish] Jahnz-Rózyk K, Kucharczyk A, Chciałowski A, Płusa T.
Klinika Chorób Wewnetrznych, Pneumonologii i Alergologii IMW CSK WAM w Warszawie. Pol merkur lekarski 2001 Sep;11(63):239-‐43. Abstract
It was a randomised, double-blind, placebo controlled comparative study of the clinical symptoms and chosen parameters of ventilation of inhaled ambroxol in patients hospitalized with exacerbation of chronic obstructive pulmonary disease (COPD). Eligible patients--30 patients (13 men and 17 women) aged of mean value 70.5 +/- 6.9 years who fulfilled the clinical traits of exacerbation of chronic bronchitis entered the study. 15 patients were treated with inhaled ambroxol and 15 were treated with placebo. Moreover all patients were treated with concomitant medications typical for exacerbation of COPD (systemic steroids, intravenous infusions with euphillin, antibiotics, Berodual nebulizations and oxygen therapy). Spirometry and data related to clinical symptoms were taken at the beginning of the study and after 1 and 3 days and after the end of the treatment.
At the end of the treatment period in both groups (inhaled ambroxol therapy vs. placebo) there wasn't found statistically significant difference in the number of cough and dyspnoe attacks. There was found the difference in FEV1 and FEF 50 in both groups, but improvement in patients treated with ambroxol was statistically significantly faster, that can influence the cost of treatment. Moreover there were not found important adverse events in ambroxol group.
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[N-acetylcystein in the therapy of chronic bronchitis]. [Article in German] Reichenberger F, Tamm M. Pneumologie 2002 Dec;56(12):793-‐7. Pneumologie, Departement Innere Medizin, Universitätskliniken Basel, Schweiz, Germany. Abstract
Chronic bronchitis (CB) shows an increasing global morbidity and mortality with major impact on socioeconomics. N-Acetylcysteine (NAC), previously used as a mucolytic compound in CB, has also antioxidative effects. Furthermore it influences intrabronchial bacterial colonisation. In a randomised pilot study of 24 patients (16-male, 8 female, mean age 66 +/- 10 years) with acute exacerbation of CB and positive bacterial culture in the sputum, the addition of twice daily 600 mg NAC to standard antibiotic therapy lead to a significantly higher bacterial eradication rate (70 % versus 36 %, p < 0.03). However, further placebo controlled studies are undergoing to definitively establish the role of NAC for the treatment of CB and COPD.
Clinical studies suggest that treatment with NAC has different effects in CB including a reduction of the number and duration of acute exacerbation episodes and possibly influences lung function. The improvement of symptoms and quality of life also has an impact on socio-economic costs.. The use of N-acetylcystein in CB as an antioxidative rather than a mucolytic compound should be considered
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Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. Poole PJ, Black PN.BMJ 2001 May 26;322(7297):1271-4. Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. Abstract OBJECTIVE: To assess the effects of oral mucolytics in adults with stable chronic bronchitis and chronic obstructive pulmonary disease. DESIGN: Systematic review of randomised controlled trials that compared at least two months of regular oral mucolytic drugs with placebo. STUDIES: Twenty three randomised controlled trials in outpatients in Europe and United States. MAIN OUTCOME MEASURES: Exacerbations, days of illness, lung function, adverse events. RESULTS: Compared with placebo, the number of exacerbations was significantly reduced in subjects taking oral mucolytics (weighted mean difference -0.07 per month, 95% confidence interval -0.08 to -0.05, P<0.0001). Based on the annualised rate of exacerbations in the control subjects of 2.7 a year, this is a 29% reduction. The number needed to treat for one subject to have no exacerbation in the study period would be 6. Days of illness also fell (weighted mean difference -0.56, -0.77 to -0.35, P<0.0001). The number of subjects who had no exacerbations in the study period was greater in the mucolytic group (odds ratio 2.22, 95% confidence interval 1.93 to 2.54, P<0.0001). There was no difference in lung function or in adverse events reported between treatments.
CONCLUSIONS: In chronic bronchitis and COPD, treatment with mucolytics is associated with a reduction in acute exacerbations and days of illness. As these drugs have to be taken long term, they could be most useful in patients who have repeated, prolonged, or severe exacerbations of COPD.
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Mucoactive therapy in COPD. Decramer M, Janssens W. Eur Respir Rev 2010 Jun;19(116):134-40. Respiratory Division, University of Leuven, Herestraat 49, Leuven, Belgium. [email protected] Abstract It has been shown that mucus hypersecretion is associated with greater susceptibility for chronic obstructive pulmonary disease (COPD), excess forced expiratory volume in 1 s decline, hospitalisations and excess mortality. The effects of mucoactive drugs on outcomes have been reviewed in several meta-analyses, the largest one including 26 studies. 21 studies were performed in patients with chronic bronchitis and 5 in patients with COPD. The majority of these trials were performed with N-acetylcysteine (n = 13) and carbocysteine (n = 3). Overall, there was a significant reduction in exacerbations (0.05 per patient per month) and the number of days with disability (0.56 days per patient per month). Mucolytics were well tolerated and the number of adverse events was lower than with placebo (odds ratio 0.78). In the largest and best designed study with N-acetylcysteine in 523 patients with COPD, the reduction in exacerbations was only observed in patients not taking inhaled corticosteroids. In addition, a 374 mL reduction in functional residual capacity was found. A recent large study (n = 709) with high-dose carbocysteine (1,500 mg·day⁻¹) demonstrated a significant effect on exacerbations (25% reduction) and also reported an improvement in health-related quality of life (-4.06 units in St George's Respiratory Questionnaire). PMID: 20956182 [PubMed - indexed for MEDLINE]
It is unclear what the mechanisms underlying these effects may be and which phenotypes benefit from this treatment. On the basis of this evidence mucoactive drugs may deserve consideration in the long-term treatment of COPD.
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Prevention of exacerbations of COPD with pharmacotherapy. Miravitlles M. Eur respire rev 2010 Jun;19(116):119-26. Servei de Pneumologia, Hospital Clınic,Villarroel 170, Barcelona, Spain. [email protected] Abstract Exacerbations are a frequent event in the evolution of chronic obstructive pulmonary disease (COPD) patients. Individuals with COPD have a mean of 1-3 episodes per year, some of which lead to hospital admission and may even be a cause of death. The importance of COPD exacerbations has become increasingly apparent due to the impact these episodes have on the natural history of disease. It is now known that frequent exacerbations can adversely affect health-related quality of life and short- and long-term pulmonary function. Optimising treatment for stable COPD will help to reduce exacerbations. Long-acting bronchodilators, alone or combined with inhaled corticosteroids, have demonstrated efficacy in reducing the rate of exacerbations in patients with COPD. Other innovative approaches are being investigated, such as the long-term use of macrolides or the use of antibiotics in an effort to suppress bronchial colonisation and consequent exacerbations.. Non-pharmacological interventions such as rehabilitation, self-management plans and the maintenance of high levels of physical activity in daily life are also useful strategies to prevent exacerbations in patients with COPD and should be implemented in regular clinical practice. PMID: 20956180 [PubMed - indexed for MEDLINE] Other drugs, such as mucolytics and
immunomodulators, have recently provided positive results SERVIC
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Revisited role for mucus hypersecretion in the pathogenesis of COPD. Eur Resp Rev 2010 Jun;19(116):109-12. Cerveri I, Brusasco V. Clinica di Malattie dell'Apparato Respiratorio, Fondazione Ricovero e Cura a Carattere Scientifico Policlinico
S. Matteo, Università di Pavia, Via Taramelli, Pavia, Italy. [email protected] Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the basic pathophysiological mechanisms remain largely unknown. On the basis of recent results from pathological studies and large clinical trials, the presence of airway inflammation does not seem to be sufficient to explain the complexity of the disease and the relatively poor response to treatment. It is probably time to abandon the concept of COPD as a unique disease and define, identify and treat the various aspects, which may differ between individuals. Among the different phenotypic distinctions, the classical distinction "chronic bronchitis" has mucus hypersecretion as the key presenting symptom. Its role in COPD has been the subject of an ongoing debate; however, it now appears to be being re-evaluated due to findings from recent epidemiological and pathological studies.
In this context, the view that chronic mucus hypersecretion plays a secondary role in the pathogenesis of COPD should be abandoned and instead, drugs targeting mucus hypersecretion should be considered as a treatment option. SERVIC
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In conclusion, the results of our trial demonstrate that acetylcysteine at a dose of 600 mg three 8mes daily, added to prednisone and azathioprine, in paKents with idiopathic pulmonary fibrosis preserves vital capacity and DLCO be{er than standard therapy alone. High-‐dose acetylcysteine in addiKon to standard therapy is, therefore, a raKonal treatment opKon for paKents with idiopathic pulmonary fibrosis.
High-‐Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis Maurits Demedts, M.D., Juergen Behr, M.D., Roland Buhl, M.D., Ulrich Costabel, M.D., P.N., Richard Dekhuijzen, M.D., Henk M. Jansen, M.D., William MacNee, M.D., Michiel Thomeer, M.D., Benoit Wallaert, M.D., François Laurent, M.D., Andrew G. Nicholson, M.D., Eric K. Verbeken, M.D., Johny Verschakelen, M.D., Christopher D.R. Flower, M.D., Frédérique Capron, M.D., Stefano Petruzzelli, M.D., Paul De Vuyst, M.D., Jules M.M. van den Bosch, M.D., Eulogio Rodriguez-‐Becerra, M.D., Giuseppina Corvasce, Ph.D., Ida Lankhorst, M.D., Marco Sardina, M.D., and Mauro Montanari, Ph.D. for the IFIGENIA Study Group N Engl J Med 2005; 353:2229-‐2242November 24, 2005
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3.MUCOLÍTICOS CON ADEMÁS OTRAS PROPIEDADES:
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Erdosteine: its relevance in COPD treatment. Moretti M. Expert Opin Drug Metabol Toxicol 2009 Mar;5(3):333-43. Università di Modena e Reggio Emilia, Clinica di Malattie dell'Apparato Respiratorio, Dipartimento di Oncologia, Ematologia e Patologie Apparato Respiratorio, Modena, Italy. [email protected].
Abstract BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by airflow limitation, which is largely irreversible; the oxidant/antioxidant imbalance is important in the pathogenesis of this condition. OBJECTIVE: To show that administration of erdosteine, a mucolytic agent with a prevalent antioxidant activity, could play a beneficial role in COPD. METHODS: To review the experimental and clinical trials on erdosteine in COPD and chronic bronchitis.
RESULTS: Erdosteine is a thiol agent with a multifactorial mechanism of action, namely: mucolytic, antibacterial, antioxidant and anti-inflammatory activity. In the acute exacerbation of chronic bronchitis/COPD, addition of erdosteine 300 mg twice a day for 7 - 10 days to standard treatment improves the symptoms and reduces the time of disease. In clinically stable COPD, long-term treatment is associated with a reduction in acute exacerbation and hospitalization rate and a significant improvement of quality of life. Erdosteine could be most beneficial in patients who have repeated, prolonged or severe exacerbations of COPD.
ERDOSTEINA: DERIVADO DEL AMINOÁCIDO METIONINA, NO COMERCIALIZADO EN ESPAÑA SERVIC
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4.EN FIBROSIS QUÍSTICA:
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Dornase alfa for cystic fibrosis. Jones AP, Wallis C. Cochrane Database Syst Rev 2010 Mar 17;(3):CD001127.Institute of Child Health, University of Liverpool, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, Merseyside, UK, L12 2AP. Abstract BACKGROUND: Dornase alfa is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other mucolytics and to identify any adverse events associated with its use. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences.Date of the most recent search of the Group's Cystic Fibrosis Register: 17 July 2009. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials where dornase alfa was compared to placebo, standard therapy or another mucolytic. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials for inclusion criteria; the lead author and a colleague carried out analysis of methodological quality and data extraction. MAIN RESULTS: The searches identified 43 trials, of which 15 met our inclusion criteria, including a total of 2469 participants. Three additional studies examined the healthcare cost from one of the clinical trials. Twelve studies compared dornase alfa to placebo or no dornase alfa treatment; one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa; and two compared daily dornase alfa to hypertonic saline. Study duration varied from six days to two years. The number of deaths was not significant between treatment groups. Spirometric lung function improved in the treated groups, with significant differences at one month, three months, six months and two years, there was a non-significant difference at three years. There was no excess of adverse effects except voice alteration and rash, which were reported more frequently in one trial in the treated groups. Insufficient data were available to analyse differences in antibiotic treatment, inpatient stay and quality of life.
AUTHORS' CONCLUSIONS: There is evidence to show that therapy with dornase alfa over a one-month period is associated with an improvement in lung function in CF; results from a trial lasting six months also showed the same effect. Therapy over a two-year period (based on one trial) significantly improved FEV(1) in children and there was a non-significant reduction in the risk of infective exacerbations. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials.
Comercializado en España, (Desoxirribonucleasa, PULMOZYME® Roche) inhalado, rompe el DNA extracelular de las secrecciones y disminuye asi la viscosidad del esputo
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Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Nash EF, Stephenson A, Ratjen F, Tullis E. Department of Respiratory Medicine, Birmingham
Heartlands Hospital, Bordesley Green East, Birmingham, UK, B9 5SS. [email protected] Cochrane Database Syst Resp 2009 Jan 21;(1):CD007168. Abstract BACKGROUND: Cystic fibrosis is an inherited condition resulting in thickened, sticky respiratory secretions. Respiratory failure, due to recurrent pulmonary infection and inflammation, is the most common cause of mortality. Muco-active therapies (e.g. dornase alfa and nebulized hypertonic saline) may decrease sputum viscosity, increase airway clearance of sputum, reduce infection and inflammation and improve lung function. Thiol derivatives, either oral or nebulized, have shown benefit in other respiratory diseases. Their mode of action is likely to differ according to the route of administration. There are several thiol derivatives, and it is unclear which of these may be beneficial in cystic fibrosis. OBJECTIVES: To evaluate the efficacy and safety of nebulized and oral thiol derivatives in people with cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, hand searches of relevant journals, abstract books and conference proceedings.Most recent search: November 2008. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing nebulized or oral thiol derivatives to placebo or another thiol derivative in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently assessed trials for inclusion, analysed methodological quality and extracted data. MAIN RESULTS: Searches identified 18 trials; eight (seven older than 10 years) (234 participants) are included. Three trials of nebulized thiol derivatives were identified (one compared 20% n-acetylcysteine to 2% n-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and another compared glutathione to 4% hypertonic saline). Although generally well-tolerated with no significant adverse effects, there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.Five studies of oral thiol derivatives were identified. Three studies compared n-acetylcysteine to placebo; one compared n-acetylcysteine, ambroxol and placebo; and one compared carbocysteine to ambroxol. Oral thiol derivatives were generally well-tolerated with no significant adverse effects, however there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments.
AUTHORS' CONCLUSIONS: We found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.
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5. EN ASMA:
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Una alternaKva bien conocida sería la uKlización de la N-‐ace8l-‐l-‐cisteína (NAC), sustancia con grupos Koles y capacidad anKoxidante directa al Kempo que es un donante de cisteína y precursor de la síntesis de GSH. La acKvidad de NAC se ha demostrado en modelos animales de asma experimental [5, 6] y en modelos in vitro con eosinófilos y neutrófilos aislados [7-‐9] y
músculo liso de vías aéreas [10]. El NAC se encuentra disponible en una diversidad de presentaciones (oral, parenteral, inhalatoria) que se corresponden con sus aplicaciones clínicas como anKoxidante en el tratamiento de la intoxicación por paracetamol, y como mucolí8co y an8oxidante en diversas indicaciones pero especialmente en la EPOC donde puede reducir la frecuencia de exacerbaciones, y como coadyuvante en la fibrosis pulmonar idiopá8ca. Sin embargo, entre sus indicaciones clínicas autorizadas no está reconocido el tratamiento an8-‐asmá8co como tal, y de hecho su u8lización no figura en las guías de consenso del tratamiento del asma (GINA/ GEMA).
Actualidad en Farmacología y Terapéu9ca AFT Vol.7 Nº2, Junio 2009, revista trimestral, F u n d a c i ó n E s p a ñ o l a d e F a r m a c o l o g í a, F u n d a c i ó n T e ó f i l o H e r n a n d o, Fármacos an3oxidantes para el asma, J. Cor9jo1,2,3 y E.J. Morcillo1,2,4
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CONCLUSIONES
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MUCOLÍTICOS: TIOLES (MERCAPTANOS): ACETILCISTEÍNA CARBOCISTEÍNA BROMHEXINA AMBROXOL NO COMERCIALIZADOS EN ESPAÑA: METILCISTEINA, ERDOSTEÍNA, preparados con yodo (GLICEROL YODADO) EN LA LISTA DE MEDICAMENTOS HUÉRFANOS, USADOS COMO MUCOLÍTICOS EN F.Q.: -‐ DORNASA ALFA INHALADA -‐ MANITOL INHALADO EN TTO F.QUÍSTICA -‐ HEPARINA SÓDICA INHALADA (NO EN ESPAÑA): USADO COMO MUCOLÍTICO EN F.QUÍSTICA
MEDICAMENTOS HUERFANOS: grupo que combatan enfermedades que afecta a un número muy escaso de personas. La ley los obliga a fabricar, porque no son rentables.
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UpToDate (3-2012) SUMMARY AND RECOMMENDATIONS — Increased tracheobronchial mucus contributes to the symptoms of COPD. General recommendations focus on the treatment of the underlying pulmonary obstructive process, airway inflammation, or infection by the use of bronchodilators, inhaled glucocorticoids, and antibiotics. Maintenance treatment with mucoactive agents is generally not associated with improved lung function and cannot be recommended in the absence of additional supportive evidence of benefit. Simple measures may include adequate hydration and trials of guaifenesin or saturated solution of potassium iodide (SSKI). Nebulized acetylcysteine is a potent mucolytic, but its use at best must be individualized because of the potential for inducing bronchospasm. Oral acetylcysteine and carbocisteine may have a role in patients with repeated exacerbations of COPD who are not on inhaled glucocorticoids. Future therapies may include agents that decrease sputum adhesiveness (including surfactants), prostaglandin inhibitors, macrolide antibiotics, and new mucolytics, such as erdosteine and nacystelyn. Treatment should be individualized as certain therapeutic options shown effective in a specific disease, such as the use of hypertonic saline or DNase in cystic fibrosis, are not be applicable to a COPD population. SERVIC
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BIBLIOGRAFÍA • UpToDate: Role of mucoac8ve agents in the treatment of COPD,
Lou�i Sami Aboussouan, MD, James K Stoller, MS, MD,Helen Hollingsworth, MD,last updated: mar 16, 2012.
• TIEMPOS MEDICOS/N.° 660 -‐ SepKembre2009, ENFERMEDAD PULMONAR OBSTRUCTIVA CRÓNICA, C. Marlín-‐Carbajo, P. Cano, R. Me. Girón Moreno, Servicio de Neumología, Hospital Universitario de la Princesa. Madrid
• Actualidad en Farmacología y Terapéu9ca AFT Vol.7 Nº2, Junio 2009, revista trimestral, F u n d a c i ó n E s p a ñ o l a d e F a r m a c o l o g í a, F u n d a c i ó n T e ó f i l o H e r n a n d o, Fármacos an3oxidantes para el asma, J. Cor9jo1,2,3 y E.J. Morcillo1,2,4
• UpToDate y otros recursos de Internet. • High-‐Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis N Engl J Med 2005;
353:2229-‐2242November 24, 2005 AGRADECIMIENTOS A RAQUEL VEGA AMPUDÍA (BIBLIOTECA COMPLEJO ASISTENCIAL
UNIVERSITARIO DE LEÓN): • Flu8casone and N-‐acetylcysteine in primary care pa8ents with COPD or chronic bronchi8s.
Respir Med 2009 Apr;103(4):542-‐51. Epub 2009 Jan 9.Radboud University Nijmegen Medical Centre, Department of General PracKce, Nijmegen, The Netherlands.
• RecommendaKons for Guidelines on Clinical Trials of MucoacKve Drugs in Chronic BronchiKs and Chronic ObstrucKve Pulmonary Disease, Chest 1994;106;1532-‐1537, Chest is the official journal of the American College of Chest Physicians.
• Mucoly8c agents for chronic bronchi8s or chronic obstruc8ve pulmonary disease. Poole PJ, Black PN. University of Auckland, Private Bag 92019, Auckland, New Zealand. [email protected], 2006 Jul 19;(3):CD001287, Cochrane Database Syst Rev. 2010;(2):CD001287
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BIBLIOGRAFÍA ABSTRACTS: • [The effect of inhaled ambroxol treatment on clinical symptoms and chosen parameters of ven8la8on in pa8ents with
exacerba8on of chronic obstruc8ve pulmonary disease pa8ents].[ArKcle in Polish] Jahnz-‐Rózyk K, Kucharczyk A, Chciałowski A, Płusa T. Klinika Chorób Wewnetrznych, Pneumonologii i Alergologii IMW CSK WAM w Warszawie. Pol merkur lekarski 2001 Sep;11(63):239-‐43.
• [N-‐acetylcystein in the therapy of chronic bronchi8s]. [ArKcle in German], Reichenberger F, Tamm M. Pneumologie 2002 Dec;56(12):793-‐7.
• Oral mucoly8c drugs for exacerba8ons of chronic obstruc8ve pulmonary disease: systema8c review. Poole PJ, Black PN. Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. BMJ 2001 May 26;322(7297):1271-‐4.
• Mucoac8ve therapy in COPD. Decramer M, Janssens W. Respiratory Division, University of Leuven, Herestraat 49, Leuven, Belgium. [email protected] Eur Respir Rev 2010 Jun;19(116):134-‐40.
• Preven8on of exacerba8ons of COPD with pharmacotherapy. Miravitlles M. Servei de Pneumologia, Hospital Clınic,Villarroel 170, Barcelona, Spain. [email protected], Eur respire rev 2010 Jun;19(116):119-‐26.
• Revisited role for mucus hypersecre8on in the pathogenesis of COPD. Cerveri I, Brusasco V.Clinica di Mala�e dell'Apparato Respiratorio, Fondazione Ricovero e Cura a Cara{ere ScienKfico Policlinico S. Ma{eo, Università di Pavia, Via Taramelli, Pavia, Italy. icerveri@sma{eo.pv.it Eur Resp Rev 2010 Jun;19(116):109-‐12.
• Dornase alfa for cys8c fibrosis. Jones AP, Wallis C. Cochrane Database Syst Rev 2010 Mar 17;(3):CD001127.InsKtute of Child Health, University of Liverpool, Alder Hey Children's NHS FoundaKon Trust, Eaton Road, Liverpool, Merseyside, UK, L12 2AP.
• The evidence for the use of oral mucoly8c agents in chronic obstruc8ve pulmonary disease (COPD). Davies L, Calverley PM. Br Med Bull 2010;93:217-‐27. Epub 2009 Dec 22. Aintree Chest Centre, University Hospital Aintree, Lower Lane, Liverpool, UK.
• Erdosteine: its relevance in COPD treatment.More� M. Expert Opin Drug Metabol Toxicol 2009 Mar;5(3):333-‐43. Università di Modena e Reggio Emilia, Clinica di Mala�e dell'Apparato Respiratorio, DiparKmento di Oncologia, Ematologia e Patologie Apparato Respiratorio, Modena, Italy. more�@unimo.it.
• Nebulized and oral thiol deriva8ves for pulmonary disease in cys8c fibrosis.Nash EF, Stephenson A, Ratjen F, Tullis E. Cochrane Database Syst Resp 2009 Jan 21;(1):CD007168.Department of Respiratory Medicine, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, UK, B9 5SS. [email protected] SERVIC
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