Macrolides for the Treatment of Chronic Sinusitis,Asthma,and COPD Mark H. Gotfried,, MD, FCCP (CHEST 2004; 125:52S-61S) Ri 邱立忠
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1 Macrolides for the Treatment of Chronic Sinusitis,Asthma,and COPD Mark H. Gotfried,, MD, FCCP (CHEST 2004; 125:52S-61S) Ri 邱立忠
2 Abstract Sinusitis:mucociliary clearance,sinusitis symptoms,nasal secretions/polyp size, inflammatory response. Asthma:airway hyperresponsiveness, pulmonary function,"steroid-sparing" effect. COPD:symptom scores, FEV 1
3 Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation Inhibit synthesis/secretion of proinflammatory cytokines Effects on neutrophils Decrease neutrophil oxidative burst Inhibit neutrophil migration (chemotaxis) to inflammatory sites Increase apoptosis of neutrophils (?) Neutrophil degranulation (?) Inhibit neutrophil adhesion Inhibit phagocytosis
4 Summary of Effects of Macrolides Relevant to Respiratory Tract Inflammation Eosinophilic inflammation Mucociliary transport Goblet cell secretion Bronchoconstriction endothelin-1 release,cholinergic responses of airway smooth muscle
5 Benefit of Macrolides on respiratory tract diseases Anti-inflammatory benefits? Antimicrobial action?
6 Chronic Sinusitis Anti-inflammatory inflammatory benefits (1) First article:1996, Hashiba and Baba 45 p ts,clarithromycin400 mg daily 8-12 weeks (or roxithromycin,150 mg daily) symptoms,rhinoscopic findings improved α duration Improvement rates:5%/48%/63%/71% after 2/4/8/12 weeks therapy
7 Chronic Sinusitis Anti-inflammatory inflammatory benefits After 12 weeks of therapy: 64% : viscosity of nasal secretions 56% :quantity of nasal secretions 62%:postnasal drip 51%: nasal obstruction
8 Chronic Sinusitis Anti-inflammatory inflammatory benefits (2) 1997,Rubin :Nasal mucus properties 10healthyVS10 p ts clarithromycin, 500 mg twice daily for 2 weeks Before therapy: secretions from p ts wetability/sneeze clearability ; solids and cohesion (VS healthy)
9 Chronic Sinusitis Anti-inflammatory inflammatory benefits After therapy:secretions of healthy/ p ts:similar(~rheology, hydration, cohesion,transportability) Methacholine secretory response :not affected Effect on mucus properties :based on the modulation of inflammation.
10 Chronic Sinusitis Anti-inflammatory inflammatory benefits Prospective, open-label study at a single center in USA :25 p ts (mean age:45 y/o), clarithromycin, 500 mg twice daily for 14 days Biopsy of the maxillary sinus mucosa (Before VS 7 days after treatment)
11 Chronic Sinusitis Anti-inflammatory inflammatory benefits Markers of sinus mucosal inflammation :macrophages (CD68)/elastase/IL-6, IL-8/TNF-α/activity of eosinophils (EG2) clarithromycin may modulates the immune response Edema score :41%,clinical signs and symptoms 1 and 2week F/U : improved
12 Chronic Sinusitis Anti-inflammatory inflammatory benefits Yamada: effect on the size of nasal polyps / IL-8 levels in nasal lavage fluid. 20 p ts (24-84 y/o; mean age:57 y/o) clarithromycin, 400 mg daily 8 to 12 weeks P ts (polyps size ) during therapy, IL-8 levels (significantly) at baseline more than fivefold
13 Chronic Sinusitis Anti-inflammatory inflammatory benefits P ts :polyps size(-)after therapy:il-8 (-) before/after therapy Ichimura: 20 p ts,nasal polyps with CPS roxithromycin, 150 mg daily for 8 weeks: > 50% polyp size Nasal polyps αsuppression of cytokine production
14 Asthma Anti-inflammatory inflammatory benefits Amayasu :bronchoconstriction caused by inhalation of methacholine, 17 p ts,clarithromycin, 200 mg,twice daily for 8 weeks, After 8 weeks treatment symptoms,blood/sputum eosinophil, sputum eosinophilic cationic protein, bronchial hyperresponsiveness
15 Asthma Anti-inflammatory inflammatory benefits This paper:21 p ts with corticosteroid-dep asthma(ie 5 mg prednisone for 6 months before study) clarithromycin, 500 mg twice daily for 6 weeks FVC,FEV 1,nocturnal dyspnea, social concerns,chest discomfort
16 Asthma Anti-inflammatory inflammatory benefits Nighttime symptoms : marker for inflammation clinical benefit αanti-inflammatory effects During study: steroid dosage(-) majority:reduced two elderly p ts: discontinued
17 Asthma Anti-inflammatory inflammatory benefits Anti-inflammatory bronchial effect also has been reported with roxithromycin (Kamoi and Shoji T,Yoshida S,Sakamoto H) 2 months therapy required for demonstrable clinical improvement!!
18 Asthma Antimicrobial action Atypical intracellular pathogens (Chlamydia pneumoniae/mycoplasma pneumoniae):pathogenesis of reactive airway diseases.? M pneumoniae or C pneumoniae in > 50% stable chronic asthma airways (CHEST2002;121:1782-8)
19 Asthma Clinical Experience The benefit of Macrolides in some asthma p ts Anti-inflammatory or Antimicrobial effects???????
20 Asthma Clinical Experience Kraft: 52 p ts,clarithromycin,500 mg,twice daily for 6 weeks mean FEV 1 levels (2.50 ± 0.16 L)to(2.69 ± 0.19 L) Chlamydia(+) or Mycoplasma(+) No improvement in FEV 1: PCR(-) Inflammatory mediators (IL-5, IL-12, TNF-α), eosinophil/neutrophil levels in bronchoalveolar lavage fluid (immunomodulatory activity )
21 Asthma Clinical Experience Black :232 p ts,c.pneumoniae(+)roxithromycin150 mg, twice daily After 6 weeks of therapy : nighttime PEF, daytime PEF:(-) ( disappeared within 3 months stopping therapy!) Macrolide :temporarily chlamydial infection,infection/sequelae after stopping therapy!!
22 COPD Clinical Experience Banerjee :moderate-to-severe COPD ( FEV 1 < 60%) clarithromycin, 500 mg daily (24 p ts)vs placebo (33 p ts) for 3 months of therapy sputum total cell count/inflammatory cytokine levels/sputum pathogen count :No changed!! Total cell count/absolute neutrophil count VS total health status impact, respiratory symptoms,activity scores:significant,not to pulmonary function (Eur Respir J 2001;18:94S)
23 COPD Clinical Experience Nixon: 25 p ts,copd with exacerbation, clarithromycin, 500 mg twice daily for 2 weeks Absolute FEV 1 :1.12 L 1.34 L posttreatment, the mean total scores for signs/symptoms : Improvement in symptoms After 1 week: most profound; After 2 week sustained. After 4 week :continued (not significant)
24 Discussion Macrolides for COPD: to be determined!! Macrolides on respiratory tract diseases :anti-inflammatory benefits or antimicrobial action: debate!! Large-scale/placebo-controlled studies:needed!!
25 Thank you for your attention!!
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