Medical Clinic II. Department Pneumology / Allergology / Sleepmedicine. 1,8-Cineole in asthma and COPD - from bench to bedside. Uwe R.

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1 Medical Clinic II Department Pneumology / Allergology / Sleepmedicine 1,8-Cineole in asthma and COPD - from bench to bedside Uwe R. Juergens

2 Therapy options for phytopharmaceuticals in acute and chronic respiratory diseases Natural Substances and Mixtures Well known: secretolytic effects antiinfectious antioxidant bronchodilatory systemic availability good compatibility New Approach: Longterm Co-medication: Optimisation of guideline therapies by availability+synergy - Reaching the lung periphery - Control of systemic Inflammation Control of exacerbations -Improvement of steroid resistance New interactions with VD3-levels? Juergens, Bonn 2015

3 Mechanisms of the antioxidative effects of 1,8-Cineole in FCS-stimulated human monocytes in vitro O 2 - SODs H 2 O 2 % Inhibition of control (mean±sem) Inflammation Juergens, Bonn 2007

4 Cough and sputum production correlate with increased risic of exacerbations Chronic Inflammation Chronic Cough and Sputum Frequent Exacerbations Number of Exacerbations per patient per year Patients WITH chronic cough and sputum p< Patients WITHOUT chronic cough and sputum Nach Burgel PR et al. Chest 2009;135:

5 COPD-Phenotype: Exacerbations, Prognosis und Therapeutic needs COPD-Subgroups (138) ECLIPSE Pat. (300) 3 Years (208) Increase in Exacerbationen: Severity Health Status History of Reflux Leukocytosis (Granulocytes) Hurst, JR et al., N Engl J Med 2010, 363;12:

6 Hazard Function of Successive Hospitalised Chronic Obstructive Pulmonary Disease Median Time to Subsequent Exacerbation Number of Exacerbations Suissa S, et al. Thorax 2012; 67:

7 Decreasing inhibition of superoxides by combined incubation with Formoterol (F) + Budesonide (BUD) % Inhibition of LPS-control (mean±sem) *p= vs. FCS-control of Juergens, Bonn 2009

8 Inhibition of cytokine production by 1,8-cineole in LPS-stimulated human monocytes in vitro % Inhibition of control Inhibition TNF- of cytokine production by 1.8-Cineole IL-1 in LPSstimulated human monozytes in vitro IL-6 IL-8 % Inhibition of control % Inhibition of control % Inhibition of control Juergens, Bonn 2012

9 Antiinflammatory Synergies: 1.8-Cineol+Budesonide IL-6 IL-8 IL-6 suppression versus LPS % Log Bud concentration (M) Juergens, Bonn 2008

10 Co-medikation with 1,8-cineole (Soledum R forte Capsl.) for intensification of guideline therapies in COPD and Asthma TNF- inhibition vs. LPS% Log concentration (M) Juergens, Bonn 2013

11 Increase of system inflammation according to GOLD Stage CRP TNF- GOLD III/IV GOLD III/IV GOLD II GOLD II GOLD I GOLD I Gesunde Kontrolle Serum C-Reactive Protein (mg/l) Gesunde Kontrolle Serum TNF-Alpha (pg/ml) Franciosi LG, et al, Pulm Pharmacol Ther 2006; Vol 19: pp

12 Anti-inflammatory systemic effects of 1,8- cineole (3x200mg) in steroid-dependent Asthma and healthy subjects in monocytes ex vivo a) LTB 4 b) IL-1 Normal Subjects *p= **p= (-40,3±13%) (-57,9±5,5%) *p= **p=0.021 (-44,5±8,6%) (-54,3±7,9%) Asthma: n=10; NS: n=12 NS: n=4 Juergens UR, et al. Eur J Med Res 1998; 3,9:

13 Reduction of exacerbations in COPD (GOLD II-III) by comedications with 1.8-Cineol (Soledum R forte) 220 Patients (n=242) with COPD GOLD II-III FEV ± 31% Pack-yrs 31.4± Cineol 3x200mg/day Placebo 2x3months Exacerbations Frequency, Severity, Duration, Lungfunction Quality of life [AQLQ] %Reduction of exacerbation compared to placebo Worth H et al., Respiratory Research 2009,10:69

14 Reduction of exacerbations in COPD Clinical Studies in COPD: 1) Tiotropium 18 g (UPLIFT): Tashkin DP et al., N Engl J Med ) Roflumilast 500 g (Mw von 2 Studien): Calverly PMA et al., Lancet ) Tiotropium 18 g: Niewoehner DE et al.,an Int Med, ) FP 2x500 g (Mw von 3 J.): Burge PS et al., (ISOLDE), BMJ ) 2x F 4.5 g+bud 160 g: Szafranski W et al., Eur Respir J ) 2x F 4.5 g+bud 400 g: Calverley PMA et al., Eur Respir J ) 2x SFP 50/500 g (TORCH) Calverley PMA et al., N Engl J Med ) 1.8-Cineol 3x200mg: Worth H et al., Respiratory Research 2009 % Reduction of exacerbations compared to placebo Clinical studies Juergens, Bonn 2011

15 Improvement of asthma control by co-medication with 1,8-cineole (Soledum R forte) 0Patients (n=247) with persistent Asthma (FEV1 82%) Design: PC,R,DB,MZ FEV1 1.8-Cineol 3x200mg/Day Placebo Nocturnal dyspnea 6-months Primary Endpoint Lung-function Frequency of night symptoms Quality of life [AQLQ] Asthma- Quality of Live Worth H et al., J of Asthma 2012, Oct;49(8):

16 Synergistic anti-inflammation of VD3 and 1.8-Cineol Inhibition of TNF- TNF- inhibition vs. LPS%a Log 1,25 Vit. D3 concentration (ng/ml) Juergens, Bonn 2011

17 Working principle of 1.8-cineole: control of inflammation as cause of hypersecretion Cellactivation 1.8-Cineole Exacerbation Mediators Thank you Hypersecretion for your attention! Inflammation COPD/Asthma Resp. Infect Progress Juergens, Bonn 2012