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PROSPAN® A Herbal Preparation with a Proven Mode of Action 1 PROSPAN® Aug 2005 Differences in medicinal products Chemical – Herbal Chemical products Herbal products • First chemical products derived from herbal pattern • Long-time experience in phytotherapy • Application of plants or parts of plants is historically the basis for any therapy 2 PROSPAN® Aug 2005 Differences in medicinal products Chemical – Herbal Chemical products Herbal products • Defined substance(s) as active ingredient(s) • Whole plant extract as active ingredient • This active ingredient is chemically synthetizised and exactly characterized • These extracts are complex multisubstance mixtures 3 PROSPAN® Aug 2005 Differences in medicinal products Chemical – Herbal Chemical products Herbal products • Defined doses of the active ingredient must have equivalent efficacy in every final product • Every substance of the extract may contribute to the efficacy (and tolerability) of the extract • Pharmacokinetic studies are nearly impossible to perform due to multisubstance character • Pharmacokinetic studies are easy to perform due to monosubstance character 4 PROSPAN® Aug 2005 Differences in medicinal products Chemical – Herbal Chemical products Herbal products Products with the same active ingredient must guarantee the same efficacy Products with an extract of the same plant from different manufacturers may differ in efficacy and tolerability – proven by studies respective to bioavailability or bioequivalence 5 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Herbal extracts of the same plant may be different in efficacy and tolerability ! 6 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Herbal extracts are characterized by: Kind of extract – Fluid extract – Spissum extract – Dried extract 7 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Herbal extracts are characterized by: Extractive agent – Influences the kind and amount of extracted substances (lipohilic or hydrophilic) 8 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Herbal extracts are characterized by: Drug-Extract-Ratio (DER) – How many drug is used to get 1 g of extract? More or less concentrated! 9 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Herbal extracts are characterized by: Composition of the extract itself – respective to quality and quantity of all contained substances 10 PROSPAN® Aug 2005 Dependency of the composition of a herbal extract from manufacturing and quality parameters drug extracting agent content of active substance content of water cutting size specific extracting agent concentration amount portion of powder flow rate homogeneity herbal extract extraction time filling quantity extraction pressure filling height / density extraction temperature method of extraction batch size manufact. process static pressure facility Differences in medicinal products Herbal – Herbal • Efficacy and safety of a herbal extract depends on its very special quality! • Extracts from the same part of the same plant can show different clinical properties 12 PROSPAN® Aug 2005 Differences in medicinal products Herbal – Herbal Results of clinical studies with an extract of manufacturer A are not automatically valid for the extract of manufacturer B The preparation of an extract and the production process for the medicinal product is based on a very special knowledge in each company! 13 PROSPAN® Aug 2005 PROSPAN® Dried extract of Ivy leaves (DER 5-7.5 : 1) Efficacy and safety for this extract has been proved in various clinical studies secretolytic 14 broncholytic PROSPAN® cough relieving Aug 2005 PROSPAN® Documented improvements Objective (Lung function) Subjective - vital capacity (VC), - forced vital capacity (FVC), - forced expiratory volume/sec. (FEV1), - intrathoracic gas volume (ITGV), - residual volume (RV), - airway resistance (RAW, obstruction marker) - peak expiratory flow (PEF) - coughing frequency - coughing intensity - painful coughing - sputum production - expectoration - dyspnoea - general well-being 15 PROSPAN® Aug 2005 „Ivy: mode of action evidenced by cell biological investigations“ In cooperation with Prof. Dr. Hanns Häberlein Physiological Chemistry University of Bonn 16 PROSPAN® Aug 2005 Main constituents of Hedera helix L. Triterpensaponins COO R H -L-rhamnose)1 2 -L-arabinose)1 O H HOCH2 -hederin: hederacoside C:C: hederacoside R -hederin: R=H 17 R=H =R1(β-D-glucose)6 = 1( -D-glucose)6 –1(1(β-D-glucose)4 -D-glucose)4 1(– 1(α-L-rhamnose) -L-rhamnose) PROSPAN® Aug 2005 Mode of action of Ivy indirect increase of ß2-adrenergic effects key role Ca2+ channel lamellar bodies surfactant PKA ß2-adrenergic receptor cAMP [Ca2+i] cAMP lung cell unstriated muscle cell Regulation of β2-adrenergic receptor density Accumulation of RL - complexes in „coated pits“ Ligand (L) RL-complex in „lipid rafts“ Endocytosis β2-adrenergic receptor (R) Recycling early endosome Degradation Degradation How to increase ß2-adrenergic effects on living cells? accumulation of receptor-ligandcomplexes ligand (L) RL-complex in lipid rafts (coated pit) ß2-adrenergic receptor (R) clathrin endocytosis α-hederin recycling early endosome degradation degradation Fluorescence Correlation Spectroscopy 21 PROSPAN® Aug 2005 FCS: Free ligand Detection volume Ligand SO3 SO3H + NH O HN CH3 HC Diffusion time of3 free ligand 45 µs H3C Ligand H3C CH3 CH3 HO C HO NH OH 22 O Cell membrane Alexa-NA (ß2-adrenergic agonist) PROSPAN® Aug 2005 FCS: Ligand-Receptor-Complex Detection volume Receptor-ligand complex Diffusion time of ligand-receptor-complex 3.3 ms Cell membrane 23 PROSPAN® Aug 2005 FCS: Accumulated Ligand-Receptor-Complex Detection volume Accumulated receptor-ligand complex Diffusion time of accumulated ligand-receptor-complex 95 ms Cell membrane 24 PROSPAN® Aug 2005 Receptor-ligand-complex cell + a-hederine + Alexa-NA cell + Alexa-NA 49,6% 32,8% 21,9% 11,8% 38,6% 45,3% Free ligand 25 Accumulated complex PROSPAN® Aug 2005 Inhibition of internalization of 2-adrenergic receptors in pulmonary epithelial cells (A549) by -hederin. control, untreated 10µM terbutaline 20 min pretreatment with 1µM -hederin for 24 h, then 10 µM terbutaline 20 min Prospan: mode of action -hederin influences regulatory processes of ß2-adrenergic receptors: -hederin inhibits redistribution as well as internalisation of even redistributed ß2adrenergic receptors after ligand binding. 27 PROSPAN® Aug 2005 Ivy: Mode of action – consequences I An increased ß2-adrenergic receptor density and an increased signal transduction lead to an increased production of cAMP: increased exocytosis of surfactant in pulmonary epithelial cells (alveolar type II cells) (secretolytic effect, decrease in mucus viscosity, decrease in coughing intensity and frequency). lamellar bodies ß2-adrenergic receptor surfactant PKA 28 cAMP PROSPAN® Aug 2005 Ivy: Mode of action – consequences II An increased ß2-adrenergic receptor density and an increased signal transduction lead to an increased production of cAMP: decrease in intracellular [Ca2+i] with subseeding bronchial muscle relaxation (formation of less active myosin kinase via phosphorylation by phosphokinase A). Ca2+ channel cAMP ß2-adrenergic receptor [Ca2+i] 29 PROSPAN® Aug 2005 Ivy - Resorption In vitro (CaCo-2-cells) Transport α-Hederin Transport ofofalpha-hederin kumulierte Konzentration [µg/ml] cumulated concentration [µg/ml] Transport of C C Transport ofHederacosid Hederacosid 0,45 0,4 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 0 50 100 Timetime (min)[min] 30 0,6 0,5 0,4 0,3 0,2 0,1 0 0 20 40 60 80 time(min) [min] Time PROSPAN® Aug 2005 100 Ivy - Resorption In vivo – first results alpha-hederin • discovered in blood of treated animals and humans • the amount of hederacosid C given in an extract seems to support the concentration of alphahederin in blood (prodrug??) Actually: Ongoing works on the sensitivity of analytical methods for further clarification 31 PROSPAN® Aug 2005 Ivy- mode of action -hederin increased β2 –adrenergic stimulation lung epithelium bronchial muscle surfactantproduction Ca++ (intracellular) secretolytic broncholytic dilatation of bronchial musculature reduction of mucus viscosity Expectorant 32 PROSPAN® Aug 2005 Ivy: Effect on ß2-receptors in general In theory -hederin supports indirectly the stimulaton of all ß2-receptors but given by the smooth and indirect effect, a result will only be seen in those organs with a pathological condition (e.g. ivy will have no bronchiolytic effect in case of „normal“ bronchial muscles) 33 PROSPAN® Aug 2005 Thank you very much for your kind attention!