A Herbal Preparation with a Proven Mode of Action

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PROSPAN

• A Herbal Preparation with a Proven Mode of Action

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Differences in medicinal products Chemical
Herbal

• Chemical products
• First chemical products derived from herbal
  pattern

• Herbal products
• Long-time experience in phytotherapy
• Application of plants or parts of plants is
  historically the basis for any therapy

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Differences in medicinal products Chemical
Herbal
Chemical products
Herbal products

• Defined substance(s) as active ingredient(s)
• This active ingredient is chemically
  synthetizised and exactly characterized

• Whole plant extract as active ingredient
• These extracts are complex multisubstance
  mixtures

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Differences in medicinal products Chemical
Herbal
Chemical products
Herbal products

• Defined doses of the active ingredient must have
  equivalent efficacy in every final product
• Pharmacokinetic studies are easy to perform due
  to monosubstance character

• 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

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Differences in medicinal products Chemical
Herbal
Chemical products
Herbal products

• Products with the same active ingredient must
  guarantee the same efficacy
• proven by studies respective to bioavailability
  or bioequivalence

• Products with an extract of the same plant from
  different manufacturers may differ in efficacy
  and tolerability

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Differences in medicinal products Herbal Herbal

• Herbal extracts of the same plant may be
  different in efficacy and tolerability !

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Differences in medicinal products Herbal Herbal

• Herbal extracts are characterized by
• Kind of extract
• Fluid extract
• Spissum extract
• Dried extract

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Differences in medicinal products Herbal Herbal
Herbal extracts are characterized by

• Extractive agent
• Influences the kind and amount of extracted
  substances (lipohilic or hydrophilic)

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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!

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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

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Dependency of the composition of a herbal extract
from manufacturing and quality parameters
drug
extracting agent
specific extracting agent
content of active substance
content of water
concentration
cutting size
amount
portion of powder
flow rate
homogeneity
herbal extract
extraction time
filling quantity
extraction pressure
extraction temperature
filling height / density
method of extraction
batch size
static pressure
facility
manufact. process
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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

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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!
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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
broncholytic
cough relieving
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PROSPAN
Documented improvements

• Objective (Lung function)
• 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)

• Subjective
• - coughing frequency
• - coughing intensity
• - painful coughing
• - sputum production
• - expectoration
• - dyspnoea
• - general well-being

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Ivy mode of action evidenced by cell
biological investigations
In cooperation with Prof. Dr. Hanns
Häberlein Physiological Chemistry University of
Bonn
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Main constituents of Hedera helix L.
Triterpensaponins
hederacoside C R 1(ß-D-glucose)6
1(ß-D-glucose)4 1(a-L-rhamnose)
a-hederin R H
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Mode of action of Ivy
indirect increase of ß2-adrenergic effects
ß2-adrenergic receptor
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Regulation of ß2-adrenergic receptor density
Accumulation of RL - complexes in coated pits
Ligand (L)
RL-complex in lipid rafts
ß2-adrenergic receptor (R)
Recycling
early endosome
Degradation
Degradation
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a-hederin
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Fluorescence Correlation Spectroscopy
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FCS Free ligand
Diffusion time of freeligand 45 µs
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FCS Ligand-Receptor-Complex
Diffusion time ofligand-receptor-complex 3.3 ms
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FCS Accumulated Ligand-Receptor-Complex
Diffusion time ofaccumulated ligand-receptor-comp
lex 95 ms
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Receptor-ligand-complex
Free ligand
Accumulated complex
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Inhibition of internalization of ?2-adrenergic
receptors in pulmonary epithelial cells
(A549) by ?-hederin.
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Prospan mode of action
?-hederin influences regulatory processes of
ß2-adrenergic receptors ?-hederin inhibits
redistribution as well as internalisation of even
redistributed ß2-adrenergic receptors after
ligand binding.
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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).

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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 Ca2i with subseeding
  bronchial muscle relaxation (formation of less
  active myosin kinase via phosphorylation by
  phosphokinase A).

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Ivy - Resorption
In vitro (CaCo-2-cells)
Transport of Hederacosid C
Transport of alpha-hederin
Time (min)
Time (min)
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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
  alpha-hederin in blood (prodrug??)
• Actually Ongoing works on the sensitivity of
  analytical methods for further clarification

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Ivy- mode of action
Expectorant
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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)
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Thank you very much for your kind attention!