Post on 20-Jan-2016
Aug 2005PROSPAN®1
PROSPAN®
A Herbal Preparation with a Proven Mode of Action
Aug 2005PROSPAN®2
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
Differences in medicinal products Chemical – Herbal
Aug 2005PROSPAN®3
• 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
Differences in medicinal products Chemical – Herbal
Chemical products Herbal products
Aug 2005PROSPAN®4
• 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
Differences in medicinal products Chemical – Herbal
Chemical products Herbal products
Aug 2005PROSPAN®5
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
Differences in medicinal products Chemical – Herbal
Chemical products Herbal products
Aug 2005PROSPAN®6
Differences in medicinal products Herbal – Herbal
Herbal extracts of the same plant may
be different in
efficacy and tolerability !
Aug 2005PROSPAN®7
Differences in medicinal products Herbal – Herbal
Herbal extracts are characterized by:
Kind of extract
– Fluid extract– Spissum extract– Dried extract
Aug 2005PROSPAN®8
Differences in medicinal products Herbal – Herbal
Extractive agent
– Influences the kind and amount of extracted substances (lipohilic or hydrophilic)
Herbal extracts are characterized by:
Aug 2005PROSPAN®9
Differences in medicinal products Herbal – Herbal
Drug-Extract-Ratio (DER)
– How many drug is used to get 1 g of extract? More or less concentrated!
Herbal extracts are characterized by:
Aug 2005PROSPAN®10
Differences in medicinal products Herbal – Herbal
Composition of the extract itself
– respective to quality and quantity of all contained substances
Herbal extracts are characterized by:
drug
facility manufact. process
herbal extract
extracting agent
Dependency of the composition of a herbal extract from manufacturing and quality parameters
specific extracting agent
concentration
amount
flow rate
filling quantity
filling height / density
static pressurebatch size
extraction pressure
extraction temperature
extraction time
method of extraction
homogeneity
portion of powder
cutting size
content of water
content of active substance
Aug 2005PROSPAN®12
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
Aug 2005PROSPAN®13
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!
Aug 2005PROSPAN®14
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
Aug 2005PROSPAN®15
PROSPAN®
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
Documented improvements
Aug 2005PROSPAN®16
„Ivy: mode of action evidenced by cell biological investigations“
In cooperation with
Prof. Dr. Hanns Häberlein
Physiological Chemistry University of Bonn
Aug 2005PROSPAN®17
Main constituents of Hedera helix L.
-hederin: R = Hhederacoside C: R = 1(β-D-glucose)6 – 1(β-D-glucose)4 – 1(α-L-rhamnose)
Triterpensaponins
Mode of action of Ivy
indirect increase of ß2-adrenergic effects
ß2-adrenergicreceptor
key role
lamellar bodies
cAMP
surfactant
PKA
lung cell
cAMP
SR[Ca2+i]
Ca2+ channel
unstriated muscle cell
Endocytosis
Regulation of β2-adrenergic receptor density
Degradation
Recycling
Ligand (L)
Accumulation of RL - complexes in „coated pits“
β2-adrenergic receptor (R)
RL-complex in „lipid rafts“
Degradation
early endosome
endocytosis
How to increase ß2-adrenergic effects on living cells?
degradation
degradation
recycling
ligand (L)
accumulation of receptor-ligand-complexes
(coated pit)
clathrin
early endosome
ß2-adrenergic receptor (R)
RL-complex in lipid rafts
α-hederin
Aug 2005PROSPAN®21
FluorescenceCorrelation Spectroscopy
Aug 2005PROSPAN®22
FCS: Free ligand
Cell membrane
Detection volume
Ligand
Ligand
Diffusion time of freeligand 45 µs
OHN NH
H3C CH3
CH3
SO3SO3H
H3C
H3C CH3
CONH
HO
HO
OH
-
+
Alexa-NA(ß2-adrenergic agonist)
Aug 2005PROSPAN®23
FCS: Ligand-Receptor-Complex
Diffusion time ofligand-receptor-complex
3.3 ms
Cell membrane
Detection volume
Receptor-ligandcomplex
Aug 2005PROSPAN®24
Diffusion time ofaccumulated ligand-receptor-complex
95 ms
Cell membrane
Detection volume
FCS: Accumulated Ligand-Receptor-Complex
Accumulated receptor-ligand
complex
Aug 2005PROSPAN®25
cell + a-hederine + Alexa-NA
38,6%
49,6%
11,8%
cell + Alexa-NA
45,3%
32,8%
21,9%
Free ligand
Receptor-ligand-complex
Accumulated complex
10µM terbutaline 20 mincontrol, untreated
pretreatment with 1µM -hederin for 24 h, then 10 µM terbutaline 20 min
Inhibition of internalization of 2-adrenergic receptors in pulmonary epithelial cells (A549)
by -hederin.
Aug 2005PROSPAN®27
-hederin influences regulatory processes of ß2-adrenergic receptors:
-hederin inhibits redistribution as well as internalisation of even redistributed ß2-
adrenergic receptors after ligand binding.
Prospan: mode of action
Aug 2005PROSPAN®28
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).
Ivy: Mode of action – consequences I
lamellar bodies
cAMP
surfactant
PKA
ß2-adrenergicreceptor
Aug 2005PROSPAN®29
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).
cAMPSR[Ca2+
i]
Ca2+ channel
ß2-adrenergicreceptor
Ivy: Mode of action – consequences II
Aug 2005PROSPAN®30
Ivy - Resorption In vitro (CaCo-2-cells)
Transport of Hederacosid C Transport of alpha-hederin
Time (min) Time (min)
Aug 2005PROSPAN®31
Ivy - ResorptionIn 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
Aug 2005PROSPAN®32
Ivy- mode of action
-hederin
reduction of mucus viscosity
dilatation of bronchial musculature
increased β2 –adrenergic stimulation
lung epithelium bronchial muscle
surfactant-production
Ca++
(intracellular)
secretolyticbroncholytic
Expectorant
Aug 2005PROSPAN®33
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)
Thank you very much for
your kind attention!