Transcript Read more - Jal pharma

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
– 1(α-L-rhamnose)
 -D-glucose)4 1(
 -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!