prospan ®

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


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



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



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


Herbal extracts are characterized by:

Kind of extract

– Fluid extract– Spissum extract– Dried extract

Aug 2005PROSPAN®8


Extractive agent

– Influences the kind and amount of extracted substances (lipohilic or hydrophilic)


Aug 2005PROSPAN®9


Drug-Extract-Ratio (DER)

– How many drug is used to get 1 g of extract? More or less concentrated!


Aug 2005PROSPAN®10


Composition of the extract itself

– respective to quality and quantity of all contained substances


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 sizecontent of water

content of active substance

Aug 2005PROSPAN®12


• 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


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


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


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)

secretolytic broncholytic

Expectorant

Aug 2005PROSPAN®33

Ivy: Effect on ß2-receptors in general

In theory -hederin supports indirectly the stimulaton of all ß2-receptors

butgiven 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!

prospan ®

Documents