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27th International Congress of Applied Psychology Issues and challenges in the ‘Seed to Patient’ concept: Remotiv and Gincosan case studies Andrea Zangara [email protected] Research and Development Director, SOHO-Flordis International Adjoined with: Swinburne University, Au (Brain Sciences Institute) Newcastle University, UK (Medicinal Plants Research Centre)

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27th International Congress of Applied Psychology

Issues and challenges in the ‘Seed to Patient’ concept:

Remotiv and Gincosan case studies

Andrea Zangara

[email protected]

Research and Development Director, SOHO-Flordis International

Adjoined with:

Swinburne University, Au (Brain Sciences Institute)

Newcastle University, UK (Medicinal Plants Research Centre)

27th International Congress of Applied Psychology

Natural products vary enormously

Wine – grapes can become a bottle of premium wine or a cheap cask wine

The quality of the finished wine is a result of how the grapes have been handled - from

the growing on the vine to processing by the wine maker, to its ultimate arrival into the

hands of the person drinking the glass of wine

Natural medicines are no different – therefore What is the journey

that a medicinal plant has to take to become a tablet taken by the

patient?

2

27th International Congress of Applied Psychology

Product quality - variability of products

PLANT(Species, sub-species, growth conditions, methods of cultivation)

Harvesting/storage(Time of year/month & stage of growth cycle, storage conditions 0C, packaging)

Extraction (Method, conditions & equipment used,

solvent/s used, concentrations)

FINISHED PRODUCT(Formulation, manufacturing, packaging,

storage conditions)

Enormous

variability

can occur

at all these

stagesClinical Trials

On Finished Products

27th International Congress of Applied Psychology

Variation due to harvesting time

Source: Prof Rudi Bauer

University of Graz, Austria

27th International Congress of Applied Psychology

Seasonal variation

Source: Prof Rudi Bauer

University of Graz, Austria

27th International Congress of Applied Psychology

Multi-target therapy

PLANT IS A LIVE FACTORY PRODUCING A VARIETY

OF CHEMICAL COMPOUNDS

27th International Congress of Applied Psychology

Because phytochemical profiles are so complex,

pharmacoequivalence (common with synthetic medicines

based on single chemicals) is very hard to obtain

Pharmacoequivalence vs. Phytoequivalence

HPLC Chromatograms: (A) Bacopa monnieri

Extract, (B)Acetaminophen, Caffeine, Aspirin

A B

27th International Congress of Applied Psychology

Phytoequivalence

27th International Congress of Applied Psychology

The Swiss Zeller AG is today one of

the leading companies in the

development and production of

phytopharmaceuticals on a

scientific basis worldwide

Remotiv (Ze 117)

• Formal indication:

Relief of mild to moderate

depression, anxiety & restlessness

• Ingredient:

Special extract of Hypericum (St John’s wort)

Ze 117

Ethanolic extract -manufactured using Seed to

patient standardisation

Equivalent to dry hypercum perforatum herb

1.375g

.

Remotiv Ze 117 (Zeller AG, Switzerland)

27th International Congress of Applied Psychology

Facts about St John’s wort drug interactions

Fact 1. Hyperforin is the main constituent in St John’s wort

responsible for drug interactionsHyperforin has been identified as a very potent and selective inducer of CYP

enzymes

Fact 2. Clinical drug Interactions with St John’s wort depend on the

hyperforin content in the extract1

The higher the levels of hyperforin the higher the risk of interactions with

concomitant drugs

Fact 3. Remotiv® (Ze 117) has negligible levels of hyperforin2

Remotiv has the lowest level of hyperforin compared to other Australian St

John’s wort products3

1. Madabushi R et al Eur Clin Pharmacol 2006: 62 (3):225-233

2. Wurglics M et al Am Pharm Assoc 2001; 41(4):560-566

3. Kimble B et al Variations in active components of Hypericum perforatum products in Australia ICCMR Mar 2008 Poster 197

27th International Congress of Applied Psychology

Hyperforin content of Australian SJW Products

0

2

4

6

8

10

12

14

P1 P2 P3 P4 P5 P6 P7

Products

mg

Source: ICCMR P1197 Kimble B. et al (University of Sydney, Department of Pharmacy

April 1st 2008)

1) Blackmores 2) Mediherb 3) Herron 4) Remotiv/Flordis 5) Nature’s Own 6) Blooms

7) Herbs of Gold

Hyperforin is a big

issue as it is

responsible for

interactions

27th International Congress of Applied Psychology

0

2

4

6

8

10

12

14

16

18

Remotiv Brand 2 Brand 3 Brand 4 Brand 5 Brand 6 Brand 7 Brand 8

Hyperforin/Dosage Unit (mg)

Hyperforin content of 8 different St John's Wort products1*

Batch 1

Batch 2

Batch 3

Batch 4

Batch 5

1. Wurglics M et al Am Pharm Assoc 2001; 41(4):560-566

* Study was conducted on products purchased in Germany.

Variablity of Hyperforin within same products

27th International Congress of Applied Psychology

Probable Mode of Action

• Centrally acting in synaptic cleft

– inhibits reuptake of serotonin & noradrenaline

and dopamine

– most similar to Tricyclics and SNRIs

Class Noradrenaline Serotonin Dopamine Histamine

Remotiv ++ ++ ++ ---

Tricyclics ++ (strong) ++ ++ (increase) ++ (block)

SNRI ++ ++ + ---

SSRI --- ++ --- +

27th International Congress of Applied Psychology

Clinical trialsH

am

ilto

n D

epre

ssio

n R

ati

ng S

cale

1. Schrader E Human Psychopharmacol 1998;13:163-169

2. Woelk H et al BMJ 2000; 321:536-539

3. Schrader E et al Int Clin Psycopharma 2000; 15:61-68

27th International Congress of Applied Psychology

Clinical trials cont.

1. Schrader E Human Psychopharmacol 1998;13:163-169

2. Woelk H et al BMJ 2000; 321:536-539

3. Schrader E et al Int Clin Psycopharma 2000; 15:61-68

4. Brattström A Phytomedicine 2009; 16:277-283

5. Dr. D Mazza, Aust Doctor 6 July (2001) 55:57

6. Will-Shahab L et al Eur J Clin Pharmacol 2009;65(3):287-94

27th International Congress of Applied Psychology

Features and Benefits

Feature Benefit

Specifically clinically proven to be equally

effective as synthetic anti-depressants yet better

tolerated

Can be confident patients will get proven relief of mild to

moderate depression and anxiety without experiencing the

adverse events commonly associated with other anti-

depressants

Fully controlled „Seed-to-Patient' manufacturing

process Reliable and consistent results with every tablet

Negligible levels of hyperforin

Can be used with a wider audience because of the

reduced risk of interactions with other medications

Clinically proven to not interact with the

pharmacokinetics of the oral contraceptive pill

Unlike some other anti-depressants, Remotiv can be

recommended to women who are currently taking the OCP

27th International Congress of Applied Psychology

Gincosan GK501+G115

Ginsana‟s products are the result

of the most rigorous scientific

research from the Pharmaton

legacy and the experience

acquired over many years activity

within the Boehringer Ingelheim

Group

• Formal indication:

– To improve

memory, concentration,

reduce mental fatigue

• Ingredient:

– Ginkgo biloba leaf 2.16 standardised to ginkgo

flavonglycosides 14.7 mg,

ginkgolides and bilobalide 3.6

mg(GK501)

– Panax ginseng root 212.5

mg

standardised to ginsenosides 4

mg(G115)

27th International Congress of Applied Psychology

• Ginkgo extract GK501

– Improved supply of oxygen to the brain: vasodilatory

effect

– Neuroprotective properties

– Terpene lactones inhibit platelet activating factor-

receptors of the target cells

• Ginseng extract G115

– Improved oxygen/ glucose utilisation in the brain

– Neuroprotective properties

– Anti-fatigue

Mode of action

27th International Congress of Applied Psychology

Seed to Patient: quality of ginseng roots

Ginseng roots : batches accepted vs. batches rejected

0

10

20

30

40

50

60

70

80

90

100

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

years

% o

f th

e t

ota

l b

atc

hes a

naly

zed

% accepted

% rejected

27th International Congress of Applied Psychology

The Gincosan synergy

27th International Congress of Applied Psychology

COGNITION DOMAINS

ATTENTION, CONCENTRATION, VIGILANCE

WORKING(SHORT-TERM ) MEMORY

EPISODIC (LONG-TERM) MEMORY

27th International Congress of Applied Psychology

Im pairm ents in various d isease conditions com pared to age-m atched contro ls

Pow er of A ttention

Eld

erly B

orderli

ne Hypert

ensives

MC

I

Chro

nic F

atigue C

linic

a l Tria

l

Adult

AD

HD

Caro

tid A

rtery

Bypass G

raft

Patie

nts P

re-O

p

Fib

rom

yalgia

Young H

ypertensiv

es

Epile

psyM

S

Park

inson 's

unm

edicate

d

Caro

tid A

rtery

Bypass G

raft

Patie

nts P

ost-O

p

Caro

tid S

inus H

ypersem

sitiv ity

Orthosta

tic H

ypotensio

n

Chro

nic F

atigue S

elf-H

elp g

roup

Stroke

AD

- M

ild

AD

- M

oderate

AD

- S

evere

Vascula

r D

ementia

Park

inson 's

dis

ease dem

entia

Sta

nd

ard

de

via

tio

ns

fro

m N

orm

0

1

2

3

4

5

6

7

8

9

27th International Congress of Applied Psychology

Pow er of A ttention

A ge B and18-2

5

26-30

31-35

36-40

41-45

46-50

51-55

56-60

61-65

66-70

71-75

76-80

81-90

ms

ec

1000

1100

1200

1300

Attention and aging

27th International Congress of Applied Psychology

27th International Congress of Applied Psychology

Gincosan and Serial SevensC

hange

fro

m b

aselin

e

Scholey AB & Kennedy DO (2002) Human Psychopharmacology 17, 35-44

Number of responses

0 1 h r 2 .5 h r 4 h r 6 h r

1 0 . 0

0 . 0

2 . 5

5 . 0

7 . 5

1 2 . 5placebo

******** **** **

320mg

**

640mg

960mg

27th International Congress of Applied Psychology

Gincosan and Serial SevensC

hange

fro

m b

aselin

e

Scholey AB & Kennedy DO (2002) Human Psychopharmacology 17, 35-44

Number of responses

0 1 h r 2 .5 h r 4 h r 6 h r

1 0 . 0

0 . 0

2 . 5

5 . 0

7 . 5

1 2 . 5placebo

******** **** **

320mg

**

640mg

960mg

blood

flow?

blood

glucose?

27th International Congress of Applied Psychology

Background

• Six randomized placebo controlled trials on Gincosan

• Cognitive Drug Research (CDR) computerised assessment

system as the primary cognitive outcome tool

• All have identified beneficial effects on cognitive

function

• Over 600 volunteers, comprising student populations,

healthy middle aged adults, healthy elderly people, and

volunteers with neurasthenia

27th International Congress of Applied Psychology

Gincosan-main clinical trial

Randomised

Double-blind

Placebo-controlled

Parallel group

14 week repeated assessment trial

in 256 normal middle aged (40-65)-volunteers

27th International Congress of Applied Psychology

• Screening period: Training

• Week 0 Pre-dose 1h 3h 6h post

• Week 4 Pre-dose 1h 3h 6h post

• Week 8 Pre-dose 1h 3h 6h post

• Week 12 Pre-dose 1h 3h 6h post

• Week 14 Pre-dose 1h 3h 6h post

Gincosan: main clinical trial

27th International Congress of Applied Psychology

Gincosan: main clinical trial

27th International Congress of Applied Psychology

Hypothesis on ‘Quality of Memory’ factor and Aging

27th International Congress of Applied Psychology

Features and Benefits

Feature Benefit

Natural cognitive enhancer containing

extracts of Ginkgo biloba (GK501) and

Panax ginseng (G115)

Unique synergistic effect which improves cognitive function

Specifically clinically proven to be

effective in improving memory and

cognition in 6 „gold standard‟ double-

blind, placebo-controlled trials

You can be confident that you will be using the EXACT

product proven to be effective in clinical trials

Ginkgo biloba (GK501) improves the

supply of oxygen and nutrients to the

brain whilst Panax ginseng

complements this by improving oxygen

and nutrient use in the brain

Improves cognitive results in memory and concentration,

including all 5 measures of cognitive function:

long term memory for words and pictures,

working memory for numbers and locations,

speed of memory processes,

power of concentration and

consistency of concentration

27th International Congress of Applied Psychology

Gincosan: Safety Profile

No serious adverse events reported

2000 – 2004 Worldwide

• Total patient exposure: 33,632 patient-years

(including clinical trials)

• Total cases: 18 (all were non-serious)

– Nervous system disorders (37.0%)

– Gastrointestinal disorders (33.3%)

– Psychiatric disorders (11.1%)

27th International Congress of Applied Psychology

Gincosan and Remotiv: the value of evidence

• Reliability and confidence

– Reproducible effective results

– High level of safety

• Natural products with specific evidence

are credible mainstream medicines

• Seed to Patient control and Specific

Clinical Trials add extra value and insure

long life to product

27th International Congress of Applied Psychology

“The Seed to Patient” Journey…

35The result of a fully controlled Seed to Patient Journey is a properly standardised

herbal medicine which can be used in clinical trials.

Unknown origin of seed/plant

Unknown growing, harvesting and storage methods

Raw materials bought on world market

– processing unknown

Only the finished product is standardised

Clinical trials

Known origin of seed/plant

Consistent growth, harvesting and storage

Consistent processing methods

Entire seed to patient journey is standardised

Clinical trials using the specific product

Commodity

Herbal Product

Specifically Clinically Proven

Herbal Medicine

27th International Congress of Applied Psychology

The health professionals and Flordis

• Flordis relies on the clinical feedback and advices from health professional

• Health professionals have the ability to understand the value of our philosophy and to propose our products to patients as solutions

• Our products are very effective, a trained health professional provides guidance to patients in their use

• Prescribing SCP products is a professional and ethical choice and provides the patient with a safe, effective, and informed solution

27th International Congress of Applied Psychology

Conclusions

• The variability that can occur at any stages in herbal medicines development, is due to many controllable factors

• By controlling them, unique products are developed

• Evidence based herbal medicine requires proof of safety, quality and efficacy

• If products are not equivalent, individual clinical evaluation is needed

• Specifically clinically proven refers to the use of the EXACT product that has been studied in clinical trials

• “Generic” (untested) products and borrowed science represent a threat to consumers and the whole reputation of the market

• Consumers should be increasingly aware of the need to ask for specific evidence

27th International Congress of Applied Psychology