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Issues and challenges in the ‘Seed to Patient’ concept:
Remotiv and Gincosan case studies
Andrea Zangara
andre.zangara@sfihealth.com
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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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?

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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
stages
Clinical Trials
On Finished Products

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Variation due to harvesting time
Source: Prof Rudi Bauer
University of Graz, Austria

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Seasonal variation
Source: Prof Rudi Bauer
University of Graz, Austria

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Multi-target therapy
PLANT IS A LIVE FACTORY PRODUCING A VARIETY
OF CHEMICAL COMPOUNDS

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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

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Phytoequivalence

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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)

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Facts about St John’s wort drug interactions
Fact 1. Hyperforin is the main constituent in St John’s wort
responsible for drug interactions
Hyperforin 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

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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

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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

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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 --- ++ --- +

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Clinical trials
HamiltonDepressionRatingScale
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

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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

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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

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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)

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• 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

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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
%ofthetotalbatchesanalyzed
%accepted
%rejected

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The Gincosan synergy

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COGNITION DOMAINS
ATTENTION, CONCENTRATION, VIGILANCE
WORKING(SHORT-TERM ) MEMORY
EPISODIC (LONG-TERM) MEMORY

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Im pairm ents in various disease conditions com pared to age-m atched controls
Pow er of A ttention
E
lderly
B
orderline
H
ypertensives
M
C
I
C
hronic
F
atigue
C
linicalT
rial
A
dultA
D
H
D
C
arotid
A
rtery
B
ypass
G
raftP
atients
P
re-O
p
F
ibrom
yalgia
Y
oung
H
ypertensivesE
pilepsy
M
S
P
arkinson's
unm
edicated
C
arotid
A
rtery
B
ypass
G
raftP
atients
P
ost-O
p
C
arotid
S
inus
H
ypersem
sitivity
O
rthostatic
H
ypotension
C
hronic
F
atigue
S
elf-H
elp
group
S
trokeA
D
-
M
ild
A
D
-
M
oderate
A
D
-
S
evere
V
ascular
D
em
entia
P
arkinson's
disease
dem
entia
StandarddeviationsfromNorm
0
1
2
3
4
5
6
7
8
9

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P o w e r o f A tte n tio n
A g e B a n d
1
8
-2
5
2
6
-3
0
3
1
-3
5
3
6
-4
0
4
1
-4
5
4
6
-5
0
5
1
-5
5
5
6
-6
0
6
1
-6
5
6
6
-7
0
7
1
-7
5
7
6
-8
0
8
1
-9
0
msec
1000
1100
1200
1300
Attention and aging

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Gincosan and Serial Sevens
Changefrombaseline
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 . 5
placebo
****
**** **** **
320mg
**
640mg
960mg

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Gincosan and Serial Sevens
Changefrombaseline
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 . 5
placebo
****
**** **** **
320mg
**
640mg
960mg
blood
flow?
blood
glucose?

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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

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Gincosan-main clinical trial
Randomised
Double-blind
Placebo-controlled
Parallel group
14 week repeated assessment trial
in 256 normal middle aged (40-65)-volunteers

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• 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

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Gincosan: main clinical trial

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Hypothesis on ‘Quality of Memory’ factor and Aging

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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

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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%)

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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

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“The Seed to Patient” Journey…
35
The 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

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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

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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

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