On May 29, 7:31*pm, Taka <taka0...[at]gmail.com> wrote:31. Srivastava KC.
(1984). Effects of aqueous extracts of onion, garlic and ginger on
platelet
aggregation and metabolism of arachidonic acid in the blood vascular
system : in vitro study. Prostglandins Luekot Med. 13: 227-235. <<

That's it .. ?

It's mentioned in passing.. ? .. in the credits .. ?

Who loves ya.
Tom


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- quote -

A COMPOSITION FOR DECREASING THE RISK OF LONG-HAUL TRAVELLER'S SYDROME
COMPRISING A MIXTURE OF PYCNOGENOL AND STANDARDIZED GINGER ROOT
EXTRACT Use of Pycnogenole and standardized ginger extract in a well-
defined proportion (e. g. 1: 1.5) in a newly invented combination
product as a Health care composition with the trade name
Zinopin&commat;, targeting Long-haul Traveller's Syndrome in
passengers travelling by air, land or sea is described. The active
ingredients work synergistically to reduce the risk of Deep Vein
Thrombosis and/or oedema associated with or without motion sickness.
The mechanism of action of the combination in Long-haul Traveller's
Syndrome is discussed in light of the established physiological
effects of both as Generally Recognized As Safe (GRAS) active
components. The innovative steps towards the development of Zinopine
and preferred dosage ranges and forms are discussed.

The invention refers to a newly developed, innovative health care
product for decreasing the risk of Deep Vein Thrombosis (DVT) in leg
veins, leg and/or feet oedema and motion sickness which may occur
particularly in long-haul travellers by air, road or sea while sitting
in the constrained position.

According to references 1 and 2, Venous thrombo-embolism (VTE) has
been associated with periods of prolonged immobility during air, sea
and road travel (Cruikshank et al., 1988; Tardy et al., 1993).
Travellers, who have to sit motionless and in a restricted space upon
a seat for example in an aircraft often suffer from pain and oedema in
their legs and feet due to venous stasis. According to references 3
and 4 Simulated or real long flights have been reported to bring about
blood changes including high fibrinogen levels, haemo-concentration
and low fibrinolytic activity (Servesvaren, 1986; Kraaijenhagen et
al., 2000) contributing to increased clot formation, which may lead to
a Deep Vein Thrombosis (Economy Class Syndrome). Motion sickness (MS)
has also been reported during both long and short journeys. Motion
sickness is triggered by sensory conflicts involving the sensory
system, occurring when sensory inputs regarding body position in a
strange situation (during journey) are contradictory from those
adapted from the experience.

A preparation including acetylsalicylic acid, which inhibits the
aggregation of thrombocytes, is often administered to the patients as
a remedy from their pain.

Such preparations, however, involve the risk of inner bleeding out of
the vascular capillaries into the surrounding tissue. It is known that
ugly blue spots appear easily upon the skin in case such tissue is
compressed from the exterior.

It therefore, has been proposed to utilise an agent for inhibiting
aggregation of thrombocytes which may be extracted from the bark of
the French maritime pine tree (Pinus pináster-Ait.),
Pycnogenol&commat;. Pycnogenole includes among other active
ingredients, procyanidins. Extended clinical tests confirmed that
Pycnogenole is not only superior to acetylsalicylic acid in inhibiting
aggregation but is also free of any side effects particularly it does
not cause any inner bleeding. Preparation and qualities of Pycnogenol
are disclosed in US Patent 5,720, 956 listed as reference 5. This
patent discloses a method of controlling human platelet reactivity by
Pycnogenolo.

For the following description it should be understood that the
phrase"French pine bark extract"means in essence the product
Pycnogenol&commat;.

Pycnogenole has been subject of a number of studies for finding out
scientifically confirmed qualities and effects on the human body. Such
studies are enlisted in Reference list (6-18). Regarding venous
insufficiency & Oedema a double blind, placebo controlled study is
disclosed in reference 6. This study shows that 4 days of Pycnogenol
treatment statistically and significantly reduced the leg volume
increase while remaining seated, while placebo had no significant
effect. The authors conclude that Pycnogenole displays a significant
inhibition of oedema during hydrostatic burden (Schmidtke and Shoop,
1984). Reference 7 presents a double blind, placebo controlled study.
Already one month of treatment with Pycnogenole relieved a
statistically relevant number of patients from the typical venous
insufficiency symptoms, while placebo showed no effect.

Particularly the relief from pain was very efficient already after 1
month. At the end of the 2 months trial the majority of patients in
the Pycnogenol group showed no signs of swelling or pain (Arcangeli,
2000).

According to reference 8, Pycnogenole statistically and significantly
improved symptoms of heaviness and swellings, and the symptoms
completely disappeared in 33% (heaviness) and 88% (swellings) of
patients. Placebo showed no signifi- cant benefit (Petrassi et al.,
2000).

In reference 9, the efficacy of Pycnogenole for treatment of venous
insufficiency was compared to another active ingredient widely used
for this purpose: horse chestnut seed extract. Pycnogenolo was
statistically and significantly more effective for reduction of leg
swelling than horse chestnut seed extract, despite the fact that the
latter was given in higher dosage. Further, Pyonogenole was
statistically and significantly more effective than horse chestnut
seed extract for reducing the symptoms"heaviness","cramps"and"night-
time swelling"Koch, 2001). Clinical efficacy of Pycnogenole is
reviewed by Gulati in reference 10 (Gulati, 1999) In a study
(reference 11) on oedema formation in ears and paws of rodents it was
shown that the higher oligomeric procyanidins in Pycnogenole are
particularly effective (Blazso et al., 1994). These results support
the theory put forwarded by Rohdewald (Reference 12) that large
procyanidins bind to proteins of defective blood capillaries to yield
a lower capillary permeability (Rohdewald, 1998). This activity is the
basis for Pycnogenol'sewidespread use in humans (Reference 13)
particularly for its beneficial effects in vascular disorders
(Rohdewald, 2002).

Clinical studies with PyenogenolX (reference 14) have shown with
elevated platelet activity, such as smokers and elderly, that the
activation of platelets is prevented.

Pycnogenole was found to dose-dependently reduce platelet activity,
with statistical significance after using a single dose of at least
100 mg Pycnogenole.

The authors of that study propose that stimulation of nitric oxide
production by Pycnogenole inhibits aggregation of platelets. Thus,
Pycnogenole supports body- own mechanisms to maintain healthy platelet
functions. In a dose range finding part of this study, it was shown
that the maximum platelet inhibitory effect was evident at a dose of
200 mg (Putter et al., 1999).

A single dose of 100 mg of Pycnogenol° was found to be as effective
for reduction of platelet activity as acetyl-salicylic acid, a
substance widely used for suppression of platelet aggregation.
However, acetyl-salicylic acid irreversibly inhibits the enzyme COX
involved in platelet aggregation. As a result acetyl-salicylic acid
dramatically increases the bleeding time causing severe adverse
effects, primarily gastro-intestinal bleeding problems. Pycnogenolo
does not significantly increase bleeding time allowing a long term use
for preventing of thrombotic events.

Pycnogenole has been demonstrated in various studies to be one of the
most powerful natural antioxidants.

The study quoted in reference 15, carried out at the University of
California demonstrated that Pycnogenole is more powerful that vitamin
C &amp; vitamin E. Dr.

Packer and his colleagues found that Pycnogenol is so powerful that it
recycles oxidised (spent) vitamin C back to the bioactive form and
protects vitamin E from oxidation (Cossins et al., 1998). An in vitro
study (reference 16) made at the University of Tokyo showed that
Pycnogenol&commat; is a more powerful antioxidant than other
antioxidants tested (coenzyme Q 10, vitamin C, a-lipoic acid, vitamin
E, grape seed extract) to protect fragile lipids of the eye (Chida et
a/., 1999). This study further demonstrated that when Pycnogenol° is
mixed with grape seed extract, the antioxidant activity of the
combination for some unknown reason is abolished. These observations
were found useful during our combination product development phase,
where we decided to shift from using OPC product (representing
combination of pine bark extract and grape seed extract). Moreover,
PycnogenolW has been shown to be more powerful than grape seed extract
and therefore was a good reason for our choice of Pycnogenole instead
of grape seed extract. These observations are well explained in
our"Product Development Overview" (See script No. 1).

The clinical study according to reference 17 was carried out with 45
healthy volunteers at the University of Texas to demonstrate the
increased antioxidant capacity (ORAC) in the blood following
consumption of Pycnogenole. The result was a striking increase of
antioxidant capacity by 40%, both after three weeks and six weeks,
while the ORAC value fell back to baseline when Pycnogenole was not
ingested for four weeks (Devraj et a/., 2002).

The Medical Guidelines for Airline Travel, 2nd edition. Volume 74
Number 5 Section 11, Supplement Pay 2003 states"Today's aircrafts have
very low cabin humidity, usually ranging from 10-20%. This is
unavoidable because the air at high altitude is practically devoid of
moisture. As a result, there can be drying effect of the airway
passages, the cornea (particularly under contact lenses) and the
skin." Further, a recent study conducted by the French Skin Research
Centre"CERIES" has revealed that the ultra dry air in the cabin of an
aircraft on a long-haul flight (the humidity can fall below that of
the Sahara) can dehydrate the skin in just three hours. Researchers
have dubbed this phenomena"Hydrative Stress". In a study (Reference
18) by Wang in 1999 PycnogenolW was shown to inhibit adhesion and
aggregation of platelets, improve micro-circulation of the tiny skin
capillaries, supporting a better oxygen and nutrient supply and
producing better hydration (Wang et al., 1999).

Reference 19 is made to the US Patent 4,698, 360 titled"Plant Extract
with a Proanthocyanidins Content as Therapeutic Agent having Radical
Scavenger Effect (RSE) and Use Thereof"according to which the radical
scavenger effect of pine bark extract is some 20 times higher than
that of vitamin C.

For oral administration and antioxidant effect it is recommended
generally from 1.5 mg to 3 mg per day per kilogram of body weight for
warm blooded animals which represents for an adult man weighing 70 kg
a daily dose of about 100 to 200 mg of Pycnogenole to be administered
by unit dose, for example 50mg to 100 mg, so as to obtain a radical
scavenger effect in the above mentioned therapeutic indications. These
findings were helpful for us to choose the right dose in our newly
invented combination product Zinopin&commat;. A dose of 200 mg was
selected as the loading dose for the proposed chosen health care
indication"Long-haul Traveller's Syndrome". These observations are
well explained in our"Dosage Rationale" (See script No. 2).

One of the objects of the invention resides in creating a health care
composition having improved platelet aggregation inhibiting function
and being substantially free of side effects. To this end the
invention provides for a health care product for decreasing the risk
of thrombosis particularly within the human leg veins. This includes a
standardized mixture of Pycnogenole and Standardized Ginger Root
Extract in a newly invented, well-defined proportion (1: 1.5) of these
two innovative, Generally Recognized As Safe (GRAS) ingredients. Tests
showed that the adding of Standardized Ginger Root Extract, to
Pycnogenole in a well defined proportion, allowed us to produce a
preparation having improved platelet aggregation inhibiting function,
relieving the symptoms of pain, oedema and inflammation, in addition
to having beneficial effects in travel-induced motion sickness, which
are of particular importance for passengers of long haul flights at
increased altitudes.

Qualities and so far known effects of the dried rhizome of Zingiber
officinale Roscoe, herein after simply called ginger, are disclosed,
apart from different documents, in the WHO Monographs on Selected
Medical Plants, pages 277- 287. So references 20-23 report on the
prophylaxis of nausea and vomiting associated with motion sickness,
supported by clinical data related to ginger. The prophylaxis of
pernicious vomiting in pregnancy is subject of reference 24. The
studies according to references 25-26 refer to the prophylaxis of
seasickness.

References 21 & 27-30 represent monographies on ginger revealing
results as to the treatment of dyspepsia, flatulence, colic, vomiting,
diarrhoea, spasms and other stomach complaints. According to
references 31-36 ginger may have beneficial effects on thrombosis,
owing to its ability to inhibit platelet aggregation, thromboxane
synthase and to act as a prostacyclin agonist causing vasodilatation
and increase in blood flow.

As to antioxidant effects of ginger the authors of the study
(Krishanakantha and Lokesh, 1993) according to reference 37
investigated the effect of zingerone among other spice principles on
the scavenging of superoxide anion. The superoxide anions, as measured
by nitrobluetetrazolium (NBT) reduction in xanthine-xanthine oxidase
system were inhibited in a dose dependent manner.

Zingerone (ginger) inhibited NBT reduction to a maximum of 23%. In
other words, superoxide radicals were inhibited by zingerone from
ginger.

According to reference 38, (Cao et a/. J 1993) studied scavenging
effects of ginger on superoxide anion and hydroxyl radical. Ginger can
significantly scavenge 02-in hypoxanthinexanthine oxidase system and-
OH in ultraviolet exposure of H202 system. The scavenger effects of
ginger on O2-and-OH may contribute to explaining some of the
physiological mechanisms of this active substance.

The anti-oxidative effect of more than 50 ethanol extracts of Chinese
drugs on the air oxidation of linoleic acid was studied as mentioned
in reference 39. Ethanol extract of zingiber officinale among others,
was found having strong anti-oxidative effect (Zhou et a/., 1992).
Reference 40 reports that zingerone from ginger inhibited lipid
peroxidation (Reddy, 1992).

Ginger's action against oedema and anti-inflammatory activity of
ginger are demonstrated in reference 41 according to which ginger (100
mg/kg) was effective as acetyl-salicylic acid (100 mg/kg) in reducing
carrageenin induced oedema in rats (Jana et al., 1999). Similar
results for the anti-inflammatory and analgesic activities of ginger
(references 42 and 43) were reported by (Mascolo et al, 1989 ; Thomson
et al., 2002). It is thought that that these anti-inflammatory actions
are a result of inhibition of prostaglandin release, and hence ginger
may act in a similar fashion to other non-steroidal anti-inflammatory
agents which interfere with prostaglandin release or biosynthesis.

The authors of reference 44 examined the effect of ginger rhizome on
gastro- intestinal motility based on its ability to enhance charcoal
meal transport in mice (Yamahara et al., 1990). Oral administrations
of the acetone extract of ginger (which contains volatile oils and
bitter substances) at 75 mg/kg (6)-shogaol at 2. 5mg/kg, or a (6) -,
(8)-or (10)-gingerol at 5 mg/kg enhanced the transport of a charcoal
meal. The effects of these substances were similar to or slightly
weaker than those of metoclopramide and donperidone. According to
reference 45 experiments were conducted to evaluate the scientific
basis of the use of the trikatu group of acrids (long pepper, black
pepper and ginger) in the large number of prescriptions in Ayurveda.
(3H) vascine and (3H) sparteine were taken as test drugs. The results
suggest that these acrids have the capacity to increase the
bioavailability of certain drugs. It appears that the trikatu group of
drugs increase the bioavailability either by promoting rapid
absorption from the gastrointestinal tract, or by protecting the drug
from being metabolised/oxidised in its first passage through the liver
after being absorbed, or by a combination of these two mechanisms
(Atal et a/., 1982). Reference 46 provides evidence that Ginger may
increase the absoroption of other drugs taken orally (Skidmore-Roth,
2003).

According to reference 47, Ginger has also been shown to produce
decrease in fibrinogen levels and increased fibrinolytic activity
(Verma and Bordia, 2001).

According to reference 48 ginger decreases the levels of cholesterol,
phospholipids and free fatty acids in tissues and serum. Serum
glycerdies levels were also significantly reduced. Ginger increases
the concentration of HDLs and decreases the concentrations of LDLs and
VLDLs in serum (Murgaiah et al, 1999).

Particularly, the health care composition Zinopino according to the
present invention includes a well-proportioned and well-defined
mixture of Pycnogenol and Standardized Ginger Root Extract. The
proposed mechanism of action in the proposed healthcare
indication,"Long-haul Traveller's Syndrome"is included (see Script No.
3).

At present, best results are obtained by the here discussed health
care product manufactured according to the present invention which
preferably includes a mixture of 100 weight units of a 100%
Standardised Pine Bark Extract from the French Maritime pine bark
Pinus pinaster Ait. and 150 weight units of Standardised Ginger Root
Extract which includes a content of approximately 5% of the 150 weight
units of gingeroles and approximately 1,. 5% of the 150 weight units
of shagoals.

Thus, the invention represents a unique combination of Pycnogenole and
standardised Ginger Root Extract in a preferred and well-defined
proportion (1: 1.5). The invention offers the physiological benefits
in newly defined syndrome in healthy subjects. A newly invented
term,"Long-haul Traveller's Syndrome (LTS) "is defined as "occurrence
of deep vein thrombosis and/or oedema in legs and/or feet, associated
with or without motion sickness, in travellers going on long-haul
journey by air, land or sea". (see below script 4 for further
explanation on this syndrome).

As part of our invention we propose a number of unique applications
and extensions for Zinopine inclusive of application of the unique
formulation and ratio of 1: 1.5 Pycnogenole to Standardized Ginger
Root Extract in a maintenance product application, in the Fast Moving
Consumer Goods (FMCG) market for application as a flavouring and or
nutraceutical agent in chewing gums, travel sweets, beverages and oral
care (such as mouth sprays) For the various applications mentioned,
and inclusive of our"Long-Haul Travellers Syndrome" (LTS) posology as
elucidated, we-have developed a dosage scale as is highlighted in
Script No 5 covering an effective dosage scale of. 5mg-350mg of
Pycnogenol and. 75mg-525mg Standardized Ginger Root Extract.

Proposed mechanism of action of the invention : 1) Inhibitory effect
on venous thrombosis: Clinical research made on individual components
clearly demonstrates that Pycnogenole inhibits platelet aggregation.
Ginger has also been shown to have inhibitory effects on platelet
aggregation. Zinopine thus inhibits the coagulation phenomenon
occurring due to venous stasis resulting from prolonged sitting in a
constrained place, and increased fibrinogen levels induced by high
altitude.

2) Inhibition of the onset of oedema & pain in the legs & feet:
Swollen and heavy legs, ankles (lower extremities) is a common problem
for people sitting for extended periods of time. Research in animals
reveals the anti-oedema and anti- inflammatory properties of
Pycnogenol&commat;. Clinical Research clearly demonstrates that
Pycnogenole inhibits significantly the likelihood of the onset of
oedema for people sitting for extended periods of time, or those
suffering from chronic venous insufficiency. Ginger has also been
shown to produce anti-inflammatory effects.

3) The Standardized Ginger Root Extract according to the invention is
effective as an anti-nausea and anti-emetic: Clinical studies have
demonstrated that the oral administration of ginger is more effective
than dimenhydrinate in preventing the gastrointestinal symptoms of
kinetosis (motion sickness). Having a Standardised Ginger Root Extract
with a minimum 10: 1 concentration to that of ginger rhizomes means
the recommended posology of the WHO Monograph of. 5 g 2-4 times daily
is easily met with one capsule containing the medicament according to
the invention offering the equivalent of 1.5 g of ginger rhizomes.

4) Unique posology-schedule : for long-haul trips of 1 capsule one day
before departure to initiate the kinetics of the two components, 2
capsules at least one hour before departure as a boosting dose to
achieve maximum therapeutic levels, 1 capsule per day for two days
after arrival, to maintain the therapeutic levels for the next two
days to counteract the factors affecting the signs and symptoms of
long-haul travel (all the three components of LTS)..

5) The antioxidant capacity of the newly invented and claimed
combination: Zinopino reduces free radical damage during long haul
flights: Pycnogenol (o and Ginger are both powerful antioxidants which
help to reduce the damage caused by free radicals generated as a
result of long haul flights. Cosmic radiation exposure is much higher
for long haul flights due to the increased altitude of long haul
flights as compared to short haul flights and this is particularly
magnified near the respective poles. Further, research shows that the
electromagnetic fields which are also pronounced on aircraft might
actually increase the half life of free radicals which both oligomeric
proanthocyanidins and ginger are known to scavenge.

Several studies support the possibility that magnetic fields inhibit a
cell's ability to protect itself from ionising radiation.

6) Hydration of the skin: Pycnogenole has been demonstrated to improve
the microcirculation and therefore improving the hydration of the skin
which is particularly important for passengers of long haul flights
where moisture levels in the cabin can be as severe as that of a
desert placing passengers'skin under hydrative stress.

7) Effective enhancer of the bioavailability : Research shows that
ginger is an effective enhancer of the bioavailability of other
nutrients and vitamins when it is present within the human
gastrointestinal tract. Therefore, the Standardised Ginger Root
Extract in Zinopin&commat; according to the invention may increases
the level of active principles of Pycnogenole in the blood.

Ongoing clinical research on Zinopin&commat; : Zinopine is currently
being taken by long-haul travellers, travelling for more than eight
hours, and who are over eighteen years of age. There have been no
exclusions from this study. Prior to entering the study, a full
medical history is obtained, including a history of recent flights and
the duration of those flights. Any current medication is noted and
passengers are asked to record any use of medication during the study
period. No specific advice about travel was given to any passenger,
and the passengers took one Zinopine capsule the day before flight,
two on the day of flight, and a further capsule on each of the two
following days. On their return all passengers completed a
questionnaire looking specifically for leg and chest symptoms.
Passengers took the Zinopin on both the outward bound and the return
flights.

The study is ongoing and passengers are still being recruited. So far
84 subjects (37 males, 47 females) have been recruited. 67 passengers
did not develop asymptomatic Deep Vein Thrombosis or Phlebitis. More
than 50% of the passengers taking Zinopino commented spontaneously
that they had no ankle swelling.

The results will be analyzed on an intention-to-treat basis. It will
form the basis of a pilot study, leading to a full double blind study
to assess the benefits of taking a travel supplement Zinopine.

The manufacturing process of newly invented combination product
According to our invention, PycnogenolX and Standardized Ginger Root
Extract are blended in a weight ratio of 1: 1 to 1: 2, preferred 1:
1.5 weight units of such blend were granulated in a planetary mixer
with a suspension of 10 to 15, preferred 11.7 weight units of Plasdone
K 29-32 and 10 to 15, preferred 11.7 weight units of Aerosil 200 in
250 weight units isopropyl alcohol. The mass is wetted with additional
400 weight units isopropyl alcohol for better granulation. The wet
mass was sieved for this preparation through a 10.8 mm sieve and dried
on hurdles at 40-45°C. The dry granules were sieved for this
preparation again through a 0.8 mm sieve. The mass was thereafter
encapsulated.

In an alternative the material may be granulated and dried in a ROTO
vacuum mixer and drier with inlet air of 60°C and the product
temperature up to 30-40°C.

The standardised ginger root extract is a concentrated form from 5: 1
to 15: 1, preferred 10: 1. Therefore, at 10: 1 concentration 150 mg of
standardised ginger extract in each capsule is equivalent to 1500 mg
of ginger rhizome material satisfying the recommended posology of the
WHO Monograph.

For motion sickness in adults and children older than 6 years it is
recommended: 0.5 g 2-4 times daily. Dyspepsia : 2-4 g daily as
powdered plant material or extracts.

SCRIPT NO. 1"Product Development Overview" Formulation & Product
Background As a first stage, and upon request by a leading airline
catering group, a natural, safe drink was developed (after two years
of research and development) which their airline clients could hand to
passengers to reduce the risk of Deep Vein Thrombosis on long haul
flights.

However, the preferred option of Airline clients was to formulate
a"pill"which people could purchase on their own.

Production Trials & Product Development (December 2002-May 2004) 15t
Production Development Trial (December 2002) The initial formulation
comprised: - 250 mg of Dried Ground Rhizomes Powder - 50 mg of OPC's
blend (Oligomeric Proanthocyanidins) from Pinus Maritima (pine bark
extract) 25% & Vitis Vinifera (grape seed extract) 75%.

Encapsulated in a size 0 vegetable capsule (20 capsules test- hand
filled) , 2"a production Development Trial (December 2002) An
increased dosage of the OPC's was used in this 2"d trial formulation :
- 250 mg of Dried Ground Rhizomes Powder - 100 mg of an OPC's blend
(Oligomeric Proanthocyanidis) from Pinus Maritima (pine bark extract)
25% & Vitis Vinifera (grape seed extract) 75%.

Encapsulated in a size 2 vegetable capsule (20 capsules test- hand
filled) Pack of 2 blisters of 10 capsules was the selected dosage
format.

3rad Production Development Pilot Trial (January 2003) The formulation
for the first pilot trial comprised: - 250 mg of Dried Ground Ginger
Rhizomes - 100 mg of a blend of OPC's (Oligomeric Proanthocyanidis)
from Pinus Maritima (pine bark extract) 25% & Vitis Vinifera (grape
seed extract) 75%.

Encapsulated in a size 0 vegetable capsule (8900 capsules test, which
was effected on scaled down machine that replicated full production)
Pack of 3 blisters of 10 vegetable capsules.

At this stage, we became aware of a study in vitro made by (Chida et.
al, 1999), where it was observed, that when Pycnogeno) is mixed with
grape seed extract, the antioxidant activity of the mixture is
abolished due to some unknown reason.

This observation made us to think choosing either Grape seed extract
or Pycnogenolo.

Pycnogenole was chosen at this stage because of it being relatively
more potent and more researched particularly on clinical aspects in
venous area (chronic venous insufficiency) with a USA Patent 5,720,
956 on"Decreasing platelet reactivity".

After the first three initials trials it was clear that the criteria
of choice in respect of the raw materials had to change and here the
decision to select two standardized products as the Standardized
Ginger Root Extract 10: 1 and Standardized Pine Bark Extract
(Pycnogenol). The reasons why the two standardized materials were
selected in opposition to the first materials, was for a number of
reasons: a. Having both materials as"standardized"meant that it could
be reliably demonstrated that both materials had guaranteed levels of
key actives extant in the"Zinopin (fi)"product at the end of the shelf
life of 2 years. b. Pycnogenolo, had a number of clinical studies and
indeed patents to support claims such as anti-platelet activity as
well as being a prophylaxis for oedema. c. Research, has shown that a
combination of grape seed extract and pine bark extract per OPC's
blend (used in the first three trials) nullified one another thereby
offering no physiological benefit with respect to free radical
scavenging activity. d. Standardized Ginger Root Extract 10: 1
concentration, meant compliance with the WHO (World-Health
Organisation) Monograph's posology for "motion sickness"in ginger
rhizome equivalent for the day of travel.

Product Development Pilot Trial (June 2003) A new formulation was
developed comprising the standardized materials of: - 250 mg
standardized Ginger Root Extract 10: 1 - 100 mg standardized Pine Bark
Extract (Pycnogenol&commat Encapsulated in a size 0 vegetable
capsule.

The powder characteristics of the new materials were different to the
former products (ie. OPC blend & dried ground ginger powder). The new
blend resulted in being much finer and suitable for formulation. Also
the flow and filling characteristics were not sufficient for a
production run. It was tried to encapsulate the new blend, but stopped
after 1500 capsules because of insufficient capacity of the machine
and strong deviation in the uniformity of the capsules mass.

It was decided to optimize the blend with the addition of excipients
and therefore the product was again reformulated. The addition of
excipients alone was not sufficient. Therefore the materials were
granulated to increase the density and flow characteristics.

For this purpose the blend was granulated with a solution of 0.5%
Povidone and 0.5% Silicone Dioxide in isopropanol, in a planetary
mixer. After drying and sieving a granulate with sufficient
encapsulation characteristic resulted. The colour of the granulate was
a little darker than a blend without granulation but acceptable.

From this granulate was produced approx 3,300 capsules on production
equipment and the results were sufficient.

Production Development (September 2003) Following the 4t production
trial and after a consumer trial (*) was effected it was decided to
reduce the level of ginger from 250 mg to 150 mg, the new formulation
comprised: - 150 mg Standardized Ginger Root Extract 10: 1 100 mg
Standardized Pine Bark Extract (Pycnogenolo) Encapsulated in a size 0
vegetable capsule Pack of 1 blister of 10 vegetable capsules (*) The
consumer trial revealed that a number of people were experiencing a
burning sensation in the stomach and in the throat and it was
determined that the Standardized Ginger Root Extract at 250mg was too
aggressive therefore the inclusion level was reduced to 150mg which
still meant (on the day of travel) we complied with the WHO
monograph's posology on ginger (in terms of ginger root equivalent) to
be able to claim our product was a prophylactic for motion sickness.

At this time the unique posology of Zinopin&commat; was developed and
the number of capsules in a consumer unit was reduced from 30 to 20 to
finally 10 capsules.

These 10 capsules on a single blister was uniquely designed for return
long haul trip in any form of automotive travel. Yield being 2, 680
capsules.

A proposed final Commercial Production 150 mg standardized Ginger Root
Extract 10: 1 100 mg standardized Pine Bark Extract
(Pycnogenol&commat Encapsulated in a size 1 vegetable capsules, Pack
of 1 blister of 10 vegetable capsules, Final yield being 135,000
capsules SCRIPT NO. 2"Dosage Rationale" Dosage 1 st proposal, a"dosage
concept"of 1 pack of 3 blisters with 10 vegetable capsules for a total
of 30 capsules per pack: Result : not appropriate for the application
of long haul travel.

2nd proposal, a"dosage concept"of 1 pack of 2 blisters with 10
vegetable capsules for a total of 20 capsules per pack. Result : not
appropriate for the application of long haul travel.

3rd and preferred proposal, a"dosage concept"of 1 pack of 1 blister
with 10 vegetable capsules. Result : appropriate for the application
of prophylaxis of Traveller's Syndrome specifically for long haul
travel i. e. one blister of 10 capsules specifically tailored to
accommodate a return long haul journey, Proposed and accepted a unique
concept of perforated blister with a definite, descriptive and
scheduled dosage to guide consumer's use is as shown in figure 3: 1
capsule 1 day before departure 2 capsules at least 1 hour before
departure 1 capsule per day for 2 days after arrival The same dosage
schedule for the return journey.

The rationale for this dosage schedule is shown in figure 4. Figure 4
shows the Zinopine dosage schedule and the recommended posology for
long haul travel.

The 1 capsule the day before the trip was introduced to prime the
metabolism prior to the journey and to already have a beneficial
effect on the blood.

The two capsules one hour before the trip was based on the specific
research by Putter [Putter at a/., 1999] on Pycnogenole which
demonstrated that the greatest reduction in platelet reactivity was
achieved with a single dose of 200 mg of PycnogenolX and therefore we
were achieving this dosage with 2 capsules of Zinopin with before
departure.

The recommendation of 1 capsule per day for two days after the journey
has been recommended since DVT can be contracted hours and possibly
days after a long haul trip. Therefore consuming Zinopine for a two
day period poste trip greatly reduces the possibility of a DVT being
contracted.

Zinopin&commat; is also long lasting so even after a journey of 10-12
hours, therapeutic levels of Zinopine are still extant in the blood.

Further, an effective dosage of 300mg of Standardized Ginger Root
Extract with a 10: 1 concentration (i. e. two capsules of 150 mg of
Standardized Ginger Root Extract each) complies with the WHO
Monograph's posology for motion sickness in ginger root equivalent i.
e. "for motion sickness in adults and children more than 6 years:
0.5g, 2-4 times daily.

Packaging The choice to utilize vegetable capsules versus tablets has
been dictated by safety and marketing reasons: Firstly, both raw
materials Ginger Root Extract and Pycnogenole have very pungent and
astringent notes respectively. A tablet would therefore require some
form of flavoring process to mask the strong taste of the product with
a coating resulting in a more elaborated process.

In conclusion, vegetable capsules are: - Easy to swallow - Effectively
mask taste and odor - Formulated with HPMC (Hydroxypropyl
Methylcellulose) - Satisfy vegetarian and cultural needs - Convenient
SCRIPT NO. 3"Proposed Mechanism of action of Zinopin
(Pycngenol&commat; and Standardized Ginger Extract) in Long-haul
Traveller's Syndrome (LTS)" Definition of LTS: Long-haul travelerr's
syndrome is defined a occurrence of Deep vein thrombosis and/or oedema
in legs and/or feet associated with or without motion sickness.

There are three main components of this syndrome: 'Deep vein
thrombosis and/or, 'Oedema of the legs and/or feet associated with or
without, Motion sickness.

Pathophysiology of LTS: Sitting in the restrained status, with bending
legs, hanging down position, during the long-haul travel, lead to
venous stasis. Oxidative stress due to restrained and strange
environment and venous stasis associated are with endothelial cell
injury lead to increased hydrostatic pressure in veins, decreased
capillary fragility, increased vascular permeability contributing to
swelling (oedema formation) of legs and feet.

Oxidative stress and/or other kind of chemical stimuli released due to
venous stasis cause endothelial cell injury producing platelets
adhesions and aggregation producing micro-thrombus. Increased,
fibrinogen levels, haemo-concentration and blood viscosity further
contribute to clot formation in the veins producing deep vein
thrombosis.

Physiological activities of Pycnogenole : Potent antioxidant, Anti-
oedema &amp; anti-inflammatory, Provides endothelial cell protection,
inhibits platelet aggregation & improves microcirculation.

Physiolgical activities of Standarized Ginger extract&commat; : Strong
anti-nausea and anti-motion sickness profile, 'Antioxidant, Anti-
inflammatory, Inhibits platelets aggregation, Fibrinolytic action.

It seems both active components Pycnogenol and standardized ginger
extract work in synergistic manner by virtue of their multiple factor
physiological actions target towards one or more of the sites on the
patho-physiolgical axis of Long-haul Traveller's Syndrome.

SCRIPT NO. 4"Long-haul Traveller's Syndrome" Comprises of Thrombosis,
and/or Oedema with or without Motion Sickness resulting from Long Haul
Travel by air, road and/or sea. The causal factors are increased
platelet reactivity, increased fibrinogen levels leading to
thrombosis, increase hydrostatic venous pressure leading to Oedema in
strange environment, and sitting posture leading to motion sickness.
These three conditions globally constitute: Figure 2 SCRIPT NO. 5
"Zinopin# delivery formats & applications" The unique combination and
ratio of 1: 1.5 Pycnogenoloto Standardized Ginger is a ratio we
propose to elaborate into various delivery formats for various health
and physiological applications, namely : Zinopin&commat;Maintenance-
product---this product is presently being developed and is aimed at
people who are constantly traveling or sat immobile for extended
periods of time. The dosage of Pycnogenol&commat;and standardized
ginger will be reduced although the ratio of 1: 1.5 of
Pycnogenol&commat;to Standardized Ginger Root extract will be
maintained. People will be able to take a daily maintenance dose and
still reduce the risks associated with Traveler's Syndrome at an
affordable price.

Zinopin Beverage application and flavoring inclusion. It is proposed
to have Zinopin&commat; as a flavor ingredient, with GRAS status, with
inclusion in beverage formats since airlines (for instance) may still
wish to hand their passengers a beverage on long haul flights.

Zinopin Confectionary and Chewing gum... Zinopin# can also be included
in confectionary and chewing gum applications so people obtain a
benefit for reducing the risk of Traveler's Syndrome from the likes of
Travel Sweets for instance.

F. Dose range For the various applications listed above in Section D
Zinopino Delivery Formats and Applications the range of dosage levels
of Pycnogenol# and Standardized Ginger Root Extract, maintaining the
unique ratio of 1: 1.5, should be: Table 1. Zinopin&commat;
application dosages spectrum ngl 0. 5'p 25.. 2 00 5'10 25 5",'200 ""I
°,. i'd.. 5 T. l 75 1. ; e 1. _ 7 2fi2. '3 5''z5 1 A50'< 4 G 5 0 . Ex
Zinopin 1. 25 2. 5 12. 5 25 62. 5 125 187. 5 250 312. 5 375 437. 5 500
562. 5 625 687. 5 750 812. 5 875 fent ma mg, mg'ma ma ma mg mg mAg %
mg, mg mg : mg mg ma _ mgTable 1.

Zinopin# spectrum of applications/dosages schedule with a ratio of 1:
1.5 Pycnogenol° &amp; Ginger Root Extract Table 2. Zinopine
application"Long Haul Dosages,, ingredients mg mg mg mg mg mg mg mg mg
mg Pyonogenol Ginger Root 5 : 300 337, 5 375 412. 5 Ex. Zlnopln 25 2.
5 12. 5 25 62. 5 125 187. 5 250 312. 5 375 437. 5 500 562. 5 625 687.
5 750 812. 5 875 mg mgTable 2 Zinopin# spectrum"Long Haul Dosages"
Table 3. Zinopin# application "Maintenance Daily Dosages" Ingredients.
mg mg mg mg mg mg mg Pycnogeno 75 100,,,' 275 300 S . 75 l,'. 5 15'75
5 225 262, s 300 337. . 5 450 5 525 x, Zinop 1. 25 2. 5 12. 5 25 5 125
187. 5 250 312. 5 375 437. 5 500 562. 5 625 687. 5 750 812. 5 875 mg
mg'mg mg. mg mgTable 3 Zinopin's spectrum"Maintenance Daily Dosages"
Table 4. Zinopin&commat; application"Drinks &amp; Ampoule, Daily Shot
Dosages' ngredient Pyqnogeb, '25 . 5 Ginger '75 5 75 112. 87. 225 262.
337. 525 Ex. Zinopin 1. 25 2. 5 12. 5 25 62. 5 125 187. 5 312. 5 375
437. 5 500 562. 5 625 687. 5 750 812. 5 875 rng mg rng mg mg mg, mg q
mg mg mg-nag. k mg mg mg tig mg 2 mgTable 4 Zinopin0 spectrum"Drink &
Ampoule, Daily Shot Dosages" Table 5. Zinopinsapplication
"Confectionary, Chewing gum, Mouthspray Flavoring Ingredients Dosages'
Ingredients mg mg mg mg mg mg,, mg mg mg mg pygenoi[at] 0. 5 1 5 lO 25
50'75 325 350 GingerRoot 75 1. 112, 5 150 187. 5 225 2625 5 450 487
Exil, ;, Z 5 25 62. 125 187. 5 250 312. 5 375 437. 5 500 562. 5 625
687. 5 750 812. 5 875 mg mg Mg mg mgTable 5 ZinopinX
spectrum"Confectionary, Chewing gum, Mouthspray, Flavoring Ingredients
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