Folate Updates

Kamran Ali Zaman

Abbasi Shaheed Hospital, Jan. 26, 2016
 Overview of Folate

Folate plays an essential role in cell division and DNA synthesis and is involved
in human growth and development.

Humans need to maintain an adequate dietary intake of folate during various stages of
their lives.
 Folate and Foods
Folates contained in foods are unstable and susceptible to oxidation and
rapidly lose activity during food processing, manufacturing and storage.

 Bioavailability range of 25-50%, depending on the kind of food

 Room temperature storage may lose up to 70% of their folate activity within
three days
FOLATE DEFICIENCY
 Folate Deficiency is an
“Imminent Health Hazard”
Causing a Worldwide Birth
Defects Epidemic

Godfrey P. Oakley, Jr.* 2003 Wiley-Liss ifglobal.sitehosting.be/uploads/documents/Godfrey1.pdf

Folate deficiency represents one of the most common
nutritional deficiencies
Humans cannot synthesize folate and because of its water soluble nature, the body
stores folate to a limited extent.

Typical folate intakes are poor in the diets of many individuals for several
reasons. Natural folates are susceptible to oxidation, they rapidly loose activity in
foods and are largely destroyed by cooking till 90%. Moreover they have a low
and incomplete bioavailability.

Folate deficiency reasons:

 Dietary intake is inadequate

 Increased need is not matched by an increased intake
 Enzyme defects involved in the metabolization
 Malabsorption
 Digestive system pathology
 Drug use that interferes with the ability of the body to use folate.
 Folate deficiency
in Pakistan
is
39.7%*
Journal of the College of Physicians and Surgeons Pakistan 2009, Vol. 19 (5): 308-312
 What are the
consequences
of
Folate Deficiency?
 Folic Acid
Deficiency

Mother Child

Neural Tube
Anemia
Defects

Peripheral
Neuropathy
NEURAL TUBE DEFECTS
Neural tube defects are birth
defects that can occur early
in pregnancy when the spinal
cord, brain, and related
structures do not form
properly
Spina bifida

Anencephaly
Encephalocele
 NTDs across the World

“There are 3,000 pregnancies affected by Spina

Bifida or anencephaly, which are neural tube
defects (NTDs) caused by the incomplete
closing of the spine and skull”

http://www.cdc.gov/ncbddd/folicacid/data.html
Estimated Annual Cases in the US

http://www.cdc.gov/ncbddd/birthdefects/data.html
Prevalence of Folic Acid Deficiency
UMFA (Un-Metabolized Folic Acid)
 NTDs in Pakistan
“46 out 3310 (1.4%) babies were affected
by Neural Tube Defects”

Gomal Journal of Medical Sciences January–June 2008, Vol. 6, No. 1

“Of 46 women with affected
babies,
ALL had not taken folic acid
supplements in their first
trimester”
Gomal Journal of Medical Sciences January–June 2008, Vol. 6, No. 1
“Only two (4.35%) women had
previous history of a fetus with
NTD”

Gomal Journal of Medical Sciences January–June 2008, Vol. 6, No. 1

“Of children with an NTDs,
95%
are born to couples with
no family history
of these defects”
http://pediatrics.aappublications.org/content/104/2/325.full
 So how can
NTDs
be prevented?
“Studies have demonstrated
that periconceptional
folic acid supplementation
can prevent 50% or more of
NTDs”
http://pediatrics.aappublications.org/content/104/2/325.full
 But is the
Folic Acid
available in the market
reliable?
Folic Acid Metabolism?
Unfortunately…..
 40% to 60%
of the population has
genetic polymorphisms
that
impair the conversion
of supplemental
folic acid
to its
active form
L-Methylfolate
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250974/
“The final stage is done with the enzyme
methyltetrahydrofolate
reductase
(MTHFR)
Those with certain polymorphisms have
inadequate MTHFR activity”
Solution?
Quatrefolic
Folate: the evolution of a species – Key points
1st
st generation

Food folate

• Unstable
• Requires metabolism
2 generation
st
st
• Hardly controlled
Folic acid

• Requires metabolism
• Stable
• Dosable
• Highly active

3st
st generation
(6S)-5-methyltetrahydrofolate calcium salt

• Slightly soluble
• Lower Biodisponibility
• Stable
• Dosable
• Highly active

The 4th generation folate:

(6S)-5-methyltetrahydrofolate glucosamine
salt
 Highly soluble  Dosable
 No metabolism needed  Highly active
 Stable  MORE SAFE
Introducing
for the
First time
in
Pakistan
5-methyltetrahydrofolate is the metabolic active form

All the natural folates

It is immediately and
ingested are turned into
completely bioavailable
5‑methylfolate as unique
transportable form

(6S)-5-Methyltetrahydrofolate

It is the only folate It is the essential form

crossing the blood-brain in which folates occur
barrier and are stored in the
It does not mask human body
Vitamin B12 deficiency
 Quatrefolic® triumphes versus FA

FOLIC ACID

High bioavailability NO YES

YES
UMFA in the blood
at minimum doses > 200 µg/day
NO

Possible toxicity of UMFA YES NO

NO
Requires Metabolism YES
It is the metabolically active form
Reduction pathway affected by
saturable activity of DHFR in the liver
YES NO

Metabolization affected by enzyme

polymorphisms (DHFR)
YES NO

Metabolism affected by MTHFR

polymorphisms
YES NO

Masking effect of Vitamin B12 YES NO

Controversy about the roles of chonic
high intake in cancer promotion
YES NO

As suggested by Patanwala 2014 FA could be replaced with Quatrefolic ®, the 6S-5-MTHF, with
multiple advantages.
 Quatrefolic® Comparision with 5-MTHF Calcium Salt

5-MTHF Calcium Salt

Quatrefolic
Water Solubility Slightly soluble Very Soluble (100 times more)
The most bioavailable form of
folate, higher of ≈ 10% vs calcium
salt
Bioavailability Good • Higher solubility of salt
• Intrinsic higher solubility of amorphous
status
• Homogeneous and reproducible solubility
process

Limited
(Requires refrigereted
Stability 18 months at RT
conditions,
2-8°C)
Widen
(Room temperature stability
Formulation flexibility and allows handling without specific and
Limited
stability restrictive conditions, facilitating
manufacturing of combinatiomns
formulations)
The safety of Quatrefolic® has been extensively proven
Quatrefolic® was rigorously tested for safety and consistency.

2010 – USA: GRAS (Generally recognized as safe)

✓ For use as a source of folate in conventional and medical foods

2010 – USA: NDIN (New Dietary ingredient notification)

✓ As a source of the naturally-occurring form of folate for use in dietary supplement
-

2013 - EUROPE: EFSA Positive Scientific Opinion trend

✓ As a source of folate added for nutritional purposes to food supplements

2014 - EUROPE: EFSA Novel Food approval

✓ As a source of folate added for nutritional purposes to food supplements

2015 - EUROPE: EFSA Novel Food (Annex II to Directive 2002/46/EC)

✓ As a source of folate added for nutritional purposes to food supplements

Awards
conducted by
European Food
and Safety
Authority.
Folate: quatrefolic the «safe folate»
FDA has
recognized Quatrefolic® as a
New Dietary Ingredient (NDI)
opening the USA market for
the 4th generation folate.
Quatrefolic® is the most bioavailable form
Thanks for your attention