Download Vitamins for pharmaceutical applications

Vitamins for
pharmaceutical
applications
Executive summary
Micronutrients play a critical role in overall nutrition and health. This
is highlighted by the plethora of continuous research published in
high profile scientific journals focused on the benefits of vitamins and
minerals. However, evidence shows that many people worldwide fail
to meet recommended intake levels. The impact of low micronutrient
intake is a major public health concern, resulting in vulnerability to
infection and disease.
Optimal intake is therefore essential to reduce these and other risks.
But what is an optimal intake? Existing data indicates that there is a
need to revisit approaches to defining appropriate nutritional
requirements for a variety of vitamins, such as vitamin E. Recent
January 2017
studies demonstrate the benefits for specific groups when they take
high dose vitamins. Studies also show that vitamins taken in
pharmaceutical applications support human health.
This whitepaper explains the role and importance of vitamin dietary
reference intakes (DRIs) and draws on the latest clinical data to show
the benefits of vitamin intake beyond currently recognized health
effects and the nutritional range. Highlighting key studies, it also
describes the vital function of nutrition under clinical conditions and
demonstrates the significance of drug-nutrient interactions on health.
In addition, a summary of the use of vitamins in pharmaceutical
applications is provided.
Vitamins for
pharmaceutical applications
Introduction
Emerging data suggest that intake of micronutrients in higher doses
holds promise for roles beyond currently recognized health effects for
selected individuals and population groups. For example, research
shows that vitamin E protects essential fatty acids from lipid
peroxidation and that improved vitamin E status is protective for
cognitive function.1,2 Understanding the role of vitamins beyond the
nutritional range and their use in the pharmaceutical industry can lead
to the creation of innovative, safe and high quality products that will
serve the interests of consumer health.
Recommended intakes and requirements
Micronutrient
intake
in Germany,
US,
and NL
Figure 1: Micronutrient
intake
panelpanel
in Germany,
US, UK and
theUK
Netherlands
Vit A
Vit D
Vit E
Thiamin Riboflavin
Niacin
Vit B6
Vit B12
Folic acid
Vit C
Germany
United States
United Kingdom
The Netherlands
<5%
Page 2
5–2.5%
25–50%
50–75%
>75% below recommendations
Modern lifestyles may lead to suboptimal
vitamin intakes, even in affluent countries. A
recent study reviewed vitamin intakes in
Germany, the UK, The Netherlands and the
USA and compared the data with respective
national recommendations. Data on adults
from the most recently published national
dietary intake surveys for the first three
countries and on adults from the US National
Health and Nutrition Examination Survey from
2003 to 2008 were used as a basis for the
analysis. The proportions of the populations
with intakes below recommendations were
categorized as < 5, 5–25, >25–50, >50–75 and
>75 % for each vitamin. The data generated
are presented in a ‘traffic light display’,
illustrated in figure 1, using colors from green
to red to indicate degrees of sufficiency.
The data was compared with the results from
the European Nutrition and Health Report
2009. The study demonstrated that, although
inter-country differences exist, intakes of several
Vitamins for
pharmaceutical applications
vitamins are below recommendations in a large
part of the population in each country. The
most critical vitamin appears to be vitamin D.
The variation between the countries is most
probably due to differences in
recommendations, levels of fortification
and local dietary habits. The findings
demonstrate that a gap exists between
vitamin intakes and requirements for a
significant proportion of the population,
even though diverse foods are available.3
DRIs can play an important role in addressing
nutritional inadequacies. Stakeholders across
the healthcare, nutrition and pharmaceutical
industries can use DRIs and the latest clinical
evidence on the benefits of vitamins on
human health to understand appropriate
nutritional requirements for populations
worldwide. They can then pave the way in
revisiting approaches to defining appropriate
dietary requirements and educating
consumers on their health needs.
Nutrition inadequacies and malnutrition are even more prevalent under clinical conditions.
There is a particularly high prevalence of malnutrition and low vitamin intake in vulnerable
populations, such as ill and or elderly patients, as well as patients recovering in hospitals and
other care facilities. Malnutrition for such patients can lead to a higher risk of infection and a
longer time spent in hospital.
Figure 2: Nutritional status of elderly persons in different settings6
47%
20
40
60
14%
At Risk
53%
Wellnourished
• up to 60% in care homes.5
33%
0
20
40
60
40
60
Community
Malnourished
6%
At Risk
32%
Wellnourished
62%
0
20
Rehabilitation
Malnourished
41%
9%
0
Page 3
50%
91%
At Risk
Wellnourished
Those affected by, or at risk of,
malnutrition in Europe:
• 35-40% of all hospital
admissions; and
Nursing Home
Malnourished
Did you
know?
• 15% in ages 75-80 living at
home;
14%
0
• Tolerable Upper Intake Level4
• 10% in those over 65 years;
39%
86%
At Risk
• Recommended Dietary
Allowances (RDA)
• 5% of the entire population;
Hospital
Wellnourished
• Estimated Average
Requirements (EAR)
• Adequate Intakes
Nutrition under clinical conditions
Malnourished
DRIs are used by healthcare
providers and government
agencies to establish the
guidelines for how much of
each nutrient an individual
needs. The DRIs include four
types of information:
20
40
60
Vitamins for
pharmaceutical applications
The implications for malnourished patients does not always stop there. A recent study
investigated undernutrition and risk of mortality in elderly patients within one year of hospital
discharge and found that being undernourished at the time of hospital discharge is an
independent risk factor for 1-year mortality in elderly patients. The severity of the nutritional
depletion was assessed using body mass index (BMI), weight loss indices, and arm
circumferences. Even after controlling for functional status and other indicators of illness
severity, the relationship between each of these nutritional indices and the outcome remained
significant — the more nutritionally depleted, the greater the risk. The study found indicators
of chronic nutritional depletion (e.g. low BMI and long-term weight loss) to be the best
predictors of post discharge mortality.7
Predicted Probability of Survival
0.98
0.96
0.94
BMI (kg/m2)
0.92
> 20 (n = 455)
0.90
0.88
0.86
0.84
0.82
≤ 20 (n = 205)
0
100
200
Days
Reduced
mobility
Reduced capacity
to feed oneself
Malnutrition
Loss of
muscle mass
Apathy, depression,
reduced attention
Figure 4
Page 4
• need of care;
• risk for infections;
• risk for complications
(morbidity);
• need for treatments in
hospitals;
• length of stay; and
• risk of dying from
diseases (mortality).
1.00
Figure 3 estimates of the
survivorship function as
generated by the Cox
regression model for
specific sets of covariate
values. The upper curve is
for body mass index (BMI)
> 20 kg/m2 with all of the
other independent
variables in the model set
equal to their population
means. The lower curve
was produced in the same
manner except it is for
BMI <20 kg/m2.
Malnutrition can
lead to increased:
Reduced
appetite
300
400
Factors predisposing
malnutrition and micronutrient
deficiency can include poor
nutrient intake, caused by
issues like having difficulty
eating, medication, depression
and dementia, as well as
suboptimal nutrient utilization,
such as malabsorption or
nutrient loss. In the elderly
particularly, malnutrition is a
prevalent issue which can form
a cycle that is difficult to break
if left untreated:
20-30 Million Europeans are
affected by malnutrition and
the cost for Europe is €120-170
billion/year.8
Did you
know?
Nutritional management can
be introduced as
part of a medically supervised
diet to meet specific dietary
needs as a result of a disease
or condition. This management
could help support optimal
patient health before, during
and after medical treatment
and subsequently help reduce
predisposition to higher risk of
infection and mortality after
hospital discharge.
Vitamins for
pharmaceutical applications
Examples of additional benefits
provided by vitamins in higher doses
Emerging scientific findings show the benefits of vitamin intake
beyond currently recognized health effects and the nutritional range
for risk groups like elderly or people with certain malfunctions. The
following examples highlight how a higher intake of nutrients beyond
nutritional requirements may provide additional benefits in defined
groups; playing a part in supporting human health during illness. The
diseases listed include diabetes, cancer, multiple sclerosis (MS),
cardiovascular disease (CVD), non-alcoholic fatty liver disease and
Alzheimer’s disease. These are prevalent issues worldwide, affecting
a significant number of people.
Vitamin B1 and diabetic patients
There is evidence of thiamine (vitamin B1) deficiency in diabetics.
Vitamin B1 is important for maintaining a healthy nervous system and
improving the cardiovascular functioning of the body. Its benefits
stretch further according to a new study. A high-dose therapy with
vitamin B1 in a rat model (experimentally induced diabetes in rats)
prevented development of diabetic nephropathy, otherwise known as
kidney disease. In humans, these preliminary results led to a doubleblinded, placebo-controlled pilot study. In this study, high dose
vitamin B1 therapy was shown to reverse early stage diabetic
nephropathy – 300 milligrams (mg) vitamin B1 per day decreases
microalbuminuria. The use of vitamin B1 in this range is safe and
further large-scale long-term clinical studies are still required.
Figure 5: Effect of thiamine on urinary albumin excretion (UAE) 9
Study period (months)
Change in urinary albumin (mg/24 h)
0
0
1
2
3
4
5
*
-5
-10
-15
-20
-25
*
***
††
**
†
Placebo
***
A recent study investigated 197 premature CVD patients, prescreened
for the MTHFR 677C-->T polymorphism, from an original cohort of 404
to select those with the TT genotype (n = 60) and a similar number
with heterozygous (CT; n = 85) or wild-type (CC; n = 75) genotypes. Of
these, 181 completed an intervention in which participants were
randomized within each genotype group to receive 1.6 mg per day
vitamin B2 (riboflavin) or placebo for 16 weeks. Among patients
taking one or more antihypertensive drugs at recruitment (82%), the
results show that target blood pressure (<140/90 mmHg) had been
achieved in only 37% patients with the TT genotype compared with
59% with the CT and 64% with the CC genotype (P < 0.001).
Vitamin B2 intervention reduced mean blood pressure specifically in
those with the TT genotype (from 144/87 to 131/80 mmHg; P < 0.05
systolic; P < 0.05 diastolic), with no response observed in the other
genotype groups. The systolic blood pressure response to vitamin B2
intervention in patients with MTHFR 677 TT genotype therefore
demonstrates that genetically susceptible individuals may benefit the
most from vitamin B2 supplementation. The study demonstrates that
it would take about 10 kilos of weight loss to achieve the blood
pressure lowering that was reported by vitamin B2.10,11 The findings of
the study may have important implications for the prevention and
treatment of hypertension, especially as the TT genotype has a high
prevalence in many countries.12
Lifestyle factor
SBP decreas (mmHg)
Weight loss (per 10 kg)
5–20
Riboflavin (genotype-specific)
6–13
Physical activity
4–9
Sodium reduction
2–8
Limit alcohol
2–4
***
†
***
Thiamine
***
†
-30
Change from baseline of UAE in type 2 diabetic patients receiving Thiamine | Placebo.
Median values are shown: *p < 0.05 ** p < 0.01 *** p < 0.001 compared with baseline;
† p < 0.05 †† p < 0.01 compared with baseline change for the placebo.
Page 5
Vitamin B2 and CVD patients
Did you know?
Elevated blood pressure is a leading risk for
death worldwide. Optimizing vitamin B2 status
offers a promising low-cost targeted strategy for
managing elevated blood pressure in genetically
at-risk groups.
Vitamins for
pharmaceutical applications
A recent Phase III clinical trial on vitamin B7 and patients suffering from
progressive multiple sclerosis (MS) produced positive results. The
study found evidence of the efficacy and safety of a highlyconcentrated pharmaceutical-grade vitamin B7 administered at a dose
of 300 mg per day in the treatment of primary and secondary
progressive MS, a major area of unmet medical need.
The vitamin B7 studied will require a chronic administration of a very
high dose to treat patients with progressive MS, corresponding to
10,000 times the recommended daily intake, which requires a
pharmaceutical grade extra-pure source of vitamin B7.13
Incidence of colds
100
80
Percentage
Percentage
Biotin (Vitamin B7) and MS patients
Figure 6: Vitamin C may reduce the incidence,
Incidence of colds
duration and severity of a common cold20
100
80
60
60
40
20
0
0
Vitamin C and cancer
New research demonstrates that cancer cells are much less efficient in
removing hydrogen peroxide than normal cells, and more disposed to
damage and death from a high amount of hydrogen peroxide. This
explains why the high levels of vitamin C do not affect normal tissue,
but can be damaging to tumor tissue.18
Vitamin C and the common cold
The common cold is a viral infectious disease of the upper respiratory tract.
Colds can lead to the upper respiratory system becoming less resistant
to secondary bacterial infection, resulting in issues such as middle ear
infection, pneumonia, bronchitis, sinus infection or strep throat.19
The body’s immune system can fight the infection after producing
antibodies, but there are currently no medicines that will cure the
common cold. However, there may be a way to reduce the risk of
contracting the common cold. A recent Cochrane meta-analysis shows
that vitamin C reduces the incidence, duration and severity of the
common cold when ≥ 200 mg/d is taken daily.20
Page 6
Total colds
> 200mg
Vitamin
C
Total
colds
> 200mg
Vitamin C
General
population
+ General
Vitamin C
population
+ Vitamin C
~50%
less
~50%
less
Severe
stress
+ Vitamin
Severe C
stress
+ Vitamin C
Duration of common cold
10
Duration of common cold
10
8
8
6
Days Days
Despite the FDA not having approved the use of IV high-dose vitamin C
as a treatment for cancer, studies show that application of high-dose
IV vitamin C improved quality of life for cancer patients.14, 15
Improvements in physical, mental and emotional functions, symptoms
of fatigue, nausea, vomiting, pain and appetite loss were
documented.16 In addition, a meta-analysis on vitamin C and breast
cancer indicates that post-diagnosis use of vitamin C supplementation
may be associated with a reduced risk of mortality.17
~3%
less
~3%
less
40
20
64
24
2
0
0
Without
Vitamin C
supplement
Without
Vitamin C
Severity of supplement
the colds
~1
day
less
~1
8%
day
less
8%
Children
~1
day
less
~1
14%
day
less
14%
Adults
> 200mg
> 200mg
Children
> 200mg
Adults
> 200mg
~1
day
less
~1
18%
day
less
18%
Children
1–2g
Vitamin
ChildrenC
1–2g
Vitamin C
Indicators of common cold severity:
• 0.1% less days indoors of off work or school (7 trials) (p=0.00035)
• 0.14% less on symptom severity score (9 trials) (p=0.0018)
• Total: 0.12% (p<0.00001)
Vitamins for
pharmaceutical applications
Vitamin E and a range of health issues
Figure 7: Results from ICARE study (Milman 2008)21
Non-alcoholic fatty liver disease
Meanwhile, vitamin E has also been shown to reduce the risk of nonalcoholic fatty liver disease, which is a prevalent and increasing issue
worldwide, due to rising obesity levels. Data shows that
supplementation with vitamin E at a dose of 400 mg was superior to a
placebo for the treatment of nonalcoholic steatohepatitis in adults
without diabetes.22
Cognitive health
Vitamin E (at a dose of 2000 IU) has also been proven to delay
pathologies in Alzheimer’s disease – an age-dependent and
progressive neurological disease and the fourth-leading cause of
death in industrialized societies.
Figure 8: Alzheimer’s disease and vitamin E study: survival time
without pathological “event”:23
Event free survival (%)
100
80
α-tocopherol
60
40
Placebo
20
0
0
Page 7
100
200
300
400
Days
500
600
700
1.00
Event free survival (%)
CVD
New research indicates that genotype matters also when it comes to
vitamin E; sub-populations with specific genetic makeup may profit
from this vitamin. A recent study into vitamin E and CVD showed that
vitamin E supplementation at a dose of 400 mg reduces and
normalizes the risk for cardiovascular events in diabetics with
haptoglobin genotype 2-2 (Hp 2-2). The Hp gene exists in two variants,
the Hp1 and the Hp2 variant. In Western societies, 36% have Hp 2-2.
Diabetic individuals with Hp 2-2 have a marked increased oxidative
stress. Increased risk for cardiovascular events has been linked to Hp
2-2 genotype in diabetics.
0.98
0.96
0.94
HP 1-1 | Hp 2-1
Hp 2-2: Vitamin E
Hp 2-2: Placebo
Log-Rank P = 0.003
0.92
0.90
0
100
200
Days
300
400
500
Burns
In a study to test whether burn injury reduces body stores of vitamin
E, α-tocopherol concentrations were measured in adipose tissue
samples. After receiving a burn injury, pediatric patients were
assessed. Surgically obtained samples were taken at various
intervals and stored at −80°C in a biorepository. α- and
γ-Tocopherols, cholesterol, and triglycerides were measured in the
same tissue.
The results found that the burn injury experienced by the pediatric
patients changed their metabolism so that vitamin E status
decreased during the month after injury. Further studies are needed
to evaluate the mechanism and consequences of the observed
vitamin E depletion. In addition, research on vitamin E
supplementation in a higher dose in burn patients should be
undertaken to determine whether it could help restore the depleted
stocks of vitamin E in the body.24
Vitamins for
pharmaceutical applications
EPA and DHA consumption for CVD patients
A systemic review and meta-analysis of the lipid-modulating effects of n-3 PUFAs combined
evidences from 10 randomized controlled trials including 557 patients with end-stage renal
disease. Pooled analysis revealed that n-3 PUFA intake significantly reduced serum triglyceride
levels by 0.78 mmol/L (95% confidence interval: -1.12 to -0.44 mmol/L, P < .0001).25
How should vitamins be used
in pharmaceutical applications?
So far, it is clear from emerging scientific
research that vitamins can go beyond
currently recognized health effects and the
nutritional range, supporting human health in
higher doses. Such clinical data and a clear
understanding of drug-nutrient interactions
must be used to define how vitamins should
be used within the pharmaceutical industry.
Grading of Recommendations Assessment,
Development and Evaluation (GRADE) is a
method for assessing the quality of the
evidence found for specific vitamins for use in
pharmaceutical applications. This can be
used as a reference, for example, by
pharmaceutical and healthcare professionals.
In addition, certificates of suitability (CEPs)
and US Drug Master Files (DMFs) for essential
micronutrients are a necessary measure to
ensure that new products are developed to
be safe and of high quality for high dose
applications and specific claims. Pharma-grade
vitamins, carotenoids and lipids can be used
as Active Pharmaceutical Ingredients (APIs)
to support the development of customized
solutions to suit specific applications.
The pyramid (figure 9) shows the distinction
between general food and nutrition,
specialist nutrition or dietary
supplementation and pharmaceuticals or
prescribed medical treatments.
Rx
OTC
Dietary
Supplements
Fortification
Nutrition
Figure 9
Page 8
Did you
know?
•Lipid-lowering therapy with
statins can significantly
reduce the incidence of
cardiovascular disease and
the risk of coronary events.
However, aggressive
lowering of lipids by statins
comes with the risk of
decreasing EPA and DHA
levels simultaneously. EPA
and DHA can be considered
as an alternative way to help
reduce plasma triglyceride
levels and to beneficially
influence the levels of other
blood lipids as well. Clinical
trials have shown that EPA
and DHA as supplementation
is also effective when
added in combination with
other lipid-lowering drugs
like statins.26
•Nonsteroidal anti-flammatory
drugs (NSAIDs), such as
Aspirin, Ibuprofen and
Naproxen, can cause peptic
ulcus, diminish renal
function and impair Vitamin
B6 metabolism. However,
they may have additive or
synergistic effects with certain
micro- or macronutrients, for
example, to reduce pain. If an
adequate dose of EPA and
DHA (which have antiinflammatory properties)
is provided, NSAIDs might
be taken at a lower dose to
have a clinical benefit and
reduce potential side effects
of the drug.27
Vitamins for
pharmaceutical applications
How to develop safe and customized treatments
Food-drug interactions are defined as
alterations of pharmacokinetics or
pharmacodynamics of a drug or nutritional
element or a compromise in nutritional status
as a result of the addition of a drug.
Pharmacokinetic is the word used to describe
when the absorption, distribution,
metabolism, or elimination (ADME) is altered.
Meanwhile, pharmacodynamic refers to a
situation where the pharmacological effects
of two products are additive or oppositional.
Examples of where drug-nutrient interactions
occur include statins, contraceptives, proton
pump inhibitors, and cases where vitamins
have a synergistic effect with drugs. Drugnutrient interactions can lead to a raising or
lowering of bioavailability of a nutrient induced
by drug intake. For example, according to a
study, drug-nutrient interactions can result in
reduced absorption of certain oral antibiotics.
This can lead to suboptimal antibiotic
concentrations at the site of infection,
increasing the risk of treatment failure.
Nutrients can lead to an induction or inhibition
of enzymes in the gut, which may cause a
change in oral bioavailability of drugs or vice
versa. Grapefruit juice acts as a selective
intestinal CYP3A4 inhibitor, and can be used as
an example. The exposure of some drugs can
be increased by more than fivefold when taken
with grapefruit juice and increase the risk of
adverse effects. The use of certain drugs may
affect gastrointestinal (GI) tract function and
result in a loss of bodily electrolytes and fluid.
Therefore, limiting drug prescriptions to
essential medications for as short a period as
possible and periodic re-evaluations of the
treatment chosen are needed to minimize
adverse drug-nutrient interactions.28
The same study indicates that some people
are more at risk of nutritional compromise.
For example, elderly patients are particularly
at risk because more than 30% of all the
prescription drugs are taken by this
population. Failure to identify and properly
manage drug-nutrient interactions can lead
to serious consequences. Other patients at
increased risk include those with cancer, AIDS
and organ transplant recipients.
Successful organ transplantation has become
the norm, now that improved
immunosuppressive agents have been
introduced. The emphasis of
immunosuppressive therapy has moved from
preventing rejection to balancing acceptable
rates of rejection with moderation in adverse
effects of the immunosuppressive agents.
According to scientific research, among the
many possible adverse effects of
immunosuppressive therapy is the potential for
Conclusion
Vitamins are essential micronutrients that the
body needs. The health of populations
worldwide can benefit from optimal intake.
The review of recent clinical data heralds an
exciting new phase for the role of vitamins in
pharmaceutical applications. The knowledge
that vitamins can play an important role in
patient health beyond their traditional part in
Page 9
essentiality, can open up new opportunities in
the pharmaceutical and healthcare industries.
More investigation into the effects of
micronutrient supplementation on health
when used in combination with
pharmaceuticals is needed, as well as a clear
understanding on drug-nutrient interactions,
to ensure optimal and safe patient treatment.
these agents to affect the nutrition status of
the transplant recipient. As many patients
undergoing transplantation are catabolic and
vulnerable to malnutrition, it is particularly
important for carers of these patients to be
familiar with the nutrition implications of
immunosuppressive drugs.29
Comprehensive clinical data on the effects of
combining pharmaceuticals with
supplements can help companies understand
how to develop safe, individualized treatment
strategies for patients.30
Key take-away messages
• Stakeholders across the
healthcare, nutrition and
pharmaceutical industries
should use DRIs and the
latest clinical evidence on the
benefits of vitamins, EPA and
DHA on human health to
understand appropriate
nutritional requirements for
populations worldwide
• Emerging research suggests
that micronutrient intake in
higher doses can play a role
beyond essentiality for
selected individuals and
population groups
• Clinical data on the effects of
combining pharmaceuticals
with supplements can
support development of safe
individualized treatment
strategies for patients
• More investigation into the
effects of micronutrient
supplementation on health
when used in combination with
pharmaceuticals is needed
Vitamins for
pharmaceutical applications
DSM is currently the only company in the world to hold both US DMFs
and CEP certificates for all 13 essential vitamins. DSM offers its
pharmaceutical customers worldwide unparalleled sustainability of
supply and speed to market, accelerating the registration process to get
products to market faster. With extensive experience in pharma-grade
vitamins, carotenoids and lipids Active Pharmaceutical Ingredients
(APIs), DSM provides customers with entirely customized support
throughout every stage of a project. DSM’s full regulatory, scientific and
quality expertise and GMP-qualified production sites ensure that
projects are both safe and compliant. In addition to its strong IP
portfolio, including carotenoids and DHA and EPA, DSM’s 400-strong
R&D team provide expertise in clinical trials. DSM also has a global
network of regulatory specialists, equipped to cater support in response
to customers’ local regulations.
For further information, please visit:
www.dsm.com/pharmaceuticalsolutions
Or contact: Kristina Cselovszky:
[email protected],
Business Development Director
Pharma at DSM Nutritional Products.
Manfred Eggersdorfer:
[email protected],
Senior Vice-President Nutrition
Science and Advocacy at DSM
Nutritional Products
For DSM, quality is a way of life. Quality for Life™ symbolizes quality,
reliability and traceability. This means that our customers are getting
the best ingredients, knowing the source on which they depend. Quality
for Life™ means sustainability. It is our commitment to our environment,
consumers, our business partners, our people and the regulatory
framework that governs our operations.
References
1 Traber et al, Vitamins C and E: beneficial effects from a mechanistic
perspective. Free Radic Biol Med 2011
2 Witting et al, Effect of degree of fatty acid unsaturation in
tocopherol deficiency-induced creatinuria. J Nutr 1964
3 Troesch et al, Dietary surveys indicate vitamin intakes below
recommendations are common in representative Western
countries. Br J of Nutr 2012
4 https://fnic.nal.usda.gov/sites/fnic.nal.usda.gov/files/uploads/
recommended_intakes_individuals.pdf
5 Nutrition Day Conference 2010, Malnutrition and appropriate
nutritional care, Cornel Christian Sieber, Chair Geriatric Medicine
Friedrich-Alexander-University Erlangen-Nürnberg Institute for
Biomedicine of Aging Centre for Medicine of Aging Nuremberg
6 Kaiser et al, Frequency of Malnutrition in Older Adults: A
Multinational Perspective Using the Mini Nutritional Assessment.
J of the Am Geriatrics Society 2010. Institute for Biomedicine of
Aging, Friedrich-Alexander University Erlangen-Nürnberg
7 Liu et al, Undernutrition and Risk of Mortality in Elderly Patients
Within 1 Year of Hospital Discharge. J Gerontol 2002
8 Nutrition Day Conference 2010, Malnutrition and appropriate
nutritional care, Cornel Christian Sieber, Chair Geriatric Medicine
Friedrich-Alexander-University Erlangen-Nürnberg, Institute for
Biomedicine of Aging Centre for Medicine of Aging Nuremberg
9 Rabbani et al, High-dose thiamine therapy for patients with type
2 diabetes and microalbuminuria: a randomised, double-blind
placebo-controlled pilot study. Diabetologia 2009
10 Horigan et al, Riboflavin lowers blood pressure in cardiovascular
disease patients homozygous for the 677C-->T polymorphism in
MTHFR. J Hypertens 2010
11 Modified from Chobanian et al, The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003
12 McNulty et al, Riboflavin, MTHFR genotype and blood pressure:
A personalized approach to prevention and treatment of
hypertension. Mol Aspects Med 2016
13 http://www.dsm.com/corporate/media/informationcente
rnews/2015/06/2015-06-17-medday-and-dsm-announceapartnership-to-produce-pharmaceutical-grade-d-biotin-totreatprogressive-multiple-sclerosis.html
14 Padayatty et al, Vitamin C Pharmacokinetics: Implications for Oral
and Intravenous Use. Ann Intern Med 2004
15 Fritz et al, Intravenous Vitamin C and Cancer: A Systematic Review.
Integrative Cancer Therapies 2014
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