RRTL Lecture

Primary Prevention and Medical Treatment with Nutritional Supplements

in Primary Care

A Brief Overview by William R. Rogers D.O., CCN

Flow of the Lecture

Introduce the topic of Nutrigenomics Discuss landmark study on the need for one year

preconceptional vitamins with folic acid to reduce preterm labor by 70%

Discuss Co Enzyme Q 10 and its importance for supplementation

Discuss Omega 3 oils, digestive enzymes, probiotics, and vitamin D

Discuss cGMP Case histories

University of California Davis

Nutrigenomics

The goal of nutritional genomics is to identify those positive and negative interactions between the common constituents of diet and the genetic determinants they interact with

the use of genetic/genomic/ epigenomic information and nutritional inventions to promote health and prevent disease.

Nutrigenetics

Nutrigenomics is a rapidly growing field making use of molecular biology methodologies, such as microarray technology, to study how specific nutrients or diets affect gene expression

Recently the word "nutrigenetics" is being used to refer to study of the effects of genetic variation and gene-nutrient interactions in the management of chronic diseases

Labor-Associated Gene Expression in the Human Uterine Fundus, Lower Segment, and Cervix

The elucidation of the mechanisms of gene expression likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems—including prematurity, with its long-term consequences to the health of mother and offspring.

Radek Bukowski, 2006 http://dx.doi.org/10.1371%2Fjournal.pmed.0030169

Fetal growth in early pregnancy and risk of delivering low birth weight infant

Adverse outcome of pregnancy in a considerable proportion of women is likely to be determined before their first prenatal visit. These findings underline the importance of detailed study of the periconceptional period and first trimester of pregnancy when assessing factors that influence the risk of adverse outcome and in the development of predictive tests.

Radek Bukowski BMJ. 2007 April 21; 334(7598): 836.

Preterm Delivery an Enigma

The severity of health problems depends on the degree of prematurity; preterm babies born between 34 and 36 weeks of pregnancy rarely develop severe disabilities, but a quarter of babies born before 28 weeks of pregnancy develop serious lasting disabilities and half have learning and behavioral problems

it is impossible to predict who will have an early birth and there is no effective way to prevent preterm births.

Infant Mortality rates Effected

Every year, half a million babies in the United States (12.5% of all babies) are born prematurely (before 37 completed weeks of pregnancy). Sadly, premature babies are more likely to die than full-term babies and many have short- and/or long-term health problems.

Preconceptional Folate: May 2009

In a cohort of 38,033 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy

Duration of pregnancy was estimated based on first trimester ultrasound examination

Preconceptional Folate

Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications

UTMB Cohort Retrospective study published Feb 2009

Multiple Vitamins with folic acid taken by pregnant women 1 year continuously prior to getting pregnant reduced risk of preterm labor by 70%

Review of NIH data on 38 thousand women surveyed.

Although the study did not ask the amount taken, the assumption is that the women took the currently recommended 400-μg daily dose.

Preconceptional Folate

The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis.

Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010).

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

Low plasma folate concentrations in pregnancy are associated with preterm birth.

Radek Bukowski ET. AL. shows an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.

every woman of childbearing age should consume 400 micrograms of folic acid daily."

Limitations of the study on Preconceptional folate

Nicholas Fisk and colleagues also point out limitations to the study -

information on folic acid dose, formulation (with or without other supplements), and daily compliance is incomplete. The study design was observational, so the presence of other factors, such as healthier behaviors on the part of women who take folate supplements, may explain the findings. Further evidence as to whether folic acid prevents spontaneous preterm birth will require a randomized controlled trial.

http://www.medicalnewstoday.com/articles/150078.php

Poor Periconceptional Nutrition and Idiopathic Preterm Labor

Leonie Callaway,1,2 Paul B. Colditz,2,3 and Nicholas M. Fisk2,3*

Poor periconceptional nutrition is implicated in idiopathic preterm labor in both animal models and human studies.

Women taking supplements for at least one year before conception had a 70% reduction in spontaneous preterm birth between 20–28 weeks, and a 50% reduction between 28–32 weeks, when compared to those with no additional supplementation. Long-term compared to no supplementation was associated with a reduction in the risk of spontaneous preterm birth before 32 weeks from one in 154 to one in 423.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2671593

Preconceptional Folate

However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation contained in a multiple vitamin (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer.

Folic Acid From Leafy Green Vegetables, Fruits, and dried Beans

Preconceptional Folate

Folate (folic acid), a vitamin found in leafy green vegetables, fruits, and dried beans, helps to prevent neural tube birth defects.

In this study, the researchers test this idea by analyzing data collected from nearly 38,000 pregnant women enrolled in a study that was originally designed to investigate screening for Down's syndrome.

one of the very few opportunities to prevent first preterm births.

Oral Contraceptives and Nutritional Depletion

Back in the mid-1970's studies reporting that oral contraceptives depleted a variety of nutrients began appearing in the scientific literature. Numerous studies now document the fact that oral contraceptives deplete the following nutrients: folic acid, vitamin B6, vitamin B12, vitamin B2, vitamin C, magnesium and zinc. http://www.healingwithnutrition.com/newsclips/archive/drugdepletion.html

Reversing Congestive Heart Failure with Co Q 10

Coenzyme Q10

Coenzyme Q10 (Co Q 10) or ubiquinone is essentially a vitamin or vitamin-like substance.

The biosynthesis of CoQ10 from the amino acid tyrosine is a multistage process requiring at least eight vitamins and several trace elements.

Co Q 10

Coenzyme Q10 is the coenzyme for at least three mitochondrial enzymes (complexes I, II and III) as well as enzymes in other parts of the cell. Mitochondrial enzymes of the oxidative phosphorylation pathway are essential for the production of the high-energy phosphate, adenosine triphosphate (ATP), upon which all cellular functions depend. The electron and proton transfer functions of the quinone ring are of fundamental importance to all life forms;

Nutritional Deficiencies Lead to TO COENZYME Q10 Deficiencies

In 1958, Professor Karl Folkers and coworkers at Merck, Inc determined the precise chemical structure of CoQ10

Biosynthesis of this complex, 17 step process, requiring at least seven vitamins (vitamin B2 - riboflavin, vitamin B3 - niacinamide, vitamin B6, folic acid, vitamin B12, vitamin C, and pantothenic acid) and several trace elements, is, by its nature, highly vulnerable. Karl Folkers argues that suboptimal nutrient intake in man is almost universal and that there is subsequent secondary impairment in CoQ10 biosynthesis. PETER H. LANGSJOEN, M.D., F.A.C.C., http://faculty.washington.edu/ely/coenzq10.html

Statins deplete Co Q 10

Statin drugs decreases cholesterol synthesis by inhibiting the conversion of acetyl CoA to mevalonate. Mevalonate is also necessary in the production of ubiquinone, or coenzyme Q10 (CoQ10).

CoQ10 is necessary for mitochondrial energy production as well as exhibits potent antioxidant activity.

Crane FL Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001 Dec;20(6):591-8.

Use Supplement CoQ10 for Heart Failure

HMG-CoA reductase inhibitors used to treat elevated blood cholesterol levels by blocking cholesterol biosynthesis also block CoQ10 biosynthesis

In patients with heart failure this is more than a laboratory observation. It has a significant harmful effect which can be negated by oral CoQ10 supplementation.

Folkers K., Langsjoen Per H., Willis R., Richardson P., Xia L., Ye C., Tamagawa H. (1990) Lovastatin decreases coenzyme Q levels in humans. Proc. Natl. Acad Sci. Vol. 87, pp.8931-8934.

Co Enzyme Q 10

CoQ10 is known to be highly concentrated in heart muscle cells due to the high energy requirements of this cell type

Specifically, congestive heart failure (from a wide variety of causes) has been strongly correlated with significantly low blood and tissue levels of CoQ10

The severity of heart failure correlates with the severity of CoQ10 deficiency

Dosage is 100 to 300 mg/day

Supplement Co Q 10 in Heart Failure

nine studies on heart failure have confirmed the effectiveness of CoQ10 as well as its remarkable safety

There have now been eight international symposia on the biomedical and clinical aspects of CoQ10 (from 1976 through 1993 ). These eight symposia comprised over 300 papers presented by approximately 200 different physicians and scientists from 18 different countries.

consistent in their conclusions: that treatment with CoQ10 significantly improved heart muscle function while producing no adverse effects or drug interactions.

It has no known toxicity or side effects. http://faculty.washington.edu/ely/coenzq10.html

Controversy on Co Q 10 Political and Economic

The controversy surrounding CoQ10 likewise is political and economic as the previous 30 years of research on CoQ10 have been remarkably consistent and free of major controversy. Although it is not the first time that a fundamental and clinically important discovery has come about without the backing of a pharmaceutical company.

PETER H. LANGSJOEN, M.D., F.A.C.C, http://faculty.washington.edu/ely/coenzq10.html

Omega-3 Fish Oils

Omega-3 supplementation

Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths.

Circulation. 2002;105:1897-1903

Statistically Significant Decrease Sudden Death in Just 4 Months

Conclusions— The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

Circulation. 2002;105:1897-1903

N-3 polyunsaturated fatty acids help reduce coronary death

randomized controlled trials, published in all languages from 1966 to 1999.

7,951 patients in the intervention groups (range 31 to 5,666) and 7,855 patients in the control groups (range 28 to 5,658). The mean age was 49 to 66 years; between 33% and 100% had a previous myocardial infarction; and the average follow-up lasted 20 months (range 6 to 46 months).

N-3 polyunsaturated fatty acids help reduce coronary death

In patients with coronary heart disease, diets enriched with n-3 polyunsaturated fatty acids:

had no effect on nonfatal myocardial infarction (risk ratio 0.8, 95% confidence interval 0.5 to 1.2);

reduced the risk of fatal myocardial infarction (risk ratio 0.7, 95% confidence interval 0.6 to 0.8);

reduced the risk of sudden death (risk ratio 0.7, 95% confidence interval 0.6 to 0.9; 5 trials);

reduced the risk of overall mortality (risk ratio 0.8, 95% confidence interval 0.7 to 0.9; 9 trials).

Cost-Effectiveness Analysis of n-3 Polyunsaturated Fatty Acids (PUFA) after Myocardial Infarction

The cost effectiveness of long term treatment with n-3 PUFA is comparable with other drugs recently introduced in the routine care of secondary prevention after MI. Since the clinical benefit provided by n-3 PUFA is additive, this therapy should be added to the established routine practice, with additive costs. http://ideas.repec.org/a/wkh/phecon/v19y2001i4p411-420.html Franzosi , Maria Grazia , 2001

Understanding Benefits Of Omega-3 Fatty Acids

n−6 arachidonic acid was converted by the body into pro-inflammatory agents called prostaglandinE2 series while Eicosapentaenoic (EPA) acid produces prostaglandin E 3 series. The Arachnodonic acid metabolites and the EPA metabolites have opposing actions.

Eicosanoids made from n−3 fats often have opposing functions to those made from n−6 fats, anti-inflammatory rather than inflammatory

Standard American Diet

Typical Western diets provide ratios of between 10:1 and 30:1 - i.e., dramatically skewed toward n−6. Here are the ratios of n−6 to n−3 fatty acids in some common oils: canola 2:1, soybean 7:1, olive 3–13:1, sunflower (no n−3), flax 1:3, cottonseed (almost no n−3), peanut (no n−3), grape seed oil (almost no n−3) and corn oil 46 to 1 ratio of n−6 to n−3.

Hibbeln et al., 2006

http://efaeducation.nih.gov/sig/esstable.html

Prenatal Exposure to n-3 Polyunsaturated Fatty Acids Protects Against Asthma CME

Participants were randomized 2:1:1 to receive four 1-g gelatin capsules per day containing fish oil providing 2.7 g n-3 PUFAs (n = 266); four 1-g, similar-appearing capsules per day containing olive oil (n = 136); or no oil capsules (n = 131).

16-year follow-up, an asthma-related diagnosis was reported in 19 children from the fish oil and olive oil groups, including 10 diagnosed with allergic asthma. For the fish oil vs. the olive oil group, the hazard rate of asthma was reduced by 63% (95% confidence interval [CI], 8% - 85%; P = .03), and the hazard rate of allergic asthma was reduced by 87% (95% CI, 40% - 97%; P = .01). July 2008,American Journal of Clinical Nutrition

Effect of n-3 Polyunsaturated Fatty Acids in Asthma after Low-Dose Allergen Challenge

dietary supplementation with an n-3 PUFA-enriched fat blend (0.69 g/day) for 5 weeks

Conclusion: Our results provide evidence that dietary supplementation with n-3 PUFA is able to reduce bronchial inflammation even after low-dose allergen challenge.

Int Arch Allergy Immunol 2009;148:321-329

Digestive Enzymes

Most food today is processed and enzymes have been deactivated.

Irradiation of whole foods destroys some enzyme activity.

Cooking destroys enzyme activity. Use of proton pump inhibitors blocks stomach acids. Removal of the gallbladder removes bile acids. Humans use to consume fresh whole foods.

Computer Controlled Gastrointestinal Model

The T NO gastro- I ntestinal tract M odel (TIM) is a dynamic computer-controlled in vitro system that mimics the human physiological conditions in the stomach and small intestine. In the current TIM physiological parameters such as pH, temperature, peristaltic movements, secretion of digestion enzymes, bile and pancreatic juices, and absorption of digested products— http://www.sciencedirect.com/science

Computer Controlled Gastrointestinal Model

A Study was done comparing healthy digestion and healthy digestion with plant based digestive enzymes

A Study was done with 70% impaired digestion without and with adding digestive enzymes

http://www.infinity2.net/office/docs/1920.pd

Digestive Enzymes

In the perfect digestive function, digestive enzymes improved absorption of carbohydrates 4 fold and protein 2 fold.

In the 70% impaired digestive function, plant based digestive enzymes showed increased absorption of proteins 1.75fold,and carbohydrates 7 fold in the jejunum and ileum.

http://www.infinity2.net/office/docs/1920.pdf

Probiotics

One of the primary defenses of the GI tract is friendly bacteria.

Lactobicillus DDF-1 and bifidobacterium bifidum are two of the commonly supplemented normal flora. FOS is a sugar often included in the formula.

I take probiotics daily.

Probiotic Usage

Use to replace flora during and after antibiotic usage Prevention of c dif colitis. In irritable bowel syndrome. For treatment of viral or bacterial gastroenteritis. May add Saccharmyces boulardii. http://www.mayoclinic.com/health/probiotics/

AN00389

Sunshine in a Bottle

The Sun Through a DermatologistEye

Making Vitamin D

Vitamin D Found To Stimulate A Protein That Inhibits The Growth Of Breast Cancer Cells

Calcitrol, the active form of vitamin D, has been found to induce a tumor suppressing protein that can inhibit the growth of breast cancer cells, according to a study by researcher Sylvia Chistakos, Ph.D., of the UMDNJ-New Jersey Medical School.

Vitamin D3 is synthesized by humans in the skin when it is exposed to ultraviolet-B (UVB) rays from sunlight.

New Model Of Cancer Development: Low Vitamin D Levels May Have Role

"Vitamin D may halt the first stage of the cancer process by re-establishing intercellular junctions in malignancies having an intact vitamin D receptor,"

Garland said that diet and supplements can restore appropriate vitamin D levels, and perhaps help in preventing cancer development. "Vitamin D levels can be increased by modest supplementation with vitamin D3 in the range of 2000 IU/day," he noted.

http://www.sciencedaily.com/releases/2009/05/090522081212.htm

Consider Taking 2,000 Units Vitamin D3 a Day

The major biologic function of vitamin D is to maintain normal blood levels of calcium and phosphorus. Vitamin D aids in the absorption of calcium, helping to form and maintain strong bones. Recently, research also suggests vitamin D may provide protection from osteoporosis, hypertension (high blood pressure), cancer, and several autoimmune diseases.

http://www.mayoclinic.com/health/vitamin-d/NS_patient-vitamind

cGMP TGA certification

Good Manufacturing Practices (GMPs)

meets required specifications for quality and purity is evaluated and monitored for potential

contaminants such as filth, heavy metals, pesticides, and microbiological organisms (Designs for Health packaging is also monitored to ensure against contamination)

is analyzed to confirm the quantity of all dietary ingredients, thereby ensuring the consistency and accuracy of label claims

NSF

NSF International is The Public Health and Safety Company™, providing public health and safety risk management solutions to companies, governments and consumers around the world.

http://www.nsf.org/regulatory/

Dietary Supplements

A dietary supplement is defined under the Dietary Supplement Health and Education Act of 1994 (DSHEA) as a product that is intended to supplement the diet and contains any of the following dietary ingredients:

a vitamin, mineral, herb or other botanical, or amino acid a dietary substance for use by people to supplement the diet by

increasing the total dietary intake a concentrate, metabolite, constituent, extract, or combination of any of

the above Furthermore, it must also conform to the following criteria: intended for ingestion in pill, capsule, tablet, powder or liquid form not represented for use as a conventional food or as the sole item of a

meal or diet labeled as a "dietary supplement" The hormones DHEA , pregnenolone (also a steroid) and the pineal

hormone melatonin are marketed as dietary supplements in the US.

Dietary Supplement Health and Education Act of 1994

all dietary supplement manufacturers to ensure by June 2010 that production of dietary supplements complies with current good manufacturing practices, and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling.“

exception on quality assurance for raw material suppliers (with the burden placed on manufacturers) will lead to continued quality problems.

The Need for Daily Supplements

Every day our bodies need certain raw materials to support the vast biological mechanisms that fuel our physical and mental activity, support our immune defenses, and regenerate skin, muscle, blood, tissue, and bone. This fuel comes in the form of macronutrients — protein, carbohydrates, and fat — and micronutrients: vitamins and minerals (which fall into four more categories: water-soluble vitamins, fat-soluble vitamins, major minerals, and trace minerals).

The Best Multivitamin

Complete. Based on the latest nutritional science, women need at least 30 vitamins and minerals, plus a rich essential fatty acid formula (i.e., EPA and DHA).

Bioavailable. The nutrient forms must be the most bioavailable. There are six patented chelated formulas we recommend be included. And of course it must meet USP standards for solubility.

Natural. No artificial preservatives, dyes, allergens or other contaminants. The fatty acid formula (derived from marine lipids) must be certified to be free of mercury and lead.

Reliable. NSF and GMP labeled. Laboratory tested. As is true for pharmaceutical drugs, every production batch

of a nutritional supplement must be tested in a laboratory (i.e., “standardized”) to ensure that it contains exactly what is on its label.

Makes a difference. You are the final test. If the nutritional supplement doesn’t make you feel better within the first 30 days, try another formula. It may not resolve all your symptoms in that time, but you should feel a real improvement.

Case History: Wayne 60

Wayne the Tennis Partner/Banker

Birthday:11/4/48 Medications: none 6 foot 190 pounds BMI 28 Days absent from work for illness past 14 years:

none Supplements; CLO, B complex, occuvite, mega

minerals, Co Q 10, red yeast rice, saw palmetto, glucosamine ,chon, MSM

Exercise; daily life as hunter, president bank

Wayne

CT calcium scoring zero calcium this year Past surgical history-adrenal pheochomocytoma age

3.5 years Meniscus surgery 2000, missed one day work Total cholesterol 2009 190 ldl 100 hdl 55 Income up 300% Diet wild game, many vegetables, little fruit or grain Mild occasional aching in knee

Case History: John 56

John : The Golf Partner

56 year old male Medications’ none Supplements: Omega pure 600, vitamin D3

2000 units, angi nox one packet, panothenic acid, it C 500, multi vitamin

Exercise: daily stretching, sit ups push ups Golf 2x a week Weight 170 height 68 inches BMI 26

John

Days absent from work past two years while religiously taking supplements;0

Diet; Cave man diet lost 30 pounds past two years on the program

CT calcium scoring heart 0 Cholesterol was over 200 now 140 Pain free

Case History: Cindy 56

Cindy

56 year old female Medications: estradiol and progesterone 14 years essentials for life, Nordic natural cod

liver oil, eye vitamins, bone guard, vit D 2000, Co q 10 50 mg, resviratrol,

Daily exercise 1 hour P-2 g-2 Past surgical history- oopherectomy

Cindy

Days absent from work for illness 2 in 14 years

Prior to supplements 6 sinus infections a year and gastroenteritis twice a year requiring IVs

Height 62 inches, weight 100 pounds Pain free Modified low carb diet, few grains

Case History: Will 60

Will; Golfer, Tennis Player

Birthday 9/19/1048 Medications; none Supplements past 15 years essentials for life,

Co Q 10 50 mg, Nordic natural cod liver oil and omega pure 600, resviratrol, Vit D3 2000, angi nox

Surgery ACL knee 2008 5 days back to work Pain free

Will

Prior to supplements severe nasal allergies, hair loss, irritability, depression

Since supplements no allergies, missed one half day work for illness, mood stable

CT calcium scoring 0 HDL cholesterol went from 42 to 56 in 14 years Height 67 inches weight 163 Diet modified low carb

Case History: Judy 58

Judy

58 year post menopausal Past medical history fibromyalgia, chronic fatigue,

depression Meds; estradiol, progesterone, testosterone Supplements m foundation Pac with multiple

vitamins, minerals, omega 3DHA/EPA, and antioxidants x 3 years

After one month, patient started to feel really good. If she missed two days, she feels the ill effect.

Pain free, no depression, and no fatigue

National Nutritional Survey

Nutrient % Below RDA Vitamin B-6 80% Magnesium 75% Calcium 68% Vitamin A 50% Vitamin B-1 45% Vitamin C 41% Vitamin B-2, B-3, B-12 34% Pao EM, Mickle SJ. “Problem Nutrients in the United

States.” Food Technology 35:58-62, 1981.

Offer Your Patients Quality Supplements and Take Them Yourself

Try to make sure every patient in your practice is on a sound foundation of a pharmaceutical-grade multivitamin, multi-mineral, and essential fatty acids (EFA’s).

you have to rely on the quality of the research and the manufacturing methods that are behind your vitamin supplements when choosing a multivitamin