Introducing vita Med MD Prenatal Vitamins Developing a

Introducing vita. Med. MD™ Prenatal Vitamins Developing a new standard in prenatal care “A specialty pharmaceutical company developing a full line of unique products for women’s health issues from menarche through the menopause”

Therapeutics. MD Clinical Focus ∗ 1. ∗ 2. Clinical focus IS on achieving levels of nutrient intake that optimizes pregnancy outcome before, during, and after pregnancy Why is that “Clinical Focus” important: ∗ Nearly 50% of pregnancies are unplanned ∗ Nutritional needs ARE considerably higher prior to conception, during implantation, during pregnancy, and highest during lactation ∗ Recommendations from the CDC and U. S. Public Health Service is that ALL women of childbearing age should take 400 mcg of supplemental folic acid daily ∗ Problem: only 30% of non-pregnant women of childbearing age in the U. S. “report” taking 400 mcg or more routinely

Therapeutics. MD Proactively Reducing Pregnancy Induced Risk Factors ∗ 1. ∗ 2. ∗ ∗ 3. ∗ 4. ∗ 5. Importance of folic acid use pre-conception vita. Med. MD PNVs advantages over 3 rd generation FA Importance of folic acid use throughout a woman’s life Introduction of Quatrefolic – 4 th generation folic acid Importance of DHA in pregnancy and breast feeding MTHFR mutations/polymorphism Importance of elevated homocysteine (HHC) Understanding Thrombophilia and its consequences

Why is It So Important in a Prenatal Vitamin? • Folic acid role well established in prenatal care ‒ Reduction of NTDs, birth defects, anemia, preterm birth, other • MTHFR Polymorphism ‒ ‒ > 50% of women cannot metabolize folic acid Few women tested • Quatrefolic® bypasses MTHFR folate polymorphisms and is immediately available for its biological action • More bioavailable than other forms of folate 4

Importance of Adequate Folate Levels ∗ Known that humans need to maintain an adequate dietary intake of folate during various stages of their lives ∗ Folate plays an essential role in cell division and DNA synthesis ∗ Folate is involved in human growth and development ∗ Folate deficiency has far-reaching NEGATIVE health consequences at all stages of life ∗ Folate deficiency has been implicated in the etiology of a variety of disorders including but not limited to:

Benefits of Folic Acid “It has been estimated that as many as half of all birth defects can be prevented if women of childbearing age consume an adequate amount of folic acid. . . ” † ∗ Prevention of neural tube defects (NTDs) ∗ Reduction of other birth defects 1 ∗ (congenital heart disease, urinary tract anomalies, oral facial clefts, limb defects, pyloric stenosis) ∗ Reduction in anemia ∗ Reduction of implantation failure ∗ Reduction in incidence of early (1 st trimester) miscarriages ∗ Reduction in preterm birth ∗ Reduction in postpartum blood clots

Benefits of Folic Acid ∗ Reduction in language delay in offspring ∗ Reduction in various forms of cardiovascular diseases ∗ Reduction in age-related dementia ∗ Reduction in onset and severity of Alzheimer’s disease ∗ Reduction in prevalence of Osteoporosis ∗ Reduction in male infertility (Abnormal DNA) ∗ Reduction in all consequences of thrombophilia (increased tendency of excessive clotting) ∗ Reduction in pregnancy-induced headaches

Folic Acid and Autism: The Link A recent study, “The Association Between Maternal Use of Folic Acid Supplements and the Risk of Autism Spectrum Disorders in Children”, by Pal Suren, MD, MPH, was published in The Journal of the American Medical Association (JAMA). This study examined the association between maternal use of prenatal folic acid supplements and subsequent risk of Autism Spectrum Disorders (ASDs). 8

Folic Acid and Autism: The Link Key Quotes from the Study “A recent study of 38, 954 children in the Norwegian Mother and Child Cohort Study found that maternal intake of folic acid supplements from 4 weeks to 8 weeks after the start of pregnancy was associated with a lower risk of severe language delay at age 3 years. ” “A case-control study from California of autism spectrum disorder (ASD) showed that maternal intake of folic acid and prenatal vitamins during the 3 months prior to pregnancy and the first month of pregnancy was associated with a lower risk of ASD in offspring, and complementary genetic analysis indicated that the association was modified by gene variants that determine the ability to utilize available folate. ” (Referencing MTHFR polymorphism) “There is also evidence that maternal folic acid supplementation during pregnancy may be associated with reduced risk of other neurodevelopmental disorders in children. ” 9

Telomere dynamics: the influence of folate and DNA methylation Telomere shortening/dysfunction is now recognized as increasing generative disease risk. Recent studies have suggested that both dietary patterns and individual cronutrients--including folate--can influence telomere length and function. Folate is an important dietary vitamin required for DNA synthesis, repair, and e-carbon metabolism within the cell. 4. Recent published knowledge identifies the residual knowledge gaps. Specifically, this review addresses whether it is plausible that folate deficiency may (1) cause accelerated telomere shortening (2) intrinsically affect telomere function (3) cause increased telomere-end fusions and subsequent breakage-fusion-bridge cycles in the cell Ann N Y Acad Sci. 2011 Jul; 1229: 76 -88. doi: 10. 1111/j. 1749 -6632. 2011. 06101. x. 10

Telomere dynamics: the influence of folate and DNA methylation A telomere is a region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes Telomere regions deter the degradation of genes near the ends of chromosomes by allowing chromosome ends to shorten, which necessarily occurs during chromosome replication Without telomeres, the genomes would progressively lose information and be truncated after cell division Over time, due to each cell division, the telomere ends become shorter (aging!!!) 11

Telomeres 12

Therapeutics. MD Neural Tube Defects (NTDs)

Therapeutics. MD Folic Acid in Preventing NTDs

Therapeutics. MD Folate intake and NTDs: dose-response ∗ Epidemiology 2003, March; 14(2): 200 -5 ∗ Used data from 23, 228 women ∗ Predominantly from the NE area of the U. S. ∗ Enrolled 1984 -1987 ∗ Prospective study of early prenatal exposure and pregnancy outcomes ∗ NTDs ascertained through PN testing and by report of the delivering physician ∗ Diet and vitamin intake data gathered in early 2 nd trimester

Therapeutics. MD Folate intake and NTDs: dose-response ∗ Dietary folate equivalents (DFEs) ∗ Compared with women having the lowest total intakes of 0149 folate equivalents (in mcg): ∗ Prevelance of NTDs declined by ∗ ∗ 34% with intake between 150 -399 mcg 30% with intake between 400 -799 mcg 56% with intake between 800 -1199 mcg 77% with intake of > or = to 1200 mcg

Therapeutics. MD Dose-Response Relation of FA & NTDs

Folate/Folic Acid: Is There a Difference? • Folate is the naturally occurring form of this B-vitamin that is found in foods ‒ Only ~50% of natural folate is utilized by the body • Folic Acid ‒ ‒ ‒ Synthetic form Variable absorption in both food and multivitamin preparations Requires absorption and transformation into the biologically active form • MTHFR Polymorphisms 18

Folic Acid • 1 st Generation ‒ Folate (food) • 2 nd Generation ‒ Folic acid (synthetic folic acid) • 3 rd Generation (Metafolin®) ‒ 5 -methyltetrahydrofolate calcium salt (reduced folate) • 4 th Generation (Quatrefolic®) ‒ Glucosamine salt of (6 S)-5 -methyltetrahydrofolate (L-Methylfolate) 19

Folic Acid: Absorption and Transformation Folate must be transformed into the 5 -methyltetrahydrofolate (5 -MTHF) form which then passes by diffusion from blood into all body cells and then can convert homocysteine to methionine for DNA and protein synthesis. 20

Folate Methylation • Methylenetetrahydrofolate reductase (MTHFR): metabolizes folic acid to the active form of folic acid 5 -methylfolate • Over 50% of pregnant women have MTHFR polymorphism and cannot fully metabolize folic acid to its active form ® • 4 th generation Quatrefolic® is structurally analogous to 5 -methylfolate available for its immediate biological action 21

4 th Generation Folic Acid • Glucosamine salt of (6 S)-5 -methyltetrahydrofolate • Structurally equivalent to the reduced and active form of folic acid (5 -methyltetrahydrofolate) • Immediately available and active form • Greater bioavailability and stability when compared to the 3 rd generation calcium salt S. Ismaili. Crossover Comparative Bioavailability Study of 5 -Methyltetrahydrofolate Glucosmaine Salt (GN 10 G) Compared to the Reference Metafolin in Healthy Volunteers. Institute for Pharmacokinetic and Analytical Studies. Ligornetto, Switzerland. 22

vita. Med. MD MTHFR and Quatrefolic ∗ MTHFR = Methylenetetrahydrofolate Reductase ∗ The enzyme limiting step responsible for metabolizing folic acid to 5 -methyltetrahydrofolate ∗ Due to a genetic variation, up to 50% of patients may have an enzyme that functions less efficiency ∗ 4 th-generation Quatrefolic, the glucosamine salt of (6 S)-5 methyltetrahydrofolate is structurally analogous to the reduced and active form of folic acid 5 methyltetrahydrofolate

Quatrefolic ∗ Quatrefolic does not require transformation and exists in the active form of folate for its immediate biological action ∗ Quatrefolic has been shown to be more bioavailable than other forms of folate ∗ Quatrefolic increases hemoglobin levels better than folic acid ∗ Quatrefolic reduces homocysteine levels better than folic acid

vita. Med. MD MTHFR Mutation/Polymorphism ∗ Polymorphism (biology)(meaning "many" "forms") is a discontinuous genetic variation where two or more forms exist in the same species within the same population. It can apply to biochemical, morphological, and behavioral characteristics, but must be discontinuous ∗ Types of MTHFR polymorphisms ∗ Homozygous (C 667 T) both alleles ∗ Heterozygous (C 667 T) single allele ∗ Compound Heterozygous (C 667 T and A 1298 C) alleles

Prevalence of MTHFR Polymorphism Among Ethnic Groups Ethnicity MTHFR Variant Frequency C 677 T A 1298 C Caucasian 24 -37% 29 -37% Hispanic 31 -48% 15 -24% African American 8 -15% 12 -19% Asian Indian 10% 27% Asian – Chinese, Japanese, Korean 33 -51% 15 -25%

vita. Med. MD Thrombophilia ∗ 1. Thrombophilia is a medical term used to describe the condition where the blood has an increased tendency to clot secondary to: ∗ Excess of certain proteins, called blood clotting factors, or ∗ Inadequate anti-clotting proteins that limit clot formation ∗ 2. ∗ 3. Can be inherited (15% of people in U. S. ) or acquired later Estimated that > 600, 000 Americans die/year of blood clots ∗ 4. Acquired type usually related to a specific cause like trauma, prolonged periods of bed rest after surgery, cancer, ingestion of oral hormones (BCPs, HRT)

vita. Med. MD Thrombophilia ∗ 5. ∗ 6. Most people with a thrombophilia have no symptoms Others develop thrombosis like: ∗ ∗ ∗ ∗ DVTs (legs) VTEs (Pulmonary emboli) Strokes Heart attacks Dementia Alzheimer’s Migraine Headaches Pregnancy-induced Headaches

vita. Med. MD Thrombophilia • • • 7. Most common inherited (autosomal dominant) types Factor V Leiden mutation (2 -8%) = mutation causes protein to be inherited as an abnormal shape preventing it from being broken down properly by proteins C and S which leads to blood clot formation Prothrombin mutations (2%) Antithrombin deficiency (<1%) Protein C deficiency (<1%) Protein S deficiency (<1%)

vita. Med. MD Thrombophilia ∗ 8. Most common acquired type is (APS) antiphospholipid syndrome ∗ Occurs in 5 -10% of pregnant women ∗ Body makes antibodies (autoimmune disorder) that attack certain fats (phospholipids) that line the blood vessels leading to blood clot formation

vita. Med. MD APS and Pregnancy ∗ 1. ∗ 2. ∗ 3. ∗ 4. ∗ 5. ∗ 6. ∗ 7. ∗ 8. Spontaneous miscarriage Repeated miscarriages Repetitive pregnancy losses (at any gestational age) Pre-term labor Placental abruption Preeclampsia PIH Postpartum hemorrhage

vita. Med. MD APS and Rx in Pregnancy ∗ 1. ∗ 2. ∗ 3. Depends on specific type of thrombophilia Past history of repetitive pregnancy loss Past history of a blood clot ∗ Anticoagulant therapy (ASA, Lovenox, Progesterone supplementation, vita. Med. MD products) ∗ Treat throughout pregnancy and postpartum

vita. Med. MD Importance of DHA ∗ 1. ∗ 2. ∗ 3. ∗ 4. DHA (Docosahexaenoic acid) is the most abundant omega-3 fatty acid in the human body It is found in every tissue of the body and makes up 97% of the omega-3 fatty acid in the brain and 93% in the retina Few individuals get the recommended daily amount of DHA from our diets Numerous studies support supplementing your diet with DHA with positive benefits for your health

vita. Med. MD Importance of DHA ∗ Brain (increased cognitive activity, decreased risk of dementia or memory loss, may slow progression of Alzheimer’s disease, supports cognitive function throughout life) ∗ Eyes (decreased progression of ARMD, decreased progression of Glaucoma, decreased symptoms of DES) ∗ Heart (stabilizes heart rhythm and improved vascular reactivity) ∗ Increased gestational length of pregnancy ∗ Improved blood lipid profiles for individuals with high lipids (lowers triglycerides, lowers LDL, increases HDL) ∗ Improvement in attention and intellectual performance ∗ Anti-inflammatory effects (arthritis, SLE, SS, bowel inflammatory disease)

vita. Med. MD Life’s DHA Advantage ∗ 1. Unlike other sources of DHA omega-3, DHA Advantage comes from a vegetarian source (algae) ∗ 2. As not from fish, there is no worry of ocean-borne contaminants or risk of fish-related allergies ∗ 3. Grown in an FDA-inspected facility ∗ 4. Scientific evidence showing DHA much more important than EPA (eicosapentaenoic acid), major omega-3 in fish oils ∗ 5. Presence of EPA, present in fatty fish, is less important in advancing health issues and often demonstrates the opposite effects on bodily function than the benefits of DHA alone

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