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The Nutrition InvestigatorThe health and nutrition blog by Dr. Roc Ordman.

A Product for Health Span based on the Synergy between Vitamins C and K

by Roc (click here for full post)

Ordman, Alfred “Roc”, Beloit College, Beloit, WI, USA

Abstract The Federal law DSHEA prohibits manufacturers from making medical claims for nutritional supplements without FDA approval.  For the label on the supplement described on this poster, I am required to state “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” This prevents people learning of the benefits of nutritional supplements like vitamins C & K1 (VC, VK1), despite peer-reviewed scientific reports of their benefits.  In addition, it is difficult to obtain funding for methods to prevent cancer: “Despite more than 2.4 million papers published on cancer research to date, conventional medicine has largely failed to identify safe, low-cost, effective methods of cancer intervention and prevention.” 

    Here I report on a safe, low-cost, scientifically justified method likely to have multiple health benefits, including reducing the risk for cancer and heart disease. Both VC and VK1 are GRAS substances with individual and synergistic health benefits. I developed a tablet that combines VC and VK1. It is likely to produce the benefits which are reported in the literature, justified by research, but cannot be claimed on the product.

   VC at high dosages becomes a pro-oxidant generating free radicals that kill cancer cells. A dosage of 2g VC twice a day for 2 consecutive days produces a bladder [VC] able to kill cancer tissues in vitro.  VK1 at high dosages activates enzymes that remove calcium from arteries, reducing risk for heart disease. VK1 is converted in vivo to generate VK3, which enhances free radical production from VC up to 40x, so that serum [VC] may kill cancer cells.

   Three years of clinical trials for patients who have had bladder cancer have been planned to determine the health benefits of taking a supplement of vitamins C and K at the dosage we have published [Folk 2015].  The trial is planned and physicians will monitor cancer, heart disease, Alzheimer’s, and injuries from falls. Contact ordman@beloit.edu for information about obtaining the tablet or participating as a physician or volunteer in the clinical trial.

ABBREVIATIONS  VC – vitamin C; VK – vitamin K; VK1 – vitamin K1

Introduction “Despite more than 2.4 million papers published on cancer research to date, conventional medicine has largely failed to identify safe, low-cost, effective methods of cancer intervention and prevention.”  The great majority of cancer research is focused on curing late cancers that have already spread throughout the body by the time they are detected… the financial incentives to develop new therapeutics are far more lucrative than those for new diagnostic tests for early detection and prevention. [Song 2018]

Method  A collaboration of bladder cancer surgeons and cancer and VC researchers have planned a multicentre clinical trial to test the efficacy of a VC/VK formulation likely to prevent recurrence of non-invasive bladder cancer (Table 7).  The members have received many NIH RO1s. Our proposals to NIH and DOD [Ordman 2018] were rejected. The only reason given by reviewers was “if this is so easy, why hasn’t it been done before”. We concluded that rejection was based on the reasons above; the financial incentives to develop new therapeutics are far more lucrative than those for new diagnostic tests for prevention.

    In response, my patent attorney recommended developing, patenting, and manufacturing a tablet. The profits will be used to fund the clinical trials, and apply for FDA approval of our claims.

Results  A provisional patent [Weiss 2019] has been submitted based on my novel formulation (Table 7).  Weiss has contacted many entrepreneurs who have approached investors to fund manufacturing, marketing, and/or clinical trials.  Confidentiality statements were signed before discussing the results (Figure C).

    Contact was made with a manufacturer, MDR (Medical Doctors Research), with which I had previously consulted.  MDR developed AM/PM vitamins in response to the headline in USA Today (Figure D).  It reported Ordman’s clinical trial [King 1994] demonstrating that 500 mg vitamin C twice a day provided the highest level of C that can be attained by oral supplementation. 

   Weiss has determined that since the product is not yet available, it is permissible to disclose the published scientific evidence that provides the basis for development of the formulation of the tablet and its possible benefit to those who take it (Tables 2 thru 6).  Chemical structures and functions of VC and VK are shown in Figures A and B resp.  The logo is shown in Figure E. A brochure is being developed to disseminate this information (request at ordman@beloit.edu).

Discussion With the exponentially expanding knowledge of the benefits of proper nutrition, and the rapidly increasing population of older humans, medical and scientific professionals ought to educate the public, as the Linus Pauling Institute does.  We can develop products to fulfil the promise of nutrition research evident at this meeting.  Moving from the laboratory and publications to public education and product development and sales is hampered by DSHEA and the FDA. Tremendous expense is required for clinical trials and FDA legal hurdles.  As legitimate information on supplements is difficult to obtain, I hope to develop a Nutrition Consensus website for expert testimony from those taking supplements.

Conclusion The pharmaceutical industry expands on the expensive drugs which our aging population requires to treat diseases.  To achieve longer healthspans, I urge those who understand the potential of inexpensive nutrition to prolong health, to inform those who are not aware. I present this poster as an example of the process by which these goals, public education and product availability, can be achieved..

Figure A: Vitamin C is anti-oxidant at low concentrations, pro-oxidant at high concentrations [Olney 2013]

 It can also reduce metal ions which leads to the generation of free radicals through the Fenton reaction. The metal ion in this reaction can be reduced, oxidized, and then re-reduced, in a process called redox cycling that can generate reactive oxygen species.

2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH

2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate

Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC 50 values of< 4 mM [Chen 2005]

Figure B: Chemistry of human metabolism on Vitamin K isomers

Researchers confirmed the conversion of vitamin K1 through intermediate K3 to end product K2 takes place in humans [Thijssen 2006].  Results suggest that cerebral menaquinone-4 (VK2) originates from oral phylloquinone (VK1) intake and that there are two routes of accumulation. [Okano 2008]

K1, phylloquinone                  à   K3 Menadione            à     K2 Menaquinone 7

FIGURE C: CONFIDENTIALITY AGREEMENT
FIGURE D: USA Today Oct 18, 1994

page1image59960288

FIGURE E: Logo

Anti-oxidant benefits of 500mg BID Pro-oxidant benefits of 2g BID for 2 days [Folk 2015]
Serum level 80 mM Bladder level is 4 mM Able to kill cancer cells  [Chen 2005]
Highest concentration by oral dose Highest concentration by oral dose
  vitamin C at concentrations of 0.25–1.0 mM induced a dose- and time-dependent inhibition of proliferation in acute myeloid leukemia [Park 2013]
Prospective cohort studies indicate that higher vitamin C status, assessed by measuring circulating vitamin C, is associated with lower risks of hypertension, coronary heart disease, and stroke. [LPI, 2019] Experiments using purified DNA or isolated nuclei confirm that in the presence of added metal ions, vitamin C acts as a pro-oxidant in vitro [Carr, 1999]  

TABLE 2 Vitamin K types, functions, and sources [Schwalfenberg, 2017]

Vitamin K1, phylloquinone – Participates in blood clotting. [Schwalfenberg 2017]

-significantly fewer fractures in the treatment group (50% reduction) [Cheung 2008]

-may reduce risk for Alzheimer’s [Presse 2008]

SOURCE: Green leafy vegetables and some plant oils

Vitamin K2, menaquinone-4 (MK-4) – for the treatment of osteoporosis, along with vitamin D and calcium, rivaling bisphosphonate therapy without toxicity [Schwalfenberg 2017]

-enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. Osteocalcin is synthesized in bone. Low level of osteocalcin is considered a marker for hip fracture risk [Szulc 1996]

-inhibits vascular calcification by matrix GLa proteins (synthesized in cartilage and in blood vessel walls), reducing heart disease, renal calculi, diabetes, and cancer [Lamson 2003]

-in a prospective population-based study (LOE-A) of 4807 subjects free from myocardial infarction at baseline followed up for 7 years, the odds ratio of the highest tertile intake of menaquinone (vitamin K2) compared to the lowest resulted in a significant risk reduction in coronary heart disease, 0.43; all-cause mortality, 0; and severe aortic calcification, 0.48 [El Asmar 2014]

-is involved in calcium transport, preventing calcium deposition in the lining of blood vessel walls, and helps improve bone density [Flore 2013]

-may also significantly reduce morbidity and mortality in cardiovascular health by reducing vascular calcification [Schwalfenberg 2017]

– appears promising in the areas of diabetes, cancer, and osteoarthritis[Schwalfenberg 2017]

-deficiency has recently been recognized as a protagonist in the development of vascular calcification and osteoporosis. Data reported so far are promising and, dietary supplementation seems a useful tool to contrast these diseases. [Flore 2013]

SOURCE: (i)Butter, eggs yolks, lard, and animal based foods 
(ii) Synthesis by bacteria in the intestinal tract (however, synthesized MK-4 is bound to the membranes of bacteria in the gut and very little is absorbed in humans) [Okano 2008]
(iii) Over-the-counter (OTC) supplements

Vitamin K2, menaquinone-7 (MK-7) As for MK-4,  Long chain form with longer half-life

SOURCE: Fermented foods, some cheese 

Vitamin K3, menadione – (i) has been banned by the FDA in the USA because of potential toxicity (hemolytic anemia) [Vetrella 1972]
(ii) Is presently being studied as a potential prostate/hepatocellular cancer therapy and potential treatment for skin toxicities secondary to kinase inhibitor therapy [Mizuta 2007, Life 2010]

SOURCE: Synthesized in humans from VK1; Synthetic analogue of vitamin K considered a provitamin

Vitamin K combination – may reduce requirement for coumadin, which is hazardous. The evidence that coumadin may increase fractures, arterial calcification, and mortality is still in conflict. [Schwalfenberg 2017]

-Considerations of vitamin K supplementation with anticoagulation should include dose and type of vitamin K used. Extended intake of vitamin K1 of 700 μgm reduced INR values from 2 to 1.5. Vitamin K2 supplementation is more potent at reducing INR and 200 μgm of K2 will reduce INR values from 2 to 1.5. Thus, supplementation of >50 μgm of vitamin K2 requires INR monitoring [Schurgers 2007]

TABLE 3: Synergy of Vitamin C and Vitamin K

-Redox cycling quinones, such as vitamin K3 (VK3), are known to trigger apoptosis or cause cell necrosis depending on the dose and duration of exposure (Dypbukt 1994). Vitamin C (VC) in the form of ascorbate has been shown to reduce VK3 via single-electron reduction and to increase the rate of redox cycling of the quinone. These results suggest that coadministration of VC and VK3 to tumour cells may enhance the oxidative stress and thus the cytotoxicity of the VK3 (Jarabek, 1995).

-Co-administration of VC and VK3 (in a VC:VK3 ratio of 100:1) to breast carcinoma, epidermoid carcinoma and endometrial adenocarcinoma cell lines resulted in 50% cytotoxic doses (cd50) which are 10–50 times lower than when either vitamin is administered alone (Noto 1989).

-Vitamin K2, which has a geranylgeranyl group as a side chain,and vitamin K3 induces apoptosis of various cultured cells including osteoclasts and osteoblasts, by elevating peroxide and superoxide radicals. Synergistic apoptosis-inducing actions have been found between vitamins C and K, and between these vitamins and antiproliferative agents. The possible therapeutic application of these vitamins is discussed. [Sakagami 2000]

-Vitamin test solutions were serially diluted with media in twelve 2-fold dilutions.  300:3 μM VK3 – there is a growing body of evidence demonstrating the benefit of combining vitamins C and K3 for the treatment of: acute lymphoblastic leukemia, acute myelogenous leukemia, bladder, breast, glioblastoma, glioma, kidney, liver, lung, ovarian and prostate cancers. Unlike the majority of chemotherapeutic agents which target rapidly dividing cells, VC:VK3 appears to target tumor cells by inflammation. [McGuire 2013]

TABLE 4: Nutritional effects of chromium nicotinate supplementation

-GRAS substance [FDA 2015]

-Clinical trials for benefit of chromium for weight loss, diabetes, and lipid metabolism have been inconclusive. [NIH Chromium Dietary Supplement Fact Sheet]

-Chromium has long been of interest for its possible connection to various health conditions. Among the most active areas of chromium research are its use in supplement form to treat diabetes, lower blood lipid levels, promote weight loss, and improve body composition. [NIH 2019]

TABLE 5: Nutritional effects of Turmeric [curcumin] 

-Turmeric extract from the rhizomes, commonly called curcuminoids, is mainly composed of curcumin. The research on curcumin has received considerable attention due to its pronounced anti-inflammatory, anti-oxidative, immunomodulating, anti-atherogenic, and anti-carcinogenic activities. [Sarkar 2010]

-Turmeric curcumin can help promote healthy joints, keep our hearts in top shape, and maintain our cognitive functioning. Researchers are also suggesting that, when taken as a supplement, it can help keep our immune system balanced and working correctly [Menon 2007, Gupta 2013, Jagetia 2007]

TABLE 6: Nutritional effects of Sulforaphane Glucosinolate

Extensive epidemiological evidence and animal experimental studies suggest that cruciferous vegetables may prevent or delay various inflammatory disorders, including cancers. Much of this chemopreventive effect has been attributed to the physiological effect of the isothiocyanates, especially sulforaphane (SF). Sulforaphane has been proven as a potent protector against oxidative damage and carcinogens. A plethora of clinical effects are reported in various experimental diseases as well as human clinical studies. [Elbarbry 2011]

TABLE 7: “Triumph” dosage and planned clinical trials

Each tablet contains 500 mg vitamin C, 1 mg K1, 25 mcg chromium, 25 mg turmeric, and 20 mg sulforaphane glucosinolate.  Four tablets are taken at a time, twice a day, on days 1, 2, 15, and 16 of each month

A clinical trial is planned to evaluate medical benefits.  Outcomes to be examined include:

  * Decrease in recurrence of non-invasive muscle carcinoma. Bladder cancer currently kills 17,000 annually in the US, and recurs within 5 years in up to 90% of patients receiving SOC BCG therapy.

  *  Decrease in all forms of cancer based on redox cycling of vitamin C/K3 combination [see tables 4-5]

   * Reduction in: requirement for coumadin; hip fractures ; Alzheimer’s ; Osteoporosis; heart disease, esp myocardial infarction; renal disease; diabetes ;  osteoarthritis ; all-cause mortality

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