Over fifty years ago, most scientific and medical therapeutic approaches focused on cellular metabolism. With the advent of genetics a concentrated shift toward genomics, and subsequently proteomics (protein profiles), dominated the therapeutic stage. The area of metabolism (metabolomics) is now being revisited as an attractive target.

One such regulatory approach is via the manipulation of cellular energy. Cellular energy is synonymous with metabolic power. As we age there is a decrease in metabolism, furthermore, numerous disease states involve metabolic dysfunction (i.e. ischemia/stroke, cancer). As we all know, the major power plant of the cell is the mitochondria. It utilizes high energy intermediates (NADH and FADH) to donate electrons and drive the production of ATP, our functional energy source. Can we alter metabolic fitness by providing an alternative electron source?

WHAT IS POLY-MVA?

Poly-MVA is a dietary supplement that contains a patented lipoic acid palladium complex (LAPd). LAPd is a composed of the element palladium irreversibly bound to the antioxidant lipoic acid in a trimer about thiamine (B1). The name Poly-MVA was coined by Dr. Albert Sanchez since Poly-MVA is composed of minerals, vitamins, and amino acids (MVA). In addition to the LAPd, the proprietary formulation contains riboflavin, cyanocobalamin, formyl-methionine and acetyl-cysteine. Dr. Sanchez became its principle proponent in his search for non-invasive support/treatment for cancer patients, following his wife's tragic battle with colon cancer.

The lipoic acid palladium complex family of compounds was discovered by Dr. Merrill Garnett. While Dr. Garnett was formally trained as a dentist, this was followed by substantial graduate work in biochemistry and electrochemistry, followed by over 40 years of scientific bench work. His inquiry and screening into thousands of organo-metallic compounds, led to the discovery of the non-toxic LAPd chemotherapeutic agent. The principles that led to this finding in the early 90s still drive Dr. Garnett's principle laboratory interests today; that ultra-low frequency electrical currents are at the heart of all physiological processes and determine such events as the polarization, charge and folding of enzymes, nucleic acids and membrane phospholipids. He believes that the regulation of charge transfer may form the basis of several new methods of medicinal management.

Q & A

I am frequently contacted at my laboratory, on the radio, or approached at conferences with common questions regarding Poly-MVA.

A number of people are under the impression that Poly-MVA is merely a cocktail of palladium, alpha-lipoic acid, thiamine, riboflavin, cyanocobalamin, formylmethionine and acetyl-cysteine. There is no free lipoic acid or palladium in Poly-MVA; it is bound irreversibly with thiamine. Therefore, comparisons to free palladium or lipoic acid are irrelevant. This was done by Dr. Garnett to create a metallic polymer that is both fat and water soluble. Furthermore, it is prepared in a unique fashion so it does not metabolize, dissociate, and liberate the metal, which could accumulate in tissues and eventually become toxic like most chemotherapeutics.

Is Poly-MVA safe? LAPd has undergone extensive toxicology study (Calvert Laboratories, Inc; Pharmakon USA, Inc.). The toxicology was conducted both intravenously and orally with LAPd. Mice were administered doses of 5,000 mg/kg (a typical human dose is 20 mg/kg). No deaths or signs of organ damage occurred in the test animals. It was concluded that the LD50 of LAPd exceeds 5,000 mg/kg. The Ames test was conducted by the same independent lab and demonstrated not to cause any mutations. LAPd was also studied for its effectiveness in halting the growth of glioblastoma cells in vivo. Tumors were allowed to establish and mice were divided into 8 groups of 10. Four groups were given daily intravenous (IV) doses LAPd or placebo; four groups were given intraperitoneal doses of .05, 1.0 or 2.0 mg per mouse for a total of four weeks and tumor volume was measured throughout the study. Compared to the controls who received no LAPd, mice receiving the test material orally or intravenously at 0.5, 1.0 or 2.0 mg had a significantly reduced growth of the glioblastoma (50% or greater reduction in tumor size).

Palladium is a precious metal and quite expensive. Why was it used? Dr. Garnett discovered during his electrochemistry studies that DNA (and other biological cellular entities) has select electrical frequencies that it resonates at. After testing thousands of chemicals, Dr. Garnett found that only a limited few metals shared the same resonance frequencies with DNA. This characteristic facilitates electron flow between them. This is analogous to the propulsive energy provided to a surfer by a wave. If the surfer is in "sync" with the wave he can ride it all the way in to the beach. However, if he or she isn't, they will crown right over the top of the wave. Palladium is important since this is the only one that Dr. Garnett could "cook" with the lipoic acid and thiamine to form this irreversible crystal polymer.

Why are the other components added to the dietary supplement? Most people feel the other components are added without regard to the LAPd complex, but this is not true. Any molecule that transfers electrons has the ability to generate heat. In very early studies, patient temperatures elevated. The proprietary blend in Poly-MVA is not inert, but plays a role in buffering the temperature alterations.

Is Poly-MVA just a super free radical scavenger? This was my initial thought after my first transient global ischemia experiments with the lipoic acid palladium complex in Poly-MVA. However, the LAPd complex is a liquid crystal polymer. There is extensive data supporting the dramatic redox potential of polymers versus monomolecular structures, such as vitamins. Any redox molecule can certainly absorb electrons, but it also donates them. Dr. Garnett's electrochemistry papers demonstrate LAPd's significant redox potential versus its monomolecular competition. After my initial ischemia research findings, I sent some Poly-MVA to Brunswick Labs, Inc. (Wareham, MA) for an ORAC analysis. An ORAC assay measures the oxygen radical absorbance capacity of a compound as compared to Trolox (vitamin E). The table below demonstrates the potent antioxidant capacity of Poly-MVA (expressed as Trolox equivalent per gram):

Vitamin A = 1.6 (2,800) Vitamin C = 1.12 (1,890) Vitamin E = 1.0 (1,700) Melatonin = 2.04 (3,468) Lipoic Acid = 1.4 (2,400) Poly-MVA = 5.65 (9,605)

Why is this supplement often credited or associated with providing energy? While Poly-MVA does indeed have the ability to be a highly effective free radical scavenger, its ability to donate electrons to the mitochondria of the cell is critical to explaining its dramatic benefits. Anecdotal clinical evidence of the reports of additional energy led to my early hypotheses regarding its possible benefits in stroke and ischemia. Following an interruption of blood flow to any tissue, in my particular case it is the brain, there is deprivation of oxygen and glucose. Providing an alternative energy source can maintain the integrity of the electron transport chain within the mitochondria. The LAPd complex was demonstrated, by Dr. Garnett, to shuttle electrons to oxidized DNA, however, this energy flow does not appear to proceed directly to DNA. By conducting a competition assay with lipoic acid, which works at complex I of the mitochondria as a cofactor as pyruvate is converted to acetyl CoA, one can attenuate the beneficial effects. This is critical since mitochondrial health is a major concern during myocardial and cerebral ischemia. By providing this alternative energy source, the electron transport chain components do not readily dissociate (coenzyme Q-10 = ubiquinone; cytochrome C). In a normal cell this would obviously provide a boost, but serve as a supplement to an ischemic cell.

Can Poly-MVA be taken with other vitamins and free radical scavengers? Since lipoic acid palladium complex is a highly efficient redox molecule, normal daily recommended values of vitamins have not been of consequence in our laboratory studies. However, excessive doses of anti-oxidants may attenuate Poly-MVA's benefits. As mentioned above, administration of alpha lipoic acid in our competition assay hindered the redox benefits of Poly-MVA. However, alpha lipoic acid alone only offers a fraction of the ischemic protection offered by the polymer.

MECHANISMS OF ACTION

Poly-MVA's proposed mechanisms of action directly related to its structural formulation. Dr. Garnett's complex is a liquid crystal polymer and provide a unified redox. Redox polymers more efficiently accept charge, and therefore serve as potent anti-oxidants. Furthermore, they can also donate charge and serve as alternative energy sources. This electron transfer appears to be the key to its physiological effectiveness. When glucose enters a cell it is broken down under anaerobic conditions (absence of oxygen) into pyruvate. Pyruvate subsequently enters the mitochondria, via complex I, and is quickly oxidized, in the presence of alpha-lipoic acid, to acetyl-CoA. In aerobic respiration, acetyl-CoA is then channeled into the Krebs/Citric Acid Cycle to create the reduced form of nicotinamide adenine dinucleotide (NADH). NADH donates its electron to the electron transport chain to drive the phosphorylation of adenosine triphosphate (ATP). The energy needs of the body are supplied by splitting ATP into adenosine diphosphate (ADP) and a free phosphate molecule.

Studies have demonstrated that LAPd provides electrons to DNA (to replace the electrons lost in normal cells as a result of the oxidative damage associated with radiation and chemotherapy) via the mitochondria. This electron transfer will provide an additional energy source to normal cells. However, cancer cells are metabolically challenged, as well as, function in a hypoxic environment. Since excess electrons have less oxygen to accept them in the cancer cell, a local generation of free radicals occurs at the mitochondrial membrane. This activates apoptosis by facilitating the release of cytochrome C from the inner mitochondrial membrane, allowing the formation of an apoptotic complex in the cytoplasm. This complex, results in the subsequent activation of the caspase cascade of enzymes that destroy the malignant cells. Given that healthy cells are richly oxygenated, LAPd is nontoxic to them and they actually benefit from the energy boost.

Recent findings have focused on the role of Poly-MVA and a malignant cell's ability to physiologically adapt to a hypoxic environment. These physiological changes are mediated by a molecule called HIF-1 (hypoxia inducible factor-1), which increases in hypoxic conditions to promote an increases in: Vascular Endothelial Growth Factor (VEGF) - a promoter of angiogenesis; Glucose Transport 1 (GLUT1) and glycolytic enzymes - critical components in anaerobic respiration; and Erythropoietin (EPO) - responsible for the differentiation of red blood cells). Poly-MVA appears to decrease the production of HIF-1 thus restricting the ability of the cells to adapt to its environment and subsequently making it more vulnerable to the apoptotic cell death discussed above.