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Protandim: Another Kind of Antioxidant

Four years ago I received an e-mail inquiry about Protandim. I had never heard of it; but I looked it up and wrote a quick, informal, somewhat snarky answer that got posted on the Internet. It got a lot of attention. Googling for Protandim now brings up my critique right after the Protandim website itself: that can’t be good for sales. Over the years, several e-mails and blog comments have informed me that I was wrong (usually offering testimonials or calling me closed-minded), and recently I’ve been getting inquiries asking if I’ve changed my mind now that a clinical study has been published. I haven’t.

Instead of providing antioxidants directly, Protandim is supposed to stimulate the body to produce its own antioxidants. The website tells us it is “the only supplement clinically proven to reduce oxidative stress by 40%, slowing down the rate of cell aging to the level of a 20 year old.” It provides “thousands of times more antioxidant power than any food or conventional antioxidant supplement.” It signals the body’s genes to produce the enzymes SOD (superoxide dismutase) and CAT (catalase) that act as catalysts to neutralize free radicals and are not “used up” like ingested antioxidants are. It “creates a cascade of your body’s natural catalytic antioxidants that are able to destroy millions of free radicals per second.” It raises the level of glutathione by 300%. Glutathione is good, apparently.

What is Protandim? It’s a combination of Milk thistle, Bacopa extract, Ashwagandha, Green tea extract, and Turmeric extract. I looked these up in the Natural Medicines Comprehensive Database. None of them is known to have any significant clinical benefit from antioxidant effects. Some of them are listed as “not enough information” to know if they are safe. One has estrogenic properties and more than one has known side effects and potential interactions with other drugs. The only one that even sounds remotely like it might have some pertinent data behind it is green tea. Green tea contains antioxidant catechins that are “thought to possibly have a protective effect against atherosclerosis and heart disease” and contains flavonoids that “might reduce lipoprotein oxidation; however benefits have not yet been described in humans.”

A Pubmed search for “Protandim” yielded only 3 studies: One in mice, one in cell cultures and one in humans.

1. The mouse study. Protandim reduced the development of skin cancers in a mouse model.
2. The cell culture study. Cells in cell culture produced more glutathione in the presence of Protandim. There was a synergistic effect of components in the induction of heme oxygenase-1.
3. The human study. The only clinical study so far.

After 30 days of supplementation, TBARS declined by an average of 40% (p = 0.0001) and the age-dependent increase was eliminated. By 120 days, erythrocyte SOD increased by 30% (p < 0.01) and catalase by 54% (p < 0.002). We conclude that modest induction of the catalytic antioxidants SOD and catalase may be a much more effective approach than supplementation with antioxidants (such as vitamins C and E) that can, at best, stoichiometrically scavenge a very small fraction of total oxidant production.

The concept is intriguing, and it may have promise, but the current evidence is not sufficient to make clinical recommendations. There is only one study to date in humans, and it only measured markers in the blood. TBARS (thiobarbituric acid reactive substances) is a measurement that has not demonstrated clinical usefulness. I could only find one study suggesting that TBARS levels might be helpful in predicting outcome in patients who already have cardiovascular disease. This review article critiques TBARS and other measures of antioxidant activity and suggests that measuring isoprostanes might be more meaningful.

It’s all very well to show that a remedy changes blood test results or even a known marker for disease; but what we really need to know is whether it improves health, prevents cancer, prolongs life…We need POEMS: Patient Oriented Evidence that Matters. Avandia improves hemoglobin A1C levels in diabetics but increases mortality. Mortality matters a lot; Hgb A1C levels don’t matter so much. “The operation was a success but the patient died” is not good enough.

I went to Wikipedia not as a reliable source but because it often has links to more information from primary sources. For what it’s worth, the Wiki article on Protandim concurs with my assessment, stating “There is no acceptable evidence that it improves health.” Wiki links to a very useful “Protandim Watch” website that has gathered a lot of information in one place, including information about the company and its multilevel marketing. It is skeptical and recommends caution. Wikipedia also questions Protandim’s claim of life extension, listing several studies on animals suggesting that increasing production of those catalytic enzymes might not increase life span and possibly might shorten it.

From the Protandim Watch website I learned that a second patent was awarded to Protandim in 2008. In the patent application, they claimed that

The compositions of the present invention are useful to prevent or treat the following disorders and diseases: memory loss; Parkinson’s disease; aging; toxin-induced hepatotoxicity, inflammation; liver cirrhosis; chronic hepatitis; and diabetes due to cirrhosis; indigestion; fatigue; stress; cough; infertility; tissue inflammation; cancer; anxiety disorders; panic attacks; rheumatism; pain; manic depression; alcoholic paranoia; schizophrenia; fever; insomnia; infertility; aging; skin inflammations and disorders; alcoholism; anemia; carbuncles; convalescence; emaciation; HIV; AIDS; immune system problems; lumbago; multiple sclerosis; muscle energy loss; paralysis; swollen glands; ulcers; breathing difficulties; inflammation; psoriasis; cancer (e.g.; prostate cancer, lung cancer and breast cancer); pain; cardiovascular disease (e.g.; arteriosclerosis and atherosclerosis); ischemia/reperfusion injury; anxiety; attention deficit disorder; leprosy; arthritis (e.g., psoriatic arthritis; ankylosing spondylitis; and rheumatoid arthritis); hemorrhoids; tuberculosis; high blood pressure; congestive heart failure; venous insufficiency (pooling of blood in the veins; usually in the legs); sore throat; hepatitis; syphilis; stomach ulcers; epilepsy; diarrhea; asthma; burns; piles; sunburn; wrinkles; headache; insect bites; cuts; ulcers; sores; herpes; jaundice; bursitis; canker sores; sore gums; poison ivy; gastritis; high cholesterol; heart disease; bacterial infection; viral infection; acne; aging; immune disorders; dental caries; periodontitis; halitosis; dandruff; cardiovascular disease (e.g., hypertension; thrombosis; arteriosclerosis); migraine headaches; diabetes; elevated blood glucose; diseases of the alimentary canal and respiratory system; age-related physical and mental deterioration (e.g., Alzheimer’s Disease and age-related dementia); cardiovascular disease; cerebral vascular insufficiency and impaired cerebral performance; congestive symptoms of premenstrual syndrome; allergies; age-related vision loss; depression; Raynaud’s disease; peripheral vascular disease; intermittent claudication; vertigo; equilibrium disorder; prevention of altitude sickness; tinnitus (ringing in the ear); liver fibrosis; macular degeneration; asthma; graft rejection; and immune disorders that induce toxic shock; bronchpulmonary disease as cystic fibrosis; chronic bronchitis; gastritis; heart attack; angina pectoris; chronic obstructive pulmonary disease; kidney damage during coronary angiography; Unverricht-Lundborg disease; pseudoporphyria; pneumonia; and paracetamol hepatotoxicity.

Did they leave anything out?

Clearly, these claims can’t be substantiated, and they can’t legally list them on their website. LifeVantage Corporation’s website still states that it

does not market and sell Protandim® for the purposes of preventing, treating, curing, or mitigating any disease, including MS.

I guess we can assume they only market and sell it for the purposes of making money.

The second study listed above really intrigues me. They tested the individual components and apparently established that there was a marked synergism when the ingredients were combined. If this is true, it is unusual and deserves further investigation. In general, mixing natural medicines has produced additive but not synergistic effects, despite the claims of naturopaths that synergistic effects are common and are a basic principle of herbal medicine.

Some 20 studies in humans are said to be in progress. I’ll watch developments with great interest. Meanwhile, I can’t recommend taking Protandim. There has been a lot of hype about antioxidants. Most of the research indicates that eating fruits and vegetables is beneficial, but taking antioxidant supplements is either useless or counterproductive.

If you did want to raise your antioxidant levels, how could you rationally choose from all the products on the market? For instance, how about Seanol? – they say it has some of “the most powerful antioxidants on earth” and is responsible for the longevity of Okinawans.

I’m not buying.

Posted in: Herbs & Supplements

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41 thoughts on “Protandim: Another Kind of Antioxidant

  1. colli037 says:

    Of course, this entire discussion assumes that there is a medically valid reason for increasing anti-oxidants, and that all free radicals are “bad”.

    There is some evidence that the “oxidants” serve a useful function in the human body, such as killing bacteria, limiting or killing mutant cells/cancer cells, which suggests that interfering with this would result in increased health problems. I believe this was discussed in a Nov 2008 post here as well.

    t

  2. Scott says:

    It always amuses me that the “natural” way to obtain proper nutrition and maintain good health is to take a lot of pills, while those “nasty doctors in the pockets of Big Pharma” recommend eating right and getting plenty of exercise.

    Because, you know, oranges are patented by Merck, and jogging by Pfizer. Or something like that.

  3. Sam says:

    Until reading this post I had never heard of Protandim. There is a considerable amount of research behind Curcumin, an extract of Turmeric. Here is a review of its biological activities:

    http://www.ncbi.nlm.nih.gov/pubmed/16413584

    “As a result of extensive epidemiological, clinical, and animal studies several molecular mechanisms are emerging that elucidate multiple biological effects of curcumin. This review summarizes the most interesting in vitro and in vivo studies on the biological effects of curcumin.”

    The best supplement for raising levels of superoxide dismutase and catalase is Glisodin, a patented product made by a French company. Here is a monograph on the research behind Glisodin:

    http://www.glisodin.org/glisodin_monograph.htm

  4. hatch_xanadu says:

    HH, have you seen this?

    http://www.bioshieldpill.com/

    They’re marketing it to folks undergoing radiation therapy, any kind of imaging procedure, riding in an airplane, and . . . oh, anybody, really. I presume they’re running with the idea of a recent preliminary study that showed red wine had some effect on skin toxicity during radiation therapy. They’re marketing to radiologist groups. And the “facts” they provide are basically statistics on the harmful effects of ionizing radiation — which we’re all already aware of. There’s nothing, of course, demonstrating that these pills have provided any benefit. The site looks pretty sharp, and the information seems quite sound . . . if you don’t realize that the information has really nothing to do with whether the pills work or not.

  5. Sivi Volk says:

    I’ve heard this several times now, that herbal medicines generally show additive and not synergistic effects when adding and subtracting components from compounds.

    Could someone provide a source to back this up? It’s not so much that I doubt it, but I’d very much like to be able to point some friends of mine at it during arguments about modern conventional medicine.

  6. Regarding ‘markers’ relevant to the oxidation hypothesis, a 2002 editorial in Circulation, which is still valid, concluded with this:

    We lack markers that would let us evaluate the efficacy of any given antioxidant intervention, and we lack criteria for rational selection of patients under high oxidative stress. Until we have such basic information, we should put a hold on further clinical trials. Instead, we should concentrate on developing the scientific base that will enable us to design an appropriate trial to test the oxidation hypothesis.

  7. shipthechicken says:

    Maybe you should watch a recent video of the historic and scientific explanation of “anti-oxidants” (uh, protandim isn’t an anti-oxidant Dr.)… and your statement “It raises the level of glutathione by 300%. Glutathione is good, apparently.” I would assume (but assuming makes an ass out of both you and me) that you’d understand the power of Glutathione.

    Watch the video and please then let your viewers know your opinion. No hubris please. http://lifevantage.com/truetv.aspx

    Oh, and the effects of glutathione??? maybe you should watch this http://www.youtube.com/watch?v=wxno30sQkyU

  8. Todd W. says:

    Once again, the USPTO fails! According to the USPTO web site:

    The patent law specifies that the subject matter must be “useful.” The term “useful” in this connection refers to the condition that the subject matter has a useful purpose and also includes operativeness, that is, a machine which will not operate to perform the intended purpose would not be called useful, and therefore would not be granted a patent.

    So, a composition that does not work to “prevent or treat the following disorders and diseases” (e.g., tuberculosis) is not useful, and therefore would not be granted a patent.

    And yet, they have one. When will the USPTO wisen up and stop handing out patents to everyone that comes along, whether their product works or not?

  9. qetzal says:

    Todd W.,

    In this case, at least, I don’t think you can fault the USPTO.

    While the patent certainly doesn’t prove the product treats any of those diseases, it does (apparently) provide data to show that Protandim is “useful” for increasing things like SOD in a mammal (e.g. a mouse).

    Also, they don’t actually include any disease treatments in the patent claims. They only claim the specific mixtures of ingredients. (More precisely, they claim the process of mixing the specific ingredients together.)

    IIRC, you’re normally pretty free to speculate about possible uses of your invention, as long as you prove at least one, and don’t attempt to specifically claim anything that you haven’t proven.

  10. DVMKurmes says:

    There is a paper in Nature last week that demonstrates a biological mechanism for the effect of antioxidants on tumor cells;

    http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08268.html

    It is an in vitro study, but it has some interesting implications.
    An interesting sentence from that paper-

    “These data also demonstrate that antioxidants promote the survival of cells that lack attachment to the ECM and raise the possibility that antioxidants may have dichotomous activities with respect to tumorigenesis-that is, suppressing tumorigenesis by preventing oxidative damage to DNA, and promoting tumorigenesis by allowing survival of cells that are metabolically impaired (for example, in altered matrix environments).”

    It appears that the effects of antioxidants are a bit more complicated than some would like to think.

  11. daedalus2u says:

    The level of “proof” required by the patent office for utility is quite low. I looked at the patent application and the demonstration of utility is sufficient (I think). They show that the mixture has pharmacological effects on various things, SOD, catalase, glutathione peroxidase in animals; that is likely sufficient “proof”.

    However the most important aspect of a patent is the claims. Their claims are not so good. They claim a product containing five different things with the composition and purity of the components specified quite precisely, i.e. at least 75 mg of an extract containing at least 98% of something. There are multiple ways around this. You use 60 mg or less, or you use something that contains only 90% or you use only four of the five things.

    If you use a green tea extract that has only 90% polyphenols, then you can’t make their claimed product (if the claims issue as filed which I doubt). In other words, if you make something that is pretty close to what they are selling, except you start with a 90% green tea extract, there is nothing they can do to stop you. When you buy your green tea extract, tell the manufacturer you want 90% and they will be happy to supply you with something that says 90%.

    I doubt that this patent will issue. Each of the herbal components has shown some antioxidant properties separately, combining them into a product that shows antioxidant properties is not an invention. The combination is obvious, unless there is some very unique synergy associated with this particular combination, and there isn’t. In one of their examples they use a useful range of from 0.001 mg to 1000 g, a dose range of a million.

    I don’t see any value in this patent application, even if it issues. In my opinion, the only value in the Protandim product is from its aggressive marketing and its production of a placebo effect. A patented product may produce a better placebo effect, but only marginally so. Another product could be virtually identical, contain an ingredient list and say “compare to Protandim”. A comparison would show they are virtually identical, the customer would buy the cheaper one, the one without the marketing overhead.

    It really isn’t the PTOs job to police whether or not patented products work or not. The PTOs job is to ensure that the patented subject matter is new, that is it has not been described before. A patent examiner only gets a few thousand for examining a patent. They simply don’t have the resources to evaluate claims of efficacy. They don’t have the expertise to evaluate the claims of efficacy, they shouldn’t even try.

  12. reily says:

    After reading this entry i felt compelled to write something, as i have been researching this exact topic for my thesis for 4 years now. In the free radical field we are trying to get rid of the idea of “oxidative stress” because that model does not accurately reflect the data gathered over the last 30-40 years. Oxidative stress really only applies when using gamma radiation for cancer therapy, during which the production of hydroxyl radicals kills the cells. Free radicals are produced endogenously by cells under normal conditions and are important in cell signaling. “Antioxidant supplementations” have not proved efficacious to any significant degree in large scale clinical trials; in fact high vitamin E supplementation was shown to increase mortality in patients with cardiovascular disease. Companies can claim that their product can be used to treat any number of diseases, because most diseases we know of have alterations in free radical signaling. This is not necessarily due to increased free radical production.
    The only oxidant marker that has been shown to be predictive in medicine is oxidized LDL for cardiovascular disease, and that has yet to be fully analyzed.

  13. It appears that the effects of antioxidants are a bit more complicated than some would like to think.

    Exactly so. We found the same sorts of complications when reviewing the purported antioxidant effects of NaEDTA chelation:

    There is evidence of EDTA’s paradoxical generation of reactive oxygen species in the presence of iron, and a possible augmentation of that effect by high ascorbate concentrations, such as those in the chelation solution advocated by the ACAM and used in the TACT.[147–150] Thus, “instead of protecting against and neutralizing metallic free radicals, EDTA in the presence of iron and ascorbate produces free radicals and potentially induces the changes that it is intended to prevent.[148]”

    (References in the original).

  14. pmoran says:

    It is only natural that there will be effects if you expose tissue culture cells directly to any chemical. The medical literature is awash with such studies now that herb promoters have observed how easily their competitors have been able to produce such “proof” of their medical claims. We have seen how anything can cure cancer if you bathe cancer cells in culture with enough of it.

    The question with Protandim (assuming the results are replicable) is this: “are these useful effects, or are they non-specific cellular responses to external insult”, in this instance exposure of cells to up to five potentially toxic chemicals in an exceedingly artificial way.

    When looked at this way it is not surprising that exposure to five different chemicals at once produces more dramatic effects than the constituent chemicals (in the same concentrations) individually. This is not clear evidence for beneficial synergism.

    The rather simplistic antioxidant theory upon which such work is based has also not yet stood the test of time. As others have said, a good diet still looks healthier than pills.

  15. trrll says:

    And there are reasons to expect it to be complicated. A free radical is a molecule with an unpaired electron. But when you add an odd number to an even number, you always end up with an odd number. The only way to get a free radical to actually “go away” and stop being a free radical is to react it with another free radical. So when a free radical “scavenger” reacts with a free radical, it becomes a free radical. So the hope is that the new free radical will be less reactive than the old one, and that somewhere downstream there will be another reaction in which two free radicals are be combined to get rid of both of them. It is quite possible that excessive levels of a free radical scavenger could interfere with this, and cause free radicals to hang around longer. Maybe cells actually have a good reason for not being more loaded up with free radical scavengers…

  16. daedalus2u says:

    NO is an excellent antioxidant, several thousand times better than vitamin E. NO does have a single unpaired electron, so it does quench free radical chain reactions at near diffusion limited kinetics.

    All the large, long, double blind placebo controlled trials of supplemental antioxidants have shown no positive effects and sometimes slight negative effects. The state of oxidative stress is too important for organisms to depend on dietary quantities of antioxidants for its regulation.

    This stuff may increase expression of antioxidant defenses because physiology is generating more free radicals to destroy it and so needs more antioxidant defenses.

    The normal response to xenobiotic chemicals is the phase I response which generates more superoxide and electrophiles to react with the xenobiotic chemical (the cytochrome P450 enzymes generate superoxide), and then the phase II enzymes are expressed to deal with the reactive species generated in phase I (glutathione and glutathione transferases).

  17. qetzal says:

    deadalus2u,

    I agree the patent claims are pretty limited. I’m really not sure why they bothered, unless they think there’s marketing value in being able to tout that Protandim is “patented.”

    The patent is already issued, though (#7,384,655).

  18. trrll says:

    NO is an excellent antioxidant, several thousand times better than vitamin E. NO does have a single unpaired electron, so it does quench free radical chain reactions at near diffusion limited kinetics.

    Although when it reacts with superoxide radical, the product peroxynitrite is highly reactive

  19. daedalus2u says:

    trll, yes, peroxynitrite is pretty reactive, that is a feature, making peroxynitrite part of the signaling cascade that regulated the transition from a NO dominated physiological state to a superoxide dominated state.

    Peroxynitrite oxidizes the zinc-thiol couple that is a part of nitric oxide synthase. When that is oxidized, NOS becomes uncoupled and makes superoxide instead of NO. That allows for a very rapid and robust transition because once NO and superoxide are produced simultaneously NOS rapidly becomes uncoupled and makes only superoxide.

    NO does quench the peroxidation chain reaction that occurs in unsaturated fatty acids.

    http://www.jbc.org/cgi/content/full/275/15/10812

    Superoxide is mostly confined to the inside of vesicles which NO can freely enter. As an anion, peroxynitrite would be confined there too, but peroxynitrite can decompose into NO2 and hydroxyl. The hydroxyl is too reactive to go anywhere, but the NO2 can diffuse and nitrate things. Nitration usually happens on tyrosine and is another regulatory pathway.

  20. Sam says:

    # daedalus2u: “All the large, long, double blind placebo controlled trials of supplemental antioxidants have shown no positive effects and sometimes slight negative effects. The state of oxidative stress is too important for organisms to depend on dietary quantities of antioxidants for its regulation.”

    Here’s a just released Glisodin study showing that some antioxidants may have therapeutic uses:

    http://www.nutraingredients-usa.com/Research/SOD-supplement-may-protect-against-sunburn-from-within

  21. Scott says:

    Small and short, so doesn’t really contradict daedalus’s statement. The link also doesn’t mention statistical significance, so no actual conclusions may be drawn from it as to whether there is any value to the supplementation. Hopefully the full paper does, but the link does not. And apparently the “full” paper was only 2 pages – which makes me even more skeptical.

    Not “just-released”, either – it’s more than 2 years old.

  22. Sam says:

    Just one more 2007 Glisodin study:

    “Cloarec and colleagues used ultrasound-B imaging to measure carotid artery intima media thickness (IMT), a sign of atherosclerosis, and found that IMT decreased significantly in the SOD group, compared to the control group.”

    This quote suggests that Glisodin use can actually reverse the process of artherosclerosis.

  23. daedalus2u says:

    The full paper was not even 1 page.

    http://www.john-libbey-eurotext.fr/e-docs/00/04/2F/3E/vers_alt/VersionPDF.pdf

    The paper says the results were not statistically significant. They only used 10 subjects with the lightest skin color, with 5 controls and 5 in the treatment group.

    The SOD product they are using is derived from melons and then linked to gliadin, a wheat storage protein with a lot of thiols.

    I agree with reily, but with a slight caveat. The only way to get non-physiologic levels of free radicals in the cytoplasm is via something like ionizing radiation (UV counts as ionizing radiation), free Fenton active metals (such as copper, iron, manganese), or peroxidases (damaged SOD can sometimes act like a peroxidase).

    http://www.ncbi.nlm.nih.gov/pubmed/16169521

    Exactly what is going on when the gliadin is attached to SOD isn’t well described. Usually eating SOD will be ineffective because it will be digested in the gut before it is absorbed. The idea behind binding it to gliadin is to retard that digestion so it is absorbed undegraded. I looked a little bit and didn’t find any data to indicate that is happening, only that SOD activity was increased after oral dosing (but not that the increased SOD came from the exogenous source). It could be that the SOD-gliadin increases oxidative stress because the SOD is denatured enough to form a peroxidase and is protected from degradation, and then endogenous SOD is upregulated to compensate for the hydroxyl being produced. Hydroxyl is a lot worse that superoxide (many orders of magnitude worse). There are no antioxidants that are effective against hydroxyl. Hydroxyl is simply too reactive with everything.

    Usually superoxide is confined to vesicles such as mitochondria and microsomes. That affects the redox and oxidative stress in the cytosol via destruction of NO (but that is quite complicated because the gradients in concentration are sub-cellular and not measurable with present techniques). I think it is the drop in NO that communicates the level of what is called oxidative stress to the rest of the cell and between cells.

  24. Sam says:

    “There are no antioxidants that are effective against hydroxyl. Hydroxyl is simply too reactive with everything.”

    According to some studies, melatonin, lipoic acid, resveratrol, and chlorophyllin can be effective against the hydroxyl radical.

  25. reily says:

    Daedalus2U is right, the hydroxyl radical in biological settings is too reactive to be efficiently scavenged, it reacts on the order of 10^9 which is diffusion limited. Most studies that say an antioxidant reacts with it either A) dont know how to interpret their data or B) are doing their testing in a tube with just that antioxidant and the hydroxyl radical, which then really doesnt have any biological relevance.

    It should be noted that just because a free radical modifies some residue on a protein does not mean anything. The function of that protein has to be modified for that free radical interaction to have any significance. For example: the canonical use of nitrotyrosine as a marker of oxidative stress is misleading because to date there is no good evidence that nitrated tyrosine changes anything. Therefore, there is no “stress” because no enzyme/protein function is changed. Thiol residues are another matter.

  26. Joe says:

    Sivi Volk on 25 Aug 2009 at 11:10 am “I’ve heard this several times now, that herbal medicines generally show additive and not synergistic effects when adding and subtracting components from compounds.”

    Herbalists often claim synergy where evidence is insufficient to distinguish that from mere additive activity. For example, they will isolate salicin from willow bark and compare its analgesic effect to bark containing the same amount of salicin and find the bark is more effective. From that data, one cannot distinguish the nature of the interaction.

    In chapter 10 of Michael Heinrich et al “Fundamentals of Pharmacognosy and Phytotherapy” the notion of synergy is covered. The authors seem to favor synergy. You can also search PubMed and see which articles are available to you.

  27. daedalus2u says:

    reily, there is some pretty suggestive evidence that nitration of tyrosine is in some cases (many?) a protective modification, i.e. a control mechanism.

    http://www.jbc.org/cgi/content/abstract/279/26/27257

    I think a potentially good example of this is in MnSOD, the superoxide dismutase in the inner matrix of mitochondria. In human MnSOD, the nitration of a single tyrosine (#34) causes inhibition. In the homologous bacterial FeSOD, nitration of 8 out of 9 tyrosines (including #34) has no effect on activity. The presence of homologous bacterial SOD that is resistant to nitration shows that inhibition following nitration is not a necessary aspect of SOD. That human MnSOD is inhibited despite that, implies that the inhibition following nitration is a “feature”, not a “bug”.

    My hypothesis is that the inhibition of MnSOD following nitration is one of the “fail-safe” circuit interrupters of mitochondria. Mitochondria have the capacity to produce superoxide limited only by the supply of reducing equivalents and O2. To prevent the run-away consumption of substrates, mitochondria producing too much superoxide must be turned off.

    As mitochondria are called on to produce more ATP, they lower the NO level in their vicinity by consuming it with superoxide. This forms peroxynitrite, which can be reduced by cytochrome c oxidase. If the superoxide level gets too high in the presence of too much NO, then too much peroxynitrite is produced, the MnSOD gets inhibited, the superoxide level goes way high, the peroxynitrite level goes way high and the respiration chain gets first S-nitrosylated and then nitrated. The first stages of that are reversible, the later stages are not. The irreversibly inhibited mitochondria are then recycled via autophagy.

    All mitochondria have a finite lifetime and are recycled. The longest last about a month (in rat CNS). When the turn-off rate gets higher than they can be replaced is when cells go down an energy crisis death spiral. I think that is what happens in sepsis. The high NO level causes high ATP levels via sGC regulation. That ATP is supplied by glycolysis and the mitochondria are “off” due to the high ATP. If the ATP level falls because there is insufficiently glycolysis to maintain it, then the mitochondria “turn on” and start producing superoxide to pull down the NO level to disinhibit cytochrome c oxidase to pull down the O2 level and generate an O2 gradient so O2 can diffuse to the mitochondria. In the high NO environment of sepsis, this can lead to mitochondria turn-off and multiple organ failure.

  28. shipthechicken says:

    The Quackbuster is a QUACK!! Maybe she can’t read (comprehend?). See the newest study release. http://finance.yahoo.com/news/American-Heart-Association-prnews-3691610912.html?x=0&amp;.v=1

    and the study abstract – http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.109.883843v1

  29. Harriet Hall says:

    I would have had a hard time reading/comprehending a study that was not published until 3 months after I wrote my article. But it wouldn’t have changed my mind.

    This was just another study in rats. It concluded
    “Although it would be premature to conclude that similar benefits would be seen in humans, these remarkable results open the door to the possibility of future research on pulmonary hypertension and Protandim in humans.”

    I’m still waiting for human studies showing clinical benefits.

  30. shipthechicken says:

    That’s a quote from the press release… doh! I would assume you’d know that officers of the company in a press release need to follow fda/ftc gudelines? read the study.

  31. Harriet Hall says:

    shipthechicken,

    I read the abstract of the study. I don’t have access to the full study, but I have no interest in reading it since even assuming the conclusions are valid it is only an animal study. We need human clinical studies. What part of that do you not understand?

  32. shipthechicken says:

    the part i don’t understand is your flippant attitude. there are two, peer reviewed human clinicals. if you took about 5 minutes, you could find them. the first HUMAN clinical shows a 43% average reduction in ox stress – in fact, if you dig (try not to work too hard), you’d find that age related ox stress was totally flatlined. the other peer reviewed study – independent – shows glutathione is increased by 300%. try not to put yourself out but you may want to check out glutathione.

    as a doc, how do you not have access to the full aha/vcu study? it’s pulished in circulation journal.

  33. Harriet Hall says:

    shipthechicken,

    There are no human CLINICAL trials. My post makes it clear that that is what I meant. The studies that you refer to only measure blood tests without showing whether the findings have any clinical significance. The glutathione study was in vitro -in cell culture. I mentioned both of these studies in my post and explained why I thought they did not justify clinical recommendations.

    Did you even read what I wrote?

  34. Harriet Hall says:

    shipthechicken,

    If a pharmaceutical company tried to market a new drug based only on one cell culture study, one mouse study, and one human study showing a change in an unvalidated blood test, do you think the FDA should approve it? Would you want to take it on the basis of that kind of evidence?

  35. stressless says:

    Harriett, you are closed minded to a fault. You do realize that the reason clinical researchers use rats, mice, monkey and pigs is becuase the findings in those mammals often transalates to humans. You do realize that last week’s INDEPENDENT study was published in a journal by the American Heart Association (Circulation)–not the American Rat Heart Association. Sham products do not find their way into prestigous journals such as this unless something significant is going on.

    Do you even know what osteopontin is? Do you know that it is one of the causes of muscle fibrosis–at the root of things like heart failure, muscular dystrophy, cystic fibrosis. Do you know what nrf2 is? Did you know Protandim activates nrf2? Did you know drug companies are racing to come up with synthetic nrf2 activators? Regarding glutathione, do you know that prestigous neurologists are prescribing Protandim to their Parkinson’s patients because of Protandim’s ability to upregulate glutathione? Are these doctors nuts? No, Harriet, they are called EARLY ADOPTERS, who look at the weight of the current evidence and say that it is crazy not to try this on their patients now.

    You are NOT an early adopter, Harriet, you are the type that will adopt when a product is mature–after everyone and their brother has already used their brain and logic to figure out what is already evident. Bummer that you will not be eliminating up to 1 million free radicals per second that you could eliminate with Protandim RIGHT NOW. Those extra free radicals could be the genesis of something nasty–like a tumor. You do know that is how tumor’s start, don’t you? Oxidative stress, free radicals? You do realize Protandim has the only peer reviewed science that shows a reduction in oxidative stess? You can lead a horse to water, but you cannot make them drink. C’est la vie.

    Protandim is still the only drug or supplement with a human clinical showing a reduction in oxidative stress. It is a scientific fact that oxidative steress is at the root cause of most cancers and heart disease and roughly 100 other diseases. The implications of having the only oxidative stress reducing product are obvious–you don’t need a degree in logic.

    Studies like VCU’s will spawn more independent studies. There is a human study underway now and there will be more. Normally researchers start with rats and mice and then move on to human studies.

    You can wait ten more years for 100 human studies if you want, but the evidence available now is more than enough for me to be taking it. I’d hate to be 80 years old and find out I should have been taking it for thirty years.

  36. shipthechicken says:

    you’re correct on the clinicals. my bad and i take responsibility. it would be nice though if you realized your mistake(s). this is not a drug (certainly could have gone down that road), it’s a nutraceutical or “supplement” as defined.

    so, you’re saying that peer reviewed studies (4 in this case) are bunk? that’s extremely bold. I’ve read the four studies (which have spawned over 25 additional studies – all independent) and take, and will continue to take the product. so… only post phase fda approved drugs work for you? that’s extremely shortsighted imo. especially given the fda’s record.

  37. Scott says:

    this is not a drug (certainly could have gone down that road), it’s a nutraceutical or “supplement” as defined.

    A distinction without a difference. The nature of the claims being made demands the same evidence as for a “drug.” Essentially, the ONLY meaningful difference is that quacks have successfully conned Congress into giving them carte blanche to make unsupported claims so long as they claim to be “nutritional supplements”.

    so, you’re saying that peer reviewed studies (4 in this case) are bunk? that’s extremely bold.

    More bold is such a blatant (deliberate?) misrepresentation. Harriet very clearly and explicitly argued that they are inadequate, not “bunk”.

  38. Harriet Hall says:

    A drug is a drug, whether it is classified as a pharmaceutical or a supplement. If you would not accept a pharmaceutical drug based on this kind of evidence, it is irrational to accept a supplement.

    I’m definitely not an early adopter. Do you have any idea how often claims like these are disproven by further studies? Do you have any idea how often treatments that help are later proven to harm more than they help? Over the years, I’ve seen too many promising things like this crash and burn.

    I’m quite willing to accept that Protandim improves health outcomes in humans. As soon as I see the same kind of evidence we require to show the efficacy of any treatment. There is only one science, not a double standard.

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