As many forum users know, I have been interested in the Randle Cycle (glucose/fat competition for oxidation) for quite some time. The topic of limiting fatty acid oxidation (FAO) and promoting glucose oxidation is pretty central to the metabolic theory of health. Peat has written many times on that topic and has mentioned numerous chemicals that can improve glucose oxidation, as well as reduce (excessive) FAO. Niacinamide, aspirin, and vitamin E are probably the ones most commonly mentioned in his wrings and interviews and we have had many discussions about them on the forum. However, all of these substances do not really inhibit FAO directly. That simply limit (excessive) lipolysis. There are chemicals out there that do inhibit FAO directly and perhaps the most well known one is Mildronate (Meldodium). Other ones include trimetazidine, etomoxir, ranolazine, etc. Unfortunately, with the exception of Mildronate all other clinically used FAO have severe side effects, which greatly limit their use.
So, I spend a lot of time over the last year looking for chemicals that work similarly to Mildronate but without toxic side effects. It turns out that there are not many other such chemicals, and the ones that I found could not really be developed into a topical product due to their skin irritating effects. However, as I was reading some of Peat's old articles and newsletter I stumbled upon two naturally present chemicals that seemed very promising as pro-metabolic substances. One of them was pyruvate and the other one was acetoacetate. Both are technically ketones. Pyruvate is the ketoacid of the amino acid alanine, and acetoacetate is the ketone version of the fatty acid butyrate. Both are used as biomarkers of the redox status in the form of tests for pyruvate/lactate ratio and acetoacetate/3β-hydroxybutyrate ratio. As I kept digging, it turned out that both chemicals are not only indicators of redox status but also modulators of it - i.e. administration of either one of these shifts the redox balance in favor of oxidation. As a result, the more familiar NAD/NADH and GSSG/GSH ratios also rise. The former needs no introduction, but the latter is extremely important in cancer. Cancer cells accumulate massive amounts of GSH and they use it to protect themselves from the ROS generated by chemotherapy. In fact, the high GSH levels is considered the primary factor in "chemotherapy resistance" and Big Pharma has spend a lot of money on trying to identify chemicals that can deplete GSH. Well, as one of the studies in the references section below shows, administering high dose acetoacetate for just one day dropped GSH levels to zero, while a more moderate dose (available in our product) also dropped GSH levels down to zero after 3-4 days of administration. As it turns out, pyruvate is also capable of such effects GSH-depleting effects. But perhaps the most intriguing effects discovered for both pyruvate and acetoacetate is their ability to inhibit FAO. Both substances show FAO inhibition of at least 50% in concentrations easily achievable with a single dose in the range provided by our product. While the exact mechanism of action for FAO inhibition of both chemicals is not really known, one older study found that pyruvate works similarly to the known FAO etomoxir. In addition, subsequent studies demonstrated that both pyruvate and acetoacetate stimulate the activity of the enzyme pyruvate dehydrogenase (PDH), which is the limiting step in the oxidation of glucose. Low activity of PDH has been demonstrated in virtually all chronic diseases, especially diabetes, cancer, dementias, liver disease, kidney disease, CVD, etc. We have numerous threads on this forum discussing studies on downregulated PDH in various diseases and ways to increase its activity. The (in)famous drug dichloroacetate (DCA) is not much different structurally from acetoacetate and its primary mechanism of action is inhibition of of PDK and thus re-activation of PDH. Big Pharma is well-aware of the benefits of activating PDH and has several drugs being tested on animals to see whether activating PDH can treat "non-metabolic" conditions like dementias, muscular dystrophies, and even ALS. They have not tried PDH activation for cancer yet (aside from unofficial studies with DCA) but all the evidence points to PDH being a huge factor in cancer treatment as well.
Now, the problem with pyruvate is that it is unstable in solution and also has to be administered in really high doses in order to exert its beneficial effects. The human studies typically use 15g-50g pyruvate daily. Acetoacetate is also unstable, but at least lower doses still have powerful oxidizing and pro-glucose oxidation effects. As it turns out, the research community was aware of the potential of pyruvate as far back as the 1970s and tried to find an alternative to plain pyruvate that would have all of the benefits but would be stable and would produce benefits at much more reasonable doses. And they found it! As it turns out, the ester known as ethyl pyruvate (EP) is highly stable at a wide range of temperatures and when mixed with other chemicals. It is also more lipohilic than plain pyruvate and this is the proposed explanation behind EP's ability to exert the same beneficial effects in doses up to two orders of magnitude (100-fold) lower than plain pyruvate. In addition, a number of studies comparing EP and plain pyruvate demonstrated robust benefit with EP but no benefit from pyruvate. Several studies (listed below) tried to discover the reason for the differential effects between EP and pyruvate, and as it turned out EP's effects are unique and not shared by either ethanol or pyruvate when administered together as separate chemicals. Similarly, ethyl acetoacetate (EC) was also found to be stable and have similarly beneficial effects to the non-esterified version. We already use EC as one of the solvents for several of our products. It is listed on the label as FEMA 2415, which is its food-additive designation, but I had no idea it had so many other beneficial effects. While the research with EC is sparse, the research with EP seems to have really taken off over the last 30 years as can be seen from the studies in the references section below. Some of the more notable benefits of EP include powerful and broad spectrum anti-inflammatory, preventing ATP decline and energetic dysfunction in a wide variety of acute and chronic conditions, anti-bacterial/anti-viral/anti-fungal, neuroprotective, hepatoprotective, nephroprotective, cardioprotective, anti-cancer, anti-septic and endotoxin blocker, immunoprotective, gonadoprotective, thymoprotective, etc. The list goes on and on and on and the amount of research on EP is just staggering. I am both surprised and not that we have not heard anything on mainstream media about this very promising endogenous metabolite. Given the plethora of studies on its benefits across such a wide variety of conditions, I can only assume its generic nature and unpatentability are to blame for it being completely unknown in the clinical world.
So, that's pretty much it. The stable lipophilic esters of two endogenous metabolites are apparently capable of a wide gamut of beneficial effects while having virtually no known side effects (at least in the doses used in the studies below). In fact, both EC and EP have been designated by the FDA as "generally recognized as safe" (GRAS) and are widely used as food-flavoring additives. However, the amounts needed for the beneficial effects seen in studies are much bigger than what can be obtained from food. The typical doses of both EC and EP used in rodent studies were 40mg/kg daily. The HED of that protocol is about 6.5mg/kg daily.
As far as the name - it is a combination of the words pyruvate and acetoacetate.
Disclaimer: The fact that this post and product description contain quotes from Ray Peat does not mean he endorses/approves of this product. His opinions on a chemical may change when new evidence becomes available in the future, so future inquiries about a chemical, solvent, ingredients, etc contained in this product may elicit a different response than his quotes included in this post. Please seek his opinion independently on any chemical, solvent, ingredient, etc that you may have concerns/questions about.
The units listed on the label are just for measurement purposes. They do not indicate or suggest optimal dose.
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Pyrucet is a combination of the ethyl esters of the endogenous metabolites/ketones pyruvate and acetoacetate. Numerous studies have demonstrated that those ethyl esters are more stable and more lipophilic than their unesterified versions. A large number of studies have examined the effects of ethyl pyruvate (EP) and ethyl acetoacetate (EC) on issues ranging from glucose metabolism, fatty acid oxidation, ATP synthesis, redox status, inflammation, autoimmunity, kidney, heart, liver, brain, thymus, spleen, joint, etc health and most of those studies call for urgent human trials considering the robust benefits displayed by these chemicals in animal models.
Serving size: 20 drops
Servings per container: about 30
Each serving contains the following ingredients:
Ethyl Acetoacetate: 500mg
Ethyl Pyruvate: 500mg
Other ingredients: add product to shopping cart to see info
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REFERENCES:
1. Miscellaneous