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Pyrucet - Liquid (ethyl) Pyruvate/Aceatoacetate Mix

  1. 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. The product can be ordered from the link below:
    http://www.idealabsdc.com/lab

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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
    Mutagenic investigation of flavourings: dimethyl succinate, ethyl pyruvate and aconitic acid are negative in the Salmonella/mammalian-microsome test. - PubMed - NCBI (EP)
    A 28-day feeding study with ethyl acetoacetate in rats. - PubMed - NCBI (EA)
    Ethyl pyruvate improves skin flap survival after ischaemia reperfusion injury. - PubMed - NCBI (EP)
    Roles of nitric oxide and ethyl pyruvate after peripheral nerve injury. - PubMed - NCBI (EP)
    “… Due to poor solubility and stability, therapeutic potential of pyruvate is limited. Ethyl pyruvate (EP) is now considered as a suitable replacement of pyruvate. In this paper, we will try to focus the effect of NO and EP in Schwann cell dedifferentiation, proliferation, nerve degeneration, and regeneration during Wallerian degeneration (WD) of peripheral nerve injury along with their neuroprotective effects, cardiovascular functioning, support in hepatic complication, etc.”
    Inhibitory effects of ethyl pyruvate on platelet aggregation and phosphatidylserine exposure. - PubMed - NCBI (EP)
    “…Ethyl pyruvate (EP) is a stable lipophilic pyruvate derivative. Studies demonstrated that EP shows potent anti-oxidation, anti-inflammatory and anti-coagulant effects. Inflammation and coagulation are closely interacted with platelet activation.”
    Acetoacetic acid - Wikipedia
    "...Acetoacetic acid (also diacetic acid) is the organic compound with the formula CH3COCH2COOH. It is the simplest beta-keto acid group, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stable, are produced on a large scale industrially as precursors to dyes."
    Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries. - PubMed - NCBI (EP)
    ethyl_pyruvate_inflammation_targets.png

    Ethyl pyruvate for the treatment of acetaminophen intoxication: alternative to N-acetylcysteine? - PubMed - NCBI (EP)
    “…Pyruvate, however, is unstable in aqueous solutions due to a rapid aldol-like condensation reaction forming parapyruvate, a potent inhibitor of the Krebs cycle blocking the α-ketoglutaric dehydrogenase [7]. This problem can be circumvented by using the ethanol ester of pyruvate (that is, EP) - the effects of which qualitatively resemble that of pyruvate, but which only require molar doses that are lower by one to two orders of magnitude [7]. In addition to the properties of pyruvate, EP also exerts anti-apoptotic effects, increases heme oxygenase-1 expression, attenuates peroxynitrite-related DNA damage, and stabilizes the hypoxia-inducible factor 1α via stimulation of the Krebs cycle.”
    “…Ethyl pyruvate (EP) is a simple derivative of pyruvic acid, which is an important endogenous metabolite that can scavenge reactive oxygen species (ROS). Treatment with EP is able to ameliorate systemic inflammation and multiple organ dysfunctions in multiple animal models, such as acute pancreatitis, alcoholic liver injury, acute respiratory distress syndrome (ARDS), acute viral myocarditis, acute kidney injury and sepsis. Recent studies have demonstrated that prolonged treatment with EP can ameliorate experimental ulcerative colitis and slow multiple tumor growth. It has become evident that EP has pharmacological anti-inflammatory effect to inhibit multiple early inflammatory cytokines and the late inflammatory cytokine HMGB1 release, and the anti-tumor activity is likely associated with its anti-inflammatory effect. EP has been tested in human volunteers and in a clinical trial of patients undergoing cardiac surgery in USA and shown to be safe at clinical relevant doses…”
    Higher hypochlorous acid scavenging activity of ethyl pyruvate compared to its sodium salt. - PubMed - NCBI (EP)
    “…The potential effect of ethanol was also evaluated, and hypochlorous acid was used as an oxidant. Our data indicate the concentration-dependent scavenging potency of both sodium and ethyl pyruvate, with the ester having higher activity. This effect was not related to the presence of ethanol. Better protection of the liver homogenate by ethyl pyruvate was also apparent, despite the fact that cell membrane transport was omitted.”
    Ethyl pyruvate. - PubMed - NCBI
    “…This ester was originally regarded as a way to administer pyruvate, while avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including ethyl pyruvate, have pharmacological effects, such as suppression of inflammation, which are distinct from those exerted by pyruvate anion. Ethyl pyruvate has been tested in human volunteers and shown to be safe at clinically relevant doses. Ethyl pyruvate is a simple molecule that has been shown to have salutary effects in numerous large and small animal models of critical illness. It remains to be determined whether this ester can be used successfully to treat human diseases.”


    2. Metabolism
    Inhibition of free fatty acid oxidation by acetoacetate in normal dogs. - PubMed - NCBI (EA)
    “…The rate of turnover and oxidation of plasma free fatty acids (FFA) waa measured in 7 normal anaesthetized dogs infused at a constant rate with 1-W-palmitate for 5 h. After a control period, sustained hyperketonaemia was induced by infusing sodium aceto-acetate (AA). This produced a fall in plasma FFA (33%) and in blood sugar (24%), without changes in immuno-reactive insulin (IRI) concentrations. During the control period, the turnover rate of carbon of FFA averaged 131 uat.C/kg/min, 32% of which were oxidized, thus supplying 17.7% of the total CO, production. At the end of the AA infusion, the mean turnover rate of FFA was reduced to 75 uat. C/kg/min; since only 13.9% of these were oxidized, the contribution of FFA to total CO, production was reduced to 4.3% .”
    Effect of pyruvate and acetoacetate on the metabolism of fatty acids by the perfused rat heart. - PubMed - NCBI (EA + P)
    “…About 75% of the fatty acids removed were oxidized to carbon dioxide accounting, at this concentration of fatty acids in the perfusate, for 37% of oxygen consumption of the heartIn the presence of 10mM pyruvate or acetoacetate, the uptake of fatty acids from the medium was reduced approximately 50% and the oxidation of the extracted acids was reduced further so that only 25% of the fatty acids oxidized by the control group appeared as carbon dioxide in the presence of competing substrate…The competing substrates, thus, contributed 75%-85% to the fuel of the respiration and reduced the contribution of the fatty acids to 8%-9% of the total respiration of the heart…It may be of considerable interest to examine the competition between pyruvate and free fatty acid over a range of concentrations bracketing physiological concentrations of both substances…Both acetoacetate and pyruvate can enter the tricarboxylic acid cycle without resort to a kinase, and this may be one reason why they compete successfully with fatty acids which require the action of adenosine triphosphate and a thiokinase.”
    EFFECT OF CARNITINE ON THE OXIDATION OF ALPHA-OXOGLUTARATE TO SUCCINATE IN THE PRESENCE OF ACETOACETATE OR PYRUVATE. - PubMed - NCBI (EA)
    Inhibition of palmitoylcarnitine oxidation by pyruvate in rat heart mitochondria. - PubMed - NCBI (P)
    “…The oxidation of 1 -‘4C-palmitoylcarnitine by rat heart mitochondria has bean measured by assessing both the disappearance of substrata and the appearance of labelled products. Pyruvate inhibited palmitoylcarnitine oxidation by about 40%. Fifty percent inhibition occurred at about 20 umol/L pyruvate. The inhibitory effect of pyruvate required entry of pyruvate into mitochondria since it did not occur in the presence of a-cyano4hydroxycinnamic acid, an inhibitor of the mitochondrial pyruvate transporter. “
    “…Earlier work by Olson and by Evans et al had demonstrated significant inhibition (40% to 50%) of palmitate oxidation in the retrogradely perfused heart by lactate and by pyruvate. In addition, experiments by Harris et al5 and by Hirche and Langor have shown that lactate could compete effectively with fatty acids for oxidation by the heart in vivo. These observations have led us to investigate the possible inhibition of fatty acid oxidation by pyruvate in isolated rat heart mitochondria. We have demonstrated a significant inhibition of fatty acid oxidation by pyruvate.”
    Fatty acid accumulation during ischemia and reperfusion: effects of pyruvate and POCA, a carnitine palmitoyltransferase I inhibitor. - PubMed - NCBI (P)
    “…During reperfusion, however, the tissue FA level dramatically increases, indicating that the inhibitory effects of pyruvate and POCA on FA utilization are additive. Pyruvate is known to activate pyruvate dehydrogenase and, hence, to stimulate its own conversion to acetyl-CoA (Kobayashi and Neely, 1983). As a consequence, the availability of mitochondrial free CoA will be diminished and beta-oxidation becomes inhibited (Brosnan and Reid, 1985). In this manner pyruvate probably inhibits the removal of FAs released from endogenous lipid pools during reperfusion.”
    “…In summary, the present findings show that POCA and pyruvate markedly increase the FA content of reperfused hearts, most likely through inhibition of the oxidation of FAs released from endogenous lipid pools.”
    Studies on inactivation of pyruvate dehydrogenase by palmitoylcarnitine oxidation in isolated rat heart mitochondria. - PubMed - NCBI (P)
    Single pyruvate intake induces blood alkalization and modification of resting metabolism in humans. - PubMed - NCBI (P)
    “…CONCLUSION: Pyruvate intake induced mild alkalization in a sex-dependent fashion. Moreover, it accelerated carbohydrate metabolism and delayed the rate of glycerol appearance in the blood, but had no effect on the resting energy expenditure. Furthermore, sodium salt seems to have had a greater effect on the blood buffering level than calcium salt.”
    Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes. - PubMed - NCBI (P)
    Pyruvate reverses fatty-acid-induced depression of ventricular function and calcium overload after hypothermia in guinea pig hearts. - PubMed - NCBI (P)
    The action of pyruvate on ethanol oxidation by intact isolated liver cells. - PubMed - NCBI (P)
    Stimulation by acetoacetate of DPNH oxidation by liver mitochondria. - PubMed - NCBI (EA)
    Effect of acetoacetate on the oxidation of reduced diphosphopyridine nucleotide by intact rat liver mitochondria. - PubMed - NCBI (EA)
    “…The oxidation of DPNH (NADH) by intact rat liver mitochondria, isolated in 0.25 M sucrose or 2.5% polyvinylpyrrolidone-0.25 M sucrose, was found to be stimulated 4 to 6 times by catalytic quantities (0.3 to 1.0 uM) of acetoacetate or D-b-hydroxybutyrate. Coupled phosphorylation was also stimulated, with P:O ratios in the range of 1.5 to 2.2. The increased respiration was completely inhibited by Amytal and antimycin A, and phosphate uptake abolished by 2,4-dinitrophenol. Catalytic quantities of succinate, a-ketoglutarate, malate, citrate, glutamate, and pyruvate stimulated the endogenous respiration, but had no effect on DPNH oxidation.”
    Acetoacetate induced dehydroascorbic acid accumulation in blood and tissues and its prevention by glucose-cyclo-acetoacetate. - PubMed - NCBI (EA)
    “…The effect of acetoacetate injections in doses of 500 mg/kg on ascorbic and dehydroascorbic acid contents of blood and tissues, and their excretion in urine, was studied. 2. Animals injected with aceto-acetate excrete more dehydroascorbic acid and less ascorbic acid. Their tissues (liver, kidney, spleen and adrenal) also accumulate more dehydroascorbic acid, and the amount of ascorbic acid in them is diminished. 3. Glucose-cyclo-acetoacetate or its hydrolysed product has been found to prevent this increased accumulation of dehydroascorbic acid in blood and tissues. 4. Acetoacetate has been shown to cause oxidation of ascorbic acid to dehydroascorbic acid in vitro in presence of a few drops of CuSO4 solution at a faster rate than that in the control. 5. The mechanism for prevention of acetoacetate induced accumulation of dehydroascorbic acid by hydrolysed glucose-cyclo-acetoacetate has been suggested.”
    Progressive depletion in the reduced glutathione content of the blood following acetoacetate injections. - PubMed - NCBI
    “…The experimental data presented indicate that acetoacetate causes a fall in the blood GSH content, although it is not as sharp and rapid as is reported in the case of alloxan (Leech & Bailey, 1945). It is only natural that this should be so since acetoacetate is an intermediary fat metabolite which normally occurs in very minute proportions in the system. Repeated daily injection brings the blood GSH value to zero in 3-5 days, less time being required with higher dose.”
    Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-s... - PubMed - NCBI (EP)
    “…Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cell-permeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.”
    Effect of acetoacetate upon utilization of carbohydrate. - PubMed - NCBI (EA)
    Hypochlorous acid inhibition by acetoacetate: implications on neutrophil functions. - PubMed - NCBI (EA)
    Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis. - PubMed - NCBI (EA)
    Acetoacetate and malate effects on succinate and energy production by O2-deprived liver mitochondria supplied with 2-oxoglutarate. - PubMed - NCBI (EA)
    [The effect of acetoacetate on 3-hydroxybutyrate oxidation by rat liver mitochondria]. - PubMed - NCBI (EA)
    The effect of acetoacetate on plasma insulin concentration. - PubMed - NCBI (EA)
    Effect of ethyl pyruvate on skeletal muscle metabolism in rats fed on a high fat diet. - PubMed - NCBI (EP)
    Ethyl pyruvate preserves IGF-I sensitivity toward mTOR substrates and protein synthesis in C2C12 myotubes. - PubMed - NCBI (EP)
    Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle. - PubMed - NCBI (EP)
    The effect of ethyl pyruvate on dapsone-induced methemoglobinemia in rats. - PubMed - NCBI (EP)


    3. Inflammation/Endotoxin/Sepsis/Trauma
    Ethyl pyruvate: a novel treatment for sepsis. - PubMed - NCBI (EP)
    Ethyl pyruvate: a novel anti-inflammatory agent. - PubMed - NCBI (EP)
    Ethyl pyruvate: a novel treatment for sepsis and shock. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates inflammatory arthritis in mice. - PubMed - NCBI (EP)
    Anti-encephalitogenic effects of ethyl pyruvate are reflected in the central nervous system and the gut. - PubMed - NCBI (EP)
    Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits the acetylation and release of HMGB1 via effects on SIRT1/STAT signaling in LPS-activated RAW264.7 cells and peritoneal mac... - PubMed - NCBI (EP)
    Effects of insulin combined with ethyl pyruvate on inflammatory response and oxidative stress in multiple-organ dysfunction syndrome rats with seve... - PubMed - NCBI (EP)
    Effects of N-acetylcysteine and ethyl pyruvate on ischemia-reperfusion injury in experimental electrical burn model. - PubMed - NCBI (EP)
    Ethyl pyruvate protects against sepsis by regulating energy metabolism. - PubMed - NCBI (EP)
    “…RESULTS: Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate (ATP), total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP. CONCLUSION:
    The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis.”
    Ethyl pyruvate reduces hepatic mitochondrial swelling and dysfunction in a rat model of sepsis. - PubMed - NCBI (EP)
    Effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation during early sepsis treatment. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates murine allergic rhinitis partly by decreasing high mobility group box 1 release. - PubMed - NCBI (EP)
    A comparative analysis of multiple sclerosis-relevant anti-inflammatory properties of ethyl pyruvate and dimethyl fumarate. - PubMed - NCBI (EP)
    “…Production of two other proinflammatory cytokines, IL-6 and TNF, and NO was suppressed by EP in macrophages and microglia. Reactive oxygen species production in macrophages, microglia activation, and the development of Ag-presenting phenotype in microglia and macrophages were constrained by EP. The release of IL-6 was reduced in astrocytes. Finally, EP inhibited the activation of transcription factor NF-κB in microglia and astrocytes. Most of these effects were also found for DMF, implying that EP and DMF share common targets and mechanisms of action. Importantly, EP had in vivo impact on experimental autoimmune encephalomyelitis, an animal model of MS. Treatment with EP resulted in delay and shortening of the first relapse, and lower clinical scores, whereas the second attack was annihilated. Further studies on the possibility to use EP as an MS therapeutic are warranted.”
    “…Our results speak in favor of this possibility. Maybe the most favorable facts are that EP reduced IFN-γ and IL-17 generation in human PBMCs, alleviated EAE in rats, and even more it practically prevented the second relapse.”
    Endoplasmic reticulum stress mediates the anti-inflammatory effect of ethyl pyruvate in endothelial cells. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits HMGB1 phosphorylation and release by chelating calcium. - PubMed - NCBI (EP)
    Ethyl pyruvate decreases airway neutrophil infiltration partly through a high mobility group box 1-dependent mechanism in a chemical-induced murine... - PubMed - NCBI (EP)
    Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates endotoxin-induced corneal inflammation. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation. - PubMed - NCBI (EP)
    Ethyl pyruvate induces heme oxygenase-1 through p38 mitogen-activated protein kinase activation by depletion of glutathione in RAW 264.7 cells and ... - PubMed - NCBI (EP)
    [Ethyl pyruvate inhibited HMGB1 expression induced by LPS in macrophages]. - PubMed - NCBI (EP)
    Preventive effects of ethyl pyruvate on endotoxin-induced uveitis in rats. - PubMed - NCBI (EP)
    Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses. - PubMed - NCBI (EP)
    Ethyl pyruvate decreases proinflammatory gene expression in lipopolysaccharide-stimulated equine monocytes. - PubMed - NCBI (EP)
    In vivo anticoagulant effect of ethyl pyruvate in endotoxemic rats. - PubMed - NCBI (EP)
    Ethyl pyruvate therapy attenuates experimental severe arthritis caused by type II collagen (CII) in the mouse (CIA). - PubMed - NCBI (EP)
    Interaction of ethyl pyruvate in vitro with NF-κB subunits, RelA and p50. - PubMed - NCBI (EP)
    Ethyl pyruvate diminishes the endotoxin-induced inflammatory response of bovine mammary endothelial cells. - PubMed - NCBI (EP)
    Ethyl pyruvate downregulates tumor necrosis factor alpha and interleukin (IL)-6 and upregulates IL-10 in lipopolysaccharide-stimulated canine perip... - PubMed - NCBI (EP)
    Inhibition by ethyl pyruvate of the nuclear translocation of nuclear factor-kappaB in cultured lung epithelial cells. - PubMed - NCBI (EP)
    Ethyl pyruvate prevents inflammatory responses and organ damage during resuscitation in porcine hemorrhage. - PubMed - NCBI (EP)
    [Effects of ethyl pyruvate on injuries of sepsis in mice]. - PubMed - NCBI (EP)
    Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate. - PubMed - NCBI (EP)
    Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis. - PubMed - NCBI (EP)
    Effect of ethyl pyruvate on physical and immunological barriers of the small intestine in a rat model of sepsis. - PubMed - NCBI (EP)
    Ethyl pyruvate improves survival in awake hemorrhage. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces the development of zymosan-induced generalized inflammation in mice. - PubMed - NCBI (EP)
    Ethyl pyruvate and ethyl lactate down-regulate the production of pro-inflammatory cytokines and modulate expression of immune receptors. - PubMed - NCBI (EP)
    Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF-kappaB pathway. - PubMed - NCBI (EP)
    Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats. - PubMed - NCBI (EP)
    [Protective effect of ethyl pyruvate on barrier function of intestinal mucosa in dogs with septic shock]. - PubMed - NCBI (EP)
    [Effect of ethyl pyruvate on indices of tissue oxygenation and perfusion in dogs with septic shock]. - PubMed - NCBI (EP)
    Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on msP rat leukocytes damaged by alcohol intake. - PubMed - NCBI (EP)
    Beneficial effects of ethyl pyruvate in septic shock from peritonitis. - PubMed - NCBI (EP)
    Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells. - PubMed - NCBI (EP)
    [Effect of treatment with ethyl pyruvate on multiple organ dysfunction and mortality following delayed resuscitation after burn injury in rat]. - PubMed - NCBI (EP)
    Ethyl pyruvate improves systemic and hepatosplanchnic hemodynamics and prevents lipid peroxidation in a porcine model of resuscitated hyperdynamic ... - PubMed - NCBI (EP)
    [Effects of ethyl pyruvate on splenocyte proliferation and apoptosis in burn rats with delayed resuscitation]. - PubMed - NCBI (EP)
    [Effects of ethyl pyruvate on cell-mediated immune function in rats with delayed resuscitation after burn injury]. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits nuclear factor-kappaB-dependent signaling by directly targeting p65. - PubMed - NCBI (EP)
    Ringer's ethyl pyruvate solution: a novel resuscitation fluid for the treatment of hemorrhagic shock and sepsis. - PubMed - NCBI (EP)
    Ethyl pyruvate: a novel anti-inflammatory agent. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers. - PubMed - NCBI (EP)
    Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat mod... - PubMed - NCBI (EP)
    Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. - PubMed - NCBI (EP)
    Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability i... - PubMed - NCBI (EP)
    Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. - PubMed - NCBI (EP)
    Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential be... - PubMed - NCBI (EP)
    Ringer's ethyl pyruvate solution: a novel resuscitation fluid. - PubMed - NCBI (EP)


    4. CVD
    Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism. - PubMed - NCBI (EA)
    Ethyl pyruvate: A promising feasible therapeutic approach for myocardial ischemia-reperfusion injury under both normoglycemia and hyperglycemia. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates myocardial ischemia-reperfusion injury exacerbated by hyperglycemia via retained inhibitory effect on HMGB1. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits oxidation of LDL in vitro and attenuates oxLDL toxicity in EA.hy926 cells. - PubMed - NCBI (EP)
    Ethyl pyruvate protects PC12 cells from oxygen-glucose deprivation: A potential role in ischemic cerebrovascular disease. - PubMed - NCBI (EP)
    Anti-apoptotic and myocardial protective effects of ethyl pyruvate after regional ischaemia/reperfusion myocardial damage in an in vivo rat model. - PubMed - NCBI (EP)
    Impact of ethyl pyruvate on Adriamycin-induced cardiomyopathy in rats. - PubMed - NCBI (EP)
    Effects of Ethyl Pyruvate in Preventing the Development of Diet-induced Atherosclerosis by Blocking the HMGB1 Expression in ApoE-Deficient Mice. - PubMed - NCBI (EP)
    Role of high-mobility group box-1 in myocardial ischemia/reperfusion injury and the effect of ethyl pyruvate. - PubMed - NCBI (EP)
    Effects of ethyl pyruvate on cardiac function recovery and apoptosis reduction after global cold ischemia and reperfusion. - PubMed - NCBI (EP)
    Ethyl pyruvate prevents methyglyoxal-induced retinal vascular injury in rats. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. - PubMed - NCBI (EP)
    Ethyl pyruvate has anti-inflammatory and delayed myocardial protective effects after regional ischemia/reperfusion injury. - PubMed - NCBI (EP)
    Ethyl pyruvate enhances intra-resuscitation hemodynamics in prolonged ventricular fibrillation arrest. - PubMed - NCBI (EP)
    Effects of ethyl pyruvate on myocardial apoptosis and expression of Bcl-2 and Bax proteins after ischemia-reperfusion in rats. - PubMed - NCBI (EP)
    Ethyl pyruvate enhances ATP levels, reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass. - PubMed - NCBI (EP)
    Ethyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. - PubMed - NCBI (EP)


    5. GI/Liver/Kidney/Pancreas/Lungs
    Prevention of maleate-induced tubular dysfunction by acetoacetate. - PubMed - NCBI (EA)
    Ethyl pyruvate and analogs as potential treatments for acute pancreatitis: A review of in vitro and in vivo studies. - PubMed - NCBI (EP)
    Prophylactic effect of ethyl pyruvate on renal ischemia/reperfusion injury mediated through oxidative stress. - PubMed - NCBI (EP)
    Ethyl Pyruvate Attenuates CaCl2-Induced Tubular Epithelial Cell Injury by Inhibiting Autophagy and Inflammatory Responses. - PubMed - NCBI (EP)
    Ethyl pyruvate can alleviate alcoholic liver disease through inhibiting Nrf2 signaling pathway. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine. - PubMed - NCBI (EP)
    Ethyl Pyruvate Improves Pulmonary Function in Mice with Bleomycin-induced Lung Injury as Monitored with Hyperpolarized 129Xe MR Imaging. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation a... - PubMed - NCBI (EP)
    Ethyl pyruvate is renoprotective against ischemia-reperfusion injury under hyperglycemia. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces acute lung damage following trauma and hemorrhagic shock via inhibition of NF-κB and HMGB1. - PubMed - NCBI (EP)
    Hepatoprotective effects of ethyl pyruvate against CCl4-induced hepatic fibrosis via inhibition of TLR4/NF-κB signaling and up-regulation of MMPs/T... - PubMed - NCBI (EP)
    Ethyl pyruvate alleviates radiation-induced lung injury in mice. - PubMed - NCBI (EP)
    The potential beneficial effects of ethyl pyruvate on diabetic nephropathy: an experimental and ultrastructural study. - PubMed - NCBI (EP)
    Protective effects of ethyl pyruvate on lipopolysaccharide‑induced acute lung injury through inhibition of autophagy in neutrophils. - PubMed - NCBI (EP)
    Treatment response of ethyl pyruvate in a mouse model of chronic obstructive pulmonary disease studied by hyperpolarized 129 Xe MRI. - PubMed - NCBI (EP)
    Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat ... - PubMed - NCBI (EP)
    Preventive Effect of Ethyl Pyruvate on Postoperative Adhesion Formation Following Abdominal Surgery. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates experimental colitis in mice by inhibiting the HMGB1-Th17 and Th1/Tc1 responses. - PubMed - NCBI (EP)
    Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity. - PubMed - NCBI (EP)
    Pre- or post-treatment with ethanol and ethyl pyruvate results in distinct anti-inflammatory responses of human lung epithelial cells triggered by ... - PubMed - NCBI (EP)
    Decreased inflammatory responses of human lung epithelial cells after ethanol exposure are mimicked by ethyl pyruvate. - PubMed - NCBI (EP)
    Preventing intraperitoneal adhesions with ethyl pyruvate and hyaluronic acid/carboxymethylcellulose: a comparative study in an experimental model. - PubMed - NCBI (EP)
    Role of ethyl pyruvate in systemic inflammatory response and lung injury in an experimental model of ruptured abdominal aortic aneurysm. - PubMed - NCBI (EP)
    Ethyl pyruvate pretreatment attenuates concanavalin a-induced autoimmune hepatitis in mice. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates monocrotaline-induced pulmonary arterial hypertension in rats. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1-RAGE and AKT pathways. - PubMed - NCBI (EP)
    Ethyl-pyruvate reduces lung injury matrix metalloproteinases and cytokines and improves survival in experimental model of severe acute pancreatitis. - PubMed - NCBI (EP)
    The effect of ethyl pyruvate supplementation on rat fatty liver induced by a high-fat diet. - PubMed - NCBI (EP)
    Ethyl pyruvate significantly inhibits tumour necrosis factor-α, interleukin-1β and high mobility group box 1 releasing and attenuates sodium tauroc... - PubMed - NCBI (EP)
    Ethyl pyruvate prevents inflammatory factors release and decreases intestinal permeability in rats with D-galactosamine-induced acute liver failure. - PubMed - NCBI (EP)
    Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on liver injury in streptozotocin-induced diabetic rats. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on pancreas injury in rats with severe acute pancreatitis. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces ventilation-induced neutrophil infiltration and oxidative stress. - PubMed - NCBI (EP)
    Therapeutic treatment with ethyl pyruvate attenuates the severity of liver injury in rats with severe acute pancreatitis. - PubMed - NCBI (EP)
    Ethyl pyruvate improves healing of colonic anastomosis in a rat model of peritonitis. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates albuminuria and glomerular injury in the animal model of diabetic nephropathy. - PubMed - NCBI (EP)
    Ethyl pyruvate protects rats from phosgene-induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces acute lung injury via regulation of iNOS and HO-1 expression in endotoxemic rats. - PubMed - NCBI (EP)
    [Effect of ethyl pyruvate on expression of inflammatory factors and mitogen-activated protein kinase proteins in renal ischemic/reperfusion injury ... - PubMed - NCBI (EP)
    Effects of ethyl pyruvate and other α-keto carboxylic acid derivatives in a rat model of multivisceral ischemia and reperfusion. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model. - PubMed - NCBI (EP)
    Ethyl pyruvate prevents intestinal inflammatory response and oxidative stress in a rat model of extrahepatic cholestasis. - PubMed - NCBI (EP)
    Ethyl pyruvate modulates adhesive and secretory reactions in human lung epithelial cells. - PubMed - NCBI (EP)
    Ethyl pyruvate protects colonic anastomosis from ischemia-reperfusion injury. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates liver injury secondary to severe acute pancreatitis. - PubMed - NCBI (EP)
    The role of high-mobility group box-1 in renal ischemia and reperfusion injury and the effect of ethyl pyruvate. - PubMed - NCBI (EP)
    Delayed ethyl pyruvate therapy attenuates experimental severe acute pancreatitis via reduced serum high mobility group box 1 levels in rats. - PubMed - NCBI (EP)
    [Effect of ethyl pyruvate on renal high mobility group box-1 protein expression and acute kidney injury in rats with delayed resuscitation after th... - PubMed - NCBI (EP)
    The protective effect of ethyl pyruvate on lung injury after burn in rats. - PubMed - NCBI (EP)
    Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis. - PubMed - NCBI (EP)
    Intrapulmonary delivery of ethyl pyruvate attenuates lipopolysaccharide- and lipoteichoic acid-induced lung inflammation in vivo. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression. - PubMed - NCBI (EP)
    The effect of ethyl pyruvate on oxidative stress in intestine and bacterial translocation after thermal injury. - PubMed - NCBI (EP)
    [Effect of ethyl pyruvate on peroxidation injury of intestinal mucosa in rats with severe abdominal infection]. - PubMed - NCBI (EP)
    Bench-to-bedside review: Amelioration of acute renal impairment using ethyl pyruvate. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates ileus induced by bowel manipulation in mice. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces liver injury in a murine model of extrahepatic cholestasis. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice. - PubMed - NCBI (EP)
    Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. - PubMed - NCBI (EP)
    Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. - PubMed - NCBI (EP)
    Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion. - PubMed - NCBI (EP)
    Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. - PubMed - NCBI (EP)


    6. Brain/CNS/Mood/Muscle/Vision
    Neuronal inhibition and seizure suppression by acetoacetate and its analog, 2-phenylbutyrate. - PubMed - NCBI (EA)
    Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice. - PubMed - NCBI (EA)
    Acetoacetate protects neuronal cells from oxidative glutamate toxicity. - PubMed - NCBI (EA)
    Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition. - PubMed - NCBI (EA)
    Acetoacetate is a cholesterogenic precursor for myelinating rat brain and spinal cord. Incorporation of label from [3-14C]acetoacetate, [14C]glucos... - PubMed - NCBI (EA)
    Ethyl pyruvate prevents from chronic cerebral hypoperfusion via preserving cognitive function and decreasing oxidative stress, caspase 3 activation... - PubMed - NCBI (EP)
    Ethyl pyruvate does not require microglia for mediating neuroprotection after excitotoxic injury. - PubMed - NCBI (EP)
    Ethyl Pyruvate Attenuates Early Brain Injury Following Subarachnoid Hemorrhage in the Endovascular Perforation Rabbit Model Possibly Via Anti-infla... - PubMed - NCBI (EP)
    Ethyl pyruvate modulates delayed paralysis following thoracic aortic ischemia reperfusion in mice. - PubMed - NCBI (EP)
    The effect of ethyl pyruvate and N-acetylcysteine on ischemia-reperfusion injury in an experimental model of ischemic stroke. - PubMed - NCBI (EP)
    Ethyl pyruvate alleviates early brain injury following subarachnoid hemorrhage in rats. - PubMed - NCBI (EP)
    Neuroprotective effect of ethyl pyruvate against Zn(2+) toxicity via NAD replenishment and direct Zn(2+) chelation. - PubMed - NCBI (EP)
    “…However, when cortical neurons were exposed to acute treatment of Zn(2+) (400 μM, 15 min), EP, but not pyruvate, significantly suppressed neuronal death, despite the fact that NAD replenishment by EP was weaker than that by pyruvate. Spectrophotometric studies revealed that EP directly chelates Zn(2+), and this was confirmed in physiological contexts, such as, NMDA-treated primary cortical cultures and OGD-subjected hippocampal slice cultures, in which EP suppressed intracellular Zn(2+) elevation and neuronal cell death. In addition, EP markedly reduced the expressions of PARP-1 and of the NADPH oxidase subunit in Zn(2+)-treated primary cortical neurons, well known Zn(2+)-induced downstream processes. Together, these results show EP suppresses Zn(2+) induced neurotoxicity via dual functions, chelating Zn(2+) and promoting NAD replenishment.”
    Short term exposure to ethyl pyruvate has long term anti-inflammatory effects on microglial cells. - PubMed - NCBI (EP)
    Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic... - PubMed - NCBI (EP)
    Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits HMGB1 phosphorylation and secretion in activated microglia and in the postischemic brain. - PubMed - NCBI (EP)
    Neuroprotective effects of α-ketoglutarate and ethyl pyruvate against motor dysfunction and oxidative changes caused by repeated 1-methyl-4-phenyl-... - PubMed - NCBI (EP)
    Ethyl pyruvate treatment mitigates oxidative stress damage in cultured trabecular meshwork cells. - PubMed - NCBI (EP)
    Ethyl pyruvate ameliorates intracerebral hemorrhage-induced brain injury through anti-cell death and anti-inflammatory mechanisms. - PubMed - NCBI (EP)
    Effect of ethyl pyruvate on Paclitaxel-induced neuropathic pain in rats. - PubMed - NCBI (EP)
    Improvement of hypoxia-ischemia-induced white matter injury in immature rat brain by ethyl pyruvate. - PubMed - NCBI (EP)
    Ethyl pyruvate protects against lipopolysaccharide-induced white matter injury in the developing rat brain. - PubMed - NCBI (EP)
    Effects of Ethyl Pyruvate on Allodynia, TNF-α Expression, and Apoptosis in the Dorsal Root Ganglion after Spinal Nerve Ligation Injury. - PubMed - NCBI (EP)
    Ethyl pyruvate promotes spinal cord repair by ameliorating the glial microenvironment. - PubMed - NCBI (EP)
    Beneficial effects of ethyl pyruvate through inhibiting high-mobility group box 1 expression and TLR4/NF-κB pathway after traumatic brain injury in... - PubMed - NCBI (EP)
    Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson's disease. - PubMed - NCBI (EP)
    Inhibitory mechanism of MMP-9 gene expression by ethyl pyruvate in lipopolysaccharide-stimulated BV2 microglial cells. - PubMed - NCBI (EP)
    Postischemic treatment with ethyl pyruvate prevents adenosine triphosphate depletion, ameliorates inflammation, and decreases thrombosis in a murin... - PubMed - NCBI (EP)
    Beneficial effects of sodium or ethyl pyruvate after traumatic brain injury in the rat. - PubMed - NCBI (EP)
    Ethyl pyruvate has a neuroprotective effect through activation of extracellular signal-regulated kinase in Parkinson's disease model. - PubMed - NCBI (EP)
    Responses of cultured human keratocytes and myofibroblasts to ethyl pyruvate: a microarray analysis of gene expression. - PubMed - NCBI (EP)
    Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms. - PubMed - NCBI (EP)
    Ethyl pyruvate inhibits peroxynitrite-induced DNA damage and hydroxyl radical generation: implications for neuroprotection. - PubMed - NCBI (EP)
    Combination treatment with ethyl pyruvate and aspirin enhances neuroprotection in the postischemic brain. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates spinal cord ischemic injury with a wide therapeutic window through inhibiting high-mobility group box 1 release in rabbits. - PubMed - NCBI (EP)
    Antioxidant effect of ethyl pyruvate in respiring neonatal cerebrocortical slices after H(2)O(2) stress. - PubMed - NCBI (EP)
    Neuroprotective effects of ethyl pyruvate on brain energy metabolism after ischemia-reperfusion injury: a 31P-nuclear magnetic resonance study. - PubMed - NCBI (EP)
    Beneficial effects of ethyl pyruvate in a mouse model of spinal cord injury. - PubMed - NCBI (EP)
    Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia. - PubMed - NCBI (EP)
    Exogenous ethyl pyruvate versus pyruvate during metabolic recovery after oxidative stress in neonatal rat cerebrocortical slices. - PubMed - NCBI (EP)
    Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. - PubMed - NCBI (EP)
    Oxidative damage to lens in culture: reversibility by pyruvate and ethyl pyruvate. - PubMed - NCBI (EP)
    Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. - PubMed - NCBI (EP)
    Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window. - PubMed - NCBI (EP)
    Ethyl pyruvate protects PC12 cells from dopamine-induced apoptosis. - PubMed - NCBI (EP)
    Attenuation of sugar cataract by ethyl pyruvate. - PubMed - NCBI (EP)


    7. Sexuality/Reproduction
    Attenuation of Methotrexate-Induced Embryotoxicity and Oxidative Stress by Ethyl Pyruvate. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on mice sperm parameters in phenylhydrazine induced hemolytic anemia. - PubMed - NCBI (EP)
    Ethyl Pyruvate Ameliorates The Damage Induced by Cyclophosphamide on Adult Mice Testes. - PubMed - NCBI (EP)
    Protective effects of ethyl pyruvate on sperm quality in cyclophosphamide treated mice. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on ischemia-reperfusion injury in rat ovary: biochemical and histopathological evaluation. - PubMed - NCBI (EP)
    Protective effect of ethyl pyruvate on epididymal sperm characteristics, oxidative stress and testosterone level in methotrexate treated mice. - PubMed - NCBI (EP)
    A comparison of the effects of N-acetylcysteine and ethyl pyruvate on experimental testicular ischemia-reperfusion injury. - PubMed - NCBI (EP)
    Ethyl pyruvate reduces germ cell-specific apoptosis and oxidative stress in rat model of testicular torsion/detorsion. - PubMed - NCBI (EP)


    8. Cancer
    Pyruvic acid/ethyl pyruvate inhibits melanogenesis in B16F10 melanoma cells through PI3K/AKT, GSK3β, and ROS-ERK signaling pathways. - PubMed - NCBI (EP)
    Suppressed epithelial-mesenchymal transition and cancer stem cell properties mediate the anti-cancer effects of ethyl pyruvate via regulation of th... - PubMed - NCBI (EP)
    HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. - PubMed - NCBI (EP)
    Ethyl Pyruvate Combats Human Leukemia Cells but Spares Normal Blood Cells. - PubMed - NCBI (EP)
    Immunomodulating effect of ethyl pyruvate on nonsyngenic transplanted tumor in mice. - PubMed - NCBI (EP)
    Exploring glyoxalase 1 expression in prostate cancer tissues: targeting the enzyme by ethyl pyruvate defangs some malignancy-associated properties. - PubMed - NCBI (EP)
    Ethyl pyruvate administration suppresses growth and invasion of gallbladder cancer cells via downregulation of HMGB1-RAGE axis. - PubMed - NCBI (EP)
    Accelerated rejection of the second transplants of immunogenic tumor in mice under inhibition of indoleamine 2,3-dioxygenase activity by ethyl pyru... - PubMed - NCBI (EP)
    Ethyl pyruvate, an anti-inflammatory agent, inhibits tumor angiogenesis through inhibition of the NF-κB signaling pathway. - PubMed - NCBI (EP)
    Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. - PubMed - NCBI (EP)
    “…Our findings that IDO is effectively blocked by EP treatment deepens emerging links between IDO and inflammatory processes. Further, these findings rationalize oncological applications for this agent, by providing a compelling basis to reposition EP as a low cost immunochemotherapy for clinical evaluation in cancer patients.”
    Ethyl pyruvate administration inhibits hepatic tumor growth. - PubMed - NCBI (EP)
    Ethyl pyruvate induces necrosis-to-apoptosis switch and inhibits high mobility group box protein 1 release in A549 lung adenocarcinoma cells. - PubMed - NCBI (EP)


    9. Infection/Pathogen
    Acetoacetate and ethyl acetoacetate as novel inhibitors of bacterial biofilm. - PubMed - NCBI (EA)
    Ethyl pyruvate (EP) suppressed postharvest blue mold of sweet cherry fruit by inhibiting the growth of Penicillium oxalicum. - PubMed - NCBI (EP)
    Ethyl Pyruvate: An Anti-Microbial Agent that Selectively Targets Pathobionts and Biofilms. - PubMed - NCBI (EP)
    “…The microbiota has a strong influence on health and disease in humans. A causative shift favoring pathobionts is strongly linked to diseases. Therefore, anti-microbial agents selectively targeting potential pathogens as well as their biofilms are urgently demanded. Here we demonstrate the impact of ethyl pyruvate, so far known as ROS scavenger and anti-inflammatory agent, on planktonic microbes and biofilms. Ethyl pyruvate combats preferably the growth of pathobionts belonging to bacteria and fungi independent of the genera and prevailing drug resistance. Surprisingly, this anti-microbial agent preserves symbionts like Lactobacillus species. Moreover, ethyl pyruvate prevents the formation of biofilms and promotes matured biofilms dissolution. This potentially new anti-microbial and anti-biofilm agent could have a tremendous positive impact on human, veterinary medicine and technical industry as well.”
    Ethyl pyruvate attenuated coxsackievirus B3-induced acute viral myocarditis by suppression of HMGB1/RAGE/NF-ΚB pathway. - PubMed - NCBI (EP)
    Ethyl Pyruvate Emerges as a Safe and Fast Acting Agent against Trypanosoma brucei by Targeting Pyruvate Kinase Activity. - PubMed - NCBI (EP)
    Decontamination of green onions and baby spinach by vaporized ethyl pyruvate. - PubMed - NCBI (EP)
     
  2. I can see servings per container but what is the individual serving
     
  3. Good catch. Sorry about that. Serving size is 20 drops.
     
  4. I can’t seem to find it on the idealabs site but maybe it’s to soon . Also how should one test this one full dose or broken throughout the day . And if there any benefits you have noticed . Thanks this seems likely to be huge in the case of cancer.
     
  5. It is on the main page. Since they are in alphabetical order it is one of the last products on that page.
    www.idealabsdc.com

    Maybe you have a cached version of the page in which case hit Ctrl+R when the page loads and it should hard reload it instead of getting it from cache.
    As far as the product, it is meant to be used as a single daily dose as per the studies but I see no reason why more than one dose cannot be used. It seems to drop blood glucose pretty reliably, so I always use it with sugar. When used with sugar it seems to have a very quick diuretic effect, which suggests it probably lowers cortisol too. Aside form that, it seems to have a calming effects, almost sedative when used at night. And it does give a big energy boost, especially when used with Energin and/or Oxidal.
     
  6. Have these, or maybe plain pyruvate, ever been used to treat any diseases in the medical field?
     
  7. There are many human studies with pyruvate for things like kidney disease, CVD, performance improvement, etc. The results are all positive but the limiting factor has always been the instability of plain pyruvate and the high doses required. So, now there are several trials underway with ethyl pyruvate and we will see how they go. As far as acetoacetate goes, I think all the studies so far have been on animals. Acetoacetate has been given to humans before but mostly as a test for glucose tolerance, not to test its health effects.
     
  8. Thanks I found it now. I don’t know how freely your allowed to talk about things ( and if so I understand ) but I’ve have talked in the past about my sons brain tumor ( which has been in remission 8 months thanks to God and the very kind people on this forum ) And was wondering if this would be a helpful addition. Also if you take this oral or topically.
     
  9. Can't talk about specific diseases but you can take a look at the section with cancer studies in the original post. At least I can say that I don't think it would hurt, if his doctor is OK with using it.
     
  10. Should it be used topically?
     
  11. Nice. Maybe this product can reverse some of the damage I did to myself with taking NAC daily (1500 mg) for the last few months. My GSH (glutathione) must be really high. I was under the impression that glutathione was a very important antioxidant and that it levels go down drastically in serious diseases like AIDS and Cancer.
     
  12. As with all our other products, we can only advertise external use, even though we use food-grade materials. Both the EP and EC in Pyrucet are Kosher, food-grade materials.
     
  13. Actually cancer patients have too much intracellular GSH, especially inside the tumor. It does have a role in helping get rid of carcinogens like acetaldehyde, but once a tumor forms GSH is rather harmful.
    Glutathione metabolism in cancer progression and treatment resistance
    "...Glutathione (GSH) is the most abundant antioxidant found in living organisms and has multiple functions, most of which maintain cellular redox homeostasis. GSH preserves sufficient levels of cysteine and detoxifies xenobiotics while also conferring therapeutic resistance to cancer cells. However, GSH metabolism plays both beneficial and pathogenic roles in a variety of malignancies. It is crucial to the removal and detoxification of carcinogens, and alterations in this pathway can have a profound effect on cell survival. Excess GSH promotes tumor progression, where elevated levels correlate with increased metastasis. In this review, we discuss recent studies that focus on deciphering the role of GSH in tumor initiation and progression as well as mechanisms underlying how GSH imparts treatment resistance to growing cancers. Targeting GSH synthesis/utilization therefore represents a potential means of rendering tumor cells more susceptible to different treatment options such as chemotherapy and radiotherapy."
     
  14. I just wanted to reinforce the point because I know a lot of people on the forum struggle with candida and find it difficult to treat.

    Here’s another interesting article about EP...maybe you can help me understand it’s implications. Is this one of the mechanisms by which it reduces inflammation?

    Ethyl Pyruvate Inhibits HMGB1 Phosphorylation and Release by Chelating Calcium

    Calcium imaging assays revealed that EP significantly and dose-dependently suppressed high K+ -induced transient [Ca2+]i surges in primary cortical neurons and, similarly, fluorometric assays showed that EP directly scavenges Ca2+“

    “Together, these results indicate that EP directly chelates Ca2+, and that it is, at least in part, responsible for the suppression of HMGB1 release by EP.”

    2014 - Viewing Issue Article - Molecular Medicine
     
  15. I think they are saying EP prevents intracellular calcium overload, which is the ultimate mechanism through every cell dies. Most carboxyllic and keto acids are quite good at chelating metals, so I suspect both EP and EC prevent iron overload as well, and this could be much more important factor in the anti-inflammatory effects.
     
  16. Ordered. Very excited for this
     
  17. Great, thanks for ordering.
     
  18. Does this suggest that this supplement should be avoided on days that a person plans to drink an alcoholic beverage?
     
  19. Over the last 5 years, whenever I've tried going low fat I haven't been able to make it work.

    Does the mechanism of action with this supplement increase the likelihood that the body can utilize glucose and find reduction in fat intake as the cells can accept sugar better?
     
  20. Tony Robbins Burns a Staggering Number of Calories During Live Events. I Tried His Fitness and Diet Routine to Find Out How

    "Tests show that on a typical event day Tony burns approximately 11,300 calories. (Think running two marathons.)"

    "And his lactic acid levels are staggeringly high.

    During exercise, lactic acid naturally builds up faster than it can be burned off and causes levels to increase. For example, a blood lactate concentration of 4.0 is typical for people who run hard enough to feel out of breath.

    Tony? His lactate measured 14.1."
     
  21. To the contrary, considering how many studies found a protective effect and the fact that it raises the NAD/NADH ratio (which is crucial for metabolizing ethanol) I would actually use it a few hours before the planned drinking.
     
  22. That's what the available evidence for EP and EC shows.
     
  23. Can the mods change the study-references to text-versions?
     
  24. Wow, that would turn out well.../s
     
  25. I thought it did that automatically over time but I guess not.
    @charlie
     
  26. @haidut, the system can only do so many at a time. So you have to go click "edit", and then "save changes" and cycle through that a few times till it finishes. I went ahead and took care of it. :hattip
     
  27. Thank you! I will do the repeated editing next time. Did not know editing made the system continue fetching. I thought it just processes some and then stops for good when it reaches a limit on a number of links or something.
     
  28. EA has impressive neuroprotection effects it seems .... And the sheer amount of potential uses / positive physiological modulations of EP is astonishing.
    EA is naturally found in coffee by the way, thhough in miniscule amounts I guess.
    Both are also flavouring agents.
     
  29. Studies also show that Pyruvate can activate stem cells in the scalp for hair growth. studies done a UCLA I think.
     
  30. I read it’s by blocking pyruvate and forcing mitos to produce lactate which in turn activated quiscent stem cells.
     
  31. oh, ok , thanks
     
  32. Ordered. If nothing else at least my green onions can finally get the vaporising they richly deserve :D
     
  33. Coming back and back to fly over the referenced publications.
    EP ... why is it not yet part of a acute subcranial hemorrhage treatment-Protocol? The murine studies are impressive on that issue.
     
  34. Fully agree. The amount of studies and the diversity of issues EP can apparently address is astounding. But the same is true of aspirin and instead of embracing it the medical industry still parrots that "aspirin risks outweigh the benefits for most people".
    Like, are you f-ing kidding me!?? But such is the world we live in...
     
  35. I guess FAOfew and Ethel-tuMorban were already trademarked ? :^P
     
  36. Congrats on another interesting release!
    My history of IBD 20 years ago always has me interested in that topic. Turns out Ethyl Ester has a very important role as anti-irritable bowel disease. Apologies if this was already posted, a couple just scratching the surface:
    Anti-inflammatory and antioxidant effects of ethyl pyruvate on colitis: In a rat model.
    "Pyruvate is an important metabolic derivative and an important scavenger of reactive oxygen radicals and hydrogen peroxide. It induces anti-inflammatory effects through NF-κβ inhibition."
    They actually also go on to mention how the Ester form is key for solutions:
    "As pyruvate is not stable in aqueous solutions, its aliphatic ester EP has been utilized in many studies, and has also been shown to exert antiinflammatory effects."

    Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis
     
  37. Thanks. Yes, I think we have those in the list but it never hurts to highlight interesting parts because frankly I doubt people will meticulously go one by one through all 100+ studies listed as references.
    Yeah, both EP and EA seem quite promising as anti-inflammatory agents. They also combine quite well with MB, not only for metabolic boost but for inflammation too.
    Methylene Blue Is A Potent Anti-inflammatory, With Possibly The Broadest Spectrum
     
  38. Really excited to start reading people's reports on it.
     
  39. Lol, not sure, did not look these up. But FaoFew seems a rare word on Google so maybe if I do another similar product I will use that name.
     
  40. I've been experimenting even more lately with MB, been going nicely. By the way, you mentioned the dosage isn't a hard and fast rule for Pyrucet, did you mean that we could use less and still get benefits?
     
  41. I am bit confused, and I admit that I am not up on the science as some of the more educated members, but why would you want the glutathione to be zero (meaning for non-cancer people)? I thought glutathione is good, or is it the oxidized form we want?
     
  42. Wow! Great new product! I am blown away by the amount of positive studies these substances have behind them. Can't believe this is the first time I'm hearing of them. The anti-dementia aspect is particularly interesting to me.

    The studies you referenced for Parkinson's disease if applicable to humans are incredible!

    "The selective death of dopaminergic neurons in substantia nigra was prevented by EP in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. EP also suppressed the 1-methyl-4-pyridinium-induced cell death of SH-SY5Y cells and restored the phosphorylation of extracellular signal-regulated kinase."

    Correct me if I'm wrong but that sounds to me that in mice at least it is a cure for Parkinson's or at the very least greatly slows the progression of the disease.

    It really is tragic that just like aspirin substances like these are hiding in plain site and countless people are suffering unnecessarily because of the Government and Medical industry mafia.
     
  43. Would you be kind enough to share a link to where you read that.

    Thanks

    Could you link that study please.
     
  44. I got my Pyrucet today. 2-day shipping FTW. I applied 20 drops topically to my torso. It kind of smells like nail polish remover and leeks, which is not unexpected from ketone derivatives.

    I'm not sure what to look for with this, but here are some things I noticed:

    Wider field of vision
    More prone to seeing spots in my eyes in reaction to bright light
    I started to get a bit anxious, but some sugar solved that
    Some pressure in my head

    It seems very reminiscent of lowered serotonin. These are effects I've experienced with adamantane, methylene blue, and ritanserin. This is something to approach carefully, but it still has a lot of potential.
     
  45. My experience with twenty non uniform drops this Saturday mid day
    was to experience a shift fifteen minutes later
    that had a pleasant demeanor
    of a very fine activity taking place throughout my body
    in a brightening of consciousness
    as yes I would say that the metabolism of my brain
    was being supported
    now hours later I still feel a shift has taken place
    but I have taken Cardenosine as well today.....

    What I will do tomorrow is a guess
    but I think that I like this formula
    and thus I may go for a full dose
    or see how I respond to a fraction
    perhaps fearing a full dose might not
    provide the full shift again as the first time
    which indicates that I liked the first taste
    topically that was, with two drops in the mouth.

    Thanks to Haidut!!!!
    A bit of genius and hard work to come up with a novel combination
    is a relevant invention & Art.

    Bruce Marshall
     
  46. Thanks @Pointless and @LeeLemonoil. Just reading it now all seems very promising think I'm going to have to experiment with this for hair growth.

    One quote from the article I think sums up the underlying problem with all health research at present,

    "I think we’ve only just begun to understand the critical role metabolism plays in hair growth"

    Yea not just hair growth but all elements of health.
     
  47. But the UCLA-paper would suggest that additional external pyruvate dors not activate stem cells but lactate does, they do it by forcing mitochondria to produce more lactate. From a metabolic health point of view, that’s not a very nice sounding approach.
    It’s intriguing that lactate would do that, and it’s certainly involved in some form growth induction and cell signaling - see excercise- but to force mitos into such a mode by pharmaceuticals long ten doesn’t seem „sustainable“
     
  48. Very interesting haidut. As you know, pdh function has been demonstrated to be impaired in me/cfs. I will make other patients aware of this product. Several ppl have been trying to find an ethyl pyruvate source
     
  49. @haidut I always assumed that pyruvate reduction /reductive stress, in which pyruvate is reduced to lactate instead of oxidized into acetylcoa , was caused by impaired pyruvate dehydrogenase function in a way that was independent of the amount of pyruvate. Hence I assumed that adding more pyruvate would just result in reduction to lactate if there’s a problem with pyruvate dehydrogenase. Otherwise ppl with pyruvate dehydrogenase complex deficiency could just eat more carbs? Whereas I think some of them do Keto somewhat successfully to manage it Bc they can’t seem to oxidize glucose at all??
     
  50. The neurological studies seem suggest EP functions also under conditions you described - pyruvat dehydrogenase impairment and lactic acid increase is a hallmark of many forms of subcranial bleeding. Maybe the ethyl group is key? Does it prevent from reduction and this functionally replaces the lacking physiological pyruvste?
     
  51. I just wanted to report that I woke up after my first dose of Pyrucet with chest pains, which usually indicates magnesium deficiency for me. I took 5 drops of Magnoil, and it went away. I think that this is increasing my magnesium requirements. It seems to be optimizing my metabolism at a very high level. I'm very intrigued by this product.
     
  52. Where did I say that? The suggested dosage is based on what the animal studies used. I explained that in the thread. Since the HED I gave is mg/kg bodyweight this means there will be a slight variation across people depending on their weight.
     
  53. Well, it is explained in the thread. GSH is VERY high in cancer and many other chronic degenerative conditions. I did not say it should be brought down to zero, not sure where you saw that suggestion. I pointed out the bringing GSH down to zero as an example of how these two chemicals can shift the balance strongly towards oxidation. Most people have their redox status shifted towards reduction and by lowering GSH, NADH, lactate, etc their status shifts towards oxidation, which increases metabolism.
     
  54. Yes to both. And considering both of these chemicals are approved as GRAS food flavoring ingredients, have been used for decades, and no serious side effects have been seen makes it criminally negligent to not pursue those further as pharmaceuticals.
    As my more cynical colleagues in the IT world say "the best ideas never win, they would just decimate so many employed imbeciles. so, those ideas are quashed from the start". Usually what ends up getting implemented is something that barely works so that the company behind it can perform thousands of incremental "improvements" and charge a ton of money for each one.
     
  55. Oh I see, my mistake then, I think I misinterpreted "The units listed on the label are just for measurement purposes. They do not indicate or suggest optimal dose."
     
  56. This. I should have probably emphasized this in the main thread, but some of the studies explicitly stated that EP/EA should be given with sugar since it increases its metabolism and (similar to thyroid) may cause hypoglycemia. Also, EP/EA in these doses are just catalysts, not actual fuel. So, there should be enough food to enable their positive effects.
     
  57. Thanks Bruce! Keep us posted please.
     
  58. So, are you saying EP is already known in the CFS community? Can you please send some links where they discuss it on other forums?
     
  59. Well, the studies that I posted show that pyruvate does activate PDH in a sort of a positive feedback cycle. So, even if come pyruvate gets converted to lactate the net effect is still increases glucose oxidation. Also, the acetoacetate should be able to reduce/prevent the lactate formation as it is another oxidizing agent that can keep PDH running. PDH activity depends primarily on the redox ratio (assuming deficiency of cofactors like thiamine is not an issue), and since both agents increase strongly NAD/NADH ratio that is probably what prevents the lactate buildup.
     
  60. That's what one of the studies seemed to show, because neither ethanol nor pyruvate were able to replicate the effects, and giving ethanol + pyruvate together did not either. So, there is something about ethyl pyruvate as whole molecule that enables these effects and it is probably its stability and resistance to metabolism by LDH.
     
  61. Thanks. Magnesium is also a cofactor for glucose metabolism so sounds plausible. Also, as I mentioned earlier in the thread, make sure it is always consumed with sugar as t increases its metabolism and some of the studies in the original post showed that the benefits of EP/EA manifest mostly when given together with glucose/carbs.
     
  62. Could You please elaborate on Mildronate toxicity you are mentionig in this thread?
     
  63. I didn't mean to say that you suggested it, I was just trying to understand why GSH depletion would be a good thing in a non-cancer person. I see where it says about the anti-inflammatory effects. I also was under the impression that having high amounts of cellular GSH was a good thing for a healthy person. Like I said, I am still learning so this may make sense to me as i become more educated (I am self taught, I don't have a degree in biochemistry, medicine, etc.)
     
  64. For most people GSSG/GSH ratio is too low for optimal health and lowering GSH increases that ratio.
     
  65. Where did you see me saying Mildronate is toxic?
     
  66. So, we try to both actually and it gets confusing. The units are for measurement purposes but as far as the supplements are concerned we also try to make a dosage split that would make the bottle last 30 days if used at that dose. It just so happens that the 500mg EP/EA daily more or less match the doses used in the animal studies.
     
  67. Do you have a reference for that?
    Very often the exact opposite is claimed.

    Not saying that I disagree, but I would like to read more evidence.
     
  68. Day 2 mid morning

    7 drops of Pyrucet on wrist
    4 drops Diamant
    4 drops Cardenosine

    While taken at the same time, I did feel a 'shift' similar to my first experience with
    Pyrucet, so definitely there is a signature to the substance, and one that I certainly like!.

    Distinct and unique and one different from that of Daimat and Cardenosine which I am familiar with.

    I took the smaller dose to try to understand what the parameters of response to it might be, and where there
    might be the option to pace one's dose through out the day, or towards understanding what might constitute
    a minimum booster dose.

    My understanding, and this is not a 'lab rat' experiment, but a experience with a GRAS combo, thus far is that Pyrucet
    has some important components towards addressing "learned-helplessness" and perhaps thus serve as a nutritional adjunct
    to mitigating addiction strategies such that Broda Barnes for example said that alcoholism was a problem of sugar
    nutrition and thus alcohol a form of rocket fuel per say, or that marijuana is an addiction to a blood rush of what is
    a temporary head feeding....

    While my reflections are topical, time will tell with further experimentation, without other substances, to further
    understand one's response of which today I had a few smiles that I believe were gently induced by such nutritional
    support.
     
  69. I think this is on the Phoenix Rising forums?
    Would lowering the GSH/GSSH be negative for someone with heavy metal toxicity?
     
  70. Methylene blue raises Serotonin
     
  71. Methylene blue doesn't raise serotonin an appreciable amount in the dosages frequently recommended on these forums - only outsize doses seem to do that. Anything under 1mg seems to have a negligible/non-significant effect on serotonin.
     
  72. "So, I spend a lot of time over the last year looking for chemicals that work similarly to Mildronate but without toxic side effects."
     
  73. From the sentence just above your quote: “Unfortunately, with the exception of Mildronate all other clinically used FAO have severe side effects, which greatly limit their use.”

    So he was saying that other clinical chemicals that inhibit FAO, like mildronate does, have toxic effects, not mildronate itself.
     
  74. I have purchased some and will look forward to seeing if it can help my CFS/POTS symptoms. I can see it going either way, either forcing glucose use with a stubborn PDH could result in even less energy and even more lactate accumulation, or perhaps it turns on PDH and allows carbs to be used with minimal heart symptoms.

    @haidut I have had limited success with using MCT oil with carbs in order to supply excess acetylCoA and force pyruvate down to oxaloacetate and avoid PDH (at least I think that's why it helps). Could ethyl aceatoacetate act in a similar mannor in high enough dose? Could it supply suffient acetyl CoA to help pyruvate avoid PDH? Do you know of any other substances that could do this (aside from alcohol and exogenous ketones)? Problem with MCT is I get diarhea even at relatively small doses.
     
  75. Is it ok to take pyrucet if a person also takes Niacinamide and Aspirin? Or is it better to drop those?
    Since Niacinamide and Aspirin also inhibit free fatty acids, adding Pyrucet might be too much inhibition of free fatty acids?
     
  76. Got 2 Bottles in the mail 30 minutes ago

    Got a spoon. 20 drops. I ate it. Nearly Died. DO NOT DO THIS! tastes super bad and burns! Washed down with coffee. Ok Now. No Permanent Damage.

    Put 10 drops on GF forearm.

    Gotta run to a lunch meeting. Fingers seem to be typing really fast.
     
  77. I too ordered Pyrucet the day it was available. 20 drops orally seems to palpably increase hunger so definitely make sure you're in a thoroughly fed state or give with sugar to offset. Other than that, nothing profound to report yet. I am primarily taking for exercise performance as an analog to Mildronate as discussed a few times elsewhere, so that makes me a minority use case. I am particularly interested to see if there is any synergy with Cardenosine as well.
     
  78. @haidut, what would happen if someone was doing Keto or low carb diet, and used Pyrucet?
     
  79. It's 5:31 pm in Texas. In my 62 yr old body, 20 drops internally provided major energy and focus boost. As noted above, the need for fuel increased as one would expect when your energy level is doubled or tripled. I think I will keep doing the 20 drops internally right when I wake up in the morning for a week and see how long I can keep this power surge going. I need the extra energy to get all my CPA work done for sure, so if the surge keeps going, it will be a great blessing to my bank account. It's no problem for me to snack along the way all day.

    GF had 10 drops on arm and received a boost but not as dramatic as my boost and She also needed snacks to keep from sinking. I think I will adjust her daily dose to 3 drops 3 times a day - topical - and keep her fed along the way. She has a lot better normal energy than I do so I don't think she would really like a rocket boost.

    There seems to be a myriad of ways to use this stuff. Getting extra energy on demand with the 20 drop bomb can come in handy. I hope some peoples will experiment with something like a topical drop or two per hour to see if they can keep their motor running at high speed hour after hour.

    Very very interesting product with lots of options for people with different needs and requirements.

    I will probably go dancing tonight and see how much extra quickness and speed I have 9 hours after a 20 drop shot. Say a prayer for my GF/dance partner...
     
  80. Thanks for the feedback. Please do share your experience when you combine with Cardenosine.
     
  81. I think both of the chemicals trigger insulin release and may interrupt the ketosis. I don't think it should be used by people in ketosis, this product tries to do the very opposite of what ketosis does.
     
  82. I think the effects of the ethylated esters of the chemicals in Pyrucet are not (mainly) due to their usage as fuel precursors but rather because they activate PDH. Maybe higher doses could have the circumventing effect you mention but at the doses in Pyrucet the main effects should be simply activation of PDH and then if glucose is available it should flow through PDH and form acetyl-CoA.
     
  83. Thanks.
    @mirc12354
     
  84. That I don't know, but I think in that case the ratio would the least of these people's worry. If the toxicity is severe enough then chelation needs to be considered or organ damage can easily occur.
     
  85. @haidut Would taking Niacin/Niacinamide at the same time as Pyrucet be counterproductive (as far as the interaction with acetoacetate)?


    Cancer Addiction To Fat Confirmed; Niacinamide As Possible Treatment

    "This is the latest of a number of studies over the last year or so that point the finger at fat (and not sugar) as the primary factor in tumor growth. I posted a few studies in the past showing that tumor cells are highly dependent on fat for growth and proliferation, and a number of hypolipidemic agents like orlistat or even niacinamide can help curb, or even completely reverse tumor growth. In combination with a fatty acid oxidation inhibitor like Mildronate, the effect will probably be even more potent. And adding a fatty acid synthase (FAS) inhibitor like vitamin D or aspirin on top of that can create a well-rounded cancer treatment for most cancer types.
    Cancer Cells Addicted To Fat And Use Fat Oxidation For Survival
    Achilles Heel Of Cancer Found - Its Addiction To Fat
    Niacinamide Can Cure Liver (and Maybe Pancreatic) Cancer
    This study adds to the evidence for the role dietary fat and diet-induced ketogenesis in the progression of tumors. Interestingly, just like the study on liver and pancreatic cancer I posted just a few days ago, administering niacin was very effective as an anti-cancer agent. Ray has written quite a bit about the tendency of cancer patients to fall into ketosis, and this study confirms his statements. Niacin lowered the levels of acetoacetate (a biomarker of ketosis) and greatly inhibited tumor growth. The HED of nacin was about 15mg/kg and treatment was for 3.5 weeks. For the record, niacinamide is even more effective than niacin in interrupting ketosis, so using niacinamide at that dose would probably achieve even better results. Interestingly, this same dose of about 1.5g niacinamide daily was successfully used to improve type II diabetes in human trials and in animal trials it basically reversed the condition. I doubt these findings are just a coincidence given the link between lipolysis, ketogenesis, diabetes, and cancer.
    As the study says, while the study only focused on one type of cancer (and its mutation), the morale of the story is that high-fat, low-carb diets are probably not good for cancer patients. Fasting also accelerated tumor growth, due to the increase in ketogenesis. Finally, the ketone acetoacetone not only served as fuel for the tumors but also had genomic/receptor effects, which also promoted tumor growth.

    Melanoma mutation likes fat for fuel: Diet can modulate growth-spurring effect in mice
    "...Cancer cells love glucose, so a high-fat, low-carb diet should starve them, right? Not cancers driven by a notorious melanoma mutation. Research in mice suggests that cancers with BRAF V600E will grow faster in response to a high-fat 'ketogenic' diet. In addition, lipid-lowering agents such as statins curb these cancers' growth, even in the context of a more normal diet."

    "...Most cancer cells display enhanced glucose uptake, a phenomenon known as the Warburg effect. A low-carb diet has been tried as a clinical countermeasure in a limited way, mainly in brain cancer. In contrast, a possible implication of the Winship researchers' results is that people fighting a cancer with a BRAF V600E mutation should avoid low-carb diets."

    "...One of the alternative energy sources produced by ketogenesis is acetoacetate. Within cancer cells with the V600E mutation, acetoacetate production is stimulated, the Winship researchers had found. On top of that, acetoacetate binds the mutated B-raf protein and promotes its oncogenic activity, forming a cycle of positive feedback.

    "...The Winship researchers wanted to test whether V600E cancer cells would respond to external acetoacetate. A ketogenic diet with very low carbohydrates, like an Atkins diet, can cause acetoacetate levels in the body to rise. Fasting can also trigger the same effect. Lipid-lowering agents commonly used to treat high cholesterol, such as statins (in this case, fluvastatin), niacin and fenofibrate, could slow the expansion of V600E tumors in mice, even when they were fed a normal diet. Those drugs reduced acetoacetate levels, and when the researchers injected acetoacetate to compensate, tumor growth sped up again."


    http://www.cell.com/cell-metabolism/abstract/S1550-4131(16)30643-X
    "...We chose three drugs that are clinically used to treat hypercholesterolemia: fluvastatin, which belongs to a class of cholesterol-lowering statins that are HMG-CoA reductase inhibitors (Avis et al., 2007); niacin (a.k.a. vitamin B3), which lowers triglycerides and is also clinically used to treat cardiovascular patients not taking a statin (Jacobson et al., 1994); and fenofibrate, a fibric acid derivative that also lowers triglycerides (Superko, 1989). We found that fluvastatin and niacin treatment effectively attenuated tumor growth potential of BRAF V600E-expressing A375 cells in xenograft mice; this could be reversed by intraperitoneal injection with acetoacetate (Figures 3A, top, and S4A, left)...Consistent with these findings, treatment with fluvastatin, niacin, or fenofibrate resulted in reduced serum levels of acetoacetate, but not b-hydroxybutyrate, in mice(Figures 3B and 3C, respectively), while acetoacetate injection rescued the decreased serum acetoacetate levels but did not affect 3HB levels."

    "...We next sought to determine whether functional inhibition of acetoacetate would attenuate BRAF V600E tumor growth. We examined a group of commercially available acetoacetate analogs and found that dehydroacetic acid (DHAA) (Figure 4A) is an inhibitory homolog of acetoacetate."
    "...Consistent with these findings, DHAA treatment for 3.5 weeks effectively inhibited tumor growth rates, sizes, and masses in nude mice with BRAF V600E-expressing human melanoma A2058 and A375 cell xenografts, but not in mice carrying control xenografts derived from HMCB cells expressing NRAS Q61K (Figures 6A and S6A)."
    "...DHAA is a synthetic organic compound that is used mostly as a fungicide and bactericide (Stedman et al., 1954); it shows little to no clinical toxicity or irritating potential and has been safely used in skin-care products. Consistently, chronic injection of DHAA to nude mice for 4 weeks revealed that 200 mg/kg/day administered intraperitoneally is a well-tolerated dose that did not cause notable differences in histopathological analyses and weights of diverse organs (Figures S6C and S6D, respectively). Moreover, chronic treatment with DHAA had no obvious effect on the mouse gut microbiome, as evidenced by an unaltered total-DNA amount extracted from bacteria in mouse feces; this suggested no change in total bacterial number in the mouse gut (Figure S6E), and by altered proportions but no loss of any components of the gut microbiota (Figure S6F). DHAA treatment did not alter complete blood counts (CBC) or hematopoietic properties in representative A375 xenograft mice compared to the water-treated group (Table S1). These results together suggest that DHAA treatment does not cause obvious toxicity in vivo."
    "...Further studies revealed that the inhibitory effect of DHAA treatment on tumor growth potential of A375 cells in xenograft mice was not reversed by intraperitoneal injection with acetoacetate (Figure 6G) despite increased serum levels of acetoacetate in DHAA-treated mice that received acetoacetate injection (Figure 6H). DHAA treatment did not affect serum levels of 3HB, cholesterol, or glucose in mice in either the presence or the absence of acetoacetate injection (Figures 6I, 6J, and S6G, respectively). Consistently, acetoacetate injection did not reverse the inhibitory effects of DHAA on phosphorylation of MEK1 and ERK1/2 (Figure 6K), BRAF V600E-MEK1 binding (Figure 6L), or cell proliferation rates assessed by IHC staining of Ki67 (Figures 6M and S6H) in tumors derived from A375 cells in mice. These data are consistent with previous results (Figures 5D–5E, 5I, and S5C) showing that acetoacetate was insufficient to reverse the effect of DHAA on BRAF V600E-expressing cells."
    "...Consistent with our findings presented above, we found that treatment with a high-fat diet promoted—while DHAA alone inhibited—tumor growth rates, sizes, and masses in nude mice with BRAF V600E-expressing A2058 or A375 cell xenografts; co-treatment with DHAA effectively reversed the enhanced tumor growth potential of A2058 or A375 cells in xenograft mice fed with a high-fat diet (Figures 7A and S7A)."


    An interesting side note from the above study is the use of a functional antagonist to acetoacetate instead of inhibiting its synthesis with niacin/niacinamide. The functional inhibitor used was dehydroacetic acid (DHAA) and it was very effective in curbing tumor growth when used in the same doses as niacin - i.e. HED of 15mg/kg. What is more important, just like niacin / niacinamide, DHAA was able to curb tumor growth even in the presence of high-fat diet and even injecting additional acetoacetate was not able to reverse the beneficial effect of DHAA. Given that DHAA is widely used and has very well-known safety profile (unlike orlistat), and is cheaply available as OTC chemical / supplement it could become one of the alternatives for people who cannot get access to other chemical like mildronate or want to potentiate the effects of niacinamide.
    Dehydroacetic acid - Wikipedia"
     
  86. That study used mutated tumor cells. I sent it to Ray back when that thread was posted and he said that the increase in acetoacetate production is protective, and that the benefit of niacin was due to lowering lipolysis and improving glucose metabolism. The lowering of acetoacetate by niacin, according to Peat, was just a corollary of it lowering lipolysis. As far as DHAA, he said it likely has other mechanism of action because as the study itself showed, adding acetoacetate to DHAA treatment did NOT reverse its beneficial effects.
    So, I don't see a problem combining acetoacetate with niacinamide. In fact, they should be synergistic.
     
  87. Do you have any experience regarding the topical absorption rate? Recently ordered and not sure if I will chose to do topical or oral. Was curious just because it seems like it does not contain any solvents like SFA ester or MCT.
     
  88. Ethyl acetoacetate itself is a powerful penetration enhancer, so it absorbs quite well through the skin. That is why we use it as one of the solvents in some other products. It is listed s FEMA 2415 on the label. As far as absorption, I feel about the same from using the same dose topically or orally. The topical route takes longer to manifest systemically though, maybe about 30min.
     
  89. Day 2 - 20 Drop oral first thing this morning in a shot glass of OJ. All day energy and wakefulness and focus (snacks required).

    GF....4 drops on arm in the morning...she was good all day.

    Now, going out dancing.

    Good stuff so far. Slept good last nite.
     
  90. Excellent, thanks for sharing!
     
  91. Day 3 20 drop shot in OJ. Had a strong alert productive day - made lots of $ today. Forgot to smudge 4 drops on GF this morning.

    I won't keep boring everyone but plan is to keep up the 20 drop shots daily until 4/15 at least. If it quits working and I start pooping out I will report in. Otherwise assume the stuff is still helping my naturally sputtering engine run a lot better.
     
  92. I just wanted to thank Haidut for his outstanding research here.
     
  93. Narouz in disguise?
    Thats the only person who writes exactly this way.
     
  94. Waiting on my 2 bottles making it to Oz. Then the experiments shall begin.
     
  95. Widely known may have been a stretch , discussed in this thread Pyruvate Dehydrogenase Deficiencies and Cures?
    And also on Reddit /nootropics there were people trying to find ethyl pyruvate , which they had got in gas station energy drinks awhile ago
     
  96. @haidut, What is the BEST thing we can do, to ensure the Pyruvate goes to CO2. Most likely is to make sure we have enough sugar on hand, right?