IngredientsThiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase, is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. The compound occupies a pivotal position in biochemistry as the biologically active, phosphorylated coenzyme form of vitamin B1.
The synonyms of cocarboxylase are thiamine pyrophosphate, thiamine pyrophosphate chloride, and thiamine diphosphate. The IUPAC name of cocarboxylase is 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethyl phosphono hydrogen phosphate;chloride. The CAS number of cocarboxylase is 154-87-0.
This compound belongs to the class of organic compounds known as thiamine phosphates β thiamine derivatives in which the hydroxyl group of the ethanol moiety is substituted by a phosphate group.
K. Lohmann and Ph. Schuster isolated in 1937 the coenzyme of the carboxylase from yeast in the form of the aneurin-pyrophosphoric acid-ester-chloride. The term cocarboxylase defines the inner salt of the aneurin-pyrophosphoric acid ester.
Cocarboxylase, aka thiamine pyrophosphate (TPP), is present in all life forms. It is a nonprotein coenzyme for biochemical reactions. As such, it is found in virtually every organism that has been studied, from yeast to mammals.
It consists of a thiazolium ring linked to a pyrimidine moiety via a methylene bridge, with a pyrophosphate group attached to the pyrimidine, enabling its role as an electrophilic catalyst in enzymatic reactions.
The discovery of cocarboxylase in plants dates to 1937, when Tauber found it to be present in a variety of vegetables, fruits, and nuts in amounts ranging from 0.4% to 30% of the total thiamine content. In tissues of animals and humans, it is the predominant phosphorylated form of thiamine, with the highest concentrations found in metabolically active organs.
The main dietary source of thiamine (and thus its coenzyme form, TPP) is plants, such as wheat germ, seeds, whole grains, and legumes, while some thiamine is also provided by meats and fish. Foods with high levels of naturally occurring thiamine include pork, nuts, seeds, yogurt, peas, and beans.
Thiamine pyrophosphate (cocarboxylase) is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. Pancreatic cells obtain thiamine from their surroundings and enzymatically convert it into thiamine pyrophosphate (TPP) in the cytoplasm; TPP is then taken up by mitochondria via a specific carrier, the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene).
The hydrochloride salt is the predominant article of commerce and is also often referred to as cocarboxylase. It is more stable than the parent compound and has a water solubility of 220 g/L.
Cocarboxylase is available in several dosage forms, including injectable solutions for intramuscular (IM) or intravenous (IV) administration, as well as oral formulations including tablets and capsules. It is used as a medication to treat metabolic, neurological, and cardiovascular disorders. As the bioactive form of thiamine, it is also a nutritional supplement.
A specific hydrated salt, cocarboxylase tetrahydrate (CAS 68684-55-9), is also found in commerce. It is one of the active ingredients in a medication called Cernevit, which is a multivitamin preparation used in various medical settings.
Thiamin (also known as vitamin B1 and aneurin) was the first B vitamin identified. Lack of thiamin causes the deficiency disease called beriberi, which has been known since antiquity. First descriptions of states compatible with thiamine deficiency in the form of beriberi appeared in Japan in the 9th century.
Beriberi is often caused by eating a diet with a very high proportion of calorie-rich white rice (common in Asia) or cassava root (common in sub-Saharan Africa), without much thiamine-containing animal products or vegetables. It principally affects precarious communities where children and adults are most vulnerable and where dietary habits rely on refined processed cereals or tubers (e.g., rice, wheat, cassava), notably in Southeast Asia and Africa.
In 1884, Japanese naval surgeon Kanehiro Takaki demonstrated that dietary modifications could prevent beriberi in sailors, though the specific nutrient remained unknown. Pure crystalline thiamine was successfully isolated in 1926 by Dutch chemists Barend Coenraad Petrus Jansen and Willem Frederik Donath from rice bran, confirming its identity and paving the way for structural analysis.
Thiamine was shown to be involved in the decarboxylation of pyruvate to acetaldehyde in alcohol fermentation and was named "cocarboxylase" in 1932. In 1936β1937, Rudolf Peters utilized thiamine-deficient pigeons to demonstrate that TPP restores pyruvate decarboxylation in brain tissue, establishing its essential coenzyme function in oxidative processes.
The definitive identification of cocarboxylase as thiamine pyrophosphate was achieved in 1937 by Karl Lohmann and Philipp Schuster. Lohmann and Schuster devised a multi-step purification protocol to isolate cocarboxylase from brewer's yeast, a rich source of the coenzyme. Through elemental analysis and chemical degradation studies of the crystalline cocarboxylase, they determined its empirical formula and identified its constituent parts: a pyrimidine ring, a thiazole ring (the components of thiamine, which had been recently characterized), and two phosphate groups. They concluded that cocarboxylase was the pyrophosphoric acid ester of thiamine.
The structure proposed by Lohmann and Schuster was unequivocally confirmed in 1938 by John Weijlard and Henry Tauber, who successfully synthesized cocarboxylase chemically.
In the 1960s, numerous biochemistry and physiology reports mentioned TPP, but few focused on the molecule as a standalone therapeutic agent. In a 1964 instance, Soviet scientist A. Malachovskis used TPP in laboratory rats to decrease the toxicity of chemotherapy medications and restore the activities of several enzymes.
Historical clinical interest in cocarboxylase as a therapeutic agent, distinct from thiamine itself, arose substantially in Eastern European and Soviet medical traditions from the 1950s onward. Observations on the cortisone-simulating action of cocarboxylase in allergic subjects, including local action of cocarboxylase in allergic rhinitis, were published in Italian clinical literature in the 1950s. Publications from this era, catalogued in PubMed, include comparative clinical studies on the effects of thiamine and cocarboxylase dating to 1957, and investigations into cocarboxylase's effect on resistance to experimental hypoxia. These early studies largely lacked modern clinical trial design and were published without detailed available abstracts.
Since cocarboxylase, derived from thiamine, is necessary for normal utilization of pyruvate by heart muscle, the importance of adequate body stores of thiamine in patients with chronic heart disease was investigated by measuring blood cocarboxylase concentrations in the mid-20th century. In patients with congestive heart failure, thiamine deficiency was demonstrated by measurement of blood cocarboxylase.
Cocarboxylase is itself the active compound of interest. It is not a botanical extract or herbal preparation, but rather a discrete, well-characterized small molecule β the phosphorylated coenzyme form of thiamine.
TPP (thiamin pyrophosphate), the coenzymatic form of thiamin, is involved in two main types of metabolic reactions: decarboxylation of Ξ±-ketoacids (e.g., pyruvate, Ξ±-ketoglutarate, and branched-chain keto acids) and transketolation (e.g., among hexose and pentose phosphates).
It is an essential micronutrient with dual coenzymatic and non-coenzymatic functions. It is involved in carbohydrate and branched-chain amino acid metabolism, as well as in the production of neurotransmitters, myelin, and nucleic acids. There is also evidence that thiamine plays a role in immune and anti-inflammatory processes and gene regulation.
One of the primary functions of cocarboxylase is its role in the oxidative decarboxylation of alpha-keto acids, a reaction that is critical for energy production. Specifically, thiamine pyrophosphate (TPP) is a coenzyme in the pentose phosphate pathway for transketolation of glucose-6-phosphate to ribose-5-phosphate. In the Krebs cycle, TPP is needed for the functioning of the pyruvate dehydrogenase complex (which converts pyruvate to acetyl CoA) and alpha-ketoglutarate dehydrogenase (which converts alpha-ketoglutarate to succinate). These reactions are needed for aerobic metabolism and production of ATP.
TPP is also the coenzyme for branched-chain dehydrogenase, the enzyme that catalyzes the oxidative decarboxylation of Ξ±-keto acids derived from leucine, isoleucine, and valine β three essential amino acids. The reaction follows a scheme similar to pyruvate oxidation, only this time the carbon skeleton of the amino acid condenses with coenzyme A (CoA).
Cocarboxylase also plays a significant role in the non-oxidative phase of the pentose phosphate pathway. In this pathway, TPP-dependent transketolase catalyzes the transfer of two-carbon units between sugar phosphates. This reaction is essential for the interconversion of sugar phosphates, enabling the cell to balance its needs for ribose-5-phosphate (for nucleotide synthesis) and NADPH (for reductive biosynthesis).
Thiamine pyrophosphate is synthesized in the cytosol and is required in the cytosol for the activity of transketolase and in the mitochondria for the activity of pyruvate-, oxoglutarate- and branched chain keto acid dehydrogenases. Transport into the mitochondria depends on a specific carrier β the mitochondrial TPP transporter (MTPPT; product of the SLC25A19 gene).
Thiamine also helps in the conduction of nerve impulses, independent of its coenzyme functions. It is important for maintenance of nerve membrane stability and modulates membrane ion channels for efficient nerve conduction.
The citric acid cycle is a central metabolic pathway involved in the regulation of carbohydrate, lipid, and amino acid metabolism, and its disruption due to thiamine deficiency inhibits the production of many molecules including the neurotransmitters glutamic acid and GABA.
Magnesium is an essential cofactor for thiamine pyrophosphokinase; magnesium deficiency impairs TPP formation even with adequate thiamine. This has clinical implications for patients with combined deficiencies.
Lack of thiamin causes the deficiency disease called beriberi, which has been known since antiquity. More recently, at least in industrialized nations, thiamin deficiency has been mainly found in association with chronic alcoholism, where it presents as the Wernicke-Korsakoff syndrome.
Wet beriberi is characterized by increased heart rate, swollen legs, and shortness of breath, while dry beriberi is characterized by difficulty walking and paralysis of lower limbs, confusion, pain, nausea, and vomiting. Thiamine deficiency can result in wet beriberi, which primarily affects myocardial energy metabolism and reduces peripheral vascular resistance, leading to high-output heart failure, characterized by cardiac enlargement, edema, and increased venous pressure. Thiamine supplementation is an effective treatment for wet beriberi and can lead to significant improvement in clinical symptoms.
Evidence strength: The link between thiamine deficiency and beriberi is one of the most firmly established relationships in nutritional medicine, underpinned by over a century of clinical, epidemiological, and biochemical evidence. The role of cocarboxylase (TPP) as the active metabolite mediating these effects is biochemically well established.
Wernicke encephalopathy (WE) and Korsakoff psychosis (KP), together termed Wernicke-Korsakoff syndrome (WKS), are distinct yet overlapping neuropsychiatric disorders associated with thiamine deficiency. Thiamine pyrophosphate, the biologically active form of thiamine, is essential for multiple biochemical pathways involved in carbohydrate utilization. Both genetic susceptibilities and acquired deficiencies as a result of alcoholic and non-alcoholic factors are associated with thiamine deficiency or its impaired utilization. WKS is underdiagnosed because of the inconsistent clinical presentation and overlapping of symptoms with other neurological conditions.
The mechanism is well characterized at the molecular level. In cell culture of patients with WE, the transketolase enzyme had reduced affinity for its cofactor, thiamine pyrophosphate, in contrast to a control group of cells from normal individuals. The abnormality persisted across continuous cell culture passages.
Wernicke's encephalopathy is an acute neuropsychiatric condition caused by an insufficient supply of thiamine to the brain. If undiagnosed or inadequately treated, it is likely to proceed to Korsakoff's syndrome. Thiamine diphosphate acts as a co-factor for a number of thiamine-dependent enzymes. Thiamine deficiency leads to a reduction in the activity of these enzymes, and this leads to alterations in mitochondrial activity, impairment of oxidative metabolism, decreased energy status, and eventually selective neuronal death.
There is insufficient evidence from randomized controlled clinical trials to guide clinicians in the dose, frequency, route, or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse. Thiamine has been established as the treatment of choice for over 50 years, but there is uncertainty about appropriate dosage and duration. Current practice guidelines are based on case reports and clinical experience.
Evidence from randomized controlled trials and other intervention studies is virtually absent for the specific conditions under which cocarboxylase or thiamine preparations should be used in WE.
Evidence strength: The mechanistic evidence linking TPP deficiency to Wernicke-Korsakoff syndrome is robust. However, formal high-quality RCT evidence for specific dosing protocols of thiamine (or cocarboxylase directly) in WE treatment remains scarce, and guidelines rest primarily on clinical consensus and case series.
In patients with congestive heart failure, thiamine deficiency has been demonstrated by determination of blood cocarboxylase. The oxidation of pyruvate to acetate requires thiamine in the form of cocarboxylase (thiamine pyrophosphate).
Multiple studies have shown that thiamine deficiency is more prevalent in heart failure patients than in the general population. Cell experiments have demonstrated that furosemide, a type of loop diuretic, can impede thiamine uptake by cardiac cells via its impact on the sodium gradient.
Thiamine deficiency appears to be not uncommon in patients with heart failure (HF), and supplementation with thiamine has been shown to improve cardiac function, urine output, weight loss, and signs and symptoms of HF. Recent evidence has indicated that supplementing with thiamine in HF patients has the potential to improve left ventricular ejection fraction.
A double-blind, randomized, controlled trial was conducted to assess the effect of thiamine supplementation on thiamine status and cardiac muscle function in patients with chronic heart failure (CHF), enrolling 30 patients with CHF and New York Heart Association (NYHA) class II to IV. Thiamine repletion improved left ventricular ejection fraction (LVEF) by 7% in the treatment group versus 0.7% in the placebo group.
In the experimental setting, the effects of a stable cocarboxylase solution were evaluated in the treatment of an experimentally created acute myocardial infarction in 14 healthy mongrel dogs. The left anterior descending artery was ligated for 60 minutes. In one group, cocarboxylase (150 mg/kg) was given systemically via a central line at 15 minutes and 45 minutes after ligation, while in a control group an equal amount of D5W was given. This animal study provides mechanistic support but cannot be directly extrapolated to human therapy.
CHF is a multifactorial clinical syndrome and thiamine supplementation alone may not be sufficient for effective treatment. However, it may be beneficial in cases of HF primarily caused by thiamine deficiency. In addition, correcting thiamine deficiency may confer benefits in terms of preventing further cardiac function deterioration and reducing the incidence of other complications in patients with CHF.
Evidence strength: Moderate. Several small RCTs and a systematic review indicate benefit of thiamine supplementation on cardiac function parameters, particularly LVEF, in thiamine-deficient heart failure patients. Most studies are small, and large-scale high-quality RCTs specifically using cocarboxylase (rather than thiamine hydrochloride) as the intervention are absent.
Thiamine and its derivatives have been demonstrated to prevent the activation of biochemical pathways induced by hyperglycemia in diabetes mellitus, including increased flux through the polyol pathway, formation of advanced glycation end-products (AGEs), activation of protein kinase C, and increased flux through the hexosamine biosynthesis pathway. Thiamine definitively has a role in the diabetic endothelial vascular diseases (micro- and macroangiopathy), lipid profile, retinopathy, nephropathy, cardiopathy, and neuropathy.
The reductive pathway of pentose phosphates is altered in clinical and experimental diabetes due to thiamine deficiency. The expression and activity of the thiamine-dependent enzyme transketolase is consequently reduced. Correction of thiamine deficiency in experimental diabetes with high-dose thiamine therapy restores the disposition of triose phosphates by the pentose phosphate reductive pathway in hyperglycemia.
A screening study of patients with type II diabetes found that 76% of patients tested had a low serum thiamine level. Basic research has suggested that thiamine deficiency may also be involved in the etiology of diabetic neuropathy by preventing the glycation of nerve fibers as well as apoptosis of endothelial cells.
Evidence strength: Mechanistic and animal/in-vitro evidence is strong. Human clinical evidence for the use of cocarboxylase (TPP) specifically β as distinct from thiamine or its more lipophilic derivative benfotiamine β in treating diabetic complications is limited. Benfotiamine has more RCT-level evidence in this domain. Most claims for cocarboxylase's role in diabetes involve biochemical pathways rather than endpoint-driven clinical trials.
A 2020 PMC-indexed study examined cocarboxylase in lung adenocarcinoma cells. Thiamine diphosphate (ThDP, cocarboxylase) is an essential activator of the 2-oxoglutarate dehydrogenase enzyme and inhibits p53βDNA binding in cancer cells. The researchers hypothesized that the pleiotropic regulator ThDP may be of importance for anticancer therapies. Despite the well-known antioxidant properties of thiamine, A549 cells exhibited decreases in their reducing power and glutathione level after incubation with 5 mM ThDP, not observed in non-cancer epithelial cells Vero. Moreover, thiamine deficiency elevated glutathione in A549 cells.
Evidence strength: This research is entirely at the cell-culture level and is preliminary. No human clinical evidence for anticancer use of cocarboxylase exists.
A clinical study examined cocarboxylase treatment in end-stage renal disease (ESRD) patients on maintenance hemodialysis. The administration of high doses of cocarboxylase (CC) to ESRD patients on maintenance hemodialysis was successful in terms of increasing erythrocyte transketolase activity (ETKA) value and thiamine levels in blood without any side effects. Supplementation with large doses of CC was noted to deserve further study because it promises to be another adjunct in the treatment of potential thiamine deficiency and metabolic disturbances in the course of dialysotherapy.
Evidence strength: Preliminary. This is a small, single study. The finding that cocarboxylase can increase biological markers of thiamine adequacy in dialysis patients is of interest but requires confirmation in larger, controlled trials.
Thiamine is converted in the liver, kidney, and leukocytes to its coenzyme forms, including thiamine diphosphate (thiamine pyrophosphate / cocarboxylase), thiamine monophosphate, thiamine triphosphate, and adenosine thiamine triphosphate.
The oral absorption and bioavailability of thiamine monophosphate and thiamine pyrophosphate (cocarboxylase) in humans have been reported in the scientific literature. However, doses above 2.5β5 mg of conventional thiamine salts are reported to be largely unabsorbed. Cellular absorption is entirely dependent on an active transport mechanism, further limiting tissue uptake.
Thiamine is rapidly absorbed after intramuscular (IM) injection. It is widely distributed to tissues, with the highest concentrations found in the heart, brain, liver, and kidneys. It is metabolized in the liver and excreted in the urine.
Because it is water-soluble and constantly excreted, the duration of action is short (approximately 24 hours), necessitating daily dosing during the treatment phase.
At physiological doses, little thiamine is present in the urine. With high oral doses, unchanged thiamine and metabolites are excreted.
Thiamine in the human body has a half-life of 17 days and is quickly exhausted, particularly when metabolic demands exceed intake.
The following dosages are reported directly from peer-reviewed literature and clinical references, not from product labeling or marketing sources:
Note: Because cocarboxylase is most commonly administered as a pharmaceutical (injectable) rather than an over-the-counter dietary supplement in most markets, standardized population-level dosage recommendations specific to cocarboxylase (as distinct from thiamine) are not established in the literature available from the sources reviewed here.
Cocarboxylase, also known as thiamine pyrophosphate or TPP, is a coenzyme form of thiamine (vitamin B1). While cocarboxylase is generally considered safe when used appropriately under medical supervision, it is important to be aware of potential side effects.
There are no withdrawal symptoms associated with stopping thiamine, other than the potential recurrence of deficiency symptoms if the underlying cause (e.g., poor diet) is not addressed.
One of the most commonly reported side effects of cocarboxylase is injection site reactions. When administered intramuscularly or intravenously, patients may experience pain, redness, swelling, or irritation at the site of injection. These reactions are typically mild and resolve on their own without needing further medical intervention.
Allergic reactions are a concern when taking cocarboxylase. Although rare, some individuals may develop hypersensitivity to the compound.
Among the etiological factors, thiamine deficiency may be suspected in subjects at risk for malnutrition by chronic alcohol abuse, long-term fasting, hunger strike, gastric surgery, bariatric surgery, malabsorption, hyperemesis gravidarum, cancer, HIV infection, chronic renal failure, severe sepsis, burns, or chronic long-term parenteral nutrition.
Deficiency may develop in alcoholics, elderly people, those with malabsorption, those using diuretics, those undergoing prolonged administration of antacids, dialysis, or folate deficiency, and in diets with a high content of refined grain products lacking fruits and vegetables.
Previous research has suggested that loop diuretics β commonly prescribed for heart failure β may contribute to thiamine deficiency by increasing urine flow. Cell experiments have demonstrated that furosemide, a type of loop diuretic, can impede thiamine uptake by cardiac cells via its impact on the sodium gradient. This interaction is clinically significant because heart failure patients who receive furosemide may be at compounded risk for TPP depletion.
Magnesium is an essential cofactor for thiamine pyrophosphokinase. Magnesium deficiency impairs TPP formation even with adequate thiamine. Concurrent magnesium deficiency can therefore blunt the clinical response to thiamine or cocarboxylase supplementation.
Raw fish and shellfish contain thiaminases that destroy thiamine, making regular raw fish consumption a deficiency risk factor. Some nutrients contain thiaminases which have the ability to break down vitamin B1 in the food, including raw fish, coffee, and tea leaves. Regular consumption of these items can reduce the effective supply of thiamine available for conversion to cocarboxylase.
Others reporting on bioavailability of conventional thiamine salts state that doses above 2.5β5 mg are largely unabsorbed. This is a pharmacokinetic limitation that directly applies to cocarboxylase as well, and is the primary reason parenteral administration is preferred in acute-deficiency settings.
Health conditions that Cocarboxylase may help support.
Body systems that Cocarboxylase may help support.
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