benfotiamine

What is benfotiamine

Benfotiamine (S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine or vitamin B1 (thiamin) 1). Benfotiamine is converted to thiamine, which serves as a key factor for three enzymes involved in generating energy from glucose 2). Oral administration of benfotiamine raises thiamine (vitamin B1) levels in blood and tissues to a much higher degree than the water-soluble thiamine salts. Benfotiamine is mainly dephosphorylated in the intestinal mucosal cells to generate a lipid-soluble compound, S-benzoythiamine 3). S-benzoythiamine can be promptly transformed to water-soluble thiamine (vitamin B1) and further transformed to several phosphorylated metabolites, such as thiamine monophosphate and thiamine diphosphate (TDP; also known as thiamine pyrophosphate) 4). Originally, benfotiamine was developed in Japan to treat alcoholic neuropathy and other painful neurological complications 5). Nowadays benfotiamine is largely used for treatment of type 2 diabetes and diabetic complications such as diabetic neuropathy 6), diabetic nephropathy, diabetic retinopathy 7) and cardiac angiopathy 8). Other reports suggest that benfotiamine can reverse cardiomyocyte contractile dysfunction 9) and reduce the neuropathic pain 10). During the last few years, there is considerable interest in the therapeutic potential of benfotiamine and its protective effect was elucidated in diabetic complications, such as diabetic neuropathy 11) and alcoholic neuropathy 12). Also, benfotiamine’s beneficial effect was shown in the animal model of Alzheimer’s disease 13), 14), 15). Although a pilot study of benfotiamine has found cognitive improvement in Alzheimer’s disease patients, no clinical studies have determined whether it can prevent age-related cognitive decline or dementia in healthy adults. Benfotiamine significantly reduced the formation of amyloid plaques in APP/PS1 mice 16) and was able to attenuate the glucose-induced increase in beta-amyloid protein synthesis in isolated HEK293 cells 17) and that it also could decrease the tau hyperphosphorylation and improve cognitive deficits in animal Alzheimer’s disease model 18). Further study has shown that benfotiamine has cognitive improvement in patients with mild to moderate Alzheimer’s disease 19). In spite of beneficial effects mentioned above, it also has been proposed that benfotiamine as a protective agent for Alzheimer’s disease treatment was based on the prevention of abnormal glucose metabolism 20). Benfotiamine appears to be safe when used at standard doses.

Unlike thiamine, benfotiamine’s structure contains an open thiazole ring that closes once it is absorbed, producing biologically active thiamine (see Figure 1). Several clinical trials in healthy adults have demonstrated the superior absorption of benfotiamine, a lipid-soluble thiamine analogues, compared to water-soluble thiamine salts 21). Higher plasma thiamine levels are achieved with oral benfotiamine administration and blood and tissue concentrations are maintained longer. Oral benfotiamine dosages in these studies ranged from 40-250 mg daily 22). Benfotiamine is absorbed via passive diffusion through the intestinal mucosa and is rapidly converted to biologically active thiamine. Peak plasma concentrations of thiamine after oral benfotiamine administration are at least five times greater than those observed after oral administration of water-soluble thiamine salts. Half-life of benfotiamine is similar to thiamine salts, but oral bioavailability of benfotiamine eight days after administration is roughly 25 percent of the original dose, about 3.6 times greater than after an oral dose of a thiamine salt 23).

Figure 1. Benfotiamine chemical structure

Benfotiamine chemical structure

What is thiamine?

Thiamine also known as thiamin or vitamin B1, is naturally present in some foods, added to some food products, and available as a dietary supplement. Thiamine or vitamin B1 plays a critical role in energy metabolism and, therefore, in the growth, development, and function of cells 24). Thiamine is found naturally in many foods and is added to some fortified foods. Food sources of thiamine include whole grains, meat, and fish 25). Breads, cereals, and infant formulas in the United States and many other countries are fortified with thiamine 26). The most common sources of thiamine in the U.S. diet are cereals and bread 27). Pork is another major source of thiamine vitamin. Dairy products and most fruits contain little thiamine 28). About half of the thiamine in the U.S. diet comes from foods that naturally contain thiamine; the remainder comes from foods to which thiamine has been added 29).

You can get the recommended amounts of thiamine by eating a variety of foods, including the following:

  • Whole grains and fortified bread, cereal, pasta, and rice
  • Meat (especially pork) and fish
  • Legumes (such as black beans and soybeans), seeds, and nuts

Heating foods containing thiamine can reduce their thiamine content. For example, bread has 20%–30% less thiamine than its raw ingredients, and pasteurization reduces thiamine content (which is very small to begin with) in milk by up to 20% 30). Because thiamine dissolves in water, a significant amount of the vitamin is lost when cooking water is thrown out 31). Processing also alters thiamine levels in foods; for example, unless white rice is enriched with thiamine, it has one tenth the amount of thiamine in unenriched brown rice 32).

Data on the oral bioavailability of thiamine from food are very limited 33). Some studies do show, however, that thiamine absorption increases when intakes are low 34). Several food sources of thiamine are listed in Table 2 below.

Ingested thiamine from food and dietary supplements is absorbed by the small intestine through active transport at nutritional doses and by passive diffusion at pharmacologic doses 35). Most dietary thiamine is in phosphorylated forms and intestinal phosphatases hydrolyze them to free thiamine before the vitamin is absorbed 36). The remaining dietary thiamine is in free (absorbable) form 37). Humans store thiamine primarily in the liver, but in very small amounts 38). Thiamine (vitamin B1) has a short half-life, so people require a continuous supply of it from the diet.

About 80% of the approximately 25–30 mg of thiamine in the adult human body is in the form of thiamine diphosphate (TDP; also known as thiamine pyrophosphate), the main metabolically active form of thiamine. Bacteria in the large intestine also synthesize free thiamine and thiamine diphosphate (TDP), but their contribution, if any, to thiamine nutrition is currently unknown 39). Thiamine diphosphate (TDP) serves as an essential cofactor for five enzymes involved in glucose, amino acid and lipid metabolism 40).

Levels of thiamine in the blood are not reliable indicators of thiamine status. Thiamine status is often measured indirectly by assaying the activity of the transketolase enzyme, which depends on thiamine diphosphate (TDP), in erythrocyte hemolysates in the presence and absence of added thiamine diphosphate (TDP) 41). The result, known as the “TDP effect,” reflects the extent of unsaturation of transketolase with TDP. The result is typically 0%–15% in healthy people, 15%–25% in those with marginal deficiency, and higher than 25% in people with deficiency. Another commonly used measure of thiamine status is urinary thiamine excretion, which provides data on dietary intakes but not tissue stores 42). For adults, excretion of less than 100 microgram (mcg)/day thiamine in urine suggests insufficient thiamine intake, and less than 40 mcg/day indicates an extremely low intake 43).

How much thiamine do I need?

The amount of thiamine (vitamin B1) you need depends on your age and sex. Average daily recommended amounts are listed below in milligrams (mg). In the US the average dietary thiamine intake for young adult men is about 2 mg/day and 1.2 mg/day for young adult women. A survey of people over the age of 60 found an average dietary thiamine intake of 1.4 mg/day for men and 1.1 mg/day for women 44). However, institutionalization and poverty both increase the likelihood of inadequate thiamin intake in the elderly 45). Wholegrain cereals, legumes (e.g., beans and lentils), nuts, lean pork, and yeast are rich sources of thiamin 46). Because most of the thiamine is lost during the production of white flour and polished (milled) rice, white rice and foods made from white flour (e.g., bread and pasta) are fortified with thiamin in many Western countries. A number of thiamin-rich foods are listed in Table 2 below, along with their thiamine content in milligrams (mg). For more information on the nutrient content of foods, search USDA’s FoodData Central.

Table 1. Recommended Dietary Allowances (RDAs) for Thiamine

AgeMaleFemalePregnancyLactation
Birth to 6 months*0.2 mg0.2 mg
7–12 months*0.3 mg0.3 mg
1–3 years0.5 mg0.5 mg
4–8 years0.6 mg0.6 mg
9–13 years0.9 mg0.9 mg
14–18 years1.2 mg1.0 mg1.4 mg1.4 mg
19-50 years1.2 mg1.1 mg1.4 mg1.4 mg
51+ years1.2 mg1.1 mg

Footnote: * Adequate Intake (AI) = an intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA). Recommended Dietary Allowance (RDA) = average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

[Source 47) ]

Food sources of thiamine

Food sources of thiamine include whole grains, meat, and fish 48). Breads, cereals, and infant formulas in the United States and many other countries are fortified with thiamine 49). The most common sources of thiamine in the U.S. diet are cereals and bread 50). Pork is another major source of thiamine vitamin. Dairy products and most fruits contain little thiamine 51). About half of the thiamine in the U.S. diet comes from foods that naturally contain thiamine; the remainder comes from foods to which thiamine has been added 52).

Table 2. Thiamine content of selected foods

FoodMilligrams
(mg) per
serving
Percent
Daily Value*
Rice, white, long grain, enriched, parboiled, ½ cup1.4117
Breakfast cereals, fortified with 100% of the daily value for thiamine, 1 serving1.2100
Egg noodles, enriched, cooked, 1 cup0.542
Pork chop, bone-in, broiled, 3 ounces0.433
Trout, cooked, dry heat, 3 ounces0.433
Black beans, boiled, ½ cup0.433
English muffin, plain, enriched, 1 muffin0.325
Mussels, blue, cooked, moist heat, 3 ounces0.325
Tuna, Bluefin, cooked, dry heat, 3 ounces0.217
Macaroni, whole wheat, cooked, 1 cup0.217
Acorn squash, cubed, baked, ½ cup0.217
Rice, brown, long grain, not enriched, cooked, ½ cup0.18
Bread, whole wheat, 1 slice0.18
Orange juice, prepared from concentrate, 1 cup0.18
Sunflower seeds, toasted, 1 ounce0.18
Beef steak, bottom round, trimmed of fat, braised, 3 ounces0.18
Yogurt, plain, low fat, 1 cup0.18
Oatmeal, regular and quick, unenriched, cooked with water, ½ cup0.18
Corn, yellow, boiled, 1 medium ear0.18
Milk, 2%, 1 cup0.18
Barley, pearled, cooked, 1 cup0.18
Cheddar cheese, 1½ ounces00
Chicken, meat and skin, roasted, 3 ounces00
Apple, sliced, 1 cup00

Footnotes: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed daily values to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The Daily Value for thiamine is 1.2 mg for adults and children age 4 years and older 53). FDA does not require food labels to list thiamine content unless thiamine has been added to the food. Foods providing 20% or more of the Daily Value are considered to be high sources of a nutrient, but foods providing lower percentages of the Daily Value also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) Food Data Central website (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing thiamine arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/Thiamin-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/Thiamin-Food.pdf).

[Source 54) ]

Who is at risk of thiamine deficiency?

The following groups are among those most likely to have inadequate thiamine (vitamin B1) status. Thiamine levels are significantly lower than normal in about 20 percent of alcoholics for several reasons: (1) the diet of an alcoholic tends to be heavy in carbohydrates, resulting in decreased thiamine intake; (2) absorption of thiamine and other nutrients is impaired due to the effects of chronic alcohol in-take on the gut’s absorptive mechanisms; (3) chronic alcohol consumption reduces the liver’s ability to store thiamine; and (4) acetaldehyde, an ethanol metabolite, interferes with thiamine utilization 55). These factors result in thiamine deficiency, which in many alcoholics does not respond to supplementation with oral water-soluble thiamine salts. Thiamine deficiency is also frequently observed in patients with diabetic neuropathy 56) and in patients who have undergone gastrectomy 57) or bariatric surgery 58) who subsequently develop neuropathies due to malabsorption.

People with alcohol dependence

In highly industrialized countries, chronic alcohol use disorders appear to be the most common cause of thiamine deficiency 59). Chronic alcohol abuse is associated with thiamine deficiency due to low dietary intake, impaired absorption and utilization, and increased excretion of the vitamin 60). Up to 80% of people with chronic alcoholism develop thiamine deficiency because ethanol reduces gastrointestinal absorption of thiamine, thiamine stores in the liver, and thiamine phosphorylation 61). Also, people with alcoholism tend to have inadequate intakes of essential nutrients, including thiamine.

Chronic alcohol feeding to rats showed a decrease in the active absorption of thiamine linked to the inhibition of thiamine membrane transporter thiamine transporter 1 (THTR-1) in the intestinal epithelium 62). Alcohol consumption in rats also decreases the levels of thiamine transporter 1 (THTR-1) and thiamine transporter 2 (THTR-2) in renal epithelial cells, thus limiting thiamine re-uptake by the kidneys 63).

Older adults

Up to 20%–30% of older adults have laboratory indicators that suggest some degree of thiamine deficiency 64). Possible reasons include low dietary intakes, a combination of chronic diseases, concomitant use of multiple medications, and low absorption of thiamine as a natural result of aging 65). Some small studies have found that the risk of thiamine deficiency is particularly high in elderly people who reside in an institution 66).

People with HIV or AIDS

People with HIV (human immunodeficiency virus) infection have an increased risk of thiamine deficiency and its complications, including beriberi and Wernicke-Korsakoff syndrome 67). Autopsies of 380 people with AIDS (acquired immunodeficiency syndrome) found that almost 10% had Wernicke’s encephalopathy 68) and some experts believe that thiamine deficiency is underdiagnosed in this population 69). The association between thiamine deficiency and HIV or AIDS is probably due to malnutrition as a result of the catabolic state associated with AIDS 70).

People with diabetes

Some small studies have found that thiamine levels in plasma are up to 76% lower in people with type 1 diabetes than in healthy volunteers and 50%–75% lower in people with type 2 diabetes 71). Other studies have shown a higher risk of thiamine deficiency in people with type 1 and/or type 2 diabetes based on tests of erythrocyte transketolase activity 72). These lower thiamine levels might be due to increases in clearance of thiamine by the kidneys. The relevance of these effects to clinical prognosis or outcomes is not known 73).

People who have undergone bariatric surgery

Bariatric surgery is surgery that affects the stomach and how food is digested. Bariatric surgery is designed to make the stomach much smaller, which causes the person to feel full after eating only a small amount of food. Bariatric surgery for weight loss is associated with some risks, including severe thiamine deficiency due to malabsorption that can lead to beriberi or Wernicke’s encephalopathy. A 2008 literature review identified 84 cases of Wernicke’s encephalopathy after bariatric surgery (primarily gastric bypass surgery) between 1991 and 2008 74). About half of these patients experienced long-lasting neurologic impairments. Micronutrient supplements that include thiamine are almost always recommended for patients following bariatric surgery to avoid deficiencies 75).

What are health risks from excessive thiamine?

Your body excretes excess amounts of thiamine in the urine 76). Because of the lack of reports of adverse effects from high thiamine intakes (50 mg/day or more) from food or supplements, the Food and Nutrition Board at the Institute of Medicine of the National Academies did not establish upper limits (ULs) for thiamine 77). They hypothesize that the apparent lack of toxicity may be explained by the rapid decline in absorption of thiamine at intakes above 5 mg. However, the Food and Nutrition Board at the Institute of Medicine of the National Academies noted that in spite of the lack of reported adverse events, excessive intakes of thiamine could have adverse effects.

What is benfotiamine used for?

Wernicke-Korsakoff syndrome

Wernicke-Korsakoff syndrome is a brain disorder, due to thiamine deficiency and one of the most severe neuropsychiatric complication of alcohol abuse that has been associated with both Wernicke’s encephalopathy and Korsakoff syndrome. The term Wernicke-Korsakoff syndrome refers to two different syndromes, each representing a different stage of the disease. Wernicke’s encephalopathy represents the “acute” phase and Korsakoff’s syndrome represents the “chronic” phase 78). However, they are used interchangeable in many sites. Wernicke’s encephalopathy is characterized by confusion, abnormal stance and gait (ataxia), and abnormal eye movements (nystagmus). Korsakoff’s syndrome is observed in a small number of patients. It is a type of dementia, characterized by memory loss and confabulation (filling in of memory gaps with data the patient can readily recall) and involvement of the heart, vascular, and nervous system. Wernicke-Korsakoff syndrome mainly results from chronic alcohol use, but also from dietary deficiencies, prolonged vomiting, eating disorders, systemic diseases (cancer, AIDS, infections), bariatric surgery, transplants, or the effects of chemotherapy 79). Studies indicate that there may be some genetic predisposition for the disease. Treatment involves supplementing the diet with thiamine. Wernicke encephalopathy is an acute syndrome and requires emergency treatment to prevent death and neurologic complications. In cases where the diagnosis is not confirmed, patients should still be treated while additional evaluations are completed 80).

The authors of a 2013 Cochrane review of thiamine to treat or prevent Wernicke-Korsakoff syndrome found only two studies that met their inclusion criteria, and one of these studies has not been published 81). These randomized, double-blind, placebo-controlled trials compared thiamine 5 mg/day by mouth for 2 weeks or daily intramuscular doses of 5 to 200 mg/day thiamine over 2 consecutive days in a total of 177 people with a history of chronic alcohol use. The Cochrane review authors concluded that the evidence from randomized clinical trials is insufficient to guide healthcare providers in selecting the appropriate dose, frequency, duration, or route of thiamine supplementation to treat or prevent Wernicke-Korsakoff syndrome in patients with alcohol abuse 82).

The authors of the European Federation of Neurological Societies guidelines for diagnosing, preventing, and treating Wernicke’s encephalopathy note that even high doses of oral thiamine supplements might not be effective in raising blood thiamine levels or curing Wernicke’s encephalopathy 83). They recommend 200 mg thiamine, preferably intravenously, three times daily (total of 600 mg/day) until the signs and symptoms stop, along with a balanced diet. In its guidelines for managing Wernicke’s encephalopathy in emergency departments, the Royal College of Physicians in London supports the administration of oral thiamine hydrochloride (100 mg three times a day) in patients with adequate dietary intakes of thiamine and no signs or symptoms of Wernicke’s encephalopathy 84). However, the authors recommend parenteral thiamine supplementation for patients at high risk, such as those with ataxia, confusion, and a history of chronic alcohol misuse, because oral supplementation is unlikely to produce adequate blood levels.

Diabetes

The proportion of people with type 1 or type 2 diabetes who have poor thiamine status based on erythrocyte transketolase activity ranges from 17% to 79% in studies conducted to date 85). In a study of 76 consecutive patients with type 1 or type 2 diabetes, for example, 8% had mild thiamine deficiency and 32% had moderate deficiency based on assays of the transketolase enzyme 86).

Some small studies have shown that oral supplementation with 150–300 mg/day thiamine can decrease glucose levels in patients with type 2 diabetes or impaired glucose tolerance 87). However, the authors of these studies did not assess the potential clinical significance of these findings.

A few small randomized studies have assessed the effects of benfotiamine supplements on diabetic neuropathy. Three studies found that, compared to placebo, 120–900 mg/day benfotiamine with or without other B-vitamins decreased the severity of neuropathy symptoms and lowered urinary albumin excretion (a marker of early-stage diabetic nephropathy) 88), 89). However, another study found no effect of 900 mg/day benfotiamine on urinary excretion of albumin or kidney injury molecule-1, a marker of kidney injury 90).

Well-designed studies with larger sample sizes and longer durations are required to determine whether thiamine supplements can reduce glucose levels in patients with diabetes or decrease diabetic compications.

Diabetic neuropathy

Benfotiamine is a transketolase activator that reduces tissue advanced glycation end-products (AGEs). Several independent pilot studies have demonstrated benfotiamine’s effectiveness in diabetic polyneuropathy 91). The Benfotiamine in the treatment of diabetic polyneuropathy (BEDIP) 3-week study used a 400 mg daily dose 92) and the Benfotiamine in Diabetic Polyneuropathy (BENDIP) 6-week study used 300 and 600 mg daily doses 93); both studies demonstrated subjective improvements in neuropathy scores in the groups receiving benfotiamine, with a pronounced decrease in reported pain levels 94). In a 12-week study, the use of benfotiamine plus vitamin B6 or vitamin B12 significantly improved nerve conduction velocity in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine (100 mg) has been shown to improve diabetic polyneuropathy in a small number of diabetic patients 95). The use of benfotiamine in combination with other antioxidant therapies such as alpha-Lipoic acid are commercially available.

In a double-blind, randomized, placebo-controlled pilot study, 20 subjects with diabetic polyneuropathy were given two 50-mg tablets benfotiamine four times daily (400 mg total daily dose), and 20 subjects received placebo 96). Study duration was three weeks, and assessment was via neuropathy symptoms and vibration sensation scores from both physician and patient. In the treatment group a statistically significant improvement in the neuropathy score was reported compared to placebo. The most significant improvement reported was decrease in pain, whereas, there was no significant improvement in the tuning fork test – a measure of vibration perception 97).

Several studies have investigated the effect of benfotiamine in combination with other B vitamins in the treatment of diabetic neuropathy 98). One study included 45 patients with painful peripheral polyneuropathy. Thirty patients received Milgamma (50 mg benfotiamine and 250 μg vitamin B12 as cyanocobalamin per tablet) at a dose of two tablets four times daily for three weeks (total daily dose: 400 mg ben-fotiamine and 2,000 μg cyanocobalamin), followed by one tablet three times daily for nine weeks 99). The second group of 15 patients received a conventional B-vitamin supplement at a dose of two tablets three times daily for the entire 12-week period. Changes in pain severity and vibration perception thresholds were measured at baseline and at the end of three months 100). All Milgamma-treated patients experienced significant relief in neuropathic pain and a dramatic improvement in vibration perception thresholds. In patients receiving the conventional B-vitamin treatment, slight, non-statistically significant improvement was noted 101).

In a second trial lasting six weeks, 36 subjects with painful diabetic neuropathy were divided into three groups of 12 each. The first group re-ceived Milgamma-N (40 mg benfotiamine, 90 mg pyridoxine, and 250 μg man-made vitamin B12 as cyanocobalamin per capsule) at a dose of two capsules four times daily (320 mg benfotiamine, 720 mg pyridoxine, and 2,000 μg cyanocobalamin daily) 102). The second group received Milgamma-N at a lower dose of one capsule three times daily (120 mg benfotiamine, 270 mg pyridoxine, and 750 μg cyanocobalamin daily), while the third group received one capsule three times daily of straight benfotiamine (150 mg benfotiamine daily). Neuropathy was assessed via pain and vibration sensation at baseline and after three and six weeks. Patients in all three groups reported beneficial therapeutic effects, even at three weeks, although the most significant improve-ment was reported by patients receiving the highest-dose benfotiamine 103).

A double-blind, randomized, placebo-controlled 12-week study examined the effectiveness of another benfotiamine combination containing both vitamins B6 and vitamin B12 in 24 diabetic patients with polyneuropathy. A statistically significant improvement in nerve conduction velocity in the peroneal nerve was observed in the treatment group compared to placebo. A trend toward improvement in vibration sensation was also reported in the treatment group; long-term observation of nine patients over a nine-month period supported the results 104).

Alcoholic neuropathy

Chronic alcoholics commonly develop polyneuropathy as a result of dietary deficiency and poor absorption of thiamine. Benfotiamine’s effect on neuropathy in alcoholics was investigated and compared to thiamine in a randomized, multicenter, placebo-controlled, double-blind study of 84 subjects over an eight-week period 105). Benfotiamine was given orally at 320 mg daily during weeks 1-4, followed by 120 mg daily during weeks 5-8. A second group received Milgamma-N (providing a total daily dose of 320 mg benfotiamine, 720 mg pyridoxine, and 2,000 μg man-made vitamin B12 cyanocobalamin) during weeks 1-4 and a total daily dose of 120 mg benfotiamine, 270 mg pyridoxine, and 750 μg cyanocobalamin during weeks 5-8; a third group received placebo 106).

Parameters measured included vibration perception in the great toe, ankle, and tibia; neural pain intensity; motor function and paralysis; sensory function; and overall neuropathy score and clinical assessment. Neuropathy was scored from 0 (maximum clinical expression of neuropathy symptoms) to 16 (free of symptoms) with scores of ≥10 representing a mild clinical picture. Although benfotiamine therapy was superior to Milgamma-N and placebo for all parameters, results reached statistical significance only for motor function and paralysis and overall neuropathy score. Patients taking benfotiamine had a significantly lower degree of paralysis (90%) than those in the placebo group (60.7%) or the Milgamma-N group (53.9%). Overall neuropathy scores in the benfotiamine group were ≥10 in 93.3 percent of patients, compared to 67.9 percent in the placebo group and 76.9 percent in the Milgamma-N group 107).

Why the benfotiamine-alone group had better results than the Milgamma-N group, despite the fact that the benfotiamine dosage was equivalent, is not completely understood. The authors hypothesize the vitamin B6 and vitamin B12 might compete with the effects of thiamine (vitamin B1) in the Milgamma-N group. On the other hand, in the case of diabetic neuropathy, the positive effects of the combination may be due to the fact that deficiencies of vitamins B1, B6, and B12 are implicated in its possible pathogenesis; whereas, alcoholic neuropathy is associated with primarily a thiamine (vitamin B1) deficiency.

Diabetic retinopathy

In diabetics, the development of microvascular disease is a leading cause of retinopathy and blindness 108). In a study with both animal and in vitro arms, researchers in Germany discovered benfotiamine administration prevented experimental diabetic retinopathy in rats 109).

Advanced glycation end-products (AGE) are the result of non-enzymatic addition of glucose or other saccharides to proteins, lipids, and nucleotides 110). In diabetes, excess glucose accelerates AGE generation that leads to intra- and extracellular protein cross-linking and protein aggregation. Activation of AGE receptors alters intracellular signaling and gene expression, releases pro-inflammatory molecules, and results in an increased production of reactive oxygen species (ROS) that contribute to diabetic microvascular complications 111).

Protein kinase C (PKC) activation is a critical step in the pathway to diabetic microvascular complications 112). It is activated by both hyperglycemia and disordered fatty-acid metabolism, resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), endothelin (ET-1), and intercellular adhesion molecules (ICAMs) 113).

Diabetic retinopathy is associated with increased advanced glycation end-products (AGE) (a sign of oxidative stress) and elevations in retinal protein kinase C (PKC) activity. In vitro, a 50 μM concentration of benfotiamine completely prevented increases in advanced glycation end-products (AGE) and protein kinase C (PKC) 114).

These same researchers also examined the in vivo effect of benfotiamine on retinas of diabetic rats; non-diabetic rats and untreated diabetic rats served as controls 115). Diabetic rats receiving benfotiamine for 36 weeks demonstrated a 2.5-fold increase in transketolase activity compared to untreated diabetic rats. Hexosamine pathway activity, protein kinase C (PKC) activity, advanced glycation end-products (AGE) formation, and nuclear factor-kappa B (NF-κB) activation in retinas of all three groups were analyzed. In diabetic rats, benfotiamine administration for 36 weeks reduced UDP-GlcNAc to levels lower than those observed in non-diabetic rats, normalized AGE levels and PKC activity, and inhibited activation of NF-κB in diabetic rat retinas. The results of this study indicate lipid-soluble benfotiamine may be of therapeutic benefit in patients with diabetic retinopathy by preventing or delaying the onset and progression of microvascular changes in the retina 116).

Heart failure

Severe thiamine deficiency (wet beriberi) can lead to impaired cardiac function and ultimately congestive heart failure (CHF). Although cardiac manifestations of beriberi are rarely encountered in industrialized countries, congestive heart failure due to other causes is common, especially in the elderly. The rates of poor thiamine status in patients with heart failure have ranged in studies from 21% to 98% 117). Explanations for this association include older age, comorbidities, insufficient dietary intake, treatment with diuretics, and frequent hospitalizations 118).

The authors of one study reported that 33% of 100 patients with chronic heart failure had thiamine deficiency compared to 12% of 50 healthy volunteers 119). Rates of thiamine deficiency were even higher when the investigators excluded those who used thiamine supplements. The different rates of thiamine deficiency in patients with heart failure in these and other studies are probably due to differences in nutrition status, comorbidities, medications and dietary supplements used, and techniques used to measure thiamine status 120).

Diuretics used in the treatment of congestive heart failure, notably furosemide, have been found to increase thiamine excretion, potentially leading to marginal thiamine deficiency 121). A number of studies have examined thiamine nutritional status in congestive heart failure patients and most found a fairly high incidence of thiamine deficiency, as measured by assays of transketolase activity. As in the general population, older congestive heart failure patients were found to be at higher risk of thiamine deficiency than younger ones 122). An important measure of cardiac function in congestive heart failure is the left ventricular ejection fraction (LVEF), which can be assessed by echocardiography. One study in 25 patients found that furosemide use, at doses of 80 mg/day or greater, was associated with a 98% prevalence of thiamine deficiency 123). In a randomized, double-blind study of 30 congestive heart failure patients, all of whom had been taking furosemide (80 mg/day) for at least three months, intravenous (IV) thiamine therapy (200 mg/day) for seven days resulted in an improved left ventricular ejection fraction (LVEF) compared to IV placebo 124). When all 30 of the congestive heart failure patients in that study subsequently received six weeks of oral thiamine therapy (200 mg/day), the average LVEF improved by 22%. This finding may be relevant because improvements in LVEF have been associated with improved survival in congestive heart failure patients 125). However, conclusions from studies published to date are limited due to the small sample sizes of the studies, lack of randomization in some studies, and a need for more precise assays of thiamine nutritional status. Presently, the need for thiamine supplementation in maintaining cardiac function in congestive heart failure patients remains controversial.

The authors of a systematic literature review and meta-analysis found two randomized, double-blind, placebo-controlled trials of thiamine supplementation in people with heart failure that met their eligibility criteria 126). In these trials, thiamine supplements significantly improved net change in left ventricular ejection fraction. The authors did not assess the clinical significance of this finding, however.

More research is needed to determine whether thiamine supplements might benefit people with heart failure, even if they have normal thiamine status.

Alzheimer’s disease

Alzheimer’s disease is the most common type of dementia. Dementia is a syndrome (a group of related symptoms) associated with an ongoing decline of brain functioning. It can affect memory, thinking skills and other mental abilities. The exact cause of Alzheimer’s disease is not yet fully understood, although a number of things are thought to increase your risk of developing the condition. These include:

  • increasing age
  • a family history of the condition
  • untreated depression, although depression can also be one of the symptoms of Alzheimer’s disease
  • lifestyle factors and conditions associated with cardiovascular disease

According to animal model studies, thiamine deficiency might play a role in the development of Alzheimer’s disease 127). For example, thiamine deficiency produces oxidative stress in neurons, death of neurons, loss of memory, plaque formation, and changes in glucose metabolism—all markers of Alzheimer’s disease. Autopsy studies have shown that transketolase and other thiamine-dependent enzymes have decreased activity in the brains of people with Alzheimer’s disease 128).

Few studies have assessed the prevalence of thiamine deficiency in people with Alzheimer’s disease. One of these studies found that 13% of 150 patients with cognitive impairment and acute-onset behavioral disturbances were considered thiamine deficient based on plasma levels 129).

The authors of a 2001 Cochrane review assessed three double-blind, randomized trials (including two crossover trials) that compared the effects of 3 g/day oral thiamine to placebo on cognitive function in patients with Alzheimer’s type dementia 130). The three studies randomly assigned fewer than 20 patients each, and the two crossover studies did not include a washout period 131), 132), 133). The review authors stated that it was not possible to draw any conclusions from these three studies because they were small and the publications describing them did not provide enough detail to combine these data in a meta-analysis 134). Larger, well-designed studies are needed to determine whether thiamine supplements are beneficial for Alzheimer’s disease.

There is only one small open-label, uncontrolled study which showed that benfotiamine treatment for 18 months resulted in improved cognitive function in Alzheimer’s patients, though the treatment did not decrease levels of beta-amyloid, a protein common in people with Alzheimer’s disease 135). An ongoing phase II placebo-controlled clinical trial is testing whether benfotiamine can slow cognitive decline in patients with amnestic mild cognitive impairment and Alzheimer’s disease is now underway, however results have not yet been published 136).

End-stage renal disease

The thiamine pool in the body exists mainly as thiamine diphosphate (TDP), 80 percent of which is found in the erythrocytes (red blood cells). Many patients with chronic renal insufficiency demonstrate decreased erythrocyte transketolase activity (a sign of thiamine deficiency) compared to healthy subjects. Consequently, many of these patients also develop neuropathies secondary to kidney disease 137). In a clinical trial of 20 patients with end-stage renal disease, the effect of benfotiamine or thiamine nitrate on TDP blood levels and red blood cell transketolase activity was evaluated. Patients were given single oral doses of 100 mg thiamine nitrate or benfotiamine and blood levels analyzed via high-performance liquid chromatography over a 24-hour period. Compared to patients in the thiamine nitrate group, patients receiving benfotiamine experienced higher TDP concentrations in red blood cells as well as significantly improved erythrocyte transketolase activity. Benfotiamine may be of clinical benefit in thiamine-deficient patients with chronic renal insufficiency 138).

Peripheral vascular disease

In two separate studies, a group of Italian researchers from the University of Turin examined the effect of benfotiamine on endothelial defects and apoptosis in human umbilical vein endothelial cells cultured in the presence of high glucose 139), 140). Either thiamine or benfotiamine prevented AGE production 141) and apoptosis 142) in these cell cultures.

Aldose reductase activity and sorbitol levels are increased in human endothelial cells cultured in glucose, providing one mechanism for endothelial dysfunction in diabetes. Researchers found the addition of either thiamine or benfotiamine resulted in normalized intracellular glucose levels, decreased sorbitol concentrations, and reduction in aldose re-ductase activity 143).

Using an animal model of hind limb ischemia in diabetic mice, researchers in England investigated whether benfotiamine administration was of benefit in reparative neovascularization. Mice were randomly assigned to receive 80 mg/kg/day benfotiamine or placebo in drinking water. Two weeks after benfotiamine initiation, ischemia was surgically induced in the left hind limb, and limb recovery was determined at two weeks post-surgery. Parameters of limb recovery were analyzed via Doppler flowmetry and histological analysis of adductor muscles in the affected limb. It was demonstrated that benfotiamine improves healing and neovascularization in ischemic limbs of diabetic animals, probably via protein kinase B potentiation of angiogenesis, manifesting in increased perfusion and oxygenation of ischemic tissue and improved blood flow to the limb. Benfotiamine also stimulated capillarization and reduced apoptosis in ischemic muscle tissue 144).

Metabolic diseases

Thiamine supplementation is included in the clinical management of genetic diseases that affect the metabolism of carbohydrates and branched-chain amino acids (BCAAs).

Thiamine-responsive pyruvate dehydrogenase complex deficiency

Mutations in pyruvate dehydrogenase complex (PDHC) prevent the efficient oxidation of carbohydrates in affected individuals. Pyruvate dehydrogenase complex (PDHC) deficiency is commonly characterized by lactic acidosis, neurologic and neuromuscular degeneration, and death during childhood. The patients who respond to thiamine treatment (from few mg/day to doses above 1,000 mg/day) exhibit PDHC deficiency due to the decreased affinity of PDHC for thiamine pyrophosphate (TPP) 145). Although thiamine supplementation can reduce lactate accumulation and improve the clinical features in thiamine-responsive patients, it does not constitute a cure 146).

Maple syrup urine disease

Inborn errors of branched-chain amino acid (BCAA) metabolism lead to thiamine-responsive branched-chain ketoaciduria, also known as maple syrup urine disease. Alterations in the BCAA catabolic pathway result in neurologic dysfunction caused by the accumulation of branched-chain amino acids (BCAAs) and their derivatives, branched-chain ketoacids. The therapeutic approach includes a synthetic diet with reduced BCAA content, and thiamine (10-1,000 mg/day) is supplemented to patients with mutations in the E2 subunit of the BCKDH complex 147). In thiamine-responsive individuals, the supplementation has been proven effective to correct the phenotype without recourse to the BCAA restriction diet.

Thiamine-responsive megaloblastic anemia

Mutations in thiamine transporter 1 (THTR-1) that impair intestinal thiamine uptake and cause thiamine deficiency have been found in patients affected by thiamine-responsive megaloblastic anemia. This syndrome is characterized by megaloblastic anemia, diabetes mellitus, and deafness. A review of 30 cases reported additional neurologic, visual, and cardiac impairments 148). Oral doses of thiamine (up to 300 mg/day) maintain health and correct hyperglycemia in prepubescent children. However, after puberty, a decline in pancreatic function results in the requirement of insulin together with thiamine to control the hyperglycemia. One study also reported that the treatment of a four-month-old girl with 100 mg/day of thiamine did not prevent hearing loss at 20 months of age 149).

Biotin-responsive basal ganglia disease

Biotin-responsive basal ganglia disease, also called thiamine metabolism dysfunction syndrome-2, is caused by mutations in the gene coding for thiamine transporter 2 (THTR-2). The clinical features appear around three to four years of age and include sub-acute encephalopathy (confusion, drowsiness, altered level of consciousness), ataxia, and seizures. A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia was recently conducted. The data showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamine supplementation started (300-400 mg/day) and for a five-year follow-up period. Early diagnostic and immediate treatment with biotin and thiamine led to positive outcomes 150).

Cancer

Thiamine deficiency has been observed in some cancer patients with rapidly growing tumors. Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamine 151). All rapidly dividing cells require nucleic acids at an increased rate, and some cancer cells appear to rely heavily on the TPP-dependent enzyme, transketolase, to provide the ribose-5-phosphate necessary for nucleic acid synthesis. A recent study found that the levels of THTR-1, transketolase, and TPP mitochondrial transporters were increased in samples of human breast cancer tissue compared to normal tissue, suggesting an adaptation in thiamine homeostasis in support of cancer metabolism 152). Thiamine supplementation in cancer patients is common to prevent thiamine deficiency, but Boros et al. 153) caution that too much thiamine may actually fuel the growth of some malignant tumors, suggesting that thiamine supplementation be reserved for those cancer patients who are actually deficient in thiamine. Presently, there is no evidence available from studies in humans to support or refute this theory. However, it would be prudent for individuals with cancer who are considering thiamine supplementation to discuss it with the clinician managing their cancer therapy.

Benfotiamine dosage

Benfotiamine supplements are available over-the-counter (OTC), often in capsules containing 150–300 mg. Based on clinical studies to date, daily doses of oral benfotiamine range from 300-450 mg daily in divided doses. In an open-label uncontrolled trial, a daily dose of 300 mg showed cognitive improvement in Alzheimer’s disease patients 154). Other studies in clinical populations have used Benfotiamine doses ranging from 200–600 mg/day 155), 156), 157).

Benfotiamine side effects

Benfotiamine is generally considered safe for most people when taken at standard doses, though long-term safety has not been studied. Benfotiamine administration appears to be safe with no reports of toxicity in the scientific literature. In clinical trials, side effects were mild and included gastrointestinal issues and skin reactions 158). Because benfotiamine gets converted to thiamine (vitamin B1), and thiamine may cause low blood pressure or low blood glucose, people taking drugs or herbs to lower blood pressure or blood glucose should exercise caution 159).

Toxicity

The Food and Nutrition Board did not set a tolerable upper intake level (UL) for thiamine because there are no well-established toxic effects from consumption of excess thiamine in food or through long-term, oral supplementation (up to 200 mg/day). A small number of life-threatening anaphylactic reactions have been observed with large intravenous doses of thiamine 160).

Interactions with medications

Although benfotiamine is not known to interact with any medications, certain medications can have an adverse effect on thiamine levels. Some examples are provided below. Individuals taking these and other medications on a regular basis should discuss their thiamine status with their healthcare providers.

  • Furosemide: Furosemide (Lasix®) is a loop diuretic used to treat edema and hypertension by increasing urinary output. Research has linked the use of furosemide to decreases in thiamine concentrations, possibly to deficient levels, as a result of urinary thiamine loss 161). Whether thiamine supplements are effective for preventing thiamine deficiency in patients taking loop diuretics needs to be determined in clinical studies.
  • Chemotherapy with fluorouracil: Fluorouracil (also known as 5-fluorouracil; Adrucil®) is a chemotherapy drug that is commonly used to treat colorectal and other solid cancers. The published literature includes several cases of beriberi or Wernicke’s encephalopathy resulting from treatment with this drug, possibly because the drug might increase thiamine metabolism and block the formation of TDP, the active form of thiamine 162). Thiamine supplements might reverse some of these effects.
  • Phenytoin: Reduced blood levels of thiamine have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time 163).

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