Overview and Information of BENFOTIAMINE

About Author: Sayani Chakrabarti
M.Pharm in Pharmaceutical Chemistry
SIPS, Jharpokharia
Mayurbhanj-757086
Orissa

ABSTRACT
Benfotiamine (rINN, or S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine (vitamin B1). It has potential anti oxidant effect. A three-armed, randomized, multicentre, placebo-controlled double-blind study was used to examine the efficacy of benfotiamine vs a combination containing benfotiamine and vitamins B6 and B12 in out-patients with severe symptoms of alcoholic polyneuropathy (Benfotiamine in treatment of Alcoholic Polyneuropathy. BAP I). The study period was 8 weeks and 84 patients fulfilled all the prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly improved in the course of the study, as did motor function, and the overall score reflecting the entire range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain and co-ordination, no therapy-specific adverse effects were seen.

INTRODUCTION
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions. They do this by being oxidized themselves, so antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols.
Antioxidants are widely used as ingredients in dietary supplements and have been investigated for the prevention of diseases such as cancer, coronary heart disease and even altitude sickness. Although initial studies suggested that antioxidant supplements might promote health, later large clinical trials did not detect any benefit and suggested instead that excess supplementation may be harmful. In addition to these uses of natural antioxidants in medicine, these compounds have many industrial uses, such as preservatives in food and cosmetics and preventing the degradation of rubber and gasoline.

HISTORY
As part of their adaptation from marine life, terrestrial plants began producing non-marine antioxidants such as ascorbic acid (Vitamin C), polyphenols and tocopherols. Further development of angiosperm plants between 50 and 200 million years ago, particularly during the Jurassic period, produced many antioxidant pigments evolved during the late Jurassic period as chemical defences against reactive oxygen species produced during photosynthesis. The term antioxidant originally was used to refer specifically to a chemical that prevented the consumption of oxygen. In the late 19th and early 20th centuries, extensive study was devoted to the uses of antioxidants in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines.[6]
Early research on the role of antioxidants in biology focused on their use in preventing the oxidation of unsaturated fats, which is the cause of rancidity. Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However, it was the identification of vitamins A, C, and E as antioxidants that revolutionized the field and led to the realization of the importance of antioxidants in the biochemistry of living organisms.
The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that is itself readily oxidized. Research into how vitamin E prevents the process of lipid peroxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions, often by scavenging reactive oxygen species before they can damage cells.

THE OXIDATIVE CHALLENGE IN BIOLOGY
A paradox in metabolism is that while the vast majority of complex life on Earth requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species.  Consequently, organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular components such as DNA, proteins and lipids. In general, antioxidant systems either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. However, since reactive oxygen species do have useful functions in cells, such as redox signaling, the function of antioxidant systems is not to remove oxidants entirely, but instead to keep them at an optimum level.
The reactive oxygen species produced in cells include hydrogen peroxide (H₂O₂), hypochlorous acid (HOCl), and free radicals such as the hydroxyl radical (^•OH) and the superoxide anion (O2⁻). The hydroxyl radical is particularly unstable and will react rapidly and non-specifically with most biological molecules. This species is produced from hydrogen peroxide in metal-catalyzed redox reactions such as the Fenton reaction. These oxidants can damage cells by starting chemical chain reactions such as lipid peroxidation, or by oxidizing DNA or proteins. Damage to DNA can cause mutations and possibly cancer, if not reversed by DNA repair mechanisms, while damage to proteins causes enzyme inhibition, denaturation and protein degradation.
The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species.  In this process, the superoxide anion is produced as a by-product of several steps in the electron transport chain.  Particularly important is the reduction of coenzyme Q in complex III, since a highly reactive free radical is formed as an intermediate (Q^•−). This unstable intermediate can lead to electron "leakage", when electrons jump directly to oxygen and form the superoxide anion, instead of moving through the normal series of well-controlled reactions of the electron transport chain.  Peroxide is also produced from the oxidation of reduced flavoproteins, such as complex I. However, although these enzymes can produce oxidants, the relative importance of the electron transfer chain to other processes that generate peroxide is unclear.  In plants, algae, and cyanobacteria, reactive oxygen species are also produced during photosynthesis, particularly under conditions of high light intensity. This effect is partly offset by the involvement of carotenoids in photoinhibition, which involves these antioxidants reacting with over-reduced forms of the photosynthetic reaction centres to prevent the production of reactive oxygen species.

PRO-OXIDANT ACTIVITIES
Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,  however, it will also reduce metal ions that generate free radicals through the Fenton reaction.
2 Fe³⁺ + Ascorbate → 2 Fe^₂+ + Dehydroascorbate
2 Fe²⁺ + 2 H₂O₂ → 2 Fe³⁺ + 2 OH^• + 2 OH⁻
The relative importance of the antioxidant and pro-oxidant activities of antioxidants are an area of current research, but vitamin C, which exerts its effects as a vitamin by oxidizing polypeptides, appears to have a mostly antioxidant action in the human body. However, less data is available for other dietary antioxidants, such as vitamin E, or the polyphenols.

ADVERSE DRUG REACTIONS
Structure of the metal chelator phytic acid.
Relatively strong reducing acids can have antinutrient effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed. Notable examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets. Calcium and iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread.

Nonpolar antioxidants such as eugenol—a major component of oil of cloves—have toxicity limits that can be exceeded with the misuse of undiluted essential oils.  Toxicity associated with high doses of water-soluble antioxidants such as ascorbic acid are less of a concern, as these compounds can be excreted rapidly in urine.  More seriously, very high doses of some antioxidants may have harmful long-term effects. The beta-Carotene and Retinol Efficacy Trial (CARET) study of lung cancer patients found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer. Subsequent studies confirmed these adverse effects.
These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 230,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality but saw no significant effect from vitamin C.  No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected only when the high-quality and low-bias risk trials were examined separately. However, as the majority of these low-bias trials dealt with either elderly people, or people already suffering disease, these results may not apply to the general population. This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the Cochrane Collaboration; confirming the previous results.  These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality  and that antioxidant supplements increased the risk of colon cancer.  However, the results of this meta-analysis are inconsistent with other studies such as the SU.VI.MAX trial, which suggested that antioxidants have no effect on cause-all mortality.  Overall, the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health, or that they cause a small increase in mortality in elderly or vulnerable populations.
While antioxidant supplementation is widely used in attempts to prevent the development of cancer, it has been proposed that antioxidants may, paradoxically, interfere with cancer treatments. This was thought to occur since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments. As a result, by reducing the redox stress in cancer cells, antioxidant supplements could decrease the effectiveness of radiotherapy and chemotherapy.  On the other hand, other reviews have suggested that antioxidants could reduce side effects or increase survival times.

CHEMISTRY
SYSTEMIC(IUPAC) NAME: S-[(2Z)-2-{[(4-amino-2-methylpyrimidin-5-yl)methyl](formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate

CHEMICAL DATA
Formula: C₁₉H₂₃N₄O₆PS
Mol. mass: 466.448 g/mol

USES
The primary use of this antioxidant is as an "anti-AGE" supplement.  In a trial, benfotiamine lowered AGE by 40%. However, in Germany doctors have been known to combine benfotiamine with pyridoxine hydrochloride and use it to treat patients with nerve damage and nerve pain such as sciatica.
At high doses, benfotiamine was shown to be effective for the treatment of diabetic retinopathy, neuropathy, and nephropathy. It is thought that treatment with benfotiamine leads to increased intracellular thiamine diphosphate levels, a cofactor of transketolase. This enzyme directs advanced glycation and lipoxidation end products (AGE's, ALE's) substrates to the pentose phosphate pathway, thus reducing tissue AGEs.
Benfotiamine IS USED IN TREATMENT OF ALCOHOLIC POLYNEUROPATHY

MECHANISM OF ACTION
Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.

ACUTE HEALTH EFFECTS
SWALLOWED
? Although ingestion is not thought to produce harmful effects, the material may still be damaging to the health of the individual following ingestion, especially where pre-existing organ (e.g. liver, kidney) damage is evident. Present definitions of harmful or toxic substances are generally based on doses producing mortality (death) rather than those producing morbidity (disease, ill- health). Gastrointestinal tract discomfort may produce nausea and vomiting. In an occupational setting however, ingestion of insignificant quantities is not thought to be cause for concern.
EYE
? Although the material is not thought to be an irritant, direct contact with the eye may cause transient discomfort characterized by tearing or conjunctival redness (as with windburn). Slight abrasive damage may also result. The material may produce foreign body irritation in certain individuals.
SKIN
? The material is not thought to produce adverse health effects or skin irritation following contact (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting.
? Open cuts, abraded or irritated skin should not be exposed to this material.
? Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected.
INHALED
? The material is not thought to produce adverse health effects or irritation of the respiratory tract (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting.
? Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.
Not normally a hazard due to non-volatile nature of product.

CHRONIC HEALTH EFFECTS
? Limited evidence suggests that repeated or long-term occupational exposure may produce cumulative health effects involvingorgans or biochemical systems.
Long term exposure to high dust concentrations may cause changes in lung function i.e. pneumoconiosis; caused by particles less than 0.5 micron penetrating and remaining in the lung.
Prime symptom is breathlessness; lung shadows show on X-ray.
Exposure to small quantities may induce hypersensitivity reactions characterized by acute bronchospasm, hives (urticaria), deep dermal wheals (angioneurotic edema), running nose (rhinitis) and blurred vision . Anaphylactic shock and skin rash (non-thrombocytopenic purpura) may occur. An individual may be predisposed to such anti -body mediated reaction if other chemicalagents have caused prior sensitization (cross-sensitivity).
Thiamine is absorbed from the body and is widely distributed to most body tissues. It is not stored to an appreciable degree and quantities in excess to the body's needs are excreted in urine as unchanged thiamine or its metabolites.
Anaphylactic reactions have occasionally been produced by injections of thiamine given alone and sudden death has been reported. The risk of anaphylactic shock increases with repeated administration by the parental route. Other B group vitamins also have produced allergy following injection.

BRAND OF BENFOTIAMINE IN MARKET
Doctor's Best, Best Benfotiamine 150, 150 mg, 120 Veggie Caps

It treats chronic Lyme, diabetic retinopathy, dysautonomia and neuropathy.

STRUCTURE-ACTIVITY RELATIONS
Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration.

CONCLUSION
It shows that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.

Reference ID: PHARMATUTOR-ART-1025

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