Administration Of Benfotiamine Research Articles

Benfotiamine improves dystrophic pathology and exercise capacity in mdx mice by reducing inflammation and fibrosis.

Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease. Cycles of myofibre degeneration and regeneration are hallmarks of the disease where immune cells infiltrate to repair damaged skeletal muscle. Benfotiamine is a lipid soluble precursor to thiamine, shown clinically to reduce inflammation in diabetic related complications. We assessed whether benfotiamine administration could reduce inflammation related dystrophic pathology. Benfotiamine (10mg/kg/day) was fed to male mdx mice (n = 7) for 15weeks from 4weeks of age. Treated mice had an increased growth weight (5-7weeks) and myofibre size at treatment completion. Markers of dystrophic pathology (area of damaged necrotic tissue, central nuclei) were reduced in benfotiamine mdx quadriceps. Grip strength was increased and improved exercise capacity was found in mdx treated with benfotiamine for 12weeks, before being placed into individual cages and allowed access to an exercise wheel for 3weeks. Global gene expression profiling (RNAseq) in the gastrocnemius revealed benfotiamine regulated signalling pathways relevant to dystrophic pathology (Inflammatory Response, Myogenesis) and fibrotic gene markers (Col1a1, Col1a2, Col4a5, Col5a2, Col6a2, Col6a2, Col6a3, Lum) towards wildtype levels. In addition, we observed a reduction in gene expression of inflammatory gene markers in the quadriceps (Emr1, Cd163, Cd4, Cd8, Ifng). Overall, these data suggest that benfotiamine reduces dystrophic pathology by acting on inflammatory and fibrotic gene markers and signalling pathways. Given benfotiamine's excellent safety profile and current clinical use, it could be used in combination with glucocorticoids to treat DMD patients.

Harnessing the neuroprotective effect of oral administration of benfotiamine in MPTP induced Parkinson's disease in rats

The study was performed to evaluate the neuroprotective effects of Benfotiamine (BFT) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in rats. The rats were given daily doses of BFT (100 mg/kg, 200 mg/kg) through oral administration for 42 days. The rats were given a single bilateral dosage of MPTP (0.1 mg/nostril) intranasally once before the drug treatment to induce PD. On day 42, the animals were subjected to various behavioral paradigms. Post-treatment with BFT for 42 days significantly improved the motor and nonmotor fluctuations of MPTP. The results demonstrated that treatment with BFT ameliorated MPTP-induced disorders in behavior, body balance, and dopamine levels in the mid-brain. Among the post-treated groups, a high dose of BFT was the most effective treatment. Mean values are indicated in ±SEM, n = 5***(p < 0.001) when compared with the vehicle control, n = 5 ### (p < 0.001) when compared with the disease control; (p < 0.001) when compared with the BFT per se; (p < 0.001) when compared with the low dose of BFT; (p < 0.001) when compared with the high dose of BFT. Our finding suggests that BFT contributed to superior antioxidant, and anti-inflammatory and could be a novel therapeutic method for PD management. In conclusion, BFT could be a potential drug candidate for curbing and preventing PD.

Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy

Malignant cells frequently demonstrate an oncogenic-driven reliance on glycolytic metabolism to support their highly proliferative nature. Overexpression of pyruvate dehydrogenase kinase (PDK) may promote this unique metabolic signature of tumor cells by inhibiting mitochondrial function. PDKs function to phosphorylate and inhibit pyruvate dehydrogenase (PDH) activity. Silencing of PDK expression has previously been shown to restore mitochondrial function and reduce tumor cell proliferation. High dose Vitamin B1, or thiamine, possesses antitumor properties related to its capacity to reduce PDH phosphorylation and promote its enzymatic activity, presumably through PDK inhibition. Though a promising nutraceutical approach for cancer therapy, thiamine’s low bioavailability may limit clinical effectiveness. Here, we have demonstrated exploiting the commercially available lipophilic thiamine analogs sulbutiamine and benfotiamine increases thiamine’s anti-cancer effect in vitro. Determined by crystal violet proliferation assays, both sulbutiamine and benfotiamine reduced thiamine’s millimolar IC50 value to micromolar equivalents. HPLC analysis revealed that sulbutiamine and benfotiamine significantly increased intracellular thiamine and TPP concentrations in vitro, corresponding with reduced levels of PDH phosphorylation. Through an ex vitro kinase screen, thiamine’s activated cofactor form thiamine pyrophosphate (TPP) was found to inhibit the function of multiple PDK isoforms. Attempts to maximize intracellular TPP by exploiting thiamine homeostasis gene expression resulted in enhanced apoptosis in tumor cells. Based on our in vitro evaluations, we conclude that TPP serves as the active species mediating thiamine’s inhibitory effect on tumor cell proliferation. Pharmacologic administration of benfotiamine, but not sulbutiamine, reduced tumor growth in a subcutaneous xenograft mouse model. It remains unclear if benfotiamine’s effects in vivo are associated with PDK inhibition or through an alternative mechanism of action. Future work will aim to define the action of lipophilic thiamine mimetics in vivo in order to translate their clinical usefulness as anticancer strategies.

D-Ribose Plays a Crucial Role in Type 1 Diabetic Encephalopathy

Diabetic encephalopathy is the brain damage caused by diabetes mellitus and has been recognized and diagnosed in both type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Although many mechanisms have been proposed for diabetic encephalopathy in type 2 diabetes mellitus, the risk factors for cognitive impairment in T1DM are less clear. Here, T1DM patients had abnormally high D-ribose levels in both urine and serum. In streptozotocin-induced T1DM rats, blood and urine D-ribose levels were also significantly increased, accompanied by spatial cognitive impairment in Y maze and Morris water maze assays. Furthermore, advanced glycation end product (AGE) formation, Tau hyperphosphorylation and neuronal death in the hippocampal CA4/DG region were detected in T1DM rats. The expression and activity of transketolase, an important enzyme in the pentose shunt, were decreased, indicating that transketolase may control D-ribose metabolism in T1DM. This assumption was confirmed by the activation of transketolase with benfotiamine. Decreased D-ribose levels; reduced AGE accumulation, Tau hyperphosphorylation, and neuronal death; and improved cognitive ability in T1DM rats were shown after benfotiamine administration. Our work suggests that D-ribose plays a crucial role in the cognitive impairment in T1DM and may provide a novel target for treating diabetic encephalopathy. Funding: This work was supported by grants from Natural Scientific Foundation of China NSFC (31670805), National Key Research and Development Program of China (2016YFC1305900; 2016YFC1306300), Beijing Municipal Science and Technology Project (Z161100000217141 and Z161100000216137), and Youth Innovation Promotion Association CAS (2017132). Declaration of Interest: All authors declared no competing interests in this study. Ethical Approval: The handling of rats and experimental procedures have been approved by the Animal Welfare and Research Ethics Committee of the Institute of Biophysics, Chinese Academy of Sciences (Permit Number: SYXK2016-32).

D-Ribose as a Contributor to Glycated Haemoglobin

Glycated haemoglobin (HbA1c) is the most important marker of hyperglycaemia in diabetes mellitus. We show that d-ribose reacts with haemoglobin, thus yielding HbA1c. Using mass spectrometry, we detected glycation of haemoglobin with d-ribose produces 10 carboxylmethyllysines (CMLs). The first-order rate constant of fructosamine formation for d-ribose was approximately 60 times higher than that for d-glucose at the initial stage. Zucker Diabetic Fatty (ZDF) rat, a common model for type 2 diabetes mellitus (T2DM), had high levels of d-ribose and HbA1c, accompanied by a decrease of transketolase (TK) in the liver. The administration of benfotiamine, an activator of TK, significantly decreased d-ribose followed by a decline in HbA1c. In clinical investigation, T2DM patients with high HbA1c had a high level of urine d-ribose, though the level of their urine d-glucose was low. That is, d-ribose contributes to HbA1c, which prompts future studies to further explore whether d-ribose plays a role in the pathophysiological mechanism of T2DM.

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer's Disease.

To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300mg daily) over 18months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with β-amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of disease-modifying therapy.

BENFOTIAMINE IMPROVES COGNITIVE ABILITY OF ALZHEIMER’S PATIENTS INDEPENDENT OF AMYLOID DEPOSITION

Alzheimer’s disease (AD) is the most commonly neurodegenerative disease and lacks method to halt or delay the disease progression. The development of the disease-modifying therapies will produce remarkable impact on modern society. In this study, the effects of benfotiamine, a thiamine derivative, on cognitive ability of mild to moderate AD cases were investigated. A non-control and open clinical observation that benfotiamine treats mild to moderate AD was designed and performed at the outpatient clinic of the Department of Neurology at Zhongshan Hospital, Fudan University, Shanghai, China. AD patients continued the previous drug therapies during benfotiamine administration. Five AD patients with mild to moderate AD were voluntarily recruited from August, 2013 to December, 2015. Benfotiamine (300 mg/day) was orally taken by five cases over 18 months. Case I to IV continued donepezil administration (5 mg/day) during benfotiamine administration. Case V had no other drug administration for AD. The Mini-Mental Status Examination (MMSE), Activity of Daily Living (ADL), Clinical Dementia Rating (CDR), and Hamilton Depression Rating Scales were evaluated before and during the period of benfotiamine administration (more than 18 months). All the cases received the examination of positron emission tomography with Pittsburgh compound-B (PiB-PET). Case I, II, and V received a follow-up of PiB-PET scan after benfotiamine administration. The MMSE scores were increased by 2 to 6 points in four patients and did not significantly change in case IV, with the average of 3.2 ± 1.3 points (n = 5) at the 18th month of benfotiamine administration. In case I, II, and V, who had the second scan of PiB-PET, the average SUVR of the frontal, parietal, and temporal cortices at the second PiB-PET imaging was 2.42 ± 0.79, with a 36.7% increase from that at the first scan. Benfotiamine significantly improves cognitive decline and disease progression of the dementia stage of AD independent of amyloid accumulation. Our study provides new insight into AD disease-modifying therapy.

Synergistic neroprotective activiity of benfotiamine co administered with erythropoietin in chemotherapy induced peripheral neuropathy in rats

Chemotherapeutic drugs like Cisplatin, Taxols used in cancer are associated with the development of peripheral neuropathy (PN). Severe neuropathy can occur in 3% to 7% of treated cases with single agents but the severity can increase to 38% with combined regimens. The treatment options for PN currently include anti-depressants, anti-convulsants and opioid analgesics. These agents are modestly effective for symptomatic relief, but they neither affect the underlying pathology nor do they slow progression of the disease. Therefore, effective treatment for chemotherapy induced neuropathy would be a major advantage for cancer patients. Benfotiamine (BT) a lipid soluble form of thiamine plays important role in various biological pathways reported beneficial effect in diabetic retinopathy. Erythropoietin (EPO) has recently been considered as a tissue protective cytokine.EPO is reported to protect neurons from ischemia reperfusion-induced injury, metabolic stress, HIV-induced damage or even mechanical injury such as nerve compression or trauma . Thereforethe present study was undertaken to evaluate the individual and combination effects of BT and EPO in cisplatin induced peripheral neuropathy in rats . PN was induced by Cisplatin - 2mg/kg,i.p. twice weekly for 8 weeks. The degree of protection was determined by measuring electrophysiological properties of sciatic nerve like nerve conduction velocity, behavioralparameters like motor in-coordination, thermal & cold hyperalgesia, grip strength, biochemal parameters like measurement of endogenous antioxidants and histopathological studies.PN was evidenced in Cisplatin control rats and ameliorated with administration of BT (100 mg/kg p.o daily)and EPO (500U/kg i.p. thrice weekly) for 8 weeks by augmenting all the above parameters.T4 exhibited neuroprotective activity, which would be attributed to its activity as neurotrophic effect.

Pharmacokinetics of the transdermal delivery of benfotiamine.

Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. A single application of 10mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24h. At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.

Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride

Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride.

Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: A comparison of thiamine and benfotiamine administration

Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively. Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics. This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes. The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells. The benfotiamine-treated group had its total plasma thiamine increased by 100%. In erythrocytes, thiamine levels were 4- and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups. Liver thiamine was increased by 60% in the treated groups compared with the untreated groups. Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration.

Extinction of fear memory and cell proliferation in adult mouse hippocampus are increased by benfotiamine

Event Abstract Back to Event Extinction of fear memory and cell proliferation in adult mouse hippocampus are increased by benfotiamine Julie Vignisse1, 2*, Nicolas Caron3, Natalia Markova4, Alexander Revishchin5, Pierre Wins1, Sergej Bachurin4, Harry W. Steinbusch2, 6, Tatyana Strekalova2, 6 and Lucien Bettendorff1, 2 1 University of Liege, GIGA-Neurosciences, Belgium 2 School for Mental Health and Neuroscience, Maastricht University, EURON - European Graduate School for Neuroscience, Netherlands 3 University of Liege, GIGA-Neurosciences, Belgium 4 Russian Academy of Sciences, Institute of Physiologically Active Compounds, Russia 5 Russian Academy of Sciences, Institute of Gene Biology, Russia 6 Maastricht University, Department of Translational Neuroscience, School for Mental Health and Neuroscience, Netherlands Because of the rising prevalence of Alzheimer’s disease (AD), new strategies to slow, halt and prevent the neurodegenerative process are urgently needed. Recently, it has been shown that chronic administration of benfotiamine, a precursor of thiamine, in a mouse model of AD (APP/PS1 mice) significantly reduced key features of this disease namely memory impairment, β-amyloid accumulation and tau hyperphosphorylation. However, it is unclear whether the observed effects are mediated by an unknown degradation product of benfotiamine or by phosphorylated derivatives synthesized from thiamine in neurons. We investigated whether benfotiamine (200 mg/kg) or thiamine (200 mg/kg) orally administered in water to 3-month old C57BL wild-type mice for 2 weeks could affect hippocampus and cortex-dependant memory and hippocampal cell proliferation. Memory extinction of contextual fear conditioning was significantly enhanced by both treatments. On the other hand, the amount of Ki67- and BrdU-positive cells was increased in the dentate gyrus of benfotiamine-treated mice when examined 5 days after the BrdU injection. In comparison, the number of positive cells in thiamine-treated mice was not different from the control. Although benfotiamine and thiamine seem both able to enhance memory, only benfotiamine stimulated cell proliferation. These results can be explained by a higher bioavailability of benfotiamine than thiamine and could account for the beneficial effects of this compound in a mouse model of Alzheimer’s disease. Keywords: Alzheimer Disease, benfotiamine, Cell Proliferation, thiamine and derivatives, Memory Conference: Belgian Brain Council, Liège, Belgium, 27 Oct - 27 Oct, 2012. Presentation Type: Poster Presentation Topic: Higher Brain Functions in health and disease: cognition and memory Citation: Vignisse J, Caron N, Markova N, Revishchin A, Wins P, Bachurin S, Steinbusch HW, Strekalova T and Bettendorff L (2012). Extinction of fear memory and cell proliferation in adult mouse hippocampus are increased by benfotiamine. Conference Abstract: Belgian Brain Council. doi: 10.3389/conf.fnhum.2012.210.00014 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Sep 2012; Published Online: 12 Sep 2012. * Correspondence: Miss. Julie Vignisse, University of Liege, GIGA-Neurosciences, Liège, 4000, Belgium, julievignisse@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Julie Vignisse Nicolas Caron Natalia Markova Alexander Revishchin Pierre Wins Sergej Bachurin Harry W Steinbusch Tatyana Strekalova Lucien Bettendorff Google Julie Vignisse Nicolas Caron Natalia Markova Alexander Revishchin Pierre Wins Sergej Bachurin Harry W Steinbusch Tatyana Strekalova Lucien Bettendorff Google Scholar Julie Vignisse Nicolas Caron Natalia Markova Alexander Revishchin Pierre Wins Sergej Bachurin Harry W Steinbusch Tatyana Strekalova Lucien Bettendorff PubMed Julie Vignisse Nicolas Caron Natalia Markova Alexander Revishchin Pierre Wins Sergej Bachurin Harry W Steinbusch Tatyana Strekalova Lucien Bettendorff Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Ameliorative effect of combination of benfotiamine and fenofibrate in diabetes-induced vascular endothelial dysfunction and nephropathy in the rat

The study has been designed to investigate the effect of benfotiamine and fenofibrate in diabetes-induced experimental vascular endothelial dysfunction (VED) and nephropathy. The single administration of streptozotocin (STZ) (50 mg/kg, i.p.) produced diabetes, which was noted to develop VED and nephropathy in 8 weeks. The diabetes produced VED by attenuating acetylcholine-induced endothelium dependent relaxation, impairing the integrity of vascular endothelium, decreasing serum nitrite/nitrate concentration and increasing serum TBARS and aortic superoxide anion generation. Further, diabetes altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. The nephropathy was noted to be developed in the diabetic rat that was assessed in terms of increase in serum creatinine, blood urea, proteinuria, and glomerular damage. The benfotiamine (70 mg/kg, p.o.) and fenofibrate (32 mg/kg, p.o.) or lisinopril (1 mg/kg, p.o., a standard agent) treatments were started in diabetic rats after 1 week of STZ administration and continued for 7 weeks. The treatment with benfotiamine and fenofibrate either alone or in combination attenuated diabetes-induced VED and nephropathy. In addition, the combination of benfotiamine and fenofibrate was noted to be more effective in attenuating the diabetes-induced VED and nephropathy when compared to treatment with either drug alone or lisinopril. Treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, whereas benfotiamine treatment has no effect on lipid alteration in diabetic rats. It may be concluded that diabetes-induced oxidative stress, lipids alteration, and consequent development of VED may be responsible for the induction of nephropathy in diabetic rats. Concurrent administration of benfotiamine and fenofibrate may provide synergistic benefits in preventing the development of diabetes-induced nephropathy by reducing the oxidative stress and lipid alteration, preventing the VED and subsequently improving the renal function.

Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives

BackgroundLipid-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.ResultsBenfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200 mM hydroxypropyl-β-cyclodextrin and the mice received a single oral administration of 100 mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 μM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed.ConclusionOur results show 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.

Comparative Study of the Effects of Enzyme Inhibitors and Inducers on Serum and Tissue Availability of Thiamine After Single Oral Dose of the Pro-drug Benfotiamine in Rats.

Thiamine is known to have an important role in the protection of different types of cells and tissues against the damage produced by many drugs and toxins. The most important problem limiting the clinical applications of this approach is the poor absorption and bioavailability of thiamine from the sites of administration, a problem which can be solved by the use of the lipid soluble pro-drug for thiamine, benfotiamine. Accordingly, this project was designed to evaluate the serum and tissues availability of thiamine in rats after the administration of single oral dose of benfotiamine compared with that producedby the same oral dose of thiamine, in addition to study the effects of enzyme inducers and inhibitors in this respect utilizing HPLC technique. According to the results obtained in this study one can conclude that thiamine availability after administration of benfotiamine was more in serum, liver, kidney while in the brain more time may be required to reach maximum level.

Benfotiamine Counteracts Glucose Toxicity Effects on Endothelial Progenitor Cell Differentiation via Akt/FoxO Signaling

Dysfunction of mature endothelial cells is thought to play a major role in both micro- and macrovascular complications of diabetes. However, recent advances in biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. To determine the effect of glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of high glucose (33 mmol/l) or high glucose plus benfotiamine to scavenge glucotoxicity. Morphological analysis revealed that high glucose significantly affected the number of endothelial cell colony forming units, uptake and binding of acLDL and Lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2-positive cells. Functional analysis outlined a reduced EPC involvement in de novo tube formation, when cocultured with mature endothelial cells (human umbilical vein endothelial cells) on matrigel. To explain the observed phenotypes, we have investigated the signal transduction pathways known to be involved in EPC growth and differentiation. Our results indicate that hyperglycemia impairs EPC differentiation and that the process can be restored by benfotiamine administration, via the modulation of Akt/FoxO1 activity.

Benfotiamine relieves inflammatory and neuropathic pain in rats

Benfotiamine has shown therapeutic efficacy in the treatment of painful diabetic neuropathy in human beings. However, so far there is no evidence about the efficacy of this drug in preclinical models of pain. The purpose of this study was to assess the possible antinociceptive and antiallodynic effect of benfotiamine in inflammatory and neuropathic pain models in the rat. Inflammatory pain was induced by injection of formalin in non-diabetic and diabetic (2 weeks) rats. Reduction of flinching behavior was considered as antinociception. Neuropathic pain was induced by either ligation of left L5/L6 spinal nerves or administration of streptozotocin (50 mg/kg, i.p.) in Wistar rats. Benfotiamine significantly reduced inflammatory (10–300 mg/kg) and neuropathic (75–300 mg/kg) nociception in non-diabetic and diabetic rats. Results indicate that oral administration of benfotiamine is able to reduce tactile allodynia from different origin in the rat and they suggest the use of this drug to reduce inflammatory and neuropathic pain in humans.