Abstract
Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Thiamine fortification strategies in low- and middle-income settings: a review. Ann. NY Acad. Sci. 1498(1), 29–45 (2021).
- 2. . Thiamine and diabetes: back to the future? Acta Diabetol. 58(11), 1433–1439 (2021).
- 3. . Thiamin function, metabolism, uptake, and transport. Biochemistry 53(5), 821–835 (2014).
- 4. Impaired hippocampal neurogenesis is involved in cognitive dysfunction induced by thiamine deficiency at early pre-pathological lesion stage. Neurobiol. Dis. 29(2), 176–185 (2008).
- 5. . Neuropathology of thiamine deficiency: an update on the comparative analysis of human disorders and experimental models. Metab. Brain Dis. 11(1), 19–37 (1996).
- 6. Role of thiamin in health and disease. Nutr. Clin. Pract. 34(4), 558–564 (2019).
- 7. . Thiamin. Adv. Food Nutr. Res. 83, 1–56 (2018).
- 8. . Thiamine supplementation for the treatment of heart failure: a review of the literature. Congest. Heart Fail. 19(4), 214–222 (2013).
- 9. . Prevention and treatment of Wernicke–Korsakoff syndrome. Alcohol Alcohol. 35(1), 19–20 (2000).
- 10. . “Dry” and “wet” beriberi mimicking critical illness polyneuropathy. Ann. Indian Acad. Neurol. 16(4), 687–689 (2013).
- 11. . Update on thiamine triphosphorylated derivatives and metabolizing enzymatic complexes. Biomolecules 11(11), 1645 (2021).
- 12. . Thiamine. In: Basic Nutrition and Metabolism; Present Knowledge in Nutrition (11th Edition). Marriott BBirt DStalling VYates A (Eds). Academic Press, MA, USA, 676 (2020).
- 13. . Thiamine derivatives in excitable tissues: metabolism, deficiency and neurodegenerative diseases. Recent Res. Devel. Neurochem. (2), 37–62 (1999). • This is an excellent article that describes the role of various thiamine derivatives in neurological complications.
- 14. Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PloS One 5(10), e13616 (2010).
- 15. Dibenzoylthiamine has powerful antioxidant and anti-inflammatory properties in cultured cells and in mouse models of stress and neurodegeneration. Biomedicines 8(9), 361 (2020).
- 16. . Thiamine and selected thiamine antivitamins – biological activity and methods of synthesis. Biosci. Rep. 38(1), BSR20171148 (2018).
- 17. . Bioavailability assessment of the lipophilic benfotiamine as compared to water-soluble thiamin derivative. Ann. Nutri. Metab. 35(5), 292–296 (1991).
- 18. . A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid. Based Complement. Alternat. Med. 3, 49–59 (2006). • This is an important review article to learn in detail about thiamine and its derivatives.
- 19. . Comparative bioavailability of various thiamine derivatives after oral administration. Int. J. Clin. Pharmacol. Ther. 36, 216–221 (1998).
- 20. . Predictable irreversible switching between acute and chronic inflammation. Front. Immunol. 9, 1596 (2018).
- 21. . Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxid. Med. Cell Longev. 5698931
doi.org/10.1155/2016/5698931 (2016). - 22. The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis. J. Inflamm. (Lond.) 11, 11 (2014).
- 23. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit. Care Med. 44(2), 360–367 (2016).
- 24. Association between IV thiamine and mortality in patients with septic shock: a nationwide observational study. Crit. Care Med. 48(8), 1135–1139 (2020).
- 25. . Prevention of endotoxin-induced uveitis in rats by benfotiamine, a lipophilic analogue of vitamin B1. Invest. Ophthalmol. Vis. Sci. 50(5), 2276–2282 (2009).
- 26. Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia. PLoS One 10(2), e0118372 (2015).
- 27. . Protective role of benfotiamine, a fat-soluble vitamin B1 analogue, in lipopolysaccharide-induced cytotoxic signals in murine macrophages. Free Radic. Biol. Med. 48(10), 1423–1434 (2010).
- 28. . Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic. Biol. Med. 52(1), 182–190 (2012).
- 29. . Beneficial effects of benfotiamine, a NADPH oxidase inhibitor, in isoproterenol-induced myocardial infarction in rats. PLoS One 15(5), e0232413 (2020).
- 30. Neurological disorders. In: Mental, Neurological, and Substance Use Disorders: Disease Control Priorities (3rd Edition, Volume 4). Patel VChisholm DDua TLaxminarayan RMedina-Mora ME (Eds). The World Bank, DC, USA (2016).
- 31. . Aging and Alzheimer's disease pathology. Neuropathology 40(1), 22–29 (2020).
- 32. . Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell 18(6), e13031 (2019).
- 33. The prion protein binds thiamine. FEBS J. 278(21), 4002–4014 (2011).
- 34. . Clinical characteristics and outcomes associated with high-dose intravenous thiamine administration in patients with encephalopathy. Psychosomatics 59(4), 379–387 (2018).
- 35. . Neuro-ophthalmic manifestations of Wernicke encephalopathy. Eye Brain 12, 49–60 (2020).
- 36. . Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern. Med. J. 44(9), 911–915 (2014).
- 37. . Neuroprotective effects of thiamine and precursors with higher bioavailability: focus on benfotiamine and dibenzoylthiamine. Int. J. Mol. Sci. 22(11), 5418 (2021).
- 38. . Double-blind, randomized placebo-controlled clinical trial of benfotiamine for severe alcohol dependence. Drug Alcohol Depend. 133(2), 562–570 (2013).
- 39. Thiamine as a neuroprotective agent after cardiac arrest. Resuscitation 105, 138–144 (2016).
- 40. . Vitamin B1 (thiamine) and dementia. Ann. NY Acad. Sci. 1367(1), 21–30 (2016).
- 41. . A pivotal role for thiamine deficiency in the expression of neuroinflammation markers in models of alcohol-related brain damage. Alcohol. Clin. Exp. Res. 43(3), 425–438 (2019).
- 42. Thiamine deficiency disorders: a clinical perspective. Ann. NY Acad. Sci. 1498(1), 9–28 (2021).
- 43. . Thiamine for preventing dementia development among patients with alcohol use disorder: a nationwide population-based cohort study. Clin. Nutr. 38(3), 1269–1273 (2019).
- 44. . Studies of transketolase abnormality in Alzheimer's disease. Arch. Neurol. 45, 841–845 (1988).
- 45. Long-term improvement after benfotiamine administration in patients with Alzheimer's disease. Neurosci. Bull. 32(6), 591–596 (2016).
- 46. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum. Mol. Genet. 27(16), 2874–2892 (2018).
- 47. Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels. Mol. Cell. Neurosci. 82, 126–136 (2017).
- 48. Thiamine and benfotiamine protect neuroblastoma cells against paraquat and β-amyloid toxicity by a coenzyme-independent mechanism. Heliyon 5(5), e01710 (2019).
- 49. Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 75, 148–156 (2017).
- 50. Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice. Neuropharmacology 156, 107543 (2019).
- 51. Benfotiamine and cognitive decline in Alzheimer's disease: results of a randomized placebo-controlled phase IIa clinical trial. J. Alzheimers Dis. 78(3), 989–1010 (2020).
- 52. Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not. Alzheimers Res Ther. 10(1), 26 (2018).
- 53. . Evidence for altered thiamine metabolism in diabetes: is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J. Diabetes 5(3), 288–295 (2014).
- 54. . Mechanisms of diabetic complications. Physiol. Rev. 93(1), 137–188 (2013).
- 55. . Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr. Rev. 26(3), 380–392 (2005). •• This is an important review article that describes how the polyol pathway mediates secondary diabetic complications.
- 56. . Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern. Med. Rev. 11(4), 294–329 (2006).
- 57. . Pathophysiology of diabetic retinopathy. Int. Sch. Res. Notices 2013, 343560 (2013).
- 58. . Role of pseudohypoxia in the pathogenesis of Type 2 diabetes. Hypoxia (Auckl.) 7, 33–40 (2019).
- 59. . Dietary sugars and endogenous formation of advanced glycation endproducts: emerging mechanisms of disease. Nutrients 9(4), 385 (2017).
- 60. Glyceraldehyde-derived advanced glycation end products in Alzheimer's disease. Acta Neuropathol. 108(3), 189–193 (2004).
- 61. . Polyphenols and AGEs/RAGE axis. Trends and challenges. Food Res. Int. 129, 108843 (2020).
- 62. . Protein kinase C activation and the development of diabetic complications. Diabetes 47(6), 859–866 (1998).
- 63. Protein kinase C-β contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation 127(1), 86–95 (2013).
- 64. Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. J. Med. Chem. 52(8), 2515–2530 (2009).
- 65. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc. Natl Acad. Sci. USA 97, 12222–12226 (2000).
- 66. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000). •• This is an important article that identifies three major pathways activated during hyperglycemia-induced secondary complications.
- 67. . Low thiamine levels in children with Type 1 diabetes and diabetic ketoacidosis: a pilot study. Pediatr. Crit. Care Med. 16(2), 114–118 (2015).
- 68. Thiamine level in Type I and Type II diabetes mellitus patients: a comparative study focusing on hematological and biochemical evaluations. Cureus 12(5), e8027 (2020).
- 69. . Thiamine deficiency in tropical pediatrics: new insights into a neglected but metabolic challenge. Front. Nutr. 3, 16 (2016).
- 70. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol. 45, 131 (2008).
- 71. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat. Med. 9(3), 294–299 (2003). •• This is a landmark paper on benfotiamine where the results indicate that benfotiamine prevents major pathways responsible for diabetic complications.
- 72. Diabetic neuropathy. Nat. Rev. Dis. Primers 5, 41 (2019).
- 73. New perspective in diabetic neuropathy: from the periphery to the brain, a call for early detection and precision medicine. Front. Endocrinol. 10, 3389 (2020).
- 74. . Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr. Neurol. Neurosci. Rep. 14, 473 (2014).
- 75. . Diabetic peripheral neuropathy: current perspective and future directions. Pharmacol. Res. 80, 21–35 (2014).
- 76. . Benfotiamine reduced collagen IV contents of sciatic nerve in hyperglycemic rats. J. Diabetes Metab. Disord. 20(1), 21–30 (2021).
- 77. Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. Diabetologia 49(2), 405–420 (2006).
- 78. Benfotiamine relieves inflammatory and neuropathic pain in rats. Eur. J. Pharmacol. 530(1–2), 48–53 (2006).
- 79. . Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha. Neurosci. Lett. 394(2), 158–162 (2006).
- 80. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp. Clin. Endocrinol. Diabetes 109(6), 330–336 (2001).
- 81. . B vitamins as a treatment for diabetic pain and neuropathy. J. Clin. Pharm. Ther. 46(5), 1199–1212 (2021).
- 82. . Benfotiamine in the treatment of diabetic polyneuropathy – a three-week randomized, controlled pilot study (BEDIP study). Int. J. Clin. Pharmacol. Ther. 43(2), 71–77 (2005).
- 83. . Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp. Clin. Endocrinol. Diabetes 116(10), 600–605 (2008).
- 84. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with Type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial. Diabetes Care 35(5), 1095–1097 (2012).
- 85. . The pathology associated with diabetic retinopathy. Vision Res. 139, 7–14 (2017).
- 86. . Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes. Diabetes Metab. Res. Rev. 25(7), 647–656 (2009).
- 87. . Classification and differential diagnosis of diabetic nephropathy. J. Diabetes Res. 2017, 8637138 (2017).
- 88. . Therapeutic advances in diabetic nephropathy. J. Clin. Med. 11(2), 378 (2022).
- 89. . Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52(8), 2110–2120 (2003).
- 90. Effect of benfotiamine in podocyte damage induced by peritoneal dialysis fluid. Front. Med. (Lausanne) 2, 10 (2015).
- 91. . Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 53(7), 1506–1516 (2010).
- 92. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 33(7), 1598–1601 (2010).
- 93. Effect of benfotiamine on advanced glycation end products and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PLoS One 7(7), e40427 (2012).
- 94. . Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin. Tissue Cell 49(6), 691–696 (2017).
- 95. Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis. J. Am. Soc. Nephrol. 22(5), 914–926 (2011).
- 96. Could vitamins help in the fight against COVID-19? Nutrients 12(9), 2550 (2020).
- 97. Thiamine concentrations in newly hospitalized elderly patients with infectious diseases at a community hospital in Japan. J. Nutr. Sci. Vitaminol. (Tokyo) 64(3), 209–214 (2018).
- 98. . Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Int. J. STD AIDS 12(6), 407–409 (2001).
- 99. An allosteric drug, o,o'-bismyristoyl thiamine disulfide, suppresses HIV-1 replication through prevention of nuclear translocation of both HIV-1 Tat and NF-kappa B. Biochem. Biophys. Res. Commun. 249(3), 745–753 (1998).
- 100. . The role of thiamine in HIV infection. Int. J. Infect. Dis. 17(4), e221–e227 (2013). • This study describes how vitamin B1 could be involved in infectious diseases.
- 101. Thiamine attenuates the hypertension and metabolic abnormalities in CD36-defective SHR: uncoupling of glucose oxidation from cellular entry accompanied with enhanced protein O-GlcNAcylation in CD36 deficiency. Mol. Cell. Biochem. 299(1–2), 23–35 (2007).
- 102. . Thiamine in nutrition therapy. Nutr. Clin. Pract. 27(1), 41–50 (2012).
- 103. Evaluation of thiamine as adjunctive therapy in COVID-19 critically ill patients: a two-center propensity score matched study. Crit. Care 25(1), 223 (2021).
- 104. Encephalopathy responsive to thiamine in severe COVID-19 patients. Brain Behav. Immun. Health 14, 100252 (2021).
- 105. Therapeutic prospects for Th-17 cell immune storm syndrome and neurological symptoms in COVID-19: thiamine efficacy and safety, in-vitro evidence and pharmacokinetic profile. Front. Pharmacol. 11, 598128 (2021).
- 106. . Antiglycation activity of thiamin-HCl and benfotiamine in diabetic condition. J. Pak. Med. Assoc. 62(10), 1033–1038 (2012).
- 107. Diabetic neuropathy: a narrative review of risk factors, classification, screening and current pathogenic treatment options (review). Exp. Ther. Med. 22(1), 690 (2021).
- 108. Safety, tolerability and pharmacokinetics of single and multiple ascending doses of benfotiamine in healthy subjects. Drug Des. Devel. Ther. 15, 1101–1110
doi.org/10.2147/DDDT.S296197 (2021). •• An important clinical study that demonstrates benfotiamine safety and tolerability in healthy humans. - 109. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 8
doi.org/10.1186/1471-2210-8-10 , 10 (2008). - 110. Allithiamine alleviates hyperglycaemia-induced endothelial dysfunction. Nutrients 12(6), 1690 (2020).
- 111. . Allithiamine exerts therapeutic effects on sepsis by modulating metabolic flux during dendritic cell activation. Mol. Cells 43(11), 964–973 (2020).
- 112. . Pharmacologic and therapeutic features of sulbutiamine. Drugs Today 35, 187–192 (1999).
- 113. Effects of sulbutiamine (Arcalion 200) on psycho-behavioral inhibition in major depressive episodes. Encephale 26(2), 70–75 (2000).
- 114. . Cardiac action of thiamine derivatives in guinea pig atria. J. Nutr. Sci. Vitaminol. 22, 29–34 (1976).
- 115. Fursultiamine alleviates choroidal neovascularization by suppressing inflammation and metabolic reprogramming. Invest. Ophthalmol. Vis. Sci. 61(12), 24 (2020).
- 116. BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with Type 2 diabetes with symptomatic polyneuropathy. BMJ Open 12(2), e057142 (2022).
- 117. . Pathophysiology, prevention, and treatment of beriberi after gastric surgery. Nutr. Rev. 78(12), 1015–1029 (2020).
- 118. . Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity. Drug Alcohol Depend. 152, 257–263 (2015).
- 119. Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy. Biomed. Pharmacother. 121, 109648 (2020).
- 120. Thiamine deficiency and neurological symptoms in patients with hematological cancer receiving chemotherapy: a retrospective analysis. J. Neurosci. Rural Pract. 12(4), 726–732 (2021).
- 121. Association between thiamine decrease and neuropsychiatric symptoms in gastrointestinal and hematological cancer patients receiving chemotherapy. Biomed. Pharmacother. 141, 111929 (2021).
- 122. . B vitamins and their role in immune regulation and cancer. Nutrients 12(11), 3380 (2020).
- 123. . Developmental maturation of the colonic uptake process of the microbiota-generated thiamin pyrophosphate. Am. J. Physiol. Gastrointest. Liver Physiol. 320(5), G829–G835 (2021).
- 124. Gut microbiota compositions and metabolic functions in Type 2 diabetes differ with glycemic durability to metformin monotherapy. Diabetes Res. Clin. Pract. (174), 108731
doi:10.1016/j.diabres.2021.108731 (2021). - 125. Gut microbiome in people living with HIV is associated with impaired thiamine and folate syntheses. Microb. Pathog. 160, 105209 (2021).
- 126. Be well: a potential role for vitamin B in COVID-19. Maturitas 144, 108–111 (2021). • This article nicely describes the significance of B-vitamins in reducing the symptoms associated with COVID-19.
- 127. Serum level of vitamin D is associated with COVID-19 mortality rate in hospitalized patients. J. Res. Med. Sci. 26, 112 (2021).
- 128. High-dose vitamin D substitution in patients with COVID-19: study protocol for a randomized, double-blind, placebo-controlled, multi-center study-vitcov trial. Trials 23(1), 114 (2022).