Benfotiamine Monograph - Anaturalhealingcenter.com

BenfotiamineMonographH 3 CNNNH 2CH 2 NCH 3OC C CH 2 CH 2 O POHCHOSOCOHBenfotiamineIntroductionNeurological disorders, particularly diabetic neuropathy, have been treated with vitamin B1 (thiamine)for decades; however, the bioavailability of orally administered, water-soluble thiamine salts is low compared tofat-soluble analogs. For treatment to be successful, high levels of thiamine are needed in both blood and tissues. In1954, Fujiwara discovered a group of lipid-soluble thiamine derivatives, subsequently named allithiamines becausethey occur naturally in Allium family vegetables – roasted, crushed garlic, onions, leeks, shallots, etc. Of these,benfotiamine is the most effective and has an excellent safety profile. Oral administration of benfotiamine raisesthiamine levels in blood and tissues to a much higher degree than the water-soluble salts. Benfotiamine also inhibitsthree major biochemical pathways implicated in diabetes-induced vascular damage and neuropathy. In addition todiabetic neuropathy, benfotiamine appears to be of value in treating diabetic retinopathy and nephropathy. It hasalso been shown to have beneficial effects in patients with end-stage renal disease and alcoholic neuropathy.Biochemistry and PharmacokineticsUnlike thiamine, benfotiamine’s structure contains an open thiazole ring that closes once it is absorbed,producing biologically active thiamine. Several clinical trials in healthy adults have demonstrated the superiorabsorption of lipid-soluble thiamine analogues, such as benfotiamine, compared to water-soluble thiamine salts.Higher plasma thiamine levels are achieved with oral benfotiamine administration, and blood and tissue concentrationsare maintained longer. Oral benfotiamine dosages in these studies ranged from 40-250 mg daily. 1-3Benfotiamine is absorbed via passive diffusion through the intestinal mucosa and is rapidly converted tobiologically active thiamine. Peak plasma concentrations of thiamine after oral benfotiamine administration areat least five times greater than those observed after oral administration of water-soluble thiamine salts. Half-lifeof benfotiamine is similar to thiamine salts, but bioavailability of benfotiamine eight days after administration isroughly 25 percent of the original dose, about 3.6 times greater than after an oral dose of a thiamine salt. 4Mechanisms of ActionBenfotiamine exerts it beneficial effects via a number of mechanisms. In the case of diabetes, benfotiamineincreases transketolase activity, an important enzyme in glucose metabolism, and as a result, blocks three of themajor molecular pathways leading to hyperglycemic damage. It prevents the increase in UDP-N-acetylglucosamine(UDP-GlcNAc) and enhances hexosamine pathway activity that decreases the buildup of detrimental glucose metabolitesthat can lead to advanced glycation end products (AGE). Benfotiamine also normalizes protein kinasePage 238 Alternative Medicine Review u Volume 11, Number 3 u 2006Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005

MonographBenfotiamineC (PKC) activity and prevents nuclear factor-kappaB(NF-κB) activation in the retina of diabetics. 5 In addition,benfotiamine corrects imbalances in the polyolpathway by decreasing aldose reductase activity, sorbitolconcentrations, and intracellular glucose, therebyprotecting endothelial cells from glucose-induceddamage. 6 Benfotiamine also corrects glucose-inducedendothelial cell damage by normalizing cell replicationrates 7 and decreasing apoptosis. 8 Animal modelsof diabetic limb ischemia demonstrated these mechanismsare responsible for improved post-ischemichealing. 9 Research has also shown benfotiamine’senhancement of transketolase activity in erythrocytesand renal glomeruli protects the kidneys fromglucose-induced damage and prevents the developmentof diabetic nephropathy. 10,11 In alcoholics 12 andpatients with chronic renal disease, 10 benfotiaminecorrects thiamine deficiency and can decrease the incidenceof neuropathies. 12Thiamine Deficiency StatesThiamine levels are significantly lower thannormal in about 20 percent of alcoholics for severalreasons: (1) the diet of an alcoholic tends to be heavyin carbohydrates, resulting in decreased thiamine intake;(2) absorption of thiamine and other nutrientsis impaired due to the effects of chronic alcohol intakeon the gut’s absorptive mechanisms; (3) chronicalcohol consumption reduces the liver’s ability tostore thiamine; and (4) acetaldehyde, an ethanol metabolite,interferes with thiamine utilization. 13 Thesefactors result in thiamine deficiency, which in manyalcoholics does not respond to supplementation withoral water-soluble thiamine salts. Thiamine deficiencyis also frequently observed in patients with diabeticneuropathy 14 and in patients who have undergonegastrectomy 15 or bariatric surgery 16 who subsequentlydevelop neuropathies due to malabsorption.Clinical IndicationsDiabetic NeuropathyIn a double-blind, randomized, placebo-controlledpilot study, 20 subjects with diabetic polyneuropathywere given two 50-mg tablets benfotiaminefour times daily (400 mg total daily dose), and 20subjects received placebo. Study duration was threeweeks, and assessment was via neuropathy symptomsand vibration sensation scores from both physicianand patient. In the treatment group a statisticallysignificant improvement in the neuropathy score wasreported compared to placebo. The most significantimprovement reported was decrease in pain, whereas,there was no significant improvement in the tuningfork test – a measure of vibration perception. 17Several studies have investigated the effectof benfotiamine in combination with other B vitaminsin the treatment of diabetic neuropathy. Onestudy included 45 patients with painful peripheralpolyneuropathy. Thirty patients received Milgamma ®(50 mg benfotiamine and 250 µg B12 as cyanocobalaminper tablet) at a dose of two tablets four timesdaily for three weeks (total daily dose: 400 mg benfotiamineand 2,000 µg cyanocobalamin), followedby one tablet three times daily for nine weeks. Thesecond group of 15 patients received a conventionalB-vitamin supplement at a dose of two tablets threetimes daily for the entire 12-week period. Changesin pain severity and vibration perception thresholdswere measured at baseline and at the end of threemonths. All Milgamma-treated patients experiencedsignificant relief in neuropathic pain and a dramaticimprovement in vibration perception thresholds. Inpatients receiving the conventional B-vitamin treatment,slight, non-statistically significant improvementwas noted. 18In a second trial lasting six weeks, 36 subjectswith painful diabetic neuropathy were dividedinto three groups of 12 each. The first group receivedMilgamma-N ® (40 mg benfotiamine, 90 mgpyridoxine, and 250 µg cyanocobalamin per capsule)at a dose of two capsules four times daily (320 mgbenfotiamine, 720 mg pyridoxine, and 2,000 µg cyanocobalamindaily). The second group received Milgamma-Nat a lower dose of one capsule three timesdaily (120 mg benfotiamine, 270 mg pyridoxine, and750 µg cyanocobalamin daily), while the third groupreceived one capsule three times daily of straight benfotiamine(150 mg benfotiamine daily). Neuropathywas assessed via pain and vibration sensation at baselineand after three and six weeks. Patients in all threegroups reported beneficial therapeutic effects, even atthree weeks, although the most significant improvementwas reported by patients receiving the highestdosebenfotiamine. 19Alternative Medicine Review u Volume 11, Number 3 u 2006 Page 239Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005

BenfotiamineMonographA double-blind, randomized, placebo-controlled12-week study examined the effectiveness ofanother benfotiamine combination containing bothvitamins B6 and B12 in 24 diabetic patients withpolyneuropathy. A statistically significant improvementin nerve conduction velocity in the peronealnerve was observed in the treatment group comparedto placebo. A trend toward improvement in vibrationsensation was also reported in the treatment group;long-term observation of nine patients over a ninemonthperiod supported the results. 20Alcoholic NeuropathyChronic alcoholics commonly develop polyneuropathyas a result of dietary deficiency and poorabsorption of thiamine. Benfotiamine’s effect on neuropathyin alcoholics was investigated and comparedto thiamine in a randomized, multicenter, placebocontrolled,double-blind study of 84 subjects over aneight-week period. 12 Benfotiamine was given orallyat 320 mg daily during weeks 1-4, followed by 120mg daily during weeks 5-8. A second group receivedMilgamma-N (providing a total daily dose of 320 mgbenfotiamine, 720 mg pyridoxine, and 2,000 µg cyanocobalamin)during weeks 1-4 and a total daily doseof 120 mg benfotiamine, 270 mg pyridoxine, and 750µg cyanocobalamin during weeks 5-8; a third groupreceived placebo.Parameters measured included vibration perceptionin the great toe, ankle, and tibia; neural painintensity; motor function and paralysis; sensory function;and overall neuropathy score and clinical assessment.Neuropathy was scored from 0 (maximumclinical expression of neuropathy symptoms) to 16(free of symptoms) with scores of ≥10 representing amild clinical picture. Although benfotiamine therapywas superior to Milgamma-N and placebo for all parameters,results reached statistical significance onlyfor motor function and paralysis and overall neuropathyscore. Patients taking benfotiamine had a significantlylower degree of paralysis (90%) than thosein the placebo group (60.7%) or the Milgamma-Ngroup (53.9%). Overall neuropathy scores in the benfotiaminegroup were ≥10 in 93.3 percent of patients,compared to 67.9 percent in the placebo group and76.9 percent in the Milgamma-N group.Why the benfotiamine-alone group had betterresults than the Milgamma-N group, despite thefact that the benfotiamine dosage was equivalent, isnot completely understood. The authors hypothesizethe B6 and B12 might compete with the effects ofB1 in the Milgamma-N group. On the other hand, inthe case of diabetic neuropathy, the positive effects ofthe combination may be due to the fact that deficienciesof B1, B6, and B12 are implicated in its possiblepathogenesis; whereas, alcoholic neuropathy is associatedwith primarily a B1 deficiency.Diabetic Vascular ComplicationsDiabetic RetinopathyIn diabetics, the development of microvasculardisease is a leading cause of retinopathy and blindness.21 In a study with both animal and in vitro arms,researchers in Germany discovered benfotiamineadministration prevented experimental diabetic retinopathyin rats. Diabetic retinopathy is associatedwith increased AGE (a sign of oxidative stress) andelevations in retinal PKC activity. In vitro, a 50 µMconcentration of benfotiamine completely preventedincreases in AGE and PKC activity. 5These same researchers also examined the invivo effect of benfotiamine on retinas of diabetic rats;non-diabetic rats and untreated diabetic rats servedas controls. Diabetic rats receiving benfotiamine for36 weeks demonstrated a 2.5-fold increase in transketolaseactivity compared to untreated diabetic rats.Hexosamine pathway activity, PKC activity, AGEformation, and NF-κB activation in retinas of all threegroups were analyzed. In diabetic rats, benfotiamineadministration for 36 weeks reduced UDP-GlcNActo levels lower than those observed in non-diabeticrats, normalized AGE levels and PKC activity, andinhibited activation of NF-κB in diabetic rat retinas.The results of this study indicate lipid-soluble benfotiaminemay be of therapeutic benefit in patientswith diabetic retinopathy by preventing or delayingthe onset and progression of microvascular changesin the retina. 5Peripheral Vascular DiseaseIn two separate studies, a group of Italianresearchers from the University of Turin examinedthe effect of benfotiamine on endothelial defects andPage 240 Alternative Medicine Review u Volume 11, Number 3 u 2006Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005

MonographBenfotiamineapoptosis in human umbilical vein endothelial cellscultured in the presence of high glucose. 7,8 Either thiamineor benfotiamine prevented AGE production 7and apoptosis 8 in these cell cultures.Aldose reductase activity and sorbitol levelsare increased in human endothelial cells cultured inglucose, providing one mechanism for endothelialdysfunction in diabetes. Researchers found the additionof either thiamine or benfotiamine resulted innormalized intracellular glucose levels, decreasedsorbitol concentrations, and reduction in aldose reductaseactivity. 6Using an animal model of hind limb ischemiain diabetic mice, researchers in England investigatedwhether benfotiamine administration wasof benefit in reparative neovascularization. Mice wererandomly assigned to receive 80 mg/kg/day benfotiamineor placebo in drinking water. Two weeks afterbenfotiamine initiation, ischemia was surgicallyinduced in the left hind limb, and limb recovery wasdetermined at two weeks post-surgery. Parameters oflimb recovery were analyzed via Doppler flowmetryand histological analysis of adductor muscles in theaffected limb. It was demonstrated that benfotiamineimproves healing and neovascularization in ischemiclimbs of diabetic animals, probably via protein kinaseB potentiation of angiogenesis, manifesting in increasedperfusion and oxygenation of ischemic tissueand improved blood flow to the limb. Benfotiaminealso stimulated capillarization and reduced apoptosisin ischemic muscle tissue. 9Cerebrovascular and CardiovascularOxidative StressAnimal studies in diabetic male mice demonstratehigh-dose benfotiamine (100 mg/kg/day) givenvia intraperitoneal injection for 14 days alleviatesoxidative stress in both cerebral cortex tissue 22 andleft ventricular myocytes. In cardiomyocytes, benfotiamineimproved contractile function. 23Diabetic NephropathyHigh glucose concentrations in diabetes cancause an accumulation of triosephosphates, whichsubsequently trigger biochemical changes that resultin the development of diabetic nephropathy, a complicationoften associated with cardiovascular diseaseand higher mortality rates. The effects of high-dosethiamine and benfotiamine (70 mg/kg daily) ontriosephosphate accumulation were investigated indiabetic rats over a 24-week period. Both therapiesinhibited the accumulation of triosephosphates, increasedtransketolase expression in renal glomeruli,decreased PKC activation, decreased oxidative stressand protein glycation, and inhibited the developmentof microalbuminuria. These results indicate boththiamine and benfotiamine might be of therapeuticbenefit in renal complications of diabetes. Due to superiorpharmacokinetics, benfotiamine appears to bethe better choice. 11End-Stage Renal DiseaseThe thiamine pool in the body exists mainlyas thiamine diphosphate (TDP), 80 percent of which isfound in the erythrocytes. Many patients with chronicrenal insufficiency demonstrate decreased erythrocytetransketolase activity (a sign of thiamine deficiency)compared to healthy subjects. Consequently, many ofthese patients also develop neuropathies secondary tokidney disease. 10,24 In a clinical trial of 20 patients withend-stage renal disease, the effect of benfotiamine orthiamine nitrate on TDP blood levels and erythrocytetransketolase activity was evaluated. Patients weregiven single oral doses of 100 mg thiamine nitrateor benfotiamine and blood levels analyzed via highperformanceliquid chromatography over a 24-hourperiod. Compared to patients in the thiamine nitrategroup, patients receiving benfotiamine experiencedhigher TDP concentrations in erythrocytes as wellas significantly improved erythrocyte transketolaseactivity. Benfotiamine may be of clinical benefit inthiamine-deficient patients with chronic renal insufficiency.25Drug/Nutrient InteractionsThere are no reports of benfotiamine-druginteractions.Safety and ToxicityBenfotiamine administration appears tobe safe with no reports of toxicity in the scientificliterature.Alternative Medicine Review u Volume 11, Number 3 u 2006 Page 241Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005

BenfotiamineMonographDosage and AdministrationBased on clinical studies to date, daily dosesof oral benfotiamine range from 300-450 mg daily individed doses.References1. Greb A, Bitsch R. Comparative bioavailabilityof various thiamine derivatives after oraladministration. Int J Clin Pharmacol Ther1998;36:216-221.2. Ziems M, Netzel M, Bitsch I. Biokinetic parametersand metabolism of S-benzoylthiamine-Omonophosphate.BioFactors 2000;11:109-110.3. Bitsch R, Wolf M, Moller J, et al. Bioavailabilityassessment of the lipophilic benfotiamine ascompared to a water-soluble thiamin derivative.Ann Nutr Metab 1991;35:292-296.4. Loew D. Pharmacokinetics of thiamine derivativesespecially of benfotiamine. Int J Clin PharmcolTher 1996;34:47-50.5. Hammes HP, Du X, Edelstein D, et al.Benfotiamine blocks three major pathways ofhyperglycemic damage and prevents experimentaldiabetic retinopathy. Nat Med 2003;9:294-299.6. Berrone E, Beltramo E, Solimine C, et al.Regulation of intracellular glucose and polyolpathway by thiamine and benfotiamine in vascularcells cultured in high glucose. J Biol Chem2006;281:9307-9313.7. Pomero F, Molinar Min A, La Selva M, et al.Benfotiamine is similar to thiamine in correctingendothelial cell defects induced by high glucose.Acta Diabetol 2001;38:135-138.8. Beltramo E, Berrone E, Buttiglieri S, Porta M.Thiamine and benfotiamine prevent increasedapoptosis in endothelial cells and pericytescultured in high glucose. Diabetes Metab Res Rev2004;20:330-336.9. Gadau S, Emanueli C, Van Linthout S, et al.Benfotiamine accelerates the healing of ischaemicdiabetic limbs in mice through protein kinase B/AKT mediated potentiation of angiogenesis andinhibition of apoptosis. Diabetologia 2006;49:405-420.10. Mestyan I, Jobst K, Hazafi K, Green A. Erythrocytetransketolase activity in patients with chronic renaldisease. Acta Med Hung 1986;43:315-319.11. Babaei-Jadidi R, Karachalias N, Ahmed N, et al.Prevention of incipient diabetic nephropathy byhigh-dose thiamine and benfotiamine. Diabetes2003;52:2110-2120.12. Woelk H, Lehrl S, Bitsch R, Kopcke W.Benfotiamine in treatment of alcoholicpolyneuropathy: an 8-week randomized controlledstudy (BAP I Study). Alcohol Alcohol 1998;33:631-638.13. Thomson AD. Mechanisms of vitamin deficiencyin chronic alcohol misusers and the development ofthe Wernicke-Korsakoff syndrome. Alcohol AlcoholSuppl 2000;35:2-7.14. Abbas ZG, Swai AB. Evaluation of the efficacyof thiamine and pyridoxine in the treatment ofsymptomatic diabetic peripheral neuropathy. EastAfr Med J 1997;74:803-808.15. Koike H, Misu K, Hattori N, et al. Postgastrectomypolyneuropathy with thiamine deficiency. J NeurolNeurosurg Psychiatry 2001;71:357-362.16. Malinowski SS. Nutritional and metaboliccomplications of bariatric surgery. Am J Med Sci2006;331:219-225.17. Haupt E, Ledermann H, Kopcke W. Benfotiaminein the treatment of diabetic polyneuropathy – athree-week randomized, controlled pilot study(BEDIP Study). Int J Clin Pharmacol Ther2005;43:71-77.18. Simeonov S, Pavlova M, Mitkov M, et al.Therapeutic efficacy of “Milgamma” in patientswith painful diabetic neuropathy. Folia Med(Plovdiv) 1997;39:5-10.19. Winkler G, Pal B, Nagybeganyi E, et al.Effectiveness of different benfotiamine dosageregimens in the treatment of painful diabeticneuropathy. Arzneimittelforschung 1999;49:220-224.20. Stracke H, Lindemann A, Federlin K. Abenfotiamine-vitamin B combination in treatmentof diabetic polyneuropathy. Exp Clin EndocrinolDiabetes 1996;104:311-316.21. No authors listed. The effect of intensive treatmentof diabetes on the development and progressionof long-term complications in insulin-dependentdiabetes mellitus. The Diabetes Control andComplications Trial Research Group. N Engl JMed 1993;329:977-986.22. Wu S, Ren J. Benfotiamine alleviates diabetesinducedcerebral oxidative damage independent ofadvanced glycation end-product, tissue factor andTNF-alpha. Neurosci Lett 2006;394:158-162.23. Ceylan-Isik AF, Wu S, Li Q, et al. High-dosebenfotiamine rescues cardiomyocyte contractiledysfunction in streptozotocin-induced diabetesmellitus. J Appl Physiol 2006;100:150-156.24. Lange K, Lonergan ET, Semar M, Sterzel RB.Transketolase inhibition as a mechanism inuremic neuropathy. Trans Assoc Am Physicians1971;84:172-181.25. Frank T, Bitsch R, Maiwald J, Stein G. Highthiamine diphosphate concentrations inerythrocytes can be achieved in dialysis patientsby oral administration of benfotiamine. Eur J ClinPharmacol 2000;56:251-257.Page 242 Alternative Medicine Review u Volume 11, Number 3 u 2006Copyright © 2005 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 10, Number 4 December 2005