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Benfotiamine in the treatment of diabetic polyneuropathy—a three-week randomized, controlled pilot study (BEDIP Study). Haupt E, Ledermann H, Köpcke W. Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. 40 inpatients with diabetes and polyneuropathy received either 400mg benfotiamine daily or placebo for 3 weeks. Statistically significant improvement (p=0.0287) in neuropathy score in active group. Most pronounced effect on pain (p=0.0414).

Benfotiamine in the treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP study). Woelk H, Lehrl S, Bitsch R, Köpcke W. Alcohol Alcohol. 1998 Nov-Dec;33(6):631-8. Three-armed RCT in 84 outpatients with severe alcoholic polyneuropathy. Benfotiamine produced significant improvement in vibration perception, motor function, and overall score. No therapy-specific adverse effects.

Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Arzneimittelforschung. 1999 Mar;49(3):220-4. 36 patients in three groups; greatest improvement seen in high-dose group (320mg/day benfotiamine).

A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Stracke H, Lindemann A, Federlin K. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. 12-week double-blind RCT in 24 diabetic patients. Significant improvement (p=0.006) of nerve conduction velocity in peroneal nerve.

The pathobiology of diabetic complications: a unifying mechanism. Brownlee M. Diabetes. 2005 Jun;54(6):1615-25.

The multifaceted therapeutic potential of benfotiamine. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. Pharmacol Res. 2010 Jun;61(6):482-8. Comprehensive review of benfotiamine's anti-AGE properties and effectiveness in diabetic neuropathy, nephropathy, and retinopathy.

Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Hammes HP, Du X, Edelstein D, et al. Nat Med. 2003 Mar;9(3):294-9. Demonstrates benfotiamine inhibits the hexosamine, AGE, and PKC pathways by activating transketolase. Prevented experimental diabetic retinopathy.

The potential role of thiamine (vitamin B1) in diabetic complications. Thornalley PJ. Curr Diabetes Rev. 2005 Aug;1(3):287-98. Argues for thiamine therapy in preventing diabetic complications via the reductive pentose phosphate pathway.

High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Thornalley PJ, Babaei-Jadidi R, Al Ali H, et al. Diabetologia. 2007 Oct;50(10):2164-70. Plasma thiamine concentration was decreased 76% in type 1 and 75% in type 2 diabetic patients. Renal clearance of thiamine increased 24-fold (type 1) and 16-fold (type 2).

Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease. Page GL, Laight D, Cummings MH. Int J Clin Pract. 2011 Jun;65(6):684-90.

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. de Jager J, et al. BMJ. 2010 May 20;340:c2181. Metformin treatment associated with -19% decrease in vitamin B-12 concentration; long-term metformin use increases risk of B-12 deficiency.

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Liang X, et al. Mol Pharm. 2015 Dec 7;12(12):4301-10. Demonstrates metformin transports via and inhibits thiamine transporter THTR-2 in the small intestine. Implications for thiamine deficiency in metformin-treated diabetics.

Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Pan, et al. Brain. 2010 May;133(Pt 5):1342-51. Benfotiamine dose-dependently enhanced spatial memory and reduced amyloid plaque and phospho-tau in mouse AD model.

Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes. Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J. Mol Cell Neurosci. 2013 Jul;55:17-25.

Alterations of Thiamine Phosphorylation and of Thiamine-Dependent Enzymes in Alzheimer's Disease. Heroux M, et al. Metabolic Brain Disease, Vol. 11, No. 1, 1996. Significantly reduced activities of thiamine phosphate dephosphorylating enzymes and thiamine-dependent enzymes in AD brain tissue.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. Rieck J, Halkin H, Almog S, et al. J Lab Clin Med. 1999 Sep;134(3):238-43.

Mechanisms of thiamin deficiency in chronic alcoholism. Hoyumpa AM Jr. Am J Clin Nutr. 1980 Dec;33(12):2750-61. Reviews ethanol inhibition of intestinal thiamine transport via reduced Na-K ATPase activity.

Axonal degeneration in beriberi neuropathy. Takahashi K, Nakamura H. Arch Neurol. 1976 Dec;33(12):836-41.

Mitochondrial dynamics and peripheral neuropathy. Baloh RH. Neuroscientist. 2008 Feb;14(1):12-8.

Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy. Fernyhough P, Huang TJ, Verkhratsky A. J Peripher Nerv Syst. 2003 Dec;8(4):227-35. Insulin and NT-3 modulate mitochondrial membrane potential in adult sensory neurons via PI 3 kinase pathway.

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Flatters SJ, Bennett GJ. Pain. 2006 Jun;122(3):245-57. Paclitaxel produces atypical (swollen and vacuolated) mitochondria in both C-fibres and myelinated axons in painful peripheral neuropathy.

Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Bennett GJ, Doyle T, Salvemini D. Nat Rev Neurol. 2014;10:326-336. Reviews how mitochondrial injury from chemotherapy, HIV proteins, and hyperglycemia leads to chronic neuronal energy deficit and distal axonal degeneration.

Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. Lehmann HC, Chen W, Borzan J, Mankowski JL, Höke A. Ann Neurol. 2011 Jan;69(1):100-10.

Peripheral neuropathy associated with mitochondrial disease in children. Menezes MP, Ouvrier RA. Dev Med Child Neurol. 2012 May;54(5):407-14.

The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients. Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M. J Am Board Fam Pract. 2004 Sep-Oct;17(5):309-18. Prevalence of bilateral sensory deficits rose from 26% (65-74 yrs) to 54% (85+). Only 40% of cases had a known cause.

Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. Brasky TM, White E, Chen CL. J Clin Oncol. 2017 Oct 20;35(30):3440-3448. High-dose B6 and B12 supplementation linked to almost 2-fold increase in lung cancer risk in men, especially smokers.

Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment. Solomon LR. Blood Rev. 2007 May;21(3):113-30.

An update on cobalamin deficiency in adults. Dali-Youcef N, Andrès E. QJM. 2009 Jan;102(1):17-28.

Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort. Lee CC, Perkins BA, et al. Diabetes Care 2015;38:793-800. Prevalence of peripheral neuropathy: 29% in normal glycemia, 49% in prediabetes, 50% in new-onset diabetes (p<0.001 for trend). Prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes.