Bibliography

1. Benfotiamine in Diabetic Polyneuropathy (BENDIP): Results of a Randomised, Double Blind, Placebo­controlled Clinical Study. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG Medical Clinic und Policlinic III, University Hospital Giessen and Marburg, Location Giessen, Germany. Exp. Clinic Endocrinol Diabetes, 2008 Nov; 116(10):600-5. Epub 2008 May 13.
AIM: Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. METHODS: Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-­‐out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). RESULTS: After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. CONCLUSION: Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

2. Benfotiamine in the treatment of diabetic polyneuropathy ­ a three­week randomized, controlled pilot study (BEDIP Study). Haupt E, Ledermann H, Köpcke W. Saale­Klinik, Bad Kissingen, Lindenfels, Germany. Int J Clin Pharmacol Ther. 2005 Feb; 43(2):71-­7.

OBJECTIVE: The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-­‐soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-­‐controlled, double-­‐blind, two-­‐center pilot study. MATERIAL AND METHODS: Forty inpatients (23 male, 18 female, age range 18 -­‐ 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-­‐week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented. RESULTS: A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-­‐treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-­‐treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. CONCLUSION: This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.

3. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. P. J. Thornalley & R. Babaei-Jadidi & H. Al Ali & N. Rabbani & A. Antonysunil & J. Larkin & A. Ahmed & G. Rayman & C. W. Bodmer ; Diabetologia, 2007 October; 50(10): 2164-2170

Aims/hypothesis: To assess thiamine status by analysis of plasma, erythrocytes and urine in type 1 and type 2 diabetic patients and links to markers of vascular dysfunction. Methods Diabetic patients (26 type 1 and 48 type 2) with and without microalbuminuria and 20 normal healthy control volunteers were recruited. Erythrocyte activity of transketolase, the concentrations of thiamine and related phosphorylated metabolites in plasma, erythrocytes and urine, and markers of metabolic control and vascular dysfunction were determined. Results Plasma thiamine concentration was decreased 76% in type 1 diabetic patients and 75% in type 2 diabetic patients: normal volunteers 64.1 (95% CI 58.5-69.7) nmol/l, type 1 diabetes 15.3 (95% CI 11.5-19.1) nmol/l, p<0.001,

4. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications Elena Beltramo, Elena Berrone, Sonia Tarallo, Massimo Porta; Acta Diabetol (2008) 45:131-141

Abstract: Thiamine (vitamin B1) is an essential cofactor in most organisms and is required at several stages of anabolic and catabolic intermediary metabolism, such as intracellular glucose metabolism, and is also a modulator of neuronal and neuro-muscular transmission. Lack of thia- mine or defects in its intracellular transport can cause a number of severe disorders. Thiamine acts as a coenzyme for transketolase (TK) and for the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism. In particular, TK is able to shift excess fruc- tose-6-phosphate and glycerhaldeyde-3-phosphate from glycolysis into the pentose-phosphate shunt, thus eliminat- ing these potentially damaging metabolites from the cytosol. Diabetes might be considered a thiamine-deficient state, if not in absolute terms at least relative to the increased requirements deriving from accelerated and amplified glucose metabolism in non-insulin dependent tissues that, like the vessel wall, are prone to complications. A thiamine/TK activity deficiency has been described in diabetic patients, the correction of which by thiamine and/or its lipophilic derivative, benfotiamine, has been demon- strated in vitro to counteract the damaging effects of hyperglycaemia on vascular cells. Little is known, however, on the positive effects of thiamine/benfotiamine adminis- tration in diabetic patients, apart from the possible amelioration of neuropathic symptoms. Clinical trials on diabetic patients would be necessary to test this vitamin as a potential and inexpensive approach to the prevention and/or treatment of diabetic vascular complications.

5. 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. 2nd Department of Internal Medicine, Municipal St. John's Hospital, Budapest, Hungary. Arzneimittelforschung. 1999 Mar; 49(3):220-­4.

The therapeutic effectiveness of a benfotiamine (CAS 22457-89-2)-vitamin B combination (Milgamma-N), administered in high (4 x 2 capsules/day, = 320 mg benfotiamine/day) and medium doses (3 x 1 capsules/day), was compared to a monotherapy with benfotiamine (Benfogamma) (3 x 1 tablets/day, = 150 mg benfotiamine/day) in diabetic patients suffering from painful peripheral diabetic neuropathy (DNP). In a 6-­‐week open clinical trial, 36 patients (aged 40 to 70 yrs) having acceptable metabolic control (HbA1c < 8.0%) were randomly assigned to three groups, each of them comprising 12 participants. Neuropathy was assessed by five parameters: the pain sensation (evaluated by a modified analogue visual scale), the vibration sensation (measured with a tuning fork using the Riedel-­‐Seyfert method) and the current perception threshold (CPT) on the peroneal nerve at 3 frequencies: 5, 250 and 2000 Hz). Parameters were registered at the beginning of the study and at the end of the 3rd and 6th week of therapy. An overall bneneficial therapeutic effect on the neuropathy status was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy (p < 0.01). The greatest change occurred in the group of patients receiving the high dose of benfotiamine (p < 0.01 and 0.05, resp., compared to the othr groups). Metabolic control did not change over the study. It is concluded that benfotiamine is most effective in large doses, although even in smaller daily dosages, either in combination or in monotherapy, it is effective.

6. Benfotiamine in the treatment of alcoholic polyneuropathy: an 8­week randomized controlled study (BAP I Study). H. Woelk, S. Lehrl, R. Bitsch and W. Köpcke. Alcohol and Alcoholism, 1998 Nov-Dec;33(6):631-8.

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.

7. Therapeutic efficacy of "Milgamma" in patients with painful diabetic neuropathy. Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev D. Endocrinology and Metabolic Disorders Clinic, Higher Medical Institute, Plovdiv, Bulgaria. Folia Med (Plovdiv). 1997;39(4):5-­10

Forty-five diabetes patients with painful peripheral polyneuropathy were enrolled in a 3-­‐month observational study comparing the therapeutic efficacy of Milgamma tablets (50 mg benfothiamine and 0.25 mg cyancobalamine) with parallel randomized treatment assignment with the conventional vitamin B complex treatment regimen Neurobex. Thirty patients in group one were randomized to receive two Milgamma tablets qid for three weeks followed by 1 Milgamma tablet tid for 9 weeks. In group two 15 patients received two Neurobex tablets tid for the entire 3-­‐month study period. Therapeutic efficacy was assessed on the basis of within-­‐patient differences in pain severity between Milgamma and Neurobex-­‐treated patients and in vibration perception thresholds using the Rydel-­‐Seiffer biothesiometer at baseline and at the end of the study. Statistically significant relief of both background and peak neuropathic pain was achieved in all of the Milgamma-­‐treated patients and vibration perception thresholds dramatically improved with a median of 1.56 measured on the biothesiometer scale (t = 3.24, P < 0.01). The sensory symptoms improvement was insignificant in the Neurobex-­‐treated patient group and the changes in the vibration perception thresholds failed to reach statistical significance. The therapeutic efficacy of Milgamma was greater in patients with early-­‐stage diabetes as compared with those with advanced diabetic neuropathy. No adverse reactions were observed following the administration of the medication. Our results underscore the importance of Milgamma tablets as an indispensable element in the therapeutic regimen of patients with painful diabetic polyneuropathy.

8. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Stracke H, Lindemann A, Federlin K, Third Medical Department, University of Giessen, Germany. Exp Clin Endocrinol Diabetes. 1996;104(4):311‐6

In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long‐term observation of 9 patients with verum over a period of 9 months support the results. Therapy‐specific adverse effects were not seen. The results of this double-­‐blind investigation, of the long‐term observation and of the reports in the literature support the contention that the neurotropic benfotiamine‐vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.