Benfotiamine

Structural formula
	Structure of the ( Z ) isomer
General
Non-proprietary name	Benfotiamine
other names	6- (4-Amino-2-methyl-5-pyrimidinyl) -3-benzoylthio-5-formyl-4-methyl-5-aza-3-hexenyl dihydrogen phosphate; Benfotiamine; Benfotiaminum; Benphothiamine;
Molecular formula	C 19 H 23 N 4 O 6 PS
External identifiers / databases
EC number	245-013-4
ECHA InfoCard	100.040.906
PubChem	3032771
ChemSpider	2297665
Wikidata	Q409953
Drug information
ATC code	A11 DA03
Drug class	Provitamin
properties
Molar mass	466.45 g mol −1
Physical state	firmly
Melting point	155-165 ° C (dec.)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
Toxicological data	15 g kg −1 ( LD 50 , mouse , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Benfotiamine is a fat-soluble precursor ( prodrug ) of vitamin B ₁ and is quickly broken down in the body to form the effective vitamin B ₁ . The fat-soluble benfotiamine differs from the water-soluble vitamin B ₁ in that it is absorbed ( resorbed ) in the body in a significantly higher proportion (about 5 to 7 times as high) . Due to its high bioavailability , benfotiamine is used both to prevent and treat vitamin B ₁ deficiency.

Chemical properties

Isomerism

Benfotiamine is a compound of which two isomers , more precisely ( E , Z ) isomers , exist due to the different substitution options at the C = C double bond . These isomers differ in chemical and physical properties as well as physiological effects. The individual isomers can be separated and thus isolated in pure form by means of suitable synthesis strategies or separation processes.

Bioavailability

Equimolar doses of 100 mg benfotiamine (approx. 210 μmol thiamine) and thiamine mononitrate resulted in a five-fold higher AUC and an approx. Seven-fold higher maximum plasma concentration after administration of benfotiamine.

Mechanism of action

In diabetics, the increased blood sugar level activates various pathogenic metabolic pathways: the hexosamine metabolic pathway, the protein kinase C metabolic pathway, the formation of " advanced glycation end products" (AGEs - end products of advanced glycation) and the polyol metabolic pathway. Benfotiamine inhibits these nerve and vascular damaging metabolic pathways by activating a central enzyme of glucose metabolism , transketolase . Transketolase leads excess glucose to the harmless pentose phosphate metabolic pathway and thus removes it from the pathogenic metabolic pathways.

application areas

Treatment of neuropathies (diseases of the nerves) and cardiovascular disorders caused by vitamin B ₁ deficiency. Therapy or prophylaxis of clinical vitamin B ₁ deficiencies, if these cannot be remedied nutritionally.

Studies on therapeutic use

Diabetic neuropathy

A secondary disease that often occurs in diabetics is peripherally sensitive neuropathy . The nerve fibers in the legs and arms are damaged by the increased blood sugar. This can lead to abnormal sensations such as tingling, stinging or burning. In addition, the sensitivity of the affected parts of the body - mainly the feet - can completely decrease. A “ diabetic foot ” can develop as a possible consequence .

Some studies show very low thiamine levels in diabetics. Compared to healthy people, the plasma thiamine concentrations in diabetics are reduced by an average of 75 percent. This deficit can cause the above Promote pathogenic metabolic pathways and thereby the development and progression of diabetic secondary diseases such as neuropathy. The treatment of symptomatic diabetic polyneuropathy consists of optimal blood sugar control and symptomatic therapy. The substitution with benfotiamine represents a pathogenetically oriented therapeutic approach. Efficacy and tolerability could be demonstrated in several pilot studies.

Diabetic retinopathy

Diabetes is a common cause of blindness . An in vitro study from 2009 shows that benfotiamine and thiamine prevent apoptosis of the pericytes . In the early phase of retinopathy, benfotiamine may have a regulating effect.

Kidney protection

Harmful metabolic products (see also AGEs ) occur more frequently during peritoneal dialysis treatment. They damage the peritoneum and the rest of the kidney. This limits the duration of the dialysis treatment. In a 2011 animal study, benfotiamine protected the peritoneum and kidneys from these harmful effects.

Heart protection

Hyperglycemia is damaging and debilitating to the heart. In a study on rats, benfotiamine improved the resistance of heart cells to damage caused by diabetes. Treatment with the provitamin made it possible to significantly increase the survival rate of diabetic rats after a heart attack: Benfotiamine slowed the apoptosis of heart cells and promoted the formation of new blood vessels.

Deficiency symptoms ( hypovitaminosis )

(Corresponding to those of thiamine / vitamin B1 )

Symptoms:

Disorders of the carbohydrate metabolism and nervous system (including polyneuropathy )
Irritability and depression
Fatigue, visual disturbances, loss of appetite, poor concentration, muscle atrophy
Anemia
frequent headaches
Memory disorders ( Korsakoff syndrome ), confusion
Heart failure, edema, tachycardia, low blood pressure, shortness of breath (dyspnoea)
Decreased antibody production in infections
disturbed energy production

Diseases:

Beriberi , Wernicke encephalopathy , Strachan's syndrome

literature

R. Bitsch et al: Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamine derivative. In: Ann Nutr Metab. 35, 1991, pp. 292-296. PMID 1776825 .
J. Geyer et al: Bioavailability of water- and lipid-soluble thiamin compounds in broiler chickens. In: Int J Vitam Nutr Res. 70, 2000, pp. 311-316. PMID 11214357 .
A. Greb et al .: Comparative bioavailability of various thiamine derivatives after oral administration. In: Int J Clin Pharmacol Ther . 36, 1998, pp. 216-221. PMID 9587048 .
N. Rabbani et al .: High dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a pilot randomized, double-blind, placebo-controlled study. In: Diabetologia . 52, 2009, pp. 208-212. DOI: 10.1007 / s00125-008-1224-4 . PMID 19057893 .

Trade names

Monopreparation

milgamma protekt

Individual evidence

↑ ^a ^b Data sheet S-Benzoylthiamine O-monophosphate from Sigma-Aldrich , accessed on June 10, 2011 ( PDF ).
↑ Entry on benfotiamine. In: Römpp Online . Georg Thieme Verlag, accessed on June 12, 2011.
↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of benfotiamine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), retrieved on July 19, 2019, is reproduced from a self-classification by the distributor .
↑ ^a ^b K. H. Schreeb et al: Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. In: Eur J Clin Pharmacol . 52 (4), 1997, pp. 319-320. PMID 9248773 .
↑ D. Loew: Pharmacokinetics of thiamine derivatives especially of benfotiamine. In: Int J Clin Pharmacol Ther. 34 (2), Feb 1996, pp. 47-50. PMID 8929745 .
↑ H.-P. Hammes et al .: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy . In: Nature Medicine . 9, 2003, pp. 294-299.
^ PJ Thornalley et al .: High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. In: Diabetologia. 50, 10, 2007, pp. 2164-2170. PMC 1998885 (free full text).
↑ Diagnosis, Treatment and Follow-up of Diabetic Neuropathy. (PDF; 347 kB), DDG, May 2004, accessed June 23, 2011 (current guideline 2011 not yet published).
Jump up ↑ H. Stracke, W. Gaus, U. Achenbach, K. Federlin, RC Bretzel: Benfotiamine in diabetic polyneuropathy (BENDIP): Results of a randomized, double blind, placebo-controlled clinical study. In: Exp Clin Endocrinol Diabetes. 116, 2008, pp. 600-605. doi: 10.1055 / s-2008-1065351 .
↑ E. Haupt et al .: Benfotiamine in the treatment of diabetic polyneuropathy - a three-week randomized, controlled pilot study (BEDIP Study). In: Int J Clin Pharmacol Ther. 43, 2005, pp. 71-77. PMID 15726875 .
↑ E. Beltramo et al: Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes. In: Diabetes Metab Res Rev. 25, 2009, pp. 647-656; doi: 10.1002 / dmrr.1008 .
↑ LP Kihm include: Benfotiamine Protects against peritoneal and kidney damage in Peritoneal Dialysis. In: J Am Soc Nephrol. 22, 2011, pp. 914-926, doi: 10.1681 / ASN.2010070750 .
↑ R. Katare et al: Benfotiamine improves functional recovery of the infracted heart via activation of pro-survival G6PD / Akt signaling pathway and modulation of neurophormonal response. In: Journal of Molecular and Cellular Cardiology . 2010. PMID 20542491 .

[Sigma-1] Data sheet S-Benzoylthiamine O-monophosphate from Sigma-Aldrich , accessed on June 10, 2011 ( PDF ).

[roempp-2] Entry on benfotiamine. In: Römpp Online . Georg Thieme Verlag, accessed on June 12, 2011.

[3] Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of benfotiamine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), retrieved on July 19, 2019, is reproduced from a self-classification by the distributor .

[Schreeb-4] K. H. Schreeb et al: Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. In: Eur J Clin Pharmacol . 52 (4), 1997, pp. 319-320. PMID 9248773 .

[Loew-5] D. Loew: Pharmacokinetics of thiamine derivatives especially of benfotiamine. In: Int J Clin Pharmacol Ther. 34 (2), Feb 1996, pp. 47-50. PMID 8929745 .

[Hammes-6] H.-P. Hammes et al .: Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy . In: Nature Medicine . 9, 2003, pp. 294-299.

[Thornalley-7] PJ Thornalley et al .: High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. In: Diabetologia. 50, 10, 2007, pp. 2164-2170. PMC 1998885 (free full text).

[8] Diagnosis, Treatment and Follow-up of Diabetic Neuropathy. (PDF; 347 kB), DDG, May 2004, accessed June 23, 2011 (current guideline 2011 not yet published).

[BENDIP-9] Jump up ↑ H. Stracke, W. Gaus, U. Achenbach, K. Federlin, RC Bretzel: Benfotiamine in diabetic polyneuropathy (BENDIP): Results of a randomized, double blind, placebo-controlled clinical study. In: Exp Clin Endocrinol Diabetes. 116, 2008, pp. 600-605. doi: 10.1055 / s-2008-1065351 .

[BEDIP-10] E. Haupt et al .: Benfotiamine in the treatment of diabetic polyneuropathy - a three-week randomized, controlled pilot study (BEDIP Study). In: Int J Clin Pharmacol Ther. 43, 2005, pp. 71-77. PMID 15726875 .

[11] E. Beltramo et al: Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes. In: Diabetes Metab Res Rev. 25, 2009, pp. 647-656; doi: 10.1002 / dmrr.1008 .

[Kihm-12] LP Kihm include: Benfotiamine Protects against peritoneal and kidney damage in Peritoneal Dialysis. In: J Am Soc Nephrol. 22, 2011, pp. 914-926, doi: 10.1681 / ASN.2010070750 .

[13] R. Katare et al: Benfotiamine improves functional recovery of the infracted heart via activation of pro-survival G6PD / Akt signaling pathway and modulation of neurophormonal response. In: Journal of Molecular and Cellular Cardiology . 2010. PMID 20542491 .