Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: P&G Health Germany GmbH, Sulzbacher Strasse 40, 65824 Schwalbach am Taunus, Germany
Pharmacotherapeutic group: Vitamin B1 in combination with vitamin B6 and/or vitamin B12
ATC Code: A11DB
Neurobion ampoules contain a combination of neurotropic active substances of the vitamin B complex. The vitamins thiamine (B1), pyridoxine (B6) and cobalamin (B12) contained play a particular role as coenzymes in the intermediary metabolism of the central and peripheral nervous system.
Like all other vitamins, they are essential nutrients which the body cannot synthesise itself.
Therapeutic supply of vitamins B1, B6 and B12 balances deficiencies due to inadequate nutritive vitamin intake and thus ensures the availability of the required quantities of coenzymes.
Thiamine pyrophosphate (TPP) is the effective form of vitamin B1 and acts as a coenzyme for a number of enzymes (e.g. pyruvate dehydrogenase and transketolase). Accordingly, vitamin B1 is primarily involved in the carbohydrate metabolism; however, it also intervenes in the synthesis of lipids and amino acids. Nerve cells cover their energy requirement exclusively via enzymatic oxidation and decarboxylation of glucose, so that an adequate supply of vitamin B1 is of crucial importance. Thiamine is also involved in the conduction of nerve impulses. Furthermore, results obtained in experiments indicate an analgesic effect.
Manifestations of vitamin B1 deficiency are very multifaceted and can involve the central and peripheral nervous system, the cardiovascular system, the skin and other body systems. Specific symptoms can include polyneuropathy with paraesthesia (tingling, burning, numbness), hyperesthesia (increased sensitivity), muscle weakness, altered temperature sensitivity, oedema, and others.
Pyridoxal phosphate, the biologically active form of pyridoxine, is the determinative coenzyme in amino acid metabolism. It is involved in the formation of physiologically active amines (e.g. serotonin, histamine, adrenalin) through decarboxylation processes, as well as in anabolic and catabolic processes through transamination.
Pyridoxal phosphate plays an essential role in the nervous system, especially in the enzymatically controlled neurotransmitter metabolism. As a catalyst of the first biosynthesis steps of sphingosine, pyridoxal phosphate also has a key role in the metabolism of sphingolipids. Sphingolipids are essential constituents of the myelin sheaths of nerve cells. Animal experimental models have demonstrated that vitamin B6 has an analgesic effect.
Vitamin B6 deficiency can be associated with peripheral neuritis and neuropathy, paresthesia, burning, painful dysesthesia, disorders of oxalate metabolism, depression of immune responses, anemia, lesions of the mucous membranes and other symptoms.
Vitamin B12 in its coenzyme forms (5-deoxyadenosyl cobalamin and methyl cobalamin) is involved in enzymatically catalysed intramolecular hydrogen displacements and in intramolecular transfers of methyl groups. Vitamin B12 is also involved in methionine synthesis (closely coupled to the synthesis of nucleic acids) and in lipid metabolism, via the conversion of propionic acid into succinic acid.
Vitamin B12 is involved in the methylation of the myelin basic protein, a constituent of the myelin sheaths of the nervous system. Methylation increases the lipophilic properties of the myelin basic protein, which favours increased integration in the myelin sheaths.
Vitamin B12 deficiency can result in neurological symptoms like paresthesia, numbness, gait impairment, impaired vibration sense, polyneuritis (particularly sensory, in the distal extremities), ataxia and others. Further symptoms can be anaemia, optic atrophy, altered mental status and others.
Neurotropic vitamins B1, B6 and B12 alone, and in combination as the result of biochemical synergy, have special significance for the metabolism of the nervous system, which justifies their combined use.
Further, in most of the patient populations such as elderly, diabetic patients and others, deficiency of all three neurotropic vitamins is present.
Animal studies have shown that this combination of neurotropic B vitamins accelerates regenerative processes in damaged nerve fibres, which finally leads to enhanced restoration of function and muscle innervation. In the model of experimental diabetes in rats, administration of B complex vitamins prevented or attenuated the characteristic nerve damage, so that deterioration of the functional properties was counteracted (antineuropathic effect).
Further, the combination of B1, B6 and B12 has been proven to have a synergistic effect when combined with NSAIDs in the treatment of pain.
Animal and clinical studies have indicated antinociceptive activity of vitamin B1, B6 and B12.
Combined administration of vitamins B1, B6 and B12 is not expected to have a negative effect on the pharmacokinetics of the individual vitamins.
The biological half-life of thiamine in humans is about 9.5 to 18.5 days, with an elimination half-life of approx. 4 hours.
The reserve capacity is 4‑10 days. The high turnover rate and limited storage of thiamine (20-30 mg, mainly in the heart, brain, liver, and kidneys) require an adequate daily thiamine intake to meet requirements. Deficiency can present within 2-3 weeks of intake ceasing. Typical symptoms are tiredness, nausea, vomiting, obstipation, headache, tachycardia, and weak muscle reflexes.
Vitamin B6 is phosphorylated mainly in the liver, forming the biologically active pyridoxal phosphate. To cross cell membranes, phosphorylated vitamin B6 must be hydrolysed by alkaline phosphatase to free vitamin B6. Transport into the cells is by simple diffusion followed by rephosphorylation. Peak concentrations are reached after 3.5 to 4 hours. The biological half-life of pyridoxal phosphate is about 15-25 days with an elimination half-life of approximately 3 hours. The storage capacity for vitamin B6 is 14 to 42 days. Approx. 40 to 150 mg can be stored, 1.7 to 3.6 mg is excreted in the urine per day.
Oral vitamin B12 is known to have a low absorption rate which may be further decreased, following bariatric surgery, in elderly patients, dialysis patients and patients with other conditions of malabsorption. Apart from saturable active absorption of oral vitamin B12, leading to daily absorption of approximately 1.5µg, vitamin B12 is also absorbed by passive diffusion. The proportion absorbed by passive diffusion is only approximately 1% of the ingested quantity. This is further reduced in patients who have had bariatric surgery or have an impaired gastrointestinal absorption due to other diseases. In these patients, parenteral application may be indicated.
About 90% of plasma cobalamin is bound to proteins (transcobalamins). Most of the Vitamin B12 not circulating in the plasma is stored predominantly in the liver, the daily requirement is 1 µg. The turnover rate is 2.5 µg B12 per day, or 0.05% of the stored quantity.
Vitamin B12 is mainly excreted via the bile and largely reabsorbed during the enterohepatic circulation. If the body’s storage capacity is exceeded as a result of high-dose and, in particular, parenteral administration, the portion not retained is excreted in the urine.
Results of pharmacokinetic studies using parenteral vitamin B preparations suggest that intramuscular and intravenous B-vitamins lead to higher cyanocobalamin plasma levels than high oral doses. In addition, parenteral and oral preparations of vitamins B1, B6 and B12 are equally well tolerated. Consequently, parenteral application of vitamins B1, B6 and B12 may be adequate for rapid restoration of vitamin stores in acute deficiencies and in patients with vitamin B absorption problems and in patients with an increased need due to certain pathological conditions.
The toxicity of vitamins B1, B6 and B12 is very low. The data available to date do not suggest any potential risk for humans.
The literature available on the subject does not contain any findings indicating that vitamins B1, B6 and B12 have carcinogenic, mutagenic or teratogenic properties.
Chronic toxicity: In animals, very high doses of vitamin B1 cause bradycardia. Other symptoms are blockade of vegetative ganglia and motor end plates. The oral administration of 150–200 mg of vitamin B6/kg body weight/day over a period of 100-107 days caused ataxia, muscular asthenia, disorders of balance, as well as degenerative changes of axons and myelin sheaths in dogs. Animal studies also showed incidences of convulsions and impaired coordination after high doses of vitamin B6.
Mutagenic and tumorigenic potential: Mutagenic effects of vitamin B1 and vitamin B6 are not to be expected under the conditions of clinical use.
There are no long-term animal studies available on the tumorigenic potential of thiamine and vitamin B6.
Reproduction toxicity: Thiamine is transported actively to the foetus. Concentrations in the foetus and the newborn exceed maternal concentrations of vitamin B1. Systematic investigations on human embryonal and foetal development in connection with the use of vitamin B1 at doses exceeding the stated daily requirements are not available.
Vitamin B6 is insufficiently investigated in animal studies. An embryotoxicity study in rats gave no indications of a teratogenic potential. In male rats the administration of very high doses of vitamin B6 induced damage to spermatogenesis.
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