Milgamma Review Article
Milgamma is a vitamin b complex drug, composed vitamin B1 (either as thiamine or its derivative, benfotiamine), vitamin B6 (Pyridoxine) and vitamin B12 (cyanocobalamin). It is used as a replenisher, to treat neurological symptoms associated with the deficiencies of these B vitamins as well as neuropathy associated with different disease states such as diabetes mellitus. Milgamma, Milgamma-N or Milgamma-Neuro is available as an oral tablet preparation which is composed of different combinations of benfotiamine, pyridoxine HCl and cyanocobalamin, depending on the country. It is also available as Milgamma mono, which is composed of benfotiamine alone.
Milgamma is used to treat neurological disorders, neuropathies, polyneuropathies, neuralgia, herpes and facial paralysis. It is also highly effective in patients with diabetic neurophaty. Milgamma exist in three forms which are the dragees, injection and capsules. It works by restricting the build up process of the blood sugar level in the different cells in the body. Continue reading...
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Vitamin B1 (Thiamine HCl) and its derivative (Benfotiamine)
Vitamin B1 is a B complex vitamin classified as an energy releaser. This is because it serves as an essential coenzyme for carbohydrate metabolism. Thiamine, or its derivative, benfotiamine (Loew, 1996), is converted in vivo to its active form, thiamine pyrophosphate (TPP). TPP is involved in the oxidative decarboxylation of pyruvate and α-ketoglutarate, which plays a major role in energy metabolism, particularly of the nervous system cells (Harvey and Champe, 2004).
Vitamin B1 requirements in the body is dependent in the amount of carbohydrate intake; if there is a high amount of carbohydrate intake, then high levels of thiamine is necessary to metabolise the carbohydrates. However, if vitamin B1 intake does not suffice, deficiency (otherwise called beriberi) occurs.
Other causes of vitamin B1 deficiency may also occur, which may be due to impaired intestinal absorption (as seen with chronic alcoholics, called as Wernicke-Korsakoff syndrome), and congenital beriberi wherein nursing mothers do not have sufficient vitamin B1 to give to their child.
Because it affects mainly the metabolism of nervous system cells, the most commonly observed signs and symptoms of vitamin B1 deficiency are neurologic – convulsions for infants; irritability, disorderly thinking, and progressive paralysis for adult beriberi; and loss of memory, apathy and rhythmical movement of the eyeballs for Wernicke-Korsakoff syndrome.
Vitamin B6 (Pyridoxine HCl)
Vitamin B6 is a vitamin B complex primarily used as a coenzyme in several reactions. Its active form, pyridoxal phosphate, acts on amino acid metabolism such as transamination (transfer of amino group to oxaloacetate), deamination (removal of amino group to free ammonia), decarboxylation (removal of carboxyl group) and condensation reactions (as seen with glycine and succinyl CoA condensation). It also acts on glucose metabolism in the body, facilitating the conversion of glycogen (stored form) to glucose and fat metabolism, therefore releases energy (Harvey and Champe, 2004).
Pyridoxine deficiency rarely occurs because it is widely distributed in foods. Causes of deficiency may be due to drugs that increases its excrtetion (like isoniazid) and genetically determined errors in metabolism.
Signs and symptoms of pyridoxine deficiency include pyridoxine-responsive anemia (acquired or hereditary sideroblastic anemia), dermatitis, atrophic glissits (smooth, glossy tongue), cheilosis, conjunctivitis, and neurologic symptoms like peripheral neuritis, somnolence (drowsiness) and convulsions.
Vitamin B12 (Cyanocobalamin)
Vitamin B12 or cyanocobalamin is a cobalt containing vitamin B complex. It is primarily required for two enzymatic reactions, for the synthesis of methionine (an amino acid needed in the body) and isomerisation of methylmalonyl Coa, a by-product of amino acid and fatty acid (odd numbered carbon atom fatty acid) metabolism. It also acts as a coenzyme in nucleic acid synthesis. The active forms of cyanocobalamin are 5’-deoxyadenosylcobalamin (or cobamamide), methylcobalamine (or mecobalamin) and hydroxocobalamin (Harvey and Champe, 2004).
Vitamin B12 is considered a dietary essential together with vitamin B9 (folic acid). When vitamin B12 is deficient, nucleic acid synthesis is impaired, which is an essential component of DNA. This leads to failure of replication and cell division, affecting any cell in the body. Aside from that, deficiency of the said vitamin leads to accumulation of abnormal fatty acids which is then incorporated into cell membranes, particularly cells of the nervous system. This leads to neurological symptoms observed.
Meat is the main source of vitamin B12. Thus, deficiency occurs in strict vegetarians, but these may take years to occur (around 5 years). The most probable cause of deficiency is malabsorption disorders, like inefficient intrinsic factor (used as a transporter for B12), extensive ileal resection, and drug induced (nitrous oxide).
The most common manifestation of B12 deficiency is megaloblastic anemia. As stated, it affects cell division; blood cells have the highest cell division rate, thus the hematopoietic cells are mostly affected. Another manifestation is demyelination of neuroligic tissues, due to abnormal fatty acid incorporation (Al-Shubaili, et al., 1998).
Diabetes Mellitus and Neuropathy
Peripheral neuropathy is the most common complication of diabetes mellitus. Diabetic neuropathy consists of paresthesias (needle prick feeling), numbness and pain in the peripheries, such as hands, arms, legs and feet, where it is felt most often. These signs and symptoms are a frequent source of complaints for diabetic patients (Stratone, et al., 2002).
Several studies have pointed out the link between diabetic neuropathy and these three B vitamins. In fact, in a study by Stratone and colleagues (2002), they stated that deficiencies in vitamin B6 and B12 contribute to the development of peripheral diabetic neuropathy. In a study made by Thornalley et al. (2007), they found that patients with diabetes have low plasma levels of vitamin B1, as well as an increase in thiamine clearance. In a study made by Ungar and colleagues (1968), symptoms similar to pernicious anemia (B12 deficiency) is seen with diabetic patients, which may suggest that problems with B12 may occur with diabetes.
Since all of these B vitamins are directly related to relief of neurologic symptoms and the proper functioning of the nervous system (Stratone, et al., 2002), it is rational to determine if it can be used for treatment.In a study made by Bernstein and Lobitz (1988), they found that pyridoxine treatment for diabetic patients with painful neuropathies provided relief and is beneficial.
Mechanism of Action
Because neurological symptoms or neuropathy may be caused by deficiencies of different B vitamins or problems with metabolism (like diabetes), a drug that replenishes lost amounts of these vitamins or maintain high levels of it in the body is an effective method of therapy. Milgamma effectively addresses possible deficiency states, and improves the levels of these B vitamins in the body. When there are higher levels of these coenzymes in the body, there is a faster rate for the reactions to occur, and thus bring about improvement and resolution of the symptoms felt.
Several studies have already proven the therapeutic efficacy of Milgamma. In a study made by Sadekov et al. (1998), they found that Milgamma effectively addressed polyneuropathy felt by patients, with an amazing 8.2 to 2.3 decrease in visual analogue pain assessment (ten being the highest). The study found that about 93% of the cases were significantly improved. In a study made by Simeonov et al. (1997), they compared Milgamma with a different brand of vitamin B complex. In the said study, they concluded that Milgamma provided a significant improvement compared to the other drug. Both Sadekov et al.’s and Simeonov et al.’s studies concluded that Milgamma is a safe and effective therapeutic regimen for patients experiencing diabetic polyneuropathy.
Aside from the resolution of the symptoms of polyneuropahty, significant reductions in glucose, triglyceride and cholesterol concentrations in the blood were also observed (Stratone, et al., 2002).
Side Effects, Precautions
Adverse effects associated with vitamin B complex are rare. For vitamin B1, hypersensitivity has been reported to occur after parenteral administration. Hypersensitivity includes anaphylaxis, dyspnea, bronchospasms, rashes and flushing (Committee on Safety of Medicines, 1989).
Vitamin B6 toxicity has been observed for doses of up to 2g/day (Schaumberg, et al., 1983). Severe peripheral neuropathies occur. It is also excreted into breastmilk. Daily doses of up to 25 mg can be taken safely during pregnancy and for breast-feeding mothers.
Vitamin B12 has been observed to cause hypersensitivity reaction when administered parenterally. Arrhythmias have also been reported. B12 is contraindicated to patients with Leber’s disease.
Milgamma has been reported to have caused profuse perspiration, acne, skin reactions with itching and urticaria, and tachycardia Vertigo, vomiting, bradycardia, arrhythmias, obnubilation and cramps have also been reported to occur.
Al-Shubaili, A. F., Farah, S. A., Hussein, J. M., et al., 1998, Axonal and demyelinating neuropathy with reversible proximal conduction block, an unusual feature of vitamin B12 deficiency
Boulton, A. J., Malik, R. A., et al., 2004, Diabetic somatic neuropathies
Bernstein, A. L., and Lobitz, C. S., 1988, A clinical and electrophysiologic study of the treatment of painful diabetic neuropathies with pyridoxine
Committee on Safety and Medicines, 1989, Parentrovite & allergic reactions, Current Problems, 24:1
Harvey, R. A., and Champe, P. C., ed, 2004, Biochemistry, 3rd ed, Lippincott Williams and Wilkins
Loew, D., 1996, Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther, 34:pp. 47–50.
Sadekov, R. A., Danilov, A. B., and Vein, A. M., 1998, Diabetic polyneuropathy treatment by milgamm-100 preparation
Schaumburg, H., Kaplan, J., Windebank, A., et al., 1983, Sensory Neuropathy from Pyridoxine Abuse — A New Megavitamin Syndrome
Simeonov, S., Pavlova, M., Mitkov, M., et al., 1997, Therapeutic efficacy of “Milgamma” in patients with diabetic neuropathy
Stratone, A., Stratone, C., Chiruta, R., et al., 2002, The effectiveness of Milgamma-N therapy in patients with peripheral diabetic neuropathy
Sweetman, S. C. ed., 2009, Martindale, The complete drug reference 36th ed, London: Pharmaceutical Press, 1975-1976, 1978, 1980
Thornalley, P. J., Babaei-Jadidi, R., Al Ali, H., et al., 2007, High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease
Ungar, B., Stocks, A. E., Martin, F. I. R., 1968, Intrinsic-factor antibody, parietal-cell antibody and latent pernicious anemia in diabetes mellitus
Milgamma Review Article