Source: Υπουργείο Υγείας (CY) Revision Year: 2007 Publisher: Marketing License Holder: Medilink Pharmaceuticals Ltd., 30 Armenias, 2003 Strovolos, Nicosia, Cyprus Manufacturer: Eisai Co. Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, Japan
The active ingredient of Methycobal is mecobalamin (INN, JAN), that is an analogue of vitamin B12 developed by Eisai Co., Ltd. Vitamin B12 is known to consist of four kinds of homologues.
They are cyanocobalamin (CN-B12), hydroxocobalamin (OH-B12), 5-deoxyadenosylcobalamin (DBCC) and mecobalamin (CH3-B12). Among these homologues, DBCC and CH3-B12 have coenzymatic activity in vivo. In the human serum and the cerebrospinal fluid, greater vitamin B12 activity occurs in CH3-B12. CH3-B12 is transported to the nerve tissues more actively and extensively than other homologues of vitamin B12.
l) Mecobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Mecobalamin is better transported to nerve cell organelles than cyanocobalamin (in rats). It plays the role of coenzyme in the synthesis of methionine from homocysteine. It has been shown in experiments with cells of brain origin and spinal nerve cells to be involved in the synthesis of thymidine from deoxyuridine in promoting nucleic acid and protein synthesis.
2) Mecobalamin promotes axonal transport of skeletal protein and axonal regeneration. Mecobalamin normalizes axonal transport of skeletal protein in sciatic nerve cells from rats with streptozotocin-induced diabetes mellitus. It exhibits neuropathologically and electrophysiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine (in rats and rabbits), models of axonal degeneration in mice, and neuropathies in rats with spontaneous diabetes mellitus.
3) Mecobalamin promotes myelination (phospholipid synthesis). Mecobalamin promotes the synthesis of lecithin, the main medullary sheath constituent lipid by increasing methionine synthetase activity, thus promoting myelination.
4) Mecobalamin restores delayed synaptic transmission and diminished neurotransmitters toward normal. Mecobalamin restores end-plate potential induction early by increasing nerve fiber excitability in the crushed sciatic nerve (rats). In addition, mecobalamin, normalizes diminished brain tissue levels of acetylcholine in rats fed a choline-deficient diet.
5) Mecobalamin promotes the maturation and division of erythroblasts, thereby improving anemia. Mecobalamin promotes nucleic acid synthesis in the bone marrow and promotes the maturation and division of erythroblasts, thus increasing erythrocyte production. Mecobalamin brings about a rapid recovery of diminished WBC, hemoglobin, and hematocrit in vitamin B12-deficient rats.
When a single i.m. or i.v. Of 500μg of mecobalamin was administered to healthy adult volunteers, the time required for the serum total vitamin B12 level to reach (tmax) was 0.9 ± .1 hour after i.m. administration and immediately to 3 min. after i.v. administration, and the increment in the peak serum total vitamin B12 level (ΔCmax) was 22.4 ± 1.1 ng/mL after i.m. dministration and 85.0 ± 8.9ng/ml after i.v. administration.
The area under the blood concentration-time curve (ΔAUC) at 144 hours after administration was 204.1 ± 12.9 hr•ng/ml after i.m. administration and 358.6 ± 34.4 hr•ng/ml after i.v. administration. On the other hand, the rate of binding saturation showed a similar increase in both groups of subjects for 144 hours after administration.
500μg/day of CH3-B12 was administered intravenously to healthy adults for 10 consecutive days. Serum total vitamin 1312 levels measured before each administration (ΔCmin) increased from day to day. The serum level of total vitamin B12 24 hours after the administration on the day 2nd was 5.3 1.8ng/ml, about 1.4 times the 24 hour-value (3.9 ± 1.2 ng/ml) of the day 1st.
On the 3rd, it increased to 6.8 ± 1.5 ng/ml, about 1.7 times the 24-hour value of the day 1st, and this level was maintained until the last dosing.
In a double-blind comparison clinical trial with a low-dose group (100μg), the efficacy of mecobalamin in peripheral neuropathies in the chronic fixed stage was demonstrated.
In a placebo-controlled double-blind study trial, equivalence of mecobalamin between the intravenous and the intramuscular routes of administration was shown. When mecobalamin was administered to patients with vitamin B12 deficiency anemia, symptoms and hemogram improved.
At 24 hours after i.v. administration of 57Co-CH3-B12 to rats in a dose of 10μg/kg, the radioactivity was detected in order of high concentration in the kidneys, adrenal, intestine, pancreas and pituitary, and the concentration of radioactivity was relatively lower in the eyes, spinal cord, brain and muscle.
| Animal | ||
|---|---|---|
| Mice | >666 | >1,000 |
| Rats | >333 | >500 |
| Rabbits | >60 | - |
| Beagles | >200 | - |
Mecobalamin was administered intravenously to dogs in doses of 0.5, 5.0 and 50.0
mg/kg/day for 90 consecutive days. Changes in general conditions, body weight, blood and organ weights were unremarkable in all the dose groups. Histopathologically, increases in eosinophils and lysosomes were found in the observation with an optical microscope, and an electron microscope in the 50.0 mg/kg or higher dose respectively, in the epithelial cell of proximal renal tubule in the animals of the 50.0 mg/kg/day dose group. No change, however, was noted in the epididymides
Mecobalamin was administered intravenously to dogs at doses of 0.5, 5.0 and 50.0
mg/kg/day for 12 consecutive months. Changes in general condition, body weight, blood and organ weights were unremarkable in all the dose groups of beagles. Histopathologically, increases in eosinophils and lysosomes were found in the observation with an optical microscope and an electron microscope, respectively, in the epithelial cells of proximal renal tubule in the 5.0 mg/kg/day or higher dose groups. In the 50.0 mg/kg/day dose groups lysosomes in the mesangial cells of the renal glomerulus and Küpferr cells in the liver were increased.
Mecobalamin was administered intravenously in doses of 0.5, 5.0 and 50 mg/kg/day to rats prior to and, in the early stages of pregnancy, during the period of organogenesis, and during the perinatal and lactating periods. No abnormal findings nor signs of teratogenicity were observed in the fetuses and newborns from these dams.
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