Source: Υπουργείο Υγείας (CY) Revision Year: 2018 Publisher: Medilink Pharmaceuticals Ltd., 30 Armenias, 2003 Strovolos, Nicosia, Cyprus
Pharmacotherapeutic group: other antipsychotics
ATC code: B03BA05
The active ingredient of Methycobal Tablets is mecobalamin (INN, JAN), that is an analogue of vitamin Β12 developed by Eisai Co., Ltd. Vitamin Β12 is known to consist of four homologues. They are cyanocobalamin (CN-Β12), hydroxyl cobalamin (OH-Β12), 5-deoxyadenosylcobalamin (DBCC) and mecobalamin (CH3-Β12). Among these homologues, DBCC and CH3-Β12 have co-enzymatic activity in vivo. In the human serum and the cerebrospinal fluid, greater part of vitamin Β12 activity occurs in CH3-Β12. CH3-Β12 is transported to the nerve tissues more actively and extensively than other homologues of vitamin Β12.
1) Mecobalamin is a kind of endogenous coenzyme B12.
Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
2) 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 has been shown in experiments with cells from the brain origin and spinal nerve cells in rats to be involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabolism of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in rats more than cobamamide does.
3) Mecobalamin promotes axonal transport and axonal regeneration.
Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from rat models 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.
4) Mecobalamin promotes myelination (phospholipid synthesis).
Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipids, and increases myelination of neurons in rat tissue culture more than cobamamide does.
5) Mecobalamin restores delayed synaptic transmission and diminished neurotransmitters to normal.
Mecobalamin restores end-plate potential induction early by increasing nerve fiber excitability in the crushed sciatic nerve in rats. In addition, mecobalamin normalizes diminished brain tissue levels of acetylcholine in rats fed a choline-deficient diet.
Methycobal tablets was administered orally to patients with peripheral neuropathies at doses of 1,500 μg and 120 μg (low-dose group) daily divided into three doses for 4 consecutive weeks in a double-blind clinical trial. In the chronic stage and fixed stage in peripheral neuropathies, the improvement rate for moderately to remarkably improved was 17.6% (6/34) in 1,500 μg group and 9.7% (3/31) in 120 μg group. The improvement rate for fairly to remarkably improved was 64.7% (22/34) in the 1,500 μg group and 41.9% (13/31) in the 120 μg group. The dose of 1,500 μg/day was thus demonstrated to be useful.
In a placebo-controlled double-blind clinical trial, mecobalamin and cobamamide were administered orally to patients with peripheral neuropathies at doses of 1,500 μg daily for 4 consecutive weeks. The rates for moderately to remarkably improved for peripheral neuropathies were 38.6% (17/44) for mecobalamin, 22.2% (10/45) for cobamamide and 26.7% (12/45) for placebo. Mecobalamin was thus demonstrated to be useful.
No changes in laboratory values have been attributed to Methycobal Tablets treatment.
When Methycobal Tablets was administered orally to healthy adult male volunteers at single doses of 120 μg and 1,500 µgnote)* during fasting, the peak serum total vitamin B12 (abbreviated to B12) concentration was reached after 3 hrs for both doses, and this was dose-dependent. The half-life, increment in the serum total B12 concentration and ΔAUC102 by 12 hrs after administration are shown in the following figure and table. 40 to 90% of the cumulative amount of total B12 excreted in the urine by 24 hrs after administration was excreted within the first 8 hrs.
Note: The single doses of 1,500 μg marked with the symbol* are unapproved.
| Dose | tmax (hr) | Cmax (pg/mL) | ΔCmax (pg/mL) | ΔCmax (%) | ΔAUC (pg·hr/mL) | t1/2*2 (hr) |
|---|---|---|---|---|---|---|
| 120 μg | 2.8±0.2 | 743±47 | 37±15 | 5.1±2.1 | 168±58 | N.A. |
| 1500 μg | 3.6±0.5 | 972±55 | 255±51 | 36.0±7.9 | 2033±510 | 12.5 |
Mean±S.E., n=8
*1 Calculated by the trapezoidal method from the increment in observed 12 hr values, as compared to pre-drug values.
*2 Calculated from the average of 24-48 hr values.
Methycobal Tablets was administered orally to healthy adult male volunteers at a dose of 1,500 μg daily for 12 consecutive weeks and changes in the serum total B12 concentration were determined until 4 weeks after the last administration. The serum concentration increased for the first 4 weeks after administration, rising to about twice as high as the initial value. Thereafter, there was a gradual increase, which peaked at about 2.8 times the initial value at the 12th week of dosing. The serum concentration declined after the last administration (12 weeks), but was still about 1.8 times the initial value 4 weeks after the last administration.
In rat given a 25 μg oral dose of 57Co-labeled mecobalamin, radioactivity was found to be higher in the kidneys, adrenal glands, pancreas, liver, and stomach (listed in order of magnitude), whereas the muscles, testes, brain, and nerves did not show significant radioactivity 72 hours after administration.
| Animal | p.o. |
|---|---|
| Mice | >1,000 |
| Rats | >500 |
| Rabbits | - |
The oral administration of mecobalamin, at doses of 0.2, 2.0 and 20.0 mg/kg/day to rats of both sexes for 1 consecutive month, resulted in no remarkable changes in the general condition of the animals, the body weights, blood analytical results, organ weight, or histopathology.
In rats of both sexes, given an oral dose of 0.2, 2.0 and 20.0 mg/kg/day of mecobalamin for 6 consecutive months, no remarkable changes were noted in the general condition of the animals, the body weights, blood and urine analytical results, organ weights, or histopathology.
In mature nulliparous mice and rats, administered an oral dose of 0.2, 2.0 and 20.0 mg/kg/day of mecobalamin during organogenesis, no abnormalities or signs of teratogenicity were noted in fetuses or neonates.
In vitro, a chemical reaction occurs such that mecobalamin forms methyl mercury with mercuric chloride. The reaction, however, does not take place in the presence of proteins as in the human blood.
Experiments with rats fed a diet containing inorganic mercury have shown clearly that oral administration of mecobalamin does not increase the formation of methyl mercury in the body. In male rats fed a diet containing inorganic mercury, mecobalamin administered in oral doses of 1.5 and 15 mg/kg/day for 6 consecutive months did not affect the general condition of the animals, and no toxic signs were observed with urinalysis nor from haematological or histopathological examinations.
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