Methycobal

Mecobalamin.

Mecobalamin is α-(5,6-dimethylbenzimidazolyl)-Co-methyl-cobamide.
Molecular Formula: C₆₃H₉₁CoN₁₃O₁₄P.
Molecular Weight: 1344.4.
Mecobalamin occurs as a dark red, odorless and almost tasteless crystal or crystalline powder. It is sparingly soluble in water, methanol and ethanol and practically insoluble in acetone, ether and chloroform. Mecobalamin is hygroscopic and decomposes upon exposure to light.
Tablet: Each tablet contains 500 μg of mecobalamin.
Injection: pH 5.3-7.3.
Osmotic Pressure (to physiological saline): Approximately 1.
Excipients/Inactive Ingredients: Injection: Each ampoule also contains D-mannitol 50 mg as an additive.

Tablet: Mecobalamin is a vitamin B12 co-enzyme that occurs in the blood and the cerebrospinal fluid; it is taken up by nerve tissues more actively and extensively than other homologues of vitamin B12.
Biochemically, Methycobal accelerates the metabolic pathways of nucleic acids, proteins and lipids through its involvement in the transmethylation reaction; thus, it exerts a repairing effect on injured nerve tissues. Clinically, Methycobal is the first pharmaceutical product that has been shown, by double-blind clinical studies, to be effective and useful for the treatment of numbness, pain and paralysis due to peripheral neuropathies eg, diabetic neuropathy and polyneuritis.
Injection: Biochemically, mecobalamin is a B12-containing co-enzyme with an active methyl base. It participates in transmethylation reactions and is the most active of all B12 homologs in the body with respect to nucleic acid, protein and lipid metabolism. Methycobal acts to repair damaged nerve tissue in nerve disorders eg, axonal degeneration and demyelination; and, it is involved in erythroblast maturation, promotion of erythroblast division, and heme synthesis, thus acting to improve the status of the blood in megaloblastic anemia. Methycobal is the first preparation with which it has been documented, by double-blind clinical trials, that mecobalamin is effective not only on megaloblastic anemia but also on peripheral neuropathies eg, diabetic neurological disorders and multiple neuritis.
Pharmacology: Tablet: Promotion of the metabolism of nucleic acids, proteins and lipids: Experiments with a brain-derived cell line from albino rats have shown that mecobalamin, by acting as a co-enzyme in the formation of methionine from homocysteine, is involved in the synthesis of thymidylate from deoxyuridylate, and promotes the synthesis of DNA and RNA. It has also been demonstrated, in experiments using neuroglia, that mecobalamin enhances the formation of lecithin, a major component of the myelin sheath.
Extensive uptake by nerve tissues and improvement of metabolic disturbances: Mecobalamin, a methylated form of vitamin B12 (CH₃-B12) that occurs in high concentrations in the blood and the cerebrospinal fluid, has been observed in rats to be taken up into nerve cell organelles more actively and extensively than CN-B12. Experimentation using sciatic nerve cells from rats with experimental diabetes has also demonstrated that mecobalamin helps maintain axonal function by promoting the synthesis of structural proteins and by normalizing the transport velocity of these proteins.
Repair of nerve injury: Mecobalamin has been demonstrated, by neuropathological and electrophysiological studies, to inhibit nerve fiber degeneration in rats and rabbits with neuropathy induced by drugs eg, adriamycin and vincristine or with streptozotocin-induced diabetes. The effects of mecobalamin were also studied in guinea pig models with compression-induced facial palsy. The recovery process was evaluated using examinations of the blink reflex, evoked electromyograms and histological observations. Mecobalamin was found to be as effective as steroids in accelerating the repair of injured nerve tissue.
Injection: Mecobalamin promotes the metabolism of nucleic acids, proteins and lipids: In an experiment using brain-derived cell strains obtained from albino rats, mecobalamin acted as a co-enzyme in methionine synthesis. In particular, it was found to be involved in the synthesis of thymidine from deoxyuridine and to accelerate the synthesis of DNA and RNA. In another experiment using glia cells, mecobalamin was found to accelerate the synthesis of lecithin, a major component of the myelin sheath.
Mecobalamin is efficiently transferred to nervous tissues and improves metabolic disorders: Mecobalamin is a CH₃-vitamin B12 which is found in high concentrations in blood and cerebrospinal fluid. In an experiment in rats, it was transferred to nerve cell organelles more efficiently than CN-vitamin B12. It also accelerated the synthesis of the major structural component of the axon (protein) in sciatic nerve cells of rats with experimental diabetes and returned the protein transport rate close to normal, resulting in the maintenance of axonal function.
Mecobalamin repairs nerve tissues in experimental nerve injury models: In experiments in rats and rabbits, mecobalamin was neuropathologically and electrophysiologically shown to inhibit the onset of nerve degeneration due to nerve disturbances caused by adriamycin and vincristine and experimental diabetes caused by streptozotocin. Mecobalamin was also compared with steroids in terms of their effects on the process of nerve regeneration in experimental facial paralysis models prepared by compressing the facial nerve of guinea pigs. Mecobalamin was found to be as effective as steroids for the recovery from paralysis when evaluated based on the winking reflex, induced electromyography and histological evaluation.
Mecobalamin inhibits abnormal excitation transmission by nerve tissues: The anterior and posterior roots of the spinal nerve were separated from the spinal cord of frogs and connected to the sciatic nerve. Electrical stimulation was given to the end of the sciatic nerve in Ringer's solution and the action potentials of the anterior and posterior roots were recorded. 500 mcg/mL of DBCC, OH-vitamin B12, CH₃-vitamin B12 were dissolved in the Ringer's solution and the inhibition of excitation transmission by these compounds was compared. The inhibition of nervous excitation transmission produced by CH₃-vitamin B12 was the strongest.
Mecobalamin improves anemia by accelerating the maturation and division of erythroblasts: Mecobalamin accelerates the synthesis of nucleic acids in bone marrow, as well as the maturation and division of erythroblasts, resulting in an increase in the production of erythrocytes. Treatment with mecobalamin was shown to promptly reverse the decrease in RBC hemoglobin and hematocrit numbers, in vitamin B12-deficient rats.
Pharmacokinetics: Tablet: Single-Dose Administration: After oral administration of single doses of 120 and 1500 mcg of Methycobal to healthy adult subjects, dose-dependent peak plasma concentrations were reached in 3 hrs in both cases. The half-life, increase of plasma concentration and total B12 and AUC were shown in Table 1. (See Table 1.)

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Of the cumulative amount of total B12 recovered in the urine by 24 hrs after oral administration, 40-80% was excreted within the first 8 hrs.
Repeated-Dose Administration: Plasma concentrations of total B12 were measured in healthy subjects given an oral daily dose of 1500 mcg of Methycobal for 12 consecutive weeks. Plasma B12 concentrations were also monitored in the same patients for the 4 weeks immediately following the last administration. The plasma concentration increased for the first 4 weeks after administration, reaching a value twice as high as the initial concentration. Thereafter, there was a gradual increase which reached a peak at approximately 280% of the initial value at the 12th week of dosing. The plasma concentration declined after the last administration (12 weeks), but was still approximately 180% of the initial level 4 weeks after the last administration.
Injection: Single-Dose Administration: When a single IM or IV dose of 500 mcg of CH₃-B12 was administered to healthy adults, the time required for the serum total vitamin B12 level to reach a peak (T_max) was 0.9±0.1 hr after IM administration and immediately to 3 min after IV administration, and the increment in peak serum total vitamin B12 level (C_max) was 22.4±1.1 ng/mL after IM administration and 85±8.9 ng/mL after IV administration.
The area under the blood concentration-time curve (AUC) was 204.1±12.9 hr·ng/mL after IM administration and 358.6±34.4 hr·ng/mL after IV administration.
On the other hand, the rate of binding saturation showed a similar increase in both groups of subjects for 144 hrs after administration.
Repeated-Dose Administration: 500 mcg/day of CH₃-B12 was administered IV to healthy adults for 10 consecutive days. Serum total vitamin B12 levels measured before each administration (C_min) increased from day to day. At 2 days of administration the serum level of total vitamin B12 was 5.5±1.8 ng/mL, about 1.4 times the 24-hr value (3.9±1.2 ng/mL). At 3 days of administration it was increased to 6.8±1.5 ng/mL, about 1.7 times the 24-hr value, and this level was maintained until the last dosing.
Clinical Studies: Tablet: Clinical Effects: In clinical studies including double-blind trials, Methycobal tablets produced good or excellent relief of symptoms in 44.5% (5503/12,373) of patients with peripheral neuropathies. In double-blind controlled comparative (DBCC) trials of Methycobal tablets with cobalamin or mecobalamin administered in lower doses (120 mcg), the efficacy and usefulness of Methycobal tablets were confirmed.
Adverse Reactions: Out of 15,180 patients treated with Methycobal tablets, adverse reactions were reported in 146 patients (0.96%). The most common adverse reactions include gastrointestinal symptoms eg, anorexia in 52 patients (0.34%), gastrointestinal disorders in 38 patients (0.25%), nausea-vomiting in 18 patients (0.18%), diarrhea in 17 patients (0.11%) and skin rash in 14 patients (0.09%).
Effects on Laboratory Values: No changes in laboratory values have been attributed to Methycobal treatment.
Injection: Clinical Efficacy: It has been shown in double-blind studies that CH₃-B12 benefits peripheral neuropathies when the general improvement of symptoms is evaluated. Equivalency in effect between the IV and IM routes has been demonstrated in double-blind clinical studies.
Adverse Reactions and Influences on Laboratory Values: Adverse reactions to Methycobal have been reported in 3 (0.27%) of 1864 cases. The main adverse reactions were eruptions in 2 cases (0.11%). No changes in laboratory values have been associated with Methycobal treatment.
Others: Methycobal should not be used over a period of months if there is lack of satisfactory clinical response in patients with megaloblastic anemia probably due to vitamin B12 deficiency or with peripheral neuropathies.
Toxicology: Animal Studies: Distribution: Tablet: In rats given a 25 mcg oral dose of ⁵⁷Co-labeled mecobalamin, radioactivity was found to be higher in 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 hrs after administration.
Injection: At 24 hrs after IV administration of ⁸⁷Co-CH₃-B12 to rats in a dose of 10 mcg/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.
Acute toxicity LD₅₀ (mg/kg): Tablet: See Table 2.

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Injection: See Table 3.

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Subacute Toxicity: Tablet: The oral administration of mecobalamin, at doses of 0.2, 2 and 20 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 and urine analytical results, organ weights, or histopathology.
Injection: Mecobalamin was administered IV to beagles in doses of 0.5, 5 and 50 mg/kg/day for 90 consecutive days. Changes in general conditions, 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 tubule in the animals of the 50 mg/kg/day dose group. No change, however, was noted in the other organs.
Chronic Toxicity: Tablet: In rats of both sexes, given an oral dose of 0.2, 2 and 20 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.
Injection: Mecobalamin was administered IV to beagles at doses of 0.3, 5 and 50 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 mg/kg/day or higher dose groups. In the 50 mg/kg/day dose groups lysosomes in the mesangial cells of the renal glomerulus and Kupffer cells in the liver were increased.
Reproduction Studies: Tablet: In mature nulliparous mice and rats, administered an oral dose of 0.2, 2 and 20 mg/kg/day of mecobalamin during organogenesis, no abnormalities or signs of teratogenicity were noted in fetuses or neonates.
Injection: Mecobalamin was administered IV in doses of 0.5, 5 and 50 mg/kg/day to rats before pregnancy, in the early stage of gestation, 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.
Methylation of Inorganic Mercury: Tablet: In vitro, a chemical reaction occurs such that mecobalamin forms methyl mercury with mercuric chloride. This 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 Methycobal 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 hematological or histopathological examinations.

Peripheral neuropathies.
Injection: Megaloblastic anemia due to vitamin B12 deficiency.

Tablet: Adults: Usual Daily Dose: 3 tabs, equivalent to a total of 1500 mcg of mecobalamin, administered orally in 3 divided doses. The dose should be adjusted according to age of patient and severity of symptoms.
Injection: Peripheral Neuropathies: The usual adult dosage is 1 amp, equivalent to 500 mcg of mecobalamin administered IM or IV 3 times a week. The dosage should be adjusted according to age of patient and severity of symptoms.
Megaloblastic Anemia: The usual adult dosage is 1 amp, equivalent to 500 mcg of mecobalamin administered IM or IV 3 times a week. After approximately 2 months of medication, the dose should be reduced to a single administration of 1 amp at 1- to 3-month intervals for maintenance therapy.

Discontinue medication with Methycobal if there is no response after several months.
Methycobal injection is susceptible to photolysis. It must be used promptly after the package is opened and care must be taken not to expose the ampoule to direct light.
In IM administration, care should be exercised, suggested as follows, to avoid adverse effects on tissues or nerves: Repeated injection at the same site should be avoided. Particular care should be exercised when administering Methycobal to neonates, premature infants, infants and children.
The course of nerves should be avoided for the site of injection.
If the patient complains of pain or if blood reflux occurs when the syringe needle is stuck, withdraw it immediately and try at a different site.
Methycobal injection is a one-point-cut type ampoule. It is recommended that the cut point of the ampoule be wiped clean with an alcohol swab.

Tablet: Gastrointestinal: Symptoms eg, anorexia, nausea or diarrhea may occur infrequently.
Dermatological: Skin rash may occur rarely.
Others: Prolonged use of larger doses of Methycobal is not recommended for patients whose occupation requires handling of mercury or its compounds.
Injection: Hypersensitivity: Use of Methycobal should be discontinued if symptoms of hypersensitivity eg, eruptions, occur.
Others: Pain and induration may infrequently occur at the site of IM injection and headache, sweating or hot sensation may rarely occur.

Tablet: To be stored at room temperature.
Should be protected from moisture and light.
Injection: Ampoules are packed in Light-Protect-Easy open pack (LPE) for the quality assurance during storage; hence, remove the ampoule from the LPE package just before use.
Injection should be stored at room temperature in LPE packages.

Nootropics & Neurotonics/Neurotrophics

B03BA05 - mecobalamin ; Belongs to the class of vitamin B12 (cyanocobalamin and analogues). Used in the treatment of anemia.

Tab: NP, Inj: P₁S₁S₃