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Methycobal

(Mecobalamin Preparation)

Methycobal is a mecobalamin preparation developed by Eisai Co., Ltd. as a treatment for peripheral neuropathies. Methycobal contains mecobalamin, a vitamin B₁₂-coenzyme 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 such as diabetic neuropathy and polyneuritis.

Composition
Each tablet contains 500 µg of mecobalamin.

Indications
Peripheral neuropathies

Dosage and Administration
The usual daily dose for adults is 3 tablets, equivalent to a total of 1,500 µg of mecobalamin, administered orally in 3 divided doses.
The dose should he adjusted according to the age of patient and severity of symptoms.

Precautions
1) General
Methycobal should not be administered for extensive periods (months) to patients who show no clinical response.
2) Adverse reactions
    i) Gastrointestinal: Symptoms such as anorexia, nausea or diarrhea may infrequently occur.

    ii) Dermatological: Skin rash may rarely occur.
3) Other
Prolonged use of larger doses of Methycobal is not recommended for patients whose occupation requires handling mercury or its compounds.

Pharmacodynamics
1. 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 coenzyme in the formation of methionine from homocysteine, is involved in the synthesis of thymidylate from deoxyundylate, 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.

2. 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.

3. 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 such as 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.

Pharmacokinetics
1. Single dose administration
After oral administration of single doses of 120 µg or 1,500 µg of mecobalamin to healthy adult subjects, dose-dependent peak plasma concentrations were reached in 3 hours in both cases. The half-life, increase of plasma concentration of total B₁₂, and ^AUC¹² were as shown below.

Of the cumulative amount of total B₁₂ recovered in the urine by 24 hours after oral administration, 40 to 80 percent was excreted within the first 8 hours.

*1 Calculated by the trapezoidal formula from the increment in observed 12-hour values, as compared to pre-drug values.

*2 Calculated from the average of 24-48 hour values.

Mean ± Standard error.

2. Repeated dose administration
Plasma concentrations of total B₁₂ were measured in healthy subjects given an oral daily dose of 1,500 µg 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.
 

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