Nervagest Plus Mechanism of Action

Pharmacotherapeutic group: Other anti-epileptics with B12 Cyanocobalamin analogue (Methylcobalamin). ATC-Code: N03AX16 with B03BA05.
Pharmacology: Pharmacodynamics: Pharmacodynamic effects: Pregabalin: Pregabalin is a structural derivative of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Pregabalin does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors, does not augment GABA_A responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin binds with high affinity to the alpha₂-delta site (an auxiliary submit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha₂-delta submit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. In vitro, pregabalin reduces the calcium dependent release of several neurotransmitters, possibly by modulation of calcium channel function. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
Methylcobalamin: Methylcobalamin (Mecobalamin, MeCbl), is one of the two biologically active vitamin B12. Mecobalamin acts as an important cofactor in the reaction of one class of the B12 enzymes, the methyltransferases. The B12-dependent methyltransferases play an important role in amino acid metabolism in many organisms as well as in one-carbon metabolism and Co₂ fixation in anaerobic microbes. Among them, methionine synthase is the most extensively studied B12-dependent methyltransferase in humans. As the cofactor of the enzyme methionine synthase, mecobalamin functions to catalyse the transfer of the methyl group from methylene tetrahydrofolate to homocysteine (Hcy) to form methionine and tetrahydrofolate. Because mecobalamin acts as an important cofactor of methionine synthesis, supplements of mecobalamin enhance the efficiency of the remethylation pathway, consequently accelerating Hcy consumption and reducing its concentration. Thus, lowering homocysteine concentrations to the normal range (4-15 μmol/L) seems to be an effective therapeutic method in decreasing the risks of the diseases mentioned previously.
Pharmacokinetics: Pregabalin: Absorption: Pregabalin oral bioavailability is ≥90% and is independent of dose. Following single (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours.
Distribution: Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg.
Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects.
Methylcobalamin: Absorption: Evidence indicates methylcobalamin is utilized more efficiently than cyanocobalamin to increase levels of one of the coenzyme forms of vitamin B12. Experiments have demonstrated similar absorption of methylcoblamin following oral administration. The quantity of cobalamin detected following a small oral dose of mecobalamin is similar to the amount detected following the administration of cyanocobalamin, but significantly more cobalamin accumulates in liver tissue, which is associated with mecobalamin intake.
Distribution and Metabolism: Cobalamin circulates in plasma bound to two carrier proteins: transcobalamin (TC) and haptocorrin. TC is a 43-kDa non-glycoprotein that transfers cobalamin from the intestine into the blood stream and then into all the cells of the body. Cobalamin-saturated transcobalamin (holoTC) constitutes 6-20% of total plasma cobalamin. The unsaturated TC is called apotranscobalamin, which constitutes the major part of TC. Additionally, total homocysteine (tHcy) and methylmalonic acid are considered to be two functional markers of vitamin B12 status in adults.
Excretion: Human urinary excretion of methylcobalamin is about one third that of a similar dose of cyanocobalamin, indicating substantially greater tissue retention.