Nervolin Mechanism of Action


Zifam Pinnacle


Pinnacle House
Full Prescribing Info
Anticonvulsants, including antiepileptics with co-enzyme form of cobalamin.
Nervolin is a combination of methylcobalamin and pregabalin for the treatment of neuropathic pain.
Pharmacology: Pregabalin: While pregabalin is a structural derivative of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), it does not bind directly 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 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, which is a vitamin B-containing co-enzyme with an active methyl base. It is the one and only homologue of vitamin B, found in the brain that participates in transmethylation as a vitamin B-containing co-enzyme. It helps to restore normal levels of DNA and RNAs in the nerve cells by enhancing protein synthesis and stimulating methionine synthesis from homocysteine. Thus, methylcobalamin helps to repair damaged nerve tissues in nerve disorder like axonal degeneration and demyelination. It also enhances the formation of lecithin (another major component of the myelin sheath).
Mechanism of Action: Pregabalin binds with high affinity to the α2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system (CNS) tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (eg, gabapentin) suggest that binding to the α2-delta subunit 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.
Methylcobalamin is the biologically active form of vitamin B. Cyanocobalamin (vitamin B) gets converted into methylcobalamin in the liver.
Pharmacokinetics: Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion and has an elimination half-life of about 6 hrs.
Absorption and Distribution: Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentration occur within 1.5 hrs. Pregabalin oral bioavailability is equal to 90% and is dose independent. Following single- (25-300 mg) and multiple dose (75-900 mg daily) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24-48 hrs. Multiple-dose pharmacokinetics can be predicted from single-dose data. The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25-30% and an increase in Tmax to approximately 3 hrs. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.
Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L-transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.
Metabolism and Elimination: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits or monkeys.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hrs in subjects with normal renal function. Mean renal clearance was estimated to be 67-80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins, this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CrCl).
Pharmacokinetics in Special Populations: In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of it were not significantly affected by race (Caucasians, Blacks and Hispanics).
Gender: Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and pregabalin drug exposure is similar between genders.
Renal Impairment and Hemodialysis: Pregabalin clearance is nearly proportional to creatinine clearance (CrCl). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hr hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified.
Elderly: Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CrCl. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Pediatric Pharmacokinetics: Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.
Methylcobalamin: It is utilized more efficiently than cyanocobalamin to increase the levels of coenzyme forms of vitamin B. The peak plasma concentration (Cmax) with a single oral dose of methylcobalamin 1500 mg in healthy individuals, is reported to be 972±55, 255±51, 36±79 ng/mL and is achieved in 3.6±0.5 hrs. 40-80% of the cumulative amount of total methylcobalamin is excreted in the urine within the first 8 hrs. The half-life is reported as 12.5 hrs.
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