What is/are Vigabatrin?
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid (GABA) by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. It is sold under the brand name Sabril.
In Canada, vigabatrin is approved for use as an adjunctive treatment (with other drugs) in treatment resistant epilepsy, complex partial seizures, secondary generalized seizures, and for monotherapy use in infantile spasms in West syndrome.
As of 2003, vigabatrin is approved in Mexico for the treatment of epilepsy that is not satisfactorily controlled by conventional therapy (adjunctive or monotherapy) or in recently diagnosed patients who have not tried other agents (monotherapy). Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.
On August 21, 2009, Lundbeck announced that the U.S. Food and Drug Administration had granted two New Drug Application approvals for vigabatrin. The drug is indicated as monotherapy for pediatric patients one month to two years of age with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive (add-on) therapy for adult patients with refractory complex partial seizures (CPS) who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss.
In 1994, Feucht and Brantner-Inthaler reported that vigabatrin reduced seizures by 50-100% in 85% of children with Lennox-Gastaut syndrome who had poor results with a valproate.
Fechtner et al. found in an eight week study that vigabatrin was effective in the treatment of cocaine and/or methamphetamine dependence. Twenty-eight subjects were enrolled; twenty stayed after the escalation phase and out of those, eighteen completed the study and follow-up. Out of those, sixteen subjects tested negative for cocaine and methamphetamine during the last six weeks. No ocular adverse effects were noted.
Vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers. Vigabatrin is also used to treat seizures in succinic acid semialdehyde deficiency, which is an inborn neurotransmitter (gamma amino butyric acid) catabolism defect that causes mental retardation, hypotonia, seizures, speech disturbance, and ataxia through the accumulation of 4-hydroxybutyric acid. Vigabatrin inhibits the formation of succinic acid semialdehyde through GABA transaminase inhibition. However, this is in the brain only; it has no effect on peripheral GABA transaminase, so the 4-hydroxybutyric acid keeps building up and eventually reaches the brain.
Central nervous system
Out of 2,081 subjects, somnolence (12.5%), headache (3.8%), dizziness (3.8%), nervousness (2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%), aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision abnormalities (1.6%), confusion (1.4%), insomnia (1.3%), impaired concentration (1.2%), personality disorder (1.1%). Out of 299 children, 33 (11%) became hyperactive.
Some patients develop psychosis during the course of vigabatrin therapy, which is more common in adults than in children.This can happen even in patients with no prior history of psychosis. Other rare CNS side effects include anxiety, emotional lability, irritability, tremor, abnormal gait, and speech disorder.
Abdominal pain (1.6%), constipation (1.4%), vomiting (1.4%), and nausea (1.4%). Dyspepsia and increased appetite occurred in less than 1% of subjects in clinical trials.
Body as a Whole
Fatigue (9.2%), weight gain (5.0%), asthenia (1.1%).
A teratology study conducted in rabbits found that a dose of 150 mg/kg/day caused cleft palate in 2% of pups and a dose of 200 mg/kg/day caused it in 9%. This may be due to a decrease in methionine levels, according to a study published in March 2001. In 2005, a study conducted at the University of Catania was published stating that rats whose mothers had consumed 250–1000 mg/kg/day had poorer performance in the water maze and open-field tasks, rats in the 750-mg group were underweight at birth and did not catch up to the control group, and rats in the 1000 mg group did not survive pregnancy.
There is no controlled teratology data in humans to date.
In 2003, vigabatrin was shown by Frisén and Malmgren to cause irreversible diffuse atrophy of the retinal nerve fiber layer in a retrospective study of 25 patients. This has the most effect on the outer area (as opposed to the macular, or central area) of the retina. Visual field defects had been reported as early as 1997 by Tom Eke and others, in the UK. Some authors, including Comaish et al. believe that visual field loss and electrophysiological changes may be demonstrable in up to 50% of Vigabatrin users. The retinal toxicity of vigabatrin can be attributed to a taurine depletion
Mechanism of action
Vigabatrin is an irreversible suicide inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of GABA, which increases the level of GABA in the brain. Vigabatrin is a racemic compound, and its [S]-enantiomer is pharmacologically active.
This article uses material from the Wikipedia article Vigabatrin, which is released under the Creative Commons Attribution-Share-Alike License 3.0.