Vigabatrin: Encyclopedia - Vigabatrin

Vigabatrin

Vigabatrin is an anticonvulsant that inhibits the catabolism of GABA. It is an analog of GABA, but it is not a receptor agonist.^[2]

Vigabatrin - Mechanism of Action

Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of GABA, which increases the level of GABA in the synapses.^[3]

Vigabatrin is a racemic compound, and its [S]-enantiomer is pharmacologically active.^[4],[5]

Vigabatrin - Pharmacokinetics

With most drugs, elimination half-life is a useful predictor of dosing schedules and the time needed to reach steady state concentrations. In the case of vigabatrin, however, it has been found that the half-life of biologic activity is far longer than the elimination half-life.^[6]

For vigabatrin, there is no range of target concentrations because researchers found no difference between the serum concentration levels of responders and those of non-responders.^[7] Instead, the duration of action is believed to be more a function of the GABA-T resynthesis rate; levels of GABA-T do not usually return to their normal state until six days after stopping the medication.^[8]

Vigabatrin - Uses

Vigabatrin - Approved/Clinically Proven

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.^[9]

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).^[10]

Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.^[11]

Vigabatrin - Unapproved/Investigational

In November of 2001, a team of scientists lead by Peter Zwanzger of the University of Munich reported that vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers.^[12]

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.^[13]

In 1984, a double-blind crossover-study of six Huntington's disease patients—five of them on antipsychotics—reported that vigabatrin did little, if anything, to improve hyperkinetic movements, the ability to carry out daily activities, or normalize motor function.^[14]

Vigabatrin - Adverse Effects

Vigabatrin - 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%).^[15] Out of 299 children, 33 (11%) became hyperactive.^[16]

Some patients develop psychosis during the course of vigabatrin therapy,^[17] which is more common in adults than in children.^[18] This can happen even in patients with no prior history of psychosis.^[19] Other rare CNS side effects include anxiety, emotional lability, irritability, tremor, abnormal gait, and speech disorder.^[20]

Vigabatrin - Gastrointestinal

Abdominal pain (1.6%), constipation (1.4%), vomiting (1.4%), and nausea (1.4%).^[21]

Dyspepsia and increased appetite occurred in less than 1% of subjects in clinical trials.^[22]

Vigabatrin - Body as a Whole

Fatigue (9.2%), weight gain (5.0%), asthenia (1.1%).^[23]

Vigabatrin - Teratogenicity

A teratology study conducted in rabbits found that a dose of 150mg/kg/day caused cleft palate in 2% of pups and a dose of 200 mg/kg/day caused it in 9%.^[24] This may be due to a decrease in methionine levels, according to a study published in March of 2001.^[25] 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.^[26]

There is no controlled teratology data in humans to date.

Vigabatrin - More on Abnormal Vision

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.^[27] This has the most effect on the outer area (as opposed to the macular, or central area) of the retina.^[28]

Vigabatrin - Drug Interactions

A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine.^[29]

In 1984, Drs Rimmer and Richens at the University of Wales reported that administering vigabatrin with phenytoin lowered the serum phenytoin concentration in patients with treatment-resistant epilepsy.^[30] The concentration of phenytoin falls to 23% within five weeks, according to an experiment published in 1989 by the same two scientists that tried and failed to elucidate the mechanism behind this interaction.^[31]

Vigabatrin - Brand Names

Vigabatrin is sold as Sabril® in Canada,^[32] Mexico,^[33] and the united Kingdom.^[34]

Vigabatrin - References and End Notes

• DrugBank APRD00282
• PubChem 5665

1. ^  MedlinePlus Drug Information: Vigabatrin United States National Library of Medicine. 5 Mar 2001.
2. ^  Long, Phillip W. "Vigabatrin." Internet Mental Health. 1995-2003.
3. ^  see Long, 1995-2003.
4. ^  Sheean G, Schramm T, Anderson DS, Eadie MJ. "Vigabatrin--plasma enantiomer concentrations and clinical effects." Clinical and Experimental Neurology. 1992;29:107-16. PMID 1343855
5. ^  Gram L, Larsson OM, Johnsen A, Schousboe A (1989). Experimental studies of the influence of vigabatrin on the GABA system. British Journal of Clinical Pharmacology 27 (Suppl 1): 13S-17S. PMID 2757904
6. ^  Browne TR (1998). Pharmacokinetics of antiepileptic drugs. Neurology 51 (5 suppl 4): S2-7. PMID 9818917
7. ^  Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T (2003). Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Therapeutic Drug Monitoring 25 (4): 457-62. PMID 12883229
8. ^  see Gram et al, 1989
9. ^  see Long, 1995-2003.
10. ^  DEF MEXICO: SABRIL Diccionario de Especialdades Farmaceuticas. Edicion 49, 2003.
11. ^  see 'Diccionario de Especialdades Farmaceuticas, 2003
12. ^  Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R (2001). Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology 25 (5): 699-703. PMID 11682253 Fulltext options
13. ^  Feucht M, Brantner-Inthaler S (1994). Gamma-vinyl-GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study. Epilepsia 35 (5): 993-8. PMID 7925171
14. ^  Scigliano G, Giovannini P, Girotti F, Grassi MP, Caraceni T, Schechter PJ (1984). Gamma-vinyl GABA treatment of Huntington's disease. Neurology 34 (1): 94-6.
15. ^  see Long, 1995-2003.
16. ^  see Long, 1995-2003.
17. ^  Sander JW, Hart YM (1990). Vigabatrin and behaviour disturbance. Lancet 335 (8680): 57. PMID 1967367
18. ^  Chiaretti A, Castorina M, Tortorolo L, Piastra M, Polidori G (1994). [Acute psychosis and vigabatrin in childhood]. La Pediatria Medica e Chirurgica : Medical and surgical pediatrics 16 (5): 489-90. [Article in Italian] PMID 7885961
19. ^  Sander JW, Hart YM, Trimble MR, Shorvon SD (1991). Vigabatrin and psychosis. Journal of Neurology, Neurosurgery, and Psychiatry 54 (5): 435-9. PMID 1865207
20. ^  see Long, 1995-2003.
21. ^  see Long, 1995-2003.
22. ^  see Long, 1995-2003.
23. ^  see Long, 1995-2003.
24. ^  see Long, 1995-2003.
25. ^  Abdulrazzaq YM, Padmanabhan R, Bastaki SM, Ibrahim A, Bener A (2001). Placental transfer of vigabatrin (gamma-vinyl GABA) and its effect on concentration of amino acids in the embryo of TO mice. Teratology 63 (3): 127-33. PMID 11283969 Fulltext options
26. ^  Lombardo SA, Leanza G, Meli C, Lombardo ME, Mazzone L, Vincenti I, Cioni M (2005). Maternal exposure to the antiepileptic drug vigabatrin affects postnatal development in the rat. Neurological Sciences 26 (2): 89-94. PMID 15995825 Fulltext options
27. ^  Frisén L, Malmgren K (2003). Characterization of vigabatrin-associated optic atrophy. Acta Ophthalmologica Scandinavica 81 (5): 466-73. PMID 14510793 Fulltext options
28. ^  Buncic JR, Westall CA, Panton CM, Munn JR, MacKeen LD, Logan WJ (2004). Characteristic retinal atrophy with secondary "inverse" optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 111 (10): 1935-42. PMID 15465561 Fulltext options
29. ^  Sanchez-Alcaraz A, Quintana MB, Lopez E, Rodriguez I, Llopis P (2002). Effect of vigabatrin on the pharmacokinetics of carbamazepine. Journal of Clinical Pharmacology and Therapeutics 27 (6): 427-30. PMID 12472982 Fulltext options
30. ^  Rimmer EM, Richens A (1984). Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1 (8370): 189-90. PMID 6141335
31. ^  Rimmer EM, Richens A (1989). Interaction between vigabatrin and phenytoin. British Journal of Clinical Pharmacology 27 (Suppl 1): 27S-33S. PMID 2757906
32. ^  drugs.com Vigabatrin Drug Information
33. ^  see Diccionario de Especialdades Farmaceuticas, 2003.
34. ^  Treatments for Epilepsy - Vigabatrin Norfolk and Waveney Mental Health Partnership NHS Trust

{Lamotrigine}

{Primidone}

{Potassium bromide}

{Paraldehyde}

{Valpromide} {Valnoctamide}

{Topiramate}

{Beclamide}

{Stiripentol}

{Carbamazepine} {Oxcarbazepine}

{Pheneturide} {Phenacemide}

{Gabapentin} {Vigabatrin} {Progabide} {Pregabalin}

{Trimethadione} {Paramethadione} {Ethadione}

{Brivaracetam} {Levetiracetam} {Nefiracetam} {Seletracetam}

{Ethotoin} {Phenytoin} {Mephenytoin} {Fosphenytoin}

{Acetazolamide} {Sultiame} {Methazolamide} {Zonisamide}

{Felbamate} {Meprobamate} {Emylcamate} {Phenprobamate}

{Ethosuximide} {Phensuximide} {Mesuximide}

{Valproic acid} {Sodium valproate} {Valproate semisodium} {Tiagabine}

{Amobarbital} {Aprobarbital} {Butabarbital} {Butalbital} {Hexobarbital} {Mephobarbital} {Pentobarbital} {Phenobarbital} {Phenytoin} {Secobarbital} {Sodium thiopental} {Talbutal} {Thiobarbital}

{Diazepam} {Oxazepam} {Nitrazepam} {Temazepam} {Lorazepam} {Flunitrazepam} {Bromazepam} {Clobazam} {Clonazepam} {Chlordiazepoxide} {Triazolam} {Midazolam} {Alprazolam} {Estazolam} {Quazepam} {Clorazepate} {Medazepam} {Prazepam} {Flurazepam}

Adapted from the Wikipedia article "Vigabatrin", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki