Vigabatrin development

Chollet et al. [39] developed an isocratic HPLC method for simultaneous determination of vigabatrin and gabapentin in human serum after precolumn derivatization with o-phthaldialdehyde and fluorimetric detection at 435 nm with excitation at 235 nm. A column (25 cm x 3.0 mm) of Nucleosil Ci8 (5 /im) with a mixture of 0.022 M phosphoric acid (pH 2)-acetonitrile (45 55) as a mobile phase (flow rate 0.6 ml/min) was used. The calibration graph was rectilinear from 2.0 to... 

Of the newer anticonvulsants, lamotrigine, gabapentin, tiagabine, and vigabatrin have little or no teratogenic potential in animals, whereas oxcarbazepine and topira-mate are teratogenic in rodents. However, animal studies are not necessarily apphcable to humans and chnical data are stiU insufficient to assess the effects of newer drugs on the development of the human fetus (153). 

Like other GABAergic drugs, vigabatrin can aggravate absence seizures and may precipitate absence status in patients with generalized epilepsies. Occasionally, absence seizures are also precipitated in patients with partial epilepsy, as in a 28-year old man who developed de novo absence status 4 days after the dosage of vigabatrin was increased to 2 g/day (7). 

A 41-year-old man who had taken vigabatrin for 2 years in doses of 3-6 g/day developed bilateral concentric visual field defects, with greater loss in the nasal fields. Vigabatrin was withdrawn. Later he had a cardiopulmonary arrest and died. At postmortem there was peripheral retinal atrophy with loss of ganghon cells, severe in the peripheral retina and less severe in the maculae. 

Doses of vigabatrin up to 10 g have been taken without serious effects. Toxic manifestations include vertigo, tremor, sedation, coma, myoclonic jerks, and psychosis. Gastric lavage within 1-2 hours is recommended after doses in excess of 12 g in adults and 2 g in children (SEDA-22,85). The development of discontinuous partial complex status epilepticus in a patient with partial epilepsy who had taken a 20 g overdose 6 days earher was considered to be a possible effect of withdrawal (SEDA-22, 85). 

After an overdose of vigabatrin 45 g, a 17-year-old girl developed a behavioral disorder (73). A CT scan of the... 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

A different approach led to the development of vigabatrin (Sabril). Its ability selectively and irreversibly to inhibit GABA-transaminase from metabolically inactive GABA (as a suicide inhibitor) makes it an effective agent (Fig. 12-5), particularly in complex partial seizures. 

An algorithm has been developed for detecting peripheral visual field changes in patients taking vigabatrin for refractory epilepsy [362". ... 

One patient who developed impaired vision while taking topiramate for symptomatic epilepsy had signs of a maculopathy [309" ]. The topiramate was withdrawn, but vision failed to improve significantly over 6 months of follow-up. The authors speculated that topiramate, like vigabatrin, may cause persistent visual impairment through direct retinal toxicity. 

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