Vigabatrin: No microvacuoles in a human brain

Pedersen, Birthe; Højgaard, Knud; Dam, M.

doi:10.1016/0920-1211(87)90054-4

Cited by 51 publications

(21 citation statements)

References 4 publications

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“…GABA (3,12,29). Currently, there is no evidence of alterations in clinical (3,11,12,22,29,35,36), electrophysiological (14), and psychometric and psychophysiological tests (30), and brain histology (6,10,12,15,27) (18)(19)(20). Since reduced GAD activity should decrease GABA synthesis, the elevated GABA levels were indicative of vigabatrin's effect on prolonging GABA degradation by its profound inhibition of GABA-T.…”

Section: Histopczthologymentioning

confidence: 99%

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Yarrington¹,

Gibson²,

Dillberger³

et al. 1993

Toxicol Pathol

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Vigabatrin (Sabril®) is a γ-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fomix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

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Section: Histopczthologymentioning

confidence: 99%

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Yarrington¹,

Gibson²,

Dillberger³

et al. 1993

Toxicol Pathol

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“…Published reports of the examination of human brain tissue, either autopsy or surgical specimens, have described no evidence of VGB-induced IME or other changes (49)(50)(51)(52)(53)(54)(55)(56).…”

Section: Histologic Ime Evaluations In Human Autopsy Casesmentioning

confidence: 99%

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

Cohen¹,

Fisher²,

Brigell³

et al. 2000

Epilepsia

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Purpose: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. Methods: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. Results: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (-1 75,000 pa

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“…When viewed within the context of animal findings and human safety studies performed to date with this drug (Hammond & Wilder 1985a;Pedersen et al, 1987;Persson, 1988), these data provide further indirect evidence against the possibility of microvacuolization changes developing in the brain of epileptic patients treated with GVG.…”

Section: Discussionmentioning

confidence: 99%

Effects of vigabatrin on evoked potentials in epileptic patients.

Cosi

Callieco

Galimberti

et al. 1989

Brit J Clinical Pharma

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1. Somatosensory (SEP) brainstem auditory (BAEP) and visual (VEP) evoked potentials were determined before and after add‐on administration of vigabatrin (GVG) in patients with epilepsy. 2. At pre‐ treatment assessment SEP and BAEP parameters were usually found to be within normal limits, while P100 latencies of the VEP were abnormally prolonged in a considerable proportion of patients. 3. In a double‐ blind, placebo‐controlled trial in 22 patients GVG (1‐3 g day‐1 stratified according to body weight) given for 7 weeks did not modify any of the evoked potential parameters evaluated. 4. Eighteen patients were evaluated prospectively at regular intervals during long‐term GVG (2‐4 g day‐1) therapy with a mean follow up of 24 months (range 13‐42 months). SEP, BAEP and especially VEP parameters showed some interindividual variability, but the within patient variation was relatively small. No consistent important changes were seen in association with GVG, although a possible trend towards a shortening of BAEP latencies and P100 latencies was observed. 5. The relevance of these findings with respect to GVG safety is discussed.

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Vigabatrin: No microvacuoles in a human brain

Cited by 51 publications

References 4 publications

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

Effects of vigabatrin on evoked potentials in epileptic patients.

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