Combination Of Vigabatrin Research Articles

Real-life data comparing the efficacy of vigabatrin and oral steroids given sequentially or combined for infantile epileptic spasms syndrome

AimsThe prognosis of Infantile epileptic spasm syndrome (IESS), relates to the underlying etiology and delay in controlling epileptic spasms. Based on the spasm-free rate, a randomized controlled trial has demonstrated the superiority of combining oral steroids and vigabatrin over oral steroids alone but confirmation in real-life conditions is mandatory. MethodsWe compared two real-life IESS cohorts: a multicenter, retrospective cohort of 40 infants treated with vigabatrin followed by a sequential (ST) addition of steroids, and a prospective, single-center cohort of 58 infants treated with an immediate combination of vigabatrin and steroids (CT). ResultsThe two cohorts were similar. When the rate of spasm-free infants in the two cohorts was compared on day 14, a significant difference was observed between the ST (27,5 %) and CT cohorts (64 %) (p < 0.0004). This difference remained significant on day 30, with 55 % spasm-free patients in the ST cohort compared to 76 % in the CT cohort (p = 0.03). After the infants had received both vigabatrin and steroids, without taking into account the time point after treatment initiation, no significant difference was observed in the spasm-free rate between the two cohorts (p = 0.38). InterpretationReal-life data confirm the interest of combination therapy as a first-line treatment for IESS.

Felbamate for infantile spasms syndrome resistant to first-line treatments.

To analyse the effects of felbamate in refractory infantile spasms/West syndrome. We conducted a 10-year retrospective study of infants (including all infants younger than 18mo) treated with felbamate for electroencephalography-recorded epileptic spasms persisting after first-line treatment. In total, 29 infants (17 males, 12 females) were included in the study. Felbamate was initiated at a mean age of 13.8months (range 4.5-66mo) after sequential administration or combination of vigabatrin and oral steroids; a ketogenic diet was implemented in 23 infants. Eight infants became spasm-free at a mean dose of 34.6mg/kg/day felbamate (range 26-45mg/kg/day). Mean duration of felbamate use was 19months (range 1-67mo) for the 19 infants whose treatment was terminated. No severe side effects were observed. Reversible neutropenia led to withdrawal of felbamate in six patients. One spasm-free patient demonstrated recurrence when felbamate was withdrawn. N-methyl-d-aspartate receptors with felbamate controlled epileptic spasms in eight infants resistant to first-line treatment should be targeted.

Isobolographic and behavioral characterizations of interactions between vigabatrin and gabapentin in two experimental models of epilepsy

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the pentylenetetrazole test a CD 97 dose (100 mg/kg) was used. Potential adverse-effect profiles of interactions of vigabatrin with gabapentin at three fixed-ratios of 1:3, 1:1 and 3:1 from both seizure tests were evaluated in the chimney (motor performance) and grip-strength (skeletal muscular strength) tests. Vigabatrin and gabapentin total brain concentrations were determined with high performance liquid chromatography. Vigabatrin and gabapentin administered singly increased the electroconvulsive threshold (TID 20 — 226.2 and 70.0 mg/kg, respectively). With isobolography, the combination of vigabatrin with gabapentin at the fixed-ratio of 1:3 exerted supra-additive (synergistic) interactions whilst at 1:1 and 3:1 additivity occurred. Similarly, vigabatrin and gabapentin administered singly suppressed the pentylenetetrazole-induced seizures (ED 50 values — 622.5 and 201.1 mg/kg, respectively). Isobolography revealed that vigabatrin with gabapentin in combination at the fixed-ratio of 1:1 produced supra-additive (synergistic) interaction whilst at 1:3 and 3:1 additivity occurred. In combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes.

Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy

To characterize the type of interactions between vigabatrin (VGB) and tiagabine (TGB) — two newer antiepileptic drugs influencing GABA-ergic neurotransmitter system, the isobolographic analysis was used in two experimental models of epilepsy: the maximal electroshock seizure threshold (MEST) test and pentylenetetrazole (PTZ)-induced seizures in mice. Results indicated that VGB and TGB administered separately (i.p.) increased the electroconvulsive threshold in mice, which allowed the calculation of their TID 20 values (threshold increasing doses by 20% over the threshold of control animals) in the MEST test. The TID 20 for VGB was 226.2 mg/kg and that for TGB was 4.4 mg/kg. With isobolography, the combinations of VGB with TGB (at fixed-ratios of 1:3, 1:1 and 3:1) exerted additive interactions in the MEST test in mice. Similarly, VGB and TGB injected separately (i.p.) suppressed the PTZ-induced seizures, and their ED 50 values (median effective doses, protecting 50% of the animals tested against clonic convulsions) for VGB and TGB were 622.5 mg/kg and 0.8 mg/kg, respectively. Isobolographic analysis of interactions revealed that the combinations of VGB with TGB at the fixed-ratios of 1:3 and 1:1 produced supra-additive (synergistic) interactions against PTZ-induced seizures. Only the combination of VGB with TGB at the fixed-ratio of 3:1 was additive in the PTZ test. The evaluation of acute adverse-effect potential for all fixed-ratio combinations of VGB with TGB (administered at their TID 20 and ED 50 values from the MEST and PTZ tests) revealed that none of the examined combinations affected motor coordination in the chimney test and altered neuromuscular tone in the grip-strength test in mice. In contrast, VGB in combinations with TGB produced the antinociceptive effects with respect to suppression of acute thermal pain in animals subjected to the hot-plate test. Based on this preclinical study, one can ascertain that the combination of VGB with TGB would provide an adequate seizure control in epileptic patients.

Antiepileptic action induced by a combination of vigabatrin and tiagabine

Vigabatrin, an inhibitor of GABA breakdown by GABA transaminase and of GABA transporter isoform 1 (GAT1), and tiagabine, a highly specific inhibitor of GAT1, have successfully been applied in the treatment of epilepsy. We investigated the effects of individual and combined application of these drugs on GAT1 expressed in Xenopus oocytes, and examined the effects on epileptiform discharges in the CA3 area of brain slices of genetically epileptic El and control ddY mice, and on the occurrence of seizures in El mice. Simultaneous application of vigabatrin and tiagabine inhibited epileptiform discharges induced by high-K + solution in the brain slices in an antagonistic fashion. The degree of inhibition by tiagabine after pre-treatment with vigabatrin was additive in ddY mice and synergistic in El mice. In Mg 2+-free solution, co-treatment by the two drugs produced additive inhibition in slices from both mouse strains, but pre-treatment with vigabatrin produced synergistic inhibition in slices only from ddY mice. In the slices from El mice, a combination of drugs resulted in additive effects in both co- and pre-treatment by the drugs. Although these drugs are also effective in vivo at suppressing seizure occurrence in El mice, the combined application does not show synergistic effects, but rather is antagonistic under the experimental conditions in this particular variant of epilepsy. The synergistic inhibition of epileptiform discharges in brain slices may, in part, have originated from the complex interaction with GAT1. In experiments on the GAT1 expressed in oocytes it could be demonstrated that synergistic inhibition occurs only at low concentration (0.1 nM) of vigabatrin. This illustrates that the oocytes may form a powerful test system for drug screening and investigation of complex drug interactions. These results present a novel interpretation of synergistic inhibition of certain epileptic discharges using vigabatrin and another drug, and that for successful synergistic treatment of epilepsies carefully designed timed dosage regimens are essential.

Modulation of the in vivo effects of gabapentin by vigabatrin and SKF89976A

Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.