Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Loiseau, P

doi:10.1111/j.1528-1157.1999.tb02089.x

Cited by 31 publications

(18 citation statements)

References 33 publications

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“…The clinical relevance of these data is clear for the action of TGB on generalized seizures. The drug was successfully tested in patients with intractable partial seizures, and it was also found to be effective against secondary generalization (5,6,30). Our results regarding the efficacy of TGB against minimal seizures are in agreement with those of Smith et al (31), who found that the drug was effective against photomyoclonic seizures in baboons.…”

Section: Discussionsupporting

confidence: 90%

Two Different Anticonvulsant Actions of Tiagabine in Developing Rats

Haugvicová¹,

Škutová²,

Kubová³

et al. 2000

Epilepsia

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Summary:Purpose: Our goal was to study the anticonvulsant action of tiagabine (TGB) at different levels of brain maturation in rats.Methods: Wistar rats in five age groups (7,12,18,25, and 90 days old) were injected intraperitoneally with TGB at doses of 0.5-32 mg/kg. Thirty minutes later, motor seizures were induced by the subcutaneous adminstration of pentylenetetrazol (PTZ) in a dose of 100 mg/kg for all of the groups except the 18-day-old rat pups, which received a 90-mg/kg dose. The incidence and latency of two types of motor seizures, minimal clonic and generalized tonic-clonic seizures (GTCSs), were evaluated, and the seizure severity was scored. The time profile of TGB action at the 8-mg/kg dose was studied in the 12-and 25-day-old rats.Results: Minimal clonic seizures were reliably induced in rats 18 days old or older, and the seizures were suppressed by TGB in all of these age groups. Although TGB was very effective against this type of seizure in the 18-day-old rats, the efficacy of the drug decreased with the age of the animal. GTCSs were suppressed by TGB in the adult and 25-day-old rats, and a U-shaped dose-response curve was outlined in these two groups. The 18-and 12-day-old rat pups exhibited a selective suppression of the tonic phase of GTCSs. A mixture of these two effects was observed in the youngest group. TGB demonstrated a markedly longer action in the 12-day-old rats than in the 25-day-old rats.Conclusions: TGB exhibits anticonvulsant action against both minimal seizures and GTCSs. Ontogenetic development of these two actions is markedly different. Key Words: Tiagabine-Convulsions-PentylenetetrazolOntogeny-Rats.One of the ways of suppressing epileptogenesis is through the facilitation of brain inhibitory systems. The most important inhibitory system, which uses y-aminobutyric acid (GABA) as its mediator, is a target of many classic and new antiepileptic drugs (AEDs) (1). With these drugs, the synaptic action of GABA is terminated by the reuptake into presynaptic terminals and glial cells where the transmitter is catabolized. Inhibition of this reuptake increases the concentration of GABA in the synaptic cleft and leads to an anticonvulsant effect. Nipecotic acid was among the first known inhibitors of GABA reuptake, and its anticonvulsant effect was shown after intracerebroventricular administration and in in vivo preparations (2,3). Unfortunately, this compound, as well as some other GABA uptake blockers, do not cross the blood-brain barrier (2). Tiagabine nipecotic acid that does cross the blood-brain barrier, was the first GABA-uptake inhibitor introduced into clinical practice (4-6). It has been demonstrated that TGB specifically inhibits the GAB A transporter-1 (GAT-I), which is the one of the four known GATS that are dominant in the brain (7). GAT-1 is present in adult rats and the immature brain, where its concentration markedly increases after the second week of postnatal life (8,9).Like other new AEDs, TGB was tested preclinically in adult rodents (10,ll). It exhibits a marked an...

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Section: Discussionsupporting

confidence: 90%

Two Different Anticonvulsant Actions of Tiagabine in Developing Rats

Haugvicová¹,

Škutová²,

Kubová³

et al. 2000

Epilepsia

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“…Yet as recently reviewed by van den Pol (86), the role of GABA and glutamate in regulating energy balance has yet to be determined. It is unlikely that the ability of VPA to induce weight gain is solely due to increased GABA transmission because other anticonvulsants that increase GABA, including tiagabine, are not reported to induce weight gain (87). To determine whether an acute reduction in serum leptin levels by VPA correlates with an increase in appetite, clinical studies are required that measure leptin levels immediately after VPA treatment.…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes

Lagace¹,

McLeod²,

Nachtigal³

2004

Endocrinology

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Treatment of epilepsy or bipolar disorder with valproic acid (VPA) induces weight gain and increased serum levels for the satiety hormone, leptin, through an unidentified mechanism. In this study we tested the effects of VPA, a short-chain branched fatty acid (C8:0), on leptin biology and fatty acid metabolism in 3T3-L1 adipocytes. VPA significantly reduced leptin secretion in a dose-dependent manner. Because fatty acid accumulation has been hypothesized to block leptin secretion, we tested the effect of VPA on fatty acid metabolism. Using 14C-radiolabeled VPA, we found that the 14C was mainly incorporated into triacylglycerol. VPA did not alter lipogenesis from acetate, nor did it change the amount of intracellular free fatty acids available for triacylglycerol synthesis. Decreased leptin secretion was accompanied by a reduction in leptin mRNA, even though VPA treatment did not alter the protein levels for known transcription factors affecting leptin transcription including: CCAAT/enhancer binding protein-alpha, peroxisome proliferator-activated receptor-gamma, or steroid regulatory element binding protein 1a. VPA altered levels of leptin mRNA independent of de novo protein synthesis without affecting leptin mRNA degradation. This report demonstrates that VPA decreases leptin secretion and mRNA levels in adipocytes in vitro, suggesting that VPA therapy may be associated with altered leptin homeostasis contributing to weight gain in vivo.

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“…Although this theory can explain weight gain related to some GABA-enhancing drugs including VPA and gabapentine [15], this is not the sole mechanism. Other antiepileptic drugs that increase GABA, such as tiagabine, do not induce weight gain [36]. …”

Section: Possible Mechanisms Underlying Vpa-induced Weight Gainmentioning

confidence: 99%

Valproate-Induced Insulin Resistance and Obesity in Children

et al. 2009

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Background: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial. Methods: In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically. Results: Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic β-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects. Conclusions: The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.

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Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Cited by 31 publications

References 33 publications

Two Different Anticonvulsant Actions of Tiagabine in Developing Rats

Two Different Anticonvulsant Actions of Tiagabine in Developing Rats

Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes

Valproate-Induced Insulin Resistance and Obesity in Children

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