Explore chapters and articles related to this topic
The anterior thalamus and the pentylenetetrazol (PTZ) model
Published in Hans O Lüders, Deep Brain Stimulation and Epilepsy, 2020
Marek A Mirski, David L Sherman, Wendy C Ziai
These data were further corroborated using microinjection of proconvulsant and anticonvulsant substances directly in AN. Microinjection of muscimol (GABA agonist) into either AN or the mammillary complex could prevent and terminate ongoing PTZ seizures in paralyzed and ventilated rodents (Figure 18.5).46,48,52 To study behavioral effects, a longer acting agent gamma-vinyl-GABA (a selective GABA-transaminase inhibitor) was injected into AN. These experiments also demonstrated that enhancement of GABAergic activity within AN resulted in anticonvulsant activity (Table 18.1).46 In contrast, kainic acid (a rigid analog of glutamate) or bicuculline (an antagonist of GABA) provoked site-specific ictal responses when applied to AN (Figure 18.6). These results supported a specific facilitory role for AN in PTZ seizures and suggested the presence of glutaminergic and GABAergic transmission within the complex.
Chemoconvulsants
Published in Steven L. Peterson, Timothy E. Albertson, Neuropharmacology Methods in Epilepsy Research, 2019
Since an extensive discussion of the GHB model of absence is beyond the scope of this chapter, the reader is referred to a review by Snead6 for a more in-depth discussion of this electrographic model of absence. The GABA metabolite GHB occurs naturally in the mammalian brain and when injected into animals produces an electrographic and behavioral seizure that is similar in many respects to that observed in human generalized absence seizures.6 Gamma-butyrolactone (GBL) is often used as a pro-drug to GHB because it produces a consistent and reproducible 7- to 9-Hz spike-wave electrographic discharge that is accompanied by behavioral arrest, facial myoclonus, and vibrissal twitching similar to the human condition.6 The pharmacological profile of the GBL model is consistent with other animal models of absence. Thus, seizures induced by GBL are blocked by anti-absence drugs ethosuximide, trimethadione, and valproate. Furthermore, GBL-induced spike-wave seizures are prolonged by phenytoin and drugs that enhance GABAergic tone (e.g., direct GABA agonists, the GABA transaminase inhibitor vigabatrin). The GBL model fulfills all of the criteria outlined by Snead6 to be considered an experimental and pharmacological model of human absence seizures and should be considered as an excellent in vivo animal model for screening potential anti-absence drugs.
Pharmacological treatment of bipolar affective disorder in old age
Published in Stephen Curran, John P Wattis, Practical Management of Affective Disorders in Older People, 2018
Valproate is available in the UK in three forms: sodium valproate, valproic acid and semisodium valproate, the last having a product licence for the treatment of acute mania in the UK. Randomised controlled trials have shown valproate to be effective in the treatment of mania.21,22 It is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in the treatment of BPD. Absorption is rapid and peak levels are attained in 30–60 minutes. Protein binding is up to 95% and half-life varies with the preparation but is in the range of 5–20 hours. It is metabolised partly via the microsomal cytochrome P450 system and partly via mitochondrial oxidation. Serum level monitoring is supposedly of limited use compared with lithium and carbamazepine and is not routinely recommended, although there is a little evidence for an optimum window as discussed in the preceding section.16 Target dosages are in the range of 500–1500 mg per day in divided doses.
Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature
Published in Expert Review of Clinical Pharmacology, 2021
Adam Strzelczyk, Janina Grau, Thomas Bast, Astrid Bertsche, Ulrich Bettendorf, Andreas Hahn, Hans Hartmann, Christoph Hertzberg, Frauke Hornemann, Ilka Immisch, Julia Jacobs, Kerstin A. Klotz, Gerhard Kluger, Susanne Knake, Markus Knuf, Gerhard Kurlemann, Klaus Marquard, Thomas Mayer, Sascha Meyer, Hiltrud Muhle, Karen Müller-Schlüter, Felix von Podewils, Felix Rosenow, Susanne Ruf, Matthias Sauter, Hannah Schäfer, Jan-Ulrich Schlump, Susanne Schubert-Bast, Steffen Syrbe, Charlotte Thiels, Regina Trollmann, Adelheid Wiemer-Kruel, Bernd Wilken, Bianca Zukunft, Johann Philipp Zöllner
Similar to recommendations for the treatment of other types of structural epilepsy, monotherapy using antiseizure drugs (ASDs) is the recommended first-line therapy option for persons with TSC-associated epilepsy [7]. However, specific guidelines regarding the introduction and choice of ASDs to treat TSC have been developed following extensive studies exploring the natural history and pathophysiology of TSC-associated epilepsy, which have made this genetic disorder a ‘model disease’ for epileptogenesis [7,9]. Previous assumptions that early ASD interventions, especially using the γ-aminobutyric acid (GABA) transaminase inhibitor vigabatrin (VGB), might prevent epileptogenesis in persons with TSC [10,11] have recently been confirmed by the EPISTOP study [12]. VGB is currently the first-line ASD recommendation for ES and focal seizures in children <1 year of age [7]. Recently, studies examining the effects of the mTOR inhibitor everolimus [13–16] and the cannabinoid cannabidiol (CBD) [17] on TSC-associated seizures have also shown promising results.
Regulatory role of hippocampal PI3K and mTOR signaling pathway in NMDA-induced infant spasm rats
Published in Neurological Research, 2019
Guang Yang, Jing Wang, Lin Wan, Xiu-Yu Shi, Yan Meng, Wei-Hua Ren, Li-Ping Zou
Infantile spasms (IS) is an early infantile epileptic encephalopathy. It is classified as epileptic spasms in the International League Against Epilepsy (ILAE) classification [1], and is one part of the triad of West syndrome, with typical onset between four and 7 months of age. Because IS often is associated with developmental arrest or regression and may lead to cognitive impairment, efficient treatment as early as possible is recommended for better clinical outcomes, it has been proven that treatment within 1 month of spasm onset is associated with improved developmental outcomes of the patients with IS [2]. IS exhibits distinct phamacosensitivity since it responds poorly to nearly all classical antiepileptic drugs [3]. Adrenocorticotropic hormone (ACTH), high-dose glucocorticoids and the GABA transaminase inhibitor vigabatrin are the recommended treatments for IS currently, but the seizure control rate in IS patients still remains low [3]. The etiology of IS may affect the efficacy of treatment. It is well known that patients who develop IS due to tuberous sclerosis complex (TSC) respond well to vigabatrin; however, the structural, metabolic, and genetic etiologies of IS are highly heterogenous, and about one-third of patients have unknown etiology even after full investigation [4], these patients may not respond to vigabatrin as well as TSC. Taken together, these factors suggest that continued investigations of new and effective treatment for IS are urgent [3]. Understanding the underlying mechanism of IS would help greatly toward drug development.
Extended-release drug formulations for the treatment of epilepsy
Published in Expert Opinion on Pharmacotherapy, 2018
Christian Brandt, Theodor W. May
ER formulations aim at maintaining a more constant serum concentration of a specific drug without having to shorten the dosing interval or at allowing to prolong the dosing interval without the risk of increased fluctuations of the serum concentration. The application of an ER formulation can improve efficacy in drugs whose efficacy is linked to a constant serum concentration. This does not apply to a drug that has irreversible effects. An example is vigabatrin (VGB), an irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor. Its effect lasts until new GABA transaminase has been synthesized and has exerted its effect on GABA. Therefore, the actual serum concentration does not reflect the drug’s current effect. An ER formulation of VGB would, therefore, probably not increase its efficacy [3]. It is also more likely that an ER formulation improves efficacy when serum concentration and concentration in cerebrospinal fluid are closely related, a finding that has been shown for lacosamide (LCM) [4]. This means for ER formulations that they do not necessarily improve the efficacy of the drug. This would have to be assessed in clinical trials comparing immediate-release (IR) and ER formulations of a specific drug.