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Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Felbamate is indicated only as adjunctive therapy. It is useful for poorly controlled focal and secondarily generalized seizures and in patients of Lennox–Gastaut syndrome (Felbamate Study Group in Lennox–Gastaut Syndrome, 1993). The benefits over risk of drug-induced aplastic anemia or liver failure must be taken into consideration before the start of this drug (Sachdeo et al., 1992).
Posttraumatic epilepsy and neurorehabilitation
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Theresa D. Hernández, Sudha S. Tallavajhula, Kristina T. Legget, Paul M. Levisohn
Newer AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, lacosamide, oxcarbaxepine, pregabalin, rufinamide, vigabatrin, tiagabine, topiramate, zonisamide, perampanel, and ezogabine) have been approved by the Food and Drug Administration (FDA) since 1993. In general, they appear to have high therapeutic indices, i.e., a wide window between efficacy and toxicity, and have been demonstrated to be effective and safe in controlled studies. Improved pharmacokinetics provide an additional advantage of some of these newer AEDs, including renal clearance, the lack of significant protein binding, and the absence of CyP450 induction.59 However, serious idiosyncratic adverse effects can occur. The use of felbamate has been restricted by the FDA for use in severe intractable epilepsy because of a significant risk of aplastic anemia estimated by the FDA to be 1:2,000. Lamotrigine is associated with a risk of serious rash in approximately 1:1,000 patients, usually at onset of therapy. Additionally, treatment-emergent side effects can be troublesome. For example, topiramate is associated with word-finding difficulties in some patients, particularly at higher doses or when the drug is used in polypharmacy. Gabapentin may cause weight gain and somnolence. Levetiracetam may cause behavioral side effects. Although monitoring serum drug levels, complete blood counts, and liver function are not required with most of the new AEDs (with the notable exception of felbamate), the difficulty in assessing clinical status of patients with significant traumatic encephalopathy may make such monitoring advisable. Practitioners should take advantage of published reviews of these drugs in textbooks and journals to familiarize themselves with their use.
Critical care, neurology and analgesia
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The use of multiple antiepileptic drugs (polytherapy) increases both the risk and incidence of side effects and this again emphasises the point that no more than two antiepileptic drugs should be used simultaneously. Side effects are more commonly seen with the older drugs (phenobarbitone, phenytoin, carbamazepine, sodium valproate and the benzodiazepines), but may also be seen with the newer drugs. Adverse side effects have been linked with the premature deaths of both paediatric and adult patients with epilepsy [18]. Although side effects tend to be identified in clinical trials of new drugs (phase I-IV), some may not be recognised for some time and after years of routine clinical use. Felbamate and vigabatrin, two of the ‘newer’ generation of drugs illustrate this problem. Within months of the pivotal clinical trials of felbamate being completed (and published), it became clear that the drug caused severe, including fatal aplastic anaemia and hepatitis, resulting in the drug being withdrawn from the UK and many European countries. Approximately 10 years after vigabatrin was first prescribed, a characteristic visual field defect (symmetrical, bilateral constriction with relative temporal sparing) was reported, which appears to be specific to the use of this drug and may occur in up to 40% of adults, although in most cases the defect is asymptomatic and detected only on detailed visual field perimetry. The precise incidence of this defect in children is not known, but is thought to be lower, possibly 25%. Current evidence suggests that early visual field constriction may be seen after a minimum of six months’ exposure to the drug, but far more typically, after at least two years of continued use. Long-term follow-up data will clarify whether the visual field deficit is likely to be permanent and irreversible.
Stereoselective pharmacokinetic and pharmacodynamic analysis of a CNS-active sulphamoylphenyl carbamate derivative
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
David Bibi, Bella Shusterman, Alessio Nocentini, Claudiu T. Supuran, Meir Bialer
Among our current antiepileptic armamentarium as well as among the AEDs in development there are drugs containing carbamate or sulphonamide moieties in their chemical structure. Felbamate is a carbamate that exhibits a broad anticonvulsant activity and has been on the market since 1993. However, currently, it is seldom used due to the fatal aplastic anaemia and hepatotoxicity that is associated with its therapy16,17. Two additional carbamates, carisbamate, and cenobamate completed phase III clinical trials and their new drug application (NDA) were submitted to the Food and Drug Administration (FDA). Carisbamate regulatory application was withdrawn in 2010, due to lack of consistent efficacy across a clinically-relevant dose range18–19. Two cenobamate well-controlled studies demonstrated statistically significant reduction in seizure frequency as well as high responder rates, including seizure freedom, in patients with uncontrolled partial seizures treated with cenobamate for up to 18 weeks18–22. Due to three reported cases of drug reaction with eosinophilia and systemic symptoms (DRESS) in patients exposed to cenobamate, a large Phase III open-label study took place to evaluate the long-term safety of cenobamate when using a lower starting dose (<100 mg) and slower titration rate in order to mitigate the serious coetaneous reactions (e.g. DRESS)22. Subsequently, cenobamate-NDA submission was accepted by the FDA on 4/2/2019 and its Prescription Drug User Fee Act (PDUFA) date is set for 21/11/201923.
A viewpoint on rational and irrational fixed-drug combinations
Published in Expert Review of Clinical Pharmacology, 2018
Barbara Błaszczyk, Barbara Miziak, Piotr Czuczwar, Ewa Wierzchowska-Cioch, Ryszard Pluta, Stanisław J. Czuczwar
As already indicated earlier, co-administration of lamotrigine with CBZ was totally unfavorable. When LTG was combined with a close analog of CBZ, oxcarbazepine, the final outcome was even worse in that not only anticonvulsant antagonism was found for the dose ratio of 1:1, but the neurotoxic synergy as well [49]. For additional dose ratios (1:3, 3:1), still the final result was negative but at least the anticonvulsant antagonism was replaced by additivity. An antagonistic anticonvulsant interaction was noted for the combined treatment of oxcarbazepine with felbamate for the three standard dose ratios. The anticonvulsant antagonism was associated with neurotoxic additivity. In no case, pharmacokinetic mechanisms could be responsible for the above interactions among newer AEDs (Table 3) [49].
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Since 1975, the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, through its Antiepileptic Drug Development (ADD) Program, has collaborated with the pharmaceutical industry and academic individual in developing new therapeutic agents for the treatment of seizure disorders16. The program has made important contributions to the development of several FDA-approved drugs for epilepsy, including felbamate (Felbatol), topirimate (Topamax), lacosamide (Vimpat), and retigabine (Potiga)17. In the ADD program, maximal electroshock seizure (MES) and chemical induced seizures (scPTZ) along with toxicity screen (rotorod in mice, positional sense and gait in rats) are employed to screen the new anticonvulsants, which gradually became the most widely used animal models world-wide for the discovery of new anticonvulsant drugs at the initial stage18–20. Except the in vivo models, some mechanistically related in vitro methods are also used to evaluate the anticonvulsant potential via obtaining the compound’s affinity with excitatory (glutamate), inhibitory (GABA) receptor and other related enzymes21,22.