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Anticonvulsant Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
The dione anticonvulsants, paramethadione (Paradione) and trimethadione (Tridione) were used primarily for the treatment of petit mal seizures, and is indicated for the of petit mal seizure control that are refractory to other drug treatments. The association between trimethadione and malformed newborns was published in 1970 (German et al., 1970). Following this 1970 report, numerous reports of fetal malformations associated with maternal dione use were published. A review of 65 in utero exposures to either trimethadione or paramethadione was summarized in the statement: “a normal child resulting from such a pregnancy is the exception” (Kelly, 1984). No controlled studies have been published of birth defects following exposure during embryogenesis with either of these agents. However, a distinct syndrome has been described for trimethadione (Zackai et al., 1975), termed the “trimethadione syndrome” (Box 9.5). Note that this syndrome differs from the hydantoin and carbamazepine syndromes only in the absence of distal digital hypoplasia (Kelly, 1984). Dione anticonvulsants are contraindicated for use during pregnancy.
Generalized Epilepsies
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
A combination of VPA with ESM may be effective in patients who are not absence-free with VPA alone (83,84). Monotherapy with ESM should be considered in young children and women of child-bearing age if seizures are limited to absences with regular 3/s spike-and-wave complexes in order to avoid rare fatal hepatotoxicity and teratogenic effects. Treatment with trimethadione (TMO) is reserved for patients whose seizures have proved resistent to all other drugs, since TMO is associated with a relatively high incidence of adverse effects including hemeralopia, photophobia, sedation, nephrotic syndrome, hematopoetic toxicity (85,86), and teratogenic effects (87,88).
Neuronal Networks in Convulsant Drug-Induced Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Effects of clinically used anticonvulsants on SN neuronal activity also have been examined. Sodium valproate given systemically produced a marked reduction in spontaneous firing of SN neurons, and iontophoretically applied sodium valproate enhanced the inhibitory effects of GABA and muscimol iontophoresis on SN neurons.45 Systemic administration of effective anticonvulsant doses of phenytoin or carbamazepine did not affect SN neuronal firing, while phenobarbital or valproic acid produced small firing decreases at highest doses. Pentobarbital, which is not a clinically useful anticonvulsant, produced a marked reduction in SNR neuronal firing rate.46 As pointed out by the authors, however, the doses of these anticonvulsants were high relative to the antiepileptic doses of these agents, and we cannot be sure of the relevance of these actions on SN neurons to the anticonvulsant effectiveness of these agents. Trimethadione, a drug used to treat absence epilepsy, produced a dose-dependent decrease in SNR neuronal firing, but another drug used in the absence epilepsy, ethosuximide, markedly enhanced the firing of these neurons.46 It was suggested that the anticonvulsant activity of these drugs does not correlate well with their effect on nigral neurons.
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Since the discovery of the first anticonvulsant bromide in 1857, a large number of anticonvulsants were developed and approved for epilepsy treatment: phenobarbital, phenytoin, primidone, methsuximide, methazolamide, ethotoin, diazepam, trimethadione, sodium valproate, clonazepam, clobazam, carbamazepine, acetazolamide, valproic acid, felbamate, fosphenytoin, gabapentin, lamotrigine, lacosamide, levetiracetam, oxcarbazepine, stiripentol, vigabatrin, zonisamide, rufinamide, retigabine, and so on10–12. For patients with epilepsy, a single medication is recommended initially13. But there are about half of seizures could not be controlled by using a single medication (monotherapy), then polytherapy with multiple anticonvulsants is recommended14. Unfortunately, about 30% of people continue to have seizures despite anticonvulsants treatment15, and the side effects of anticonvulsant agents follow up. Until now, the existing drugs are far from ideal, being consistently effective in fewer than 70% of patients and tending to produce a variety of side-effects in more than 50% of patients8. Toxicity, intolerance, and a lack of efficacy represent the limitations of the available anticonvulsants, which stimulated the continual attempts for discovery of new anticonvulsants.
Lessons learned from the discovery of sodium valproate and what has this meant to future drug discovery efforts?
Published in Expert Opinion on Drug Discovery, 2020
Slobodan M. Janković, Snežana V. Janković
Anticonvulsant activity of valproic acid was serendipitously discovered after testing on pentylenetetrazole-induced seizures in mice, an early animal model of generalized epilepsy used for screening of many potential anticonvulsants [13]. PTZ is an antagonist of gamma-aminobutyric acid A (GABAA) receptor, and when given to normal mice or rats, produces a myoclonic seizure that was considered as a model of nonconvulsive, generalized seizures in humans, especially absence (PTZ-induced seizures are blocked by trimethadione, the drug once used for the treatment of absence seizures, and by phenobarbital, ethosuximide and valproate, while phenytoin and carbamazepine are not active in this sense). Although the PTZ-induced seizures model was developed more than 70 years ago (in 1944), it is still used today for screening substances with anticonvulsant effect because it is simple, inexpensive, gives immediate results and predicts clinical activity of a substance [14]. PTZ is administered subcutaneously, and then seizure severity (according to the Racine’s scale, from 1 to 5) and seizure latency are measured [15,16]. However, after numerous studies in the past we know now that the PTZ-induced seizures in rodents are not a predicting mechanism of action or clinical utility of a substance, but rather a general proconvulsive potential and ability to penetrate the blood-brain barrier; lamotrigine, which does not have GABA receptor blocking properties, is active against absence (spike-and-wave) seizures, and vice versa, enhancers of GABA-transmission, gabapentin, tiagabine and phenobarbital, aggravate absence seizures [17]. In addition, during development of levetiracetam, the PTZ-test failed to discover anti-convulsant property of this drug. Therefore, the PTZ-test as a screening tool, within the large-scale random screening approach, should be used with caution and accompanied by additional animal models (e.g. gamma-butyrolactone test, lethargic mouse test, etc.) more elaborate and difficult to perform, but with more mechanisms of action, specific and less likely to miss substances with true anticonvulsant properties [17]. When performing the PTZ and other animal tests for screening of anticonvulsant properties, stimuli should be just above the individual seizure threshold for each animal; if the stimuli of higher intensity are used, sensitivity of the test is lost and some anticonvulsants could be missed, e.g. this would happen to valproate, too [18].