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Evaluation of Associated Behavioral and Cognitive Deficits in Anticonvulsant Drug Testing
Published in Steven L. Peterson, Timothy E. Albertson, Neuropharmacology Methods in Epilepsy Research, 2019
The protective index (PI) is a numerically expressed measure of the relative safety of a drug, i.e., separation between the anticonvulsant (desired) and neurotoxic (undesired) effects of a given antiepileptic drug.8 This value is calculated according to the following equation:
Cannabis and Epilepsy
Published in Journal of Dual Diagnosis, 2020
In 1949, Davis et al. described one of the earliest clinical trials using THC in the treatment of five children with epilepsy, in which two isomeric THC homologs were tested (Davis & Ramsey, 1949). The modern scientific investigations into the use of cannabinoids in treating epilepsy began to gain greater interest in the 1970s. In 1975, in a case report, Consroe and Buchsbaum described successfully controlling seizures in a 24-year-old when smoking marijuana was added to using phenobarbital and phenytoin (Consroe, Wood, & Buchsbaum, 1975). Several experiments in the 1970s and 1980s described the antiepileptic properties of various cannabinoids. In 1976, a study described anticonvulsive potencies of various cannabinoids in the maximal electroshock test and bar-walk test. In order of potency, these cannabinoids were listed as 11-hydroxy-THC (14 mg/kg) > delta-8-THC (83 mg/kg) > delta-9-THC (101 mg/kg) > CBD (118/mg/kg) > CBN (230 mg/kg; Karler & Turkanis, 1976). The protective index (comparison of therapeutic effect to underlying toxicity) was thought to be highest with CBD, and it was comparable to phenobarbital. In 1977, Consroe et al. described the proconvulsant effects of low-dose THC on a population of New Zealand white rabbits. These seizures were later controlled with carbamazepine, diazepam, and phenytoin and, surprisingly, with CBD (Consroe, Martin, & Eisenstein, 1977). Because of the lack of toxicity and anticonvulsant properties seen in these early studies, this led to further investigation into the use of CBD as an antiepileptic in the following decades.
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Recently, a series of benzo[d]oxazoles containing triazole were designed and synthesised as new anticonvulsant agents. The pharmacology results showed that most compounds exhibited anticonvulsant activity in MES and Sc-PTZ models. Among them, compound 19 (Figure 5) was the most potent with ED50 value of 11.4 and 31.7 mg/kg in MES and Sc-PTZ models, respectively. The TD50 value of 19 was 611.0 mg/kg, which resulted in the protective index (PI) value of 53.6 and 19.3. Further, the pre-treatment of thiosemicarbazide (an inhibitor of γ-aminobutyric acid synthesis enzyme) significantly decreased the activity of 19 in MES, which suggested that the GABAergic system may contribute at least in part to the anticonvulsive action53. Meanwhile, another series of triazole-containing benzo[d]oxazoles were prepared via altering the position of triazole. In this study, compound 20 was obtained with an ED50 of 12.7 mg/kg and 29.5 mg/kg in MES and Sc-PTZ models, respectively. The rotarod test showed the TD50 of 491.0 mg/kg for 2054.
Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates
Published in Expert Opinion on Therapeutic Patents, 2019
Barnali Maiti, Balamurali M M, Kaushik Chanda
The patent mentioned in this manuscript only described about processes for the synthesis of rufinamide and intermediates thereof. Since it is already having US FDA approval in 2008, so all the patent processes described in the literature mainly discussed about the different synthetic routes. The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown[18]. Rufinamide is used as a drug for the treatment of epileptic disorders. In general, it acts by slowing down the activation of sodium channels and thus negatively influences the sodium-dependent action potentials in neurons[19]. This also helps in the prediction of efficacy towards determining the seizure types and epileptic syndromes. As indicated by patch clamp technique, rufinamide acts on the inactive sodium ion channels and slows down its activation [3,20]. This might help to block the spread of seizure activity in epileptogenesis. The results of in vitrostudies suggest that rufinamide may prolong the inactive state of plasma membrane sodium channels. In vitro studies have shown that rufinamide reduces the frequency of sodium-dependent actions potentials in the neurons of animal models. This could aid to block the spread of seizure activity during epileptogenisis. Rufinamide did not significantly interact with a number of neurotransmitter systems, including GABA, benzodiazepine, monoaminergic and cholinergic binding sites, NMDA, and other excitatory amino acid binding sites. In vivo anti-convulsant studies examined the ability of rufinamide to suppress both electrically and chemically induced seizures as well as partial seizures. Following oral or intraperitoneal administration, rufinamide potently suppressed maximal electroshock-induced seizures. Rufinamide was also effective, but comparably less potent, in antagonizing chemically induced clonic seizures. The protective index and safety ratio of rufinamide were comparable to or better than other Antiepileptic drugs.