Anticonvulsant profile and teratogenicity of 3,3‐dimethylbutanoylurea: A potential for a second generation drug to valproic acid

Abstract

SUMMARYPurpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential secondgeneration drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. The development of new antiepileptic drugs (AEDs) continues to be a major goal for both industry and Results: DBU emerged as the most potent compound having an MES-ED 50 of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED 50 of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED

Antiepileptic drugs and pregnancy outcomes

“…Bialer and colleagues utilized pharmaco- and toxico-kinetic considerations in designing various derivatives of VPA that are more potent as anticonvulsants and have the potential to be non-teratogenic and non-hepatotoxic [Bialer, 1999]. In a comparative teratogenicity studies several VPA analogs and stereoisomers were tested on mice showing variable teratogenic potential dependent on the chemical structure [Kaufmann et al, 2010; Pessah et al, 2010; Shimshoni et al, 2008; Sobol et al, 2006]. A number of hypotheses have been set forward in an attempt to elucidate the mechanism by which VPA disrupts embryonic development.…”

Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice

“…1b). We, therefore, suggest that the large variations in the seizure-inducing and lethal doses of picrotoxin reported in the literature (Cymerblit-Sabba and Schiller 2010; Klaassen et al 2006;Makinson et al 2014;Shimshoni et al 2008) are caused by variations in the time different laboratories take from preparing picrotoxin solutions to dosing animals. We recommend that picrotoxinin solutions always be freshly prepared immediately before dosing animals.…”

“…Another fact that puzzled us is that the reported seizure-inducing and lethal doses for picrotoxin, roughly 50% of which is the active picrotoxinin, vary so widely in the literature. Picrotoxin doses administered intraperitoneally to induced seizures in animal models range from as low as 0.1 mg/kg to doses as high as 30 mg/kg in mice or rats (Cymerblit-Sabba and Schiller 2010; Klaassen et al 2006), but average between 3-10 mg/kg (Makinson et al 2014;Shimshoni et al 2008). The reported LD 50 s vary from 3 to 50 mg/kg (Pericic and Bujas 1997;Pericic et al 2000;Szabo et al 1984).…”

Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder

“…VCD has 3–10 times more potent anticonvulsant activity than VPA in different animal models (Bialer and White, 2010; Bialer and Yagen, 2007; Isoherranen et al, 2003; Shekh-Ahmad et al, 2013; Shimshoni et al, 2008; Wlodarczyk et al, 2015). Racemic-VCD also has shown efficacy in BD mania in a double-blind controlled Phase IIa clinical trial as add-on to risperidone (Bersudsky et al, 2010), and in a Phase IIb study as monotherapy on patients who remained on the drug (Bialer et al, 2015).…”