Valnoctamide (VCD) (Fig. 1) is a central nervous system (CNS)–active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA) that exhibits stereoselective pharmacokinetics (PK) in humans and animals (Barel et al., 1997; Bialer & Yagen, 2007; Bialer, 2012). sec-Butyl-propylacetamide (SPD) (Fig. 1) is a one-carbon homolog of VCD (White et al., 2012). Both VCD and SPD possess two chiral centers in their chemical structure. VCD (racemate) was commercially available as an anxiolytic drug (Nirvanil) in several European countries from 1964 until as recently as 2005 (Bialer & Yagen, 2007; Bialer & White, 2010). VCD is now being developed for the treatment of patients with bipolar disorder and also has a potential in epilepsy and neuropathic pain (Bersudsky et al., 2010; Bialer et al., 2013).
sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20–60 min after seizure onset. When administered 20 and 40 min after SE onset, SPD (100–174 mg/kg) produced long-lasting efficacy (e.g., 4–8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20–60 min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .
Valnoctamide (VCD) [racemate and/or two of its individual stereoisomers: (2R,3S)-VCD and (2S,3S-VCD)] demonstrated activity in various anticonvulsant models in mice (maximal electroshock seizure [MES], subcutaneous pentylenetetrazole [Metrazol; scMet], and 6 Hz) and rats (MES and scMet) (Isoherranen, 2003; Bialer & Yagen, 2007; Kaufmann et al., 2010). In all these anticonvulsant tests, VCD (racemate or individual stereoisomers) was 3–16 times more potent than VPA. The rat (oral) MES-median effective dose (ED50) values were 29 mg/kg (racemic-VCD), 34 mg/kg [(2R,3S)-VCD], and 64 mg/kg [(2S,3S)-VCD], and the rat-scMet- ED50 values were 54 mg/kg (racemic-VCD), 11 mg/kg [(2R,3S)-VCD], and 33 mg/kg [(2S,3S)- VCD] (Kaufmann et al., 2009; Bialer et al., 2010; Kaufmann et al., 2010; Bialer et al., 2013).
SPD's wide anticonvulsant activity (compared to VCD and VPA) in various rodent epilepsy models, including MES, 6 Hz psychomotor, subcutaneous pentylenetetrazole, picrotoxin, bicuculline, audiogenic, and corneal and hippocampal kindled seizures are presented in Table 1 (White et al., 2012).
|Anticonvulsant test||SPD-ED50 (95%CI) (mg/kg)||VCD-ED50 (95%CI) (mg/kg)||VPA-ED50 (mg/kg)|
|Frings audiogenic seizures||20 (18–22)||–||155 (110–216)|
|Maximal electroshock seizure (mice-MES)||71 (55–90)||58 (41–71)||263 (237–282)|
|Maximal electroshock seizure (rats- MES)||ip: 20 (15–27) po:29 (1–53)||po:29 (19–38)||po:484 (324–677)|
|Pentylenetetrazole-induced seizure (mice-scMet)||62 (47–71)||32 (22–45)||220 (177–268)|
|Pentylenetetrazole-induced seizure (rats-scMet)||18 (13–25)||po:54 (46–63)||po:646 (466–869)|
|Picrotoxin-induced seizure (mice-Pic)||17 (9–28)||–||270 (186–356)|
|Bicuculline-induced seizure (mice-Bic)||94 (87–103)||–||589 (470–765)|
|Pilocarpine-induced status epilepticus (SE) at 0 min post-SE onset||8/8 protected at 65 mg/kg||40 (30–65)||366 (23–575)|
|Pilocarpine-induced status epilepticus (SE) at 30 min post-SE onset||84 (62–103)||0/8 at 80 mg/kg||0/8 at 300 mg/kg|
|Hippocampal kindled rats||19 (13–28)||~40||–|
|6 Hz-32 mA (mice)||27 (24–30)||37 (26–50)||126 (95–152)|
|6 Hz -44 mA (mice)||45 (40–49)||67 (61–72)||310 (258–335)|
|Mice-neurotoxicity (TD50)||88 (81–95)||81 (72–87)||398 (356–445)|
|Rat-neurotoxicity (TD50)||ip: 49 (43–55) po: 131 (94–175)||po:58 (47–66)||po:784 (503–1176)|
Activity in Benzodiazepine-Resistant Status Epilepticus
Benzodiazepines such as diazepam are generally considered first-line therapy. Traditional antiepileptic drugs (AEDs) including phenytoin and VPA, are second-line therapy for refractory status epilepticus (White et al., 2012). The anesthetics propofol and pentobarbital provide a third-line of therapy. First- and second-line therapies often do not suppress electrographic SE (ESE), and third-line therapies cannot be administered in the field (Pouliot et al., 2013). Therefore, a pressing need exists for novel AEDs to treat refractory SE.
The use of nerve agents for experimentation is highly restricted and limited to specific research sites, and nerve agents cause diverse systemic effects that can confound quantitative analyses of drug actions on repetitive seizures and ESE (McDonough et al., 2000). A widely used approach involves a single-dose intraperitoneal treatment with pilocarpine, preceded by lithium. Accordingly, electrographic activity after lithium-pilocarpine treatment has thus been used to model the severe ESE that can result from nerve-agent exposure (Lehmkuhle et al., 2009; Pouliot et al., 2013). Because it is well-established that nonconvulsive SE can persist after aggressive pharmacologic treatment, prolonged and continuous electroencephalography (EEG) recording has become increasingly important in the diagnosis of ESE (Bautista et al., 2007). The need to analyze the effects of potential therapeutic agents on ESE led to the development of an algorithm to quantify ESE activity (Lehmkuhle et al., 2009).
SPD was evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-d-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using Fluoro Jade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10–14 days post SE using the Morris water maze (White et al., 2012).
SPD was highly effective and displayed a wide protective index (PI = median toxic dose [TD50]/ED50) in the standardized seizure and epilepsy models employed (Table 1). The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the behavioral rat pilocarpine model of SE when administered 30 min after the induction of SE in rats. SPD-ED50 against convulsive SE in this model was 84 mg/kg, whereas VCD (80 mg/kg) and VPA (300 mg/kg) were inactive when given 30 min after SE onset (White et al., 2012). SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the Morris water maze test, which was associated with its antiseizure effect against pilocarpine-induced SE. SPD (130 mg/kg) strongly suppressed ESE when given 30 min after seizure onset, but not at 60 min. However, higher SPD dose (180 mg/kg) profoundly suppressed ESE similar to propofol (100 mg/kg) and pentobarbital (30 mg/kg). VCD (180 mg/kg) was also efficacious in suppressing ESE 30 min after seizure onset (Pouliot et al., 2013).
When administered 20 and 40 min after SE onset, SPD (100–174 mg/kg) produced long-lasting efficacy (e.g., 4–8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. When SPD dissolved in multisol (propylene glycol: alcohol and water for injection 5:1:4) was administered 20 min after soman-induced SE in rats, its ED50 value was 71 mg/kg and the seizure termination latency was 6.8 min. SPD-ED50 values in guinea pigs were 67 mg/kg and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively (White et al., 2012).
A stereoselective PK analysis of VCD was previously described and is summarized in the EILAT X conference manuscript (Bialer et al., 2010).
SPD PK was studied following intraperitoneal administration (60 mg/kg) to rats of racemic SPD. SPD had the following PK parameter: clearance (CL) 0.3 L/h that was mainly metabolic, given that only 0.1% of SPD dose or CL was excreted unchanged in the urine. In rats SPD displayed a sevenfold higher CL than VCD, and owing to its higher lipophilicity SPD volume of distribution (V) was 3 times more than that of VCD (White et al., 2012). As a consequence of these opposite trends in CL and V, SPD half-life was similar to that of VCD. The dose was chosen as the intermediate SPD dose among various ED50 values.
The relationship between SPD PK profile and its efficacy against soman-induced SE (pharmacodynamics, PD) was evaluated following racemic SPD (60 mg/kg, i.p.) administration in the soman SE rat model. A PK-PD correlation showed that SPD effective plasma levels in the soman-induced SE model ranged from 8 to 40 mg/L (20 min postseizure onset) and 12–50 mg/L (40 min postseizure onset). The time to peak effect (PD-tmax) occurred after the PK-tmax and may indicate slow distribution of SPD to the extraplasmatic active site responsible for SPD activity. This slower distribution to the active site may contribute to the fact that SPD effect (expressed as responders' rate) declined significantly slower than SPD plasma levels and in few rats (at the 20 min postseizure onset group) lasted for 24 h.
Ongoing and Planned Studies
Although VPA is the most prescribed AED, its clinical use is restricted in women of childbearing age and in children due to its teratogenicity and hepatotoxicity, respectively (Bialer & Yagen, 2007). Recently, a successful double-blind controlled phase IIa clinical trial with VCD racemate in patients with mania funded by the Stanley Medical Research Institute (SMRI) was completed (Bersudsky et al., 2010; Bialer et al., 2010). This study showed that VCD could be an important substitute to VPA in women of childbearing age with bipolar disorder.
The development of VCD and its introduction as a new nonteratogenic and potentially nonhepatotoxic new CNS agent that is more potent than VPA, may offer a suitable solution for these clinical needs and for the treatment of therapy-resistant patients with bipolar disorder, epilepsy, and neuropathic pain (Bialer & White, 2010). Following the successful phase IIa clinical trial, VCD is currently undergoing a 3-week (SMRI-funded) phase IIb, randomized, double-blind, placebo- and risperidone-controlled, multicenter study of 300 patients with bipolar manic episodes. The study is a three-arm monotherapy parallel group trial: placebo (n = 120), VCD (n = 120; 1,500 mg/day) and risperidone (n = 60; up to 6 mg/day). The study's major objective is to evaluate the efficacy of VCD compared to placebo in patients with acute manic or mixed episodes. The role of risperidone in the trial is as an active control to ascertain the trial's validity (Bialer et al., 2013).
Because SPD and VCD are chiral compounds with two stereogenic centers there are currently ongoing studies to comparatively evaluate the pharmacokinetics and anticonvulsant activity including pilocarpine- and soman-induced SE of each of the four individual stereoisomers of SPD and VCD.
The results demonstrate that SPD and VCD are a broad-spectrum antiseizure compounds that block SE induced by pilocarpine and soman. SPD affords in vivo neuroprotection that is associated with cognitive sparing. The activity of SPD and VCD against SE is superior to diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement. SPD activity at 30 and 60 min after seizure onset in the pilocarpine-induced SE and at 20 and 40 min after seizure onset in the soman-induced SE models differentiates SPD from benzodiazepines and all current AEDs. The fact that SPD's one-carbon homolog VCD is currently phase IIb shows that SPD has a potential beyond its parenteral antinerve gas and anti-SE activity for benzodiazepine-resistant SE.
The authors thank Dr. Tracy Chen, Dr. Jeff Jiang, and Mr. James P. Stables of the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH–NINDS) Anticonvulsant Screening Program (ASP) for testing the compounds in their anticonvulsant program. This work is abstracted from the PhD thesis of Mr. Tawfeeq Shekh-Ahmad in a partial fulfillment for the requirements of a PhD degree at The Hebrew University of Jerusalem.
The authors have no conflict of interest to declare in relation to this paper.
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