Broad Spectrum Of Anticonvulsant Activity Research Articles

Probable Topiramate-Induced Hemiparesis

1It is also indicated for migraine prophylaxis in adults. 1,2 An off-label use of topiramate is as a mood stabilizer (with no associated weight gain) in rapid-cycling and mixed bipolar episodes. 3-7 The mechanisms of action of topiramate suggest a broad spectrum of anticonvulsant activity, including blockade of voltage-gated sodium and calcium channels, increase in inhibitory transmission via enhancement of -aminobutyric acid‐stimulated chloride currents, decrease in excitatory transmission via blockade of the adenosine monophosphate-kainate subtype of the glutamate receptor, and weak inhibition of carbonic anhydrase. 8-11 Despite the benefits of topiramate as listed above, includ ing weight neutrality, patients are still prone to discontinue their medications. This problem is highly prevalent among patients with mental health conditions, most notably schizophrenia and bipolar disorders. In particular, patients may abruptly discontinue their antiepileptic medications secondary to experiencing adverse effects, even if they have been made aware of the poten tial for such adverse effects through education provided by a pharmacist. Prescribers and other health care providers must be aware of potential adverse effects that may arise with the commencment and maintenance of antiepileptic therapy.

Anticonvulsant and Neurotoxicity Evaluation of Some N4 Phenyl Substituted Pyridyl Semicarbazones

A series of 4-aryl substituted semicarbazones of pyridyl carbaldehyde and pyridyl methyl ketone were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. The structure of synthesized compounds were confirmed by IR spectroscopy, PMR spectroscopy and nitrogen estimation. All the compounds were evaluated for anticonvulsant activity and neurotoxicity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. Majority of compounds exhibited significant anticonvulsant activity after intraperitoneal administration. The results obtained showed that 85.7 % of the compounds afforded protection in the MES test and 64.2 % of the total compounds afforded protection in ScPTZ test. Some of them also showed good activity after oral administration. In this study (Methyl-4- pyridyl) ketone -N(4)- (p- chloro phenyl) substituted semicarbazone emerged as most active derivative showing activity at 100 mg/kg in both the test with prolonged duration of action. In the present study semicarbazones of pyridyl containing carbonyl compounds emerges as the lead molecule, showing broad spectrum of activity with low neurotoxicity and prolong duration of action on oral administration. Thus these may be utilized for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity.

Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.

Microwave-assisted synthesis, anticonvulsant activity and quantum mechanical modelling of N-(4-bromo-3-methylphenyl) semicarbazones

To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. A series of twenty-six compounds of N(4)-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electroshock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.

Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide

N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.

Antiepileptic Drugs: All Ages

Antiepileptic Drugs: All Ages

Zonisamide: A new drug for epilepsy therapy

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.

The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on NMDA receptor-mediated EPSCs

The N-methyl- d-aspartate (NMDA) receptor-gated ion channel is comprised of at least one NR1 subunit and any of four NR2 subunits (NR2A–D). The NR2 subunit confers different pharmacological and kinetic properties to the receptor. CGX-1007 (Conantokin G), a 17-amino acid polypeptide isolated from the venom of Conus geographus, is a novel NMDA receptor antagonist that is thought to be selective for the NR2B subunit. CGX-1007 has been reported to have highly potent, broad-spectrum anticonvulsant activity in animal seizure models. CI-1041 is an investigational compound, which also possesses anticonvulsant activity and has been shown to be highly selective for NR2B containing NMDA receptors. Although both CI-1041 and CGX-1007 are reportedly NR2B specific antagonists, they differ in their ability to block amygdala-kindled seizures, suggesting that the mechanism of action of these compounds differs. The present study was designed to test the hypothesis that CI-1041 and CGX-1007 would differentially modulate the function of NMDA receptors at excitatory synapses. Using the whole cell patch clamp technique, CGX-1007 and CI-1041 were found to block CA1 pyramidal cell, NMDA receptor-mediated excitatory postsynaptic currents (N-EPSCs) in a concentration-dependent manner in hippocampal slices from P4–P6 animals. In contrast, only CGX-1007 decreased NMDA receptor-mediated EPSC peak amplitude in slices from adult animals. The CGX-1007 block of peak amplitude was accompanied by a similar concentration-dependent decrease in decay kinetics of NMDA receptor-mediated EPSCs. These results suggest that while CI-1041 may be selective for NMDA receptors containing the NR2B subunit, CGX-1007 appears to be less selective than previously reported.

Nifedipine affects the anticonvulsant activity of topiramate in various animal models of epilepsy

Topiramate (TPM), a new generation antiepileptic drug was investigated for its anticonvulsant effects in various models of genetically determined and chemically induced epilepsy in rodents. In addition, based on recent electrophysiological data suggesting that TPM may interact with L-type Ca 2+ channels, we evaluated the effects of a concomitant administration of L-type Ca 2+ channel modulators on TPM’s antiepileptic properties. TPM, dose-dependently, protected against audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose of L-type Ca 2+ channel antagonists nifedipine or verapamil or with the L-type Ca 2+ channel agonist, S(−)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was able to increase the ED 50 for this drug. TPM also protected against seizures induced by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4-aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not significantly modified by nifedipine. TPM, dose-dependently, reduced the number and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and lethargic ( lh/ lh) mice, two genetic models of absence epilepsy. Nifedipine decreased TPM’s activity in WAG/Rij rats but paradoxically enhanced it in lh/ lh mice, whereas Bay k 8644 displayed opposite effects in both absence models. These results confirm TPM’s broad spectrum of anticonvulsant activity and support the proposal that a modulation of neuronal L-type Ca 2+ channel activity plays an important role in its antiepileptic activity.

Metabolism of a new antiepileptic drug, N-methyl-tetramethylcyclopropanecarboxamide, and anticonvulsant activity of its metabolites

N-methyl-tetramethylcyclopropanecarboxamide (MTMCD) is a new antiepileptic drug (AED) structurally related to valproic acid (VPA) that has a broad spectrum of anticonvulsant activity including models of therapy-resistant epilepsy. The purpose of this study was to identify in vivo metabolites of MTMCD that could contribute to its anticonvulsant efficacy. The metabolism of MTMCD was studied in mice, in human liver microsomes (HLM), and in recombinant human CYP isoforms with focus on formation of the hydroxylation product, N-hydroxymethyl-tetramethylcyclopropanecarboxamide (OH-MTMCD) and the N-demethylation product tetramethylcyclopropanecarboxamide (TMCD). The anticonvulsant activity of MTMCD’s metabolites was evaluated in the maximal electroshock (MES), subcutaneous metrazole (s.c. Met), and in the 6 Hz model in mice. In mice, OH-MTMCD was identified as a phase I metabolite of MTMCD and detected in plasma and brain after administration of MTMCD. In human liver microsomes MTMCD was biotransformed to OH-MTMCD but not to TMCD. Chemical inhibition studies suggested that MTMCD hydroxylation is mainly mediated by CYP 2A6 and CYP 2C19, which was confirmed using cDNA-expressed P450 isozymes. OH-MTMCD was a broad-spectrum anticonvulsant and possessed significant anticonvulsant activity in mouse models of partial and generalized seizures (ED 50 values 75–220 mg/kg), but was less potent than MTMCD. As OH-MTMCD was also present at lower concentrations than MTMCD in mouse brain, it is likely that MTMCD itself and not one of its metabolites is responsible for its activity in therapy-resistant epilepsy.

Preclinical evaluation of anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4-tetrahydroquinoline

Anticonvulsant activity of N-(p-aminobenzoyl)-1,2,3,4- tetrahydro-quinoline (NTQ), a newly synthesized ameltolide analog, was investigated with regards to efficacy and toxicity in mice. Additionally, its effect on NMDA receptors was also performed on NR1a/NR2B expressed in Xenopus oocytes. NTQ, given intraperitoneally, was able to protect the animals in both maximal electroshock seizure and pentylenetetrazole (PTZ) tests, while ameltolide was effective only in the MES. NTQ was less potent than ameltolide, exhibiting the median effective dose (ED50) of 13.33 mg/kg body weight (B.W.), whereas the corresponding value of ameltolide was 0.96 mg/kg B.W. Ameltolide seemed to possess better safety profile than NTQ as indicated by the relative safety margin (LD50/ED50) of 65.28 for ameltolide and 44.97 for NTQ. Furthermore, based on the finding that the median neurotoxic dose (TD50) established by rotarod test was 37.28 and 7.18 mg/kg B.W. for ameltolide and NTQ respectively, ameltolide appeared to have more favorable protective index (TD50/ED50) than NTQ. Further experiment using Xenopus oocyte with NMDA receptor composing of NR1a and NR2B subunits was performed to probe for the effect of NTQ and ameltolide on NMDA-induced current. While NTQ and ameltolide did not induce any changes in current or a shift in membrane potential of oocyte, both of them significantly inhibited NMDA-induced current demonstrating the IC50 of 0.10 and 0.12 ?M respectively. Therefore, it is likely that inhibition of excitation of NMDA receptor may, at least in part, accounted for its anticonvulsant activity. In conclusion, the present study has identified NTQ as a broad-spectrum anticonvulsant agent, albeit its lower safety margin and protective index. Inhibition of NMDA receptor may partly contribute to anticonvulsant activity of these two compounds. Further structural modification of NTQ to improve its safety while preserving a broad-spectrum anticonvulsant activity should be carried out.

The Effects of ACTH and Adrenocorticosteroids on Seizure Susceptibility in 15-Day-Old Male Rats

Infantile spasms are generalized convulsive seizures seen in the first year of life. They respond poorly to conventional anticonvulsants, but are often controlled by adrenocorticotropic hormone (ACTH) therapy. Other childhood seizures are also responsive to ACTH. The present study tested the effects of ACTH and related adrenocorticosteroids in prepubertal, 15-day-old rats. Compounds were tested against minimal (scMET) and maximal (MMT) pentylenetetrazol seizures, maximal electroconvulsive shock (MES) seizures, and hippocampal kindled seizures. ACTH had no significant anticonvulsant effects against any type of seizure. Several of the adrenocorticoid hormones, however, had strong anticonvulsant effects. Deoxycorticosterone (DOC) and progesterone (P4) both significantly suppressed scMET, MMT, and MES seizures 15 min after s.c. injection. DOC and P4 also shortened hippocampal discharge duration in the kindling model, and DOC, but not P4, suppressed the kindled convulsion. Aldosterone and corticosterone were effective against scMET seizures, and aldosterone was effective against MMT seizures. Dexamethasone and dihydroepiandrosterone had no anticonvulsant activity. These findings indicate that the adrenal steroid precursors, DOC and P4, have a broad spectrum of anticonvulsant activity in animal seizure models. They may play a role in mediating the anticonvulsant effects of ACTH in human infants.

Anticonvulsant profile of valrocemide (TV1901): a new antiepileptic drug.

We sought to investigate the anticonvulsant activity of the new antiepileptic drug (AED), valrocemide or TV1901 (VGD) in various animal (rodent) models of human epilepsy to determine its anticonvulsant profile and safety margin. VGD was administered intraperitoneally to CF no. 1 mice and orally or intraperitoneally to Sprague-Dawley rats. The anticonvulsant activity of VGD was examined in nine different animal models of epilepsy for its ability to block electrically, chemically, or sensorily induced seizures. In mice VGD afforded complete protection against maximal electroshock (MES)-, pentylenetetrazole-, picrotoxin-, and bicuculline-induced seizures and 6-Hz "psychomotor" seizures with median effective dose (ED50) values of 151, 132, 275, 248, and 237 mg/kg, respectively. VGD was also effective in preventing sound-induced seizures in Frings audiogenic-seizure susceptible mice (ED50, 52 mg/kg). The median neurotoxic dose in mice was 332 mg/kg. After oral administration to rats, VGD was active in the MES test, with an ED50 of 73 mg/kg, and the median neurotoxic dose was 1,000 mg/kg. Intraperitoneal administration of 300 mg/kg of VGD to hippocampal kindled Sprague-Dawley rats blocked generalized seizures and shortened the afterdischarge duration significantly. VGD also provided complete protection from focal seizures in the corneally kindled rats (ED50,161 mg/kg). The results obtained in this study suggest that VGD has a broad spectrum of anticonvulsant activity and promising potential as a new AED.

Continuum Solvent Model Studies of the Interactions of an Anticonvulsant Drug with a Lipid Bilayer

Valproic acid (VPA) is a short, branched fatty acid with broad-spectrum anticonvulsant activity. It has been suggested that VPA acts directly on the plasma membrane. We calculated the free energy of interaction of VPA with a model lipid bilayer using simulated annealing and the continuum solvent model. Our calculations indicate that VPA is likely to partition into the bilayer both in its neutral and charged forms, as expected from such an amphipathic molecule. The calculations also show that VPA may migrate (flip-flop) across the membrane; according to our (theoretical) study, the most likely flip-flop path at neutral pH involves protonation of VPA pending its insertion into the lipid bilayer and deprotonation upon departure from the other side of the bilayer. Recently, the flip-flop of long fatty acids across lipid bilayers was studied using fluorescence and NMR spectroscopies. However, the measured value of the flip-flop rate appears to depend on the method used in these studies. Our calculated value of the flip-flop rate constant, 20/s, agrees with some of these studies. The limitations of the model and the implications of the study for VPA and other fatty acids are discussed.

New non competitive AMPA antagonists

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.

Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys

NW-1015 is a novel Na + and Ca 2+ channel blocker with broad spectrum anticonvulsant activity and an excellent safety margin. As the compound also shows sigma-1 receptor ligand properties it was deemed important to determine whether it possesses anticonvulsant properties in primates without causing behavioral and EEG abnormalities. Thus, the effects of NW-1015 on limbic electrically-induced afterdischarge (AD) were evaluated in four cynomolgus monkeys, and its activity compared to a single effective dose of phenytoin (PHT). The four male cynomolgus monkeys were chronically implanted for EEG recordings, from cortex and limbic structures. AD was induced in limbic areas by electrical stimulation. The effects of NW-1015 on the duration and the behavioral component of the AD were randomly tested at doses from 25 to 75 mg/kg and compared with the effects of PHT 50 mg/kg. Similarly to PHT, 50 mg/kg of NW-1015 significantly shortened the EEG AD and almost abolished AD elicited behavioral seizure. Only the behavioral effects of AD were reduced after administration of 25 mg/kg p.o. NW-1015 did not cause EEG or interictal behavioral alterations at doses up to 75 mg/kg p.o. These data further confirm the broad-spectrum anticonvulsant activity and a good safety profile of NW-1015 even in a primate model of complex partial seizures and suggest that its affinity for sigma-1 receptors is behaviorally irrelevant.

Sodium bromide: effects on different patterns of epileptiform activity, extracellular pH changes and GABAergic inhibition.

Results regarding the anticonvulsant potency of bromide have been questioned, and the mechanisms of its action are unclear. Using combined rat hippocampus-entorhinal cortex slices we analyzed the effects of NaBr on four types of epileptiform discharges in two different models of epilepsy, the low-Ca2+ and the low-Mg2+ model. NaBr concentration-dependently reduced the frequency and finally blocked the low Ca2+-induced discharges. Low Mg2+-induced short recurrent discharges were also reduced in a concentration-dependent manner. In the entorhinal cortex the frequency of seizure-like events was reduced by 3 and 5 mM and the discharges were blocked by 7 mM NaBr. Also, the late recurrent discharges in the entorhinal cortex which do not respond to most clinically employed anticonvulsants were reduced by concentrations of 10 and 15 mM and completely blocked by 30 mM NaBr. Using pH-sensitive microelectrodes different effects of NaBr were seen than those of acetazolamide on extracellular pH under control conditions and after stimulation. Acetazolamide at 1 mM caused a reversible acidification of delta pH: 0.2+/-0.14 at rest whereas no change on extracellular pH was seen with 5 mM NaBr. Acetazolamide increased the transient alkalosis induced by repetitive stimulation of the stratum radiatum in area CA1 and reduced the subsequent acidosis. NaBr also increased the alkalosis but had no effect on the subsequent acidosis. A significant increase in paired-pulse inhibition was seen in a paired-pulse stimulation protocol used to monitor the efficacy of GABAergic inhibition at concentrations of 5 mM NaBr. This finding was confirmed in whole-cell patch clamp recordings from cultured hippocampal neurons showing an increase in inhibitory postsynaptic current amplitude. In summary, our results suggest a broad-spectrum anticonvulsant activity which is likely to be caused by its effects on membrane excitability, by an increase in GABAergic inhibition and is less likely caused by its effects on extracellular pH.

Ganaxolone: a novel positive allosteric modulator of the GABAA receptor complex for the treatment of epilepsy

Ganaxolone is a member of a novel class of neuroactive steroids which modulates the GABAA receptor complex (GRC) via an unique recognition site, distinct from those of benzodiazepines and barbiturates. Preclinical data from an array of chemically- and electrically-induced seizure models demonstrate that ganaxolone possesses broad spectrum anticonvulsant activity with potential clinical utility in both generalised and partial seizures, as well as cocaine-induced seizures. Clinical data to date support a favourable safety profile with somnolence, an extension of GABAergic activity, being the most frequently reported adverse event at higher doses. Target indications include infantile spasms and complex partial seizures. Open-label data in paediatric patients with intractable epilepsy suggest that ganaxolone may be effective in treating infantile spasms. A controlled trial utilising an in-patient, monotherapy design demonstrated that ganaxolone effectively decreases complex partial seizure activity compared to placebo. An important area of further evaluation is ganaxolone’s potential role in the treatment of women with catamenial epilepsy.

Mechanism of action of the anticonvulsant felbamate: Opposing effects on N‐methyl‐D‐aspartate and γ‐aminobutyric acidA receptors

Felbamate is a promising new antiepileptic drug whose mechanism of action is unknown. In whole-cell voltage clamp recordings from cultured rat hippocampal neurons, clinically relevant concentrations of felbamate (0.1-3 mM) inhibited N-methyl-D-aspartate (NMDA) responses and potentiated gamma-aminobutyric acid (GABA) responses. Single-channel recordings indicated that the effect on NMDA responses occurred via a channel blocking mechanism. Felbamate is the first anticonvulsant drug with dual actions on excitatory (NMDA) and inhibitory (GABA) brain mechanisms. This unique combination of effects could account for felbamate's broad spectrum of anticonvulsant activity in animal seizure models and its distinctive clinical efficacy and safety profile.

A review of the animal pharmacology of clobazam: An update

Clobazam is a 1, 5-benzodiazepine with significant activity in preclinical tests predictive of potential clinical antianxiety activity. Clinical efficacy equivalent to diazepam has been established with minimal effects on psychomotor performance. Clobazam has also been found to have a broad spectrum of anticonvulsant activity with acceptable toxicity and to be active in suppressing aggressive behavior in rodents. This compound appears to have less of an effect on motor coordination, muscle tone, behavioral depression and hyporeflexia than standard reference compounds in various species as well as little or no apparent effect on memory and learning in animals and humans. The major metabolite, desmethylclobazam, is also an anxiolytic candidate approximately 10 times less potent than diazepam and a potent anticonvulsant with a complete lack of sedation. These compounds represent a new classification of pharmaceutical agents in which antianxiety and anticonvulsant effects can be achieved without sedative or depressive side effects.