Stereoselective Pharmacokinetics and Pharmacodynamics of Propylisopropyl Acetamide,a CNS-Active Chiral Amide Analog of Valproic Acid

Purpose. The purpose of this study was to evaluate there existed stereoselective effects in the pharmacokinetics, anticonvulsant activity, microsomal epoxide hydrolase (mEH) inhibition, and teratogenicity of the two enantiomers of propylisopropyl acetamide (PID), a CNS-active chiral amide analogue of valproic acid. Methods. Racemic PID, as well as the individual enantiomers, were intravenously administered to six dogs in order to investigate the stereoselectivity in their pharmacokinetics. Anticonvulsant activity was evaluated in mice (ip) and rats (oral), mEH inhibition studies were performed in human liver microsomes, and teratogenicity was evaluated in an inbred susceptible mice strain. Results. Following intravenous administration to dogs of the individual enantiomers, (R)-PID had significantly lower clearance and longer half-life than (S)-PID, however, the volumes of distribution were similar. In contrast, following intravenous administration of racemic PID, both enantiomers had similar pharmacokinetic parameters. In rats (oral), (R)-PID had a significantly lower ED₅₀ in the maximal electroshock seizure test than (S)-PID; 16 and 25 mg/kg, respectively. PID enantiomers were non-teratogenic and did not demonstrate stereoselective mEH inhibition. Conclusions. (R)-PID demonstrated better anticonvulsant activity, lower clearance and a longer half-life compared to (S)-PID. When racemic PID was administered, the clearance of (S)-PID was significantly reduced, reflecting an enantiomer-enantiomer interaction.     

Evaluation of the enantioselective antiallodynic and pharmacokinetic profile of propylisopropylacetamide, a chiral isomer of valproic acid amide

Propylisopropylacetamide (PID) is a chiral CNS-active constitutional isomer of valpromide, the amide derivative of the major antiepileptic drug valproic acid (VPA). The purpose of this work was: a) To evaluate enantiospecific activity of PID on tactile allodynia in the Chung (spinal nerve ligation, SNL) model of neuropathic pain in rats; b) To evaluate possible sedation at effective antiallodynic doses, using the rotorod ataxia test; c) To investigate enantioselectivity in the pharmacokinetics of (R)- and (S)-PID in comparison to (R,S)-PID; and d) To determine electrophysiologically whether PID has the potential to affect tactile allodynia by suppressing ectopic afferent discharge in the peripheral nervous system (PNS). (R)-, (S)- and (R,S)-PID produced dose-related reversal of tactile allodynia with ED(50) values of 46, 48, 42 mg/kg, respectively. The individual PID enantiomers were not enantioselective in their antiallodynic activity. No sedative side-effects were observed at these doses. Following i.p. administration of the individual enantiomers, (S)-PID had lower clearance (CL) and volume of distribution (V) and a shorter half-life (t(1/2)) than (R)-PID. However following administration of (R,S)-PID, both enantiomers had similar CL and V, but (R)-PID had a longer t(1/2). Systemic administration of (R,S)-PID at antiallodynic doses did not suppress spontaneous ectopic afferent discharge generated in the injured peripheral nerve, suggesting that its antiallodynic action is exerted in the CNS rather than the PNS. Both of PID's enantiomers, and the racemate, are more potent antiallodynic agents than VPA and have similar potency to gabapentin. Consequently, they have the potential to become new drugs for treating neuropathic pain.     

Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse

The role of AMPA and GluR5-containing kainate receptors in the development and expression of amygdala kindling was examined using the selective 2,3-benzodiazepine AMPA receptor antagonist GYKI 52466 [(1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine] and the decahydroisoquinoline mixed AMPA receptor and GluR5 kainate receptor antagonist LY293558 {(3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline- 3-carboxy lic acid)}. Administration of GYKI 52466 (5-40 mg/kg, intraperitoneally) and LY293558 (10-40 mg/kg, intraperitoneally) prior to daily kindling stimulation in mice produced a dose-dependent suppression of the rate of development of behavioral kindled seizure activity and reduced the duration of the stimulation-induced electrographic afterdischarge. In drug-free stimulation sessions after the initial drug-treatment sessions, there was an acceleration in the rate of kindling development compared with the rate during the preceding drug-administration period; the "rebound" rate was also greater than the kindling rate in saline-treated control animals. In fully kindled animals, both GYKI 52466 and LY293558 produced a dose-dependent suppression of evoked seizures (ED(50), 19.3 and 16.7 mg/kg, respectively). Although AMPA receptors appear to be critical to the expression of kindled seizures, since kindling development progressed despite the suppression of behavioral seizure activity, AMPA receptors are less important to the kindling process. LY293558 was modestly less effective at suppressing behavioral seizures during kindling and was not superior to GYKI 52466 in retarding the overall extent of kindling development, indicating that GluR5 kainate receptors do not contribute to epileptogenesis in this model.     

Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala

The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.     

The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.     

The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures

Modification of the rate of acquisition of the kindled amygdaloid seizure by the convulsants pentylenetetrazol, bicuculline and strychnine was studied. Injections of saline, 25 mg/kg of pentylenetetrazol, 2 mg/kg of bicuculline or 1 mg/kg of strychnine were given 15 min prior to the daily electrical stimulation of the amygdala. The drug doses selected were capable of producing some behavioral and electrical epileptoid activity prior to stimulation without inducing generalized seizures. To determine whether pentylenetetrazol or bicuculline accelerated the rate of development of the kindled amygdaloid seizure or merely augmented the expression of each seizure, a crossover design was implemented. The crossover studies involved switching animals during the acquisition phase (between stimulations 3–6) from prestimulation saline to drug or drug to saline injections. It was found that pentylenetetrazol markedly augmented the expression of seizures during kindling development but the results of the crossover studies showed a less dramatic acceleration in the actual rate of the development of the fully generalized kindled amygdaloid seizure. The bicuculline-treated animals showed little augmentation in the expression of seizures during the kindling acquisition phase and in the actual rate of development of the kindled amygdaloid seizure. The strychnine treated animals showed no augmentation in expression of the seizures nor in the rate of development. The effects of prestimulation injections of bicuculline (1, 2 and 3 mg/kg) and strychnine (0.5, 1 and 2 mg/kg) on fully developed kindled amygdaloid seizures were also evaluated. Pretreatment with bicuculline minimally increased seizure afterdischarge duration at the highest dose. When fully kindled animals were pretreated with strychnine, a paradoxical decrease in afterdischarge length and an increase in severity (tonic hindlimb extension) was seen with the largest dose tested. This study emphasizes the potential importance of crossover studies in evaluating pharmacological manipulations of the rate of acquisition of the kindled seizure.     

The anticonvulsant effects of diazepam and phenobarbital in prek1ndled and kindled cortical seizures

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (15–60 mg/kg) were determined on prekindled (focal) and kindled (generalized) cortical seizures in the same rats. Only high sedating doses of diazepam or phenobarbital reduced the elicited afterdischarge duration (ADD) and behavioral response in the prekindled focal cortical seizure. Against the kindled seizure, both diazepam and phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest doses tested. The ADD of the kindled cortical seizures was reduced to prekindled lengths by diazepam (1–4 mg/kg) or phenobarbital (30–60 mg/kg). The increased anticonvulsant effectiveness found in this study is similar to previous findings with diazepam and phenobarbital against prekindled and kindled amygdaloid seizures, but stands in contrast to findings with prekindled and kindled pentylenetetrazol seizures.     

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy

1. The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O:-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+/-)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. 2. At doses within the analgesic range, (+/-)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (+/-)-tramadol, generalized seizures were observed at 30 mg kg(-1) in most kindled but not in nonkindled rats. The (-)-enantiomer induced myoclonic seizures at 30 mg kg(-1) in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg(-1). Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3. The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures.     

NAALADase (GCP II) inhibition prevents cocaine-kindled seizures

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutamate, would produce antiepileptogenic effects against cocaine was tested. Cocaine kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling.     

An examination of the anticonvulsant properties of voltage-sensitive calcium channel inhibitors in amygdala kindled seizures

Voltage-sensitive calcium (VSC) channels may contribute to epileptogenesis. A systematic examination of the anticonvulsant efficacy of different classes of VSC channel inhibitors, however, is lacking in chronic seizure models. The present study evaluated representatives from three different classes of VSC channel inhibitors for their protection against amygdala kindled seizures. Adult male rats (n=12) were kindled to stage 5 seizures (GS), and a threshold intensity required to evoke a GS was determined. The Ca⁺⁺-channel inhibitors (verapamil 0, 10, 20, 40 mg/kg; nimodipine 0, 5, 25, 50 mg/kg; nitrendipine 0, 25, 50, 100 mg/kg and flunarizine 0, 20, 40, 80 mg/kg) were administered 60–90 min prior to amygdala stimulation at the established threshold. None of the drugs altered threshold for inducing a seizure. Verapamil, a phenylalkylamine, and the dihydropyridines nimodipine and nitrendipine were without effect on kindled seizures. The diphenylalkylamine, flunarizine, was found to be the most efficacious, reducing AD duration and duration of clonic seizure activity by more than 60% in most animals. Flunarizine also decreased the severity of behavioral seizures, with 40% of the animals displaying Stage 1–2 seizures only. It is concluded that some VSC Ca⁺⁺-channel inhibitors do possess anticonvulsant potential. Thus influx of extracellular calcium through VSC channels may contribute to the expression of kindled seizures.Although the research described in this article has been supported by the United States Environmental Protection Agency (through contract 68-02-4450 to Mantech Environmental Technology Incorp.), it has not been subjected to Agency review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred. Mention of tradenames or commercial products does not constitute endorsement or recommendation for use.     

Opiate modification of amygdaloid-kindled seizures in rats

Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10 mg/kg) or morphine sulfate (10 mg/kg) and again stimulated parameters the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure severity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygaloid-kindled seizures, and that brain endorphins may play a role in the development of maintenance of an amygdaloid-kindled seizure focus.     

Effect of opiates on the parameters of seizures in rats with full amygdaloid-kindled convulsions

The effect on the parameters of seizures of opiates, administered in doses used clinically for analgesic effects, was studied in rats with full amygdaloid-kindled seizures. The largest dose of fentanyl studied (100 micrograms/kg) had a pronounced inhibitory effect on kindled seizures: severity of seizures, duration of seizures and duration of afterdischarge were significantly reduced to 36, 40 and 37% of controls, respectively, and the latency of seizures was significantly increased to 168% of untreated animals. The largest dose of pentazocine (16 mg/kg) also significantly inhibited the duration of seizures and duration of afterdischarge. Morphine (1-4 mg/kg) and meperidine (4-16 mg/kg) had a tendency to inhibit the duration of seizure and afterdischarges but did not significantly affect any of the measured parameters of seizures. Fentanyl, meperidine and pentazocine resulted in a lowering, whereas morphine caused a slight elevation, of the threshold for initiation of kindled seizures. The data suggest that fentanyl, in relatively small doses, may cause an inhibition of the intensity of behavioural and electrographic seizures but, paradoxically, an increased sensitivity to induction of seizures in rats with full amygdaloid-kindled seizures.     

Anticonvulsant role of adenosine

The effects of 2-chloroadenosine (2-CLA), a metabolically stable analog of adenosine, and aminophylline, an adenosine receptor antagonist, on seizures produced by pilocarpine (PILO) were examined in rats. The effects of 2-CLA on amygdaloid and hippocampal kindled seimres were also examined. In the animals pretreated with aminophylline (25-100 mg/kg), a non-convulsant dose of PILO (100 mg/kg) resulted in severe motor limbic seizures which rapidly evolved to status epilepticus. 2-CLA (5-10 mg/kg) blocked the appearance of behavioral and EEG seizures produced by a convulsant dose of PILO (380 mg/kg) and completely blocked the evolution of hippocampal and amygdaloid kindled seizures. The results indicate that purinergic mechanisms are involved in the modulation of seizure threshold within the limbic system.     

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite

We evaluated racemic zopiclone, its (S)- and (R)-enantiomers and a metabolite, (S)-desmethylzopiclone, for their actions on locomotor activity, rotarod performance, the elevated plus maze and the Vogel conflict test of anxiety, and electroconvulsive shock-induced seizures duration. Zopiclone and its (R)- and (S)-enantiomers reduced locomotor activity, and zopiclone and its (S)-enantiomer disrupted rotarod performance at 10 mg/kg. (S)-desmethylzopiclone did not alter these measures at doses of less than 200 mg/kg. (S)-desmethylzopiclone altered plus maze performance at the lowest dose of all the zopiclone derivatives tested, caused a dose-related effect on the Vogel conflict test and caused a dose-related reduction of electroconvulsive shock-induced seizure durations. The data indicate that (S)-desmethylzopiclone can bring about an anxiolytic effect without a substantial degree of central nervous system depression, and suggest that the agent may be particularly useful clinically in the treatment of anxiety.     

High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats

Summary Memantine (1-amino-3,5-dimethyladamantane) has previously been shown to attenuate or block chemically or electrically induced seizures in rodents at doses of 5–20 mg/kg i.p., suggesting that the drug might have potential utility in the treatment of seizures. In the present study, the effects of memantine were examined in amygdala-kindled and non-kindled rats. In fully kindled rats, i.e. a model of focal seizures with secondary generalization, memantine exerted no effects on seizure parameters at 5 mg/kg i.p., but reduced seizure severity and duration at 10 mg/kg. The threshold for induction of afterdischarges recorded from the amygdala was not altered after administration of 10 mg/kg. At 20 mg/kg, memantine induced spontaneous motor seizures in amygdala-kindled rats. No motor seizures were observed in non-kindled rats, but in both kindled and non-kindled animals memantine, 20 mg/kg, induced spikes in the electroencephalogram. Additional dose-dependent behavioural alterations observed after memantine included hyperactivity, ataxia and stereotypies, which may relate to the dopaminomimetic properties of the drug. The results demonstrate that kindled rats are more sensitive to central nervous system stimulating effects of memantine than non-kindled rats, which could relate to an impairment of inhibitory processes and/or alterations in synaptic transmission mediated by excitatory amino acids in the kindled brain. Send offprint requests to W. Löscher at the above address     

The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam

The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.     

Pharmacokinetics and pharmacodynamics of R- and S-gallopamil during multiple dosing

AIMS: Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). METHODS: Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. RESULTS: The apparent oral clearances (R: 4.8 l min-1 (95% CI: 2.9-6.8); S: 5.5 l min-1 (95% CI: 2.5-8.5)) and half-lives (R: 6.2 h; S: 7.2 h) of R- and S-gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026-0. 045); S: 0.051 (95% CI: 0.033-0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14. 0-57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. CONCLUSIONS: The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady-state and are therefore not substantially altered compared with the single dose administration of gallopamil.     

Pharmacological and histological characterisation of nicotine-kindled seizures in mice

The present study reports that it is possible to induce kindling by repeated injections of nicotine. The newly characterised nicotine-kindling model was compared with that of pentylenetetrazole (PTZ) kindling. Mice were kindled by repeated injection of PTZ (37 mg/kg), or nicotine (2.3 mg/kg), and the effect of the anti-epileptic drugs (AED) levetiracetam (LEV), tiagabine (TGB) and phenytoin (PHT) on seizures in kindled and naive mice were investigated. C-Fos immunoreactivity (Fos IR) was used to investigate differences in neuronal activity pattern between PTZ-, nicotine kindled and naive animals. PTZ kindled animals mainly showed increased Fos IR in limbic regions, whereas Fos IR in nicotine kindled animals was increased in the entorhinal cortex, medial habenula and the compact part of substantia nigra. Fully kindled PTZ-induced seizures were inhibited by LEV (ED50=13.6+/-7.8 mg/kg), TGB (ED50=0.3+/-0.04 mg/kg) but not PHT (ED50>40 mg/kg) whereas fully kindled nicotine-induced seizures were inhibited by LEV (ED50=1.4+/-0.4 mg/kg), TGB (ED50=0.3+/-0.06 mg/kg) and PHT (ED50=9.2+/-2.4 mg/kg). These differences in efficacy of AEDs were not due to changes in plasma levels in the various models. In conclusion, repeated administration of nicotine can induce a kindling-like phenomenon and the model showed significantly different Fos IR pattern and pharmacology to that of PTZ kindling.     

Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.     

The effect of a glycine derivative (CP 1552-S) on kindled seizures in rats

The effects of the glycine derivative, CP 1552-S (2-N-pentylaminoacetamide hydrochloride) were evaluated for potential anticonvulsant activity in rats which were cortically- or amygdaloid-kindled. Large doses (300-600 mg/kg, i.p.) of CP 1552 given 30 min before stimulation resulted in significant reductions in duration of afterdischarge after both partially-developed and fully-developed cortically-kindled seizures. The largest dose tested (600 mg/kg, i.p.) markedly reduced the duration of the elicited afterdischarge and the severity of seizure. This dose was associated with prestimulation sedation and a 50% incidence of post-afterdischarge spontaneous, electrical seizure activity. Against kindled amygdaloid seizures, CP 1552-S significantly reduced the duration of afterdischarge at 300 mg/kg (i.p.) without modifying the seizure and without prestimulation behavioral or electrical effects. The largest dose tested (600 mg/kg, i.p.) resulted in a significant reduction of the elicited duration of afterdischarge but was associated with a 25% incidence of prestimulation spontaneous electrical seizure activity and a 45% incidence of post-afterdischarge electrical seizure activity. When CP 1552-S (30-300 mg/kg, i.p.) was administered daily, prior to the amygdaloid kindling stimulus, no difference was noted in the rate of acquisition of the kindled amygdaloid response. It is concluded that the glycine derivative CP 1552-S, has little anticonvulsant activity against the acquisition or development of kindled amygdaloid seizures. It appears to have significant anticonvulsant effects against both cortically- and amygdaloid-kindled afterdischarges with little effect on the behavioral severity of the seizure. Further, large doses of CP 1552-S appeared to result in paradoxical post-afterdischarge and possibly prestimulation electrical seizure activity.