Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.     

L-deprenyl (selegiline) exerts anticonvulsant effects against different seizure types in mice

L-Deprenyl (selegiline), a selective inhibitor of monoamine oxidase type B, has recently been shown to exert anticonvulsant and antiepileptogenic effects in the kindling model of partial (focal) epilepsy. In the present study, we examined if L-deprenyl exerts anticonvulsant effects in standard rodent models of generalized seizures. In addition to anticonvulsant activity, behavioral effects induced by L-deprenyl were monitored closely. To assess the stereoselectivity of anticonvulsant and behavioral effects of deprenyl, the D-enantiomer was included in the studies. Furthermore, the antiepileptic drug phenobarbital was used for comparison. The following tests were performed in mice: 1) the threshold for tonic electroconvulsions; 2) the maximal electroshock seizure test with fixed supramaximal (suprathreshold) stimulation; 3) the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ); 4) the s.c. PTZ seizure test, with a fixed dose of PTZ (80 microgram/kg) for seizure induction; 5) the rotarod and chimney tests for determination of motor impairment. Furthermore, animals were observed in cage and open field for stereotyped behavior and other behavioral abnormalities. L-Deprenyl, tested at doses of 1 to 40 microgram/kg i.p., significantly increased myoclonic and clonic PTZ thresholds and the threshold for tonic electroconvulsions, whereas D-deprenyl was either ineffective or exhibited a lower anticonvulsant potency than L-deprenyl. Both drugs were ineffective in the maximal electroshock seizure and s.c. PTZ seizure tests. In contrast to the higher anticonvulsant potency of L-deprenyl in seizure threshold tests, D-deprenyl was more potent than L-deprenyl to induce behavioral abnormalities, such as hyperlocomotion. The data indicate that L-deprenyl exerts anticonvulsant activity against different seizure types. This anticonvulsant activity and the previously reported neuroprotective and cognition-enhancing action of L-deprenyl offer a unique combination of drug effects which might be of clinical benefit in patients with epilepsy.     

Anticonvulsant activity of felbamate in amygdala kindling model of temporal lobe epilepsy in rats

PURPOSE: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE). METHODS: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, afterdischarge (AD) duration and seizure duration either at the focal seizure threshold, or after suprathreshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test. RESULTS: FBM at doses of 12.5-50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 microA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses. CONCLUSIONS: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.     

Semiological seizure classification

We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.     

Anticonvulsant drugs differentially suppress individual ictal signs: A pharmacokinetic/pharmacodynamic analysis in the cortical stimulation model in the rat.

Antiepileptic drugs can suppress seizures completely, but they may also modify the appearance of drug-resistant seizures. In this study, the effects of three antiepileptic drugs on a seizure pattern were assessed by means of population pharmacokinetic/pharmacodynamic (PK/PD) modeling, yielding estimates of baseline response, EC??, and Hill slope. Lamotrigine did not affect eye closure, although it did suppress the other ictal signs in a concentration-dependent fashion. Midazolam suppressed forelimb clonus less potently than the other ictal signs; the same was observed for tiagabine with respect to eye closure. This study shows that ictal component analysis (ICA) in combination with PK/PD modeling may facilitate drug selection and dose optimization. The application of ICA is not restricted to a single seizure type or anticonvulsant drug and can be used to identify drug combinations that have a complementary action. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.     

Selection of phenytoin responders and nonresponders in male and female amygdala-kindled Sprague-Dawley rats

PURPOSE: We recently described that, by repeated testing of the anticonvulsant phenytoin (PHT), it is possible to select responders and nonresponders from large populations of amygdala-kindled Wistar rats. Whereas responders show marked and reproducible increases of focal seizure threshold (afterdischarge threshold: ADT) on repeated testing of PHT, 75 mg/kg i.p., nonresponders do not show any significant ADT increase after this dose, thus allowing use of these subgroups in the search for mechanisms of pharmacoresistance in temporal lobe epilepsy. In this study, we examined whether PHT responders and nonresponders can also be selected from large groups of kindled rats of the Sprague-Dawley strain. METHODS: Male and female Sprague-Dawley rats were amygdala kindled, followed by once weekly i.p. testing of PHT. RESULTS: In contrast to recent experiments in Wistar rats, 75 mg/kg PHT did not induce significant ADT increases in Sprague-Dawley rats, indicating strain differences in response to this drug after kindling. When the dose was lowered to 50 or 25 mg/kg, significant and reproducible ADT increases were obtained in Sprague-Dawley rats of both genders. Therefore these doses were used for selection of responders and nonresponders in a total of 42 rats. Almost 50% of the rats were PHT responders, whereas no rat was a nonresponder when tested in up to six subsequent drug trials. Many rats were variable responders (i.e., showed ADT increases in some but not all trials), which was not due to low or variable drug absorption after i.p. injection. CONCLUSIONS: The data indicate that, in contrast to Wistar rats, Sprague-Dawley rats are not suited for selection of PHT nonresponders, but rather are quite responsive to this drug. A further difference to the Wistar strain is the truncated dose-response with loss of anticonvulsant efficacy at 75 mg/kg in kindled Sprague-Dawley rats, which may, at least in part, explain the inconsistent results reported on the anticonvulsant efficacy of PHT in this strain in the literature. The lack of anticonvulsant activity after administration of 75 mg/kg may be a result of kindling, because administration of this dose before kindling causes a significant ADT increase in this strain. This kindling-induced alteration of the anticonvulsant activity of PHT is a phenomenon that contrasts Sprague-Dawley with Wistar rats and deserves further investigation.     

Anticonvulsant efficacy of L-deprenyl (selegiline) during chronic treatment in mice: continuous versus discontinuous administration

We have previously reported that L-deprenyl (selegiline), an irreversible inhibitor of monoamine oxidase type B (MAO-B), exerts anticonvulsant activity against different seizure types in mice and rats. The anticonvulsant effect of L-deprenyl was rapid in onset but short lasting, arguing in favor of other, reversible mechanisms of L-deprenyl as a basis for the anti-seizure activity. For further evaluation, we administered L-deprenyl continuously via subcutaneously implanted osmotic minipumps in mice and determined the threshold for myoclonic seizures induced by i.v. infusion of pentylenetetrazol repeatedly during prolonged treatment, with treatment periods lasting from 2 to 4 weeks. For comparison with continuous administration via minipumps, L-deprenyl was injected once daily at a dose (10 mg/kg) known to produce complete and irreversible inhibition of MAO-B and anticonvulsant effects after acute administration in rodents. Continuous administration of L-deprenyl, 50 or 100 mg/kg per day, led to a progressive increase in seizure threshold in the absence of any observable adverse effects, while administration of 10 mg/kg per day via minipumps was devoid of any significant anticonvulsant effect. When 10 mg/kg were administered once daily in the afternoon for 4 weeks and the seizure threshold was determined repeatedly in the morning, no significant anticonvulsant effect was observed. The data argue against a critical role of MAO-B inhibition in the anticonvulsant activity of L-deprenyl but suggest that other, reversible biochemical and cellular effects known to occur at higher doses of this drug are involved in this respect. In view of the short half-life of L-deprenyl, these reversible effects can only be maintained during chronic treatment when the drug is given continuously such as via implanted minipumps.     

Linear palmo-plantar porokeratotic hamartoma

We report a case of 30-year-old man with generalized seizure, who had received phenytoin (PHT) for more than 6 years, but developed decrease in sperm count and motility. After PHT had been discontinued and valproate (VPA) had been administered for 3 months, his sperm activity became normalized. The decrease in sperm motility was the most important cause of his infertility. Sperm motility has been reported to be inversely correlated with the ratio of the concentrations of antiepileptic drugs in the plasma and semen. In our case, the ratio was 0.21 for PHT and 0.08 for VPA. We wish to emphasize the importance of measuring the concentration of antiepileptic drugs in the semen of infertile young males if they are on anticonvulsants.     

Altered biliary bilirubin profile in patients with persistent hyperbilirubinaemia after hepatic resection: analysis of bile bilirubin subfractions by high-performance liquid chromatography

PURPOSE: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. METHODS: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. RESULTS: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated. CONCLUSIONS: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.     

Protein dynamics from NMR

Recent studies have shown that long-chain polyunsaturated fatty acids can prevent cardiac arrhythmias, attributed to the reduction in excitability of cardiomyocytes, owing mainly to a shift in hyperpolarizing direction of the inactivation curves of both Na+ and Ca2+ currents and to a slowed recovery from inactivation. Qualitatively similar effects of polyunsaturated fatty acids on inactivation parameters have been observed in freshly isolated hippocampal neurons. Since the same effects are presumed to underlie the action of some established anticonvulsant drugs, polyunsaturated fatty acids might have an anticonvulsant action as well. We have investigated this for eicosapentaenoic acid, docosahexaenoic acid, linoleic acid and oleic acid, employing cortical stimulation in rats, a seizure model allowing the determination of the full anticonvulsant effect-time profile in freely moving, individual animals. I.v. infusion of 40 micromol of eicosapentaenoic acid or docosahexaenoic acid over a period of 30 min, modestly increased the threshold for localized seizure activity after 6 h by 73 +/- 13 microA (mean +/- S.E.M.; n = 7) and 77 +/- 17 microA (n = 7), respectively, and the threshold for generalized seizure activity by 125 +/- 20 and 130 +/- 19 microA, respectively (P < 0.001). The thresholds remained elevated for 6 h after infusion, but returned to baseline the next day. Free plasma concentrations in rats treated with eicosapentaenoic acid or docosahexaenoic acid, averaged 5.7 +/- 1.6 microM (n = 4) for eicosapentaenoic acid and 12.9 +/- 1.8 microM (n = 5) for docosahexaenoic acid at the end of infusion, but declined to undetectable levels within 3 h. Linoleic acid and oleic acid were less effective. Possible mechanisms for the modest anticonvulsant effect but of long duration with the polyunsaturated fatty acids are discussed.     

Positive and negative psychotropic effects of lamotrigine in patients with epilepsy and mental retardation

PURPOSE: To describe significant positive or negative psychotropic effects of lamotrigine (LTG) observed in epilepsy patients with mental retardation (MR). METHODS: Seven mentally retarded epilepsy patients, [5 with Lennox-Gastaut syndrome (LGS)] who experienced significant behavioral improvements or worsening after addition of LTG to their medication regimen were studied. RESULTS: LTG produced behavioral improvements in 4 patients. Patient 1, a 14-year-old girl, had LTG added to valproate (VPA) and thioridazine, resulting in diminished lethargy, less hyperactivity, and more appropriate speech. In a 17-year-old boy (patient 2) LTG added to VPA, phenytoin (PHT), and gabapentin (GBP) lessened irritability and hyperactivity. In patient 3, a 41-year-old woman, LTG added to PHT, VPA, and carbamazepine (CBZ) diminished lethargy and enhanced her social interactions. In patient 4, a 27-year-old man, LTG monotherapy diminished irritability and hyperactivity. Adverse behavioral effects were noted in 3 patients. In patient 5, a 43-year-old man, LTG added to PHT, phenobarbital (PB), lorazepam, sertraline, and thioridazine produced irritability, hyperactivity, and poor cooperation. In patient 6, a 29-year-old woman, LTG added to VPA produced frequent screaming, temper tantrums, increased rocking movements, and hyperactivity. In patient 7, a 29-year-old man, LTG added to VPA and PHT resulted in severe exacerbation of baseline behaviors, including self-injurious activity, temper tantrums, and failure to obey simple instructions. CONCLUSIONS: In some patients with epilepsy and MR, LTG has significant positive or negative effects on behavior.     

Magnesium sulfate versus phenytoin for seizure prevention in amygdala-kindled rats

OBJECTIVE: Magnesium sulfate is widely used for seizure prophylaxis in preeclampsia-eclampsia. However, its anticonvulsant effects in other types of seizures have not been proved. Diphenylhydantoin has been widely characterized as the "gold standard" of anticonvulsants. In this study we compared the anticonvulsant effects of therapeutic blood levels of magnesium sulfate and phenytoin in seizures generated in amygdala-kindled rats. STUDY DESIGN: Eighteen male rats had a bipolar electrode stereotaxically implanted into the central nucleus of the amygdala. After recovery an electrical seizure threshold was determined for each rat. Rats were stimulated twice daily at their seizure thresholds (i.e., kindling) until three consecutive generalized tonic-clonic seizures occurred. Kindled rats randomly received one of the following intravenous injections in a volume of 1.5 ml/kg: saline solution, magnesium sulfate (30, 60, or 90 mg/kg), or phenytoin (12.5, 25, or 50 mg/kg). Fifteen minutes after injection rats were stimulated at their seizure thresholds, and electrical and behavioral seizure activity was assessed. Statistical comparisons were made by analysis of variance and post hoc comparisons when appropriate. RESULTS: Magnesium sulfate had no effect on any of the seizure parameters assessed. Phenytoin significantly reduced seizure duration (p < 0.01), duration of postictal depression (p < 0.01), and behavioral seizure stage (p < 0.01). CONCLUSION: Amygdala-kindled seizures are more potently inhibited by phenytoin than by magnesium sulfate.     

Fatal hyperammonemia in a patient with systemic lupus erythematosus

We treated a 31-year-old woman with systemic lupus erythematosus, renal failure with nephrotic syndrome, and a long-standing seizure disorder, who developed severe hyperammonemia with a fatal outcome. Blood chemistry examination did not indicate liver disease, and amino acid concentrations did not suggest a defect in the urea cycle. Discontinuation of anticonvulsant treatment with valproic acid (VPA) failed to bring about improvement. We speculated that hyperammonemia in this case was induced by VPA, and the existence of other underlying factors, including the administration of aspirin and cimetidine, hypoalbuminemia, and renal failure might elevate the concentration of the serum free fraction of VPA.     

Cloning and expression of the human galanin receptor GalR2

We have previously shown that the novel anticonvulsant levetiracetam exerts potent anticonvulsant activity against both focal and secondarily generalized seizures in fully amygdala-kindled rats, i.e. , a model of temporal lobe epilepsy. We examined whether levetiracetam also exhibits antiepileptogenic activity, i.e., prevents or retards acquisition or development of amygdala-kindling in rats. Before the experiments with chronic administration of levetiracetam at different doses, we determined the pharmacokinetics of the drug after i.p. injection. Levetiracetam had a relatively short half-life (about 2-3 hr) in rats, so that any lasting effects of the drug after chronic administration were certainly not due to drug accumulation. When rats were treated with levetiracetam during kindling acquisition at daily i.p. doses of 13, 27 or 54 mg/kg, the drug dose-dependently suppressed the increase in seizure severity and duration induced by repeated amygdala stimulation. After termination of daily treatment with 54 mg/kg, duration of behavioral seizures and of afterdischarges recorded from the amygdala remained to be significantly shorter compared to vehicle controls, although amygdala stimulations were continued in the absence of drug. These data thus indicate that levetiracetam not simply masked the expression of kindled seizures through an anticonvulsant action, but exerted a true antiepileptogenic effect. Adverse effects were not observed at any dose of levetiracetam tested in kindled rats. The powerful antiepileptogenic activity of levetiracetam in the kindling model indicates that levetiracetam is not only an interesting novel drug for symptomatic treatment of epilepsy but might be suited for pharmacological prevention of this disease in patients with a high prospective risk of the development of epilepsy.     

The effect of lamotrigine and carbamazepine on the development of the audiogenic seizure reaction in rats of the Krushinski?-Molodkina strain

The effect of Lamotrigine and carbamazepine on the development and character of the epileptiform seizures after strong sonic stimulation were studied on Krushinski?-Molodkina line of rats. Both drugs manifested a dose-dependent increase in the latency of motor reaction Lamotrigine administration in the dose range of 5-40 mg/kg, i.p., resulted in a moderate decrease in the seizure intensity preventing predominantly the tonic component of the seizure and failed to modify the character of convulsive reaction. Carbamazepine administered in doses of 7.5-30 mg/kg effectively prevented the epileptiform seizures. The "two-wave" motor reaction was observed in 15% of carbamazepine-treated rats.     

Antiepileptic effects of tiagabine, a selective GABA uptake inhibitor, in the rat kindling model of temporal lobe epilepsy

PURPOSE: We determined the antiepileptic profile of tiagabine (TGB), a selective gamma-aminobutyric acid (GABA) uptake inhibitor, in the rat kindling model of temporal lobe epilepsy (TLE). METHODS: The anticonvulsant and adverse effects of TGB were examined in amygdala- or hippocampal-kindled rats and compared with those of other GABA uptake inhibitors (SKF89976A and NNC-711) and conventional antiepileptic drugs [AEDs: valproate (VPA) and carbamazepine (CBZ)]. In addition, the antiepileptogenic effects of TGB on amygdala kindling development were examined. RESULTS: TGB (2.5-40 mg/kg intraperitoneally, i.p.) had potent and dose-dependent anticonvulsant effects on both amygdala- and hippocampal-kindled seizures. The order of anticonvulsant potency of the three GABA uptake inhibitors tested was: NNC-711 > TGB > SKF-89976A and paralleled the in vitro GABA uptake efficacy. In addition, daily treatment with TGB 10 mg/kg for 10 days significantly retarded kindling development. Although adverse effects of TGB on motor systems were significantly less than those of VPA and CBZ, high toxic doses of TGB often caused EEG paroxysm and myoclonus. CONCLUSIONS: Our results indicate the clinical usefulness of TGB for treatment of drug-resistant TLE.     

Surgical management of intractable epilepsy in patients with ganglioglioma

Long-standing intractable seizures are common manifestation of cerebral gangliogliomas. There is much controversy regarding the most appropriate surgical treatment (lesionectomy vs resection of the epileptogenic cortex with the lesion) for patients with intractable epilepsy associated with gangliogliomas. We reported 2 cases, in which the favorable seizure outcome was obtained following lesionectomy alone. (Case 1) Nine-year-old female developed attack of abnormal sensation in her left upper limb followed by motor seizure in her left limbs since 5 years old. MRI revealed hyperintense tumor in the right medial frontal lobe. Chronic invasive subdural recording showed that ictal onset zone was located in the hand motor area. Following lesionectomy alone, she became free from seizures. (Case 2) Eight-year-old girl had intractable generalized seizure since 6 years old. MRI revealed a cystic tumor in the right parietal lobe. She had multiple spike foci on electroencephalography and magnetoencephalography, and intraoperative electrocorticography failed to reveal the paroxysm. Following lesionectomy, she had good relief with less than one minor seizure per 1-3 months. Thus, lesionectomy, even without resection of the epileptogenic cortex, may improve seizure outcome in patients with ganglioglioma-associated epilepsy.     

Pharmacokinetic-pharmacodynamic modeling of the anticonvulsant and electroencephalogram effects of phenytoin in rats

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg . kg-1 phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination. Vmax and Km values were, respectively, 386 +/- 31 microg . min-1 and 15.4 +/- 2.2 microg . ml-1 for the anticonvulsant effect in the cortical stimulation model and 272 +/- 31 microg . min-1 and 5.9 +/- 0.7 microg . ml-1 for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean ke0 values of 0.108 and 0.077 min-1 for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid Emax model, but Emax values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E = E0 + Bn . Cn) derived from the sigmoid Emax model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that Emax values cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient (B) of 2.0 +/- 0.4 microA . ml . microg-1 and an exponent (n) of 2.7 +/- 0.9. The derived EC50 value of 12.5 +/- 1. 3 microg . ml-1 for the EEG effect coincides with the "therapeutic range" in humans.     

Attenuation of anticonvulsant effects of diazepam after chronic treatment with bicuculline

Changes in the GABAergic system after chronic treatment with bicuculline were examined in two strains of inbred rats, Fischer 344 (F344) and Lewis (LEW). Rats received an IP injection of either bicuculline (2 mg/kg) or vehicle once a day for 12 days. After this chronic treatment, the effects of diazepam (1 mg/kg, IP) and pentobarbital (20 mg/kg, IP) on bicuculline-induced convulsions were measured. Bicuculline was acutely infused into a tail vein at 0.0415 mg/min, and the infusion was terminated when rats showed seizure. Following the chronic bicuculline treatment, the anticonvulsant effect of diazepam, but not of pentobarbital, was significantly reduced as compared to its effect following chronic vehicle treatment in both strains. Both diazepam and pentobarbital showed a significant difference in anticonvulsant effects between strains (F344 > LEW). The hypnotic effects of muscimol, barbital, pentobarbital, and ethanol following chronic bicuculline treatment were examined. There was no significant difference in sleep time induced by these drugs between bicuculline- and vehicle-treated rats. These results suggest that the attenuation of diazepam's anticonvulsant effect after chronic bicuculline treatment may result from functional changes in benzodiazepine receptors and that the anticonvulsant effects of diazepam and pentobarbital may be influenced by genetic factors. Moreover, the hypnotic effects of several drugs tested are apparently not affected by chronic bicuculline treatment.