Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Purpose:   Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)–induced seizures in mice.
Methods:   Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone–AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.
Results:   Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.
Conclusions:   Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.     

Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models

Purpose:   Pentylenetetrazole (PTZ) and maximal electroshock (MES) models are often used to induce seizures in nonepileptic control animals or naive animals. Despite being widely used to screen antiepileptic drugs (AEDs), both models have so far failed to detect potentially useful AEDs for treating drug-resistant epilepsies. Here we investigated whether the acute induction of MES and PTZ seizures in epileptic rats might yield a distinct screening profile for AEDs.
Methods:   Status epilepticus (SE) was induced in adult male Wistar rats by intraperitoneal pilocarpine injection (Pilo, 320 mg/kg, i.p.). One month later, controls or naive animals (Cont) that did not develop SE postpilocarpine (N-Epi) and pilocarpine-epileptic rats (Epi) received one of the following: phenobarbital (PB, 40 mg/kg), phenytoin (PHT, 50 mg/kg), or valproic acid (VPA, 400 mg/kg). Thirty min later the animals were challenged with either subcutaneous MES or PTZ (50 mg/kg, s.c.).
Results:   VPA, PB, and PHT were able to prevent MES in all groups tested (Cont, N-Epi, and Epi groups), whereas for the PTZ model, only the Cont group (naive animals) had seizure control with the same AEDs. In addition, Epi and N-Epi groups when challenged with PTZ exhibited a higher incidence of severe seizures (scores IV-IX) and SE (p   <   0.05, Fisher's exact test).
Conclusions:   Our findings suggest that the induction of acute seizures with PTZ, but not with MES, in animals pretreated with pilocarpine (regardless of SE induction) might constitute an effective and valuable method to screen AEDs and to study mechanisms involved in pharmacoresistant temporal lobe epilepsy (TLE).     

A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion

The purpose of these experiments was to determine whether a ketogenic diet previously shown to elevate seizure threshold also reduced seizure severity. Seizure threshold was tested by intravenous infusion of pentylenetetrazole (PTZ) whereas seizure severity was determined from measuring the hindlimb extension to flexion (E/F) ratio after seizures were evoked by maximal electroshock stimulation (MES). Surprisingly, seizures evoked by MES were more severe in animals fed a calorie-restricted ketogenic diet. Controls fed an isocaloric, calorie-restricted normal diet also exhibited more severe seizures than did animals fed the same diet ad libitum. When seizure threshold was evaluated in the same animals, those animals fed a calorie-restricted ketogenic diet exhibited a significant increase in seizure resistance compared to animals fed a ketogenic diet ad libitum, a calorie-restricted normal diet or a normal diet ad libitum. These findings suggest that both the amount and type of food affect seizures in rats and show that diet-related seizure protection depends upon the method by which seizures are provoked.     

Effects of antiepileptic drugs and seizure type on operant responding in mentally retarded persons

The performance of 129 mentally retarded persons was studied on a progressive fixed-ratio schedule of reinforcement. Subjects were selected according to antiepileptic drug (AED) regimen or membership in one of four control groups. The AEDs studied were: phenobarbital (PB); phenytoin (PHT); PB in combination with PHT (PB/PHT); and valproic acid (VPA) in combination with other AEDs . The control groups were: persons without seizure disorders and on no medications (control); persons without seizure disorders, but on the chronic medication thioridazine ( TDZ ); persons with histories of one or more seizures and treatment with PB and/or PHT, but currently on no AEDs ; and, to control for the effects of multiple AEDs , persons on multiple drug regimens (i.e., PB and/or PHT in combination with carbamazepine and/or ethosuximide). Except for the VPA group, response rates per minute were decreased in high intelligence quotient (greater than 40) persons receiving AEDs or with a history of treated seizures. Deficits in responding were particularly marked in persons with partial seizures. Persons on VPA responded at rates comparable with those of the control and TDZ groups, unless they had partial seizures. This effect was independent of seizure frequency and was inversely related to serum level. Persons on PB most frequently exhibited frustration responses during testing, and when these occurred they were rated as being significantly more severe. Persons on PB also most frequently elected to "leave the experiment" and did so primarily for reasons thought to reflect deficits in inhibition. These results suggest that operant tasks can be sensitive to both AED effects and to underlying alterations of function that accompany seizure disorders in the mentally retarded.     

Clinical Science

Kirk Nylen , Sergei Likhodii , Peter A. Abdelmalik , Jasper Clarke , and W. McIntyre Burnham
The ketogenic diet (KD) is a high-fat, low-carbohydrate, and adequate-protein diet used to treat drug-resistant seizures. It is currently unknown exactly how the KD exerts its anticonvulsant effects. Animal models are used to study the KD anticonvulsant mechanism of action. In the present study, we explored the ability of two KDs, a 4:1 KD and a 6.3:1 KD (more severe ketosis), to elevate pentylenetetrazole (PTZ) seizure thresholds in adult rats and young rats. When calculating PTZ thresholds, one can use either "absolute latencies" (i.e., the number of seconds until a seizure occurs) or "threshold doses" (i.e., the milligram/kilogram dose of PTZ required to elicit a seizure). When absolute latencies were used, neither KD significantly increased the latency to seizure in adult rats and young rats. Similarly, neither KD elevated threshold doses in adult rats. The 4:1 KD did not elevate threshold doses in young rats; however, the 6.3:1 KD did. Threshold doses are sensitive to differences between group weights, and the largest difference between group weights existed between the 6.3:1 KD group and its respective control group. It remains unclear whether threshold doses, absolute latencies, or some combination of the two methods should be used when determining seizure thresholds in rats fed a KD and seizure tested by using the PTZ infusion test. We conclude that the PTZ-infusion test is not suitable for modeling the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups.



     

Seizure resistance is dependent upon age and calorie restriction in rats fed a ketogenic diet

The present study was designed to evaluate the effects of age on the efficacy of the ketogenic diet in suppressing seizures evoked by tail-vein infusion of pentylenetetrazole (PTZ). Male rats of various ages were divided into three groups and fed one of three diets: (1) a calorie-restricted ketogenic diet, (2) a calorie-restricted normal (rodent chow) diet, or (3) a normal diet, ad libitum. After animals had been on experimental or control diets for more than 20 days, seizure threshold and blood levels of beta-hydroxybutyrate (beta-OHB) were determined. Animals fed a ketogenic diet exhibited significant elevations in levels of beta-OHB and seizure resistance compared to animals fed either a calorie-restricted normal diet or a normal diet, ad libitum. The levels of beta-OHB and seizure resistance were greatest for young pups. A surprising finding was that young animals fed a calorie-restricted rodent chow diet exhibited a significantly increased resistance to seizures compared to those fed the same diet, ad libitum. Results presented here demonstrate that the ketogenic diet produces the highest levels of ketonemia and seizure threshold in young animals. Collectively, these data suggest that age and caloric restriction are important considerations for implementing the ketogenic diet.     

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Anticonvulsant properties of the novel nootropic agent nefiracetam in seizure models of mice and rats

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy. METHODS: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test. RESULTS: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models. CONCLUSIONS: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy.     

Effects of acute inhibition of fatty acid oxidation on latency to seizure and concentrations of beta hydroxybutyrate in plasma of rats maintained on calorie restriction and/or the ketogenic diet

The present study was designed to evaluate the effects of acute inhibition of fatty acid oxidation on plasma levels of beta hydroxybutyrate and latency to PTZ-induced seizures in ad libitum- (AL), calorie-restricted normal rodent chow- (CR), and calorie-restricted ketogenic diet (KD)-fed young rats. Young (day 23) Sprague-Dawley rats were fasted for 8 h and then fed their respective diets for 21 days. On day 21 of the diet rats in each group received either saline or the fatty acid oxidation inhibitor mercaptoacetate (MA; 46 mg/kg intraperitoneally (i.p.). Two hours later, all rats received pentylenetetrazole (PTZ; 10 mg/kg; i.p.) every 10 min until seizure onset. Results demonstrated that KD-fed rats had the longest (P<0.05) latency to PTZ-induced seizures. KD-fed rats administered an acute dose of MA had lower (P<0.01) levels of beta hydroxybutyrate in plasma and shorter latency to PTZ-induced seizures compared with control KD-fed rats. However, there was not a significant positive correlation (P>0.10) between plasma beta hydroxybutyrate and latency to seizure, suggesting that beta hydroxybutyrate may be indirectly involved in the antiseizure effects of the KD. Fatty acid oxidation inhibition represents an experimental manipulation that may allow for more precise establishment and evaluation of levels of beta hydroxybutyrate in plasma necessary for antiseizure effects of the KD.     

Higher ketogenic diet ratios confer protection from seizures without neurotoxicity

The present study was designed to establish a dose-response relationship for the efficacy of the ketogenic diet (KD). Sprague-Dawley rats were fed ketogenic diets containing varying ratios of fats; (carbohydrates + proteins) whereas control animals were fed rodent chow. Unless otherwise indicated, all animals were fed calorie-restricted, isocaloric diets beginning at P37 and ketonemia, seizure threshold and neurotoxic effects were determined. Despite being provided isocaloric quantities, animals fed lower ketogenic ratios gained weight relative to those fed diets having greater proportions of fats. A significantly increased metabolic rate was noted for animals fed a high-fat diet, suggesting a basis for the weight differences. Results also showed that the animals fed calorie-restricted high-fat diets exhibited significant ketonemia and protection from pentylenetetrazole (PTZ)-induced seizures. There were no detectable neurotoxic effects for any diet group. For animals of the same age, there was no correlation between beta-hydroxybutyrate (beta-OHB) and seizure threshold. These findings suggest that beta-OHB is not directly involved in the anticonvulsant mechanism of the diet. Also, data presented here show that the conventional 4:1 ketogenic diet does not confer the greatest level of seizure protection. We conclude that a 6:1 ketogenic diet, which shows no evidence of neurotoxicity, may be maximally efficacious in rats.     

A comparison of the ability of a 4:1 ketogenic diet and a 6.3:1 ketogenic diet to elevate seizure thresholds in adult and young rats

PURPOSE: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically. METHODS: Ninety adult rats and 75 young rats were placed on one of five experimental diets: (a) a 4:1 KD, (b) a control diet balanced to the 4:1 KD, (c) a 6.3:1 KD, (d) a standard control diet, or (e) an ad libitum standard control diet. All subjects were seizure tested by using the PTZ infusion test. Blood glucose and beta-hydroxybutyrate (beta-OHB) levels were measured. RESULTS: Neither KD elevated absolute "latencies to seizure" in young or adult rats. Similarly, neither KD elevated "threshold doses" in adult rats. In young rats, the 6.3:1 KD, but not the 4:1 KD, significantly elevated threshold doses. The 6.3:1 KD group showed poorer weight gain than the 4:1 KD group when compared with respective controls. The most dramatic discrepancies were seen in young rats. CONCLUSIONS: "Threshold doses" and "latency to seizure" data provided conflicting measures of seizure threshold. This was likely due to the inflation of threshold doses calculated by using the much smaller body weights found in the 6.3:1 KD group. Ultimately, the PTZ infusion test in rats may not be a good preparation to model the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups.     

An anticonvulsant profile of the ketogenic diet in the rat

The present study was designed to evaluate the anticonvulsant effects of a high-fat ketogenic diet (KD) in rats. Animals were maintained on one of four experimental diets: (1) calorie-restricted ketogenic (KCR); (2) calorie-restricted normal (NCR); (3) ad libitum ketogenic (KAL); or (4) ad libitum normal (NAL). The calorie-restricted diets were fed in quantities such that they were calorically equivalent. All animals began diet treatment at age P37 and each was subjected to one of five chemically-induced seizure tests: bicuculline (BIC; s.c.), picrotoxin (PIC; s.c.), kainate (KA, i.p. or s.c.) and γ-butyrolactone (GBL, i.p.), strychnine (s.c.). Bipolar epidural electrodes were implanted under ketamine/xylazine anesthesia to permit recording the spike and wave discharges (SWD) characteristic of electroencephalograms during absence seizures. Ketonemia was assayed by measuring blood levels of β-hydroxybutyrate (BHB) spectrophotometrically prior to induction of seizures in each experiment. Animals fed ketogenic diets (i.e. either calorie restricted or ad libitum) exhibited greater blood levels of BHB compared to control groups. Seizure results show that treatment with a KD: (1) reduced the incidence of bicuculline-induced convulsions; (2) diminished the number of picrotoxin-induced seizures (KCR group only); (3) increased latency to GBL-induced SWD and reduced both the number and duration of SWD; but (4) conferred no protection from strychnine-induced seizures; and (5) made KA-induced seizures more severe. Together these results indicate a spectrum of anticonvulsant action for the KD in rats that includes threshold seizures induced via GABA receptors (BIC, PIC, GBL) but not those induced at glycine (strychnine) or the KA-subclass of glutamate receptors. Uniquely, the KD is the only treatment described that protects against both convulsive and non-convulsive (absence) seizures in rats.     

Calorie-restricted ketogenic diet increases thresholds to all patterns of pentylenetetrazol-induced seizures: critical importance of electroclinical assessment

PURPOSE: Thresholds to pentylenetetrazol (PTZ) seizures were usually based only on clinical symptoms. Our purpose was to use electroclinical patterns to assess the efficacy of a ketogenic and/or calorie-restricted diet on PTZ-induced seizures. METHODS: Forty 50-day-old rats were divided in four weight-matched groups and fed controlled diets: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), and hypocalorie ketogenic (HK). After 21 days, blood glucose and beta-hydroxybutyrate levels were determined and seizures were induced by continuous infusion of PTZ. The clinical and EEG thresholds to each seizure pattern were compared between the different groups. RESULTS: The electroclinical course of PTZ-induced seizures was similar in all groups. The HK group exhibited higher thresholds than the other ones for most clinical features: absence (p = 0.003), first overt myoclonia (p = 0.028), clonic seizure (p = 0.006), and for EEG features: first spike (p = 0.036), first spike-and-wave discharge (p = 0.014), subcontinuous spike-and-wave discharges (p = 0.005). NK, HC, and NC groups were not significantly different from each other. Blood glucose and beta-hydroxybutyrate levels were not correlated with electroclinical seizure thresholds. After the clonic seizure, despite stopping PTZ infusion, a tonic seizure occurred in some animals, without significant difference regarding the diet. CONCLUSION: This approach permitted a precise study of the electroclinical course of PTZ-induced seizures. In addition to the usually studied first overt myoclonia, we clearly demonstrated the efficiency of a calorie restricted KD in elevating thresholds to most electroclinical seizure patterns. We confirmed the lack of efficiency of the KD to reduce seizure severity once the seizure has started.     

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

Purpose: The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second‐generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Methods: Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step‐through passive avoidance task, and grip‐strength test. Total brain and free plasma concentrations of AEDs were also determined. Results: Sildenafil raised the threshold for electroconvulsions in a dose‐dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long‐term memory in mice. Interestingly, sildenafil dose‐dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Conclusions: Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long‐term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.     

Effect of topiramate on the anticonvulsant activity of conventional antiepileptic drugs in two models of experimental epilepsy

PURPOSE: The objective of this study was to evaluate the interaction of the novel antiepileptic drug (AED), topiramate (TPM), with conventional AEDs against amygdala-kindled seizures in rats and pentylenetetrazol-induced convulsions in mice. METHODS: Experiments were performed on mice and fully kindled rats. In pentylenetetrazol test, the chemoconvulsant was used at its CD97 dose of 105 mg/kg, producing clonic seizures in 97% of mice. Adverse effects were evaluated with the chimney test and passive avoidance task. Plasma levels of AEDs were measured with immunofluorescence. RESULTS: TPM at 20 mg/kg exerted a significant anticonvulsant effect as regards seizure and afterdischarge durations in amygdala-kindled seizures in rats, being ineffective at lower doses. Coadministration of TPM (10 mg/kg) with valproate (VPA; at a subtherapeutic dose of 50 mg/kg) resulted in essential reductions of seizure and afterdischarge durations. TPM (10 mg/kg) combined with carbamazepine (CBZ; at a subtherapeutic dose of 15 mg/kg) significantly increased afterdischarge threshold, simultaneously decreasing the remaining seizure parameters (duration or severity of seizures and afterdischarge duration). TPM (10 mg/kg) given with phenobarbital (PB; 15 mg/kg) markedly shortened seizure severity and seizure and afterdischarge durations. Combinations of TPM with diphenylhydantoin (PHT) were ineffective against kindled seizures in rats. TPM combined with VPA and PB did not alter their plasma levels, but its combination with CBZ resulted in an increased free plasma CBZ concentration. TPM (10 and 20 mg/kg) alone and its combinations with conventional AEDs affected neither motor coordination nor long-term memory, evaluated in the chimney and passive avoidance tests, respectively, in rats. In pentylenetetrazol-evoked convulsions in mice, TPM (175 and 200 mg/kg) showed anticonvulsant effects per se. Moreover, TPM (at its subtherapeutic dose of 150 mg/kg), significantly potentiated the anticonvulsant action of ethosuximide (ESM), but not that of VPA, PB, or clonazepam (CZP) against pentylenetetrazol-induced seizures. Either TPM alone (150 mg/kg) or its combination with ESM did not result in significant undesired effects. CONCLUSIONS: The experimental data indicate that except for PHT, the combinations of TPM with conventional AEDs are beneficial against amygdala-kindled seizures in rats. In the pentylenetetrazol test, this novel AED potentiated only the protection offered by ESM.     

Comparative Anticonvulsant Activity of 4-Chlorobenzenesulfonamide and Prototype Antiepileptic Drugs in Rodents

The anticonvulsant and toxic properties of 4-chlorobenzenesulfonamide (ADD 55051) were compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anti-convulsant test procedures. The results indicate that ADD 55051 is a very effective anticonvulsant in the maximal electroshock seizure (MES) model in mice after either intraperitoneal (i.p.) or oral administration and in rats after oral administration. In mice treated i.p. or orally, ADD 55051 was also effective in preventing seizures induced by pentylenetetrazol (PTZ). The toxicity of ADD 55051 after oral administration was quite low, yielding high TD50 values in both mice and rats and producing a very high protective index (PI = TD50/ED50) in both species as compared with the prototype antiepileptic drugs (AEDs).     

A Ketogenic Diet Increases the Resistance to Pentylenetetrazole-Induced Seizures in the Rat

Summary: Purpose: The purpose of this study was to test the hypothesis that a ketogenic diet would increase the resistance of rats to pentylenetetrazole (PTZ)-induced seizures and to understand the relation of ketonemia to seizure resistance.
Methods: A freely consumed, high-fat (ketogenic) diet was administered to male Sprague-Dawley rats for 5–10 weeks, while control animals were fed either rodent chow or a high-carbohydrate diet. Ketonemia was measured as plasma levels of β-hydroxybutyric acid (β-OHB). Seizures were induced by tail-vein infusion of pentylenetetrazole.
Results: The ketogenic diet produced a highly significant (p <0.01) increase in β-OHB levels within 5 days. Induction of seizures by PTZ 35 days after animals were placed on their respective diets showed that ketogenic animals had a significantly (p <0.01) increased threshold for seizure induction compared with those fed an isocaloric diet of either high-carbohydrate or normal rodent chow. Ketogenic animals did not exhibit increased seizure severity relative to controls, despite receiving consistently higher doses of PTZ.
Conclusions: The ketogenic diet resulted in an increased seizure threshold, confirming the hypothesis, and seizure threshold was found to be a direct function of the level of ketonemia.     

Effects of antiepileptic drugs on sleep architecture: a pilot study

OBJECTIVES: The effects of antiepileptic drugs (AEDs) on sleep architecture are not well understood, especially in patients with localization-related epilepsy, in whom seizures themselves can disrupt sleep. To clarify the effects of AEDs on sleep architecture, we performed a prospective study, looking at sleep architecture in patients with epilepsy admitted for video-EEG monitoring. METHODS: Adult patients with localization-related epilepsy treated with a single AED and admitted between 10/1997 and 04/2001 were included. Control patients on no AEDs were also included. Both groups were withdrawn from other AEDs. Overnight polysomnography was recorded and was scored according to the standard method. Adult patients with localization-related epilepsy on no medication were also recorded and served as controls. Patients with no seizure during the recording and no seizure in the 24 h preceding the recording were analyzed in this paper. Patients with a seizure in the 24 h preceding the recording and patients with a seizure during the recording were analyzed separately. RESULTS: A total of 72 nights were recorded in 39 patients, and patients taking each AED were compared to controls. We did not find any statistically significant effect of carbamazepine (CBZ). Phenytoin (PHT) disrupted sleep by increasing stage 1 sleep (PHT: 13.2+/-7.3%; control: 7.7+/-4.8%; P=0.008), and decreasing slow wave sleep (SWS) (PHT: 7.9+/-4.2%; control: 11.3+/-4.4%; P=0.03) and REM sleep (PHT: 13.9+/-6.2; control: 18.8+/-5.1; P=0.01). Valproic acid (VPA) disrupted sleep by increasing stage 1 sleep (VPA: 16.8+/-9.8%; control: 7.7+/-4.8%; P=0.007). Gabapentin (GBP) improved sleep by increasing SWS (GBP: 19.4+/-4.2%; control: 11.3+/-4.4%; P=0.0009). PHT and VPA disrupt sleep in the absence of seizures, while CBZ and lamotrigine have no significant effects. GBP improves sleep by increasing SWS. CONCLUSIONS: AEDs have differing effects on sleep structure, which can be beneficial or detrimental. Consideration of these potential effects is important in maintaining optimal sleep in patients with epilepsy.