Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity

PURPOSE: The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model. METHODS: All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining. RESULTS: No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA. CONCLUSIONS: Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.     

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy

Purpose:   To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children.
Methods:   LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration–time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults.
Results:   LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6–20 mg/L target range for the trough concentration.
Discussion:   Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.     

Effect of age and comedication on levetiracetam pharmacokinetics and tolerability

PURPOSE: To compare pharmacokinetics and tolerability of levetiracetam (LEV) in older versus younger adults. METHODS: As part of the Columbia Antiepileptic Drug Database, we retrospectively studied the pharmacokinetics and tolerability of LEV in patients who had been seen as an outpatient at our center during a 4-year period. We compared apparent clearance (CL) of LEV in the youngest (16-31 years; n=151) and oldest (55-88 years; n=157) quartile of 629 adult outpatients who had taken LEV. We also analyzed the frequency of adverse effects leading to dose change or discontinuation ("intolerability") and specific adverse effects in the younger versus older adults. One-year retention was determined for younger and older adults newly started on LEV at our center. RESULTS: Mean LEV CL differed significantly between older (46.5 ml/h/kg) and younger adults (78.3 ml/h/kg). On average, older patients had a 40% lower LEV CL than younger patients. Comedication with an enzyme-inducing antiepileptic drug (EIAED; mostly carbamazepine) was associated with a 24% higher clearance of LEV compared to those who were not on EIAEDs. This difference was 37% in a subgroup of patients whose LEV CL was compared while they were on and off EIAEDs. Stepwise linear regression identified younger age and comedication with an EIAED as significant predictors of increased LEV CL. A total of 34.3% of the 629 patients (31.7% of younger vs. 40.7% of older patients; p=0.16) reported intolerability to LEV on at least one occasion. This difference in tolerability reached significance in the group of patients newly started on LEV (26.3% vs. 41.0%; p=0.017). Drowsiness and psychiatric/behavioral side effects were the most common adverse effects associated with LEV use in both age groups. One-year retention was 72% in the older group vs. 54% in the younger group (not significant). CONCLUSION: Older adults have lower CL than younger adults and require a mean 40% lower dose of LEV to achieve the same serum level. Comedication with an EIAED increases LEV CL by 24-37%. Younger adults tolerate LEV better than older adults, but 1-year retention was (nonsignificantly) higher in the older group.     

Levetiracetam clinical pharmacokinetics in elderly and very elderly patients with epilepsy

We aimed to compare apparent steady-state oral clearance (CL/F) of the antiepileptic drug levetiracetam (LEV) in elderly (66-80 years, n=105) and very elderly (81-96 years, n=70) vs nonelderly (30-65 years, n=97) patients with epilepsy. Median weight-normalized CL/F (mLmin(-1)kg(-1)) decreased from 1.23 (nonelderly) to 0.83 (elderly) and 0.59 (very elderly) (p<0.001). LEV CL/F significantly declines with aging, elderly and very elderly patients requiring an about 30% and 50% lower dose, respectively, compared to nonelderly adults to achieve a given LEV plasma concentration.     

Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2μg/ml and AUC was 403.7μg/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4μg/h/ml vs. 461.4μg/h/ml and 450.2μg/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4μg/ml vs. 59μg/ml and 48.2μg/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.     

Comparative stereoselective pharmacokinetic analysis of 10-hydroxycarbazepine after oral administration of its individual enantiomers and the racemic mixture to dogs

PURPOSE: 10-hydroxycarbazepine (MHD) is the active metabolite of the new antiepileptic drug oxcarbazepine. MHD is a chiral molecule with an asymmetric carbon at position 10. The purpose of this study was to evaluate the stereoselectivity in the pharmacokinetics of the enantiomers of MHD after oral administration of the individual MHD enantiomers and the racemic mixture to dogs. METHODS: A racemic mixture of MHD and the individual MHD enantiomers were administered to six dogs in a crossover design. Plasma and urine concentrations of R(-)- and S(+)-MHD were determined by a stereoselective high-performance liquid chromatography assay. RESULTS: The area under the concentration-time curve of R(-)-MHD was significantly greater than that of S(+)-MHD after the administration of the individual enantiomers but not after the administration of MHD in a racemic form. The formation clearance of the S(+)-MHD glucuronide was approximately three times greater than that of R(-)-MHD glucuronide. No difference was found in the renal clearance and protein binding of R(-)- and S(+)-MHD enantiomers. CONCLUSIONS: The pharmacokinetics of the MHD enantiomers was found to be stereoselective, mainly as a result of the stereoselectivity in the glucuronidation process. The difference in the pharmacokinetic parameters found after administration of individual MHD enantiomers compared with the administration of MHD in a racemic form suggests the possibility of interaction between the two enantiomers. Stereoselective pharmacokinetic and pharmacodynamic studies are needed to evaluate the rationale of developing MHD as a new antiepileptic drug, either in a stereospecific or racemic form.     

Levetiracetam: antiepileptic properties and protective effects on mitochondrial dysfunction in experimental status epilepticus

PURPOSE: To assess the anticonvulsant activity of the novel antiepileptic drug, levetiracetam (LEV) in a model of self-sustaining limbic status epilepticus, and to measure the consequence of LEV treatment on the pattern of mitochondrial dysfunction known to occur after status epilepticus (SE). METHODS: The rat perforant pathway was stimulated for 2 h to induce self-sustaining status epilepticus (SSSE). Stimulated rats were assigned to one of three treatment groups, receiving intraperitoneal injections of saline, 200 mg/kg LEV, or 1,000 mg/kg LEV, 15 min into SSSE and at 3 times over the next 44-h period. All animals received diazepam after 3-h SSSE to terminate seizures. Forty-four hours later, the hippocampi were extracted and prepared for electrochemical high-performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, alpha-ketoglutarate dehydrogenase, citrate synthase, complex I, and complex II/III). These parameters were compared between treatment groups and with sham-operated rats. RESULTS: LEV administration did not terminate seizures or have any significant effect on spike frequency, although rats that received 1,000 mg/kg LEV did exhibit improved behavioral seizure parameters. Significant biochemical changes occurred in saline-treated stimulated rats compared with shams: with reductions in glutathione, alpha-ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities. Complex II/III activities were unchanged throughout. Rats that received 1,000 mg/kg LEV had significantly improved biochemical parameters, in many instances, comparable to sham control levels. CONCLUSIONS: Despite continuing seizures, administration of LEV (1,000 mg/kg) protects against mitochondrial dysfunction, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects.     

Levetiracetam does not alter body weight: analysis of randomized, controlled clinical trials

INTRODUCTION: Increases in body weight gain are important, and clinically significant adverse effects of several antiepileptic drugs (AED) including valproate and gabapentin. Weight gain may contribute to medication non-compliance, discontinuation, and importantly, may have secondary medical implications as well. Levetiracetam (LEV) is indicated for adjunctive treatment of partial seizures. The objective of the present evaluation was to examine the effects of LEV treatment on body weight in adult patients. METHODS: We analyzed data derived from four prospective, placebo-controlled randomized, clinical trials conducted in both in the US and Europe. Patients included in the present analysis were both men and women, greater than 16 years old, and who had LEV exposure for at least 1 month. Body weight was measured at baseline and at the final LEV study visit. Data are analyzed for all patients, by gender, body mass index (BMI), duration of LEV exposure and by concomitant AED treatment. Wilcoxan Signed Rank, or Rank Sum test used where appropriate, with significance assigned at P<0.05. Data are presented as mean values+/-1 S.D. RESULTS: Nine-hundred and seventy patients (age=37.5 years, 54% men/46% women) were evaluated. There were no significant differences in baseline demographics between LEV (n=631) or placebo (n=339) treated patient groups. Mean LEV dose and duration of treatment were 2053 mg/day (maximum dose of 4000 mg/day) and 125 days (maximum=181 days), respectively. Concomitant AED therapy included CBZ, PHT, VPA, PB, GBP, LTG, and VGB. For LEV-treated patients, no significant changes in body weight were noted. Mean body weight at baseline versus final study visit for LEV was 74.3+/-16.6 kg and 74.3+/-16.6 kg, respectively. For placebo-treated patients, baseline versus end of treatment weight was 72.4+/-15.4 kg and 72.7+/-15.9 kg, respectively, representing a slight, yet clinically trivial increase. Clinically significant weight change as defined as >7% change from baseline weight, occurred in 9% of LEV-treated patients (4.5% had increase in weight/4.5% decrease) versus 9.4% (5.9% had increase/3.5% decrease) in placebo-treated patients. Weight changes were not significantly different between groups. Neither baseline BMI, gender, or background AEDs, appeared to predispose to significant weight change for LEV-treated patients. CONCLUSIONS: We conclude that treatment with LEV at clinically relevant dosages is not associated with significant weight change. LEV would, therefore, appear to be a weight neutral AED.     

Pharmacokinetic study of levetiracetam in children

PURPOSE: The pharmacokinetics of the novel antiepileptic drug (AED) levetiracetam and its major metabolite, ucb L057, were studied in children with partial seizures in a multicenter, open-label, single-dose study. METHODS: Twenty-four children (15 boys, nine girls), 6 to 12 years old, received a single dose of levetiracetam (20 mg/kg) as an adjunct to their stable regimen of a single concomitant AED, followed by a 24-h pharmacokinetic evaluation. RESULTS: In children, the half-lives of levetiracetam and its metabolite ucb L057 were 6.0 +/- 1.1 and 8.1 +/-2.7 hours, respectively. The Cmax and area under the curve (AUC) of levetiracetam equated for a 1-mg/kg dose were lower in children (Cmax, norm=1.33 plus minus 0.35 microg/ml; AUCnorm=12.4 +/- 3.5 microg/h/ml) than in adults (Cmax, norm=1.38 +/- 0.05 microg/ml; AUCnorm=11.48 +/- 0.63 microg/h/ml), whereas the renal clearance was higher. The apparent body clearance (1.43 +/- 0.36 ml/min/kg) was approximately 30-40% higher in children than in adults. Levetiracetam was generally well tolerated. CONCLUSIONS: On the basis of these data, a daily maintenance dose equivalent to 130-140% of the usual daily adult maintenance dosage (1,000-3,000 mg/day) in two divided doses, on a weight-normalized level (mg/kg/day) is initially recommended. Clinical efficacy trials in children are ongoing with dosages of 20 to 60 mg/kg/day.     

Levetiracetam monotherapy for late poststroke seizures in the elderly

Stroke is the most common cause of seizures in the elderly. Antiepileptic drugs are used to treat most patients with late poststroke seizures. The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) in patients aged 60 or older with late-onset poststroke seizures. This prospective study evaluated patients 60 years of age or older, who had at least two late-onset poststroke seizures and were given LEV monotherapy. Demographic data and seizure and stroke characteristics were recorded. Outpatient visits were made after 2, 4, 6, 9, and 12 months and every 3 months thereafter, and the effectiveness and tolerability of LEV were investigated. Thirty-four patients with a mean age of 69.76+/-6.41 were included in this study. Average seizure frequency before treatment was 3.61+/-3.02/month. Mean follow-up time was 17.68+/-3.24 months. At daily doses of 1000-2000 mg, 82.4% of the patients were seizure free, and 7 patients (20.6%) had side effects. LEV was discontinued in one patient because of severe somnolence. Two patients were switched to another antiepileptic drug because of uncontrolled seizures despite an increase in dose up to 3000 mg/day. LEV monotherapy can be effective and well tolerated in elderly patients with late-onset poststroke seizures.     

Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial

PURPOSE: To assess the efficacy and safety of levetiracetam (LEV) as adjunctive therapy in children with treatment-resistant partial-onset seizures. METHODS: Children (aged 6-12 years) with treatment-resistant partial-onset seizures receiving one standard antiepileptic drug (AED) were eligible. After a 4-week baseline period, children received LEV in a 6-week titration phase (target dose, 40 mg/kg/day) followed by an 8-week evaluation phase. Seizure frequency during the evaluation period with individualized LEV doses (20-40 mg/kg/day) were compared with the 4-week baseline seizure frequency. Plasma concentrations of LEV and other AEDs were determined to evaluate potential drug interactions. RESULTS: Twenty-four subjects enrolled and received LEV; 23 entered the evaluation phase, and 22 completed the evaluation phase. Compared with their baseline seizure frequency, 12 (52%) of 23 subjects entering the evaluation phase had their seizure frequency decrease by >50%. Two subjects remained seizure free during the entire evaluation period. LEV did not significantly affect plasma concentrations of any concomitant AED during this study, and no alteration of mean clinical laboratory values was observed. The most commonly reported adverse events were headache, infection, anorexia, and somnolence. CONCLUSIONS: This open-label study of adjunctive LEV therapy (at 20-40 mg/kg/day) suggests that LEV is effective, safe, and well tolerated in children ages 6-12 years with treatment-resistant partial-onset seizures. A randomized, placebo-controlled, double-blind trial of LEV adjunctive therapy in children with treatment-resistant partial-onset seizures is needed and ongoing to confirm these open-label findings.     

Rapid kindling in preclinical anti-epileptic drug development: the effect of levetiracetam

PURPOSE: This study assesses the use of the serial day Rapid Kindling with Recurrent Hippocampal Seizures (RKRHS) model in drug testing by investigating the anti-epileptic effect of levetiracetam (LEV), a novel anti-epileptic drug (AED) with a unique preclinical profile. METHODS: Male Wistar rats (n=16) were implanted with a stimulation/recording electrode unit in the right hippocampus and epidural recording electrodes. One week later, all rats received 12 stimulations each day for several consecutive days according to the serial day RKRHS protocol, until they were fully kindled. Fully kindled rats were then randomly assigned to an active (n=8) and a control (n=6) group and injected once (intraperitoneal, i.p.) with levetiracetam (54 mg/kg) or saline (0.9% NaCl, 2 ml/kg), respectively. One hour later, the rats received additional kindling stimulations, during which the effect of LEV was assessed. RESULTS: One hour following injection of LEV, mean seizure stage dropped to 1.67+/-1.03 compared to 5+/-0 in controls (p<0.05). Mean ADD was also significantly shorter in the active group than in controls; 21.16+/-5.03 s versus 57.24+/-8.16s, respectively (p<0.05). A gradual, time-dependent decline was noted in the anti-epileptic effect of LEV but this effect stayed statistically significant at least up to 2.5 h (p<0.05). CONCLUSION: LEV was demonstrated to have anti-epileptic properties in RKRHS that compared to those in traditional kindling and contrast with results from classical screening tests. RKRHS may represent a valuable and sensitive screening tool early in the drug screening process.     

Retention rate of levetiracetam in children with intractable epilepsy at 1 year.

Levetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently obtained marketing authorisation for use in children. The purpose of this study was to assess the efficacy, tolerability and retention rate of LEV in children with refractory epilepsies. It is a retrospective multicentre observational study reporting the use of LEV in 200 children, aged 0.3-19 years (median 9-years-old) over a 4-year period. All of the patients included in the study had refractory epilepsy with a median age of onset of epilepsy of 3 years (range 0-13 years). The 38% had failed and withdrawn 3 or more AEDs previously and 24% were taking at least 2 other AEDs in addition to LEV. The 47% had focal, and 58% had symptomatic epilepsies. The LEV dose ranged from 8 to 100 mg/kg/day (mean 39 mg/kg). The study comprised 215 person years of LEV exposure. RESULTS: LEV was well tolerated with a retention rate of 49% at 1 year. No serious adverse events were reported with possibly related adverse events reported in only 24% of patients (mainly emotional or behavioural changes). At more than 2, 6 and 12 months, worthwhile improvement (>50% seizure reduction) was noted in 60, 40 and 32%, including seizure freedom in 14, 14 and 5%, respectively. CONCLUSION: Our results confirm the efficacy and tolerability of LEV in children with refractory epilepsies and demonstrate good response and retention rates at 12 months. It represents the largest cohort of paediatric patients published so far on LEV with a 1-year follow-up.     

Monotherapy for partial epilepsy: focus on levetiracetam

Levetiracetam (LEV), the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (>/=50% reduction in seizure frequency) of 28%-45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures.     

Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years

PURPOSE: To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs). METHODS: Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method. RESULTS: TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs. CONCLUSIONS: Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.     

Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus

Status epilepticus (SE) is a neurological emergency, with high mortality and high morbidity among survivors, and novel therapeutic agents are needed to improve this picture. We examined the effects of the antiepileptic drug levetiracetam (LEV) in an experimental model of self-sustaining status epilepticus (SSSE), induced in rats by electrical stimulation of the perforant path. LEV's unique spectrum of anticonvulsant activity, very high therapeutic index, and neuroprotective properties, make it a potentially interesting agent in the treatment of SE. Pretreatment with LEV intravenously reduced (30 mg/kg) or prevented (50-1000 mg/kg) the development of self-sustaining seizures. Treatment during the maintenance phase of SSSE diminished (at 200 mg/kg) or aborted seizures (in doses of 500 or 1000 mg/kg). Addition of LEV significantly enhanced the anticonvulsant effects of diazepam (DZP), even when both drugs where given in doses far below their therapeutic level. We conclude that LEV deserves further evaluation in the treatment of status epilepticus.     

Effects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala-kindled seizures in rats

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy. METHODs: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED). RESULTS: In fully amygdala-kindled rats, NEF (25, 50, and 100 mg/kg, p.o.) decreased afterdischarge induction, afterdischarge duration, seizure stage, and motor seizure duration in a dose-dependent manner. LEV (25, 50, and 100 mg/kg, p.o.) had no effects on afterdischarge induction and slightly decreased afterdischarge duration, whereas it markedly decreased seizure stage and motor seizure duration. In contrast to the results in fully amygdala-kindled rats, NEF (25 and 50 mg/kg/day, p.o.) had few or no effects on the development of amygdala-kindled seizures. As well as fully amygdala-kindled seizures, LEV (50 mg/kg/day, p.o.) markedly inhibited the development of behavioral seizures without reducing daily afterdischarge duration. CONCLUSIONS: Although NEF possesses potent anticonvulsant effects on fully amygdala-kindled seizures, it has few or no effects on the development of amygdala-kindled seizures. LEV shows marked anticonvulsant effects on both phases of kindling. In fully amygdala-kindled rats, NEF inhibits both electroencephalographic and behavioral seizures, whereas LEV inhibits only behavioral seizures. This double dissociation suggests that NEF has a distinct anticonvulsant spectrum and mechanisms from those of LEV.     

Effects of Pregnancy on the Pharmacokinetics of Lamotrigine in Dogs

PURPOSE: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG). METHODS: Five pregnant dogs were given a daily dose of LTG (100 mg) for a period of 1 week. Two months after parturition, the same subjects were given the LTG dose (100 mg) over the same period. On both occasions, plasma LTG concentrations were determined by a sensitive, high-performance liquid chromatographic (HPLC) method, over a 30-h period after the last dose. RESULTS: The mean maximum plasma concentration (Cmax), volume of distribution (Vd/F), and oral body clearance (Cl/F) for LTG (+/- SD) during pregnancy were 7.63+/-2.46 microg/ml 1.74+/-0.29 L/kg, and 0.19+/-0.04 L/h/kg, respectively. After pregnancy, the same variables were 6.12+/-2.24 microg/ml, 2.36+/-1.10 L/kg, and 0.30+/-0.13 L/h/kg, respectively. None of these pharmacokinetic parameters was found to be significantly different between the two groups. CONCLUSIONS: The apparent lack of change in the relevant pharmacokinetic parameters of LTG during pregnancy may indicate that pregnancy has little or no effect on glucuronidation; the principal pathway for the drug's elimination.     

Hypokalemia and hypomagnesaemia related to levetiracetam use

Levetiracetam (LEV), used for both partial and generalized seizures, is a frequently preferred antiepileptic because of its few side effects. We present a 23-year-old man who developed hypokalemia after switching from valproate to LEV. The patient was sent to our clinic due to hypokalemia 1 month after initiation of LEV, and his neurological examination was normal. Further examinations revealed hypokalemia (3.1 mmol/L) and hypomagnesaemia (0.56 mmol/L). His hemogram, blood urea nitrogen, creatinine, total cortisol, thyroid function tests, creatinine clearance, and renal Doppler ultrasound were normal. LEV was tapered off and treatment with 200 mg/day lamotrigine begun. Potassium and magnesium levels returned to normal ranges in subsequent tests. While hypokalemia and hypomagnesaemia have not been reported before to our knowledge, interstitial nephritis and renal failure after the use of LEV have been. Hypokalemia, found in the early period in this case, may be an indicator of a recently developed renal tubular disorder. This experience indicates that unpredictable side effects of increasingly used new antiepileptic drugs should be taken into consideration.