Effect of anticonvulsant drugs on (35S)t-butylbicyclophosphorothionate binding in vitro and ex vivo

Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-gamma-vinyl GABA), we studied their abilities in vitro to displace (35S)t-butylbicyclophosphorothionate (35S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 microM, P less than 0.001), ethosuximide (500 microM, P less than 0.001), and phenytoin (40 microM, P less than 0.001) decreased the specific 35S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 microM), the number of binding sites decreased and the binding affinity (P less than 0.05) in the cortex increased. Other anticonvulsants did not modulate 35S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.     

Teratogenic acitivity of the antiepileptic drugs phenobarbital,phenytoin, and primidone in mice

The teratogenic activity of phenobarbital, phenytoin, and primidone was studied in mice derived from the ICI pathogen free strain. The drugs were administered in the diet or by gastric intubation either from days 6–16 or 12–16 of pregnancy (day of vaginal plug is day 1). This covered the period during which the mice are susceptible to agents inducing cleft palate. The mothers were killed 1 day before term and the fetuses were examined. Cleft palates were rarely seen in the controls, the incidence being only 3 out of 1103 (0.3%) fetuses. The incidence of cleft palate in mice treated with phenobarbital 50 or 150 mg/kg in the diet was 0.6 and 3.9%, with phenytoin 40 and 120 mg/kg by intubation, or 250 mg/kg in the diet was 0, 11.1 and 10.2%, and with primidone 100 to 250 mg/kg by intubation or 500–2500 mg/kg in the diet ranged up to 15%. Since changes in blood folate concentrations following the use of anticonvulsants might be related to the teratogenic effects observed, an attempt was made to antagonize the effects by the simultaneous administration of folinic acid. Folinic acid had no teratogenic action of its own, and had no effect on the incidence of cleft palate induced by phenobarbital in the diet, or by phenytoin by gastric intubation. However, it did significantly potentiate the teratogenic effects of phenytoin administered in the diet (p < 0.002) but significantly reduced the teratogenic effect of primidone given in the diet (p < 0.034).     

Evaluation of epileptic dogs as an animal model of human epilepsy

In 126 epileptic dogs with spontaneously recurring generalized tonic-clonic (grand mal) seizures, epidemiological aspects and the efficacy of chronic oral treatment with common antiepileptic drugs were studied. Furthermore, the pharmacokinetics of antiepileptic drugs in dogs was compared with the values known for man. As in man, idiopathic epilepsy appeared to be more common than symptomatic epilepsy in dogs. There was a preponderance of male vs. female animals. When the breeds of the epileptic dogs were compared to the distribution of breeds in the hospital population, breed-related differences in the prevalence of epilepsy were found. The highest prevalence was seen in Cocker spaniels, Miniature schnauzers, Collies and Bassets. The total prevalence of dogs with epilepsy was 0.55%. Comparison of pharmacokinetics of antiepileptic drugs showed that some drugs were suited for maintenance therapy in dogs (primidone, phenobarbital, ethosuximide, trimethadione) whereas others appeared not to be ideally suited because of their short half-lives (phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, nitrazepam). This was confirmed by the evaluation of antiepileptic drug efficacy in epileptic dogs. 46 dogs were treated with primidone at daily doses of 14-104 mg/kg for 6-60 months. During medication with primidone, effective plasma levels of its metabolite phenobarbital could be maintained. Complete control of seizures or a reduction of seizure frequency by at least 75% was achieved in 39% of the dogs at phenobarbital concentrations of 5-49 micrograms/ml. Similar figures were obtained during chronic treatment with phenobarbital at daily doses of 2.5-13 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of phenobarbital,clonazepam, valproic acid,ethosuximide, and phenytoin on the delayed matching-to-sample performance of pigeons

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.     

Effects of some anti-epileptic, neuroleptic and gabaminergic drugs on convulsions induced by D,L-allylglycine.

The antagonism of various seizure and time-related components of the convulsions resulting after IV injection of D,L-allylglycine into male Wistar rats were assessed in a standard test procedure. Trimethadione and ethosuximide did not antagonize the seizure components, whereas clonazepam, phenobarbital, diphenylhydantoin, primidone, valproate sodium, aminoxyacetic acid, etomidate, acetazolamide, flunarizine, pipamperone and baclofen did. The allylglycine test may thus represent a relatively specific method of differentiating between drugs effective against partial or generalized convulsive seizures from those effective against absence seizures. The neuroleptics haloperidol and pimozide were completely inactive in contrast to their reported antagonism of bicuculine seizures. The spectra of the active substances are discussed with respect to Principal Component and Cluster Analysis. Noteworthy are the similarities between baclofen and etomidate; between aminoxyacetic acid, phenobarbital and valproate sodium; and between diphenylhydantoin and flunarizine.     

The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents

1. In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra) may involve modulation of inhibitory neurotransmission. 2. GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The effect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3. LEV contrasted the reference AEDs by an absence of any direct effect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4. These minor direct effects contrasted with a potent ability of LEV (EC(50)=1 - 10 microM) to reverse the inhibitory effects of the negative allosteric modulators zinc and beta-carbolines on both GABA(A) and glycine receptor-mediated responses. 5. Clonazepam, phenobarbital and valproate showed a similar ability to reverse the inhibition of beta-carbolines on GABA-gated currents. Blockade of zinc inhibition of GABA responses was observed with clonazepam and ethosuximide. Phenytoin was the only AED together with LEV that inhibited the antagonism of zinc on glycine-gated currents and only clonazepam and phenobarbital inhibited the action of DMCM. 6. LEV (17 mg kg(-1)) produced a potent suppression of sound-induced clonic convulsions in mice. This protective effect was significantly abolished by co-administration of the beta-carboline FG 7142, from a dose of 5 mg kg(-1). In contrast, the benzodiazepine receptor antagonist flumazenil (up to 10 mg kg(-1)) was without any effect on the protection afforded by LEV. 7. The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the anti-epileptic mechanism(s) of action of LEV.     

Influence of SIB 1893, a selective mGluR5 receptor antagonist, on the anticonvulsant activity of conventional antiepileptic drugs in two models of experimental epilepsy

SIB 1893, a non-competitive antagonist of group I metabotropic glutamate receptor subtype 5, administered at doses ranging from 0.25 to 10 mg/kg, failed to influence pentetrazole-induced convulsions in mice. Moreover, SIB 1893 (10 and 20 mg/kg) did not affect the protective action of valproate, ethosuximide, phenobarbital and clonazepam in this test. Similarly, the mGluR5 antagonist did not modulate the antiseizure activity of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock in mice. The combined treatment of SIB 1893 with conventional antiepileptic drugs did not lead to motor impairment. Long-term memory disturbances were observed only in the case of the combination of SIB 1893 with phenobarbital.     

Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy

The most active growth and development of the human cerebrum and cerebellum occurs in the second half of pregnancy and in the first year of life. It is therefore not surprising that many teratogens may also affect development causing slight, moderate or even severe brain damage. The "classical" antiepileptic drugs (AEDs) valproic acid (VPA), phenytoin, phenobarbital, primidone and carbamazepine are all considered to be teratogenic. They may increase the rate of major congenital anomalies including neural tube defects (NTD), cause specific facial and other dysmorphic features--the "Anti Epileptic Drug Syndrome" (AEDS) and often some degree of mental impairment. Of these AEDs, the most teratogenic seems to be valproic acid, causing about 2% of NTD and an additional increase of 4-8% in major congenital anomalies. Phenytoin also increases the rate of various anomalies, but apparently not of NTD. Phenobarbital primidone and carbamazepine are also teratogenic and impair intellectual function but to a lesser extent than VPA and phenytoin. Cognition is mainly impaired in the children that also exhibit the AEDS. The impairment is slight to moderate, leaving the affected children with a close to borderline intelligence. Lamotrigine monotherapy in pregnancy seems to be relatively safe. In general, polytherapy is more dangerous to the fetus than monotherapy and, at least for VPA and lamotrigine, there seems to be a "threshold effect".     

Tolerance to the anticonvulsant effects of phenobarbital, trimethadione, and clonazepam in kindled rats: cross tolerance to carbamazepine.

The kindled-convulsion model was used to assess the development of tolerance and cross tolerance to the anticonvulsant effects of antiepileptic drugs. In Experiment 1, tolerance developed to the anticonvulsant effects of bidaily (one every 48 h) IP injections of phenobarbital, trimethadione, and clonazepam on convulsions elicited 1 h after each injection in kindled rats by amygdala stimulation. In Experiment 2, kindled rats that were tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily IP injections of carbamazepine, each followed 1 h later by a convulsive amygdala stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Apparently, tolerance to anticonvulsant drugs is most likely to transfer between drugs that are effective against similar kinds of clinical and experimental seizures and have similar putative mechanisms of action.     

Adaptation of microvolume EMIT assays for theophylline, phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, and gentamicin to a CentrifiChem chemistry analyzer

We have developed microvolume EMIT procedures for theophylline, phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, and gentamicin using a centrifugal analyzer (CentrifiChem and Pipettor 1000) to reduce the manufacturer's recommended manual reagent consumption by one-sixth. In addition to developing the EMIT procedure, the performance of the analyzer and pipettor were verified. The analyzer and pipettor are capable of producing within-run precision at a 3-microliters sample volume and 210-microliters analyzer cuvette volume equal to or less than 1.5%. The performance of the EMIT procedures on the analyzer yielded spike drug recoveries of 90.8 to 106.1% for drug concentrations throughout the calibration concentration range of each assay. The percent error on standard reference material of the National Bureau of Standards ranged from a +12.0% to a -0.6% for ethosuximide, phenobarbital, phenytoin, and primidone. Patient comparison data yielded slopes from 0.930 to 1.110 for all assays. The other important feature of the adapted EMIT assay is its simplicity for use on a routine basis.     

Effect of acute and chronic anticonvulsant administration on endogenous γ-hydroxybutyrate in rat brain

The effect of acute and chronic administration of ethosuximide, trimethadione, sodium valproate, clonazepam, phenobarbital, and diazepam on brain concentrations of γ-hydroxybutyrate (GHB) was determined by gas-liquid chromatography. The dose and time to sacrifice for each drug was determined by testing for effectiveness against GHB-induced absence seizures in the rat using an automated frequency analysis for quantitation of the electrocorticogram. Acute administration of ethosuximide, trimethadione, and sodium valproate, produced an increase in whole brain GHB. Ethosuximide, trimethadione, and phenobarbital given chronically produced a decrease in whole brain GHB. All changes took place in subcortex and cerebellum. Acute ethosuximide treatment produced a greater increase in GHB concentration at higher doses. The acute changes with the drugs coincided with the onset of anticonvulsant effect, but were short-lived and, in the case of ethosuximide and trimethadione, followed by a significant depression in GHB concentrations. The anti-petit mal action of these anticon-vulsants may be related to their effect on GHB in brain.     

Influence of the antagonist of the glycine site of NMDA receptors, MRZ 2/576, on the anticonvulsant activity of conventional antiepileptic drugs in mice

The purpose of this study was to evaluate the influence of the glycine site antagonist of the NMDA receptor, MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt), on the anticonvulsive activity of carbamazepine, oxcarbazepine, diphenylhydantoin, phenobarbital and valproate against maximal electroshock (MES)-induced seizures and ethosuximide, valproate and clonazepam against pentetrazole (PTZ)-induced seizures in mice. MRZ 2/576 applied intraperitoneally 5 min before electroconvulsions, at the dose of 10 and 15 mg/kg, significantly raised the convulsive threshold (from 6.9 to 8.8 and 10.8 mA respectively). At lower doses, it did not affect the threshold. MRZ 2/576 applied at the dose of 5, 10 and 20 mg/kg did not influence the clonic phase of PTZ-induced seizures, but protected the animals against the tonic phase. The anticonvulsant effect of a given antiepileptic drug was expressed as its ED(50) value (in mg/kg), which represents the dose of the drug required to protect 50% of animals against MES or PTZ seizures. MRZ2/576 co-administered at a subprotective dose (5 mg/kg) with carbamazepine, oxcarbazepine, diphenylhydantoin, phenobarbital or valproate, significantly reduced their ED(50) values in MES test. Also, at the dose of 2.5 mg/kg it enhanced the protective activity of carbamazepine and valproate. At the lowest tested dose (1.25 mg/kg), it still potentiated the anticonvulsant activity of valproate. However, MRZ 2/576 (5 mg/kg) applied with valproate, ethosuximide or clonazepam did not influence their protective effects in the PTZ test. The combinations of MRZ 2/576 with almost every studied antiepileptic drug (providing a 50% protection against maximal electroshock or PTZ-induced seizures) did not produce motor impairment in the chimney test nor long-term memory deficit measured in the passive avoidance task. Only valproate alone or combined with MRZ 2/576 impaired both of these measures. It may be concluded that MRZ 2/576 enhanced the anticonvulsive activity of antiepileptic drugs against MES without accompanying potentiation of adverse effects. However, there was no positive interaction in the PTZ test. Finally, pharmacokinetic interactions do not seem responsible for the obtained results because MRZ 2/576 (5 mg/kg) did not alter the free plasma levels of the antiepileptics tested in the present study.     

Anticonvulsant potency of common antiepileptic drugs in the gerbil

In gerbils, 'minor' (myoclonic) and 'major' (clonic-tonic) seizures were induced by blowing at the animals with compressed air. The anticonvulsant ED50 of the following drugs was determined after oral administration against both types of seizures: phenytoin, phenobarbital, carbamazepine, sodium valproate, ethosuximide, and diazepam. Valproate, ethosuximide, and diazepam were most potent against 'minor' seizures which could not or only partially be suppressed by phenytoin or carbamazepine, respectively. The 'grand mal' drugs phenytoin, phenobarbital, and carbamazepine were, on the other hand, more potent against 'major' than against 'minor' seizures. When phenobarbital was administered for several days, a strong induction of hepatic microsomal enzymes occurred.     

Systematic comparison of three basic methods of sample pretreatment for high-performance liquid chromatographic analysis of antiepileptic drugs using gas chromatography as a reference method

Sera of epileptic patients which were routinely examined by gas chromatography (GC) were also analysed using high-performance liquid chromatography (HPLC). Three basic methods for the pretreatment of samples for HPLC analysis were compared: protein precipitation by adding acetonitrile to the serum, direct serum extraction using ethylacetate, and partitioning of serum and buffer solution over a stationary phase and extraction with dichloromethane/2-propanol. The analytical performance and practicability of the three methods were tested under routine conditions. The following anti-epileptic drugs and metabolites were used in the comparison of HPLC with GC: ethosuximide, primidone, phenobarbital, phenytoin, carbamazepine, N-desmethylmethsuximide, and phenylethylmalonediamide.     

Isocratic liquid chromatographic determination of theophylline, acetaminophen, chloramphenicol, caffeine, anticonvulsants, and barbiturates in serum

An isocratic reverse-phase high-performance liquid chromatographic system is described for resolving theophylline, acetaminophen, caffeine, chloramphenicol, ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine within 7 min. A procedure for routinely measuring these drugs in serum is validated and has been extended to include the quantification of N-desmethylmethsuximide, barbital, amobarbital, secobarbital, pentobarbital, mephobarbital, and thiopental. A 250 x 4.6 mm column packed with trimethylsilyl (C-1)-coated 5-microns particles is used. The mobile phase is phosphate buffer (10 mmol/L, pH 6.3):methanol:acetonitrile, 65:17.5:17.5. A common solvent extraction procedure is used for all of these drugs. The extractant is chloroform:isopropanol (95:5), containing three internal standards: 3-isobutyl-l-methylxanthine (IMX), tolybarb, and methsuximide. Theophylline, acetaminophen, caffeine, and chloramphenicol are quantified at 273 nm with IMX as the internal standard. With two exceptions, the rest of the drugs are quantified at 204 nm using tolybarb as the internal standard; ethosuximide is quantified at 204 nm using methsuximide as the internal standard, and thiopental is quantified at 285 nm using IMX as the internal standard.     

Detection of anticonvulsants and their metabolites in urine within a “general unknown” analysis procedure using computerized gas chromatography-mass spectrometry

Detection of the anticonvulsants carbamazepine, clonazepam, diazepam, ethosuximide, mephenytoin, mesuximide, methylphenobarbital, phenobarbital, phenytoin, primidone, propylhexedrine, sultiame, trimethadion and their metabolites in urine is described. The method presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs, detecting several hundred drugs and over 1000 metabolites. It includes cleavage of conjugates by acid hydrolysis, isolation by liquid-liquid extraction, derivatization by acetylation, separation by capillary gas chromatography and identification by computerized mass spectrometry. Using mass chromatography with the selective ions m/z 58, 104, 113, 117, 165, 193, 204 and 246, the possible presence of anticonvulsants and/or their metabolites was indicated. The identity of positive signals in the reconstructed mass chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The sample preparation, mass chromatograms, reference mass spectra and gas chromatographic retention indices are documented.Part of these results was reported at the 1st German-German Symposium of theGesellschaft für Toxikologische und Forensische Chemie (GTFCh) and theArbeitsgemeinschaft Toxikologische Chemie der DDR, Leipzig (GDR), July 3–5, 1990 (Maurer 1990d).     

Certain aspects of interaction between sodium valproate and other anticonvulsant drugs in the therapy of epilepsy in children.

The serum valproate (VPA) concentration and the clinical effects of polytherapy with other antiepileptic drugs: phenobarbital (PB), clonazepam (CZP), diazepam (DZ), clobazam (CLO), ethosuximide (ESX) were estimated. VPA serum levels were reduced when this drug was combined with phenobarbital. Clobazam given together with valproate led to an increase in the serum concentration of the former drug. VPA serum levels were without significant changes when the drug was combined with either ethosuximide or 1-4-benzodiazepines. The best therapeutical effects were found after polytherapy sodium valproate with ethosuximide and clobazam in primary generalized seizures.     

Testing of prototype antiepileptics in hippocampal slices

Summary The effects of six prototype anticonvulsant drugs, phenytoin, carbamazepine, midazolam, phenobarbital, ethosuximide and sodium valproate, were evaluated in two different experimental models of epileptiform activity using the in vitro slice preparation from the rat hippocampus. The relative potencies of the agents were determined: a) in the complete absence of synaptic transmission by recording spontaneous burst firing from the CA 1 pyramidal cell layer in a low calcium high magnesium solution and b) during blocked synaptic inhibition by observing the activity of each drug upon orthodromically evoked population spikes in penicillin containing medium. The rank order of potencies was a) in low Ca²⁺: carbamazepine, phenytoin, midazolam, phenobarbital, valproate, ethosuximide; b) in penicillin containing medium: midazolam, phenobarbital, carbamazepine, phenytoin, valproate, ethosuximide. These observations illustrate that the use of multiple paradigms is warranted when examining the mechanisms of action of new anticonvulsants.     

Formation of active metabolites of anticonvulsant drugs. A review of their pharmacokinetic and therapeutic significance

All of the commonly used anticonvulsants drugs, except possibly primidone, are cleared from the human body mainly by metabolism. The metabolites of phenytoin, phenobarbital and ethosuximide have so far not been shown to possess significant pharmacological activity. However, carbamazepine-10,11-epoxide, derived from carbamazepine, has anticonvulsant activity comparable with that of its progenitor, while oxcarbazepine, a new anticonvulsant congener of carbamazepine, is essentially a prodrug for its 10-hydroxy derivative. Valproic acid forms numerous metabolites through a variety of pathways; 2-en valproic acid, a beta-oxidation derivative, probably contributes to its anticonvulsant action, though the extent of the contribution is uncertain. Another metabolite, 4-en-valproic acid, has been considered a possible hepatotoxin and teratogen. N-Methyl-phenobarbital and primidone, though both anticonvulsants in their own right, are metabolised to phenobarbital, which probably mediates much of their antiseizure effect. Primidone also yields the weaker anticonvulsant phenylethylmalonamide. The various benzodiazepine anticonvulsants form numerous metabolites, some of which possess both antiseizure and other forms of pharmacological activity. As yet, there is little understanding of how best to interpret simultaneous plasma concentration measurements of anticonvulsant drug and its active metabolite (or metabolites) in the clinical situation, and the possible roles of anticonvulsant metabolites in the idiosyncratic toxicity of these drugs remain largely unexplored.     

Differences between prescribed daily doses and defined daily doses of antiepileptics--therapeutic drug monitoring as a marker of the quality of the treatment

OBJECTIVE: Prescribed daily doses (PDDs) of antiepileptics (N03A ATC group) were recorded for drugs used in monotherapy or in combination therapy in the University Hospital in Ostrava, Czechia. Plasma levels were used as an indicator of the quality of treatment. METHOD: Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of PDDs and plasma levels. The study included 1,144 in-patients examined in the period 1993 - 2004. The differences in PDD were tested by Mann-Whitney-U-test. ATC/DDD index 2005 was used. Doses given in mono- and polytherapy were compared. RESULTS: Median PDDs in samples within the therapeutic range (in mg) in mono-/polytherapy were as follows (DDDs in parenthesis): carbamazepine 600/800 (1,000), clonazepam 2.0/2.0 (8), phenytoin 300/300 (300), ethosuximide -/1000 (1,250), lamotrigine 250/200 (300), phenobarbital -/200 (100), primidone 500/625 (1,250), topiramate -/300 (300), valproic acid 750/1,000 (1,500). Median PDDs in polytherapy with antiepileptics not analyzed for TDM were: gabapentin 900 (1,800), levetiracetam 1,500 (1,500), vigabatrin 1,500 (2,000). CONCLUSIONS: PDDs in monotherapy were similar or slightly lower than in combination therapy with an exception for lamotrigine, NS. The differences were significant in carbamazepine, p < 0.0001, and valproic acid, p < 0.001. Patients with plasma levels within the therapeutic range were usually treated with similar or slightly higher doses than the remainder. In polytherapy the PDDs were similar to DDDs in carbamazepine, ethosuximide, phenytoin, and topiramate in samples within the therapeutic range when difference +/- 20 per cent was considered as acceptable PDD of levetiracetam was also similar to actual DDD. In general plasma levels tended to be below the therapeutic range. The differences between PDD and DDD of antiepileptics have to be taken into account especially when utilization of different drugs is compared.