Concentrations of stiripentol in children and adults with epilepsy: the influence of dose, age, and comedication.

BACKGROUND: Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations. METHODS: Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis. RESULTS: Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011). CONCLUSIONS: Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.

Evolutionary loss of complexity in human vocal anatomy as an adaptation for speech.

Human speech production obeys the same acoustic principles as vocal production in other animals but has distinctive features: A stable vocal source is filtered by rapidly changing formant frequencies. To understand speech evolution, we examined a wide range of primates, combining observations of phonation with mathematical modeling. We found that source stability relies upon simplifications in laryngeal anatomy, specifically the loss of air sacs and vocal membranes. We conclude that the evolutionary loss of vocal membranes allows human speech to mostly avoid the spontaneous nonlinear phenomena and acoustic chaos common in other primate vocalizations. This loss allows our larynx to produce stable, harmonic-rich phonation, ideally highlighting formant changes that convey most phonetic information. Paradoxically, the increased complexity of human spoken language thus followed simplification of our laryngeal anatomy.

Serum concentrations of rufinamide in children and adults with epilepsy: the influence of dose, age, and comedication.

Rufinamide (RUF) is an orphan drug for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in persons aged 4 years and older. Several studies have investigated the pharmaconkinetics of RUF, but information about interactions is still limited and the results are in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily RUF dose per body weight (mg/kg), valproic acid (VPA), and enzyme-inducing antiepileptic drugs (EIAEDs) on RUF concentration-to-dose ratio (RUF serum concentration/RUF dose per body weight), RUF clearance (RUF dose/RUF serum concentration), and RUF trough concentrations. Different statistical methods were used to evaluate 292 blood samples from 119 patients who fulfilled the inclusion criteria. In summary, the results using generalized estimating equation regression models confirm a moderate but statistically significant nonlinear RUF concentration-dose relationship. At steady state, the trough concentrations of RUF increase in a less than dose proportional manner. Children (younger than 12 years) had significantly lower RUF concentrations (19.0%, P < 0.001) than adults (18 years or older) on comparable RUF doses per body weight. VPA was the most frequent comedication (51%) in our patient group. Mean RUF concentrations were 86.6% higher when VPA concentrations were greater than 90 µg/mL (P < 0.001) and 45.4% higher when VPA concentrations were between 50 and 90 µg/mL (P < 0.001) but not significantly different at VPA concentrations less than 50 µg/mL (4.4%, P > 0.1) compared with combinations without VPA. In combination with EIAEDs, mean RUF concentrations were 21.8% lower (P = 0.002) compared with combinations without EIAEDs. However, the group of AEDs classified as EIAEDs was heterogeneous and the number of patients, especially of children with EIAEDs, was relatively small. Our data indicate that oxcarbazepine and, especially, methsuximide decrease RUF concentrations as well. Therapeutic drug monitoring might be helpful because RUF concentrations differ markedly in patients on comparable RUF doses.

The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins.

PURPOSE: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One of the candidate mechanisms of pharmacoresistance is the limitation of AED access to the seizure focus by overexpression of efflux transporters, including P-glycoprotein (Pgp) and multidrug resistance proteins (MRPs).In this respect, it is important to know which AEDs are substrates for such drug transporters in humans. METHODS: In the present study, we used polarized kidney cell lines (LLC, MDCK) transfected with human drug transporters (Pgp, MRP1, MRP2 or MRP5) to evaluate whether the AED topiramate is a substrate for any of these transporters. Known Pgp and MRP substrates were used for comparison. RESULTS: Basolateral-to-apical transport of topiramate, which could be counteracted with the Pgp inhibitor, tariquidar, was determined in Pgp overexpressing LLC cells, whereas topiramate was not transported by any of the MRPs. A comparison with previous experiments in the same transport assay showed that topiramate exhibited the most pronounced Pgp-mediated efflux transport among the AEDS that have been studied as yet. CONCLUSIONS: Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.

On the role of the pontine brainstem in vocal pattern generation: a telemetric single-unit recording study in the squirrel monkey.

In a recent study, we localized a discrete area in the ventrolateral pontine brainstem of squirrel monkeys, which seems to play a role in vocal pattern generation of frequency-modulated vocalizations. The present study compares the neuronal activity of this area with that of three motoneuron pools involved in phonation, namely the trigeminal motor nucleus, facial nucleus, and nucleus ambiguous. The experiments were performed in freely moving squirrel monkeys (Saimiri sciureus) during spontaneous vocal communication, using a telemetric single-unit recording technique. We found vocalization-related activity in all motoneuron pools recorded. Each of them, however, showed a specific profile of activity properties with respect to call types uttered, syllable structure, and pre-onset time. Different activity profiles were also found for neurons showing purely vocalization-correlated activity, vocalization- and mastication-correlated activity, and vocalization- and respiration-correlated activity. By comparing the activity properties of the proposed vocal pattern generator with the three motoneuron pools, we show that the pontine vocalization area is, in fact, able to control each of the three motoneuron pools during frequency-modulated vocalizations. The present study thus supports the existence of a vocal pattern generator for frequency-modulated call types in the ventrolateral pontine brainstem.

On the role of the reticular formation in vocal pattern generation.

This review is an attempt to localize the brain region responsible for pattern generation of species-specific vocalizations. A catalogue is set up, listing the criteria considered to be essential for a vocal pattern generator. According to this catalogue, a vocal pattern generator should show vocalization-correlated activity, starting before vocal onset and reflecting specific acoustic features of the vocalization. Artificial activation by electrical or glutamatergic stimulation should produce artificially sounding vocalization. Lesioning is expected to have an inhibitory or deteriorating effect on vocalization. Anatomically, a vocal pattern generator can be assumed to have direct or, at least, oligosynaptic connections with all the motoneuron pools involved in phonation. A survey of the literature reveals that the only area meeting all these criteria is a region, reaching from the parvocellular pontine reticular formation just above the superior olive through the lateral reticular formation around the facial nucleus and nucleus ambiguus down to the caudalmost medulla, including the dorsal and ventral reticular nuclei and nucleus retroambiguus. It is proposed that vocal pattern generation takes place within this whole region.

The descending motorcortical pathway to the laryngeal motoneurons in the squirrel monkey.

The motor cortex of primates contains an area ("larynx area") which, when stimulated unilaterally, produces bilateral vocal fold adduction. In order to identify the pathway along which the cortical larynx area exerts its control on the laryngeal motoneurons, we have blocked excitatory neurotransmission in each of the main projection fields of the cortical larynx area and tested for the elicitability of vocal fold movements from this area in the squirrel monkey. Blocking was carried out by injection of the glutamate antagonist kynurenic acid. We found that injection into the dorsal reticular nucleus of the caudal medulla ipsilateral to the stimulation site blocked vocal fold movements bilaterally; injections invading major parts of the nucleus ambiguus blocked vocal fold movements exclusively ipsilateral to the injection site; and injections centered on the parvocellular reticular formation bordering the nucleus ambiguus blocked exclusively contralateral vocal fold movements. We conclude from this that the corticobulbar laryngeal control pathway synapses in the ipsilateral dorsal reticular nucleus and then divides into one component running directly to the ipsilateral nucleus ambiguus and a second component crossing to the contralateral nucleus ambiguus after having synapsed in the ipsilateral peri-ambigual reticular formation.

Acoustical correlates of affective prosody.

The word "Anna" was spoken by 12 female and 11 male subjects with six different emotional expressions: "rage/hot anger," "despair/lamentation," "contempt/disgust," "joyful surprise," "voluptuous enjoyment/sensual satisfaction," and "affection/tenderness." In an acoustical analysis, 94 parameters were extracted from the speech samples and broken down by correlation analysis to 15 parameters entering subsequent statistical tests. The results show that each emotion can be characterized by a specific acoustic profile, differentiating that emotion significantly from all others. If aversive emotions are tested against hedonistic emotions as a group, it turns out that the best indicator of aversiveness is the ratio of peak frequency (frequency with the highest amplitude) to fundamental frequency, followed by the peak frequency, the percentage of time segments with nonharmonic structure ("noise"), frequency range within single time segments, and time of the maximum of the peak frequency within the utterance. Only the last parameter, however, codes aversiveness independent of the loudness of an utterance.

Classical conditioned responses to absent tones.

BACKGROUND: Recent evidence for a tight coupling of sensorimotor processes in trained musicians led to the question of whether this coupling extends to preattentively mediated reflexes; particularly, whether a classically conditioned response in one of the domains (auditory) is generalized to another (tactile/motor) on the basis of a prior association in a second-order Pavlovian paradigm. An eyeblink conditioning procedure was performed in 17 pianists, serving as a model for overlearned audiomotor integration, and 14 non-musicians. RESULTS: During the training session, subjects were conditioned to respond to auditory stimuli (piano tones). During a subsequent testing session, when subjects performed keystrokes on a silent piano, pianists showed significantly higher blink rates than non-musicians. CONCLUSION: These findings suggest a tight coupling of the auditory and motor domains in musicians, pointing towards training-dependent mechanisms of strong cross-modal sensorimotor associations even on sub-cognitive processing levels.

Call type-specific differences in vocalization-related afferents to the periaqueductal gray of squirrel monkeys (Saimiri sciureus).

In a recent retrograde tracing study in the squirrel monkey, we found that regions in the midbrain periaqueductal gray (PAG) producing different call types when pharmacologically stimulated, receive their input largely from the same structures. The aim of the present study was to find out, whether there are quantitative differences in this input. For this reason, we counted retrogradely labeled neurons in various brain regions after injections of wheatgerm agglutinin-conjugated horseradish peroxidase (WGA-HRP) into three different vocalization-eliciting PAG sites: one site producing non-aversive contact calls (clucking); a second site producing slightly aversive social mobbing calls (cackling); and a third site producing highly aversive defensive threat calls (shrieking). Cell counting was carried out by the help of the optical fractionator technique. Six squirrel monkeys were used, two for each call type. In some regions, marked differences in the number of retrogradely labeled cells between the three call type groups occured. Such regions are the nucl. accumbens, preoptic area, posterior hypothalamus, anterior cingulate cortex, subcallosal gyrus and the nucl. striae terminalis. In some of these regions, the number of retrogradely labeled cells correlated positively (posterior hypothalamus) or negatively (preoptic area, nucl. striae terminalis) with the "aversiveness" of the elicited call type. Other regions of interest, e.g., the dorsomedial prefrontal and precallosal cortex, amygdala and hypothalamic regions surrounding the fornix, revealed no clear differences in their afferent projections to the different vocalization-eliciting PAG sites. The results make clear that distinct vocalization-controlling regions in the PAG receive a qualitatively similar but quantitatively differentiated input.

Vocal expression of emotions in normally hearing and hearing-impaired infants.

The vocalizations of seven normally hearing (NH) and seven severely hearing-impaired (HI) infants were compared to find out the influence of auditory feedback on preverbal utterances. It was tested whether there are general differences in vocalizations between NH and HI infants, and whether specific emotional states affect the vocal production of NH and HI infants in the same way. First, the acoustic structure of the three most common vocal types was analyzed; second, the composition of vocal sequences was examined. Vocal sequence composition turned out to be more affected by hearing impairment than the acoustic structure of single vocalizations. This result indicates that the acoustic structure of preverbal vocalizations is to a great extent predetermined, whereas the composition of vocal sequences is influenced by auditory input.

Afferents of vocalization-controlling periaqueductal regions in the squirrel monkey.

In order to determine the input of vocalization-controlling regions of the midbrain periaqueductal gray (PAG), wheat germ agglutinin-horseradish peroxidase was injected in six squirrel monkeys (Saimiri sciureus) at PAG sites yielding vocalization when injected with the glutamate agonist homocysteic acid. Brains were scanned for retrogradely labeled areas common to all six animals. The results show that the vocalization-eliciting sites receive a widespread input, with the heaviest projections coming from the surrounding PAG, dorsomedial and ventromedial hypothalamus, medial preoptic region, substantia nigra pars diffusa, zona incerta and reticular formation of the mesencephalon, pons, and medulla. The heaviest cortical input reaches the PAG from the mediofrontal cortex. Moderate to weak projections come from the insula, lateral prefrontal, and premotor cortex as well as the superior and middle temporal cortex. Subcortical moderate to weak projections reach the PAG from the central and medial amygdala, nucleus of the stria terminalis, septum, nucleus accumbens, lateral preoptic region, lateral and posterior hypothalamus, globus pallidus, pretectal area, deep layers of the superior colliculus, the pericentral inferior colliculus, mesencephalic trigeminal nucleus, locus coeruleus, substantia nigra pars compacta, dorsal and ventral raphe, vestibular nuclei, spinal trigeminal nucleus, solitary tract nucleus, and nucleus gracilis. The input of the periaqueductal vocalization-eliciting regions thus is dominated by limbic, motivation-controlling afferents; input, however, also comes from sensory, motor, arousal-controlling, and cognitive brain areas.

Neural pathways underlying vocal control.

Vocalization is a complex behaviour pattern, consisting of essentially three components: laryngeal activity, respiratory movements and supralaryngeal (articulatory) activity. The motoneurones controlling this behaviour are located in various nuclei in the pons (trigeminal motor nucleus), medulla (facial nucleus, nucl. ambiguus, hypoglossal nucleus) and ventral horn of the spinal cord (cervical, thoracic and lumbar region). Coordination of the different motoneurone pools is carried out by an extensive network comprising the ventrolateral parabrachial area, lateral pontine reticular formation, anterolateral and caudal medullary reticular formation, and the nucl. retroambiguus. This network has a direct access to the phonatory motoneurone pools and receives proprioceptive input from laryngeal, pulmonary and oral mechanoreceptors via the solitary tract nucleus and principal as well as spinal trigeminal nuclei. The motor-coordinating network needs a facilitatory input from the periaqueductal grey of the midbrain and laterally bordering tegmentum in order to be able to produce vocalizations. Voluntary control of vocalization, in contrast to completely innate vocal reactions, such as pain shrieking, needs the intactness of the forebrain. Voluntary control over the initiation and suppression of vocal utterances is carried out by the mediofrontal cortex (including anterior cingulate gyrus and supplementary as well as pre-supplementary motor area). Voluntary control over the acoustic structure of vocalizations is carried out by the motor cortex via pyramidal/corticobulbar as well as extrapyramidal pathways. The most important extrapyramidal pathway seems to be the connection motor cortex-putamen-substantia nigra-parvocellular reticular formation-phonatory motoneurones. The motor cortex depends upon a number of inputs for fulfilling its task. It needs a cerebellar input via the ventrolateral thalamus for allowing a smooth transition between consecutive vocal elements. It needs a proprioceptive input from the phonatory organs via nucl. ventralis posterior medialis thalami, somatosensory cortex and inferior parietal cortex. It needs an input from the ventral premotor and prefrontal cortex, including Broca's area, for motor planning of longer purposeful utterances. And it needs an input from the supplementary and pre-supplementary motor area which give rise to the motor commands executed by the motor cortex.

Telemetrically recorded neuronal activity in the inferior colliculus and bordering tegmentum during vocal communication in squirrel monkeys (Saimiri sciureus).

In order to find out whether the inferior colliculus, in addition to its auditory decoding function, also has an auditory gating function in the sense that it treats self-produced sounds differently from external ones, we have explored the inferior colliculus and bordering tegmentum for neurones reacting differently to self-produced vocalizations and vocalizations produced by conspecifics. The experiments were made in the squirrel monkey (Saimiri sciureus), using a telemetric extracellular recording technique which allowed to register neuronal activity in freely moving animals during natural vocal communication. The results show that the neurones of the central nucleus of the inferior colliculus do not react differently to self-produced and group mate vocalizations of the same type. In the external nucleus of the inferior colliculus, in addition to classical auditory neurones, neurones are found which react to the vocalizations of group mates, but not to self-produced vocalizations. In the paralemniscal area just below the inferior colliculus, there are neurones which are active during self-produced vocalization, but not during vocalization produced by other animals. The results suggest that the external nucleus of the inferior colliculus and bordering tegmentum are involved in vocalization-dependent auditory gating processes.

2-Deoxyglucose uptake during vocalization in the squirrel monkey brain.

In the squirrel monkey (Saimiri sciureus), the cerebral 2-deoxyglucose uptake was compared between animals made to vocalize by electrical stimulation of the periaqueductal grey and animals stimulated in the same structure, but sub-threshold for vocalization. A significantly higher 2-deoxyglucose uptake in the vocalizers than the non-vocalizers was found in the dorsolateral prefrontal cortex, supplementary and pre-supplementary motor area, anterior and posterior cingulate cortex, primary motor cortex, claustrum, centrum medianum, perifornical hypothalamus, periaqueductal grey, intercollicular region, dorsal mesencephalic reticular formation, peripeduncular nucleus, substantia nigra, nucl. ruber, paralemniscal area, trigeminal motor, principal and spinal nuclei, solitary tract nucleus, nucl. ambiguus, nucl. retroambiguus, nucl. hypoglossus, ventral raphe and large parts of the medullary reticular formation. The study makes clear that vocalization, even in the case of genetically pre-programmed patterns, depends upon an extensive network, beyond the well-known periaqueductal grey, nucl. retroambiguus and cranial motor nuclei pathway.

Cortico-cortical projections of the motorcortical larynx area in the rhesus monkey.

The efferent cortico-cortical projections of the motorcortical larynx area were studied in three rhesus monkeys (Macaca mulatta), using biotin dextranamine as anterograde tracer. Identification of the larynx area was made with the help of electrical brain stimulation and indirect laryngoscopy. Heavy projections were found into the surrounding ventral and dorsal premotor cortex (areas 6V and D), primary motor cortex (area 4), the homolog of Broca's area (mainly area 44), fronto- and parieto-opercular cortex (including secondary somatosensory cortex), agranular, dysgranular and granular insula, rostral-most primary somatosensory cortex (area 3a), supplementary motor area (area 6M), anterior cingulate gyrus (area 24c) and dorsal postarcuate cortex (area 8A). Medium projections could be traced to the ventrolateral prefrontal and lateral orbital cortex (areas 47L and O), the primary somatosensory areas 3b and 2, the agranular and dysgranular insula, and the posteroinferior parietal cortex (area 7; PFG, PG). Minor projections ended in the lateral and dorsolateral prefrontal cortex (areas 46V and 8B), primary somatosensory area 1 and cortex within the intraparietal sulcus (PEa) and posterior sulcus temporalis superior (TPO). Due to its close spatial relationship to the insula on the one hand and the premotor cortex on the other, the larynx area shows projections which, in some respects, are not typical for classical primary motor cortex.

Efferent subcortical projections of the laryngeal motorcortex in the rhesus monkey.

In order to better understand the descending voluntary vocal control pathway, the efferent subcortical projections of the laryngeal motorcortex were studied in the rhesus monkey (Macaca mulatta). For this purpose, the left motorcortex was exposed in three animals under narcosis. By electrical brain stimulation, sites were identified yielding vocal fold adduction. Effective sites were injected with the anterograde tracer biotin dextran amine. Subcortical projections could be traced within the forebrain to the putamen, caudate nucleus, claustrum, zona incerta, field H of Forel and a number of thalamic nuclei, with the heaviest projections to the nuclei ventralis lateralis, ventralis posteromedialis, including its parvocellular part, medialis dorsalis, centralis medialis, centrum medianum and reuniens. In the midbrain, labeling was found in the deep mesencephalic nucleus. In the lower brainstem, fibers terminated in the pontine and medullary reticular formation, locus coeruleus, nucleus subcoeruleus, medial parabrachial nucleus, nucleus of the spinal trigeminal tract, solitary tract nucleus and facial nucleus. No projections were found to the nucl. ambiguus. The fact that monkeys, in contrast to humans, lack a direct connection of the motorcortex with the laryngeal motoneurons suggests that this connection has evolved in the last few million years and might represent one of the factors that made speech evolution possible.

Neuronal activity in the inferior colliculus and bordering structures during vocalization in the squirrel monkey.

In four squirrel monkeys (Saimiri sciureus), the inferior colliculus, together with the neighboring superior colliculus, reticular formation, cuneiform nucleus and parabrachial area, were explored with microelectrodes, looking for neurons that might be involved in the discrimination between self-produced and external sounds. Vocalization was elicited by kainic acid injections into the periaqueductal gray of the midbrain. Acoustic tests were carried out with ascending and descending narrow-band noise sweeps spanning virtually the whole hearing range of the squirrel monkey. Altogether 577 neurons were analyzed. Neurons that both were audiosensitive and fired in advance of self-produced vocalization were found almost exclusively in the pericentral nuclei of the inferior colliculus and the adjacent reticular formation. Only the latter, however, contained, in addition, neurons that fired during external acoustic stimulation, but remained quiet during self-produced vocalization. These findings suggest that the reticular formation bordering the inferior colliculus is involved in the discrimination between self-produced and foreign vocalization on the basis of a vocalmotor feedforward mechanism.

Acoustic analyses of developmental changes and emotional expression in the preverbal vocalizations of infants.

The nonverbal vocal utterances of seven normally hearing infants were studied within their first year of life with respect to age- and emotion-related changes. Supported by a multiparametric acoustic analysis it was possible to distinguish one inspiratory and eleven expiratory call types. Most of the call types appeared within the first two months; some emerged in the majority of infants not until the 5th ("laugh") or 7th month ("babble"). Age-related changes in acoustic structure were found in only 4 call types ("discomfort cry," "short discomfort cry," "wail," "moan"). The acoustic changes were characterized mainly by an increase in harmonic-to-noise ratio and homogeneity of the call, a decrease in frequency range and a downward shift of acoustic energy from higher to lower frequencies. Emotion-related differences were found in the acoustic structure of single call types as well as in the frequency of occurrence of different call types. A change from positive to negative emotional state was accompanied by an increase in call duration, frequency range, and peak frequency (frequency with the highest amplitude within the power spectrum). Negative emotions, in addition, were characterized by a significantly higher rate of "crying," "hic" and "ingressive vocalizations" than positive emotions, while positive emotions showed a significantly higher rate of "babble," "laugh," and "raspberry."

Serum concentrations of pregabalin in patients with epilepsy: the influence of dose, age, and comedication.

Pregabalin (PGB) is a new antiepileptic drug (AED) approved for adjunctive therapy for partial seizures with and without generalized tonic-clonic seizures and for the treatment of peripheral neuropathic pain in adults. PGB does not bind to plasma proteins and is excreted predominantly unchanged by the kidneys. Previous studies indicated that PGB shows no relevant interactions with other AEDs. The aim of this study was to investigate the influence of PGB dose, patient age, and comedication on the serum concentration of PGB. In total, 198 samples of 167 (adult) inpatients who fulfilled the inclusion criteria (eg, trough concentration, body weight available) were investigated. A patient was considered twice only if the comedication had been changed. The PGB serum concentration (mg/L) in relation to PGB dose/body weight (mg/kg) per day (level-to-dose ratio, LDR, [(mg/L)/(mg/kg)=kg/L]) was calculated and compared for the most frequent drug combinations (n=97). Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that comedication had a slight but significant (P = 0.02) effect on PGB serum concentrations. The median LDR of PGB was 0.29 for PGB + oxcarbazepine (n=16), 0.31 for PGB + carbamazepine (n=20), 0.35 for PGB + levetiracetam (n=11), 0.35 for PGB + lamotrigine (n=15), and 0.39 for PGB + valproic acid + lamotrigine (n=35). Regression analysis including all 198 samples indicated (in accordance with analysis of covariance) that PGB concentrations were lower in combination with enzyme-inducing AEDs (phenytoin, carbamazepine, oxcarbazepine) and were age-dependent (higher in older patients). The PGB dose-concentration relationship was nearly linear (r=0.68, P<0.0001). However, patients on the same PGB dosage per body weight had rather different PGB trough concentrations, which could be explained only in part by age and comedication. The increase of PGB serum concentrations in older patients is in accordance with expectations for drugs that are predominantly renally excreted. Unexpectedly and in contrast to other studies, our data indicate that comedication with enzyme-inducing antiepileptic drugs (eg, carbamazepine) can moderately decrease PGB serum concentrations (about 20% to 30%). Further studies should clarify the effect of age and interactions on PGB concentrations.