Biomedical subjects

U Ebert

Publications and source records attributed to U Ebert.

At least 19 recordsLinked to original sources

PubMed2001

Determination of scopolamine in human serum and microdialysis samples by liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method with a rapid and simple sample preparation was developed for the determination of scopolamine in biological fluids. Scopolamine and the internal standard atropine in serum samples were extracted and cleaned up by using an automated solid phase extraction method. Microdialysis samples were directly injected into the LC-MS system. The mass spectrometer was operated in the multi reaction monitoring mode. A good linear response over the range of 20 pg/ml to 5 ng/ml was demonstrated. The accuracy for added scopolamine ranged from 95.0 to 104.0%. The lower limit of quantification was 20 pg/ml. This method is suitable for pharmacokinetic studies.

Calibration↗

PubMed2001

Spontaneous paroxysmal circling behavior in the ci2 rat mutant: epilepsy with rotational seizures or hyperkinetic movement disorder?

Circling, turning, rotating, spinning, wheeling, and cursive hyperkinesia are all synonymous terms used to describe the active movement of an animal in a circular direction. Circling behavior can be evoked by unilateral electrical and chemical stimulation or lesions of various brain sites, but can also occur after systemic drug administration or spontaneously in normal animals or mutant rodents. In humans, stereotypic body rotation can occur as a distinctive entity of generalized and focal epilepsy, and may be due to involvement of the striatum. We have previously described a Lewis rat mutant (ci2) with a behavioral phenotype characterized by lateralized circling, hyperactivity, opisthotonus, and ataxia. In these rats, circling occurs in phases or bursts either spontaneously or in response to stress. Neurochemical data indicate that the circling behavior of the ci2 mutants is related to an abnormal asymmetry in dopaminergic activity in the striatum. Because of the similarities to rotational epilepsy, we used video and electroencephalographic recordings to study whether the rotational behavior of the ci2 mutant rat is a result of a partial or generalized epilepsy. Epileptic WAG/Rij rats were used for comparison. Video monitoring of ci2 rats in the absence of any stress or disturbance showed that circling occurs in paroxysmal bursts during active wakefulness, but not during passive wakefulness or sleep. Circling was not preceded or followed by any convulsive motor seizures and was not associated with epileptiform abnormalities in the electroencephalogram, whereas WAG/Rij rats exhibited myoclonic seizures and epileptic spike-wave discharges during passive wakefulness and sleep. As a result of the association of circling with active wakefulness, ci2 rats exhibited many more rotations during the dark (active) phase compared with the light (rest) period. Increase in active wakefulness during the light phase by transfer of the rats to a new environment induced or intensified circling behavior. Most ci2 rats showed a consistent lateral preference during circling, but some rats changed their preference from one session to another. The data indicate that spontaneous paroxysmal circling behavior in the ci2 rat is not a consequence of epilepsy but reflects a hyperkinetic movement disorder with abnormal lateralization of brain function.

Animals↗

PubMed2001

Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy.

Systemic administration of pilocarpine in rats can result in a chronic behavioral state that is similar to human temporal lobe epilepsy. The pilocarpine model of epilepsy is widely used for studying the factors that contribute to the development of epilepsy as a consequence of status epilepticus (SE). For this purpose, pilocarpine is either administered alone at a high systemic dose or in combination with lithium, which markedly potentiates the convulsant effect of pilocarpine. Both experimental protocols, however, are associated with high mortality rates. In the present study, we evaluated whether mortality rate in rats can be decreased by repeated administration of low doses of pilocarpine. The time the rats spent in SE was limited by diazepam. Preliminary experiments in lithium-free rats indicated that repeated low-dose administration of pilocarpine is too time-consuming to produce SE compared to single high-dose administration. All subsequent experiments were performed in lithium-pretreated rats. Single-dose injection of 30 mg/kg pilocarpine produced SE in approximately 70% of the animals, but 45% of the rats died although SE was interrupted by diazepam after 90 min. Repeated i.p. administration of 10 mg/kg pilocarpine at 30-min intervals resulted in SE after 2-4 injections; the mean dose of pilocarpine needed to induce SE was 26 mg/kg. When SE was interrupted after 90 min, mortality rate was below 10%, which was significantly lower compared to the protocol with one single administration of 30 mg/kg pilocarpine. In contrast to mortality rate, the development of spontaneous recurrent seizures did not differ between experimental protocols. Almost all rats which had experienced a SE of at least 60 min developed chronic epilepsy. Average latency to the first spontaneous seizure was approximately 40 days. The frequency and severity of spontaneous seizures was not significantly different between protocols, although animal groups with repeated low-dose treatment tended to have higher frequencies of spontaneous seizures compared to single-dose administration. The present study demonstrates that systemic treatment of lithium-pretreated rats with several low doses of pilocarpine efficiently produces SE and chronic epilepsy with much lower mortality rates than single-dose pilocarpine.

Animals↗

PubMed2001

Auditory and vestibular defects in the circling (ci2) rat mutant.

The circling rat is an autosomal recessive mutant (homozygous ci2/ci2) that displays lateralized circling behaviour, locomotor hyperactivity, ataxia and stereotypic head-movement. These abnormal behaviours occur in phases or bursts either spontaneously or in response to stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviours. We have previously found that ci2/ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the rats turn away from the brain hemisphere with higher striatal dopaminergic activity. In view of the similarities of the motor syndrome of the ci2/ci2 mutant rat to that of mouse deafness mutants, the present study evaluated the hearing ability of the circling rat mutant by recording brainstem auditory-evoked potentials. To test for vestibular dysfunction, a swimming test was conducted. Histological methods were used to examine the cochlear and vestibular parts of the inner ear and the cochlear and vestibular brainstem nuclei for defects. The absence of auditory-evoked potentials demonstrated a complete hearing loss in the adult ci2/ci2 mutant rat, whereas heterozygous littermates exhibited auditory-evoked potentials with thresholds resembling those of other laboratory strains. Furthermore, the mutant rats were unable to swim. Histological analysis of the inner ear of adult mutants revealed virtually complete loss of the cochlear neuroepithelium, while no such hair cell degeneration was seen in the vestibular parts of the inner ear. However, part of the vestibular hair cells showed protrusions into the endolymphatic space, suggesting alterations in the cytoskeletal architecture. The histological findings in mutant circling rats strongly indicate that the hearing loss of the mutants is of the sensory neural type, the most prevalent type of hearing loss. In the cochlear nuclei of the brain stem of mutant rats, neurons exhibited an abnormal shape, reduced size and increased density compared to controls. In contrast, no abnormal neuronal morphology was seen in the vestibular nuclei, but a significantly reduced neuronal density was found in the medial vestibular nucleus. Abnormal vestibular function would be a likely explanation for the disturbed balance of mutant rats as exemplified by the ataxia and the inability to swim, whereas the previous data on these rats strongly indicate an involvement of the basal ganglia in the abnormal circling behaviour. The genetic defect in the mutant rats, thus, results in a clinical syndrome with features also seen in human genetic disorders with deafness and hyperkinesia, making the ci2/ci2 rat an excellent model for investigating both cochlear/vestibular dysfunction and hyperkinetic movement disorders.

Animals↗

PubMed2001

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers.

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the "cholinergic hypothesis" of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques. This was a randomized, three-way crossover, open-label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (i.v.) infusion over 15 minutes or an intramuscular (i.m.) injection or a placebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after i.v. infusion were clearance (CL) 205 +/- 36.6 L/h, volume of distribution (Vd) 363 +/- 66.7 L, distribution half-life (t1/2 alpha) 2.9 +/- 0.67 min, and terminal half-life (t1/2 beta) 105.4 +/- 9.94 min (mean +/- SEM). Mean peak serum concentrations (Cmax) were 4.66 and 0.96 ng/ml after i.v. and i.m. administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after i.m. administration (81.27 +/- 11.21 ng/ml/min) was significantly lower compared to the value after i.v. infusion (157.28 +/- 30.86 ng/ml/min) (mean +/- SEM, p < 0.05). Absolute bioavailability of scopolamine after i.m. injection was 57% +/- 0.08% (mean +/- SEM). After both i.v. and i.m. administration, scopolamine induced a decrease in EEG alpha power (7.50-11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration-EEG effect relationships determined after i.v. infusion of scopolamine were successfully characterized by a sigmoidal Emax model. The averaged values of the pharmacodynamic parameters were E0 = 0.58 microV2, Emax = 0.29 microV2, EC50 = 0.60 ng/ml, and gamma = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK-PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered i.v. appears to be a suitable dose.

Adult↗

PubMed2000

The new antiepileptic drugs lamotrigine and felbamate are effective in phenytoin-resistant kindled rats.

We evaluated the anticonvulsant efficacy of the antiepileptic drugs (AEDs) lamotrigine (LTG) and felbamate (FBM) in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses LTG and FBM exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both LTG and FBM proved to be effective anticonvulsant drugs in the kindling model by markedly increasing the ADT. Seizure severity and duration recorded at ADT currents were hardly reduced, indicating that both drugs predominantly affect induction of focal seizures and not seizure spread from the focus. In phenytoin nonresponders, LTG and FBM significantly increased ADT, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficacious in increasing ADT in phenytoin responders than in nonresponders, substantiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phenytoin nonresponders are a unique model for the search for new AEDs with improved efficacy in refractory partial epilepsy.

Amygdala↗

PubMed2000

Strong olfactory stimulation reduces seizure susceptibility in amygdala-kindled rats.

Seizures in human temporal lobe epilepsy are characterized by paroxysmal activity in the limbic system. The primary olfactory or piriform cortex is a central part of the limbic system. Since a relationship between olfactory sensation and limbic seizures has been described, we were interested in the effect of strong olfactory stimulation on the seizure susceptibility of amygdala-kindled rats, a model of human temporal lobe epilepsy. Olfactory stimulation with toluene was able to suppress seizures in most kindled rats after stimulation at 20% above the threshold for eliciting epileptic afterdischarges. Olfactory stimulation with toluene or ammonia increased the threshold by 27 and 25% compared to control conditions. Our data substantiate that olfactory brain regions, such as the piriform cortex, are involved in amygdala-kindled seizures and suggest that strong physiological stimulation of this nucleus interferes with on-going seizure activity in the limbic system. Thus, olfactory stimulation could contribute to anticonvulsant therapy.

Ammonia↗

PubMed2000

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects.

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.

Adult↗

PubMed2000

Kindling causes persistent in vivo changes in firing rates and glutamate sensitivity of central piriform cortex neurons in rats.

The present experiments were undertaken to study whether amygdala kindling induces persistent alterations in the functional status of neurons of the central piriform cortex, a subregion of the piriform cortex identified previously as a site involved in the kindling process. Extracellular, single-unit recordings of piriform cortex neurons were made in anesthetized fully kindled rats at an interval of at least five weeks after the last seizure. Electrode implanted but not kindled rats served as sham controls. An additional group of non-implanted rats was used as naive controls. Spontaneously firing piriform cortex neurons were characterized in all groups by smooth, sharp, biphasic (i.e. positive/negative) action potentials with a duration of 0.8-1.8 ms, and were primarily located at the border between piriform cortex layers II and III. In kindled rats, neurons in the central piriform cortex exhibited a significantly higher firing rate compared to controls. Based on median group values, the increase in basal activity in kindled rats averaged about 90%. The responsiveness of piriform cortex neurons to neurotransmitters was tested by microiontophoretic application of glutamate, N-methyl-D-aspartate and GABA. Piriform cortex neurons of kindled rats exhibited a significantly lower responsiveness to the excitatory effect of glutamate than naive controls. A lowered glutamate responsiveness was also seen in sham controls. No significantly altered transmitter sensitivities of piriform cortex neurons from kindled rats were seen with N-methyl-D-aspartate or GABA. The data indicate that amygdala kindling causes persistent interictal changes in both basal activity and glutamate responsiveness of central piriform cortex neurons which could contribute to the abnormal hyperexcitability characteristic of kindling.

Action Potentials↗

PubMed2000

Bilateral lesions of the central but not anterior or posterior parts of the piriform cortex retard amygdala kindling in rats.

The piriform cortex is thought to be involved in temporal lobe seizure propagation, such as that occurring during kindling of the amygdala or hippocampus. A number of observations suggested that the circuits of the piriform cortex might act as a critical pathway for limbic seizure discharges to assess motor systems, but direct evidence for this suggestion is scarce. Furthermore, the piriform cortex is not a homogeneous structure, which complicates studies on its role in limbic epileptogenesis. We have previously reported data indicating that the central part of the piriform cortex might be particularly involved during amygdala kindling. In order to further evaluate the role of different parts of the piriform cortex during kindling development, we bilaterally destroyed either the central, anterior or posterior piriform cortex by microinjections of ibotenate two weeks before onset of amygdala kindling. Lesions of the anterior piriform cortex hardly affected kindling acquisition, except that fewer animals exhibited stage 3 (unilateral forelimb) seizures compared to sham controls. Lesions of the central piriform cortex significantly retarded kindling, which was due to a decreased progression from stage 3 to stage 4/5 seizures, i.e. the lesioned rats needed significantly longer for the acquisition of generalized clonic seizures in the late stages of kindling development. Lesions of the posterior piriform cortex did not significantly affect kindling development. The data demonstrate that different parts of the piriform cortex mediate qualitatively different effects on amygdala kindling. The central piriform cortex seems to be a neural substrate involved in the continuous development of kindling from stage 3 to stages 4/5, indicating that this part of the piriform cortex may have preferred access, either directly or indirectly, to structures capable of supporting generalized kindled seizure expression.

Amygdala↗

PubMed2000

Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats.

We have previously shown that subgroups can be selected from large groups of amygdala kindled Wistar rats which either respond consistently or do not respond to the anticonvulsant effect of phenytoin. Phenytoin nonresponders were proposed as a model for pharmaco-resistant temporal lobe epilepsy. In the present study we examined whether the differences of individual rats in response to phenytoin are already present before kindling or are a consequence of kindling. For this purpose, 52 rats were once tested with phenytoin, then kindled, and then repeatedly tested with phenytoin for selection of subgroups. For subgroup selection after kindling, the phenytoin prodrug fosphenytoin was used because of its water solubility and its improved tolerability and absorption after i.p. administration in rats. Before kindling, phenytoin significantly increased the afterdischarge threshold (ADT), i.e. a sensitive measure of focal seizure activity, but there was large individual variation with only 32 of the 52 rats reacting with an ADT increase, while the remaining rats showed either no effect or ADT decreases. After kindling, the selection resulted in 16 rats with consistent ADT increases in response to phenytoin and ten nonresponders (the remaining 26 rats showed variable responses). Unexpectedly, in rats which were responders after kindling, phenytoin exerted no significant anticonvulsant effect before kindling, while kindled nonresponders were very sensitive to phenytoin before kindling, indicating that the kindling process was responsible for the loss of anticonvulsant efficacy in kindled nonresponders and the development of phenytoin's efficacy in kindled responders. The present results substantiate that kindled subgroups of Wistar rats with different response to phenytoin are a valuable source for studying the mechanisms underlying the development of pharmaco-resistant limbic seizures.

Amygdala↗

PubMed2000

Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats.

We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AEDs) gabapentin and levetiracetam in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e. a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses gabapentin and levetiracetam exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both gabapentin and levetiracetam proved to be effective anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedly decreased seizure severity recorded at ADT currents, indicating that these drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary generalized seizures (GST) was determined in addition to ADT, gabapentin and levetiracetam strikingly increased this threshold compared to predrug control. In phenytoin nonresponders, gabapentin and levetiracetam significantly increased ADT and GST, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom older AEDs have failed. In phenytoin responders, gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to gabapentin, levetiracetam was more efficacious in increasing ADT in nonresponders than in responders. The data of this study substantiate that phenytoin nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Acetates↗

PubMed2000

Effects of lesions of the perirhinal cortex on amygdala kindling in rats.

The perirhinal cortex (PRC), the region of temporal cortex adjacent to the rhinal sulcus, has been suggested as a critical substrate for the development and expression of generalized motor seizures in the late stages of kindling development. For further investigation of the role of the PRC in limbic kindling, excitotoxic lesions centered on PRC by microinjection of ibotenate were performed in rats 2 weeks before onset of amygdala kindling. Rats with large bilateral or unilateral PRC lesions showed the same rate and pattern of kindling development as sham-lesioned controls. The only significant difference to controls was a higher afterdischarge threshold in the fully kindled state of lesioned rats. These data do not indicate a critical role for the bilateral involvement of the PRC in kindling from other limbic brain regions.

Amygdala↗

PubMed2000

Physostigmine reversal of midazolam-induced electroencephalographic changes in healthy subjects.

OBJECTIVE: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent antagonist of midazolam-induced sedation. Physostigmine has also been shown to reverse benzodiazepine sedation in anecdotal reports. The aim of this study was to quantitatively characterize the reversal of midazolam-induced changes in electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo. METHODS: Twelve healthy male subjects received 5 mg midazolam as an intravenous infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline solution) were administered as intravenous injections in a randomized crossover fashion. Midazolam serum concentrations were measured using liquid chromatography-tandem mass spectrometry. The time from the start of injection until awakening was noted and the EEG was measured. RESULTS: Four subjects were excluded from further pharmacokinetic and pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power could be observed in each of the three study periods. The pharmacokinetics of midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P < .05). After injection of flumazenil and physostigmine, an increase in EEG alpha power was observed, whereas placebo did not affect alpha power. Subjects opened their eyes 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received flumazenil and physostigmine, respectively (mean +/- SEM; P < .001). CONCLUSION: Physostigmine and flumazenil antagonized midazolam-induced sedation. This suggests that a reversible central anticholinergic mechanism may be involved in the sedative action of midazolam.

Adult↗

PubMed2000

Universal algebraic relaxation of velocity and phase in pulled fronts generating periodic or chaotic states

We investigate the asymptotic relaxation of so-called pulled fronts propagating into an unstable state, and generalize the universal algebraic velocity relaxation of uniformly translating fronts to fronts that generate periodic or even chaotic states. A surprising feature is that such fronts also exhibit a universal algebraic phase relaxation. For fronts that generate a periodic state, like those in the Swift-Hohenberg equation or in a Rayleigh-Benard experiment, this implies an algebraically slow relaxation of the pattern wavelength just behind the front, which should be experimentally testable.

Journal Article↗

PubMed2000

Subdiffusive fluctuations of "pulled" fronts with multiplicative noise

We study the propagation of a "pulled" front with multiplicative noise that is created by a local perturbation of an unstable state. Unlike a front propagating into a metastable state, where a separation of time scales for sufficiently large t creates a diffusive wandering of the front position about its mean, we predict that for so-called pulled fronts, the fluctuations are subdiffusive with root mean square wandering Delta(t) approximately t(1/4), not t(1/2). The subdiffusive behavior is confirmed by numerical simulations: For t</=600, these yield an effective exponent slightly larger than 1/4.

Journal Article↗

PubMed2000

Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats.

PURPOSE: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). METHODS: Anticonvulsant response was tested by determining the afterdischarge threshold (ADT; i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. RESULTS: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). CONCLUSIONS: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Amygdala↗

PubMed2000

Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects.

OBJECTIVES: To investigate the effects of grapefruit juice on absolute bioavailability of scopolamine in healthy subjects and to evaluate differences in pharmacokinetics and pharmacodynamics between genders. SUBJECTS, MATERIAL AND METHODS: 14 healthy subjects (7 men and 7 women) received scopolamine 0.5 mg as intravenous infusion, and as oral ingestion with and without grapefruit juice on separate occasions. Serum and urine samples were analyzed using gas chromatography-ion trap tandem mass spectrometry. Changes in subjective state were determined up to 24 hours after drug administration. RESULTS: After oral administration, pretreatment with grapefruit juice led to a 30% increase in systemic bioavailability of scopolamine (p = 0.005) and a significant increase in time to reach peak serum concentration (tmax) of scopolamine (p < 0.001). The Cmax value (6.61+/-0.63 ng/ml) of scopolamine after i.v. administration in male subjects was significant higher compared with the value in female subjects (3.93+/-0.04 ng/ml; geometric mean +/- SEM; p = 0.007). No differences were found in urinary excretion rate of scopolamine and scopolamine glucuronide across genders and between the three different routes of scopolamine administration. Scopolamine produced time-dependent decrements in subjective alertness while contentment and calmness were not influenced. CONCLUSIONS: Pretreatment with grapefruit juice delayed the absorption and increased the bioavailability of scopolamine, whereas elimination was not significantly affected. This study identified an influence of gender on Cmax of scopolamine after i.v. infusion.

Adult↗