Clementina M. van Rijn

The Importance of Drug Interactions in Epilepsy Therapy

Summary: Long‐term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over‐the‐counter drugs and nutritional supplements are increasingly being self‐administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme‐inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme‐inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ‐epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non‐AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

Auditory event-related potentials in humans and rats: Effects of task manipulation

The purpose of this study was to compare components of the rat and human auditory event-related potential (ERP) as generated in active oddball and passive single-stimulus tasks. The rats were trained to discriminate between target and standard stimuli in an oddball task, whereas the human subjects received instructions. Task effects on various ERP components were found in both species. Interestingly, effects on the P3 component were similar in the species with regard to amplitude: Target stimuli elicited a higher amplitude in the oddball task than did standard stimuli. This might indicate that the P3 shares the same characteristics between species. However, the first four components occurred 1.82 times earlier in rats than in humans, expecting a P3 of about 200 ms in rats. The P3 in rats appeared at 380 ms. We conclude that either the relation between human and rat peak latencies is not linear, or the P3 in rats is not the equivalent of the human P3.

Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex.

Abstract The molecular mechanism underlying the activity of the novel antiepileptic drug retigabine is not yet fully understood. The aim of this study was to investigate whether retigabine interacts directly with the GABA A receptor complex (γ-aminobutyric acid). Receptor-binding assays were conducted using rat brain membranes. [ 3 H]- t -Butyl-bicyclo-orthobenzoate ([ 3 H]TBOB) was used as a tracer ligand. We determined the effects of GABA and retigabine in the presence of several concentrations of GABA on the binding of [ 3 H]TBOB. GABA inhibited [ 3 H]TBOB binding with an EC 50 of 4.8 μM. In the absence of GABA, retigabine inhibited [ 3 H]TBOB with an EC 50 of 124 μM and an EC 50 of 42 μM in the presence of 2.5 μM GABA. Isobolic analysis revealed that retigabine acts in synergy with GABA in displacing [ 3 H]TBOB. This synergy could be quantified by a molecular model in which GABA and retigabine both allosterically displace [ 3 H]TBOB, and retigabine allosterically enhances the binding of GABA and vice versa with a factor of 4. In summary, we found that retigabine does indeed interact with a site on the GABA A receptor complex, and this site is positively allosterically coupled with the GABA site. This GABA-positive effect may well contribute to the clinical anticonvulsive effects of retigabine.

Neurodegenerative Properties of Chronic Pain: Cognitive Decline in Patients with Chronic Pancreatitis

Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance), use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains (psychomotor performance, memory, executive functions) were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients.

Neurophysiological correlates of nociceptive heterosynaptic long-term potentiation in humans

Long-term potentiation (LTP) is a cellular model of synaptic plasticity and reflects an increase of synaptic strength. LTP is also present in the nociceptive system and is believed to be one of the key mechanisms involved in the manifestations of chronic pain. LTP manifested as an increased response in pain perception can be induced in humans using high-frequency electrical stimulation (HFS). The aim of this study was to induce spinal heterosynaptic LTP using HFS and investigate its heterotopic effects on event-related potentials (ERPs) to repeated nonpainful cutaneous stimuli as a possible electrophysiological cortical correlate of sensitization. Twenty-two healthy subjects were randomly assigned to one of the two experimental conditions: HFS and control stimulation. Before and after the stimulation, both conditions received heterotopic mechanical (pinprick) and paired nonpainful electrical test stimuli to quantify and confirm the effects of HFS on the behavioral level. ERPs to paired nonpainful electrical stimulation were measured simultaneously. Conditioning HFS resulted in significant heterotopic effects after 30 min, including increased perceived intensity in response to (pinprick) mechanical and paired nonpainful electrical stimulation compared with control. The paired nonpainful electrical stimuli were accompanied by significantly enhanced responses regarding the ERP N1-P2 peak-to-peak and P300 amplitude compared with control. These findings suggest that HFS is capable of producing heterosynaptic spinal LTP that can be measured not only behaviorally but also using ERPs.

WAG/Rij rats show a reduced expression of CB1 receptors in thalamic nuclei and respond to the CB1 receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges

Purpose:  Genetically epileptic WAG/Rij rats develop spontaneous absence‐like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type‐1 cannabinoid (CB1) receptors.

Anticonvulsive and antiepileptogenic effects of levetiracetam in the audiogenic kindling model

Purpose: To study anticonvulsive and antiepileptogenic effects of singe levetiracetam (LEV) administration in the model of audiogenic kindling.

The effects of vigabatrin on type II spike wave discharges in rats

The antiepileptic drug vigabatrin increases GABA concentrations by inhibiting GABA transaminase. The effects of vigabatrin on type II spike wave discharges (SWDs) in the electroencephalogram of ACI rats were studied in order to learn more about the effects of altering GABA concentration on SWDs. The incidence of type II SWDs increased after vigabatrin (60/h) as compared to saline treatment (3.7/h). This effect appeared with a halftime of 100 min. The duration of type II SWDs increased after vigabatrin (1.52 s) as compared to saline treatment (1.04 s), but the peak-frequency of the type II SWDs decreased after vigabatrin (5.6 Hz) as compared to saline treatment (7.5 Hz). Thus, vigabatrin alters the type II SWD morphology. These results are in agreement with predictions of Destexhes theoretical model, modulating both GABA(A) and GABA(B) conductances.

Decapitation in Rats: Latency to Unconsciousness and the ‘Wave of Death’

The question whether decapitation is a humane method of euthanasia in awake animals is being debated. To gather arguments in this debate, obsolete rats were decapitated while recording the EEG, both of awake rats and of anesthetized rats. Following decapitation a fast and global loss of power of the EEG was observed; the power in the 13–100 Hz frequency band, expressing cognitive activity, decreased according to an exponential decay function to half the initial value within 4 seconds. Whereas the pre-decapitation EEG of the anesthetized animals showed a burst suppression pattern quite different from the awake animals, the power in the postdecapitation EEG did not differ between the two groups. This might indicate that either the power of the EEG does not correlate well with consciousness or that consciousness is briefly regained in the anesthetized group after decapitation. Remarkably, after 50 seconds (awake group) or 80 seconds (anesthetized group) following decapitation, a high amplitude slow wave was observed. The EEG before this wave had more power than the signal after the wave. This wave might be due to a simultaneous massive loss of membrane potentials of the neurons. Still functioning ion channels, which keep the membrane potential intact before the wave, might explain the observed power difference. Two conclusions were drawn from this experiment. It is likely that consciousness vanishes within seconds after decapitation, implying that decapitation is a quick and not an inhumane method of euthanasia. It seems that the massive wave which can be recorded approximately one minute after decapitation reflects the ultimate border between life and death. This observation might have implications in the discussions on the appropriate time for organ donation.

Effects of levetiracetam on spike and wave discharges in WAG/Rij rats.

Effects of the novel anti-epileptic drug levetiracetam (50 and 100 mg/kg) on spike and wave discharges (SWDs) of WAG/Rij rats were studied. Levetiracetam decreased the incidence, average duration, total duration and peak frequency of the SWDs. There was no difference between the two doses. These results agree with results obtained in Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Furthermore, the decrease of the SWD peak frequency might support the suggestions that levetiracetam might have a GABAergic mechanism of action.