High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.

Objective: To describe a hypoalbuminemic critically ill patient with subtherapeutic total valproic acid serum concentrations but unbound valproic acid concentrations within normal limits.

Case Summary: During an intensive care unit admission, a 61-year-old woman with urosepsis and multiorgan dysfunction syndrome developed tonic-clonic seizures with respiratory failure, and tracheal intubation was performed. An intravenous loading dose of valproic acid 1500 mg (25 mg/kg) was administered and therapy was continued with valproic acid 750 mg (12.

Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy.

Purpose: Status epilepticus (SE) leads to upregulation of pro-inflammatory proteins including cyclooxygenase-2 (cox-2) which could be implicated in the epileptogenic process and epileptic seizures. Recent studies show that cox-2 can regulate expression of P-glycoprotein (P-gp) during epileptogenesis and epilepsy. P-gp could cause pharmacoresistance by reducing brain entry of anti-epileptic drugs such as phenytoin (PHT).

Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures.

Purpose: Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus-pituitary-adrenal (HPA) axis and its end-product cortisol. We tested several relevant HPA-axis functions in patients with PNES and related them to trauma history.

Methods: Cortisol awakening curve, basal diurnal cortisol, and negative cortisol feedback (using a 1 mg dexamethasone suppression test) were examined in 18 patients with PNES and 19 matched healthy controls (HCs) using saliva cortisol sampling on two consecutive days at 19 time points.

Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives.

Objective: We prospectively evaluated the fluctuation of lamotrigine (LTG) clearance during the menstrual cycle. We also assessed the effect of postmenopausal status and investigated in detail the effect of oral contraceptives (OCs) on LTG clearance.

Methods: Three groups of women with epilepsy using LTG monotherapy were evaluated.

COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats.

Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models.

Improved seizure control by alternating therapy of levetiracetam and valproate in epileptic rats.

Purpose: Tolerance to drug treatment is a serious problem in the treatment of epilepsy. We previously showed that tolerance to levetiracetam (LEV) developed within 4 days after the start of the treatment in a rat model for spontaneous seizures after electrically induced status epilepticus. In the current study we tested whether the development of tolerance to LEV could be prevented by alternating between LEV and valproate (VPA) treatment.

Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls.

This article reviews dried blood spot (DBS) sampling in therapeutic drug monitoring. The DBS method involves applying whole blood obtained via a fingerprick to a sampling paper. After drying and transportation, the blood spot is extracted and analyzed in the laboratory.

Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures.

Purpose: Psychogenic nonepileptic seizures (PNES) have long been considered as paroxysmal dissociative symptoms characterized by an alteration of attentional functions caused by severe stress or trauma. Although interpersonal trauma is common in PNES, the proposed relation between trauma and attentional functions remains under explored. We examined the attentional processing of social threat in PNES in relation to interpersonal trauma and acute psychological stress.

Development of tolerance to levetiracetam in rats with chronic epilepsy.

Purpose: Pharmacoresistance is a major problem in the treatment of epilepsy. We showed previously that pharmacoresistance, at least partially, is due to an up-regulation of the multidrug transporter (MDT) P-glycoprotein (P-gp): inhibition of P-gp improves seizure control in phenytoin-treated epileptic rats (poststatus epilepticus rat model for temporal lobe epilepsy). Since it has been suggested that levetiracetam (LEV) is no substrate for MDTs, we hypothesized that LEV would more adequately control seizures in this rat model.

Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats.

Purpose: Overexpression of multidrug transporters such as P-glycoprotein (P-gp) may play a significant role in pharmacoresistance, by preventing antiepileptic drugs (AEDs) from reaching their targets in the brain. Until now, many studies have described increased P-gp expression in epileptic tissue or have shown that several AEDs act as substrates for P-gp. However, definitive proof showing the functional involvement of P-gp in pharmacoresistance is still lacking.

Expression of multidrug transporters MRP1, MRP2, and BCRP shortly after status epilepticus, during the latent period, and in chronic epileptic rats.

Purpose: Overexpression of multidrug transporters may play a role in the development of pharmacoresistance by decreasing extracellular drug levels in the brain. However, it is not known whether overexpression is due to an initial insult or evolves more gradually because of recurrent spontaneous seizures. In the present study, we investigated the expression of different multidrug transporters during epileptogenesis in the rat.

Effects of additional oxazepam in long-term users of oxazepam.

Although additional dosages of benzodiazepines in long-term users of benzodiazepines are common, it is unknown whether these additional dosages resort any effect. The effects of an additional 20-mg dosage oxazepam were assessed in a double-blind, balanced-order, crossover randomized study comparing 16 long-term users of oxazepam (patients) with 18 benzodiazepine-naive controls (controls). The effects of 10 and 30 mg oxazepam were assessed at pretest and 2.

Effects of the combination of valproate and ethosuximide on spike wave discharges in WAG/Rij rats.

Objective: We studied the interaction between valproate (VPA) and ethosuximide (ESM) in diminishing the incidence of absence-like spike-wave discharges (SWDs) in the EEG of WAG/Rij rats.

Methods: VPA, ESM, their combination and saline were evaluated in 16 rats. The doses of VPA ranged from 0 to 280 mg/kg and the doses of ESM ranged from 0 to 40 mg/kg.

Pharmacodynamic analysis of the interaction between tiagabine and midazolam with an allosteric model that incorporates signal transduction.

Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the gamma-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake.

Methods: The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL.