John A. Messenheimer

Lamotrigine Therapy for Partial Seizures: A Multicenter, Placebo‐Controlled, Double‐Blind, Cross‐Over Trial

Summary: The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double‐blind, placebo‐controlled, cross‐over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mglday. Seizure frequency with LTG decreased by ≥50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2: 1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEds. Adverse experiences were generally minor and most frequently were CNS‐related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice‐daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.

Improvement of epileptic seizure control with treatment of obstructive sleep apnoea

Sleep deprivation increases the risk of recurrent seizures in epileptic patients. We identified 10 patients with recurrent seizures and sleep disruption related to obstructive sleep apnoea. Two patients were treated with positional therapy and the remaining eight patients were treated with continuous positive airway pressure. Three of the patients became seizure free and a fourth patient had a greater than 95% reduction in seizure frequency following only the initiation of therapy for the sleep apnoea. Three of these four patients responding to therapy, had a state-dependent seizure pattern. Two of the four responders did not exhibit the typical body habitus for obstructive sleep apnoea. Three additional patients improved in seizure frequency with change in anticonvulsant medication and treatment of the obstructive sleep apnoea. The remaining three patients had less than 50% reduction in seizure frequency with treatment of the obstructive sleep apnoea. These results indicate sleep disruption caused by sleep apnoea may increase the seizure frequency in some epileptic patients. Regardless of body habitus, epilepsy patients should be questioned carefully for a history of sleep disturbance and state dependence to their seizures. Treatment of sleep disorders in this population may lower the frequency of recurrent seizures.

Heart period variability in sleep

Analysis of heart period variability is a dynamic noninvasive technique to quantify the autonomic control over the heart period. We recorded electroencephalographic, electro-oculographic, electromyographic and electrocardiographic data from 10 normal subjects during sleep using an ambulatory polysomnographic monitor. R-R intervals were determined for 10 min segments of electrocardiographic data from wakefulness, stage 2 sleep, slow wave sleep and REM sleep. Average heart period, instantaneous changes greater than 50 msec and fractal dimension were calculated and the time domain and phase plots were depicted. The R-R interval time domain plots were subsequently analyzed using the discrete Fourier transform. We found sleep stage specific, time domain and frequency domain changes in heart period variability, particularly using spectral analysis of heart period. Increased power in the 0.2-0.4 Hz band was associated with stage 2 sleep when compared to awake and slow wave sleep states. Power in the 0.0-0.04 and 0.04-0.12 Hz bands was increased in association with REM sleep when compared to non-REM sleep, and slow wave sleep had diminished power in all frequency bands. Our results support other investigations demonstrating stage 2 sleep is associated with increased parasympathetic influences and REM sleep is associated with increased sympathetic and neurohumoral influences. We feel that spectral analysis of heart period variability is an effective noninvasive method to quantify changes in the autonomic influences over the heart during sleep.

Heart period variability during vagal nerve stimulation

Vagal nerve stimulation is an emerging therapy for epilepsy, yet little is known regarding the effects of this stimulation on heart period variability. We selected 10 patients (two female, eight male) who were receiving high-frequency, high-intensity left vagal nerve stimulation for intractable epilepsy. Electrocardiogram data were recorded for a 7 min baseline, 2.5 min of stimulation and a 7 min post-stimulation period. We found no significant changes in average heart period, instantaneous changes of successive R-to-R intervals greater than 50 ms or fractal dimension. We also found no significant changes in the total power in the 0.0-0.04 Hz, 0.04-0.12 Hz and 0.2-0.4 Hz bands with stimulation of the left vagus nerve. This study suggests that left vagal nerve stimulation has little acute effect on the cardiac rhythm or heart period variability.

Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine

In this double‐blind, randomized, crossover, placebo‐controlled study, the effect of multiple oral doses of acetaminophen on lamotrigine disposition was examined in healthy volunteers. Eight volunteers received two single 300 mg oral doses of lamotrigine, administered 20 days apart. Acetaminophen (2.7 gm/day) or placebo was taken for 24 hours before and continued for 10 days after each lamotrigine dose. Area under the plasma concentration–time curve for lamotrigine [AUC(0‐∞)] and lamotrigine half‐life were statistically decreased by 20% (229.0 ± 62.5 μg · hr/ml versus 191.2 ± 42.1 μg · hr/ml, p < 0.01) and 15% (35.7 ± 9.3 hours versus 30.2 ± 7.3 hours, p < 0.01), respectively, when concurrently administered with acetaminophen. There was no significant difference in the peak plasma concentration or the time to reach peak plasma concentration. The percentage of the dose of lamotrigine recovered in the urine (total) was significantly higher during the acetaminophen treatment (65.9% ± 12.3% versus 72.5% ± 5.7%, p = 0.048). Acetaminophen seems to facilitate lamotrigine removal through a yet to be determined mechanism(s).

Seizures in Lung Transplant Recipients

Summary: Purpose: We wished to assess organ transplant recipients, who incur a significant risk for seizures.

Bioavailability of ACC-9653 (Phenytoin Prodrug)

Summary: The bioavailability of phenytoin from ACC‐9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC‐9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC‐9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0‐inf)] after ACC‐9653 divided by the phenytoin AUC(O‐inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC‐9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC‐9653 is complete following intravenous or intramuscular administration in single‐dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC‐9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope‐labeled tracer doses of ACC‐0653 and sodium phenytoin.

Evaluation of the ames seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva

The performance of the dry-phase apoenzyme reactivation immunoassay system (ARIS) for the measurement of carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations in saliva was compared with fluorescence polarization immunoassay (FPIA). Blood and saliva samples were collected from 163 adult and pediatric epilepsy patients, then analyzed using both methods. Regressions between ARIS saliva CBZ, PB, and PHT concentrations, and FPIA unbound and total serum concentrations were highly correlated, but the ARIS technique was somewhat less precise than the FPIA. Valproic acid co-medication did not affect the relationships between ARIS and FPIA saliva concentrations and unbound serum concentrations of PHT, but did disrupt the relationship between ARIS and FPIA saliva PHT and total serum PHT. The sensitivity, specificity, predicted value positive (PV+) of a therapeutic concentration, and predicted value negative (PV-) of a concentration outside the therapeutic range for the ARIS saliva technique compared very well with FPIA for CBZ, PB, and PHT. The ARIS technique for CBZ, PB, and PHT saliva determination provides acceptable accuracy, precision, and sensitivity for therapeutic monitoring. In practice, the benefits of the ARIS saliva technique, including ease of collection, safety, patient/parent acceptance, and short analysis time, are striking.

Absolute Bioavailability of Phenytoin After 3‐Phosphoryloxymethyl Phenytoin Disodium (ACC‐9653)Administration to Humans

Summary: 3‐Phosphoryloxymethyl phenytoin disodium (ACC‐9653) is a water‐soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC‐9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC‐9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double‐blind cross‐ over fashion. The conversion half‐life (t½) of ACC‐9653 to PHT was 9.3 ± 2.7 min. ACC‐9653 was not detected in urine and >99% of ACC‐9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC‐9653 was 99 ± 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 μg/ml ACC‐9653, was significantly higher than at 180 min, when the concentration of ACC‐9653 was 0.1 μg/ml. ACC‐9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.

Monitoring heart period variability changes during seizures. II. Diversity and trends

Seizures may prompt autonomically mediated changes in heart period. Heart period variability (HPV) is a sensitive tool for quantification of autonomic control over the cardiac cycle. We used analysis of HPV to evaluate changes in the time and frequency domain autonomic regulation of heart period during seizure activity in 44 seizures from 12 patients with epilepsy: 16% of seizures were associated with changes in heart rate and variability preceding behavioral and surface electroencephalographic (EEG) onset. Patients with consecutive partial seizures had variable HPV changes. Seizures of left-sided EEG onset were associated with no change or a decrease in the power of the 0.2- to 0.4-Hz band, whereas seizures of right-sided EEG onset were associated with no change or a decrease in the power of the 0.04- to 0.12-Hz band. We believe that time- and frequency-domain analysis of HPV may provide valuable information about the temporal and spatial onset of seizure activity. Additional study using invasive EEG recordings will be needed to evaluate the reliability of HPV to lateralize or localize seizure foci.