Sodium Valproate and Valpromide: Differential Interactions with Carbamazepine in Epileptic Patients

To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ-10,11-epoxide (CBZ-E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate-treated group, plasma CBZ-E levels increased by 101% (range, 29-238%) within 1 week of combined therapy (p less than 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM-treated patients, the elevation of plasma CBZ-E levels was much greater. In this group, plasma CBZ-E increased by 330% (range, 110-864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ-E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a prodrug of VPA. Although both VPA and VPM increase CBZ-E levels--probably by inhibiting the enzyme epoxide hydrolase--the interaction caused by VPM is of much greater magnitude and potential clinical significance.     

Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients.

Twenty-four epileptic patients (16 females, 8 males; aged 13-62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300-1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10,11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P less than 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25-69 mg/l), as CBZ-E concentrations correlated significantly with total (r = 0.5, P less than 0.05, 95% CI 0 to +0.08) and free (r = 0.7, P less than 0.001, 95% CI +0.09 to +0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.     

Carbamazepine/valproic acid interaction in man and rhesus monkey

Sodium valproate (VPA) was administered for 1 week (1 g b.i.d.) to seven epileptic patients receiving chronic carbamazepine (CBZ) therapy. Steady-state CBZ levels determined before and after VPA therapy were reduced by 3-59% in six patients and were unchanged in one patient. The plasma concentration ratio of carbamazepine-10,11-epoxide ( CBZE ) to CBZ increased in all patients by 11-500%. The plasma binding of CBZ was determined in six healthy volunteers given a single 400 mg CBZ dose with and without the coadministration of 1 g VPA in a cross-over design. The mean CBZ free-fraction was increased in three of the subjects (p = 0.008-0.031), decreased in one subject (p less than 0.002), and remained unchanged in two subjects when VPA was administered. Four male rhesus monkeys were infused intravenously with CBZ (15 mg h-1) for 5 days and then three consecutive 24-h infusions were given: I, CBZ alone; II, CBZ with 75 mg h-1 VPA; III, CBZ with 150 mg h-1 VPA. The mean free-fraction of CBZ and CBZE increased during infusions II and III from 31.5 +/- 2.7% to 33.6 +/- 2.6% (p less than 0.05) and 37.7 +/- 1.3% (p less than 0.01) for CBZ and from 46.9 +/- 9.2% to 53.6 +/- 5.7% (p greater than 0.05) and 60.1 +/- 4.0% (p less than 0.01) for CBZE . The clearance of free CBZ declined from 7.96 +/- 1.75 to 4.84 +/- 1.26 (p less than 0.01) and 4.12 +/- 1.75 (p less than 0.01) 1 kg-1h-1 during infusions II and III, respectively. The mean free CBZE /CBZ ratio increased from 0.12 +/- 0.03 to 0.24 +/- 0.03 and 0.36 +/- 0.04 during infusions II and III, respectively (p less than 0.001). These findings indicate a decrease in the elimination clearance of CBZE possibly coupled with a decrease in its formation clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Discontinuation of Phenytoin, Carbamazepine, and Valproate on Concomitant Antiepileptic Medication

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.     

Meal-Dependent Absorption of Enteric-Coated Sodium Valproate

The effect of meals on valproic acid (VPA) absorption from an enteric coated (EC) formulation was investigated. In study I, six adult normal volunteers received a single 500 mg dose of sodium valproate in randomized treatments: fasting (A), with a meal (B) or 3 hours after a meal (C). There were significant differences between treatments in the latency period (Lp) defined as the time during which measured concentrations of VPA were less than 1 microgram/ml. Lp values for treatments A, B and C were: 1.67 +/- 1.25 hr, 6.75 +/- 3.98 hr and 7.63 +/- 3.15 hr respectively. In study II, six subjects (five from study I) received in a randomized fashion a 400 mg intravenous bolus dose of VPA and a 500 mg EC VPA tablet, 3 hours after a meal. The mean Lp value was 8.1 +/- 1.6 hr and the mean bioavailability was 100%. Clearance, volume of distribution and half-life values obtained after intravenous dosing were comparable to literature values. These results indicate that food intake delays but does not decrease the extent of absorption of VPA from an enteric coated formulation.     

Valproic acid doses, concentrations, and clearances in elderly nursing home residents

VPA daily dose and total VPA concentrations for 146 elderly (> or =65 years) nursing home residents collected from June 1998 to December 2000 in homes located throughout the United States are presented. Average age was 78.5+/-8.0 years old. The mean VPA daily dose was 16.2+/-11.2mg/kg and mean total VPA concentration was 48.5+/-24.8 mg/L. The majority (56.2%) of the VPA residents are being maintained at total VPA levels <50mg/L. Mean daily dose (19.4+/-11.4, 16.3+/-12.1, and 11.3+/-7.6 mg/kg/day; p=0.003) and total VPA concentration (56.4+/-25.8, 47.7+/-22.6, and 38.7+/-23.1mg/kg/day; p=0.003) decreased by age groups (65-74, 75-84, and > or =85 years). Daily dose and total VPA concentration were not different in residents receiving inhibitory or inducing co-medications, between men and women, or by albumin level. Total VPA clearance was similar between men and women, among age groups, or according to inducing or inhibiting co-medications.     

Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63-441

Systemic administration of synthetic PAF produces a number of dose-dependent circulatory effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441, for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate. In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean +/- 1 S.D.) 39 +/- 5% decrease in carotid blood pressure. Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 +/- 8% increase in hematocrit and a 50 +/- 11% elevation in bronchial resistance. The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012 mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 micrograms kg-1 PAF i.v. exhibited 28.7 +/- 6.5% increase in hematocrit 10 min after injection. The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 micrograms kg-1 i.v. PAF with a 30 +/- 6% increase in hematocrit. Using the primates in a cross-over design, the ED50 of SRI 63-441 was 0.11 mg kg-1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is approximately 1:25. The effectiveness of SRI 63-441 in these models suggest potential clinical applications in disease states involving hyperpermeability and pulmonary dysfunction.     

Valproic acid increases biliary copper excretion in the rat

The effect of valproic acid (VPA) on the copper absorption and disposition in rat small intestine was investigated using an in situ recirculating perfusion method. Following addition of VPA (20 mg) to the perfusion of 30 ml of 0.9% sodium chloride solution (2 microg/ml copper as CuSO(4)) there were no significant differences in copper decline during the perfusion. The absorption rate constant of copper (k(a)) which was estimated from the copper decline in the perfusion was unchanged without and with VPA (0.19+/-0.02 vs. 0.17+/-0.03 1/h). These results indicate that VPA does not have an effect on copper absorption from the intestine. We also assessed biliary copper excretion by measuring bile flow and biliary copper concentrations. Addition of VPA markedly increased bile flow by 47% for the first hour of bile collection and 91% for the second hour and the biliary copper excretion closely followed the increase in bile flow (without VPA: 0.93+/-0.15 vs. with VPA: 1.44+/-0.21 mg for the first and without VPA: 0.98+/-0.13 mg vs. with VPA: 1.98+/-0.22 mg for the second hour of bile collection). The total mean value for the biliary copper excretion was increased by 79%. The serum VPA concentration after the perfusion was 31.1+/-3.2 microg/ml. This high excretion of copper induced by VPA into the bile may upset the homeostatic balance of copper and cause the abnormalities of serum copper concentration. Based on the present studies, we should pay attention to copper levels in patients with VPA treatment.     

Single-dose kinetics and bioavailability of sodium-hydrogen divalproate

Sodium-hydrogen divalproate (SHD) is a new chemical entity that quickly dissociates into valproic acid (VPA) and sodium valproate in water and is absorbed as VPA from the gastrointestinal tract. SHD is formulated as an enteric-coated tablet and may also result in less gastrointestinal irritation than other preparations of VPA. The bioavailability of valproate from SHD enteric-coated tablets (Epival, Abbott-50711) and from sodium valproate enteric-coated tablets (Ergenyl) was compared in a single-dose, double-blind, crossover study. Fourteen healthy volunteers (mean age 28.7 years) participated. A single oral dose of 250 mg SHD (assayed potency 249.3 mg VPA) or 300 mg sodium valproate (assayed potency 251.1 mg VPA) was given to each volunteer. Blood samples were collected intermittently up to 48 h and VPA in serum was assayed by gas chromatography. The areas under the serum concentration-time curves (AUC0----infinity) did not show any statistically significant difference (2,925.0 +/- 189.1 versus 2,816.2 +/- 162.2 h X mumol/L) between SHD and sodium valproate. The elimination parameters for SHD were t1/2 = 12.6 +/- 0.7 h and CLs = 0.008 +/- 0.0005 L/kg/h. Vd,area was 0.146 +/- 0.004 L/kg. Data for sodium valproate were not significantly different. Thus, the extent of bioavailability and the single-dose kinetics of SHD and sodium valproate are similar with the exception of a more rapid absorption (Tmax 2.37 versus 3.23 h) and a higher concentration (Cmax 192 versus 176 mumol/L) for SHD. Both of these differences were statistically significant (p less than 0.01).     

Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy

PURPOSE: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids. METHODS: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay. RESULTS: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means +/- SD: 425 +/- 184 vs. 350 +/- 145 micromol/L, respectively, for total VPA, p = 0.002, and 55 +/- 37 vs. 39 +/- 25 micromol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 +/- 5.2 to 9.7 +/- 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 +/- 81 to 115 +/- 121 ml/h/kg, p = 0.029). CONCLUSIONS: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.     

Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children

Carbamazepine-10,11-epoxide (CBZ-E), the principal metabolite of carbamazepine (CBZ), is reported to have antiepileptic and toxic effects similar to CBZ. Steady-state CBZ and CBZ-E levels (high performance liquid chromatography, HPLC assay) were reviewed in 225 outpatient children and young adults taking CBZ with or without other antiepileptic drugs (AEDs). In patients on CBZ alone, mean serum concentration of CBZ was 7.9 +/- 1.9 micrograms/ml and of CBZ-E was 1.5 +/- 0.6 micrograms/ml. The CBZ-E/CBZ ratio was 19.6 +/- 2.4%. Serum CBZ increased with increasing age and with CBZ dose. CBZ-E increased with increasing CBZ dose but was unaffected by age. The CBZ-E/CBZ ratio progressively declined with age. Co-medication with barbiturates or valproic acid significantly increased CBZ-E. Phenytoin showed a similar trend while ethosuximide caused the least change. Patients on CBZ and two or more other AEDs had highest CBZ-E levels and CBZ-E/CBZ ratio. CBZ and CBZ-E levels are variably affected by age, CBZ dose, and co-medication with other AEDs. When other AEDs are administered, careful monitoring is especially indicated in order to avoid toxicity.     

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10, ll-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.     

Sodium valproate: a hyperammonemic drug. Study in the epileptic and healthy volunteer

Sodium valproate (VPA) consistently induces an arterial hyperammonemia in epileptics tolerant of this drug and in normal subjects. The hyperammonemia appears with the first oral or intravenous dose of the drug, 15-25 mg/kg, and is established within minutes following drug absorption. In 20 epileptics treated with VPA alone for 4 days, the mean arterial ammonemia measured 2-3 h after breakfast and the day's first VPA dose was 72 +/- 9 mumols/l in non-alcoholics, and 77 +/- 7 mumols/l in alcoholics. Hyperammonemia persisted during chronic treatment; in 10 epileptics who had had received only VPA for over a month, the mean hyperammonemia was 87 +/- 6 mumols/l (normal value means +/- 2 SD = 28 +/- 12 mumols/l). The ammonemia varied in the course of the day; sharp peaks 7 or more times the base value were observed. These variations, differing among subjects, depended on the VPA plasma concentration, and above all on the meal composition and the relative timing of the meal and the drug administration. No secondary effects were seen; in particular, hepatic and pancreatic tests were normal. The hyperammonemia would seem to be due to physiopathological mechanisms other than those giving rise to the hepatic complications occasionally observed with VPA. The permanence and the extent of the hyperammonemia raise questions as to its origin, its relation to the stuporous states induced by VPA, and its eventual repercussions on the functioning of neurons.     

IgM/IgG solid-phase antibody-capture assay with biotin/125I-streptavidin amplification: application to normal human sural nerve biopsies

A highly sensitive and specific solid-phase antibody-capture assay was developed to measure IgM and IgG in endoneurial preparations of human sural nerve biopsies. Assay amplification was obtained by utilizing biotin-labeled anti-IgM or anti-IgG antibody and 125I-streptavidin, resulting in multiple streptavidin molecules binding per biotinylated antibody molecule. A minimal detectable dose of 0.16 +/- 0.08 ng (mean +/- SD; n = 7) for IgM and 0.03 +/- 0.02 ng (mean +/- SD; n = 5) for IgG was obtained in a 100 microliters sample. When this assay was applied to normal fascicular biopsies from human sural nerve, the percent of IgM and IgG, respectively, of the total endoneurial protein was 0.026 +/- 0.015% (n = 9) and 0.27 +/- 0.15% (n = 10; mean +/- SD). When these endoneurial concentrations of IgM and IgG were related to the plasma concentrations (mg IgM or IgG/mg total plasma protein), an IgM-blood-nerve barrier (BNB) index of 4.09 +/- 1.95 and an IgG-BNB index of 2.07 +/- 1.10 were obtained (X10(2); mean +/- SD). These values were also related to the albumin (Alb) concentration in the biopsies as a percent of total endoneurial protein (2.48 +/- 1.07%; mean +/- SD) and with the Alb-BNB index (5.40 +/- 2.53; X10(2); mean +/- SD; n = 10). Although these normal values will be expected to change with age, sex, nerve, and proximal-distal distance from nerve root, they should provide a basis for the comparison of BNB indices from patients with peripheral neuropathy.     

A single blind comparison of amisulpride, fluoxetine and clomipramine in the treatment of restricting anorectics.

1. The study evaluated the efficacy of amisulpride, fluoxetine and clomipramine at the beginning of the re-feeding phase of the treatment of restricting anorexia nervosa according to DSM-IV criteria. 2. 13 patients, mean weight 37.61 kg +/- 9.80 SD, were treated with clomipramine at a mean dosage of 57.69 mg +/- 25.79 SD; 10 patients, mean weight 40.90 kg +/- 6.98 SD, were treated with fluoxetine at a mean dosage of 28.00 mg +/- 10.32 SD; 12 patients, mean weight 38.41 kg +/- 8.33 SD, were treated with amisulpride at a mean dosage of 50.00 mg +/- 0.00 SD. 3. Clinical evaluation was carried out under single-blind condition at basal time and after three months by a structured clinical interview, the Eating Disorder Interview based on Long Interval Follow-up Evaluation (LIFE II BEI). 4. Patients treated with amisulpride showed a more significant increase (p=0.016) of mean weight. Concerning weight phobia, body image disturbance and amenorrhoea, no significant difference resulted.     

Reduction of steady-state valproate levels by other antiepileptic drugs

Steady-state plasma valproate (VPA) levels were analyzed in 37 children after 6 weeks of VPA therapy. Twenty-six patients were receiving other antiepileptic drugs in addition to VPA (experimental group). Eleven patients who received VPA alone served as controls. The mean VPA dose was not statistically different for the two groups (experimental group, 35.4 mg/kg/day, 11.6 SD; control group, 31.1 mg/kg/day, SD 6.6) The mean plasma VPA level was significantly lower for the experimental group (63.0 micrograms/ml, SD 21.8) than for the control (99.3 micrograms/ml), SD 23.3) (p less than 0.01). VPA level: dose ratio (LDR) was also reduced in the experimental group (1.92, SD 0.75) as compared to controls (3.26, SD 0.65) (p less than 0.01). Within the experimental group the VPA levels and VPA LDR were significantly reduced in patients receiving either phenytoin or phenobarbital. The data suggest that other antiepileptic drugs significantly alter the steady-state level to dose relationship for VPA.     

Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake.

The antiepileptic drug valproate (VPA) may be neuroprotective. We treated rats with VPA for 14 days (300 mg/kg twice daily) before intrastriatal injection of 1.5 micromol (1 M) of the succinate dehydrogenase inhibitor malonate. VPA-treated animals developed smaller lesions than control animals: 10 +/- 2 mm(3) versus 26 +/- 8 mm(3) (means +/- SD; P = 10(-4). Injection of NaCl that was equiosmolar with 1 M malonate caused lesions of only 1.2 +/- 0.4 mm(3) in control animals, whereas physiologic saline produced no lesion. VPA pretreatment reduced the malonate-induced extracellular accumulation of glutamate. This effect paralleled an increase in the striatal level of the glutamate transporter GLT, which augmented high-affinity glutamate uptake by 25%, as determined from the uptake of [(3)H] glutamate into striatal proteoliposomes. Malonate caused a 76% reduction in striatal adenosine triphosphate (ATP) content, but the glial, ATP-dependent formation of glutamine from radiolabeled glucose or glutamate was intact, indicating that glial ATP production supported uptake of glutamate. Striatal levels of HSP-70 and fos were reduced, and the levels of bcl-2 and phosphorylated extracellular signal-regulated kinase remained unaffected, but histone acetylation was increased by VPA treatment. The results suggest that augmentation of glutamate uptake may contribute importantly to VPA-mediated neuroprotection in striatum.     

Evaluation of Carbamazepine and Carbamazepine-Epoxide Protein Binding in Patients Undergoing Epilepsy Surgery

Carbamazepine (CBZ) serum concentrations increase after epilepsy surgery. A possible mechanism may be acute changes in protein binding, specifically those involving the acute phase reactant α₁-acid glycoprotein (AAG). We prospectively evaluated 16 adults (11 receiving CBZ) with epilepsy (mean age 30 ± 8.9 years, 8 women and 8 men) undergoing temporal lobe resections and characterized AAG, albumin, CBZ, and CBZ-epoxide (CBZ-E) free fractions over time. AAG, ALB, CBZ, and CBZ-E free fractions were determined before surgery (baseline) and on postoperative days 1–5, 14, and 30. AAG was measured with a radial immunodiffusion assay method, CBZ and CBZ-E serum concentrations were determined by high-performance liquid chromatography (HPLC). Free fractions of CBZ and CBZ-E were calculated as the ratio of unbound (determined after ultracentrifugation) to total serum drug concentrations. Statistical analysis included analysis of variance (ANOVA) and Student's t test for paired data when appropriate, with significance assigned at p < 0.05. All data are mean ± SD. AAG concentrations increased significantly from baseline (61.9 ± 21.3 mg/dl), peaking at postoperative day 3 (116.8 ± 20.6 mg/dl) and decreasing to baseline levels between days 14 and 30. CBZ serum concentrations were significantly increased in the immediate postoperative period (day 3), but albumin concentrations and CBZ and CBZ-E free fractions did not differ significantly between baseline and the postoperative time points. Temporal lobe resection results in an acute phase reaction which is manifested in part by significant changes in AAG. Although CBZ and CBZ-E total serum concentrations increased significantly in the immediate postoperative period, epilepsy surgery did not appear to result in significant overall changes in drug binding to plasma proteins.     

Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis

PURPOSE: To determine the modulation of sodium currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA), before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion. Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation but selectively shifted the voltage dependence of steady-state inactivation to more hyperpolarized potentials. One day after the last kindled generalized seizure, the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls. Five weeks after kindling, these values had recovered to a level not different from control. VPA induces at a relatively high concentration a similar but smaller shift in voltage dependence of inactivation than does CBZ. After kindling, the shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls (3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4 mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage dependence of sodium current steady-state inactivation and as a consequence reduce cellular excitability. The effect of CBZ was reduced immediately after kindling epileptogenesis, apparently by a reduced affinity of its receptor. In contrast, the shift induced by VPA was not different at any stage after kindling epileptogenesis. The change in CBZ sensitivity after kindling is related to epileptic activity rather than to the epileptic state, because it almost completely recovers in a period without seizures.     

Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

PURPOSE: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. METHOD: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). RESULTS: sixty-two patients (33.6+/-11.3 years, 47+/-9.9 kg) receiving LTG monotherapy (n=19) or polytherapy with VPA (n=15), inducer(s) (n=32) or both (n=5) were evaluated. LTG dose of 369+/-236 mg per day (8.1+/-5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8+/-3.3 microg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/F) were 0. 69+/-0.2, 1.60+/-0.65 and 0.2+/-0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/F. CONCLUSION: LTG Cl/F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.