Levetiracetam,a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid

PURPOSE: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited drug-interaction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions. METHODS: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, one-sequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. RESULTS: Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 microg/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 microg/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA. CONCLUSIONS: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during short-term administration, and suggest that dose adjustment is not required when these two drugs are given together.     

Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.     

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.     

Studies on the pharmacokinetics of total and free valproate in mono- and bitherapy with carbamazepine in epileptic children and adolescents

The aim of this study was to obtain a pharmacokinetic calculation for valproic acid (VPA) and its free fraction in 50 children and adolescents (4-18 years) treated for epilepsy in VPA monotherapy and bitherapy with carbamazepine (CBZ). The diurnal fluctuation of serum concentration of total and free VPA during monotherapy was observed. The additional antiepileptic medication of VPA and CBZ was connected with prominent diurnal free VPA serum fluctuations. Pharmacokinetic parameters of total and free VPA in monotherapy were significantly different. The change of free and total VPA pharmacokinetics during bitherapy with CBZ was observed, too. No changes in half-life time of VPA in mono- and bitherapy were noticed. The variability of pharmacokinetic parameters of free VPA suggests the need for monitoring unbound VPA plasma concentrations during bitherapy with CBZ.     

Therapeutic drug monitoring of lamotrigine in patients suffering from resistant partial seizures

Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment as add-on therapy for resistant partial seizures and receiving carbamazepine (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug monitoring (TDM). The aim was to evaluate the possible relation between serum levels and the clinical effect of LTG, to verify whether CNS toxicity has to be considered the result of a pharmacokinetic or a pharmacodynamic interaction with CBZ, and to investigate whether possible changes in the clinical response during long-term treatment are dependent on LTG serum level variations. Sixteen patients achieved complete control, 26 a >or=50% reduction in seizures, the remainder did not respond. Mean LTG serum concentrations were higher in responders than in nonresponders, the difference being statistically insignificant. The best results were observed in VPA-cotreated patients with the highest LTG blood levels. CNS toxicity occurred after giving LTG to subjects who subsequently developed the highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ-epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was observed even in patients showing a reduction in the response during long-term treatment.     

Steady-State Pharmacokinetics of Topiramate and Carbamazepine in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ). Methods: We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300–800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at -2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy. Results: Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC_(0–12)), C_min(0), and C_avg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC_(0–12)) C_max, C_min(0), and C_avg values were -40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered. Conclusions: When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.     

A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.     

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

BACKGROUND: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. METHODS: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. RESULTS: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone-binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 mg. CONCLUSIONS: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.     

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.     

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug-specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20-40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.     

Pharmacokinetic variability of valproate in women of childbearing age

The purpose was to investigate pharmacokinetic variability of valproic acid (VPA) in women of childbearing age by therapeutic drug monitoring (TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006–2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14–46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) μmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150–625 mg/day), mean serum concentration was 336 μmol/L and variability in C/D ratio was 10‐fold. The variability decreased with increasing dose to eightfold (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women.     

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.     

Topiramate,carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy

OBJECTIVES: To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized. RESULTS: No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events. CONCLUSION: In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.     

Clinical Science

Dorit Mimrod, Luigi M. Specchio, Malka Britzi, Emilio Perucca, Nicola Specchio, Angela La Neve, Stefan Soback, René H. Levy, Giuliana Gatti, Dennis R. Doose, Bruce E. Maryanoff, and Meir Bialer The study's aim was to compare the influence of comedication by carbamazepine (CBZ) and valproic acid (VPA) on the pharmacokinetics and metabolism of topiramate (TPM). Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n = 13); (b) patients receiving TPM with CBZ (n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine. No significant differences were found in TPM total and renal clearance between the VPA group and the control group. Mean TPM total and renal clearance values were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6 L/h respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42% to 52% of the dose (p > 0.05). Urinary recovery of 2,3‐O‐des‐isopropylidene‐TPM (2,3‐diol‐TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10‐hydroxy‐TPM (10‐OH‐TPM) was twofold higher in the CBZ group than in controls, but it accounted for <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction by other concurrently taken seizure medications. The twofold increase in TPM metabolism and excretion in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways in the liver, leading to formation of 2,3‐diol‐TPM and 10‐OH‐TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profile. Epilepsia 2005;46(7).     

Comparison of the Steady-State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions. Methods: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy. Results: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for 2 weeks without VPA. TPM plasma peak concentration (C_max) and area under the concentration-versus-time curve during a 12–h dosing interval (AUC_0–12) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 ± 4.6 and 11.6 ± 3.2 ml/min during TPM monotherapy and were 29.8 ± 4.2 and 12.4 ± 2.7 ml/min during VPA concomitant therapy. VPA AUC_(0–12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 ± 4.1 ml/min during monotherapy and was 13.8 ± 4.0,14.1 ± 3.9, and 14.5 ± 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued. Conclusions: Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.     

Effect of sildenafil on the anticonvulsant action of classical and second‐generation antiepileptic drugs in maximal electroshock‐induced seizures in mice

Purpose: The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second‐generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Methods: Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step‐through passive avoidance task, and grip‐strength test. Total brain and free plasma concentrations of AEDs were also determined. Results: Sildenafil raised the threshold for electroconvulsions in a dose‐dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long‐term memory in mice. Interestingly, sildenafil dose‐dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Conclusions: Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long‐term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.     

Severe, isolated thrombocytopenia under polytherapy with carbamazepine and valproate

It is not known whether polytherapy with carbamazepine (CBZ) and valproate (VPA) increases the risk of thrombocytopenia. A 67-year-old woman with symptomatic epilepsy since age 6 years, classified as Lennox-Gasteau syndrome, developed severe, isolated thrombocytopenia of 5 GIGA/L (normal: 150-360 GIGA/L) after being on CBZ (1200 mg/day) for 15 days and additional VPA (300 mg/day) for 5 days in combination. After discontinuation of CBZ and VPA and two thrombocyte transfusions, the thrombocyte count normalized within 3 days. Because she had been taking VPA for only 5 days in addition to CBZ, it could not be confirmed whether it was CBZ alone or the combination of CBZ and VPA that was responsible for the severe thrombocytopenia.     

Combination of carbamazepine and valproate in different dose proportions in maximal electroshock seizure model in mice

Rational polypharmacy of antiepileptic drugs is one of the treatment strategies for refractory epilepsy. To investigate whether it may be rational to combine carbamazepine (CBZ) and valproate (VPA), we tested both the anti-convulsant effect and the toxicity of combinations of CBZ and VPA in different dose proportions. CBZ/VPA dose ratios were, respectively, 1:6.66, 1:10, 1:13.3 and 1:20. The median effect doses of monotherapy and polytherapy in maximal electroshock seizure test and the median lethal (within 3 days after administration) doses were determined. These parameters were analyzed with the isobologram method. We found that the anti-convulsant effect of all combinations was additive. The toxicity of combination 1, 2 and 3 (CBZ/VPA, 1:6.66, 1:10, 1:13.3) was additive, but the toxicity of combination 4 (CBZ/VPA, 1:20) was infra-additive. Thus, in mice, using this model, a combination of CBZ/VPA 1:20 has an advantage over each of the drugs alone.     

Early hormonal changes during valproate or carbamazepine treatment: a 3-month study

BACKGROUND: Long-term treatment with valproate (VPA) or carbamazepine (CBZ) may induce reproductive endocrine disorders in patients with epilepsy. METHODS: Serum concentrations of reproductive hormones were studied in 17 women and 22 men with recently diagnosed epilepsy before they started either VPA or CBZ medication, and 1 and 3 months later. RESULTS: No weight gain or clinical signs of hormonal disorders were observed during the follow-up. The mean serum levels of testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin (SHBG) increased, and dehydroepiandrosterone sulfate (DHEAS) decreased, in women starting VPA. Serum testosterone levels increased in half of the women on VPA. Serum concentrations of progesterone and dehydroepiandrosterone increased, and gonadotropins decreased, in men on VPA during the follow-up. Serum SHBG levels increased and DHEAS decreased during the first months of CBZ treatment in both sexes. In addition, the free-androgen index decreased in men after starting CBZ. CONCLUSIONS: Hormonal changes occur after only 1 month's use of VPA or CBZ. VPA-treatment seems to be associated with increased serum androgen levels, but the profile of hormonal changes appears to be different in women than in men. The use of CBZ, in turn, was associated with increased SHBG concentrations and thus with diminished sex steroid function in both sexes. The women with increased serum testosterone levels in the early phase of VPA medication may be at increased risk for VPA-related endocrine disorders later during treatment.     

Effect of Felbamate on Valproic Acid Disposition in Healthy Volunteers: Inhibition of β-Oxidation

Summary: We assessed the effects of felbamate (FBM) on the disposition of valproic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2–4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2–en, 4–en, and 3–oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3–oxo and 4–hydroxy metabolites in urine, were measured by gas chromatography/mass spectrometry (GUMS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 μg/ml (1,200 mg dose) to 76.8 μg/ml (3,600–mg dose). Mean plasma VPA C_max values were 32–42 μg/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4–63.8 μg/ml). The excretion of 3–oxo–VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at ∼2400 mg/day. FBM had caused significant inhibition of the β-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.