Intensive follow-up monitoring in patients with once daily evening administration of sodium valproate

For 18 previously untreated patients with absence, myoclonic, or grand mal seizures--or combinations--results of clinical and electroencephalographical monitoring are reported. Sodium valproate was given once daily in the evening. Monitoring included repeated 24-48 h EEG recordings and drug blood level measurements. Results indicated the evening monodose to be an adequate therapeutic schedule for a considerable number of patients. Apart from the aspect of simplification, a further important aim is to individually minimize the drug dose. An average of 15.6 mg/kg sodium valproate (range, 10.0-25.5 mg/kg) per day was administered. In some cases the EEG discharge activity continued to be lowered even after the drug blood level had reached steady state. With medication, frequency and total duration of paroxysms were significantly lowered (by more than 90%) in over 80% of the patients, whereas the mean duration of paroxysmal activity did not change uniformly. Before treatment, short paroxysms (1-5 s) were seen together with longer ones in 11 patients. During treatment either all paroxysms disappeared or, in cases of remaining activity, most discharges were short and not accompanied by seizure manifestations. Blood level profiles over 24 h showed maximal values between midnight and 2 a.m. The minimal values (about half of the maximum) were found between 10 p.m. and midnight. The 8 a.m. value was 70-80% of the maximum. Only three patients complained of slight side effects (temporary drowsiness, loss of hair). Because of the simplified handling, the relatively low dose per day, and the few side effects, it seems possible that for primary generalized epilepsies once daily evening administration of sodium valproate is appropriate without diminishing the antiepileptic effect.     

A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group.

The long-term efficacy and safety of sodium valproate and carbamazepine in adult outpatients with newly diagnosed primary generalised or partial and secondarily generalised seizures were compared in a randomised, open, multicentre study at 22 neurology outpatient clinics. Patients were randomised to oral sodium valproate (Epilim EC enteric coated 200 mg tablets twice daily, n = 149) or oral carbamazepine (100 mg twice daily increasing to 200 mg twice daily in week 2, n = 151) and followed up for three years. If clinically necessary, dosages were regularly increased until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine controlled both primary generalised and partial seizures equally effectively overall. Significantly more patients on sodium valproate than carbamazepine (126/140 (90%) v 105/141 (75%), p = 0.001) remained on randomised treatment for at least six months. Skin rashes occurred significantly more often in carbamazepine recipients than in sodium valproate recipients (11.2% v 1.7%, p < 0.05) and carbamazepine was associated with a higher withdrawal rate because of adverse events (15% v 5% on sodium valproate) in the first six months of treatment. There was no difference between the drugs in the rate of withdrawal because of poor seizure control at any stage, regardless of seizure type. At the end of the three year trial period, over 70% of the available patients were still on randomised treatment or had recently stopped treatment after achieving full seizure control. Sodium valproate and carbamazepine were both associated with a high degree of overall seizure control regardless of seizure type and both have good long-term tolerability in adult patients with newly diagnosed epilepsy. Recommendations are made for a higher initial dosage regime for sodium valproate in partial seizures.     

Juvenile Myoclonic Epilepsy – an experience from north western India

OBJECTIVES: The clinical data on cases of Juvenile Myoclonic Epilepsy (JME) were analysed. Response to initial small dosages (lower than usual) of sodium valproate and further lower maintenance dosages in patients who were seizure free for 2 years on drug were assessed. MATERIAL AND METHODS: Seventy-six patients who were diagnosed to have Juvenile Myoclonic Epilepsy on definite criteria were studied. All patients were put on sodium valproate in dosages (lower than usual) for initial control and further lower maintenance dosage and response evaluated. RESULTS: The clinical profile was found to be similar as in other parts of India. There was a female preponderance and average delay of 4.9 years in final diagnosis. Forty-eight (63.1%) patients showed good control on 15 mg/kg/day dosages of sodium valproate. After a seizure free interval of 2 years, 58% of patients could be maintained on small dosages ranging from 3-5 mg/kg/day to 6-8 mg/kg/day. CONCLUSION: The majority of JME patients responded well not only to sodium valproate in dosages lower than usually prescribed but required very small dosages for maintenance after a seizure free period of 2 years.     

Effectiveness, safety and practicality of delayed-release minitablets of valproate in bipolar affective disorders

Valproate has recently emerged as a drug of first choice in treating acute mania because of its efficacy and relative safety. It can be administered as an intravenous, oral non-sustained release or oral sustained release loading therapy. A new sustained release formulation of valproate consists of "mini-tablets" with the possible advantage of a less problematic and more reliable administration of the drug. We report on eleven patients with an acute manic exacerbation who were investigated for sufficient control of manic symptoms and the duration of building up and maintaining sufficient blood levels of valproate in once/d versus twice/d administration of valproate delayed release mini-tablets (VPA mrt.). Acute and prophylactic effectiveness in mania were rated with the Young-Mania Rating Scale (YMRS), respectively the Global Clinical Impression Scale for Bipolar Disorder (CGI-BP). RESULTS: Within a short period of time sufficient blood levels in both groups (once/d versus twice/d administration) were built up. Seven of eleven patients were responders according to a reduction of 50% of the YMRS. In respect of prophylactic treatment all of the ten patients showed satisfactory results and no re-exacerbation of manic symptoms or depression.     

A dosing algorithm for converting from valproate monotherapy to lamotrigine monotherapy in patients with epilepsy

A dosing algorithm was used to guide the conversion of 77 patients with epilepsy (16 years of age) from valproate monotherapy through lamotrigine adjunctive therapy at 200mg daily to lamotrigine monotherapy at 500 mg daily in an open-label study comprising a lamotrigine escalation phase (8 weeks), a valproate withdrawal phase (6 weeks), and a lamotrigine monotherapy phase (4 weeks). The algorithm was designed to maintain stable trough concentrations of lamotrigine during valproate withdrawal to minimize seizure risk. Of the 77 patients, 11 prematurely withdrew for administrative reasons (noncompliance, consent withdrawn, loss to follow-up, protocol violation). Of the remaining 66 patients, 18 withdrew because of adverse events, and 48 completed the study. Among the 67 patients with at least one lamotrigine trough serum concentration after initiation of therapy (pharmacokinetic population), mean trough serum concentrations at the end of the lamotrigine escalation phase at a lamotrigine daily dose of 200 mg (7.9 microg/mL, SD = 3.3) did not differ significantly from values during the valproate withdrawal phase (8.7 microg/mL, SD = 3.5) and the lamotrigine monotherapy phase at a lamotrigine dose of 500 mg daily (7.2 microg/mL, SD = 3.3). A similar pattern of results was observed among the 34 patients who completed the study on lamotrigine (completer population). No serious rashes were reported, and the incidence of withdrawals because of decreased seizure control was low (n = 2, or 3%; both incidents were judged to be related to noncompliance). By employment of a four-step dosing algorithm, lamotrigine serum concentrations can be maintained at a stable level with favorable tolerability during a transition from lamotrigine 200mg daily as adjunctive therapy with valproate to lamotrigine monotherapy 500 mg daily.     

Successful initiation of combined therapy with valproate sodium injection and divalproex sodium extended-release tablets in the epilepsy monitoring unit

Summary: Purpose: Patients in epilepsy monitoring units (EMUs) often require aggressive initiation or reinitiation of therapy before discharge. We developed a simple dosing scheme using valproate sodium injection (VPA‐IV) and divalproex sodium extended‐release (VPA‐ER) tablets to minimize the time required for initiation of therapy, without increasing the likelihood of seizures and adverse effects. Methods: We identified 42 patients in the EMU, naïve to VPA‐IV and VPA‐ER, for whom one of the discharge AEDs included divalproex sodium. On the day of discharge, patients were loaded with 20 mg/kg VPA‐IV at 6 mg/kg/min, followed by ～20 mg/kg VPA‐ER within 1 h. The discharge daily dose of VPA‐ER was identical to the dose given after the IV load. We assessed tolerability and seizure occurrence during infusion, at 1 h, 4 h, and 1 week after discharge. Results: All patients tolerated the VPA‐IV dose followed by VPA‐ER. Four patients reported mild nausea, and two patients reported mild dizziness within 4 h. No seizures or significant changes in heart rate or blood pressure occurred within 4 h, and all patients were discharged the same day. All patients denied systemic complaints at 1 week, and five had seizures during the week after discharge. All patients had improved seizure frequencies at the end of the first week. Conclusions: VPA‐IV is well tolerated and convenient for rapid loading in the EMU. When promptly followed by VPA‐ER, seizure control remains excellent.     

Clinical Monitoring During Carbamazepine Slow-Release, Once-Daily Monotherapy

Forty-eight patients with complex partial and/or tonic-clonic seizures were treated with an 8 p.m. single dose of carbamazepine slow release (CBZ-SR) monotherapy. The steady-state serum level profiles of carbamazepine (CBZ) and its metabolites CBZ-10,11-epoxide (CBZE) and 10,11-dihydro-CBZ-10,11-diole (CBZD) during 24 h in 21 of 48 patients treated with daily single doses of 8.4 (+/- 2.4) mg/kg body weight CBZ-SR were determined by a high-performance liquid chromatography procedure. The 8 a.m. CBZ levels correlated very well with the mean CBZ levels of the 24-h profile. Unlike CBZD, the individual 24-h mean CBZE levels also correlated well with the respective CBZ levels (CBZE = 14.2% +/- 2.9 of CBZ). Increasing CBZ-SR doses does not result in a proportional increase of CBZ levels. Clinical efficacy of changing from CBZ standard tablets under mono- or combination therapy or from therapy with other antiepileptic drugs to once-daily evening CBZ-SR monotherapy or commencement CBZ-SR therapy in previously untreated patients was monitored in 35 of 48 patients for a period of 8 months to 2 years. Complete seizure control was observed in 51% of patients and more than 75% reduction of seizure frequency in 14%. Eight of 11 previously untreated patients became seizure free. With change from CBZ monotherapy to CBZ-SR single-dose therapy, five of six patients became seizure free. Changing from other therapeutic regimens to CBZ-SR once-daily evening monotherapy was less successful.     

An observational study of first-line valproate monotherapy in focal epilepsy

The objective of this multinational open-label, prospective study was to collect, under naturalistic conditions, data on the effectiveness and tolerability of first-line monotherapy with valproate in subjects newly or recently diagnosed with focal onset epilepsy. Patients were treated with sustained release sodium valproate. Seizure control and occurrence of adverse events were assessed after 6 months. Around 1192 adults and 792 children were included. The mean daily valproate dose was 683 mg in children and 987 mg in adults. The retention rate at 6 months was 90.0%. At this time, 77% of subjects were seizure free (83.7% of children and 72.7% of adults). Adverse events possibly related to treatment were observed in 10.2% of subjects, leading to treatment modification for 1.7%. The most common adverse events were weight gain, gastro-intestinal, neurological and skin disorders. Sustained release sodium valproate is effective and shows acceptable tolerability as first-line monotherapy in focal onset epilepsy.     

Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy

In a multicenter, randomized, double-blind study the authors compared the efficacy of modafinil 400 mg once daily, 400 mg given in a split dose, or 200 mg once daily for maintaining wakefulness throughout the day in patients (N = 32) with narcolepsy reporting a positive daytime response to modafinil but late-afternoon/evening sleepiness. Efficacy evaluations included an extended Maintenance of Wakefulness Test (9:00 am to 9:00 pm), the Clinical Global Impression of Change scale, and the Epworth Sleepiness Scale. Modafinil demonstrated significant improvement in wakefulness as assessed by the Epworth Sleepiness Scale compared with placebo at baseline (all P < 0.001). Modafinil significantly improved patients' ability to sustain wakefulness, as demonstrated by mean sleep latency at week 3 compared with placebo at baseline (all P < 0.001). The 400-mg split-dose regimen improved wakefulness significantly in the evening compared with the 200-mg and 400-mg once-daily regimen (both P < 0.05). The percentage of patients rated as "much improved" or "very much improved" with respect to evening sleepiness was 27%, 82%, and 80% in the 200-mg, 400-mg once-daily, and 400-mg split-dose groups, respectively. Adverse events were mild to moderate in nature and included headache, nausea, nervousness, dyspepsia, pain, and vomiting (all 6%). Some patients may benefit from 400-mg doses of modafinil taken once daily compared with 200-mg doses. A split-dose 400-mg regimen may be superior to once-daily dosing for sustaining wakefulness throughout the entire waking day.     

A Retrospective Study of 113 Epileptic Patients Treated with Sustained-Release Valproate

Summary: A retrospective study of 113 patients treated with a sustained-release form of valproate (SRF-VPA), known as the "chrono" formulation in most European countries, led to the following conclusions: Patients treated with the old VPA formulation could immediately receive the same daily dosage of SRF-VPA without loss of seizure control when administered as a single evening dose. The tolerability of SRF-VPA was good and twice or single daily dosing was preferred by all our patients. Whether or not SRF-VPA should be used as first or second-line treatment in partial seizures that do or do not secondarily generalize is unclear. Our study demonstrates that the efficacy of SRF-VPA is comparable with that of other major antiepileptic drugs such as carbamazepine (CBZ). In refractory seizures, the combination of SRF-VPA and CBZ seemed to be the most satisfactory treatment. Based on these results SRF-VPA is a promising drug for all types of seizures even in low daily dosage, but further clinical work is required to confirm our observations.     

Long-term course of epilepsy in a large cohort of intellectually disabled patients.

This study was designed to describe the course of epilepsy (in terms of seizure frequency) and to assess the variables (antiepileptic therapy regimens and others) correlated to improvement. Seizure frequency (categories: seizure free, more than one seizure/year, monthly seizures, weekly seizures and daily seizures) and antiepileptic medication were retrospectively compared between 1992 and 2002 in a large cohort of 550 inpatients with chronic epilepsy and different degrees of intellectual disability or multiple handicaps. RESULTS: Seizure frequency decreased significantly (p<0.001). 218 of the 394 patients (55.3%) not seizure free in 1992 improved (changed into a better frequency category). The improvement rate was marginally higher in patients who had undergone a medication change (p=0.08). A high seizure frequency in 1992 (p=0.016) and older age (p=0.006), but not epilepsy syndrome or degree of intellectual disability, were predictors for improvement (stepwise logistic regression analysis). 56.4% of the improved patients were on combinations of two AEDs (17.4%, monotherapy; 20.2%, triple therapy). The most frequent therapy regimens in the improved patients were lamotrigine/valproate (48 patients), carbamazepine/phenobarbital (21) and carbamazepine only (19). Lamotrigine/valproate was effective in all kinds of epileptic syndromes. Most patients on lamotrigine had serum concentrations above 10microg/ml, approximately one half had dosages above 200mg/day. The rate of seizure freedom increased from 28.4 to 37.6%. The 84% of the patients seizure free in 1992 remained seizure free. Predictors for seizure freedom in 2002 were higher age (stepwise logistic regression, p<0.0005) and seizure freedom in 1992 (p<0.0005). CONCLUSIONS: Substantial improvement can be achieved even in intellectually disabled patients with chronic epilepsy. Although the rate of seizure freedom is reduced in comparison with a non-ID population, once seizure freedom has been achieved it is most likely to continue. For a majority of this patient population, monotherapy may not be sufficient. Lamotrigine/valproate appears to be a major therapeutic innovation.     

Levetiracetam for people with mental retardation and refractory epilepsy

Levetiracetam (LEV) is a novel antiepileptic drug (AED) with efficacy against a wide range of seizures types. The aim of this observational study was to assess its effectiveness in patients with mental retardation and refractory epilepsy. Sixty-four patients were started on adjunctive LEV after a 3-month baseline. LEV was initially dosed at 250 mg daily and increased by 250 mg every 2 weeks thereafter according to clinical response. Caregivers rated the patient's sleep, appetite, alertness, and behavior as poor (1), reasonable (2), or good (3) at each clinic visit. Patients were reviewed until one of four endpoints was reached: seizure freedom for at least 6 months, > or = 50% reduction in seizure frequency (responder) over a 6-month period, <50% reduction in seizure frequency (marginal effect) over a 6-month period, or LEV withdrawal due to lack of efficacy, adverse effects, or both. Twenty-four (38%) patients became seizure-free, 10 of whom were controlled on LEV 250 mg twice daily. An additional 18 (28%) patients were classified as responders, and 8 (12%) reported only marginal benefit from adjunctive LEV. Fourteen (22%) patients discontinued LEV (6 worsening seizures, 1 lack of efficacy, 7 adverse effects). Caregivers rated combined sleep, appetite, alertness, and behavior scores as "improved" at the end of follow-up (P<0.001). LEV improved seizure control in the majority of patients with mental retardation and may also have enhanced their quality of life.     

Effect of two different methods of initiating atomoxetine on the adverse event profile of atomoxetine

OBJECTIVE: To compare the effects of two different methods for initiating atomoxetine in terms of the incidence of early adverse events. METHOD: Data on atomoxetine treatment-emergent adverse events in youths, ages 6 to 18 years, were analyzed from five randomized, double-blind, placebo-controlled, acute-phase studies. Two studies involve once-daily dosing and titration to 1.2 mg/kg/day over 3 days (fast/once daily, n = 234) and three involve twice-daily dosing and titration to a dose of 1.2 mg/kg/day over at least 2 weeks (slow/twice daily, n = 213). RESULTS: During the first 2 weeks of treatment, fast/once daily titration patients showed higher rates of spontaneously reported adverse events than patients in the slow/twice daily titration group. This included decreased appetite (14.3% versus 8.0%, p = .036) and somnolence (14.3% versus 4.2%, p < .001). Patients in the slow/twice daily group showed higher rates of headache (7.4% versus 16.9%, p = .003). Analysis of the studies' overall acute treatment phases revealed significantly higher rates in the fast/once daily group only for somnolence. No significant differences were seen in completion rates or reasons for discontinuation. CONCLUSIONS: When starting atomoxetine, the risk of adverse events within the first few weeks of treatment may be lower if patients are dosed twice daily and titrated to the 1.2 mg/kg/day total daily dose over the first week.     

Topiramate as add-on drug in children,adolescents and young adults with Lennox-Gastaut syndrome: an Italian multicentric study

The purpose of the study was to evaluate the efficacy and safety of topiramate (TPM) as adjunctive therapy in children, adolescents and young adults with Lennox-Gastaut syndrome (LGS). We performed a prospective open label add-on study in 45 patients (age 4-34 years, mean 15.9 years) with LGS and refractory seizures. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. TPM was initiated at the daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h, up to a maximum daily dose of 12 mg/kg. After a mean period of 15.8 months of treatment (range 3-98 months), at a mean dose of 4.1 mg/kg/24 h (range 1.4-12 mg/kg), 18 patients (40%) had a seizure reduction more than 50%. TPM appeared to be effective mainly in major seizures (drop attacks, tonic and tonic-clonic seizures). Mild to moderate adverse events were present in 24 patients (53.3%), mostly represented by drowsiness, nervousness, hyporexia with or without weight loss and cognitive dulling. In conclusion, TPM adjunctive therapy reduced the number of drop attacks and major motor seizures in 40% of patients with LGS and produced only mild or moderate adverse events.     

Expanded therapeutic range of valproate

Twenty-five pediatric patients with serum valproate levels above 100μg/ml (therapeutic range: 50–100μg/ml) are reviewed for nondose-related side effects and seizure control. The dose of valproate varied from 50–100 mg/kg/day. All patients had generalized or mixed seizure disorders which were difficult to control. Seizure frequency decreased by more than 50% in 14 patients. For those patients with improved control, valproate levels ranged from 111–196 μg/ml. Patients were carefully monitored for side effects; nondose-related side effects were not encountered. Random valproate levels were between 100–200 μg/ml. The clinical response to valproate can be augmented by increasing it to the maximum tolerated dose.     

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.     

Effect of magnesium valproate on amygdala-kindled seizures in the rat: comparison with sodium valproate

The anticonvulsant activity of a salt of valproic acid (VA), magnesium valproate (MgV), was assessed against amygdala-kindled seizures in rats. The anti-epileptic power of MgV was compared with that of sodium valproate (NaV). Kindling was obtained by delivering daily to one of the amygdala a 2 s train of monophasic square-wave pulses (1 ms, 60 c.p.s., 100-130 microA) via chronically implanted electrodes. Magnesium valproate and NaV were tested once kindling was stabilized and the post-kindling threshold for generalized convulsions was determined. The drugs were administered intraperitoneally in doses ranging from 25 to 200 mg/kg. The injection/test interval was 30 min. Each animal received a single dose every 24 h. Magnesium valproate exhibited an anticonvulsant activity qualitatively and quantitatively similar to that of NaV. Statistically significant differences were not found between the two drugs with respect to the reduction of seizure severity and afterdischarge (AD) duration. The calculated ED50's were 94.58 and 97.41 mg/kg for the suppression of generalized seizures, 176.96 and 129.26 mg/kg for the suppression of partial seizures, 275.96 and 224.13 mg/kg for the suppression of the local AD in the MgV and NaV treated groups, respectively.     

A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study

OBJECTIVE: This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of several modafinil dosing regimens in children with attention-deficit/hyperactivity disorder (ADHD) to determine whether modafinil can be given once daily in pediatric ADHD. METHOD: Children and adolescents (age range, 6-13 years) (N = 248) with DSM-IV-defined ADHD were enrolled in a 4-week, double-blind, placebo-controlled study, conducted February-May 2002. The group was assigned to receive oral (100-mg tablets) modafinil 300 mg once daily (300 mg in the morning followed by placebo at midday), modafinil 300 mg as a divided dose (100/200 mg or 200/100 mg), or matching placebo. In children weighing > or = 30 kg, a higher dose of 400 mg (200/200 mg) was evaluated. Efficacy measures included the teacher-rated School Version and clinician-rated Home Version of the ADHD Rating Scale-IV and the parent-completed Conners' ADHD/DSM-IV Scales. RESULTS: 223 children completed the study. Those who received modafinil 300 mg once daily showed a significantly greater improvement (change from baseline) than those who received placebo in symptoms of ADHD across all rating scales and subscales (all p < .05). Divided 300-mg doses of modafinil provided some significant but inconsistent improvements in ADHD symptoms. In children weighing > or = 30 kg, modafinil 400 mg (200/200 mg) was significantly superior to placebo on clinician- and parent-completed scales (all p < .05). Insomnia was the only adverse event to occur with significantly greater frequency in a modafinil group (200/100) than in the placebo group (14% vs. 2%) (p = .03). CONCLUSION: Modafinil significantly improved ADHD symptoms in children. Once-daily dosing (300 mg) provided the most consistent improvement in symptoms. All dosing regimens of modafinil were well tolerated.     

Valproate and the risk for congenital malformations: Is formulation and dosage regime important?

BackgroundUse of valproate in pregnancy, especially in doses over 1000 mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate.MethodsThe UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure.ResultsOutcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000 mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000 mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1–2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67–1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58–1.70).ConclusionPrescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.     

Topiramate in refractory partial-onset seizures in children, adolescents and young adults: a multicentric open trial

PURPOSE: This study was to evaluate the efficacy and safety of topiramate (TPM) in refractory partial epilepsy in children, adolescents and young adults. Methods: We performed a prospective open label add-on study in 55 patients (age 2-30 years, mean 15 years) with refractory partial seizures. Topiramate was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. RESULTS: TPM was initiated at a daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24h, up to a maximum daily dose of 12 mg/kg. After 9 months of treatment, 11 patients (20%) had 100% fewer seizures and 25 patients (45%) had a more than 50% seizure reduction. TPM appeared to be effective both in cryptogenic (76.2%) and symptomatic (58.8%) partial epilepsies. Mild to moderate adverse events were present in 25 patients (45.4%), mostly represented by drowsiness, nervousness and hyporexia with or without weight loss. CONCLUSION: TPM was an overall effective and safe add-on drug both in cryptogenic and symptomatic childhood refractory partial seizures, the adverse reactions being generally mild or moderate.