Commission on Outcome Measurement in Epilepsy, 1994-1997: final report.
Explore the source record for details and available documents.
Anticonvulsants↗
Biomedical subjects
E Perucca
Publications and source records attributed to E Perucca.
Total and non-protein-bound fractions of 3,4-dihydroxyphenylalanine.
Explore the source record for details and available documents.
Antiparkinson Agents↗
Fluoxetine-induced movement disorders and deficient CYP2D6 enzyme activity.
Explore the source record for details and available documents.
Aged↗
A pharmacological and clinical review on topiramate, a new antiepileptic drug.
Topiramate is a new antiepileptic drug which has recently become available in the United States and in a number of European countries. Pharmacological studies suggest that its mode of action is multifactorial and involves blockade of voltage-dependent sodium channels, potentiation of GABAergic transmission and inhibition of excitatory pathways through an action at AMPA receptor sites. Carbonic anhydrase inhibiting properties have also been demonstrated but they are considered not to be relevant to anticonvulsant activity. Topiramate is well absorbed from the gastrointestinal tract, peak plasma levels being usually attained in 2-3 hours. The drug is negligibly (9-17%) bound to plasma proteins and is eliminated partly by renal excretion in unchanged form and partly by oxidation and hydrolysis. In healthy volunteers, the half-life is about 20-30 hours, but elimination rate is accelerated in patients taking concomitant enzyme inducing drugs such as phenytoin, carbamazepine and barbiturates. Topiramate has no major effects on plasma levels of concurrent anticonvulsants, except for a rise in plasma phenytoin in occasional patients. In double-blind add-on trials in refractory partial epilepsy, a significant reduction in seizure frequency has been demonstrated in over 40% of topiramate-treated patients (vs about 10% of those treated with placebo), a response rate which compares favourably with that observed with other new antiepileptic drugs. Dosages found to be effective in add-on controlled trials range between 200 and 1000 mg day-1, although most patients are likely to benefit from receiving 400 mg day-1 or less. Preliminary data suggest that topiramate may be effective also in generalized epilepsies, but this needs to be confirmed in prospective studies. The most common adverse effects of topiramate are CNS-related and include dizziness, fatigue, visual disturbances, ataxia, mental slowing and impaired concentration. Paresthesias, anorexia, weight loss and increased risk of nephrolithiasis have been also reported. Many of these effects are related to dose and/or to rate of dose titration. Based on these data, topiramate appears to be a valuable new drug, whose main current indication is in the add-on management of refractory partial and secondarily generalized seizures. Studies on its potential-value as monotherapy are in progress.
Animals↗
Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study.
OBJECTIVE: The clinical relevance of the CYP2D6 oxidation polymorphism in the treatment of depression with desipramine (DMI) was studied prospectively in depressed outpatients. METHODS: After CYP2D6 phenotype determination with dextromethorphan, 31 patients were treated with oral DMI at a dosage of 100 mg per day for 3 weeks. At the end of the 3rd week of treatment, severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale and steady-state plasma concentrations of DMI and its metabolite 2-hydroxydesipramine (2-OH-DMI) were measured by high-performance liquid chromatography (HPLC). RESULTS: Plasma DMI levels were significantly correlated with dextromethorphan metabolic ratio. The two patients with the poor metabolizer phenotype showed the highest plasma concentrations of DMI and complained of severe adverse effects, requiring dosage reduction. No significant correlation was found between plasma levels of either DMI or DMI plus 2-OH-DMI and antidepressant effect. CONCLUSION: These findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects. On the other hand, this index of CYP2D6 activity does not seem to predict the degree of clinical amelioration.
Adult↗
Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy.
OBJECTIVE: To investigate the pharmacokinetics of the four stereoisomers of valnoctamide, a mild tranquilizer endowed with anticonvulsant properties. METHODS: Racemic valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepine therapy. In the patients with epilepsy, valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs). RESULTS: In healthy subjects, stereoisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4 1/2 L/hr, a half-life (t1/2) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 +/- 0.9 L/hr) and a shorter t1/2 (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t1/2 values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose. CONCLUSIONS: Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of valnoctamide stereoisomers by carbamazepine.
Administration, Oral↗
Evaluation of drug treatment outcome in epilepsy: a clinical perspective.
This article provides a comprehensive discussion of clinical outcome measures used in trials aimed at assessing the efficacy and safety of antiepileptic drugs. For efficacy, assessment still relies on careful documentation of changes in ictal activity as determined by seizure counts based on patients recall, direct clinical observation and (for absence seizures) EEG monitoring. In selected cases, assessment of seizure severity may also be indicated. The precise choice of outcome measures is largely dependent upon the specific trial design. In short-term regulatory trials, parameters such as time to nth seizure after randomization (or after achievement of target dosage) may be used as an index of antiepileptic efficacy, but the clinical relevance of such measures is questionable. In add-on trials in refractory patients, changes, in seizure counts and proportion of patients achieving 50%, 75% and 100% reduction in seizure frequency may be appropriate. For long-term monotherapy trials in newly diagnosed patients, proportion of patients achieving prolonged remission (1-year or longer) usually represents the most clinically meaningful efficacy outcome. Retention of patients on the allocated treatment over time is also a valuable measure, but it should be regarded as a composite endpoint because decision to continue treatment is dependent on both efficacy and tolerability. At present, there is no universally accepted method for evaluating side effects, particularly those which can not be documented objectively. Spontaneous reports of symptoms or use of specific checklists have advantages and disadvantages. Studies aimed at ensuring greater standardization in safety assessment should be encouraged, especially with respect to need of obtaining quantitative estimates, and information on both prevalence and incidence of side effects should be reported in all trials.
Anticonvulsants↗
Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects.
AIMS: The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants. METHODS: The effect of oral ketoconazole (200 mg day-1 for 14 days) on the kinetics of a single oral dose of imipramine (100 mg) and desipramine (100 mg) was evaluated in two groups of six healthy male subjects. RESULTS: Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16 +/- 0.21 to 0.96 +/- 0.20 l h-1 kg-1, mean +/- s.d.; P < 0.02), a prolongation in imipramine half-life (from 16.7 +/- 3.3 to 19.2 +/- 5.4 h, P < 0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507 +/- 1707 to 3180 +/- 1505 nmol l-1 h, P < 0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment. CONCLUSIONS: These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N-demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.
Administration, Oral↗
The influence of dosage, age, and comedication on steady state plasma lamotrigine concentrations in epileptic children: a prospective study with preliminary assessment of correlations with clinical response.
The effects of age, dosage, and type of comedication on plasma lamotrigine (LTG) concentrations and the relationship between plasma drug levels and clinical response were evaluated in a prospective study of 45 patients, aged 3 to 38 years, with epilepsy uncontrolled by conventional anticonvulsant therapy. Six of the 45 patients were on single-drug therapy, and 39 were on two to five concurrently administered antiepileptic drugs when LTG was added. Thirteen patients were assessed at three or more LTG dosage levels. Within individuals, steady state plasma LTG concentrations increased linearly with increasing daily dosage over the examined dose range (25 to 575 mg/day or 0.75 to 21 mg/kg.day). Among patients also receiving enzyme-inducing agents, such as carbamazepine, barbiturates, or phenytoin, plasma LTG concentrations normalized to a 1 mg/kg daily dose were lower in children aged 3 to 6 years (0.30 +/- 0.17 microgram/ml; n = 6) than in the older children (0.43 +/-0.18 microgram/ml; n = 12) and adolescents/adults (0.68 +/- 0.26 microgram/ml; n = 10). In patients treated with valproate, the age dependency of plasma LTG was less evident, possibly because of a smaller sample size and the confounding effect of comedication. Within any given age group, dose-normalized LTG concentrations were about five-fold higher in patients comedicated with valproic acid than in those comedicated with enzyme inducers. Twenty patients showed a favorable response (with a > or = 40% reduction in seizure frequency compared with the pre-LTG period) and continued on long-term treatment. Plasma drug concentrations in these apparent responders were highly variable and did not differ significantly from those observed in nonresponders (6.6 +/- 5.2 versus 4.8 +/- 3.3 microgram/ml). These findings show that plasma LTG concentrations exhibit a wide interindividual variability under the influence of age and type of comedication, but they are predictably related to dosage within individual patients. Although there was no apparent relationship between drug levels and clinical response in this difficult-to-treat population, further studies on the potential value of monitoring plasma LTG concentrations are indicated.
Adolescent↗
Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy.
The effect of ketoconazole (200 mg/d orally for 10 days) on the plasma concentrations of carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZ-E) was assessed in eight patients with epilepsy stabilized on CBZ therapy. Administration of ketoconazole was associated with a significant increase in plasma CBZ concentrations (from 5.6 +/- 1.9 to 7.2 +/- 2.9 micrograms/ml on day 10 [means +/- SD, P < 0.02]), whereas plasma concentrations of CBZ-E were unchanged. After ketoconazole was discontinued, plasma CBZ levels decreased to pretreatment values. This interaction was probably mediated by an inhibiting action of ketoconazole on cytochrome CYP3A4, the main enzyme responsible for CBZ metabolism.
Adult↗
A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers.
PURPOSE: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. METHODS: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of > or = 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-beta-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. RESULTS: VGB treatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/- 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 +/- 3.5 vs. 14.1 +/- 2.1 h), urinary 6-beta-hydroxycortisol excretion (488 +/- 164 vs. 470 +/- 228 nmol/ day), 6-beta-hydroxycortisol-to-cortisol concentration ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransferase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUC, 874 +/- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrel (half-life, 17.7 +/- 5.2 vs. 23.1 +/- 9.8 h; AUC, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 micrograms/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. CONCLUSIONS: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.
Adult↗
Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications.
The extent and clinical significance of the pharmacokinetic interaction between fluoxetine and haloperidol was studied in 13 schizophrenic patients with prominent negative symptoms. Patients stabilized on chronic low-dose haloperidol (3-8 mg day-1) received additional fluoxetine (20 mg day-1) for 12 consecutive weeks. Mean plasma concentrations of haloperidol increased significantly from 6.5 +/- 2.4 nmol l-1 at baseline to 8.8 +/- 3.6 nmol l-1 (P < 0.01) at week 12 of fluoxetine treatment, but this effect was not associated with an increase in mean extrapyramidal side effects score on the Simpson and Angus Scale. The improvement in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, did not correlate significantly with the increase in plasma haloperidol levels. Though our findings confirm that fluoxetine impairs haloperidol clearance, this interaction is unlikely to have adverse clinical consequences, at least in patients chronically stabilized on a low dosage of haloperidol. As fluoxetine is a potent inhibitor of cytochrome P450 (CYP) 2D6, these results also provide indirect evidence for an involvement of CYP2D6 in the metabolism of haloperidol.
Adult↗
Efficacy and safety of topiramate in refractory epilepsy: a long-term prospective trial.
The effects of topiramate in 15 patients with drug refractory epilepsy or Lennox-Gastaut syndrome were assessed in an open, add-on prospective study. After a follow-up of 14-21 months, six patients are still on topiramate (mean dosage 583 mg/day, range 400-800 mg/day), and nine have discontinued treatment because of adverse events (n = 6), inefficacy (n = 2) or poor compliance (n = 1). Nine patients (69%) continued to have > or = 50% reduction in seizure frequency during the last two months of treatment, and one has been seizure-free for the last 19 months. The most common adverse events were somnolence, weight loss, mental slowing, fatigue, ataxia and irritability. Most of these events were reversible, but withdrawal of treatment was required in six cases as a result of ataxia (two patients), somnolence, metabolic acidosis, irritability or psychotic symptoms (one patient each). It is concluded that topiramate is a valuable agent for long-term management of refractory epilepsy.
Adult↗
Concentrations of L-dopa in plasma and plasma ultrafiltrates.
A sensitive and specific procedure is described for the determination of therapeutically relevant concentrations of L-dopa in plasma and plasma ultrafiltrates (free fraction) by high performance liquid chromatography with electrochemical detection. In plasma samples from healthy adult subjects (n = 15) spiked with L-dopa (500 micrograms l-1) the free fraction averaged 76 +/- = 8% (range 61-84%). Free fraction values increased by 38% with increasing plasma concentrations of L-dopa from 100-5000 micrograms 1-1. L-dopa free fraction was not affect by the presence of 3-O-methyl-dopa at concentrations up to 10,000 micrograms l-1.
Adult↗
Progress report on new antiepileptic drugs: a summary of the Third Eilat Conference.
The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues in drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.
Acetamides↗
Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients.
1. To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2. Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0 +/- 7.8 vs 53.7 +/- 14.3 h, means +/- s.d., P < 0.001) and higher apparent oral clearance (CL/F) values (15.3 +/- 3.8 vs 9.2 +/- 1.9 ml kg-1 h-1, P < 0.001). The apparent volume of distribution (V/F) of ethosuximide was slightly lower in the patients than in controls (0.6 +/- 0.1 vs 0.7 +/- 0.1 l kg-1, P < 0.05). 3. These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4. The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.
Adult↗
Phenobarbital induces the 2-hydroxylation of desipramine.
The kinetics of a single oral dose of desipramine (DMI; 100 mg) were studied in eight epileptic patients chronically treated with phenobarbital (PB) and in eight drug-free healthy controls. All subjects were extensive metabolizers with respect to the genetically determined CYP2D6-related metabolic polymorphism. Compared with controls, epileptic patients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 107 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-curve values (1,943 +/- 461 vs. 3,234 +/- 1,145 nmol L-1 h; p < 0.01), and shorter DMI elimination half-lives (15.1 +/- 2.1 vs. 20.6 +/- 3.4 h; p < 0.01). The proportion of the dose excreted as 2-hydroxydesipramine (2-OH-DMI) was significantly higher in the patients (54 +/- 8 vs. 40 +/- 9%; p < 0.05). In one single poor metabolizer volunteer, a 3-week treatment with PB was associated with no major changes in DMI kinetics, but the urinary excretion of 2-OH-DMI tended to increase. These results suggest that PB is an inducer of the 2-hydroxylation of DMI, a reaction primarily catalyzed by CYP2D6, but do not provide further information on the specific P450 isoenzyme(s) being induced.
Adult↗
The influence of ethnic factors and gender on CYP1A2-mediated drug disposition: a comparative study in Caucasian and Chinese subjects using phenacetin as a marker substrate.
To assess potential ethnic and gender-related differences in the expression of cytochrome CYP1A2-mediated activity, the pharmacokinetics of phenacetin (a CYP1A2 substrate) and its metabolite paracetamol were compared in 20 Caucasian and 20 Chinese subjects after administration of a single oral 900 mg phenacetin dose. Peak plasma concentrations and apparent oral clearance values for phenacetin did not differ between the two groups (geometric means: 3.4 micrograms/ml and 1.56 ml h-1 kg-1, respectively, for Caucasians vs. 4.7 micrograms/ml and 1.25 ml h-1 kg-1, respectively, for Chinese, after excluding one Caucasian with aberrantly low plasma phenacetin values). Pharmacokinetic parameters for metabolically derived paracetamol were also similar in the two groups. When subjects were divided into subgroups according to gender, phenacetin apparent oral clearance values were found to be lower in Chinese women compared with both Chinese men and Caucasian subjects of either sex. It is concluded that there are no major interethnic differences in the expression of CYP1A2-related activity between Caucasians and Chinese, although Chinese women as a subgroup may exhibit comparatively lower enzyme activity.
Acetaminophen↗