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Determination of antiepileptic drugs.

The present paper reviews gas and liquid chromatographic methods for the determination of the most commonly monitored antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, valproic acid and clonazepam along with a new compound, progabide. The individual classes of drugs are first treated separately to highlight specific aspects of their quantification, and this is followed by an overview of those methods permitting the concomitant analysis of two or more antiepileptic compounds. Sample preparation techniques as well as comparisons between chromatographic and other techniques are treated more fully in separate sections.

Anticonvulsants↗

Phenytoin desensitization in a child with symptomatic localization-related epilepsy.

We reported a child with refractory partial seizures successfully managed by clinical desensitization to phenytoin. The patient had ischemic brain lesions due to cardiopulmonary arrest at 39 weeks of corrected age. He had complex partial seizures refractory to several antiepileptic drugs since 4 years of age. At 8 years 1 month of age, phenytoin was first administered. Fever and maculopapular rashes appeared at 10 days after phenytoin initiation, and then the drug was discontinued. At 8 years 8 months of age, desensitization was attempted because of refractoriness of seizures to drugs other than phenytoin. Desensitization was started at 1mg daily, and then the dose was doubled every week. His seizures were controlled by 150mg/day of phenytoin in combination with primidone. No problems have been observed during desensitization.

Anticonvulsants↗

Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy.

OBJECTIVES: To describe the clinical characteristics of epilepsy in a representative sample of the UK population, including seizure frequency and severity; overall severity of epilepsy; patterns of anti-epileptic drug (AED) use; and the impact of epilepsy on patients' lives. Secondly, to determine if these characteristics differ according to age. METHOD: A large, geographically comprehensive survey of people with epilepsy by means of a postal questionnaire distributed by general practitioners to 3455 unselected patients receiving AEDs for epilepsy, regardless of age or type of epilepsy and including all regions of the UK. Data were collected on age and gender; age of onset of seizures; seizure frequency and severity; AED use and adverse effect levels; and impact on life of epilepsy. Sub-analyses were performed with stratification by epilepsy severity and age-group. RESULTS: There were 1652 completed replies. The mean age was 44.2 years; there were 47.2% males, 48.5% females (4.4% not recorded). The mean age at first seizure, 25.1 years, and the mean duration of epilepsy, 19.7 years, were comparable with previous studies. In the preceding one year, 51.7% of patients had no seizures; 7.9% one seizure, 17.2% 2-9 seizures and 23.2% 10 or more. Sixty-four percent of patients had epilepsy classified as mild and 32% severe. There was a marked and significant decrement of seizure frequency with increasing age. The most commonly used AEDs were carbamazepine (37.4%), valproate (35.7%), phenytoin (29.4%), phenobarbitone or primidone (14.2%) and lamotrigine (10.3%). Monotherapy was used in 68% of patients. Patients taking multiple AEDs reported significantly higher levels of adverse effects and worse seizure control. The major impacts of epilepsy on life were work and school difficulties, driving prohibition, psychological and social life. The impacts listed varied with the epilepsy severity and age. CONCLUSIONS: Seizures remain uncontrolled in up to half of all people with epilepsy in the UK with significant impact on work, family and social life. Previously, there has been a deficiency of data on the characteristics of epilepsy in older people, although it is recognized that the condition is of increasing epidemiological importance in this age group. We have found clear differences in the clinical characteristics of epilepsy in older people, particularly that seizure frequency appears to decline with increasing age.

Adult↗

Essential tremor: differential diagnosis and current therapy.

Essential tremor is a common movement disorder that affects between 5 and 10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. Primidone and propranolol are first-line treatments. Other medications with potential efficacy include benzodiazepines, gabapentin, topiramate, and botulinum toxin. Patients with medication-resistant tremor may benefit from thalamotomy or deep brain stimulation of the thalamus. The use of medical and surgical therapies can provide benefit in up to 80% of patients with essential tremor.

Acetates↗

Logit-log calibration curves for EMIT assays.

The logit-log and four-parameter logistic procedures when appropriate for calculation of enzyme-multiplied immunoassay (EMIT) data have the advantage that they can be applied regardless of the kinetic analyzer or reaction conditions. To use these procedures correctly one must determine the change in absorbance at an infinite drug concentration (delta A infinity). The marked variation of delta A infinity with equipment and reaction conditions and the difficulty in determining this value have hindered broad use of these otherwise universally applicable procedures. We have evaluated two simple methods for determining delta A infinity, both based on its equivalence to delta A in the absence of specific antibody: (1) cross-kit reaction using antibody/substrate and enzyme-drug reagents from kits for different drugs, and (2) substitution of an antibody-free substrate reagent with composition based on direct analysis. The cross-kit procedure was tested with EMIT assays for phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide, and theophylline. In some cases an unexpected type of cross-reaction occurred, giving an erroneously low value for delta A infinity. The antibody-free substrate reagent always permitted accurate determination of delta A infinity.

Anticonvulsants↗

Correlation of the "EMIT" antiepileptic drug assay with a gas liquid chromatographic method.

Many methodologies have been developed for determining anticonvulsant drug levels in human serum. Unfortunately, most procedures are either time consuming or subject to a variety of interferring substances. The "Enzyme Multiplied Immunoassay Technique" (EMIT) system has been evaluated for its speed, sensitivity, accuracy, and precision. When compared with a gas-liquid chromatographic procedure, the EMIT assay appeared to yield results which were statistically comparable for the drugs diphenylhydantoin, phenobarbital, and primidone. The EMIT assay also demonstrated no significant interference when challenged with extraordinarily high levels of potentially cross reacting drugs. Results obtained with the EMIT assay correlated well with GLC data and rank it as an attractive alternative to many of the existing procedures now being used.

Autoanalysis↗

Simultaneous gas chromatographic analysis for the four commonly used antiepileptic drugs in serum.

We describe a simple, sensitive method for the determination of phenobarbital, diphenylhydantoin, carbamazepine and primidone in serum, by use of gas-liquid chromatography with temperature programming. The methylated derivatives of these anticonvulsants were well resolved, as was 5-(p-methylphenyl)-5-phenylhydantoin, the internal standard. In this procedure we used an ion-exchange resin for separation of the drug from the serum. The proposed procedure requires only 1.0 ml of serum and can be done in less than 1 h. The lower limit of detection for each of the drugs is 0.5 mg/1. Analytical recoveries of drug from serum were excellent and peak height and concentration were linearly related up to twice the toxic concentration for serum.

Anticonvulsants↗

Carbamazepine and carbamazepine-10,11-epoxide serum concentrations in epileptic children.

Carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-epox) steady-state serum concentrations were measured in 82 children who had generalized tonic-clonic, or partial seizures. There was no correlation between a given dose and serum concentrations, whether other anticonvulsant drugs were used or not. Epileptic children receiving polytherapy (CBZ associated with one or more of the following drugs: phenobarbital, primidone, phenytoin, ethosuximide) had significantly different CBZ clearance values and percent CBZ-epox than did patients given CBZ alone. Even though given lower doses, girls had higher CBZ concentrations and lower CBZ clearance values than did boys. Older girls had lower serum concentrations of CBZ-epox than did younger girls. Seizure-free children had higher CBZ serum levels and lower CBZ clearance values than did those with uncontrolled seizures. The percentage of CBZ-epox in children with uncontrolled seizures was significantly higher than in children without seizures. These data indicate that serum levels of CBZ and CBZ-epox correlate more with factors such as associated drugs, age, and sex than with administered dose. Therefore, CBZ serum level monitoring represents an essential means of individualization of anticonvulsant drug therapy.

Adolescent↗

Treatment of essential tremor with methazolamide.

We treated 28 patients (16 women and 12 men) who had essential tremor with methazolamide. Their median age was 69 years (range, 34 to 89 years), and the median duration of tremor was 16 years (range, less than 1 to 69 years). Fifteen cases were familial and 13 were sporadic. Improvement in 10 patients who continued taking the drug ranged from moderate to complete relief. In addition, four patients had marked improvement and two had moderate improvement but discontinued use of the drug because of side effects. Five patients with a mild response and seven with no response also discontinued methazolamide therapy. The maximal mean daily dose was 203 mg for all patients and 129 mg (maintenance dose) for the patients who continued taking the drug. Side effects consisted primarily of somnolence, nausea, epigastric discomfort, anorexia, paresthesias, and numbness. No aplastic anemia was noted in any of the patients. The median duration of follow-up was 6 months (range, 10 weeks to 29 months). The therapeutic effect seemed unrelated to a family history of tremor, the effect of alcohol, or the responsiveness to propranolol or primidone. Methazolamide may be an effective drug in the treatment of some patients with essential tremor, particularly those with head and voice tremor.

Adult↗

Therapeutic and pharmacokinetic effects of increasing phenytoin in chronic epileptics on multiple drug therapy.

Twenty chronic epileptics receiving phenytoin and either phenobarbitone or primidone have been studied. All patients had frequent seizures and had serum concentrations of phenytoin below 410 mumol/1. Phenytoin dosage was increased to study the effect on the frequency of seizures and the serum concentrations of phenytoin and phenobarbitone. There was no effect on minor seizures but in ten out of sixteen patients major seizures were abolished or reduced. Serum concentrations of phenobarbitone rose as the phenytoin dose was increased. This may cause deviations from the expected relationship between dose and serum concentrations of phenytoin; this would explain deficiencies which were found in a nomogram for predicting the therapeutic dose of phenytoin.

Adult↗

Rapid microanalysis of anticonvulsants by high-performance thin-layer chromatography.

A rapid microanalytical method is described for phenobarbital, phenytoin, primidone and carbamazepine utilizing high-performance thin-layer chromatography (HPTLC). This procedure incorporates a single extraction of a 50-microliter plasma sample. One tenth of the extract is concentrated and applied to the HPTLC plate by a Contact Spotter, chromatographically separated and quantitated by in situ ultraviolet reflectance densitometry. The coefficient of variation is less than 4% (n = 8), the extraction efficiency is approximately 95% and the minimum detectable amount of pure drug standards applied to and developed on the HPTLC plate is 5 ng or less for all four anticonvulsants.

Anticonvulsants↗

Adsorption of drugs onto a poly(acrylic acid) grafted cation-exchange membrane.

The influence of pH, ionic strength and the concentration of albumin in the adsorption medium as well as the charge and lipophilicity of a model drug on their adsorption onto poly(acrylic acid) grafted poly(vinylidene fluoride) (PAA-PVDF) membranes was evaluated. The PAA-PVDF membrane is a responsive porous polymer membrane that we have studied for controlled drug delivery. Sodium salicylate (anionic), flunitrazepam (neutral), primidone (neutral), desipramine (cationic) and thioridazine (cationic) were used as model drugs. The extent of drug adsorption was dependent on pH. Drug adsorption was enhanced by the dissociation of the grafted PAA chains and by a positive charge and a high lipophilicity of the drug. Increasing the ionic strength of the medium retarded the adsorption of the cationic drugs. Interestingly, the present results showing that drugs are adsorbed onto the membrane while albumin is not adsorbed onto the membrane suggest that the PAA-PVDF membrane may be suitable for separating drugs from proteinaceous substances for subsequent monitoring and evaluation.

Acrylates↗

[Tremor].

Tremor is one of the most frequent neurological signs. The correct clinical classification is mainly clinical. The most frequent primarily neurological tremor is essential tremor (prevalence 2 to 5%). It presents in most cases as a more or less symmetrical postural and kinetic tremor. In about 60% of cases an autosomal-dominant inheritance is found. Tremor may manifest not only in the hands but also in the head and voice. In about 60 to 70% of the patients alcohol may improve the tremor. Parkinsonian tremor is normally a tremor at rest and it starts asymmetrically. The legs and the face are frequently involved. Cerebellar tremor is intentional. Orthostatic tremor, which has a high frequency, mainly manifests in the legs and gives rise to postural instability. Dystonic tremor is an action tremor of the affected region of the body. Drug therapy, which is purely symptomatic, mostly depends on clinical manifestation. Postural and action tremors respond to non selective betablockers (propranolol), primidone, some antiepileptics (gabapentin, toparimate) and benzodiazepines. Classical rest tremors are improved by dopaminergic substances (levodopa, dopamine agonists) or anticholinergics. Dystonic tremor may successfully be treated by injections of botulinum toxin. Orthostatic tremor responds to gabapentin or benzodiazepines in some of the patients. In severely handicapped patients with refractory tremors the implantation of thalamic stimulation electrodes may be considered. This treatment may be very successful, however, its inherent risks have to be taken into account.

Adrenergic beta-Antagonists↗

Homocysteine concentrations and methionine loading in patients on antiepileptic drugs.

OBJECTIVES: A few reports have shown elevated fasting total plasma homocysteine (tHcy) in patients taking antiepileptic drugs (AEDs). In this study we determined the influence of AEDs on plasma tHcy levels prior to and following methionine loading. MATERIAL AND METHODS: Thirty-four patients on different AEDs and 34 matched controls were recruited. Blood samples were drawn prior to and 6 h post-methionine loading (6h-PML). RESULTS: The patients on AEDs inducing the cytochrome P450 (carbamazepine, phenytoin, phenobarbital, primidone), had higher fasting and 6h-PML plasma tHcy concentrations than the controls (P = 0.01 and P<0.001). Patients on AED inhibiting the cytochrome P450 (valproate [VPA]), had lower 6h-PML p-tHcy concentrations than controls (P = 0.01). CONCLUSIONS: Our data indicate that not only fasting but also 6h-PML tHcy levels should be determined in order to identify hyperhomocysteinemia among patients on AEDs. Inducer AEDs seem to have an opposite effect than the inhibitor VPA on plasma tHcy, erythrocyte folate and serum folate levels.

Adult↗

[Pharmacotherapy of epilepsy--current problems and controversies].

Current trends and controversies in the antiepileptic drug therapy are reviewed from a clinical view. The usefulness of prophylactic therapy of febrile seizures and posttraumatic seizures or posttraumatic epilepsy is compromised by difficulties in the management of the patients especially by noncompliance. Previously untreated epilepsies can be treated successfully in 70--80% of the patients. Phenytoin or carbamazepine are equally effective for generalized tonic-clonic seizures of focal seizures, while absence seizures are controlled by ethosuximide or valproic acid. Only when the epilepsy is uncontrolled despite high plasma concentrations which cannot be raised because of side effects, a second drug should be given. A second drug is successful in about one out of six patients with focal epilepsy. Phenytoin, carbamazepine, phenobarbital and primidone seem to be equally effective for these drug-resistant cases. Status epilepticus can be treated with intravenous diazepam or phenytoin and, if necessary, with an infusion of phenytoin. Rectal diazepam is useful for acute pediatric therapy. Drugs of second choice are clonazepam, phenobarbital, lidocaine, and clomethiazole. In the pregnant epileptic patient a drop in the plasma concentration of antiepileptic drugs mainly through non-compliance and seizure provocation through sleep deprivation are major sources for the deterioration of epilepsies during pregnancy. The "fetal antiepileptic drug syndrome", malformations and an increased risk for epilepsy in the child are discussed as an interaction of parental epilepsy and drug-exposure during pregnancy. Finally, the interpretation of abnormal clinical chemistry data is reviewed. Disorders of the liver, bone, thyroid gland and blood are rarely seen in treated epileptic patients usually when specific risk factors are present. The over-interpretation of laboratory abnormalities e.g. an isolated increase of gamma-GT may lead to iatrogenic deterioration of epilepsy when the effective dose of the drug is reduced for unfounded fear of hepatic toxicity.

Adolescent↗

[Orthostatic tremor].

Two men, aged 57 and 77 years old, reported increasing unsteadiness on standing upright for the past 2 and 5 years, respectively. It had become impossible for them to remain standing for more than 10 seconds, as otherwise they might fall down. Walking, sitting and lying were possible without difficulty. Both patients were found to have a fine tremor in both legs on standing only. There were no other neurological signs or symptoms. Electromyography of the leg muscles demonstrated tremor activity at 14-16 Hz. Propranolol, 40 mg three times daily, in the 57-year-old patient brought no improvement. However, on taking primidone, in slowly increasing doses up to 250 and 500 mg daily, respectively, the condition lastingly improved in both patients.

Aged↗

[Teratogenicity of anticonvulsant drugs (author's transl)].

Investigations were done on 111 children of epileptic mothers who used anticonvulsants in 93 pregnancies and none in 18 pregnancies. Hydantoinbarbiturate embryopathy was found in 7.1% after hydantoin monotherapy, in 17.6% after combination of hydantoin and barbiturates or primidone. No embryopathy was seen in children of untreated epileptic mothers. Children of untreated and treated epileptic mothers had an approximately equal frequency of marked single malformations and cerebral damage without dysmorphia. However, malformation and cerebral damage without dysmorphia was found significantly more frequently in children of mothers on anticonvulsant drugs with convulsions during pregnancy as compared to children of mothers without convulsions. Single manifestations and cerebral damage without dysmorphia are probably not caused by anticonvulsants but by convulsions during pregnancy.

Abnormalities, Drug-Induced↗

Emit assays for five major anticonvulsant drugs. An evaluation of adaptations to two discrete kinetic analyzers.

Because of the complex reaction kinetics observed with the enzyme multiplied immunoassay technic (EMIT), each adaptation of these assays must be specifically evaluated. Evaluations were done of the totally automated adaptations of these immunoassays for diphenylhydantoin, phenobarbital, primidone, carbamazepine, and ethosuximide to two kinetic analyzers that use markedly different reaction conditions, the Gilford System 3500 and the Abbott Bichromatic Analyzer-100. Comparisons of data from EMIT assays on the Gilford 3500 with data from EMIT assays on the ABA-100 and with data from gas-liquid chromatographic analyses for the five anticonvulsant drugs showed good correlations (r greater than or equal to 0.96) and little or no additive or proportional biases, as determined by joint confidence intervals. Between-run precision for each EMIT anticonvulsant drug assay on both analyzers was less than 6%, better than that obtained with gas chromatography. No interference by more than 40 different drugs, by hemoglobin (6 g/l), or by bilirubin (200 mg/l), and no or minimal cross-reactivity with any of the five EMIT anticonvulsant drug assays on either analyzer were found.

Anticonvulsants↗