Antiepileptic Monitoring Research Articles

Five years of anticonvulsant monitoring on site at the epilepsy clinic.

The influence of antiepileptic drug monitoring on site at the epilepsy clinic was assessed in a prospective way by recording physicians' decisions before and after the drug concentration became available over the five-year period including 1986 to 1990. A total of 2,857 assays (1,121 carbamazepine, 798 phenytoin, 622 sodium valproate, and 72 phenobarbital) were performed during 2,696 hospital attendances on 618 epileptic patients. A gradual reduction in the proportion of visits monitored annually was observed (1986: 42%; 1987: 51%; 1988: 44%; 1989: 39%; 1990: 28%; p < 0.01). In 481 (17.8%) visits a change in management resulted from knowledge of the drug concentration. This was not an automatic response, as a large minority of unexpected results did not produce such an alteration. The proportion of decisions to adjust the drug dose after an unexpected result, however, tended to increase over the years of the study (1986: 43%; 1987: 70%; 1988: 60%; 1989: 78%; 1990: 54%; p < 0.01). Changes in anticonvulsant dose following an unexpected result were observed in "low" (59%), "therapeutic" (61%), and "high" (52%) concentration categories. Possible benefit for patients can be inferred from the observation that more assay results fell within the target range in the last (61%) compared with the first (33%) year of monitoring (p < 0.01).

Neurologic Disorders in Saudi Children

Neurologic Disorders in Saudi Children

Therapeutic drug monitoring improves seizure control and reduces anticonvulsant side-effects in patients with refractory epilepsy

The benefit to patients of an on-site antiepileptic drug monitoring service, in which physicians' decisions were recorded before and after the concentration became available, have been assessed retrospectively. In 109 patients with refractory epilepsy monitored on three ( n = 61) or four ( n = 48) occasions between 1986 and 1990, one or more assay result was rated as ‘unexpected’ by the consulting doctor. In 51 of these, revision of the dose was undertaken as a consequence (active group). Their clinical outcomes were compared with those of the other 54 patients in whom the initial management plan was left unchanged (passive group). Median seizure frequency decreased in both groups, but this was statistically significant only for the actively treated patients [active group: first visit 1 (0 to 26) seizures/month, last visit 0 (0 to 19) seizures/month, P < 0.01, 95% CI −2 to −0.5; passive group: first visit 2.5 (0 to 57) seizures/month, last visit 1.5 (0 to 44) seizures/month, NS, 95% CI −1 to +10]. The number of patients reporting one or more episodes of drug-related toxicity also favoured the actively managed patients (active group 25%, passive group 56%, P < 0.01). Within this selected group of patients, the anticonvulsant concentration was a better guide to clinical management than the physician's assessment.

A micro-enzyme-multiplied immunoassay technique plate assay for antiepileptic drugs.

Underutilization of antiepileptic drug monitoring in research situations has made comparison of data difficult to interpret. Experimental animal studies of the effects of antiepileptic drugs are similarly hindered by the lack of methods utilizing small blood samples to determine drug levels. To alleviate both problems, a standard enzyme-multiplied immunoassay technique (EMIT) assay was modified and scaled down. The resulting microEMIT utilizes only a fraction of the costly reagents (5.0 vs. 50.0 microliters) of the original assay and requires only 3-5 microliters of serum, easily obtainable from experimental animals. The method has been successfully tested with three major antiepileptic drugs, phenytoin (PHT), valproic acid (VPA) and carbamazepine (CBZ). The microEMIT assay, utilizing a 96-well plate, displays linear kinetics in the production of reduced nicotinamide adenine dinucleotide (NADH) for at least 8 minutes. The assay is linear from 2 to 100 micrograms PHT/ml, from 2 to 50 micrograms CBZ/ml and from 10 to 150 micrograms VPA/ml. The similarities suggest that a general adaptation for most EMIT drug assays will be possible.

Use of plasma levels for antiepileptic drug monitoring in clinical practice. Gruppo Collaborativo per lo Studio dell'Epilessia.

A multi-center survey of antiepileptic treatment was conducted in Italy on 245 previously untreated ("new") patients with epilepsy and 355 patients treated for more than three months ("old" patients). Therapeutic drug monitoring (TDM) of antiepileptic drugs was evaluated in the context of routine clinical conditions, in relation to individual therapeutic problems and mode of treatment. Plasma levels (PL) were determined in 75% of "new" patients and 78% of "old" patients, with wide intercenter variability. TDM was done at 69% of the follow-up attendences for "new" patients and at 34% for "old" patients, but was apparently unrelated to specific therapeutic problems, such as poor disease control or adverse drug reactions. Plasma drug concentration measurements were made more often among patients on polytherapy. The age of the patient and the time elapsing since diagnosis did not seem to affect request patterns significantly. From these findings it appears that TDM is largely influenced by factors unrelated to the common recommendations in the literature. In addition, the use of TDM in clinical practice reflects the limitations of the available techniques.

Possible roles for frequent salivary antiepileptic drug monitoring in the management of epilepsy

Salivary levels of phenytoin, phenobarbitone, carbamazepine and carbamazepine-epoxide correlate with the simultaneous plasma water levels of these substances, after correcting for the effects of pH differences between saliva and plasma in the case of phenobarbitone. Saliva is easy and painless to collect, and salivary levels of the drugs are conveniently measured. Frequent (often daily) monitoring of pre-dose morning anticonvulsant drug concentrations in saliva over periods of weeks or months in 3 groups of epileptic subjects showed that (i) in some but not all poorly controlled epileptic patients seizures tended to occur on days when salivary anticonvulsant levels were lower than on non-seizure days, (ii) in such subjects it was possible to estimate an anticipated optimal drug concentration and dose to minimize seizure activity from the plot of seizure frequency against drug concentrations, (iii) in women with ‘catamenial’ epilepsy, salivary anticonvulsant levels were lower on perimenstrual days than at mid-cycle in half of the subjects studied, and (iv) in pregnant epileptic women the time course of the change in drug levels relative to dose could be followed more closely throughout pregnancy and the post-natal period than was practicable when using blood level measurements. Frequent measurement of salivary anticonvulsant concentrations appears a promising and inexpensive adjunct to the investigation and management of certain problem areas in epilepsy.

Intensive Neurodiagnostic Monitoring in Psychiatry

A series of technological advances have made it possible to closely monitor electrophysiological and behavioural manifestations of episodic clinical events over prolonged periods of time, with the ability to review the records at leisure or to submit them to computer analysis. The more promising techniques are time-locked video/EEG monitoring, cable telemetry, radiotelemetry, ambulatory cassette recording, intensive plasma anti-epileptic drug monitoring and continuous neuropsychological monitoring. The greatest promise of these techniques is for the diagnosis, research and management of epilepsy. For psychiatry, they offer additional help in the differential diagnosis of non-epileptic events from epilepsy, the most important of which are psychogenic seizures and episodes of aggression. This paper discusses the potential role of these techniques in the assessment of non-epileptic events and transient cognitive impairment in clinical psychiatry.

Rapid anticonvulsant monitoring in an epilepsy clinic.

The relevance of providing a rapid anticonvulsant monitoring service was assessed over a five year period at a paediatric epilepsy outpatient clinic. Altogether 481 drug assays were performed on 144 patients when considered clinically indicated. Drugs most frequently assayed were carbamazepine and sodium valproate, singly or in combination; sodium valproate, single or in combination; 90% of assays performed for phenytoin were from patients who were also taking another anticonvulsant. There were only six assays for ethosuximide and 10 for phenobarbitone. Physician's choice of drug dosage was recorded on a questionnaire before and after each assay result was known. Comprehensive patient details were analysed by a paediatric clinical pharmacologist, whose decision as to total daily anticonvulsant dosage was affected by knowledge of the drug concentration significantly less often than that of the clinicians for all the more commonly assayed drugs. There were a large number of drug assays that had no discernable clinical application. A more discriminating use of assays may both improve patient management and reduce considerably the number of anticonvulsant assays required.

Effectiveness of a therapeutic drug monitoring service as an aid to the control of canine seizures.

The results presented were derived from an anticonvulsant monitoring service, provided for two years to practising veterinary surgeons, in which samples of serum were taken from dogs treated with either primidone or phenobarbitone. Of the 19 patients assessed, 13 were controlled after the recommended changes in dose had been made. Of the six patients not completely controlled after changes in dose, four had a much lower incidence of seizures but two did not respond to treatment in spite of having high serum phenobarbitone levels. There were large variations between the doses of anticonvulsant drugs required to reach therapeutic serum levels; these variations underlined the value of routine monitoring for improving the control of canine seizures.

S4-6 - Developmental pharmacology and blood level monitoring of antiepileptic drugs in Children

S4-6 - Developmental pharmacology and blood level monitoring of antiepileptic drugs in Children

Automated and routine liquid chromatographic analysis of antiepileptic drugs.

We describe an optimized automated liquid chromatographic method for simultaneous measurement of primidone, phenobarbitone, phenytoin, carbamazepine and clonazepam. A Waters Tri-Module automation system is used and it provides direct read-out of results after chromatography. A one-step extraction with ethyl acetate is used to extract the drugs from 100 microL serum samples. We use an isocratic mobile phase and monitor the column effluent at 210 nm. Drug levels as low as 5 mumol/L can be detected. The within-run CV's range from 1.4 to 2.7%, and the between-run CV's range from 5.2 to 6.1%. Analytical recovery is in the range from 94-108%. The method compares favourably with the enzyme multiple immunoassay technique for routine antiepileptic drugs monitoring, in accuracy, efficiency and cost-effectiveness.

Quality control in antiepileptic drug monitoring in Italy.

Measurement of drug concentrations in physiological fluids is increasingly becoming part of the routine management of drug therapy, thus calling for particular care to ensure reliability and avoid misguided management. As part of a long-term national project to set up a network of hospitals where clinical chemists, pharmacists, and physicians could interact and evaluate their activities in connection with therapeutic drug monitoring, the results of a quality control scheme for antiepileptic drugs, which included 50 national hospital laboratories, are described here.

Utility of free level monitoring of antiepileptic drugs.

Criteria that were developed for monitoring free (unbound) rather than total (free plus bound) concentrations of antiepileptic drugs include extensive and variable binding to plasma proteins. Phenytoin and valproic acid belong to this category. It is shown that free drug concentration is independent of total drug concentration, whereas total drug concentration depends on free concentration and free fraction. Because antiepileptic drugs are predominantly bound to albumin, free fraction will increase in the presence of hypoalbuminemia (hepatic and renal disease, burns, and pregnancy). Free fraction also increases because of saturable binding (valproic acid) and competitive binding (valproic acid displacing phenytoin). There is suggestive evidence that side effects may be more closely related to the free, rather than to the total, plasma concentration of phenytoin. The clinical evidence that side effects or therapeutic effects are better correlated to the free, rather than the total, concentration of valproic acid or carbamazepine is not yet convincing. Knowledge of the free concentration improves our understanding of therapeutic and toxic effects of low total plasma concentrations. Further clinical trials are necessary for definitive assessment of the clinical relevance for free drug monitoring of valproic acid, carbamazepine, and phenytoin in the management of epileptic patients.

The place of saliva in antiepileptic drug monitoring.

It has previously been shown that saliva phenytoin concentration bears a constant relationship to plasma free concentration whether protein binding of phenytoin is normal or disturbed by other drugs, pregnancy, renal failure, or hypoalbuminaemia. The present work examines the relationship between saliva (S), plasma free (F), and plasma total (P) concentrations of other anticonvulsants in 100 epileptic patients. Mean S/P ratios were for phenobarbitone 0.37 (r = 0.95), primidone 0.95 (r = 0.87), and carbamazepine 0.27 (r = 0.94). A highly significant correlation of S with F was found for these drugs, more significant than the correlation of S with P for carbamazepine in patients receiving multiple anticonvulsant drugs. Saliva valproate, however, had no predictive value for P or F. No binding to saliva proteins was demonstrated for any drug. Data for in vitro binding to plasma proteins was in good agreement with ex vivo data. Saliva is therefore a valid medium for monitoring treatment with phenobarbitone, primidone, and carbamazepine, as well as phenytoin.

Interaction between phenobarbital and thioridazine.

The effects of thioridazine (TDZ) on serum phenobarbital (PB) and phenytoin (PHT) were studied in mentally retarded persons. Persons taking these drug combinations were identified and matched on the basis of age, sex, body weight, and antiepileptic drug (AED) dosage with persons from the same population who were taking only the AEDs. Trough, steady state serum levels were obtained as part of regular AED monitoring schedules. Serum level of PB per unit dose was significantly less with concomitant administration of TDZ (100 to 200 mg/day) than when PB was given alone. This effect seemed to be TDZ dose-responsive. TDZ had no consistent effects on serum PHT.

Semi-automated continuous-flow enzyme immunoassay for antiepileptic drugs in serum.

We have developed a semi-automated method for measuring five kinds of antiepileptic drugs in serum by successfully adapting commercial competitive-binding enzyme immunoassay kits (MARKIT; Dainippon) for use with a continuous-flow analyzer (Technicon AutoAnalyzer II equipped with a dialyzer). The free enzyme-labeled drug is automatically separated by a microfilter from the competitive immunoreaction mixture between labeled and unlabeled drug for anti-drug immunoglobulin coupled to bacterial cell walls. The concentrations of the antiepileptic drugs in serum samples can be determined by automated measurement of enzyme activity of the enzyme-labeled drugs. Results of the semi-automated method correlated well with those obtained by manual enzyme immunoassay, gas-liquid chromatography, and "high-pressure" liquid chromatography. The correlation coefficients were all greater than 0.95, showing the practicality of this method for therapeutic monitoring of antiepileptic drugs.

Systematic method of development in liquid chromatography applied to the determination of antiepileptic drugs.

The object of a liquid-chromatographic analysis is to separate, identify, and quantitate the constituents of interest in a sample mixture within an acceptable analysis time. This will be achieved by a systematic analysis development rather than by a trial-and-error approach. Such a systematic procedure requires a knowledge of the chromatographic parameters governing resolution and analysis time and their relative influences on resolution and its experimental implication. Furthermore, basic information about the mechanisms of the modes of liquid chromatography (adsorption, partition, ion exchange, and steric exclusion) and about the types of sample which can be preferentially analyzed by them is necessary. This information leads to a rational selection of the separation system that promises the best chance of success. In the subsequent experimental work, the analyst systematically measures and calculates resolution and analysis time as functions of selectivity, capacity, and efficiency of the phase system under selected chromatographic conditions. The essential chromatograms, tables, and graphs resulting from this systematic method of development are documented so that it is possible to replicate the analysis procedure in the laboratories involved. The result is a set of chromatographic conditions capable of achieving an optimum compromise between resolution and analysis time. The procedure is applied to routine therapeutic drug monitoring of antiepileptic drugs in patient serum.

Serum levels of phenytoin and phenobarbital in epileptic patients treated with mixture antiepileptic tablets, Comital-L or Hydantol-F.

Serum levels of both phenytoin and phenobarbital were determined by homogenous enzyme immunoassay in 59 epileptic patients treated chronically with either Comital-L or Hydantol-F tablets. The majority of the patients receiving Comital-L tablets showed low serum levels of phenytoin and high serum levels of phenobarbital, while patients treated with the usual daily dosage of Hydantol-F tablets showed adequate therapeutic serum levels of both phenytoin and phenobarbital. From the results obtained, the dose ratio of phenobarbital to phenytoin in Comital-L tablet seemed inappropriate to obtain adequate therapeutic serum levels of both drugs simultaneously. Since the dosage of each anticonvulsant drug used concurrently should be established individually, the use of such fixed-dosage mixture tablets of antiepileptic drugs as Comital-L or Hydantol-F in daily clinical practice should be reconsidered from the viewpoint of serum level monitoring of antiepileptic drugs.

Epilepsy and pregnancy.

The management of the pregnant epileptic requires close cooperation between the neurologist and obstetrician. To prevent complications, knowledge is required about the natural history of epilepsy during pregnancy, the possible teratogenic effects of antiepileptic drugs, and changes in their absorption, biotransformation, and excretion. Close plasma antiepileptic drug monitoring is required because of the change in the handling of antiepileptic drugs during pregnancy. The treatment of status epilepticus with intravenous phenytoin is effective. Drug interactions which may lead to toxic plasma levels of some drugs and subtherapeutic plasma levels of others should be anticipated. The risk of problems resulting from antiepileptic drug therapy during pregnancy appears to be minor, provided that proper medical supervision is available. Newer antiepileptic drugs should not be administered to the pregnant epileptic until their safety in pregnancy is fully established.

Serum anticonvulsant monitoring by liquid chromatography with a methanolic mobile phase.

Serum anticonvulsant monitoring by liquid chromatography with a methanolic mobile phase.