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Twenty-three patients resident at the Chalfont Centre for Epilepsy, who have been prescribed carbamazepine either as monotherapy or in combination with other antiepileptic drugs have been monitored for a period of 6 months. Monthly hair samples along with concomitant plasma samples have been collected over this period and the 1 cm from scalp hair sections and the plasma concentrations of carbamazepine measured. The relationship between dose, hair and plasma concentrations have been assessed as well as the monthly variability in the concentration of carbamazepine in both matrices.

1. We describe the first application of microdialysis to monitor the pharmacokinetics of a drug in the blood of man. 2. The aims of the study were to ascertain patient acceptability and tolerability of a new microdialysis probe and to assess its accuracy in determining the pharmacokinetics of levodopa and its principal plasma metabolite 3-O-methyldopa (3-OMD). 3. Eight patients with parkinsonism on chronic levodopa therapy were investigated. 4. After an overnight fast, a flexible microdialysis probe, perfused with isotonic saline, was inserted into a forearm vein and a blood sampling cannula was inserted in a forearm vein of the other arm. After ingestion of a levodopa preparation (Madopar Dispersible), dialysate was collected over 5 or 10 min periods and blood samples were taken every 15 or 30 min for 2-6 h. 5. Dialysate drug profiles were similar to those of plasma, and levodopa and 3-OMD concentrations exhibited significant (P < 0.001) correlation with those observed in the corresponding plasma samples. 6. The mean (+/- s.d.) blood dialysate concentrations for levodopa and 3-OMD were 36.1 +/- 9.2% and 43.4 +/- 8.4% respectively of the plasma content. 7. The tolerability of the probe was excellent, and all eight patients found it preferable to conventional blood sampling. 8. Microdialysis of blood is less invasive than frequent intermittent direct blood sampling, and can readily be used to continuously monitor levodopa pharmacokinetics. In a clinical setting, a combination of drug monitoring by this technique together with clinical evaluation of motor function can be used to optimize levodopa treatment in patients with Parkinson's disease.

Milacemide is a glycinamide derivative which readily enters the brain and is metabolised to glycine. As its mechanism of action as an anticonvulsant drug is unknown we used the technique of microdialysis to study the temporal inter-relationship of glycinamide, glycine and other amino acid neurotransmitters in the extracellular fluid of rat hippocampus and frontal cortex. After milacemide administration (400 or 800 mg/kg i.p.), glycinamide concentrations rose linearly and dose-dependently in both hippocampus and frontal cortex. In contrast, whilst glycine concentrations rose in the hippocampus, glycine was unaffected in the frontal cortex. Concomitant increases in taurine hippocampal concentrations were observed. An increase in serine and a decrease in alanine concentrations was only observed at the highest milacemide dose (800 mg/kg). Other amino acids were affected. Thus, while glycinamide appears to be universally distributed throughout the brain, its metabolism to glycine and its effects on brain amino acids appear to be region specific.

Presently available GC and HPLC methods for analysis of piracetam, require large samples and suffer from interference. A micro scale, isocratic high-performance liquid-chromatographic method is described for the determination of piracetam in plasma (25 microL) or cerebrospinal fluid (10 microL) using ultraviolet absorbance at 215 nm. The limit of quantitation is 4 micrograms mL-1 and the within-batch and between-batch coefficients of variation are less than 10%. No interference from other commonly prescribed antimyoclonic or antiepileptic drugs was observed and thus the method can be used to monitor piracetam in patients on polytherapy antimyoclonic or antiepileptic drug regimens. Because of the sensitivity and rapidity of the method it is suitable for pharmacokinetic and mechanistic studies and for analysis of paediatric samples.

Acute administration of phenytoin (PHT) is used in the treatment of status epilepticus, yet little is known about the neuropharmacokinetics of PHT in brain extracellular fluid (ECF), the pharmacodynamically relevant compartment. To characterize the neuropharmacokinetics of brain ECF PHT we implanted microdialysis probes in rat hippocampus and frontal cortex and placed a catheter in the internal jugular vein. PHT (50 or 100 mg/kg intraperitoneally, i.p.) was then administered, and microdialysate and serum samples were collected. PHT was rapidly absorbed, with a time to maximum concentration (Tmax) of approximately 20 min for serum concentrations. PHT rapidly entered the brain ECF compartment, with Tmax values similar to those of serum. In brain ECF, PHT concentrations then plateaued for 40-60 min despite decreasing serum concentrations. The area under the brain ECF concentration-time curve (AUC) was higher in hippocampus than frontal cortex. The possible mechanisms for these observations include entry of PHT into specific brain areas both across capillaries and through the cerebrospinal fluid (CSF), extensive binding of PHT in brain white matter, and differing blood flow in different brain regions.

An isocratic high performance liquid chromatographic micromethod is described for the quantitation of levetiracetam (ucb L059) in plasma or serum of patients. The chromatography is performed on a 250 x 4 mm I.D. LiChrospher 60 RP-select B, 5-micron column, eluted with an acetonitrile/50 mM phosphate buffer (15:85 vol/vol, pH 5.6) mobile phase, and levetiracetam detected using ultraviolet absorbance at 220 nm. The limit of quantitation was 5 mumol/L and the within-batch and between-batch coefficients of variation were < 7%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, ethosuximide, gabapentin, lamotrigine, phenobarbitone, phenytoin, primidone, valproic acid, and vigabatrin) was observed, and thus the method can be used to monitor levetiracetam in patients on polytherapy antiepileptic drug regimens.

Using a newly developed microdialysis probe which allows continuous monitoring of drugs in blood, we have studied the pharmacokinetics of various antiepileptic drugs (carbamazepine, and its primary metabolite carbamazepine-epoxide, phenytoin primidone and phenobarbitone) in 5 patients (2 male, 3 female, aged 40-50 years) with intractable epilepsy. It was observed that microdialysate pharmacokinetic profiles were comparable to those obtained by direct blood sampling. Furthermore, patients found the microdialysis probe highly acceptable and desirable and indeed preferable to that of blood sampling.

Therapeutic drug monitoring of a variety of antiepileptic drugs is used routinely as a guide to individualising the drug treatment of patients with epilepsy. Thin dry film multilayer immunoassays (OPUS) for carbamazepine, phenytoin, phenobarbitone, and valproic acid were evaluated and compared with fluorescence polarisation immunoassay (TDx), using commercially available control material and patient sera. For the OPUS, the within-batch coefficient of variation (CV) for the different drugs in the control material varied between 3.9% (phenobarbitone) and 8.1% (valproic acid). The between-batch CVs varied between 5.3% (valproic acid) and 18.3% (carbamazepine). The comparative between-batch CVs for the TDx varied between 2.0% (phenytoin) and 7.0% (valproic acid). Analysis of 209 patient samples containing carbamazepine, phenytoin, phenobarbitone, or valproic acid demonstrated significant correlation between the two analytical methods, with correlation coefficients of 0.9336, 0.9560, 0.9448, and 0.9618, with slopes of the regression lines of 0.9042, 0.8663, 1.1368, and 1.1244, respectively. It is concluded that both the TDx and OPUS instruments exhibit comparable performance for the analysis of carbamazepine, phenobarbitone, phenytoin, and valproic acid in patient samples. Moreover, the OPUS instrument, with its facilities of random assay access and statim analysis, may be useful in an outpatient setting in which a major consideration would be a rapid turnaround of patient assay results.

We studied the relationship between levodopa response and antituberculous treatment in a patient with idiopathic Parkinson's disease whose parkinsonism deteriorated when treatment with rifampicin and isoniazid (Rifinah) for pulmonary tuberculosis was started. A levodopa challenge test with regular recording of motor function was performed during, and again after stopping, antituberculous treatment. Plasma levodopa and levodopa metabolite pharmacokinetic profiles were determined using standard techniques. "On" period duration was 75% longer after antituberculous treatment had been stopped. These clinical findings correlated with a 37% increase in area under the concentration versus time curve (AUC), a 103% increase in apparent elimination half-life (t1/2), a 41% increase in time to maximum concentration (Tmax), and a 33% decrease in maximum concentration (Cmax) of levodopa. A concurrent increase in plasma 3-O-methyldopa (3-OMD) and a decrease in plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the three major metabolites of levodopa, suggests an inhibition of the enzyme dopa decarboxylase, probably by isoniazid.

Marked abnormalities of the magnetic resonance intensity of N-acetylaspartate (NAA) have been reported in patients with various neurological disorders, but the neurochemical consequences of these alterations are difficult to assess because the function of NAA remains speculative. The purpose of this study was to examine whether NAA plays a role in protecting neurons against osmotic stress. Intracerebral microdialysis was used to expose a small region of the rat dorsolateral striatum to an increasingly hyposmotic environment and to measure resulting changes in NAA extracellular concentrations. NAA changes in the extracellular fluid (ECF) were compared with those of the amino acids, in particular, taurine, known to be involved in brain osmoregulation. Stepped increases in cellular hydration produced by hyposmotic perfusion media induced a marked increase in ECF NAA, reflecting a redistribution of NAA from intra-to extracellular space. Parallel experiments showed that, of all the extracellular amino acids measured, only taurine markedly increased with hyposmolar perfusion medium, indicating that the ECF NAA increase associated with hyposmotic stress was a specific response and not passive leakage out of the cells. As NAA is predominantly neuronal, it may contribute to the protection of neurons against swelling (i.e., regulatory volume decrease). In conditions with impaired blood-brain barrier and cytotoxic oedema, efflux of intracellular NAA subsequent to sustained cellular swelling might lead to a reduction in total brain NAA detectable by magnetic resonance spectroscopy. Alternatively, redistribution of NAA from intra-to extracellular space implies changes in its chemical environment that may alter its magnetic resonance visibility.

1. The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values. 2. After i.p. administration, antipyrine (35 mg kg-1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min. 3. Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected. 4. Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters. 5. Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval. 6. In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter. These considerations are particularly important in relation to microdialysis studies of pharmacokinetic-pharmacodynamic interrelationships and modelling.

The neurochemical basis of absence seizures and the mechanism of their suppression by valproate (VPA) are uncertain. We used positron emission tomography (PET) to determine whether an abnormality of [11C]flumazenil binding to benzodiazepine (BZD)-GABAA receptors exists in patients with childhood and juvenile absence epilepsy and to examine the effects of VPA on [11C]flumazenil binding. The regional cerebral volume of distribution (Vd) of [11C]flumazenil in patients not treated with VPA was not different from that in normal controls; Vd was lower in patients treated with VPA, and the number of receptors available for binding was significantly reduced in such patients as compared with normal controls. There was no evidence of a primary abnormality of the BZD-GABAA receptor in childhood and juvenile absence epilepsy (CAE/JAE), but the data suggest that treatment with VPA is associated with a reduction in [11C]flumazenil binding that may be relevant to its mode of action in CAE/JAE.

Carbon-11-labeled flumazenil combined with positron emission tomography (PET) was used to measure the concentration (Bmax) of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation constant (KD) for flumazenil in five normal subjects. The steady-state approach was used injecting the tracer as a bolus of high specific activity. In each subject two studies were carried out. The first study was performed at essentially zero receptor occupancy, the tracer alone study. The second study was performed at a steady-state receptor occupancy of about 50%, achieved by a prolonged constant infusion of nonlabeled ("cold") flumazenil starting 2h before the bolus tracer injection and continuing until the end of scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma water was measured in multiple blood samples. The observed tissue and plasma tracer curves, calibrated in the same units of radioactivity per millimeter, were analyzed in two ways: (a) by the noncompartmental (stochastic) approach making no assumptions regarding number of compartments in the tissue, and (b) by the single-compartment approach assuming rapid exchange (mixing) of tracer between all tissue compartments. The noncompartmental and the compartmental analyses gave essentially the same values for the distribution volume of the tracer, the parameter used for quantitation of the Bz receptor. As the compartmental approach could be applied to a shorter observation period (60 min instead of 120 min) it was preferred. The five subjects had a mean KD value of 12 nM/L of water and Bmax values of the grey matter ranging from 39 +/- 11 in thalamus to 120 +/- 14 nM/L of brain in occipital cortex. Most previous studies have been based on the pseudoequilibrium approach using the brain stem as a receptor-free reference region. This yields practically the same KD but lower Bmax values than the steady-state approach presented here.

We have reviewed the pharmacokinetics of six antiepileptic drugs that are marketed (felbamate, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, and zonisamide) and six drugs that are undergoing evaluation (levetiracetam, ralitoline, remacemide, stiripentol, tiagabine, and topiramate). In addition, we have compared the prodrugs eterobarb and fosphenytoin and the controlled-release formulations of valproic acid and carbamazepine with their parent compounds. Finally, we have devised a scoring system to compare the pharmacokinetics of new antiepileptic drugs. Using this system, vigabatrin, levetiracetam, gabapentin, and topiramate appea to have the most favourable pharmacokinetic profiles, whilst ralitoline and stiripentol have the least favourable.

The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum (Tmax mean range 0.15-0.38 h) and CSF (Tmax mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. Cmax, AUC and t1/2 values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus.

With the introduction of three new anti-epileptic drugs (AEDs) in the UK during the past 4 years as adjunctive add-on therapy, the possibility of AED pharmacokinetic interactions has become a relevant consideration. This review highlights the current status of AED interactions with particular emphasis on those interactions that are likely to be frequently experienced or whose outcome is potentially clinically significant.

Epilepsy is one of the most common neurological disorders. Even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications. There is, therefore, a need for more potent and effective antiepileptic drugs and drugs with fewer adverse effects, particularly CNS effects. Drugs for the treatment of partial seizures are particularly needed. With major advances in our understanding of the basic neuropathology, neuropharmacology and neurophysiology of epilepsy, numerous candidate novel antiepileptic drugs have been developed in recent years. This review comparatively evaluates the pharmacokinetics, efficacy and adverse effects of 12 new antiepileptic drugs namely vigabatrin, lamotrigine, gabapentin, oxcarbazepine, felbamate, tiagabine, eterobarb, zonisamide, remacemide, stiripentol, topiramate and levetiracetam (ucb-L059). Of the 12 drugs, vigabatrin, lamotrigine and gabapentin have recently been marketed in the UK. Five of these new drugs have known mechanisms of action (vigabatrin, lamotrigine, tiagabine, oxcarbazepine and eterobarb), which may provide for a more rational approach to the treatment of epilepsy. Oxcarbazepine, remacemide and eterobarb are prodrugs. Vigabatrin, gabapentin and topiramate are more promising on the basis of their pharmacokinetic characteristics in that they are excreted mainly unchanged in urine and not susceptible to significant pharmacokinetic interactions. In contrast, lamotrigine, felbamate and stiripentol exhibit significant drug interactions. Essentially, all the drugs are effective in partial or secondarily generalised seizures and are effective to varying degrees in other seizure types. Particularly welcome is the possible effectiveness of zonisamide in myoclonus and felbamate in Lennox-Gastaut syndrome. In relation to adverse effects, CNS effects are observed with all drugs, however, gabapentin, remacemide and levetiracetam appear to exhibit least. There is also the possibility of rational duotherapy, using drugs with known mechanisms of action, as an additional therapeutic approach. The efficacy of these 12 antiepileptic drug occurs despite the fact that candidate antiepileptic drugs are evaluated under highly unfavourable conditions, namely as add-on therapy in patients refractory to drug management and with high seizure frequency. Thus, whilst candidate drugs which do become licensed are an advance in that they are effective and/or are associated with less adverse effects than currently available antiepileptic drugs in these patients, it is possible that these drugs may exhibit even more improved risk-benefit ratios when used in normal clinical practice.

The neuropsychological effects of the GABA-reuptake blocker, tiagabine-HCl, were tested in an open trial of 22 adult patients with refractory partial epilepsy followed by a double-blind, placebo-controlled, cross-over trial in 12 subjects. Nineteen patients completed the initial open titration and fixed-dose phase of the study and 11 patients completed the double-blind phase. The median daily tiagabine dose was 32 mg during the open fixed dose and 24 mg during the double-blind periods. Neuropsychological evaluation did not show any significant effect on cognitive function in the open or double-blind phases. In this group of patients no statistically significant difference in the frequency of the total number of seizures or complex partial seizures was found in the open or double-blind stages. Seizure severity was significantly less in the open fixed dose than in the baseline period, but was not significantly different between the two double-blind periods. Reported side effects were transient, most commonly aggression/irritability, lethargy, headache and drowsiness. No significant EEG changes were observed.

After overnight drug withdrawal and in the fasting state, 11 patients with Parkinson's disease (PD) and a fluctuating response to chronic levodopa treatment were given, in random sequence on consecutive days, equivalent levodopa doses (with peripheral decarboxylase inhibitor) (a) as levodopa methyl ester (ME), (b) as Sinemet CR, or (c) as half the dose of ME together with a halved tablet of Sinemet CR. All patients turned ON rapidly after treatments a and c, but only half did so after treatment b. On period duration was longest after treatment c, intermediate after treatment a, and shortest after treatment b. Pharmacokinetic analysis in a subset of 6 patients revealed no significant difference between treatments a and c, although there was a trend for t1/2 to be longer after treatment c. We conclude that giving ME with a halved tablet of Sinemet CR provided a useful clinical balance between rapid onset and extended duration of action of at least the first levodopa intake of the day. In view of differing release profiles between whole and halved tablets of Sinemet CR, similar single-dose pharmacokinetic studies, followed by sequential-dose clinical studies, are indicated when Sinemet CR 125 tablets soon become available.

Fluctuations in motor performance are the major problems in chronic management of Parkinson's disease. Most of these fluctuations reflect the decline of levodopa availability. As a consequence, levodopa dosage might be increased and the interdose interval progressively shortened. The postsynaptic dopamine receptors at this point are exposed to a nonphysiologic shift in dopamine level, which may induce changes at the receptor site and contribute to the appearance of "on-off" phenomena and dyskinesias. We compared a group of 18 patients treated for 60 consecutive months with continuous subcutaneous lisuride infusion with a group of 20 patients treated with conventional oral levodopa treatment. The clinical evaluations performed during the study showed in the lisuride group only a worsening of dyskinesias, whereas the other symptoms remained unchanged. In the other group the evaluation scores showed a significant worsening of all long-term treatment complications. The slow-release preparations of levodopa may ensure a more continuous dopaminergic stimulation than standard formulations. However, the use of these compounds is difficult in severely fluctuating patients because the lack of a plasma peak level usually leads to a very long delay before patients turn "on." We studied the pharmacokinetic and clinical effects of the two slow-release preparations of levodopa [Madopar HBS and Sinemet controlled-release (CR)] and a combination of Sinemet CR plus standard Sinemet in 13 fluctuating parkinsonian patients. The results of this study show that the combination of standard Sinemet and Sinemet CR ensures a more prolonged clinical effect with a very short latency to the "on" phase.

A process has been developed by which ventriculoperitoneal hydrocephalus shunts, which are prone to bacterial colonisation, can be impregnated with antimicrobials in order to confer antibacterial activity. Concern that their use might be associated with an increased risk of postoperative seizures has been addressed here. Using two rat models, namely pentylenetetrazole (PTZ) and maximal electroconvulsive seizure (ECS) thresholds, the possible epileptogenic characteristics of the shunt catheters were determined. Animals implanted with impregnated catheters exhibited no significant difference in PTZ seizure threshold compared with controls. In contrast, the ECS threshold test showed an enhancement in seizure susceptibility in the non-impregnated catheter group, in accordance with that found in human subjects, but a significant reduction in the impregnated catheter group at 2 and 28 days, postoperatively. These data suggest that the use in human subjects of shunts impregnated with these antimicrobials will not increase the risk of postoperative seizures.

Objectives: This study was conducted to determine the myocardial beta-adrenoceptor density as a marker of sympathetic function in patients with hypertrophic cardiomyopathy and normal control subjects., Background: Although some cases of hypertrophic cardiomyopathy are familial with an autosomal dominant pattern of inheritance, there remains a substantial proportion of cases in which neither a family history nor genetic abnormalities can be demonstrated. Additional abnormalities, both genetic and acquired, may be important in the phenotypic expression of this condition. Clinical features of the disease and metabolic studies suggest an increased activity of the sympathetic nervous system., Methods: Eleven patients with hypertrophic cardiomyopathy, none of whom had previously received beta-blocking drugs, and eight normal control subjects underwent positron emission tomography to evaluate regional left ventricular beta-adrenoceptor density and myocardial blood flow using carbon-11-labeled CGP 12177 and oxygen-15-labeled water as tracers. Plasma catecholamines were also measured., Results: Mean (+/- SD) myocardial beta-adrenoceptor density was significantly less in the hypertrophic cardiomyopathy group than in the control group (7.70 +/- 1.86 vs. 11.50 +/- 2.18 pmol/g tissue, p < 0.001). Myocardial blood flow was similar in both groups (0.91 +/- 0.22 vs. 0.91 +/- 0.21 ml/min per g, p = NS). The distribution of beta-adrenoceptor density was uniform throughout the left ventricle in both groups. In the hypertrophic cardiomyopathy group, there was no correlation between regional wall thickness and myocardial beta-adrenoceptor density. There were no significant differences in either plasma norepinephrine or epinephrine concentrations between the two groups., Conclusions: There is a diffuse reduction in myocardial beta-adrenoceptor density in patients with hypertrophic cardiomyopathy in the absence of significantly elevated circulating catecholamine concentrations. This most likely reflects downregulation of myocardial beta-adrenoceptors secondary to increased myocardial concentrations of norepinephrine and is consistent with the hypothesis that cardiac sympathetic drive is increased in this condition.

The amino acids L-glutamate and L-aspartate have been shown to be excitatory neurotransmitters in mammalian central nervous systems. Antagonists acting selectively at excitatory amino acid receptors have shown antiepileptic properties in several animal models. We report the results of the first therapeutic trial of the competitive NMDA antagonist, D-CPP-ene (SDZ EAA-494), in eight patients with intractable complex partial seizures. All patients withdrew prematurely because of side-effects, including poor concentration (8), sedation (7), ataxia (6), depression (3), dysarthria (2), amnesia (2) and unilateral choreo-athetosis in a patient with contralateral Sturge-Weber syndrome. Seizures were unchanged in four patients and worse in three. A further patient with apparent improvement in seizures in the first week developed complex partial status epilepticus on withdrawal of DCPP-ene. EEG on treatment (5) or in the immediate post-treatment period (2) showed slowing of background activity and, in five cases, an increase in epileptiform activity. Serum concentrations of DCPP-ene were found to be unpredictable and higher than expected from pharmacokinetic data on normal subjects. There was no clear relationship between serum concentrations and the severity of side-effects. Preliminary experience with DCPP-ene in patients with refractory partial seizures is not promising. Evaluation of related compounds is warranted.

Approximately 20 to 30% of patients with active intractable epilepsy are commonly treated with polytherapy antiepileptic drug regimens, and these patients may experience complicated drug interactions. Furthermore, because of the long term nature of treatment, the possibility of drug interactions with drugs used for the treatment of concomitant disease is high. Classically, clinically significant drug interactions, both pharmacokinetic and pharmacodynamic, have been considered to be detrimental to the patient, necessitating dosage adjustment. However, this need not always be the case. With the introduction of new drugs (e.g. vigabatrin and lamotrigine) with known mechanisms of action, the possibility exists that these can be used synergistically. The most commonly observed clinically significant pharmacokinetic interactions can be attributed to interactions at the metabolic and serum protein binding levels. The best known examples relate to induction (e.g. phenobarbital, phenytoin, carbamazepine and primidone) or inhibition [e.g. valproic acid (sodium valproate)] of hepatic monoxygenase enzymes. The extent and direction of interactions between the different antiepileptic drugs are varied and unpredictable. Interactions in which the metabolism of phenobarbital, phenytoin or carbamazepine is inhibited are particularly important since these are commonly associated with toxicity. Some inhibitory drugs include macrolide antibiotics, chloramphenicol, cimetidine, isoniazid and numerous sulphonamides. A reduction in efficacy of antibiotic, cardiovascular, corticosteroid, oral anticoagulant and oral contraceptive drugs occurs during combination therapy with enzyme-inducing antiepileptic drugs. Discontinuation of the enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s) and may necessitate dosage readjustment.

1. The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats. 2. Milacemide dose-dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 3. Pretreatment with L-deprenyl (2 mg kg-1), a specific inhibitor of monoamine oxidase type B (MAO-B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. Tmax and t1/2 were significantly increased and Cmax and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg kg-1), a specific inhibitor of MAO-type A, only moderately decreased glycinamide Cmax and AUC values. 4. After milacemide administration (100, 200 and 400 mg kg-1, i.p.) serum and CSF milacemide concentrations rose linearly and dose-dependently. Serum glycinamide concentrations exhibited small dose-dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose-dependently with Cmax values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg kg-1 respectively of milacemide. 5. Serum glycine concentrations were unaffected but CSF concentrations increased dose-dependently and these were significant at the higher milacemide doses (200 and 400 mg kg-1). Animals given 400 mg kg-1 milacemide had glycine values which were still significantly elevated 7 h later. 6. In conclusion, serum milacemide rapidly enters and equilibrates with the CNS compartment where it is metabolised primarily by MAO-B to glycinamide and finally to glycine. Metabolism in the peripheral compartment is negligible.

The temporal inter-relationship of various amino acids and monoamine metabolites in rat cerebrospinal fluid was examined after acute administration of milacemide (100, 200 or 400 mg/kg i.p.), a glycine prodrug. Glycine concentrations rose linearly and dose dependently (20-190%) but were only significantly elevated at the higher milacemide dose (200 and 400 mg/kg). In animals given 400 mg/kg, glycine values were still significantly elevated 8 h later. A concomitant increase (20-25%) in serine and taurine and a decrease in alanine cerebrospinal fluid values were observed at the highest milacemide dose. Other amino acids were unaffected. While cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations were unaffected, the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, exhibited a linear dose-dependent reduction. However, only homovanillic acid values were significantly decreased after 400 mg/kg milacemide. Cerebrospinal fluid analysis may be useful as a first screen in ascertaining putative neurochemical changes associated with drug administration.

Management of trigeminal neuralgia, a severe facial pain, remains difficult. All patients are initially treated with drugs. Since the seventeenth century more than 40 different preparations have been used; some of these, although effective, had toxic side effects. The most useful drugs at present are carbamazepine, phenytoin, baclofen, and clonazepam. A new drug, oxcarbazepine, is showing therapeutic promise. The most common reason for therapeutic failure with antineuralgic drugs is inadequate dosage. We review here the pharmacokinetics, side effects, possible drug interactions, plasma and serum therapeutic concentrations, and the available formulations of each drug. On the basis of these considerations and clinical reports describing the use of these drugs, we make dosage recommendations to enable the practitioner to individualize therapeutic regimens.

Lamotrigine (LTG) is a new antiepileptic drug which is effective in refractory epilepsy and which has been shown to have weak antifolate properties in vitro. The effect of LTG on serum folate and red cell folate (RBC) concentrations was assessed in a series of 14 patients on short-term LTG treatment during a placebo-controlled double-blind study. A further 14 patients who had been treated with LTG for up to 5 years were also assessed. In the short-term double-blind study the baseline mean serum folate concentration was 2.7 ng/ml and mean RBC folate concentration was 295 ng/ml. After 12 weeks of LTG therapy mean concentrations were 3.3 ng/ml and 339 ng/ml respectively and corresponding levels after 12 weeks of placebo were 2.4 ng/ml and 288 ng/ml. Patients on chronic LTG therapy showed no significant difference in RBC folate concentrations compared to those prior to LTG therapy (346 compared to 407 ng/ml). Other biochemical and haematological parameters were unaltered by LTG therapy. Thus, neither short-term nor chronic LTG therapy appears to be associated with significant changes in serum or RBC folate concentrations.

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics [cerebrospinal fluid (CSF)] is described. The blood (jugular vein) and CSF (cisterna magna) catheters employed are simple, reliable, and inexpensive. The blood catheter was made of soft and flexible Silastic tubing and sealed with heparin. The CSF catheter consisted of intersliding polythene tubing and interlocking Silastic tubing, which allowed maneuverability within the cisternal magna space and thus prolonging patency for chronic studies. Both catheters were well tolerated by the animals, and the postoperative success rate was 80%-100%; after 8 days 80%-85% of catheters were still patent. Using a sampling protocol considered suitable for kinetic studies, we determined numerous biochemical and hematological parameters and compared them with those values obtained postsurgically and in control rats. The parameter changes associated with the sampling protocol did not affect the kinetics of the commonly prescribed antiepileptic drug carbamazepine and its primary pharmacologically active metabolite carbamazepine-10, 11-epoxide. Therefore, the model can be used to study the interrelationship between drug kinetics at central and peripheral sampling sites and mechanism(s) of drug action.

We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamazepine (CBZ) and its primary metabolite CBZ-10,11-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P less than 0.01) and the CBZ-E/CBZ ratio increased by 19% (P less than 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.

The pharmacokinetics of midazolam, a water soluble 1,4-benzodiazepine, has been studied in 12 patients (11 male, 1 female; age range 19-57 years) with epilepsy. All patients were taking hepatic enzyme inducing antiepileptic drugs (AEDs) on a regular basis. Midazolam (5 mg) was administered intravenously and 1 week later midazolam was administered intramuscularly, the dose used being dependent on the sedative response to the intravenous dose (10 mg, n = 2; 7 mg, n = 8; 5 mg, n = 2). Serial blood samples were collected at timed intervals for 5-7 h. After intravenous administration initial distribution was rapid with a mean half-life (t 1/2 alpha) of 0.06 +/- 0.03 h followed by a terminal half-life (t 1/2 beta or gamma) of 1.5 +/- 0.3 h. Volume of distribution was 0.62 +/- 0.27 l/kg. After intramuscular administration midazolam was rapidly absorbed with peak serum concentrations achieved at 25 +/- 23 min. Two patients showed delayed absorption. Mean terminal half-life was 2.8 +/- 1.7 h. The absolute bioavailability of intramuscular midazolam was calculated in 11 patients as 87 +/- 18%. Sedation was rapid (less than 1-2 min) but transient (7-75 min) after intravenous and slower (2-30 min) and for a longer period (20-120 min) after intramuscular administration. Since intravenous administration of AEDs including diazepam is not always feasible in status epilepticus there are obvious advantages in having an effective intramuscular formulation. Our data suggest that midazolam may be such a drug.

A high-performance liquid chromatographic technique is described for the determination of milacemide and its primary metabolite glycinamide in rat plasma and cerebrospinal fluid. Milacemide and glycinamide are derivatized with fluorescamine to form a chromophore and a fluorophore and subsequent analysis using ultraviolet and fluorescence detectors, respectively. The extraction procedures are simple with a limit of detection 2 and 0.5 micrograms/ml for milacemide in plasma and cerebrospinal fluid, respectively, and 0.5 micrograms/ml for glycinamide in plasma or cerebrospinal fluid. The within-batch coefficients of variation for both analytes were less than 3%. Since only a small amount of sample is required, these techniques are well suited for the study of milacemide pharmacokinetics in the rat.

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.

We report the effects of the addition of lamotrigine, a novel antiepileptic drug, to the therapy of 125 patients with severe refractory epilepsy. Forty-five patients (36%) reported adverse experiences and in 19 (15%), the drug was withdrawn. The commonest adverse experiences were diplopia, headache, ataxia, drowsiness, skin rash and deterioration in seizure control. Two patients were withdrawn for other reasons. The remaining 104 patients were followed for a mean of 11 months (range 3-27): 26 (25%) of these showed a marked improvement in seizure frequency (a 50% or more reduction when compared with the pre-trial period), but no patient was rendered seizure-free. Tolerance to the effects of the drug was not seen.

The efficacy of lamotrigine (LTG), a new antiepileptic drug (AED) chemically unrelated to drugs in current use, was evaluated in 21 in-patients (18 males, 3 females; mean age 34.6; range 23-42 years) with severe refractory epilepsy. An add-on double-blind placebo-controlled crossover design was used, with 12 week treatment periods, and a 6 week washout period. Subjects were allocated to 1 of 2 dosing schedules according to their concomitant AEDs. Doses were increased according to clinical response. Although there was no significant reduction in total seizure count during the lamotrigine treatment period compared to placebo, there appears to be a drug effect as there was a marked reduction in generalized tonic-clonic seizures in favour of lamotrigine in the last 4 weeks of the treatment period. There was no significant difference in volunteered adverse experiences during active and placebo treatment. Concomitant serum AED concentrations, biochemical and haematological parameters were unaffected by lamotrigine treatment.

Carbamazepine (CBZ) is a widely used antiepileptic drug (AED). Recently, a chewable tablet (Tegretol chewtabs) has been formulated. This open substitution study was designed to compare the two formulations with respect to efficacy and tolerability in patients with intractable epilepsy. Thirty patients (24 males, 6 females, mean age 46 years, range 28-83) were studied. Duration of epilepsy was 21-68 years (median 34 years). Four patients were taking CBZ monotherapy, 17, 6 and 3 patients were respectively taking CBZ plus 1, 2 and 3 additional AEDs. Upon entry to study, patients were switched to an equivalent dose of chewtabs and subsequently evaluated at 2, 4, 8 and 12 weeks. Two patients did not complete the study. On entry, the mean 14 day seizure rate was 2.5. On chewtabs mean 14 day rates were 2.4, 2.2, 2.4 and 2.7 after 2, 4, 8 and 12 weeks of treatment respectively. On entry the mean steady state trough serum CBZ concentration was 35 mumols/l compared to 32, 31, 32 and 34 mumols/l after 2, 4, 8 and 12 weeks respectively. Nineteen patients were classified showing good or excellent tolerability, 7 satisfactory and 2 fair. In conclusion, chewtabs were essentially equivalent to the conventional formulation in efficacy and tolerability. After 12 weeks treatment, 19 patients preferred the chewable formulation.

Oxcarbazepine, a new drug with antineuralgic properties has been evaluated in a long-term follow-up of 6 patients (2 males, 4 females; aged 42-77 years; mean 61 years), previously reported on with trigeminal neuralgia. Daily oral oxcarbazepine dose correlated significantly with both total oxcarbazepine (r = 0.851) and 10-OH-carbazepine (r = 0.958) serum concentrations. Mean percent free oxcarbazepine and 10-OH-carbazepine was 41 and 61% respectively and there was no significant difference in binding between male and female patients. Free serum concentrations of oxcarbazepine and 10-OH-carbazepine correlated significantly with total serum oxcarbazepine and 10-OH-carbazepine respectively, indicating that binding capacity of both are essentially constant within the respective ranges of 0.2-11.4 mumol.l-1 and 20-150 mumol.l-1 observed in the present study.

Antipyrine half life and clearance was compared in four patients with classical idiopathic trigeminal neuralgia during carbamazepine (CBZ) or CBZ/phenytoin (PHT) and after substitution with oxcarbazepine (OXC) monotherapy. OXC is observed to be less of a hepatic enzyme inducer than CBZ or CBZ/PHT in combination, however induction by OXC may be dose related.

Thirteen patients with epilepsy on long-term antiepileptic drug therapy and who had a persistently raised serum alkaline phosphatase (ALP) activity were investigated biochemically. Twelve patients had a raised liver ALP-isoenzyme activity and in nine of these the bone ALP-isoenzyme activity was normal. Gamma-glutamyl transferase (gamma GT) levels were raised in 12 patients. Two patients were hypoglycaemic. One patient fitted the biochemical parameters for subclinical osteomalacia. The resultant clinical picture showed 75% of patients with borderline hypocalcaemia, raised liver ALP, raised gamma GT and normal bone ALP activities in whom 1,25 dihydroxy-cholecalciferol (1,25-DHCC; vitamin D) therapy would be inappropriate, whilst 1,25-DHCC therapy might be considered for those with borderline hypocalcaemia and a raised bone ALP activity (three patients). No evidence was found of hepatotoxicity or drug induced cholestasis. It is considered that the induction of liver microsomal enzymes by antiepileptic drugs could include liver ALP (as opposed to bone ALP) as well as gamma GT and the inactivation pathways for 1,25 DHCC.

Denzimol, a new anticonvulsant drug, is currently undergoing clinical evaluation. In this paper we report its use in six patients who were also taking carbamazepine and two patients taking phenytoin. There was a striking elevation of serum carbamazepine, carbamazepine-10, 11 epoxide and phenytoin concentrations in all patients on the addition of denzimol therapy. The interaction with carbamazepine is greater in severity than any other reported to date and denzimol's interaction with both carbamazepine and phenytoin is likely to prove of major clinical significance.

Pregnant Long-Evans rats were received on day 5 of gestation and divided into 4 treatment groups: (1) 27% calories provided as ethanol in a liquid diet; (2) pairfed i.e., isocaloric liquid diet restricted to match group (1); (3) liquid diet provided ad libitum; and (4) laboratory chow and water provided ad libitum. Litters were culled to 8 pups at birth and crossfostered across dams in all 4 groups to provide offspring falling into 16 different experimental groups, including some exposed to ethanol in utero only and some exposed only during lactation. At birth, blood alcohol levels of dams, culled pups and alcohol levels in the stomach contents of culled pups were measured. All pups were weaned and fed laboratory chow and water ad libitum from 21 days onward. At ages 16, 21, 30 and 52 days, pups were sacrificed, and organ/body weight ratios and brain myelin concentrations were determined. Ethanol treated dams had longer gestational periods. The offspring of ethanol treated dams which were crossfostered to pairfed and well nourished dams during lactation had delayed eye opening, persistent lag in body growth and slightly lower brain myelin concentrations. Offspring of dams which were either pairfed or well nourished during gestation, but crossfostered during lactation to ethanol treated dams, had abnormal organ weights, abnormal brain weights and severely depressed brain myelin concentrations persisting through 52 days of age. Thus, lactational ethanol effects on brain myelin were more severe than gestational effects; body growth was affected more severely by gestational exposure, and gestational effects were generally less severe with adequate nutrition.

The effect of denzimol (DNZ) on the disposition of carbamazepine (CBZ) and its primary metabolite carbamazepine-10,11-epoxide (CBZ-E) in serum, liver, spleen and seven brain regions of the rat was assessed. Coadministration with DNZ for 5 or 10 days resulted in an increase in CBZ and a decrease in CBZ-E concentrations in serum, liver and spleen, consistent with a metabolic (hepatic cytochrome P450 mono-oxygenases) inhibitory interaction. After 15 days of co-administration the concentration of CBZ-E was also increased in these tissues, suggestive of epoxide hydratase inhibition in addition. The magnitude of these concentration changes was much greater in the brain indicating that the total serum concentration of CBZ or CBZ-E may not be a reliable index of the neuropharmacological severity of CBZ-DNZ interaction.

A method for repeated withdrawal of cerebrospinal fluid (CSF) from the cisterna magna was used in a pharmacokinetic and behavioural study of conscious, freely-moving rats, given the antiepileptic drug carbamazepine (35 mg/kg i.p.). Pharmacokinetic constants (i.e. time to peak concentration, peak concentration, area under the curve and t 1/2) for the drug and its primary metabolite carbamazepine-10,11-epoxide and also concentrations of acidic metabolites of 5-hydroxytryptamine and dopamine were obtained for the CSF of individual rats. A pharmacodynamic constant, the effective concentration of drug in CSF for 50% inhibition of motor activity was also determined for each animal. The above data provides good indices of the corresponding values for carbamazepine and its metabolite in brain insofar as a separate experiment showed good correlations between CSF and brain for concentrations of both the drug and its metabolite. Carbamazepine appeared to be largely responsible for the depression of motor activity as the metabolite, at the levels attained, seemed to have little effect. The changes in motor activity were not associated with altered concentrations of the metabolites of 5-hydroxytryptamine or dopamine in the CSF. While the investigation did not reveal major advantages in monitoring the drug under study in CSF rather than in serum it illustrates the potential of the CSF method as a simple way to obtain neuropharmacokinetic and neuropharmacodynamic profiles of the action of drugs in individual rats.

Rats were administered with 50 mg/kg phenytoin (PHT), twice a day, for five consecutive days and with a second anticonvulsant drug in addition for a further five days. Analysis of 24 hr urine samples for content of unmetabolized PHT and its major metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) indicates that PHT hydroxylation was significantly inhibited by sulthiame coadministration since during the test period (days 6-10) the concentrations of PHT and pHPPH in urine were significantly increased and decreased respectively. In contrast, sodium valproate, ethosuximide and phenobarbital had no significant effect on the urinary excretion pattern of PHT. These data correlate with changes in plasma and brain PHT concentrations.

Rats were exposed to 0.5% halothane in air for 8 h per day during the intervals (1) 5 days postconception to birth, (2) birth to 5 days postnatal age, or (3) birth to 10 days postnatal age. Controls were exposed to an equivalent flow of air. Prenatal exposure had no significant effect on body or brain weight and no subsequent effect on the relative synthesis of brain subcellular membranes. Five days of postnatal exposure caused a 10% reduction in body and brain weight and a 10% relative reduction in the synthesis of brain myelin. The effect persisted throughout the period rapid postnatal brain myelination. Ten days of postnatal exposure produced equivalent, more severe effects on body and brain weights and a more severe effect on myelin synthesis. Postnatal exposure had no apparent effect on the relative synthesis of non-myelin particulate proteins.