Search

A randomised, double-blind, placebo-controlled crossover study of add-on remacemide hydrochloride was carried out in epilepsy patients being treated with phenytoin (PHT) monotherapy. Eleven patients were recruited, ten of whom completed the study. Plasma concentration profiles of PHT, remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single and multiple dosing with remacemide hydrochloride. Following 14 days' treatment with remacemide hydrochloride 300 mg twice daily, the mean AUC of PHT was increased by 11.5% ( P =0.33), C max by 13.7% ( P =0.32) and C min by 22.2% ( P =0.12) over placebo. There was an increase in trough concentrations of PHT averaging 20% during active treatment compared with placebo ( P =0.01). No symptoms of PHT toxicity were reported by any patient. There was no evidence of autoinduction of remacemide metabolism. However, average concentrations of remacemide and its active metabolite in PHT-treated patients were around 40 and 30% lower, respectively than in healthy volunteers previously receiving the same dose of remacemide hydrochloride. Thus, remacemide hydrochloride has a small inhibitory effect on PHT metabolism, which itself induces that of remacemide and its active metabolite. This mutual interaction is predictable and modest and should not present a barrier to their clinical use in combination.

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurones and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by ≥ 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of ≥ 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of ≥ 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.

Pregnancy in women with epilepsy (WWE) is known to be associated with a higher risk of congenital malformations than is associated with pregnancy in non-epileptic women. Several factors have been identified to account for the increased risk, including the direct teratogenic effects of antiepileptic drug (AED) therapy, indirect effects of these drugs by interfering with folate metabolism, genetic abnormalities in drug or folate metabolism, and possibly an arrhythmogenic effect of maternal drug therapy on the embryonic heart, leading to ischaemia in developing tissues. A harmful effect of maternal seizures on the developing embryo has not been proven, although seizures and status epilepticus account for most of the excess maternal mortality in women with epilepsy. Abrupt withdrawal of drug therapy by the mother may be an important contributory factor. Less is known about the psychomotor development of children born to mothers with epilepsy because few studies have been designed to follow their progress throughout childhood. Retrospective studies suggest that impaired cognitive development may be associated with maternal drug therapy, particularly valproate. There is an urgent need to evaluate these risks and, with this in mind, several prospective registers have been set up to collect data from pregnancies in women with epilepsy.

In recent years, most of the published trials of new antiepileptic drugs (AEDs) have had a parallel-group design rather than cross-over. Nevertheless, in some situations the cross-over trial does have advantages, and therefore, its role needs re-appraisal. The crossover design requires a much smaller number of patients for a similar statistical power because patients act as their own controls, which is a particular advantage when the type or severity of epilepsy varies widely in the patients recruited. As a result, the financial cost is smaller and fewer patients are exposed to the new agent, perhaps with ethical arguments in favour of this type of design in proof-of-efficacy trials. Within-patient analysis also makes the detection of drug interactions more robust. On the other hand, there is a theoretical risk that the beneficial effects of the first treatment (or conversely, withdrawal seizures on stopping it) might carry over into the second treatment period and thereby confound the detection of treatment effects. The parallel-group design is more versatile in that a stable disease state is not a pre-requisite, and therefore, trials in newly diagnosed patients are possible. Multiple treatment limbs are also more practical. The duration of a parallel-group trial may be shorter because only one treatment period is involved, although this may be offset by the much larger number of patients needed to be recruited and the time involved in doing so. Parallel-group trials almost always require a multicentre approach, with the inevitable logistic problems involved. It is argued that proof-of-principle and add-on proof-of-efficacy trials of a new drug are more efficiently undertaken using a cross-over design but that subsequent evaluation will require the versatility of trials with a parallel-group design.

Epilepsy in the elderly differs from that in younger people in several respects. The incidence of seizures increases sharply with age and the seizures are more often symptomatic of underlying brain disease. The handling of antiepileptic drugs (AEDs) may be impaired by diminishing hepatic and renal function as age advances, and the pharmacodynamic response to drug therapy may be altered. In consequence, the elderly are more likely to experience adverse drug effects. Whether their seizures respond to drug treatment in a different way from younger patients is uncertain, but there are, nevertheless, convincing arguments for clinical trials being undertaken specifically in this population during the Phase II/IV development programme.

There is no doubt that the pathophysiological processes underlying the generation of epileptic spikes in the EEG are the same as those involved in clinical seizures, and therefore a drug which suppresses seizures is likely to do the same to EEG spikes. Indeed, phenytoin, the benzodiazepines, valproate and lamotrigine have been shown to do so when tested acutely in single doses in patients with frequent interictal spikes (Jawad et al., 1986) and it is reasonable to regard such studies as a useful method for screening new drugs for antiseizure activity. Also, the coincidence between spike-and-wave activity and clinical absences has made EEG monitoring an essential part of the short and long term evaluation of anti-absence drugs. In long term trials of drugs in partial and secondary generalised tonic clonic seizures, however, there is sometimes a discordance between interictal spike frequency and clinical seizures, and monitoring the EEG in such studies has proved to be unrewarding. EEG responses to photic stimuli have also been shown to be inhibited by many antiepileptic drugs, even those that do not have a role in patients who have photosensitive epilepsy (Binnie et al., 1986a). We are concerned here particularly with acute studies of interictal spikes and photic responses. Despite the evidence supporting their value, these surrogate measures of seizure activity have not been widely used in the early evaluation of new antiepileptic drugs, one exception being lamotrigine, which underwent assessment in both interictal spikes (Jawad et al., 1986) and photosensitivity (Binnie et al., 1986b). This is presumably because most advisers to the pharmaceutical industry consider that the acid test of a new drug is whether or not it suppresses seizures, and the earlier this is demonstrated, the better. However, definitive proof-of-efficacy trials in patients with seizures are time-consuming and expensive, and it can be argued that early evidence of efficacy from short studies of a small size before embarking on a major trials programme makes sense, particularly if a suitable window occurs in the development schedule for these studies to be done. If they yield positive results, encouragement will be given to the further development of the drug. If they are negative, however, a major problem will arise: should the drug be abandoned as being unlikely to be effective in suppressing seizures because it has failed in these surrogate measures? If the evidence concerning the power of these tests to identify antiseizure activity was robust, the answer to this question would be ‘yes’, but unfortunately this is not the case and few investigators would advise that a development programme was terminated because * Tel.: +44-1594-562220; fax: +44-1594-562220. E-mail address: alan.richens@btinternet.com.uk (A. Richens).

The time course of changes in serum prolactin after complex partial seizures has been determined and compared to similar changes after other types of seizure and non-epileptic attacks. Seizures in 33 subjects were recorded on video EEG telemetry. Peak serum prolactin concentrations occurred 15-20 min after tonic-clonic seizures, 10 min after complex partial seizures, and were highest after generalised tonic-clonic seizures. Serum prolactin concentrations remained less than 1000 mU/l after absences and non-epileptic attacks. Application of Bayes' theorem showed that where serum prolactin was greater than 1000 mU/l 5-10 min post event this would identify genuine tonic-clonic or complex partial seizures. The false negative rate of this test was 9% for tonic-clonic seizures and 38% for complex partial seizures. Failure of serum prolactin to rise after an attack is of little value in distinguishing complex partial seizures from non-epileptic attacks.

The acute effect of oral administration of a single dose of vigabatrin, a new antiepileptic drug which acts by irreversible enzyme-activated inhibition of the brain enzyme, GABA-aminotransferase, on the photoconvulsive response in patients with photosensitive epilepsy, was compared with that of the established antiepileptic drug, sodium valproate. Both drugs significantly suppressed the photoconvulsive response in 3 out of 6 subjects. This result was interpreted as further evidence of vigabatrin's potential value in the future treatment of patients with epilepsy.