Epilepsy Res., ll(l992)

141

141-145

Elsevier EPIRES 00461

Loreclezole monotherapy

in patients with partial seizures

Th.W. Rentmeester

and J.A.R.J.

Epilepsy Centre Kempenhaeghe,

Hulsman

Heeze (Netherlandr)

(Received 10 September 1991; revision received 18 December 1991; accepted 23 December 1991) Key words: Loreclezole; Monotherapy;

Add-on; Withdrawal comedication

Monotherapy is preferable in the treatment of epilepsy; a new antiepileptic drug has to be checked on its efficacy in monotherapy. In this study patients who had successfully been treated with loreclezole in previous studies were gradually withdrawn from their antiepileptic comedication. Nine patients participated in the study. Reduction of comedication was well tolerated in all, no serious side effects occurred. In 6 patients seizure frequency remained unchanged, i.e., within 50% limits. Two patients experienced a clear increase in seizure frequency. In 2 patients reintroduction of a second antiepileptic drug was mandatory. One patient experienced a further reduction in seizure frequency when monotherapy was reached. This observation indicates efficacy of loreclezole, also in monotherapy.

INTRODUCTION Loreclezole is a triazole derivative with potent anticonvulsant properties’*. In three articles the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures has been described’0-‘2. In the first the long-term safety and efficacy of loreclezole is studied in 13 patients with pharmacotherapy-resistant epilepsy. In 4 patients there was a reduction of seizure frequency of 50% or more. To evaluate the efficacy and safety of loreclezole a placebo-controlled, double-blind study was performed. A clinically significant response of at least 50% (to nearly 80%) reduction was seen in the loreclezole group in 6 out of 32 patients; no responders were found in the placebo group (P = 0.02). After 1 year’s treatment with loreclezole (plasma levels 5-7 mg/l) 23 Correspondence

to: Dr.

Centre Kempenhaeghe, lands.

Th.W. Rentmeester, Epilepsy P.O. Box 61,559O AB Heeze, Nether-

out of 55 patients had a reduction of seizure frequency of 50% or more (to nearly 100% in 2) (P = 0.001). In modern epilepsy treatment monotherapy is vastly preferable*. It has been shown that the majority of epilepsy sufferers (about 80%) derive sufficient benefit from treatment with one drug14. Combinations of antiepileptic drugs are seldom necessary. Polypharmacy leads more frequently and more rapidly to side-effects. The ultimate goal, freedom from seizures, is sometimes reached after withdrawal of comedication’~3’5*9”3. The loreclezole studies described so far are concerned solely with add-on treatment. Once a new antiepileptic drug like loreclezole has been added to the medication, the obvious next step is to make a gradual transition to withdrawal of the existing antiepileptic drugs”. Accordingly, as a follow-up to these studies that had already been performed a protocol was drawn up for gradual transition to loreclezole monotherapy.

0920-1211/92/$05.00 0 1992 Elsevier Science Publishers B.V. All rights reserved

142

Patients who had taken part in one of the previous studies were eligible to take part in the present study. These were patients who had derived benefit from the loreclezole treatment. In assessing this benefit, account was taken not only of the percentage reduction in seizures but also of the shift in seizures from day to night. A reduction of the severity of the seizures, sufficient to be regarded as an improvement by the patient, was also acceptable as a reason for including patients in the study, even if there had been no reduction in seizure frequency. The aim of the study was to investigate whether loreclezole is as effective against epilepsy when given as monotherapy compared to optimized antiepileptic drug therapy. METHODS

AND PATIENTS

The study was carried out at the Epilepsy Centre Kempenhaeghe, Netherlands, with the approval of the ethical committee of this centre. In principle the patients were to be treated as outpatients; they were to be hospitalized only if there was a compelling indication for hospitalization. The rate of reduction of comedication - immediate discontinuation of antiepileptic drugs - proposed by Newmark6 was rejected because it requires hospitalization The slow reduction of concomitant antiepileptic drugs proposed by Schmidt” - 25% dose reduction every 2 months - was also rejected, in view of the clinical improvement experienced by the patients after the addition of loreclezole to their medication. Thus the rate of reduction of medication was comparable to what was referred to by Duncan et al4 as the slow scheme and was described by Overweg’ in seizure-free patients. The drug which, in the opinion of the investigator, was probably the least effective or induced the most side-effects was withdrawn first’. In principle the medication was reduced in accordance with a fixed scheme and was finally withdrawn altogether (Table I). Sometimes, for the sake of the safety of the patients or for other special reasons, the comedication was reduced more slowly. After one antiepileptic drug had been completely withdrawn in accordance with this scheme, the medication was kept constant for at least 2 months. If the patient suffered an intolerable increase in seizures the old

TABLE I Medication reduction scheme: drug (in alphabetical order) and reduction of total daily dose, which was then maintained for I week

Carbamazepine: Clorazepate: Phenytoin: for plasma concentrations above 15 mgk of 7- 15 mgk below 7 mg/l: Valproate:

200 mg IOmg 25 mg 50 mg 75 mg 300-500 mg

medication was restored. Plasma loreclezole concentrations were kept between about 5 and 10 mg/l . After the 2 months of constant medication the next antiepileptic drug was withdrawn in accordance with the same scheme, its eventual total withdrawal being again followed by a 2-month ‘rest’ period, until monotherapy with loreclezole was attained. The evaluation period was 6 months. Inclusion and exclusion criteria Both men and women who had participated in one of the described studies on the efficacy of loreclezole10-‘2 were eligible for participation in the present study. As some patients had become seizure-free during the preceding loreclezole treatment, no specified number of seizures per unit time was imposed. Patients with hypersensitivity to loreclezole or with serious side-effects of loreclezole were excluded from the study. Further exclusion criteria were pregnancy or risk of pregnancy, progressive neurological diseases, serious liver or kidney dysfunction, and absence of written or oral informed consent. Patients Patients treated as outpatients from the neighbourhood of the epilepsy centre Kempenhaeghe were asked to participate in this study. Nine patients out of 22 responders to loreclezole add-on therapy were included in this study. Thirteen patients were not motivated to reduce comedication since they had experienced sufficient seizure control without adverse events. Of these 9 patients 4 had attained about 50% sei-

143 zure reduction and 5 experienced a reduction in seizure severity (no longer secondary generalization or shorter complex partial seizures) on loreclezole addition. Comedication was reduced in accordance with the scheme. At the time of inclusion in this study in addition to loreclezole, 8 patients were taking one antiepilepti~ drug (6 ~arbam~epine, 2 phenytoin) and 1 patient (No. 7) was taking two drugs (carbamazepine and phenytoin). During the study phenytoin was added to the medication for 1 week in 1 patient (No. 3) and in 1 patient (No. 9) low-dose clorazepate was added for a short time.

1

2

e

6

patient I

pretrial tllerwy

m loreclezole wtdltlon

r]

drug 1 wlthdrawn

m

drug 2 withdrawn-

Fig. 1. Transition to monotherapy loreclezole. Pretrial optiRESULTS The gradual withdrawal of the comedication was tolerated well by the patients; no adverse events arose during withdrawal.

The results of the withdrawal of the antiepileptic comedication in this group of patients are shown in Fig. 1. Four patients (Nos. 2,3,4 and 5) had an irrelevant change in seizure frequency (less than 50% change) after withdrawal of the comedication. One patient (No. 7) had an increase in the severity of the seizures, and 3 patients (Nos. 1,6 and 9) had an increase in seizure frequency. In patient No. 6 there was a shift towards nightly seizures, which was considered as a favourable outcome for the patient. In 1 patient (No. 8) there was a clear (>50%) reduction in seizure frequency. On reaching monotherapy, 2 patients (Nos. 3 and 4) experienced a temporary deterioration in the sense of a partial status epilepticus and a series of complex partial seizures. In patient No. 4 this did not require extra medicinal support. In patient No. 3 intravenous administration of clonazepam and addition of phenytoin proved ineffective. The patients continued treatment to monotherapy with loreclezole. In patient No. 9 the severity of the seizures had decreased considerably and there was no longer secondary generalization of the partial seizures. Plasma concentrations Blood tests were performed

at least every 2

mized antiepiiepti~ drug therapy (first bar) vs. withdrawal of comedication and monotherapy (last bar). Nos. l-3, patients from the first open study; Nos. 4-7, patients from the doubleblind study; Nos. 8 and 9, other patients. * If applicable.

months. Loreclezole plasma concentrations remained between 4 and 9 mg/l in all patients without major changes in the daily dose of loreclezole. Adverse events During this study there were no adverse effects that had not already been reported by the patients during the previous studies. Any existing weight loss stabilized. None of the patients had side-effects requiring a change of treatment. On the whole, loreclezole was tolerated well. Some patients reported that they felt fitter and more alert on monotherapy. This was not investigated further, e.g., by neuropsychological investigation. DISCUSSION In the first instance, loreclezole was added to the medication of hitherto pharmacotherapy-resistant epilepsy patients selected because their seizure frequency was high despite optimal antiepileptic drug therapy. Those who benefitted from addition of loreclezole to the existing treatment were offered the opportunity of reducing the comedication, in accordance with the protocol, until they were taking loreclezole monotherapy. Nine of the patients who took part in the study could be evaluated. Considering a change in seizure frequency of

144

less than 50% as irrelevant, in 6 patients the seizure frequency remained unchanged. Two patients had an increase in seizure frequency without requiring additional medication. One patient had a clear decrease in seizure frequency with respect to the polytherapy (Fig. 2).

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50

fh A

0 A

CONCLUSION Monotherapy is preferable in the drug treatment of epilepsy. Accordingly, an antiepileptic drug is truly of value only if it can be used as monotherapy. Two patients experienced an increase in seizure frequency of more than 50%, one patient had a reduction of more than 50% and in 6 patients the seizure frequency remained between these levels. The study shows that loreclezole seems to be an effective antiepileptic drug in monotherapy too, even in patients suffering from serious forms of hitherto pharmacotherapy-resistant epilepsy. However, this can only be concluded in a controlled design in which responders, i.e., seizurefree patients with loreclezole and comedication, remain seizure-free with loreclezole alone. Nevertheless, the results of this study open the way to treatment with loreclezole in comparative studies versus conventional antiepileptic drugs of newly

-1ooL rllhdrawal

2 drusa

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diagnosed patients with epilepsy. The efficacy of loreclezole in monotherapy should be investigated more closely. ACKNOWLEDGEMENT The authors thank F. de Beukelaar of Janssen Research Foundation for his help in the preparation of this article and for the supply of loreclezole.

REFERENCES 1 Andersen, G. and Pedersen, B., Valproate monotherapy in elderly patients with epilepsy, Epilepsiu, 30 (1989) 663. 2 Dean, J.C. and Penry, J.K., General principles - discontinuation of antiepileptic drugs. In: R.H. Levy, F.E. Dreifuss, R.H. Mattson, B.S. Meldrum and J.K. Penry (Eds.), Antiepileptic Drugs, Raven, New York, NY, 1989, pp. 133-142. 3 DePew, C. and Lubozynski, M., Efficacy, toxicity and compliance in the reduction of antiepileptic drugs from polytherapy to monotherapy, Epilepsia, 30 (1989) 680. 4 Duncan, J.S., Shorvon, S.D. and Trimble, M.R., Discontinuation of phenytoin, carbamazepine, and valproate in patients with active epilepsy, Epilepsiu, 31 (1990) 324-333. 5 Mirza, W., Credeur, J. and Penry, J.K., Results of antiepi-

llld

Fig. 2. Change in seizure frequency after withdrawal of comedication compared to loreclezole add-on treatment as a reference point.

6

7 8

9

leptic drug reduction in institutionalized epileptic patients with multiple handicaps, Epilepsia, 30 (1989) 663. Newmark, M.E., Elective, rapid changes of antiepileptic drug (AED) therapy: an acceptable alternative to phased, slow withdrawal, Neurology, 40 (Suppl. 1) (1990) 188. Overweg, J., Withdrawal of antiepileptic drugs in seizurefree adult patients, Ph.D. Thesis, Amsterdam, 1985. Parsonage, M., Epilepsy in adults. In: J.H. Tyrer (Ed.), The Treatment of Epilepsy, MTP, Lancaster, 1980, pp. 95-128. Ramsay, R.E., Wilder, J.M., Pellock, J.M., Dreifuss, F.E., Mattson, R.H., Smith, D.B., Penry, J.K., Sunder, T.R., Ahmann, P.A., Spitz, M.C., Murphy, J.V., Leroy. R.F., Morris, D.D., Hansen, R.G. and Pierce, M. W., Successful conversion from polytherapy to Depakote monotherapy in patients with primary generalized tonic-clonic

145 seizures, Epilepsia, 30 (1989) 662-663. 10 Rentmeester, T. and Hulsman, J., Efficacy and safety of loreclezole as add-on treatment in therapy-resistant epilepsy patients, Epilepsy Res., 8 (1991) 166-169. 11 Rentmeester, T., Janssen, A., Hulsman, J., Scholtes, F., Van der Kleij, B., Overweg, J., Meijer, J. and De Beukelaar, F., A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures, Epilepsy Res., 9 (1991) 49-58. 12 Rentmeester, T., Janssen, A., Hulsman, J., Scholtes, F., Van der Kleij, B., Overweg, J., Meijer, J. and De Beukelaar, F., Long-term evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures: a l-year open follow-up, Epilepsy Res., 8 (1991) 59-64. 13 Salvato, J.A., Torres, C. and Watt, K., Reduction of antiepileptic drug therapy in mentally retarded epileptic patients, Epilepsiu, 30 (1990) 663. 14 Schmidt, D., Two antiepileptic drugs for intractable epilep-

sy with complex-partial seizures, J. Neural. Neurosurg. Psychiatry, 45 (1980) 1119-1124. 15 Schmidt, D., Discontinuation of antiepileptic drugs. In: R.J. Porter and P.L. Morselli (Eds.), The Epilepsies, Butterworth, London, 1985, pp. 227-241. 16 Shorvon, S.D., The role of single drug and combination drug therapy in the treatment of epilepsy. In: M. Dam, L. Gram, B. Pedersen and H. Orum (Eds.), Modern Approach to Antiepileptic Drug Treatment, The Danish Epilepsy Society, Copenhagen, 1985, pp. 45-54. 17 Wagner, M.L., Graves, N.M., Marienau, K., Holmes, G.B., Remmel, R.P. and Leppik, I.E., Discontinuation of phenytoin and carbamazepine in patients receiving felbamate, Epilepsia, 32 (1991) 398-406. 18 Wauquier, A., Fransen, J., Melis, W., Ashton, D., Gillardin, J.-M., Lewi, P.J., Van Clemen, G., Vaught, J. and Janssen, P.A.J., Loreclezole (R 72 063): an anticonvulsant chemically unrelated to prototype antiepileptic drugs, Drug Dev. Res., 19 (1990) 375-392.

Loreclezole monotherapy in patients with partial seizures.

Monotherapy is preferable in the treatment of epilepsy; a new antiepileptic drug has to be checked on its efficacy in monotherapy. In this study patie...
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