71

Epilepsy Res., 9 (1991) 71-77

Elsevier EPIRES 00406

Nimodipine in refractory epilepsy: a placebo-controlled, add-on study

J.G. Larkin”, P.J.W. McKeea, J. Blacklawa, G.G. Thompsona, I.C. Morganb and M.J. Brodie” ‘Epilepsy Research Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland and bMiles Manufacturing Division, Bridgend, Wales (U.K.)

(Revision received 14 January 1991; accepted 18 February 1991) Key words: Antiepileptic

drug; Calcium antagonist; Clinical trial; Epilepsy; Nimodipine; Polypharmacy

Twenty-two patients (8 male, 14 female) with refractory epilepsy entered a balanced, double-blind, placebo-controlled crossover trial of nimodipine as adjunctive therapy. Treatment periods of 12 weeks (nimodipine 30 mg tds, 60 mg tds, 90 mg tds each for 4 weeks and matched placebo) were followed by wash-out intervals of 4 weeks. Five patients withdrew (2 side-effects, 1 intercurrent illness, 2 non-compliance). Median values (placebo vs. nimodipine) did not vary for total (17 vs. RI), partial (14 vs. 18) and general&d tonicclonic seizures (2 vs. 5) or seizure days (13 vs. 13). Monthly analysis also failed to uncover any benefit for nimodipine. Side-effects were reported no more frequently with nimodipine than with placebo and pulse and blood pressure did not alter significantly. Antiepileptic drug levels were not affected by nimodipine treatment but circulating nimodipine concentrations were low. In this trial, nimodipine did not fulfil the promise of its success in animal models of epilepsy. Enzyme induction by concurrent antiepileptic therapy may provide an explanation.

INTRODUCTION Recent interest in calcium antagonists as possible anti-epileptic drugs (AEDs) stems from a number of clinical and scientific observations. Cellular events in epilepsy include an excess of ‘intrinsic burst firing’ of neuronesi which is inhibited by all AEDs active against partial and generalised seizures*. Synchronous burst firing, which is synapseCorrespondence to: Martin J. Brodie, Epilepsy Research Unit, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Gil 6NT, Scotland, U.K. Tel: +41-339 8822 Ext. 457214176;Fax: +41-334 9329.

0920-1211/91/$03.50 fQ 1991 Elsevier Science Publishers B.V.

mediated, may lead to the production of an abnormal action potential - the paroxysmal depolarising shift (PDS) -which is associated with the initiation of epileptogenic activity. Release of excitatory neurotransmitters, and thus synapse mediation, is dependent on neuronal calcium influx4T5as is the PDS6. Calcium channel blockers can inhibit burst firing7 and the PDS in vitro’ and in vivo8Y9. Conversely, the calcium agonist Bay K8644 has been shown to enhance these epileptogenic features”. In animal seizure models, the calcium antagonists flunarizine”-‘3, nimodipine14-“, nifediand nitrendipine”T*’ have all been pine 16319321 shown to possess anticonvulsant properties.

72

Initial clinical studies suggested that the calcium antagonist, flunarizine, may be a useful AED22-24. However, while one controlled trial seemed to support this25, others have reported only modest efficacy26v27or none at a112*.Flunarizine also has the propensity to produce sedative and extrapyramidal side-effects29*30. In addition, its action may not be due to calcium antagonism but to an effect on sodium channels3*, similar to that described with carbamazepine and phenytoin32. Calcium antagonists with a dihydropyridine structure have been less extensively studied in the clinical situation. Intravenous nimodipine has been reported to control resistant epilepsia partialis continuans in 2 patients33. Adjuvant nifedipine reduced seizure frequency in one open study in refractory epilepsy34 but not in anothel-3’. A recently completed placebo-controlled trial has provided the first evidence of a concentration-response relationship with nifedipine in human epilepsy although efficacy was 10~~~. Nimodipine is a 1,4_dihydropyridine which is thought to have a preferential relaxant effect on cerebral blood vessels3’. It has been shown to improve outcome in subarachnoid haemorrhage38T39 and to be of possible benefit following ischaemic strokea, presumably by preventing tissue damage mediated by cellular calcium entry41. In view of nimodipine’s success in animal models of epilepsy and its good safety profile in clinical studies, we undertook a placebo-controlled add-on study in patients with refractory epilepsy. MATERIALS

AND METHODS

Patients

Twenty-two patients (8 male, 14 female; aged 18-53 years) with refractory epilepsy (each averaging >3 seizures/month) agreed to take part in the study. Fifteen reported complex partial seizures with secondary generalisation, 5 partial fits alone and 2 generalised tonic-clonic convulsions (GTCS) only. Ten patients were receiving anticonvulsant monotherapy (6 carbamazepine, 3 phenytoin, 1 sodium valproate) and 12 were taking 2 drugs for their epilepsy (9 carbamazepine, 5 phenytoin, 6 sodium valproate, 2 phenobarbitone, 2 primidone). All attended the Epilepsy Clinic at

the Western Infirmary in Glasgow and gave written informed consent to their participation in the study which was approved by the local ethics committee. Protocol

The trial was conducted as a balanced, placebocontrolled, crossover study preceded by a 4-week run-in period and with 4-week wash-out intervals after each treatment phase, both of which lasted 12 weeks. Patients took nimodipine tablets 30 mg tds (at 08:OOh, 15:OOh and 23:00 h) for 4 weeks, 60 mg tds for the next 4 weeks and 90 mg tds for a final 4 weeks or matched placebo in a similar fashion. During the washout period, the dose was reduced to 60 mg tds for 1 week followed by 30 mg tds for a further week before being stopped altogether. Twelve patients received placebo and 10 were given the active drugs in the first treatment phase. Previous anticonvulsant therapy was continued unchanged throughout the study. Patients attended for baseline assessment and then after 4, 8, 12, 16, 20, 24, 28 and 32 weeks of the trial. At each hospital visit, they were supplied with a seizure chart - a grid with 2-h segments which they used for recording each individual ictal event during the subsequent 4 weeks. Patients also completed a ‘tolerability profile’ consisting of 10 visual analogue scales of 10 cm length citing specific symptoms associated with nimodipine administration (e.g., flushing, headache), possible side-effects from concomitant AEDs (e.g., sedation, double vision) or unassociated ‘dummy’ symptoms (e.g., itching). Erect and supine pulse and blood pressure were measured at 09:OO h, 12:00 h and 16:00 h on each occasion. Drug compliance was checked by a tablet count. Haematological and biochemical parameters were also obtained at each hospital visit. Drug assays

Blood was withdrawn monthly from an antecubital vein for nimodipine assay at 09:OOh (‘peak’), 15:00 h (‘trough’) and 16:00 h (‘peak’) and also for measurement of other AEDs at 09:OOh and 16:00 h. Samples were centrifuged immediately under sodium light and the plasma stored in black plastic bags at -20 “C until batch analysis. Nimodipine

73 was extracted from plasma at high pIi into toluene and quantified by means of capillary gas chromatography with electron capture detection using nifedipine as internal standard. To prevent photodegradation of nimodipine, all handling of samples was carried out under ultra-violet free ‘golden light’. The mean 95% confidence interval was + 9.5% with a lower limit of detection for nimodipine of 0.5 ng ml-‘. Blood for antiepileptic drug concentrations was centrifuged at the same time and the plasma was also stored at -20 “C for batch analysis. Carbamazepine, phenytoin and sodium valproate concentrations were assayed by enzyme immunoassay (Emit, Syva, Palo Alto).

MWAN SEIZUNE DAYS

12

9

3

~ 0

1st menfh

3om9 tdr

Statistics Comparisons of seizure frequency between the nimodipine and placebo treatment phases were performed using Wilcoxon rank-pair testing for non-par~et~~ data. Calculations (revised to allow for withdrawals) suggested a power of >0.99 to pick up a fall of 50% in partial seizures, total seizures or seizure days in this group of patients. Power to detect a 25% improvement was 0.79, 0.85 and 0.75 respectively. A 50% or 25% fall in CTCS had power calculations of 0.54 and 0.18.

Indmmth 69m9 MS

3rdmonth

Total

99m9 MS

Fig. 2. Median seizure days in 17 patients with refractory epilepsy receiving adjuvant nimodipine and matched placebo for 12 weeks.

RESULTS Seventeen patients completed the study satisfactorily. Two were withdrawn because of possible side-effects while taking the active drug (1 weight loss, 1 nausea and vomiting) and 1 patient had an intercurrent pneumonia unrelated to therapy. Two patients did not complete the study because

TABLE I

16

Median seizure frequency (range) in 17 patientswithrefractory epilepsy receiving adjuvantnimodipine and matchedplacebo

I

Patients received nimodipine 30 mg tds, 60 mg tds, 90 mg tds each for a month and matched placebo in random order.

a

Partial seizures 1st month 2nd month 3rd month Total

4

0 I

1st mmth

39m9 Ys

2ndmanlh 69m9&

lnilmnlh oonsptds

Total

Fig. 1. Median seizure numbers in 17 patients with refractory epilepsy receiving adjuvant nimodipine and matched placebo for 12 weeks.

Tonic-clonic seizures 1st month 2nd month 3rd month Total

Active

Placebo

4 (O-48) 5 (O-75) 7 (0-43) 18 (O-165)

5 (O-42) 4 (O-43) 6 (O-40) 14 (O-119)

1 (O-26) 2 (O-19) 0 (O-44) 5 (O-100)

0 (O-15) 0 (O-30) 1 (O-14) 2 (O-48)

74 TABLE II

TABLE IV

Patients achieving 25% (50%) fail in seizure numbers or seizure

Anticonvulsant

days versus baseline month following adjun~t~ve therapy with ni-

with refractory

concentrations

modipine and matched placebo

matched placebo

Patients received nimodipine 30 mg tds, 60 mg tds, 90 mg tds each for a month and matched placebo in random order.

Results are from the 3rd month of treatment with the highest nimodipine dose (90 mg tds)

--.-l-Partial

Tonic-

Seizure

seizures

clonic

days

seizures

1st month

2nd month

3rd month

Total

active placebo

10 (6) 7 (6)

4 (4)

9 (6)

3 (3)

7 (4)

active placebo

6 (6) 8 (5)

40) 4 (31

5 (2) 6 (2)

active placebo

10 (7) 8 (4)

4 (2)

active placebo

9 (7) 6 (5)

5 (1)

7 (31

4 (1)

7 (2)

4(l)

7 (21 6 (1)

of inadequate compliance, one with drug therapy and the other with seizure documentation. Total median seizure numbers and days are shown in Figs. 1 and 2. Median numbers of GTCS and partial seizures are listed in Table I. The numbers of patients achieving a 50% or 25% drop in

TABLE III Mean tolerability scores during baseline and high dose therapy with nimod~pine (90 mg tds) and matched placebo

Values were computed on a scale from 1.0 to 10.0. Higher numbers support the presence of the side-effect. Side e#ect

Baseline

Active

Placebo

Sedation Poor concentration Nausea Headache Itching Agitation Unsteadiness Flushing Palpitations Double vision

6.0 6.7 1.9 3.3 2.1 3.3 2.3 1.6 1.9 2.9

5.8

4.9 6.8 2.3 5.5 3.1 3.8 3.1 2.9 1.9 1.6

5.6 1.8 3.7 1.7 3.0 3.2 1.7 1.7 3.0 _____-

~_______

Carbamazepine Phenytoin Sodium valproate

(mean It S. D.) in 17 patients

epilepsy receiving

adjuvant nimodip~ne and

._.. - _-----

n

Nimodipine

Placebo

13 7 4

10.6 * 3.6 21.9 f 8.5 71.1 * 35

9.2 t 39 19.3 i 8.9 61.6f28

_- .“.

GTCS, partial seizures or seizure days on both preparations is shown in Table II. There were no differences documented between nimodipine and placebo for any of these parameters. Patient preference was ascertained before the coding was broken. Nine chose nimodipine, 3 preferred placebo and 5 expressed no preference. These differences were not statistically significant (P = 0.073, binomial test). Haematological and biochemical indices were unchanged on nimodipine therapy and ‘tolerability scores’ did not differ from placebo for any of the potential side-effects explored (Table III). Mean systolic blood pressures were slightly lower at peak nimodipine concentrations (09:OOh, 16:00 h) than at similar times on placebo (mean difference = 3 mmHg) or at baseline (mean 5-7 mmHg) with the highest nimodipine dose, but these differences were not statistically significant. There was no evidence of postural hypotension and heart rate was unaltered by either treatment. Mean concentrations of concomitant AEDs are shown in Table IV. Although all 3 drugs exhibited slightly higher concentrations while patients were taking nimodipine, no statistically significant differences were found. Nimodipine concentrations were generally low throughout the study. Afternoon mean peak (2 S.D.) concentrations on 60 mg tds were 6.8 rt 3.0,&l (n = 17, range 2.6-13.9 ,&l) while those at 90 mg tds were only marginally higher at 7.8 + 2.0 ,~@l (range 4.8-11.5 pg/l). There were no significant correlations between nimodipine concentrations and changes in seizure control.

75 DISCUSSION Calcium antagonists with a dihydropyridine structure are effective in ameliorating seizure activity in a wide variety of animal models of epilepsy 14-*’ and nimodipine has been prominent in many of these studies. In the present placebo-controlled trial, however, it did not reduce seizure frequency when used as adjunctive therapy in patients with refractory epilepsy. The power of the study, even allowing for withdrawals, was such that we would have expected to detect an important anticonvulsant effect. There are several possible reasons for the disparity between the impressive results in seizure models and this disappointing clinical trial. Firstly, the models may be flawed or inappropriate. Secondly, the dose regimen of nimodipine may be incorrect. Thirdly, there may be an interaction between nimodipine and concomitant anticonvulsant medication. Lastly, the anticonvulsant effect of the drug may be insufficient to make a clinical impact as adjuvant therapy in severely affected patients with refractory epilepsy. With regard to the first possibility, nimodipine has been effective in a wide range of seizure models. These include chemically induced seizures with pentylenetetrazol’5917,19942, cefazolin14, picrotoxin43, kainic acid44 and strychnine’*, in addition to electro-shock seizures*’ and audiogenic seizures in DBA/2 mice16. These models have proved valuable in investigating anticonvulsant activity with other drugs45 and it seems unlikely that they are so inappropriate as to explain nimodipine’s failure in this trial. The pharmacokinetic profile of nimodipine provides a more likely explanation. Its elimination half-life in healthy subjects is around 2 he. Although it has been used 4-hourly in the successful short-term treatment of subarachnoid haemorrhage38,39, such a schedule would not be suitable for chronic administration to a group of patients in whom compliance is notoriously poor47. Daily dosage of 40 mg tcis has been used following ischaemic stroke@ despite evidence of low concentrationsa. However, a recent study disputes its efficacy at this relatively low dose49. In the present trial, an attempt was made to overcome the rapid elimi-

nation of nimodipine by increasing the dose to the uppermost range used in previous trials. However, this manoeuvre seems not to have achieved its objective in that circulating nimodipine concentrations remained low. All patients were taking enzyme-inducing antiepileptic drugs. Since nimodipine undergoes hepatic metabolism with a large first-pass effect”, enzyme induction can be expected to reduce its bioavailability in a fashion similar to that reported with another dihydropyridine, felodipine5’. Patients with subarachnoid haemorrhage given intravenous infusions of nimodipine tended to run serum concentrations between 36-72 ,~g/l~, while oral dosing (60 mg tds) gave peak levels around 17-42pg/l in the same study. Our patients failed to achieve such levels with maximum concentrations being measured around 12 ,@l. No correlation was obtained between nimodipine concentration and seizure control, as we have found previously with nifedipine36. As well as the pharmacokinetic effects of enzyme induction with other AEDs, a pharmacokinetic interaction also remains a possibility. Phenytoin51,52and carbamazepine52T53 both have calcium antagonist actions, and a detrimental interaction - again perhaps receptor-mediated - cannot be excluded. In a PTZ model in mice, we found that nifedipine and carbamazepine were effective separately but not in combination”, although an additive anticonvulsant effect of these drugs against maximal electroshock seizures has also been reported54. The final possibility is a problem which assails all new anti-epileptic drugs. Studies in patients with refractory epilepsy receiving a number of established anticonvulsants at high dosage are invariably undertaken with each potential new agent as a first step in its assessment. It is possible that a drug with genuine anticonvulsant activity might fail to impress in this situation. In summary, this trial did not support nimodipine as a useful adjuvant anticonvulsant. Failure to attain effective circulating concentrations appears the most likely explanation. Further dosage increases may improve its efficacy, but there are obvious drawbacks with a drug which has a low bioavailability and short elimination half-life in en-

76 zyme-induced epileptic patients. A controlled-release formulation is a more attractive option. It seems likely, however, that a calcium antagonist with a suitable pharmacokinetic profile will be found to capitalise on the undoubted antiepileptic properties of this group of drugs. Newcomers with longer half-lives and no first-pass metabolism, such as amlodipine, may prove of value as adju-

vant antiepileptic drugs.

REFERENCES

13 De Sarro, G.B., Nistico, G. and Meldrum, B.S., Anticonvulsant properties of flunarizine on reflex and generalised models of epilepsy, Neuropharmacology, 25 (1986)

1 Meyer, F.B., Calcium, neuronal hyperexcitability and ischemit injury, Brain Res. Rev., 14 (1989) 227-243. 2 MacDonald, R.L. and McLean, M.J., Anticonvulsant drugs: mechanisms of action, Adv. Neurol., 44 (1986) 713-736. 3 Goldensohn,

ES. and Purpura, D.P., Intracellular potentials of cortical neurons during focal epileptogenic discharges, Science, 139 (1963) 840-842. 4 Katz, B. and Miledi, R., Spontaneous and evoked activity of motor nerve endings in calcium ringer, J. Physiol., 203 (1969) 689-706. 5 Zucker, R.S. and Lando, I., Mechanism of transmitter re-

lease: voltage hypothesis and calcium hypothesis, Science, 231(1986) 574-579. 6 Wong, R.K.S. and Prince, D.A., Dendritic mechanisms underlying penicillin-induced epileptiform activity, Science, 204 (1979) 1228-1231. 7 Bingmann, D. and Speckmann, E.J., Specific suppression of pentylenetetrazol-induced epileptiform discharges in CA3 neurons (hippocampal slice, guinea pig) by the organic calcium antagonists flunarizine and verapamil, Exp. Bruin Res., 76 (1989) 239-248.

ACKNOWLEDGEMENTS Our thanks go to Mrs Moya Dewar for secretarial assistance and to Bayer U.K. Limited for financial support.

695-701. 14 Morocutti,

C., Pierelli, F., Sanarelli, E., Stefano, E., Peppe, A. and Mattioli, G.L., Antiepileptic effects of a calcium antagonist (nimodipine) on cefazolin-induced epileptogenic foci in rabbits, Epilepsia, 27 (1986) 498-503. 15 Meyer, F.B., Anderson, R.E., Sundt Jr., T.M., Yaksh, T.L. and Sharbrough, F.W., Suppression of pentylenetetrazol seizures by oral administration of a dihydropyridine Ca*+ antagonist, Epilepsia, 28 (1987) 409-414. 16 De Sarro, G.B., Meldrum, B.S. and Nistico, G., Anticonvulsant effect of some calcium entry blockers in DBA/2 mice, Br. J. Pharmacol., 93 (1988) 247-256. 17 Dolin, S.J., Hunter, A.B., Halsey, M.J. and Little, H.J., Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine, Eur. J. Pharmacol.,

activity of MK-801 and nimodipine alone and in combination against pentylenetetrazol and strychnine, Pharmacol. Biochem.

Behav., 32 (1989) 595-600. 19 Larkin, J.G., Thompson, G.G. and Brodie, M.J., Nifedi-

8 Witte, O.W.,

Speckmann, E.-J. and Walden, J., Motor cortical epileptic foci in vivo: actions of a calcium channel blocker on paroxysmal neuronal depolarisations, Electro-

encephalogr.

Clin. Neurophysiol.,

66 (1987) 43-55.

20

9 Speckmann,

E.-J., Witte, O.W. and Walden, J., Involvement of calcium ions in focal epileptic activity of the neocortex. In: U. Heinemann, M. Klee, E. Neker and W. Singer (Eds.), Calcium Electrogenesti and Neuronal Functioning, Experimental Brain Research Series 14, Springer, Berlin, 1986, pp. 386-395. 10 Walden, J., Pockberger, H., Speckmann, E.-J. and Petsche, H., Paroxysmal neuronal depolarisations in the rat motor cortex in vivo: intracellular injection of the calcium agonist Bay K8644, Exp. Brain Res., 64 (1986) 607-609. 11 Desmedt, L.K.C., Niemergeers, G.J.E. and Janssen, P.A.J., Anticonvulsive properties of cinnarizine and flunarizine in rats and mice, Arzneimitt. Forsch., 25 (1975) 1408-1413. 12 Ashton, D. and Wauquier, A., Behavioral analysis of the

effects of 15 anticonvulsants in the amygdaloid kindled rat, Psychopharmacology,

65 (1979) 7-13.

152 (1988) 19-27.

18 O’Neill, S.K. and Bolger, G.T., Anticonvulsant

21

22

23

24

pine and nimodipine are effective against pentylenetetrazol-induced seizures in mice, Brit. J. Pharmacol., 96 (1989) 138~ (Abstr.). Meyer, F.B., Anderson, R.E. and Sundt Jr., T.M., Anticonvulsant effects of dihydropyridine Ca*+ antagonists in electrocortical shock seizures, Epilepsia, 31 (1990) 68-74. Wong, W.-S. and Rahwan, R.G., Examination of the potential antiepileptic activity of calcium antagonists with different sites of action, Gen. Pharmacol., 20 (1989) 309-312. Overweg, J., Binnie, C.D., Meijer, J. W.A., Meinardi, H., Nuijten, S.T.M., Schmalz, S. and Wauquier, A., Doubleblind placebo-controlled trial of flunarizine as add-on therapy in epilepsy, Epilepsia, 25 (1984) 217-222. Ovesweg, J., Ashton, D., De Beukelaar, F., Binnie, C.D. and Wauquier, A., Add-on therapy in epilepsy with calcium entry blockers, Eur. Neural., 25 Suppl. 1, (1986) 93-101. Binnie, C.D., De Beukelaar, F., Meijer, J.W.A., Meinardi, H., Overweg, J., Wauquier, A. and Van Wieringen, A., Open dose-ranging trial of flunarizine -an add-on therapy in epilepsy, Epilepsia, 26 (1985) 424-428.

77 25 Starreveld, E., De Beukelaar, F., Wilson, A.F., McLean, D.R. and Findlay, H.P., Double-blind crossover placebocontrolled study of flunarizine in patients with therapy resistant epilepsy, Can. J. Neural. Sci., 16 (1989) 187-190. 26 Keene, D., Whiting, S., Humphreys, P. and Jacob, P., Flunarizine as a supplementary medication in refractory childhood epilepsy: a double-blind crossover study, Can. .I. Neurol. Sci., 16 (1989) 191-193. 27 Nakane, Y., Seino, M., Yagi, K., Kaji, S. and Yamauchi, T., Effects of flunarizine therapy on intractable epilepsy, Arzneimitt. Forsch.lDrug Res., 39 (1989) 793-798. 28 Alving, J., Kristensen, O., Tsiropoulos, I. and Mondrup,

K., Double-blind placebo-controlled evaluation of flunarizine as adjunctive therapy in epilepsy with complex partial seizures, Acta. Neural. Scund., 79 (1989) 128-132. 29 Chouza, C., Caamano, J.L., Aljanati, R., Scaramelli, A., De Medina, 0. and Romero, S., Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine, Lancet, i (1986) 1303-1304. 30 Micheli, F., Pardal, M.F., Gatto, M., Torres, M., Paradiso, G., Parera, I.C. and Giannaula, R., Flunarizine- and cinnarizine-induced extrapyramidal reactions, Neurology, 37 (1987) 881-884. 31 Binnie, C.D., Flunarizine

32

33

34

35

36

37

and other calcium entry blockers. In: R. Levy, R. Mattson, B. Meldrum, J.K. Penry and F.E. Dreifuss (Eds.), Antiepileptic Drugs, Raven Press, New York, 1989, pp. 971-982. Willow, M. and Catterall, W.A., Inhibition of binding of [3H]batrachotoxin in A-20-a-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine, Mol. Pharmacol., 22 (1982) 627-635. Brandt, L., Saveland, H., Ljunggren, B. and Andersson, K.-E., Control of epilepsy partialis continuans with intravenous nimodipine, J. Neurosurg., 69 (1988) 949-950. Larkin, J.G., Butler, E. and Brodie, M.J., Nifedipine for epilepsy? A pilot study, Br. Med. J., 296 (1988) 530-531. Sander, J.W.A.S. and Trevisol-Bittencourt, P.C., Nifedipine as an add-on drug in the management of refractory epilepsy, Epilepsy Res., 6 (1990) 82-84. Larkin, J.G., Besag, F.M.C., Cox, A. Williams, J. and Brodie, M.J., Nifedipine for epilepsy? A double-blind, placebo-controlled trial, Epilepsia, in press. Cauvin, C., Loutzenhiser, R. and Van Breeman, C., Mechanisms of calcium antagonist-induced vasodilatation,

Annu. Rev. Pharmacol.

trial, Br. Med. J., 298 (1989) 636-642. 40 Paci, A., Ottaviano, P., Trenta, A., Iannone, G., De San-

tis, L., Lancia, G. et al., Nimodipine in acute ischaemic stroke: a double-blind controlled study, Acta Neural. &and.,

J.H., Hickey, W.F. and Reivich, M., Nimodipine attenuates both increase in cytotoxic free calcium and histologic damage following cerebral ischaemia and reperfusion in cats, Stroke, 20 (1989) 1531-1537. 42 Moron, M.A., Stevens, C.W. and Yaksh, T.L., Diltiazem enhances and flunarizine inhibits nimodipine’s anti-seizure effects, Eur. J. Pharmacol., 163 (1989) 299-307. 43 Thomas, J., The effect of nimodipine on picrotoxin-induced seizures, Brain Res. Bull., 24 (1990) 11-15. 44 Paczynski, R.P., Meyer, F.B. and Anderson, R.E., Effects of the dihydropyridine Ca ‘+ channel antagonist nimodipine on kainic acid-induced limbic seizures, Epilepsy Res., 6 (1990) 33-38. 45 Loscher, W. and Schmidt, D., Which animal models should

be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations, Epilepsy Res., 2 (1988) 145-181. 46 Ramsch, K.-D., Graefe, K.H., Scherling, D., Sommer, J.

and Ziegler, R., Pharmacokinetics and metabolism of calcium-blocking agents nifedipine, nitrendipine and nimodipine, Am. J. Neural., Suppl. l(l986) 73-80. 47 Cramer, J.A., Mattson, R.H., Prevey, M.L., Scheyer, R.D. and Ovellette, V.L., How often is medication taken as prescribed? A novel assessment technique, JAMA, 261 (1989) 3273-3277. 48 Ramsch, K.-D., Ahr, G., Tettenborn, D. and Auer, L.M., Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid haemorrhage, Neurochirurgia, 28 (1985) 74-78. 49 Murphy, J.T., Randomised double-blind,

placebo-controlled trial of nimodipine in acute stroke, Lancer, 36 (1990) 1205-1209.

50 Capewell, S., Freestone,

51 52

Toxicol., 23 (1983) 373-396.

38 Allen, G.S., Ahn, H.S., Preziosi, T.J., Battye, R., Boone,

S.C., Chou, S.N. et al., Cerebral arterial spasm - a controlled trial of nimodipine in patients with subarachnoid haemorrhage, N. Engl. J. Med., 308 (1983) 619-624. 39 Pickard, J.D., Murray, G.D., Illingworth, R., Shaw, M.D.M., Teasdale, G.M., Foy, P.M. et al., Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine

80 (1989) 282-286.

41 Uematsu, D., Greenberg,

53

54

S., Critchley, J.A.J.H., Pottage, A. and Prescott, L.F., Reduced felodipine bioavailability in patients taking anticonvulsants, Lnncet, ii (1988) 480-482. Sohn, R.S. and Ferrendelli, J.A., Anticonvulsant drug mechanisms, Arch. Neural., 33 (1976) 626-629. Ferrendelli, J.A. and Daniels-McQueen, S., Comparative actions of phenytoin and other anticonvulsants on potassium- and veratridine-stimulated calcium uptake in synaptosomes, J. Pharmacol. Exp. Ther., 220 (1982) 29-34. Crowder, J.M. and Bradford, H.F., Common anticonvulsants inhibit Ca*+ uptake and amino acid neurotransmitter release in vitro, Epilepsia, 28 (1987) 378-382. Czuczwar, S.J., Chodkowska, A., Kleinrok, Z., Malek, U. and Jagiello-Wojtowicz, E., Effects of calcium channel inhibitors upon the efficacy of common antiepileptic drugs, Eur. J. Pharmacol.,

176 (1990) 75-83.