Nimodipine as an Add-On Therapy for Intractable Epilepsy

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Nimodipine as an Add-On Therapy for Intractable Epilepsy FREDRIC

B. MEYER, M.D., GREGORY D. CASCINO, M.D., JACK P. WHISNANT, M.D., A. GORMAN, R.N.,

FRANK W. SHARBROUGH, M.D., ROBERT J. IVNIK, PH.D., DEBORAH WANDA

L. WINDSCHITL, R.N., ELSON L. SO, M.D., AND W. MICHAEL O'FALLON, PH.D.

• Objective: To analyze the effect of nimodipine in patients with intractable epilepsy. • Design: We conducted a double-blind placebocontrolled crossover study in 95 patients. • Material and Methods: The dihydropyridine calcium antagonist nimodipine was used as add-on therapy (60 mg four times a day) in a I-year placebocontrolled crossover study in 71 patients with localization-related epilepsy and 24 with generalized seizure disorders. Of the 95 patients, 81 were receiving two or more antiepileptic drugs. Patient diaries were used to record the number of seizures and any side effects. • Results: Nimodipine seemed to be well tolerated during the study; only two patients were unable to complete the study because of probable adverse effects. The trial demonstrated no significant crossover

An interest has existed in examining the potential antiepileptic effects of calcium antagonists that penetrate the blood-brain barrier and have the theoretical advantage of For accompanying editorial, see page 715 altering neuronal function. Several lines of evidence indicate that calcium is critical for the seizure discharge. The electroencephalographic (EEG) interictal epileptiform discharge is a large extracellular field potential that is associated with paroxysmal depolarizing shifts in neuronal membrane potentials that trigger action potentials.P Paroxysmal depolarizing shifts require disinhibition of a subpopulation of neurons with intrinsic burst-generating potential. Intrinsic bursting has been demonstrated to be related to calcium fluxes across the neuronal membrane. 1,3-12 Extracellular calFrom the Department of Neurologic Surgery (F.B.M., D.A.G., W.L.W.), Department of Neurology (G.D.C., J.P.W., F.W.S., E.L.S.), Department of Health Sciences Research (J.P.W., W.M.O.), and Department of Psychiatry and Psychology (RJ.I.), Mayo Clinic Rochester, Rochester, Minnesota. This study was supported in part by Grant NS 26301 ROI from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. F. B. Meyer, Department of Neurologic Surgery, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo CUn Proc 1995; 70:623-627

effect and no significanteffect of nimodipine on either the mean or the median number of seizures or seizure days. The peak median serum nimodipine level was less than 5 ng/mL in the 78 patients who completed the study. • Conclusion: This clinical trial found no beneficial effect with use of nimodipine as add-on therapy for intractable epilepsy. Potential reasons for the absence of efficacy of nimodipine may be the inclusion of patients with very refractory seizure disorders or the relatively low serum nimodipine concentrations related to the pharmacokinetic effect of concurrent antiepileptic medication. (Mayo Clin Proc 1995; 70:623-627) AEDs =antiepileptic drugs; EEG

=electroencephalographic

cium also decreases while intracellular free calcium increases during seizure activity.Pi'" The mechanism of selected antiepileptic drugs (AEDs) may include an effect on calcium channels. At high concentrations, phenytoin interferes with both membrane calcium channels and synaptosomal calcium uptake, whereas barbiturates block both neuronal L and N calcium channels.v-" Benzodiazepines, carbamazepine, and phenytoin inhibit protein phosphorylation stimulated by calcium-calmodulin in the presynaptic terminal, an action that may attenuate synaptic-mediated synchronization of a subpopulation of discharging neurons. 17 Brain slice preparations and in vivo studies have demonstrated a flux of calcium into CA3 and CAl neurons during the period of hyperexcitability. 18,19 Antagonists to the N-methyl-D-aspartate receptor are potent AEDs by decreasing calcium influx through this receptoroperated calcium channel. Finally, calcium antagonists, including flunarizine hydrochloride, verapamil hydrochloride, and nimodipine, have been shown to be potential anticonvulsants in several experimental studies.P" The therapeutic efficacy of the calcium antagonists nimodipine, flunarizine, and nifedipine has previously been studied. The dihydropyridine calcium antagonist nifedipine significantly decreased seizures in one study" but not in a 623

© 1995 Mayo Foundation for Medical Education and Research

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NIMODIPINE IN INTRACfABLE EPILEPSY

second trial." A more current placebo-controlled trial provided some indication of a dose-response effect of nifedipine, albeit with relatively low efficacy. " Several studies have examined the antiepileptic effect of flunarizine in intractable epilepsy .P?' Overall, the results have been mixed-one trial demonstrated an effect, whereas another was unable to confirm this response. 28.35.37 One difficulty with flunarizine is its complex mechanism of action, including possible antagonism of both sodium and calcium channels." Clinically, flunarizine may produce extrapyramidal side effects and sedation.P-" The 1,4-dihydropyridine calcium antagonist nimodipine has been demonstrated to decrease the morbidity and mortality associated with subarachnoid hemorrhage.v -? The mechanism of action is not well defined; the effect of nimodipine on the cerebral vasculature has not been demonstrated by transcranial Doppler examination, cerebral blood flow studies, or angiography. As a result, investigators have proposed that the neuroprotective effect of nimodipine in subarachnoid hemorrhage may be due to a direct neuronal as opposed to a vascular effect. A direct neuronal effect of nimodipine is also supported by experimental studies that have demonstrated that this calcium antagonist decreases experimental seizures induced by bicuculline , pentylenetetrazole, electroconvulsive shock , and cefazolin. 21.23-27 On the basis of these experimental data, several trials have examined the effects of nimodipine in intractable epilepsy. The first, conducted by Larkin and colleagues," enrolled 22 patients with refractory epilepsy into a double-blind placebo-controlled crossover study. This 12-week study demonstrated no benefit with nimodipine. Alternatively, a more recent study of 21 patients reported a reduction in seizures." One anecdotal report indicated that nimodipine was successful in controlling medically refractory epilepsia partialis continua in two patients." The purpose of the current study was to analyze the safety and efficacy of nimodipine in a large placebo-controlled double-blind crossover study in patients with intractable epilepsy.

SUBJECTS AND METHODS Patient Population.-For the 95 patients (53 women and 42 men) entered into this study, the mean age was 30 years (range, 18 to 46). All patients had seizures that were refractory to maximally tolerated AED therapy and had experienced at least three seizures per month for a minimal duration of 2 years. In two patients , prior surgical treatment of epilepsy had failed. The median duration of seizure activity was 21 years (range, 2 to 41). The mean number of seizures was 33 per month (median, 8). The mean number of seizure days was 12 per month (median , 6). Of the 95 study patients, 33 (35%) were mentally retarded .

Mayo Clio Proc, July 1995, Vol 70

The seizure disorders in these 95 patients were classified by the ictal semiology and extracranial interictal or ictal (or both) epileptiform alterations. Seventy-one patients (75%) had localizat ion-related epilepsy, and 24 (25%) had generalized seizure disorders . The epileptogenic zone in patients with partial epilepsy was restricted to the temporal lobe in 54 patients (57%) and was extratemporal in 17 (18%). Most of the patients with generalized seizures had symptomatic generalized epilepsy associated with developmental delay. At the time of enrollment into the study, 81 patients were receiving more than one AED-two medications in 57 patients and three or more in 24 patients-and 14 patients were receiving monotherapy. Presumably , the use of multiple drugs in these patients reflected the previously documented lack of response to medication. At the time of entry into the study, 39 patients (41%) were employed,42 (44%) were currently not working because of their seizures but had been employed previously, and 14 (15%) had never worked . Study Design.-The study was a double-blind placebocontrolled crossover design. At baseline, the patients were randomized into two groups, A and B. Patients in group A were first treated for 6 months with nimodipine and then for 6 months with placebo. Patients in group B were first treated for 6 months with placebo followed by 6 months with nimodipine. No "washout" period was scheduled between the two study medications . Nimodipine or placebo was added to the current antiepileptic regimen for each patient. Every 3 months during the study, the patients underwent assessment by the principal investigator (F.B.M.) and a neurologist with a subspecialty expertise in epilepsy. During all visits, the patients underwent a neurologic examination, a general medical examination, and measurement of AED levels (including nimodipine). Testing at baseline and during the 6-month and 12-month appointments also included a serum chemistry group and an EEG. Before enrollment in the study, all patient s had a computed tomographic scan of the head. None of the patients enrolled in the study had evidence of a "progres sive" lesion (such as cerebral neoplasm). Each patient was given a diary for recording the number of seizures and any side effects . At each 3-month appointment, the diary was examined, and both the number of seizures and the number of days with seizures (seizure days) were counted and recorded . At the 6-month crossover, the patient was given a new diary for that period of treatment. Compliance was verified by counting the number of tablets at each visit. The investigators were blinded to the results of the nimodipine serum concentrations. Baseline variables assessed included gender, age, seizure type, seizure frequency, seizure days, interictal EEG, AEDs, blood pressure, weight , hemoglobin, serum alkaline phos-

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NIMODIPINE IN INTRACTABLE EPILEPSY

Mayo Clio Proc, July 1995, Vol 70

phatase, aspartate aminotransferase, bilirubin, creatinine , and urea. Drug Dosage.-Nimodipine was administered in a dosage of 60 mg four times per day. The placebo and the nimodipine tablets were physically identical. The concurrent AED remained unaltered during the study. Nimodipine serum levels were determined 1 hour before the next scheduled dose (trough) and 1,2, and 3 hours after administration of a dose. The blood specimens were processed and forwarded to Miles Laboratories, West Haven, Connecticut, for a blinded analysis. The serum measurements were accurate to 0.1 ng/mL. StatisticalAnalysis.-The two groups of randomized patients were compared relative to all baseline variables to determine whether differences existed in those measurements between the two treatment groups. The results of treatment were assessed by using measurements at baseline, at 6 months, and at 12 months. The response variables considered were the number of seizures and the number of seizure days. With the two 6-month periods in the crossover design of the study, we considered the possibility of two types of effect: (1) the effect of the order of treatment on measurements-that is, the crossover effect-and (2) the effect of treatment with the active drug, nimodipine, in comparison with treatment with placebo-that is, the treatment effect. The crossover effect was assessed by an analysis of the sum of the values at 6 months and at 12 months in the patients who completed this study. Analyses of the differences between the 6-month and the 12-month values were used to compare results with nimodipine and placebo. Multiple linear regression analyses were performed to determine whether any of the many variables measured served as significant covariables or effect modifiers .

RESULTS Of the 95 patients , 78 completed the l-year study, and 17 were unable to complete the study for the following reasons: medication noncompliance (N = 8), an alteration in concurrent AED medication (N = 3), an acute psychosis (N = 2), an increased serum amylase level (N = 1), transient pedal edema (N = 1), preference to pursue surgical treatment (N = 1), and serious injuries associated with a motor vehicle accident (N = 1). Only the altered serum amylase value and the pedal edema were considered likely to be related to nimodipine therapy. Assessment of the baseline variables showed no significant differences between patients randomized to group A (N = 47) and those randomized to group B (N = 48). In addition, no significant differences in baseline variables were noted between the patients in group A (N =37) and those in group B (N = 41) who completed the full year of the trial.

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Detection of no crossover effect was shown by the sums of the seizure frequencies (P =0.48) and seizure days (P = 0.51) at 6 months and at 12 months in the two groups. The absence of a difference was shown by the two-sample rank test applied to the sums of the medians and by using the t test applied to the sums of the means (Table 1). The effect of nimodipine was determined by comparing the differences in seizure frequency and seizure days in the two study groups at 6 months and at 12 months. No significant differences were found in either seizure frequency (P = 0.42) or seizure days (P = 0.66) with use of the rank test for comparing the median difference or with use of the t test for comparing the means (Table 2). Covariables were assessed relative to their effect on the 6month minus the 12-month difference in seizure frequency and seizure days and on the corresponding differences in the logarithms. Independent covariables assessed were age, sex, seizure type, EEG abnormality , abnormal behavior, duration of seizures, and AED medication. The best multivariable linear regression model for seizure frequency included only the variables partial seizures and use of clonazepam . When treatment with nimodipine was added to this model, no significant effect was noted (P = 0.36). The best multivariable model for seizure days included the use of clonazepam and primidone. When treatment with nimodipine was added to this model, no significant effect was observed (P =0.996). Five patients in group A and lOin group B were taking clonazepam; 11 patients in group A and 7 in group B were taking primidone. These differences were not significant. The mean maximal serum nimodipine level for those persons who received the drug during the first 6 months was 6.4 ng/mL, and the mean trough level was 1.1 ng/mL. The median maximal serum level during the first 6 months was 4.9 ng/mL. During the second 6 months, the mean maximal level was 7.0 ng/mL, and the mean trough level was 1.1 ng/ mL. The median maximal serum level during the second 6 Table I.-Comparison of Two Treatment Groups" of Patients With Intractable Epilepsy for Crossover Effect Variablet Seizure frequency Group A Group B Seizure days Group A Group B

Rank test Median P

t test Mean P

13 15

0.4802

67.5 45.2

0.5925

9

0.5114

15.1 17.0

0.6062

11

*Group A = nimodipine followed by placebo; group B = placebo followed by nimodipine. tSums of variables (first 6 months plus second 6 months-see text).

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NIMODIPINE IN INTRACTABLE EPILEPSY

Table 2.-Comparison of Two Treatment Groups* of Patients With Intractable Epilepsy for Effect of Nimodipine Variablet Seizurefrequency Group A Group B Seizuredays Group A Group B

Rank test Median P 1

2

0 1

t test

Mean

P

0.4154

-5.4 -2.4

0.7189

0.6593

0.54 0.27

0.7417

*Group A = nimodipine followed by placebo; group B = placebo followedby nimodipine. tDifferences of variables(first 6 monthsminus second6 monthssee text). months was 4.3 ng/mL. Only three patients who received the drug throughout the trial had maximal serum levels that exceeded 20 ng/mL. DISCUSSION In the current study, we were unable to confirm the putative beneficial effect of the dihydropyridine calcium antagonist nimodipine as an AED despite the previous experimental evidence. The results of this clinical trial do not support the use of nimodipine at the dosage administered in this trial as an add-on therapy in patients with intractable epilepsy. Our results confirm those published by Larkin and coworkers," who also failed to demonstrate a beneficial effect of nimodipine in a smaller group of patients with intractable epilepsy. The conflicting data about the therapeutic efficacy of nimodipine as an AED merit further consideration.v-" One possible explanation is that the group of patients entered into the current trial had pharmacoresistant seizure disorders that were unlikely to respond to medical treatment. The severity of the seizure disorders in these patients is best evidenced by the mean number of seizures at the time of enrollment in the study (33 per month). In addition, approximately a third of the patients in the current study were mentally retarded. Another possibility is that the dosage and pharmacokinetics of nimodipine contributed to the failure of the drug in this study. At the commencement of this trial, a dosage of 60 mg four times per day was chosen on the basis of 15 published studies in which nimodipine had been used to treat subarachnoid hemorrhage, dementia, headache, and ischemic stroke. 41,46-48 In one subarachnoid hemorrhage trial in which nimodipine was administered at 30 mg four times per day, cerebrospinal fluid concentrations in six patients were 0.77 ± 0.34 ug/ml. in comparison with plasma levels of 6.9 ± 4.9 Ilg/mL.41 In a second study, nimodipine administered in a dosage of 60 mg three times per day resulted in a peak serum level of 17 to 42 Ilg/mL.49 In our study, however, the peak

median nimodipine levels were considerably lower. AEDs that induce hepatic enzymes may affect nimodipine metabolism." Nimodipine is primarily metabolized in the liver with a large first-pass effect." This fact might explain why a similar dose of nimodipine in this study yielded a serum level far below that reported with similar doses in patients with subarachnoid hemorrhage. The potential use of calcium antagonists as AEDs will depend on the development of centrally active calcium antagonists with a longer half-life and less first-pass hepatic metabolism. Subsequent studies will be necessary to evaluate the efficacy and safety of nimodipine at higher serum concentrations in patients with intractable seizures. ACKNOWLEDGMENT We are indebted to Mary M. Soper for excellent secretarial assistance.

REFERENCES 1. Johnston D, Brown TH. Mechanisms of neuronal burst generation. In: Schwartzkroin PA, Wheal HV, editors. Electrophysiology of Epilepsy. New York: AcademicPress, 1984: 277-301 2. Matsumoto H, Marsen CA. Cortical cellular phenomena in experimental epilepsy: interictalmanifestations. Exp Neurol 1964;9:286-304 3. BrownDA, GriffithWHo Calcium-activated outwardcurrent in voltage-clamped hippocampalneurones of the guinea-pig. J Physiol 1983;337:287-301 4. Brown DA, Griffith WHo Persistent slow inward current in voltage-clamped hippocampalneurones of the guinea-pig. J Physiol 1983;337:303-320 5. Halliwell JV. Caesium-loading reveals two distinct Ca-currents in voltage-clamped guinea-pighippocampal neurons in vitro. J Physiol 1983;341:IOP-llP 6. JohnstonD, Hablitz Jl, WilsonWA. Voltageclampdiscloses slow inward current in hippocampal burst-firing neurons. Nature 1980;286:391-393 7. Owen DG, Segal M, BarkerJL. A Ca-dependent cr conductance in cultured mouse spinal neurones. Nature 1984; 311:567-570 8. Prince DA. Physiological mechanisms of focal epileptogenesis. Epilepsia 1985;26(Suppl 1):S3-S14 9. Schwartzkroin PA. Ionic and synapticdeterminants of burst generation. In: LockardJS, Ward AA Jr, editors. Epilepsy: A Window to Brain Mechanisms. New York: Raven Press, 1980: 83-95 10. WongRK, PrinceDA. Participationof calciumspikesduring intrinsic burst firing in hippocampal neurons. Brain Res 1978; 159:385-390 11. Wong RK, Prince DA, Basbaum AI. Intradendritic recordings from hippocampal neurons. Proc Nat! Acad Sci USA 1979;76:986-990 12. WongRK, TraubRD, Miles R. Epileptogenic mechanisms as revealed by studies of the hippocampal slice. In: Schwartzkroin PA, WhealHV, editors. Electrophysiology of Epilepsy. New York: AcademicPress, 1984:253-275 13. HeinemannU, Louvel J. Changesin [Ca2+]. and [K+]. during repetitive electrical stimulation and during pentetrazol in-

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14. 15. 16. 17. 18.

19.

20.

21. 22. 23. 24. 25. 26.

27.

28. 29. 30.

31. 32.

33.

duced seizure activity in the sensorimotor cortex of cats. Pflugers Arch 1983; 398:310-317 Heinemann D, Lux HD, Gutnick MJ. Extracellular free calcium and potassium during paroxysmal activity in cerebral cortex of the cat. Exp Brain Res 1977; 27:237-243 Pincus JH, Hsiao K. Calcium uptake mechanisms affected by some convulsant and anticonvulsant drugs. Brain Res 1981; 217:119-127 Pincus JH, Hsiao K. Phenytoin inhibits both synaptosomal 45Ca uptake and efflux. Exp Neurol 1981; 74:293-298 DeLorenzo RJ. Calmodulin in neurotransmitter release and synaptic function. Fed Proc 1982; 41:2265-2272 Evans MC, Griffiths T, Meldrum BS. Kainic acid seizures and the reversibility of calcium loading in vulnerable neurons in the hippocampus. Neuropathol Appl Neurobiol 1984; 10:285-302 Zanotto L, Heinemann D. Aspartate and glutamate induced reductions in extracellular free calcium and sodium concentration in area CAl of 'in vitro' hippocampal slices of rats. Neurosci Lett 1983; 35:79-84 Bingmann D, Speckmann E-J. Calcium-antagonists flunarizin and verapamil depress ictal activity in neurons of hippocampal slices [abstract]. J Neurol 1985; 232(Suppl):259 De Sarro GB, Meldrum BS, Nistico G. Anticonvulsant effects of some calcium entry blockers in DBA/2 mice. Br J Pharmacol 1988; 93:247-256 Desmedt LK, Niemegeers CJ, Janssen PA. Anticonvulsant properties of cinnarizine and flunarizine in rats and mice. Arzneimittelforschung 1975; 25:1408-1413 Dolin SJ, Little HJ. The dihydropyridine, nitredipine, prevents nitrous oxide withdrawal seizures in mice [abstract]. Br J Addict 1986; 81:708 Hoffmeister F, Benz D, Heise A, Krause HP, Neuser V. Behavioral effects of nimodipine in animals. Arzneimittelforschung 1982; 32:347-360 Meyer FB. Calcium, neuronal hyperexcitability and ischemic injury. Brain Res Brain Res Rev 1989; 14:227-243 Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW. Selective central nervous system calcium channel blockersa new Classof anticonvulsant agents. Mayo Clin Proc 1986; 61:239-247 Morocutti C, Pierelli F, Sanarelli L, Stefano E, Peppe A, Mattioli GL. Antiepileptic effects of calcium antagonist (nimodipine) on cefazolin-induced epileptogenic foci in rabbits. Epilepsia 1986; 27:498-503 Nakane Y, Seino M, Yagi K, Kaji S, Yamauchi T. Effects of flunarizine therapy on intractable epilepsy. Arzneimittelforschung 1989; 39:793-798 Larkin JG, Butler E, Brodie MJ. Nifedipine for epilepsy? A pilot study. BMJ 1988; 296:530-531 Ramsch KD, Graefe KH, Scherling D, Sommer J, Ziegler R. Pharmacokinetics and metabolism of calcium-blocking agents nifedipine, nitrendipine, and nimodipine. Am J Nephrol 1986; 6(Suppll):73-80 Larkin JG, Besag FM, Cox A, Williams J, Brodie MJ. Nifedipine for epilepsy? A double-blind, placebo-controlled trial. Epilepsia 1992; 33:346-352 Binnie CD, de Beukelaar F, Meijer JW, Meinardi H, Overweg J, Wauquier A, et al. Open dose-ranging trial of flunarizine as an add-on therapy in epilepsy. Epilepsia 1985; 26:424-428 Overweg J, Binnie CD, Meijer JW, Meinardi H, Nuijten ST, Schmalz S, et al. Double-blind placebo-controlled trial of

34. 35.

36.

37.

38.

39.

40. 41.

42.

43. 44. 45. 46. 47.

48. 49.

50.

627

flunarizine as add-on therapy in epilepsy. Epilepsia 1984; 25:217-222 Overweg J, Ashton D, de Beukelaar F, Binnie CD, Wauquier A, Wieringen A. Add-on therapy in epilepsy with calcium entry blockers. Eur Neurol 1986; 25(Suppll):93-101 Alving J, Kristensen 0, Tsiropoulos I, Mondrup K. Doubleblind placebo-controlled evaluation of flunarizine as adjunct therapy in epilepsy with complex partial seizures. Acta Neurol Scand 1989; 79:128-132 Keene D, Whiting S, Humphreys P, Jacob P. Flunarizine as a supplementary medication in refractory childhood epilepsy: a double-blind crossover study. Can J Neurol Sci 1989; 16:191-193 Starreveld E, de Beukelaar F, Wilson AF, McLean DR, Findlay HP. Double-blind cross-over placebo controlled study of flunarizine in patients with therapy resistant epilepsy. Can J Neurol Sci 1989; 16:186-190 Binnie CD. Flunarizine and other calcium entry blockers. In: Levy RH, Dreifuss FE, Mattson RH, Meldrum BS, Penry JK, editors. Antiepileptic Drugs. 3rd ed. New York: Raven Press, 1989: 971-982 Chouza C, Scaramelli A, Caamano JL, De Medina 0, Aljanati R, Romero S. Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine. Lancet 1986; I: 1303-1304 Micheli F, Pardal MF, Gatto M, Torres M, Paradiso G, Parera IC, et al. Flunarizine- and cinnarizine-induced extrapyramidal reactions. Neurology 1987; 37:881-884 Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Chou SN, et al. Cerebral arterial spasm-a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983; 308:619-624 Pickard 10, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nirnodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989; 298:636-642 Larkin JG, McKee PJ, Blacklaw J, Thompson GG, Morgan IC, Brodie MJ. Nimodipine in refractory epilepsy: a placebo-controlled, add-on study. Epilepsy Res 1991; 9:71-77 de Falco FA, Bartiromo D, Majello L, Di Geronimo G, Mundo P. Calcium antagonist nimodipine in intractable epilepsy. Epilepsia 1992; 33:343-345 Brandt L, Saveland H, Ljunggren B, Andersson KE. Control of epilepsy partialis continuans with intravenous nimodipine: report of two cases. J Neurosurg 1988; 69:949-950 Gelmers HJ. Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 1983; 23:106109 Hadjiev D. Nimodipine in cerebrovascular insufficiency. In: Lechner H, Ladumer G, editors. Progress in Pathophysiology, Diagnosis and Therapy of Cerebrovascular Disease. Amsterdam: Excerpta Medica, 1984: 117-126 Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia 1985; 5:39-43 Ramsch KD, Ahr G, Tettenbom D, Auer LM. Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage. Neurochirurgie 1985; 28(Suppll):74-78 Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H, et al. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1991; 32:335-340

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