171
Epilepsy Research, 12 (1992) 171-177 0920-1211/92/$05.00 © 1992 Elsevier Science Publishers B.V. All rights reserved EPIRES 00490
Aspects of pharmacotherapy in epilepsy H. Meinardi Instituut voor Epilepsiebestrijding and Catholic University of Nijmegen, N(jmegen (Netherlands) (Accepted 10 April 1992)
Key words: Antiepileptic drugs; Mechanism of action
Notwithstanding important advances in the treatment of epilepsy basic knowledge about the epilepsies and about the mechanism of action of antiepileptic drugs is still fragmentary. This statement is illustrated with examples from the laboratory and clinical practice. In particular it is emphasized that not only is little known about the mechanism of side-effects but also little work appears to be in progress to change that situation.
Introduction
The clinical scene
For most people with epilepsy pharmacotherapy is still the best solution available. Twenty years ago Rodin complained that notwithstanding the enormous advances in medicine in the 20th century, prognosis for people with epilepsy in the 1960s was not much better than at the beginning of this century with only 40% in remission. This picture has changed and recent epidemiological studies claim that about 70% of people with epilepsy are in remission, i.e., have not had a seizure for at least 2 years (Table I). Whether this is due to the replacement of phenobarbital and phenytoin by valproate and carbamazepine or to the introduction of therapeutic drug monitoring by measuring serum levels is hard to tell.
The shift away from the older drugs is clearly seen from data from the Instituut voor Epilepsiebestrijding in the Netherlands, a third level referral centre for epilepsy care. The data are expressed as number of defined daily doses ('defined daily dose' is the modal daily amount of drug needed for successful treatment).
Correspondence to: H. Meinardi, MD, PhD, Instituut voor Epilepsiebestrijding, P.O. Box 21, 2100 AA Heemstede, Netherlands.
TABLE I
Percentage terminal remission in adults Author
Year
Percent remitted
Turner Alstroem Kiorboe Rodin Elwes
1907 1960 1968 1968 1984
32 22 32 32 82
Community-based Juul Jensen Annegers Goodridge
1963 1979 1983
32 70 69
172
The severity of the epilepsies taken care of by this third level referral centre appears not to have changed much as gauged by the amount of defined daily doses used per patient in the phenobarbital/ phenytoin era (Fig. 1) and at present (Fig. 2). Even though monotherapy is nowadays advocated, the average 2.4 defined daily doses used by these patients in this referral centre are based on polytherapy. One of the problems in treating epilepsy is the possibility of choosing amongst at least 11 different antiepileptic drugs which can be freely combined sometimes up to four drugs at a time. A study of the drugs prescribed for partial epilepsy in 100 patients taken from the records of the EEG department of the Instituut voor Epilepsiebestrijding revealed that indeed 11 different drugs
pnenobar bital prirnidone
phenytoin car barnazepine
oxcarbazepine valproate valpromtde ethosuximide
sulthiarne
had been used for these patients. On an average 2.12 drugs were prescribed per patient. Twentytwo patients were on monotherapy. Forty-five patients were treated with 13 different combinations of two drugs. Twenty-two patients used 12 different combinations of three drugs and seven patients were treated with six different combinations of four drugs. Obviously it would be well-nigh impossible to make use of all available combinations (55 in case of two, 165 in case of three and 330 in case of four drugs out of 11) and still acquire sufficient experience to judge the efficacy of each particular set. However, if the equal number of defined daily doses per patient in 1972 as compared with 1985 notwithstanding a different profile of the antiepileptic drugs - means that defined daily doses are equipotent irrespective of the drug, then there is no true need to select different combinations. Smith '4 and even more emphatically the group at King's College in London 12 have recently stressed that with respect to efficacy there is little difference between the major antiepileptic drugs. This, however, is contrary to our expectations and the outcome of laboratory experiments.
acetazolamide
diazepam chtordlazepoxide
==,
(aitrazeparn ctonazeparn clobazam flunarizine
Laboratory investigations 40
20
60
1
BO
100
120
1972
Fig. 1. Treatment in defined daily dose units. Two hundred patients receivingapprox. 2.22 DDD.
phenobarbital
primidone phenytoin car bamazepine
oxcarbazeplne valproate valprornide
~ , ~ / / / / / / / / / / / J T / ~
ethosuximide sulthiame acetazolamide diazepam c hlordiazepoxide nitrazepam '~lonazeparn clobazam flunsrizine
~/~////~ o
50
100
150
200
~985
Fig. 2. Treatment in defined daily dose units. Two hundred patients receivingapprox. 2.26 DDD.
After an era of empirical pharmacotherapy with bromides, phenobarbital, opiates, valerian and so on, animal tests were introduced to study potential antiepileptic drugs. Pioneers in the field were Merritt and Putnam who developed the use of phenytoin by studying the electroshock seizure threshold in cats. From the beginning it was clear that different seizure types were responding to treatment to a greater or lesser extent, fewer than 60% of those treated for 'petit real' (idiopathic generalized epilepsy with absence seizures) responded while in the case of psychic equivalents (partial epilepsy with complex partial seizures) 85% were successfully treated, In particular in those early days the absence seizures, which are one of the manifestations of idiopathic generalized epilepsy, appeared to beresistant to treatment with phenobarbital or phenytoin. Trimethadione was the first effective antiepileptic that could control absence seizures, but
173
due to its toxicity it has become obsolete. Animal tests revealed that the pattern of seizure suppression by phenobarbital and phenytoin compared to that of trimethadione and later ethosuximide was clearly different (Table II). Thus the notion developed that drugs could be found specific for seizure types. As the mechanism of the different seizure types is unknown the search acts as a cake-walk. A drug which is fairly effective against a particular seizure type, say complex partial seizures, is studied in animal models to define its pattern. Next drugs under development are screened for similar patterns in the animal tests and provided the drug is without dangerous sideeffects, subsequently evaluated in complex partial seizures in humans. For example, Woodbury 16 proposed using the pattern produced by phenacemide as exemplary for a good drug against complex partial seizures or in the terminology which he used at that time 'seizures of the complex temporal lobe type'. Though he remarked that 'There is insufficient work in this area to define a test as being of predictive value in temporal lobe epilepsy', he named at least the 6Hz-EST in mice, a test
which measures the ability of drugs to increase the seizure threshold for 6-Hz stimulation of the brain, while the following were proposed as potentially useful models: (a) Focal lesions in the temporal lobe or amygdala or hippocampus: measure ability of drugs to prevent electrographic changes and inhibit behavioural responses. For example: aluminium-hydroxide cream lesions in monkeys. (b) Focal electrical stimulation with implanted temporal lobe electrodes: measure ability of drugs to raise the threshold for electrical after-discharge. Monkeys are probably the most suitable animals. (c) Potassium perfusion experiments with electrodes implanted in hippocampus: measure ability of drugs to prevent EEG changes and convulsive manifestations resulting from infusion into cerebrospinal fluid of high potassium Ringer solution. To these proposals one would nowadays add the kindling model. This method of selecting new drugs according to the pattern produced by known drugs has the inherent weakness that the selectivity of the drugs in clinical use is not all that well defined. For example
T A B L E I1
Anticonvulsant activity o f prototype drugs based on protective index a Antiepileptic d r u g
Route of
Seizure s p r e a d
Seizure t h r e s h o l d
administration
Phenytoin
Carbamazepine
Phenobarbital
Ethosuximide
Valproate
Clonazepam
MES
sc Strych
1.p. oral b
+++ + + + +
-
l.p.
+++
oral
+
l.p.
++
+++
oral
+++
+++
~.p.
-
oral
-
~.p.
+
oral
+c
+
+
sc M e t
+
+
_
+
+
+
+ + + +
+
+
+
+
+c.
++
+ + + +
-
< PI < 4; +
+
++
-
+,2
+
+ + + +
+ + + +
c Mice only. < 1; + , 1 < PI < 2; +
+
+c
a P r o t e c t i v e index ( P I ) = TDs0/EDso. b Mice a n d rats. -,PI
sc Pic
_
l.p. oral
sc Bic
+
+,4
< PI < 10; +
+
+
+,PI
> 10.
+
+
174
Woodbury selected phenacemide as a drug in particular effective in the treatment of complex partial seizures. Yet Coatsworth and Penry 5, after a review of the literature, concluded that 'Trials using phenacemide gave consistently poor results and it should be a drug of last resort, if used at all.'
Modern development of antiepileptic drugs Only recently have companies started to develop antiepileptic drugs based upon pathophysiological principles. In 1956 at the Congress of the International Union of Physiological Societies Florey presented evidence that his Inhibitory Factor was yaminobutyric acid (GABA). In the subsequent years it was shown that G A B A is present in nervous systems of animals and man as a neurotransmitter and regulates chloride conductance. When through the serendipitous finding of Carraz 4 it became known that the simple branched chain fatty acid valproic acid had antiepileptic properties
Control
Mandel 8 proposed that this activity might be due to structural similarities with GABA. In our own laboratory with my co-workers Voskuyl and ter Keurs we soon noticed that valproic acid behaved differently from G A B A when tested against penicillin-evoked epileptiform discharges in isolated olfactory cortex of the guinea pig (Fig. 3). At present most authors doubt that the antiepileptic activity of valproate can be explained by a GABA-mimetic action 3. In the meantime other compounds with a more certain relation to G A B A have been developed. At Merrell Dow y-vinyl G A B A was synthetized and recently marketed as Vigabatrin. This drug works through the irreversible inhibition of G A B A transaminase, thus increasing endogenous G A B A content. Bartholini and his group at LERS made a molecule that could act as a G A B A prodrug which they named Progabide. Notwithstanding the fact that both compounds are GABA-mimetic their action profiles in man differ.
C onlr~
~ ~ I l
Pen 50000 IUlml
~
50oo0,ulmt
~
~l~in.
6
r'n~n
I
i
f I
Recovery 18 min.
Recovery I0 rnln
I
GABA 5 mM
10
--~.._
rain.
Pen. 50000 IUIml *
DPA 6 mmolll 1,5 finn
~
I
~
GABA 5mM 7 rain.
Pen 50000 ~ . l
I mV
2msec
DF~
6
6 rnrnOlll
rain
mv[___ 5 ms~
Fig. 3. Neuronal activity in slices of guinea-pig rhinencephalon, maintained in vitro, stimulated through the lateral olfactory tract. Penicillin or GABA or DPA = valproate or a combination of penicillin and GABA or penicillin + valproate was added to the bathing fluid.
175
With the recognition that chronic treatment with antiepileptic drugs could lead to an impairment in folate metabolism and the further demonstration that folates could produce seizures in animals 1'6'1°, a series of antifolates were evaluated for anticonvulsant activity. The phenyltriazine lamotrigine emerged from this screening programme. Lamotrigine itself has only very weak antifolate activity and structure-activity studies have failed to show a correlation between antifolate activity and anticonvulsant potency. Antagonism of glutamate-mediated
excitatory neurotransmission has been invoked as a possible mechanism of action 7. In animal studies its profile is similar to that of phenytoin. At present there are further endeavours to develop antiepileptic drugs on basis of glutamate antagonism. Milacemide is an example of a glycine-mimetic drug. Notwithstanding its efficacy in the laboratory models for epilepsy the results of clinical trials have been disappointing. In the meantime there are still drugs being devel-
i
18
.......1
14
.
Dayl
i
.
.
.
.
.
\ ~:\\
: \\ \\\]
Timelhgur~
.
Il l:lay2 Progabide ~oo.~
Dey3
I
I
Na-Valproate 6oo rng 20
I ! Ii h
,100
Ii
10,
i
9
11 13 15 17
Day1
I
9
\
11 13 15 17
~--Day 2---~
9
11 13 15 17
+ Day3~
9
11 13 15. 17hours)
~---Day 4 ~-~
Figs. 4, 5. Measurement of influence of antiepileptic drugs on the photoconvulsive response in epileptic patients sensitive to photic stimulation. In the upper diagram, testing progabide, the sensitivity is expressed by the actual presentation of the highest flash rate provoking a photoconvulsive response in the EEG. In the lower diagram (valproate), the range of flash frequencies capable of provoking a photoconvulsive response is represented as the difference between the highest and the lowest frequency.
176
oped without prior reference to the pathophysiology of epilepsy. Examples are felbamate which is a congener of the anti-anxiety agent meprobamate and topiramate which is derived from a study of oral antidiabetics.
Pharmacokinetics and pharmacodynamics As a possible reason for the better results of the past 20 years the introduction of monitoring serum levels of antiepileptic drugs has been mentioned. With some of the new drugs such as milacemide and vigabatrin the serum level is irrelevant, in the case of milacemide because of the large pool of glycine in serum and in the case of vigabatrin because its effect depends on irreversible binding to GABA transaminase in the brain. Even with an older drug like valproate there is still discussion about the relevance of measuring its serum level. One of the problems in studying antiepileptic drugs in man is the impossibility of an immediate measurement of the pharmacodynamic activity: seizures are paroxysmal and unpredictable events. Binnie and co-workers 2 have pointed out that measuring the photosensitivity threshold in the 5% of people with epilepsy who are sensitive to intermittent photic stimulation offers the possibility of assessing immediately the antiepileptic efficacy of a drug. In this paradigm there is a clear difference in pharmacodynamic response to valproate and to progabide. In the case of valproate photosensitivity decreases some time after valproate has reached its peak level in serum and the reduced sensitivity remains for a long time after the valproate serum level has become insignificant (Fig. 4). In the case of progabide changes in photosensitivity closely follow the pattern of the progabide serum levels (Fig. 5).
takes seizure impairments and impairments due to medication as additive as exemplified in the model of the CII balance (Fig. 6). One of the problems in developing a clinimetric system is the consensus needed amongst experts about the values of the scales. With epilepsy in particular there are a number of 'environmental' influences on the expression of the disorder that are thus far difficult to reckon with. Rajna and Veres II for example have shown that occurrence of seizures not only relates to the severity of the epilepsy or to dosages of antiepileptic drugs, but also to life events, more seizures occurring in periods of negative life events, and fewer in periods of positive life events. Side-effects also have to be distinguished as either dose-related or idiosyncratic. If efficacy does not sufficiently differentiate between the drugs available for epilepsy treatment, the next factor to determine choice is the chance of side-effects and the severity of these side-effects. Unfortunately the incidence of idiosyncratic reactions is difficult to assess as the relevant literature often fails to mention the size of the cohorts to which the reported cases belong. Reporting of idiosyncratic side-effects follows a bell-shaped curve. It takes some time before certain adverse events are recognized such as hair loss or hepatotoxicity in the case of valproate. Next there is a period of frequent reporting followed by a decline, probably because physicians
Side-effects Treatment not only reckons with efficacy but also with possible side-effects. The goal of medical care, restitutio ad integram, in the treatment of epilepsy has to deal both with impairments due to seizures and with impairments due to medication. These can be quantitatively assessed by the development of a composite index of impairment (CII) 15. The CII
---
:~E pi Ie p s y
s e v e r i t y a n d controi ' s c a I es
Fig. 6. A model for a composite index of impairment representing reduction of the effect of seizures through increase of medication and the adverse impact of medication related to dosage.
177
accept the side-effect as a known complication not worthy of publication, like malignant lymphomas in the case of phenytoin. Dose-dependent side-effects are fairly frequent in the treatment of epilepsy as some physicians do not heed the toxic boundary of the therapeutic range of the drug they select, but prefer to find the individual's own upper limit of tolerability. At present many laboratories are studying the mechanism of antiepileptic drugs with respect to seizure control;
few or none are studying the mechanism of adverse effects. The same is true for the tolerance which often develops for adverse effects while no tolerance develops for the antiepileptic effect of the same drug. Though a number of new antiepileptic drugs have reached the phase of clinical trials 9A3, still a lot has to be learned about the drugs presently in use and, vicariously, about the epilepsy that has to be controlled.
References 1 Baxter, M.G., Miller, A.A. and Webster, R.A., Some studies on the convulsant action of folic acid, Br. J. Pharmacol., 48 (1973) 350-351. 2 Binnie, C.D., Kasteleijn-Nolst Trenit6, D.G.A. and de Korte, R., Photosensitivity as a model for acute antiepileptic drug studies, Electroenceph. Clin. NeurophysioL, 63 (1986) 35~,1. 3 Capek, R. and Esplin, B., Mechanisms of anticonvulsant action of valproate: an overview and perspective. In: M. Avoli, P. Gloor, G. Kostopoulos and R. Naquet (Eds.), Generalized Epilepsy. Neurobiological Approaches, Birkh~iuser, Basel-Berlin, 1990, pp. 436-459. 4 Carraz, G., Pharmacodynamie de l'Acide Dipropylac~tique (ou Propyl-2-Pentanoique) et de ses Amides, Imprimerie Eymond, Grenoble, 1968. 5 Coatsworth, J.J. and Penry, J.K., General principles: Clinical efficacy and use. In: D.M. Woodbury, J.K. Penry and R.P. Schmidt (Eds.), Antiepileptic Drugs, Raven Press, New York, NY, 1972, pp. 87-96. 6 Hommes, O.R. and Obbens, E.A.M.T., The epileptogenic action of Na-folate in the rat, J. NeuroL Sci., 16 (1972) 271-281. 7 Leach, M.J., Marden, C.M. and Miller, A.A., Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action, Epilepsia, 27 (1986) 490-497. 8 Mandel, P., Tactical considerations and practical achievement in research for new anticonvulsant drugs. In: H. Meinardi and A.J. Rowan (Eds.), Advances in Epileptology 1977. Proceedings of the 13th Congress of the International League Against Epilepsy and 9th Symposium of the International Bureau for Epilepsy, Swets & Zeitlinger B.V., Amsterdam, 1978, pp. 156-157.
9 Meinardi, H. and Porter, R.J., New antiepileptic drugs. In: W. Frfscher and F. Vassella (Eds.), Die Epilepsien, Walter de Gruyter, Berlin, in press. 10 Obbens, E.A.M.T. and Hommes, O.R., The epileptogenic effects of folate derivatives in the rat, J. Neurol. Sci., 20 (1973) 223-229. 11 Rajna, P. and Veres, J., Life events and seizure frequency in epileptics: a follow-up study, Acta Med. Hung., 46 (1989) 169-187. 12 Reynolds, E.H., Heller, A.J., Elwes, R.D.C., De Silva, M., Neville, B., Chadwick, D. and Johnson, A.L., Factor influencing the prognosis of newly diagnosed epilepsy, Acta Neurol. Scand., 133 (1990) 32 (F 16). 13 Rogawski, M. and Porter, R.J., Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds, Pharmacol. Rev., 42 (1990) 223-286. 14 Smith, D.B., Antiepileptic drug selection in adults. In: D.B. Smith (Ed.), Epilepsy. Current Approaches to Diagnosis and Treatment, Raven Press, New York, NY, 1990, pp. 111 139. 15 Wijsman, D.J.P., Hekster, Y.A., Keyser, A., Renier, W.O. and Meinardi, H., Clinimetrics and epilepsy care, Pharm. Weekbl., 13 (1991) 182 188. 16 Woodbury, D.M., Applications to drug evaluations. In: D.P. Purpura, J.K. Penry, D. Tower, D.M. Woodbury and R. Walter (Eds.), Experimental Models of Epilepsy. A Manual for the Laboratory Worker, Raven Press, New York, NY, 1972, pp. 557-583.
Epilepsy Research, 12 (1992) 171-177 0920-1211/92/$05.00 © 1992 Elsevier Science Publishers B.V. All rights reserved EPIRES 00490
Aspects of pharmacotherapy in epilepsy H. Meinardi Instituut voor Epilepsiebestrijding and Catholic University of Nijmegen, N(jmegen (Netherlands) (Accepted 10 April 1992)
Key words: Antiepileptic drugs; Mechanism of action
Notwithstanding important advances in the treatment of epilepsy basic knowledge about the epilepsies and about the mechanism of action of antiepileptic drugs is still fragmentary. This statement is illustrated with examples from the laboratory and clinical practice. In particular it is emphasized that not only is little known about the mechanism of side-effects but also little work appears to be in progress to change that situation.
Introduction
The clinical scene
For most people with epilepsy pharmacotherapy is still the best solution available. Twenty years ago Rodin complained that notwithstanding the enormous advances in medicine in the 20th century, prognosis for people with epilepsy in the 1960s was not much better than at the beginning of this century with only 40% in remission. This picture has changed and recent epidemiological studies claim that about 70% of people with epilepsy are in remission, i.e., have not had a seizure for at least 2 years (Table I). Whether this is due to the replacement of phenobarbital and phenytoin by valproate and carbamazepine or to the introduction of therapeutic drug monitoring by measuring serum levels is hard to tell.
The shift away from the older drugs is clearly seen from data from the Instituut voor Epilepsiebestrijding in the Netherlands, a third level referral centre for epilepsy care. The data are expressed as number of defined daily doses ('defined daily dose' is the modal daily amount of drug needed for successful treatment).
Correspondence to: H. Meinardi, MD, PhD, Instituut voor Epilepsiebestrijding, P.O. Box 21, 2100 AA Heemstede, Netherlands.
TABLE I
Percentage terminal remission in adults Author
Year
Percent remitted
Turner Alstroem Kiorboe Rodin Elwes
1907 1960 1968 1968 1984
32 22 32 32 82
Community-based Juul Jensen Annegers Goodridge
1963 1979 1983
32 70 69
172
The severity of the epilepsies taken care of by this third level referral centre appears not to have changed much as gauged by the amount of defined daily doses used per patient in the phenobarbital/ phenytoin era (Fig. 1) and at present (Fig. 2). Even though monotherapy is nowadays advocated, the average 2.4 defined daily doses used by these patients in this referral centre are based on polytherapy. One of the problems in treating epilepsy is the possibility of choosing amongst at least 11 different antiepileptic drugs which can be freely combined sometimes up to four drugs at a time. A study of the drugs prescribed for partial epilepsy in 100 patients taken from the records of the EEG department of the Instituut voor Epilepsiebestrijding revealed that indeed 11 different drugs
pnenobar bital prirnidone
phenytoin car barnazepine
oxcarbazepine valproate valpromtde ethosuximide
sulthiarne
had been used for these patients. On an average 2.12 drugs were prescribed per patient. Twentytwo patients were on monotherapy. Forty-five patients were treated with 13 different combinations of two drugs. Twenty-two patients used 12 different combinations of three drugs and seven patients were treated with six different combinations of four drugs. Obviously it would be well-nigh impossible to make use of all available combinations (55 in case of two, 165 in case of three and 330 in case of four drugs out of 11) and still acquire sufficient experience to judge the efficacy of each particular set. However, if the equal number of defined daily doses per patient in 1972 as compared with 1985 notwithstanding a different profile of the antiepileptic drugs - means that defined daily doses are equipotent irrespective of the drug, then there is no true need to select different combinations. Smith '4 and even more emphatically the group at King's College in London 12 have recently stressed that with respect to efficacy there is little difference between the major antiepileptic drugs. This, however, is contrary to our expectations and the outcome of laboratory experiments.
acetazolamide
diazepam chtordlazepoxide
==,
(aitrazeparn ctonazeparn clobazam flunarizine
Laboratory investigations 40
20
60
1
BO
100
120
1972
Fig. 1. Treatment in defined daily dose units. Two hundred patients receivingapprox. 2.22 DDD.
phenobarbital
primidone phenytoin car bamazepine
oxcarbazeplne valproate valprornide
~ , ~ / / / / / / / / / / / J T / ~
ethosuximide sulthiame acetazolamide diazepam c hlordiazepoxide nitrazepam '~lonazeparn clobazam flunsrizine
~/~////~ o
50
100
150
200
~985
Fig. 2. Treatment in defined daily dose units. Two hundred patients receivingapprox. 2.26 DDD.
After an era of empirical pharmacotherapy with bromides, phenobarbital, opiates, valerian and so on, animal tests were introduced to study potential antiepileptic drugs. Pioneers in the field were Merritt and Putnam who developed the use of phenytoin by studying the electroshock seizure threshold in cats. From the beginning it was clear that different seizure types were responding to treatment to a greater or lesser extent, fewer than 60% of those treated for 'petit real' (idiopathic generalized epilepsy with absence seizures) responded while in the case of psychic equivalents (partial epilepsy with complex partial seizures) 85% were successfully treated, In particular in those early days the absence seizures, which are one of the manifestations of idiopathic generalized epilepsy, appeared to beresistant to treatment with phenobarbital or phenytoin. Trimethadione was the first effective antiepileptic that could control absence seizures, but
173
due to its toxicity it has become obsolete. Animal tests revealed that the pattern of seizure suppression by phenobarbital and phenytoin compared to that of trimethadione and later ethosuximide was clearly different (Table II). Thus the notion developed that drugs could be found specific for seizure types. As the mechanism of the different seizure types is unknown the search acts as a cake-walk. A drug which is fairly effective against a particular seizure type, say complex partial seizures, is studied in animal models to define its pattern. Next drugs under development are screened for similar patterns in the animal tests and provided the drug is without dangerous sideeffects, subsequently evaluated in complex partial seizures in humans. For example, Woodbury 16 proposed using the pattern produced by phenacemide as exemplary for a good drug against complex partial seizures or in the terminology which he used at that time 'seizures of the complex temporal lobe type'. Though he remarked that 'There is insufficient work in this area to define a test as being of predictive value in temporal lobe epilepsy', he named at least the 6Hz-EST in mice, a test
which measures the ability of drugs to increase the seizure threshold for 6-Hz stimulation of the brain, while the following were proposed as potentially useful models: (a) Focal lesions in the temporal lobe or amygdala or hippocampus: measure ability of drugs to prevent electrographic changes and inhibit behavioural responses. For example: aluminium-hydroxide cream lesions in monkeys. (b) Focal electrical stimulation with implanted temporal lobe electrodes: measure ability of drugs to raise the threshold for electrical after-discharge. Monkeys are probably the most suitable animals. (c) Potassium perfusion experiments with electrodes implanted in hippocampus: measure ability of drugs to prevent EEG changes and convulsive manifestations resulting from infusion into cerebrospinal fluid of high potassium Ringer solution. To these proposals one would nowadays add the kindling model. This method of selecting new drugs according to the pattern produced by known drugs has the inherent weakness that the selectivity of the drugs in clinical use is not all that well defined. For example
T A B L E I1
Anticonvulsant activity o f prototype drugs based on protective index a Antiepileptic d r u g
Route of
Seizure s p r e a d
Seizure t h r e s h o l d
administration
Phenytoin
Carbamazepine
Phenobarbital
Ethosuximide
Valproate
Clonazepam
MES
sc Strych
1.p. oral b
+++ + + + +
-
l.p.
+++
oral
+
l.p.
++
+++
oral
+++
+++
~.p.
-
oral
-
~.p.
+
oral
+c
+
+
sc M e t
+
+
_
+
+
+
+ + + +
+
+
+
+
+c.
++
+ + + +
-
< PI < 4; +
+
++
-
+,2
+
+ + + +
+ + + +
c Mice only. < 1; + , 1 < PI < 2; +
+
+c
a P r o t e c t i v e index ( P I ) = TDs0/EDso. b Mice a n d rats. -,PI
sc Pic
_
l.p. oral
sc Bic
+
+,4
< PI < 10; +
+
+
+,PI
> 10.
+
+
174
Woodbury selected phenacemide as a drug in particular effective in the treatment of complex partial seizures. Yet Coatsworth and Penry 5, after a review of the literature, concluded that 'Trials using phenacemide gave consistently poor results and it should be a drug of last resort, if used at all.'
Modern development of antiepileptic drugs Only recently have companies started to develop antiepileptic drugs based upon pathophysiological principles. In 1956 at the Congress of the International Union of Physiological Societies Florey presented evidence that his Inhibitory Factor was yaminobutyric acid (GABA). In the subsequent years it was shown that G A B A is present in nervous systems of animals and man as a neurotransmitter and regulates chloride conductance. When through the serendipitous finding of Carraz 4 it became known that the simple branched chain fatty acid valproic acid had antiepileptic properties
Control
Mandel 8 proposed that this activity might be due to structural similarities with GABA. In our own laboratory with my co-workers Voskuyl and ter Keurs we soon noticed that valproic acid behaved differently from G A B A when tested against penicillin-evoked epileptiform discharges in isolated olfactory cortex of the guinea pig (Fig. 3). At present most authors doubt that the antiepileptic activity of valproate can be explained by a GABA-mimetic action 3. In the meantime other compounds with a more certain relation to G A B A have been developed. At Merrell Dow y-vinyl G A B A was synthetized and recently marketed as Vigabatrin. This drug works through the irreversible inhibition of G A B A transaminase, thus increasing endogenous G A B A content. Bartholini and his group at LERS made a molecule that could act as a G A B A prodrug which they named Progabide. Notwithstanding the fact that both compounds are GABA-mimetic their action profiles in man differ.
C onlr~
~ ~ I l
Pen 50000 IUlml
~
50oo0,ulmt
~
~l~in.
6
r'n~n
I
i
f I
Recovery 18 min.
Recovery I0 rnln
I
GABA 5 mM
10
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175
With the recognition that chronic treatment with antiepileptic drugs could lead to an impairment in folate metabolism and the further demonstration that folates could produce seizures in animals 1'6'1°, a series of antifolates were evaluated for anticonvulsant activity. The phenyltriazine lamotrigine emerged from this screening programme. Lamotrigine itself has only very weak antifolate activity and structure-activity studies have failed to show a correlation between antifolate activity and anticonvulsant potency. Antagonism of glutamate-mediated
excitatory neurotransmission has been invoked as a possible mechanism of action 7. In animal studies its profile is similar to that of phenytoin. At present there are further endeavours to develop antiepileptic drugs on basis of glutamate antagonism. Milacemide is an example of a glycine-mimetic drug. Notwithstanding its efficacy in the laboratory models for epilepsy the results of clinical trials have been disappointing. In the meantime there are still drugs being devel-
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Figs. 4, 5. Measurement of influence of antiepileptic drugs on the photoconvulsive response in epileptic patients sensitive to photic stimulation. In the upper diagram, testing progabide, the sensitivity is expressed by the actual presentation of the highest flash rate provoking a photoconvulsive response in the EEG. In the lower diagram (valproate), the range of flash frequencies capable of provoking a photoconvulsive response is represented as the difference between the highest and the lowest frequency.
176
oped without prior reference to the pathophysiology of epilepsy. Examples are felbamate which is a congener of the anti-anxiety agent meprobamate and topiramate which is derived from a study of oral antidiabetics.
Pharmacokinetics and pharmacodynamics As a possible reason for the better results of the past 20 years the introduction of monitoring serum levels of antiepileptic drugs has been mentioned. With some of the new drugs such as milacemide and vigabatrin the serum level is irrelevant, in the case of milacemide because of the large pool of glycine in serum and in the case of vigabatrin because its effect depends on irreversible binding to GABA transaminase in the brain. Even with an older drug like valproate there is still discussion about the relevance of measuring its serum level. One of the problems in studying antiepileptic drugs in man is the impossibility of an immediate measurement of the pharmacodynamic activity: seizures are paroxysmal and unpredictable events. Binnie and co-workers 2 have pointed out that measuring the photosensitivity threshold in the 5% of people with epilepsy who are sensitive to intermittent photic stimulation offers the possibility of assessing immediately the antiepileptic efficacy of a drug. In this paradigm there is a clear difference in pharmacodynamic response to valproate and to progabide. In the case of valproate photosensitivity decreases some time after valproate has reached its peak level in serum and the reduced sensitivity remains for a long time after the valproate serum level has become insignificant (Fig. 4). In the case of progabide changes in photosensitivity closely follow the pattern of the progabide serum levels (Fig. 5).
takes seizure impairments and impairments due to medication as additive as exemplified in the model of the CII balance (Fig. 6). One of the problems in developing a clinimetric system is the consensus needed amongst experts about the values of the scales. With epilepsy in particular there are a number of 'environmental' influences on the expression of the disorder that are thus far difficult to reckon with. Rajna and Veres II for example have shown that occurrence of seizures not only relates to the severity of the epilepsy or to dosages of antiepileptic drugs, but also to life events, more seizures occurring in periods of negative life events, and fewer in periods of positive life events. Side-effects also have to be distinguished as either dose-related or idiosyncratic. If efficacy does not sufficiently differentiate between the drugs available for epilepsy treatment, the next factor to determine choice is the chance of side-effects and the severity of these side-effects. Unfortunately the incidence of idiosyncratic reactions is difficult to assess as the relevant literature often fails to mention the size of the cohorts to which the reported cases belong. Reporting of idiosyncratic side-effects follows a bell-shaped curve. It takes some time before certain adverse events are recognized such as hair loss or hepatotoxicity in the case of valproate. Next there is a period of frequent reporting followed by a decline, probably because physicians
Side-effects Treatment not only reckons with efficacy but also with possible side-effects. The goal of medical care, restitutio ad integram, in the treatment of epilepsy has to deal both with impairments due to seizures and with impairments due to medication. These can be quantitatively assessed by the development of a composite index of impairment (CII) 15. The CII
---
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Fig. 6. A model for a composite index of impairment representing reduction of the effect of seizures through increase of medication and the adverse impact of medication related to dosage.
177
accept the side-effect as a known complication not worthy of publication, like malignant lymphomas in the case of phenytoin. Dose-dependent side-effects are fairly frequent in the treatment of epilepsy as some physicians do not heed the toxic boundary of the therapeutic range of the drug they select, but prefer to find the individual's own upper limit of tolerability. At present many laboratories are studying the mechanism of antiepileptic drugs with respect to seizure control;
few or none are studying the mechanism of adverse effects. The same is true for the tolerance which often develops for adverse effects while no tolerance develops for the antiepileptic effect of the same drug. Though a number of new antiepileptic drugs have reached the phase of clinical trials 9A3, still a lot has to be learned about the drugs presently in use and, vicariously, about the epilepsy that has to be controlled.
References 1 Baxter, M.G., Miller, A.A. and Webster, R.A., Some studies on the convulsant action of folic acid, Br. J. Pharmacol., 48 (1973) 350-351. 2 Binnie, C.D., Kasteleijn-Nolst Trenit6, D.G.A. and de Korte, R., Photosensitivity as a model for acute antiepileptic drug studies, Electroenceph. Clin. NeurophysioL, 63 (1986) 35~,1. 3 Capek, R. and Esplin, B., Mechanisms of anticonvulsant action of valproate: an overview and perspective. In: M. Avoli, P. Gloor, G. Kostopoulos and R. Naquet (Eds.), Generalized Epilepsy. Neurobiological Approaches, Birkh~iuser, Basel-Berlin, 1990, pp. 436-459. 4 Carraz, G., Pharmacodynamie de l'Acide Dipropylac~tique (ou Propyl-2-Pentanoique) et de ses Amides, Imprimerie Eymond, Grenoble, 1968. 5 Coatsworth, J.J. and Penry, J.K., General principles: Clinical efficacy and use. In: D.M. Woodbury, J.K. Penry and R.P. Schmidt (Eds.), Antiepileptic Drugs, Raven Press, New York, NY, 1972, pp. 87-96. 6 Hommes, O.R. and Obbens, E.A.M.T., The epileptogenic action of Na-folate in the rat, J. NeuroL Sci., 16 (1972) 271-281. 7 Leach, M.J., Marden, C.M. and Miller, A.A., Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action, Epilepsia, 27 (1986) 490-497. 8 Mandel, P., Tactical considerations and practical achievement in research for new anticonvulsant drugs. In: H. Meinardi and A.J. Rowan (Eds.), Advances in Epileptology 1977. Proceedings of the 13th Congress of the International League Against Epilepsy and 9th Symposium of the International Bureau for Epilepsy, Swets & Zeitlinger B.V., Amsterdam, 1978, pp. 156-157.
9 Meinardi, H. and Porter, R.J., New antiepileptic drugs. In: W. Frfscher and F. Vassella (Eds.), Die Epilepsien, Walter de Gruyter, Berlin, in press. 10 Obbens, E.A.M.T. and Hommes, O.R., The epileptogenic effects of folate derivatives in the rat, J. Neurol. Sci., 20 (1973) 223-229. 11 Rajna, P. and Veres, J., Life events and seizure frequency in epileptics: a follow-up study, Acta Med. Hung., 46 (1989) 169-187. 12 Reynolds, E.H., Heller, A.J., Elwes, R.D.C., De Silva, M., Neville, B., Chadwick, D. and Johnson, A.L., Factor influencing the prognosis of newly diagnosed epilepsy, Acta Neurol. Scand., 133 (1990) 32 (F 16). 13 Rogawski, M. and Porter, R.J., Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds, Pharmacol. Rev., 42 (1990) 223-286. 14 Smith, D.B., Antiepileptic drug selection in adults. In: D.B. Smith (Ed.), Epilepsy. Current Approaches to Diagnosis and Treatment, Raven Press, New York, NY, 1990, pp. 111 139. 15 Wijsman, D.J.P., Hekster, Y.A., Keyser, A., Renier, W.O. and Meinardi, H., Clinimetrics and epilepsy care, Pharm. Weekbl., 13 (1991) 182 188. 16 Woodbury, D.M., Applications to drug evaluations. In: D.P. Purpura, J.K. Penry, D. Tower, D.M. Woodbury and R. Walter (Eds.), Experimental Models of Epilepsy. A Manual for the Laboratory Worker, Raven Press, New York, NY, 1972, pp. 557-583.
