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Influence of ethosuximide on valproic acid serum concentrations
Epilepsy Research 26 (1997) 345 – 349
Influence of ethosuximide on valproic acid serum concentrations Ritva Anneli Sa¨lke-Kellermanna,*, Theo Mayb, Hans Erich Boenigka b
a Epilepsy Centre Bethel, Kidron, D-33 617 Bielefeld, Germany Biochemical Laboratory, Society of Epilepsy Research Bethel, D-33 617 Bielefeld, Germany
Received 15 August 1996; accepted 23 August 1996
Abstract In the therapy of absence epilepsies, a combination of ethosuximide (ESM) and valproic acid (VPA) is sometimes necessary for a successful seizure control. Previous studies of the interaction between ESM and VPA revealed contradictory results. We investigated the influence of ESM on VPA serum concentrations in children with epilepsy. In case of ineffectiveness of the drug, ESM was withdrawn (n= 9). Four children treated with VPA got ESM additionally because their seizure control was insufficient with VPA alone. Two children had bromide, and one clobazam as comedicament. Both of these antiepileptic drugs (AEDs) do not have any known interactions with ESM or VPA. Serum levels of VPA were higher in monotherapy than in combination with ESM (120.0 9 20.1 mg/ml; range, 88.9–153.4 mg/ml; vs. 87.0913.1 mg/ml; range, 67.4 – 108.0 mg/ml). The difference was statistically significant (PB 0.01). After stopping ESM the serum concentrations of VPA rose about 36.7%; when combined with ESM they fell about 28.3%. Neither the age of the patients nor the serum concentrations of ESM influenced significantly the changes of VPA serum levels in either group. The mechanism of ESM to influence the serum levels of VPA remains unknown. ESM has no known enzyme inducing properties. The interaction of ESM and VPA ought to be considered in a combination therapy of these drugs. © 1997 Elsevier Science B.V. Keywords: Ethosuximide; Ethosuximide–valproic acid interaction; Bromide; Clobazam
1. Introduction Ethosuximide (ESM) and valproic acid (VPA) are equally effective in the treatment of absence epilepsies [6]. Although ESM belongs to the ‘old * Corresponding author. Present address: Swiss Epilepsy Center, Bleulerstrasse 60, CH-8008 Zurich, Switzerland.
generation’ of antiepileptic drugs its clinical pharmacokinetics up to now have not yet been clarified completely. Some studies investigating interactions of ESM and VPA revealed contradictory results concerning the serum concentrations of ESM [2,7,8], or the elimination half-life of ESM [2,8,9]. We studied the influence of ESM on the serum levels of VPA in 13 children.
0920-1211/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved PII S 0 9 2 0 - 1 2 1 1 ( 9 6 ) 0 1 0 0 1 - 7
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
346
Table 1 Children treated with ESM and VPA, the serum concentrations of ESM and of VPA in combination with ESM and in monotherapy Namea (f/m)
Age (year, month)
ESM concentration (mg/ml)
VPA concentration with ESM (mg/ml)
VPA concentration without ESM (mg/ml)
B.C. (f) L.T. (m) B.K. (f) M.J.b (f) T.B.b (f) K.A. (m) K.G. (m) T.D.c (f) N.D. (m)
2.8 5.4 7.2 5.4 2.1 5.11 2.7 9.8 16.8
105.2 77.8 77.4 104.1 85.1 113.2 115.8 71.7 116.9
91.8 77.8 76.8 86.0 71.3 105.0 98.2 95.4 108.0
109.1 102.1 129.6 135.5 93.7 153.4 131.1 133.7 111.4
6.5
96.4 18.2
90.0 12.9
122.2 19.1
Mean S.D.
ESM; ethosuximide; VPA, valproic acid; f, female; m, male. n = 9, five female and four male. b Bromide addition. c Clobazam addition. a
2. Patients and methods
2.1. Patients During the years 1989 – 1994 data were collected of all the children who had a combination of ESM and VPA and in whom ESM was discontinued, or who got ESM to their pre-existing monotherapy of VPA. We included in the study only the children who met the criterion of stable serum concentrations for VPA before and after changing the dose of ESM. As additional AEDs, only bromide and clobazam were included, both of them drugs without any known interaction with ESM or VPA. All the children (n =13) were in-patients and suffered from chronic epilepsy. All epilepsies were difficult to treat. Five children (L.T., T.D., H.N., F.R., O.T.) had absences only, the others had several different types of seizures (absences, myoclonic seizures, tonic seizures, and generalised tonic-clonic seizures). The drugs were given b.i.d (8.00 a.m. and 6.00 p.m.). In the first group, nine children (mean age, 6.5 years; range, 2.1 – 16.8 years) were treated with a combination of ESM and VPA (Table 1). Two children (M.J. and T.B.) received bromide, and one child (T.D.) clobazam, additionally. In all these patients ESM was supposed to be ineffective
or unnecessary for the seizure control and was therefore abruptly withdrawn from the therapy. In the second group, we analysed the serum concentrations of VPA in four children (mean age, 6.10 years; range, 2.5–13.5 years; Table 2) after ESM was added to a pre-existing VPA monotherapy.
2.2. Methods Before discontinuing ESM, the doses and the serum concentrations of all AEDs were stable at least 7–12 days. The doses of VPA remained unchanged during the observation time. Four children took VPA suspension (B.C., L.T., M.J. and O.T.), the others VPA enteric coated tablets. The last dose of ESM was taken in the evening before stopping it. The first measurement of the serum concentrations of VPA was accomplished 12 h after the last dose of ESM. The measurements of the serum concentrations of VPA were repeated two to four times in 7–25 days after ESM disappeared in blood. In children who additionally got ESM to their VPA monotherapy the serum concentrations of VPA were controlled 6–7 and 14–15 days after starting with ESM. The serum concentrations of ESM were in usual therapeutic range (Table 2).
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
347
Table 2 Children first treated with VPA monotherapy and then with a combination of VPA and ESM; serum concentrations of VPA in monotherapy and after adding on ESM, as well as the serum concentrations of ESM in the combination therapy Namea (f/m)
Age (year, month)
ESM concentration (mg/ml)
VPA concentration monotherapy (mg/ml)
VPA concentration with ESM (mg/ml)
H.N. (f) F.R. (m) O.T. (m) B.M. (m)
13.5 5.11 5.7 2.5
89.8 63.8 127.8 106.2
120.4 88.9 146.5 105.0
95.9 80.9 76.0 67.4
6.10
96.9 27.0
115.2 24.5
80.1 11.9
Mean S.D.
f, female; m, male. n = 4, one female, three male.
a
All blood samples were taken on the early morning before the first dosage of AEDs (at 8.00 a.m.). The serum concentrations were estimated by high-performance liquid chromatography (HPLC [5]). Out of two to four available measurements, a mean serum value for each AED was calculated in every patient. The mean serum value of these estimations was taken for the interpretation. The per cent changes of the serum concentrations of VPA were calculated individually, and the mean values were determined. The statistical significance was analysed with the Wilcoxon-test. The children were continuously observed as in-patients. All seizures and possible side effects were registered.
spectively). In all patients, the serum levels of VPA rose about 39.7 9 24.1% (mean and S.D.; range, 7.8–92.7%) after stopping ESM, or they fell about 26.59 12.0% (mean and S.D., range 8.3–48.1%) when ESM was added on the therapy. Individual changes of VPA serum concentrations are scattered over a wide range. The serum levels of VPA with and without ESM are presented in Fig. 1. In these children, the changes of VPA serum concentrations were influenced neither by age nor by the serum levels of ESM (r= − 0.20, P \ 0.2; nor r= 0.28, P\ 0.2; respectively). In all patients the serum concentrations of ESM were in the
3. Results Mean serum concentrations of VPA after stopping ESM increased from 90.0 mg/ml (range, 71.3–108.0 mg/ml) up to 122.2 mg/ml (range, 93.7–153.4 mg/ml). When ESM was added to VPA monotherapy mean serum concentrations of VPA decreased from 115.2 mg/ml (range, 88.9– 146.5 mg/ml) to 80.1 mg/ml (range, 67.4 –95.9 mg/ml). Considering all the patients together, mean serum levels of VPA were statistically significantly higher in monotherapy (P B 0.01, Wilcoxon-test) than in combination with ESM (120.0920 mg/ml; range, 88.9 – 153.4 mg/ml, or 87.09 13.1 mg/ml; range, 67.4 – 108.0 mg/ml; re-
Fig. 1. All serum concentrations of VPA with and without ESM. In combination with ESM in children (n = 13), the VPA serum concentrations are lower (CVPA =87 913.1 mg/ml (mean and S.D.); range, 67.4 – 95.9 mg/ml) than in the monotherapy (CVPA =120.0 921.1 mg/ml (mean 9S.D.); range, 93.7 – 153.4 mg/ml) the difference being statistically significant (P B0.01). C, serum concentration.
348
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
therapeutically effective range (63.8 – 127.8 mg/ ml; mean, 97.2 mg/ml). Abrupt discontinuation of ESM did not provoke any withdrawal seizures. The seizure type and seizure frequency remained unchanged in all patients. No other withdrawal symptoms (like symptoms of the vegetative nervous system) were detected. Remarkable increase of VPA serum levels was not followed by any toxic clinical symptoms, like gastro-intestinal problems, sedation, or tremor, in our patients.
4. Discussion The results of this study show a clear-cut influence of ESM on the serum levels of VPA. In ESM/VPA combination therapy, serum concentrations of VPA were decreased compared with the serum concentrations of VPA in monotherapy intra-individually. This was true in every patient, but the measurements varied greatly between the individual patients. The serum levels of VPA were not influenced by the age of the patients nor by the serum concentrations of ESM. After stopping ESM, the serum levels of VPA were rather high but without ontoward reactions in these patients. Previous studies reported interactions between ESM and VPA [1,2,4,7,8]. Influence of VPA on ESM was described, but the results were partly contradictory. However, effects of ESM on VPA serum levels have not yet been studied up to now. The changes of VPA serum concentrations are statistically significant. Serum concentrations of VPA may greatly fluctuate during 24 h. The early morning values, however, change only little from day to day. Fluctuations were further compensated by taking the mean values from two to four measurements. The mechanism of the interaction is not clear. ESM has no known enzyme inducing properties and it is only minimally (5 – 10%) bound to serum proteins [3]. A change of the capacity in serum protein to bind to VPA in combination with ESM can not explain the changes of the serum levels of VPA of about 28 – 36%. Lower serum concentrations of VPA when ESM is
coadministered indicate a reduced resorption or a faster elimination of VPA. After stopping ESM, it takes several days until it disappears in blood. In this period, VPA gradually rises to a new level. This could indicate a participation of some enzyme process in the elimination of VPA. An interaction on the level of resorption should influence the serum levels of VPA not gradually, but immediately after the absorption of ESM has been completed. However, the mechanism of ESM to influence the metabolism of VPA leading to lower serum levels still remains to be cleared. In clinical practice, the influence of ESM on VPA serum concentrations should be taken into consideration. After discontinuing ESM, the increase of VPA serum concentrations may lead to better efficacy or to toxic side effects. In our patients, such clinical symptoms were not observed. On the other side, a decrease of VPA serum levels should be expected after adding ESM to a pre-existing VPA therapy.
References [1] Battino, D., Cusi, C., Franceschetti, S., Moise, A., Spina, S. and Avanzini, G., Ethosuximide plasma concentrations: Influence of age and associated concomitant therapy, Clin. Pharmacokinet., 7 (1982) 176 – 180. [2] Bauer, L.A., Harris, C., Wilensky, A.J., Raisys, V.A. and Levy, R.H., Ethosuximide kinetics: Possible interaction with valproic acid, Clin. Pharmacol. Ther., 31, 8 (1982) 741 – 745. [3] Chang, T., Dill, W.A. and Glazko, A.J., Ethosuximide: Absorption, distribution and excretion. In: D.M. Woodbury, J.K. Penry, and R.P. Schmidt (Eds.), Antiepileptic Drugs, Raven Press, New York, 1972, pp. 417 – 423. [4] Flachs, H., Wu¨rtz-Joergensen, A., Gram, L. and Wulf, K., Sodium di-n-propyl acetate - its interaction with other antiepileptic drugs, Pharm. Weekbl., 112 (1977) 320. [5] Juergens, U., HPLC analysis of antiepileptic drugs in blood samples. Micropore separation of fourteen compounds, J. Liq. Chromatogr., 10 (2 and 3) (1987) 507 – 532. [6] Martinovic, Z., Comparison of ethosuximide with sodium valproate as monotherapies of absence seizures. In: M. Parsonage (Ed.), Ad6ances in Epileptology, XIVth Epilepsy International Symposium, Raven Press, New York, 1983, pp. 301 – 305. [7] Mattson, R.H. and Cramer, J.A., Valproic acid and ethosuximide interaction, Ann. Neurol., 7 (1980) 583 – 584.
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349 [8] Pisani, F., Narbone, M.C., Trunfio, C., Fazio, A., La Rosa, G., Oteri, G. and Di Perri, R., Valproic acid-ethosuximide interaction: A pharmacokinetic study, Epilepsia, 25 (2) (1984) 229–233. [9] Sa¨lke-Kellermann, R.A., Klinische Pharmakologie von
349
Ethosuximid: Zwei prospektive Studien u¨ber die Fluktuationen der Serumkonzentrationen im Tagesverlauf, abha¨ngig vom Dosierungsschema, und u¨ber die Eliminationshalbwertszeit unter klinischen Bedingungen, Thesis, Mu¨nster, 1993.
.
Influence of ethosuximide on valproic acid serum concentrations Ritva Anneli Sa¨lke-Kellermanna,*, Theo Mayb, Hans Erich Boenigka b
a Epilepsy Centre Bethel, Kidron, D-33 617 Bielefeld, Germany Biochemical Laboratory, Society of Epilepsy Research Bethel, D-33 617 Bielefeld, Germany
Received 15 August 1996; accepted 23 August 1996
Abstract In the therapy of absence epilepsies, a combination of ethosuximide (ESM) and valproic acid (VPA) is sometimes necessary for a successful seizure control. Previous studies of the interaction between ESM and VPA revealed contradictory results. We investigated the influence of ESM on VPA serum concentrations in children with epilepsy. In case of ineffectiveness of the drug, ESM was withdrawn (n= 9). Four children treated with VPA got ESM additionally because their seizure control was insufficient with VPA alone. Two children had bromide, and one clobazam as comedicament. Both of these antiepileptic drugs (AEDs) do not have any known interactions with ESM or VPA. Serum levels of VPA were higher in monotherapy than in combination with ESM (120.0 9 20.1 mg/ml; range, 88.9–153.4 mg/ml; vs. 87.0913.1 mg/ml; range, 67.4 – 108.0 mg/ml). The difference was statistically significant (PB 0.01). After stopping ESM the serum concentrations of VPA rose about 36.7%; when combined with ESM they fell about 28.3%. Neither the age of the patients nor the serum concentrations of ESM influenced significantly the changes of VPA serum levels in either group. The mechanism of ESM to influence the serum levels of VPA remains unknown. ESM has no known enzyme inducing properties. The interaction of ESM and VPA ought to be considered in a combination therapy of these drugs. © 1997 Elsevier Science B.V. Keywords: Ethosuximide; Ethosuximide–valproic acid interaction; Bromide; Clobazam
1. Introduction Ethosuximide (ESM) and valproic acid (VPA) are equally effective in the treatment of absence epilepsies [6]. Although ESM belongs to the ‘old * Corresponding author. Present address: Swiss Epilepsy Center, Bleulerstrasse 60, CH-8008 Zurich, Switzerland.
generation’ of antiepileptic drugs its clinical pharmacokinetics up to now have not yet been clarified completely. Some studies investigating interactions of ESM and VPA revealed contradictory results concerning the serum concentrations of ESM [2,7,8], or the elimination half-life of ESM [2,8,9]. We studied the influence of ESM on the serum levels of VPA in 13 children.
0920-1211/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved PII S 0 9 2 0 - 1 2 1 1 ( 9 6 ) 0 1 0 0 1 - 7
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
346
Table 1 Children treated with ESM and VPA, the serum concentrations of ESM and of VPA in combination with ESM and in monotherapy Namea (f/m)
Age (year, month)
ESM concentration (mg/ml)
VPA concentration with ESM (mg/ml)
VPA concentration without ESM (mg/ml)
B.C. (f) L.T. (m) B.K. (f) M.J.b (f) T.B.b (f) K.A. (m) K.G. (m) T.D.c (f) N.D. (m)
2.8 5.4 7.2 5.4 2.1 5.11 2.7 9.8 16.8
105.2 77.8 77.4 104.1 85.1 113.2 115.8 71.7 116.9
91.8 77.8 76.8 86.0 71.3 105.0 98.2 95.4 108.0
109.1 102.1 129.6 135.5 93.7 153.4 131.1 133.7 111.4
6.5
96.4 18.2
90.0 12.9
122.2 19.1
Mean S.D.
ESM; ethosuximide; VPA, valproic acid; f, female; m, male. n = 9, five female and four male. b Bromide addition. c Clobazam addition. a
2. Patients and methods
2.1. Patients During the years 1989 – 1994 data were collected of all the children who had a combination of ESM and VPA and in whom ESM was discontinued, or who got ESM to their pre-existing monotherapy of VPA. We included in the study only the children who met the criterion of stable serum concentrations for VPA before and after changing the dose of ESM. As additional AEDs, only bromide and clobazam were included, both of them drugs without any known interaction with ESM or VPA. All the children (n =13) were in-patients and suffered from chronic epilepsy. All epilepsies were difficult to treat. Five children (L.T., T.D., H.N., F.R., O.T.) had absences only, the others had several different types of seizures (absences, myoclonic seizures, tonic seizures, and generalised tonic-clonic seizures). The drugs were given b.i.d (8.00 a.m. and 6.00 p.m.). In the first group, nine children (mean age, 6.5 years; range, 2.1 – 16.8 years) were treated with a combination of ESM and VPA (Table 1). Two children (M.J. and T.B.) received bromide, and one child (T.D.) clobazam, additionally. In all these patients ESM was supposed to be ineffective
or unnecessary for the seizure control and was therefore abruptly withdrawn from the therapy. In the second group, we analysed the serum concentrations of VPA in four children (mean age, 6.10 years; range, 2.5–13.5 years; Table 2) after ESM was added to a pre-existing VPA monotherapy.
2.2. Methods Before discontinuing ESM, the doses and the serum concentrations of all AEDs were stable at least 7–12 days. The doses of VPA remained unchanged during the observation time. Four children took VPA suspension (B.C., L.T., M.J. and O.T.), the others VPA enteric coated tablets. The last dose of ESM was taken in the evening before stopping it. The first measurement of the serum concentrations of VPA was accomplished 12 h after the last dose of ESM. The measurements of the serum concentrations of VPA were repeated two to four times in 7–25 days after ESM disappeared in blood. In children who additionally got ESM to their VPA monotherapy the serum concentrations of VPA were controlled 6–7 and 14–15 days after starting with ESM. The serum concentrations of ESM were in usual therapeutic range (Table 2).
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
347
Table 2 Children first treated with VPA monotherapy and then with a combination of VPA and ESM; serum concentrations of VPA in monotherapy and after adding on ESM, as well as the serum concentrations of ESM in the combination therapy Namea (f/m)
Age (year, month)
ESM concentration (mg/ml)
VPA concentration monotherapy (mg/ml)
VPA concentration with ESM (mg/ml)
H.N. (f) F.R. (m) O.T. (m) B.M. (m)
13.5 5.11 5.7 2.5
89.8 63.8 127.8 106.2
120.4 88.9 146.5 105.0
95.9 80.9 76.0 67.4
6.10
96.9 27.0
115.2 24.5
80.1 11.9
Mean S.D.
f, female; m, male. n = 4, one female, three male.
a
All blood samples were taken on the early morning before the first dosage of AEDs (at 8.00 a.m.). The serum concentrations were estimated by high-performance liquid chromatography (HPLC [5]). Out of two to four available measurements, a mean serum value for each AED was calculated in every patient. The mean serum value of these estimations was taken for the interpretation. The per cent changes of the serum concentrations of VPA were calculated individually, and the mean values were determined. The statistical significance was analysed with the Wilcoxon-test. The children were continuously observed as in-patients. All seizures and possible side effects were registered.
spectively). In all patients, the serum levels of VPA rose about 39.7 9 24.1% (mean and S.D.; range, 7.8–92.7%) after stopping ESM, or they fell about 26.59 12.0% (mean and S.D., range 8.3–48.1%) when ESM was added on the therapy. Individual changes of VPA serum concentrations are scattered over a wide range. The serum levels of VPA with and without ESM are presented in Fig. 1. In these children, the changes of VPA serum concentrations were influenced neither by age nor by the serum levels of ESM (r= − 0.20, P \ 0.2; nor r= 0.28, P\ 0.2; respectively). In all patients the serum concentrations of ESM were in the
3. Results Mean serum concentrations of VPA after stopping ESM increased from 90.0 mg/ml (range, 71.3–108.0 mg/ml) up to 122.2 mg/ml (range, 93.7–153.4 mg/ml). When ESM was added to VPA monotherapy mean serum concentrations of VPA decreased from 115.2 mg/ml (range, 88.9– 146.5 mg/ml) to 80.1 mg/ml (range, 67.4 –95.9 mg/ml). Considering all the patients together, mean serum levels of VPA were statistically significantly higher in monotherapy (P B 0.01, Wilcoxon-test) than in combination with ESM (120.0920 mg/ml; range, 88.9 – 153.4 mg/ml, or 87.09 13.1 mg/ml; range, 67.4 – 108.0 mg/ml; re-
Fig. 1. All serum concentrations of VPA with and without ESM. In combination with ESM in children (n = 13), the VPA serum concentrations are lower (CVPA =87 913.1 mg/ml (mean and S.D.); range, 67.4 – 95.9 mg/ml) than in the monotherapy (CVPA =120.0 921.1 mg/ml (mean 9S.D.); range, 93.7 – 153.4 mg/ml) the difference being statistically significant (P B0.01). C, serum concentration.
348
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349
therapeutically effective range (63.8 – 127.8 mg/ ml; mean, 97.2 mg/ml). Abrupt discontinuation of ESM did not provoke any withdrawal seizures. The seizure type and seizure frequency remained unchanged in all patients. No other withdrawal symptoms (like symptoms of the vegetative nervous system) were detected. Remarkable increase of VPA serum levels was not followed by any toxic clinical symptoms, like gastro-intestinal problems, sedation, or tremor, in our patients.
4. Discussion The results of this study show a clear-cut influence of ESM on the serum levels of VPA. In ESM/VPA combination therapy, serum concentrations of VPA were decreased compared with the serum concentrations of VPA in monotherapy intra-individually. This was true in every patient, but the measurements varied greatly between the individual patients. The serum levels of VPA were not influenced by the age of the patients nor by the serum concentrations of ESM. After stopping ESM, the serum levels of VPA were rather high but without ontoward reactions in these patients. Previous studies reported interactions between ESM and VPA [1,2,4,7,8]. Influence of VPA on ESM was described, but the results were partly contradictory. However, effects of ESM on VPA serum levels have not yet been studied up to now. The changes of VPA serum concentrations are statistically significant. Serum concentrations of VPA may greatly fluctuate during 24 h. The early morning values, however, change only little from day to day. Fluctuations were further compensated by taking the mean values from two to four measurements. The mechanism of the interaction is not clear. ESM has no known enzyme inducing properties and it is only minimally (5 – 10%) bound to serum proteins [3]. A change of the capacity in serum protein to bind to VPA in combination with ESM can not explain the changes of the serum levels of VPA of about 28 – 36%. Lower serum concentrations of VPA when ESM is
coadministered indicate a reduced resorption or a faster elimination of VPA. After stopping ESM, it takes several days until it disappears in blood. In this period, VPA gradually rises to a new level. This could indicate a participation of some enzyme process in the elimination of VPA. An interaction on the level of resorption should influence the serum levels of VPA not gradually, but immediately after the absorption of ESM has been completed. However, the mechanism of ESM to influence the metabolism of VPA leading to lower serum levels still remains to be cleared. In clinical practice, the influence of ESM on VPA serum concentrations should be taken into consideration. After discontinuing ESM, the increase of VPA serum concentrations may lead to better efficacy or to toxic side effects. In our patients, such clinical symptoms were not observed. On the other side, a decrease of VPA serum levels should be expected after adding ESM to a pre-existing VPA therapy.
References [1] Battino, D., Cusi, C., Franceschetti, S., Moise, A., Spina, S. and Avanzini, G., Ethosuximide plasma concentrations: Influence of age and associated concomitant therapy, Clin. Pharmacokinet., 7 (1982) 176 – 180. [2] Bauer, L.A., Harris, C., Wilensky, A.J., Raisys, V.A. and Levy, R.H., Ethosuximide kinetics: Possible interaction with valproic acid, Clin. Pharmacol. Ther., 31, 8 (1982) 741 – 745. [3] Chang, T., Dill, W.A. and Glazko, A.J., Ethosuximide: Absorption, distribution and excretion. In: D.M. Woodbury, J.K. Penry, and R.P. Schmidt (Eds.), Antiepileptic Drugs, Raven Press, New York, 1972, pp. 417 – 423. [4] Flachs, H., Wu¨rtz-Joergensen, A., Gram, L. and Wulf, K., Sodium di-n-propyl acetate - its interaction with other antiepileptic drugs, Pharm. Weekbl., 112 (1977) 320. [5] Juergens, U., HPLC analysis of antiepileptic drugs in blood samples. Micropore separation of fourteen compounds, J. Liq. Chromatogr., 10 (2 and 3) (1987) 507 – 532. [6] Martinovic, Z., Comparison of ethosuximide with sodium valproate as monotherapies of absence seizures. In: M. Parsonage (Ed.), Ad6ances in Epileptology, XIVth Epilepsy International Symposium, Raven Press, New York, 1983, pp. 301 – 305. [7] Mattson, R.H. and Cramer, J.A., Valproic acid and ethosuximide interaction, Ann. Neurol., 7 (1980) 583 – 584.
R.A. Sa¨lke-Kellermann et al. / Epilepsy Research 26 (1997) 345–349 [8] Pisani, F., Narbone, M.C., Trunfio, C., Fazio, A., La Rosa, G., Oteri, G. and Di Perri, R., Valproic acid-ethosuximide interaction: A pharmacokinetic study, Epilepsia, 25 (2) (1984) 229–233. [9] Sa¨lke-Kellermann, R.A., Klinische Pharmakologie von
349
Ethosuximid: Zwei prospektive Studien u¨ber die Fluktuationen der Serumkonzentrationen im Tagesverlauf, abha¨ngig vom Dosierungsschema, und u¨ber die Eliminationshalbwertszeit unter klinischen Bedingungen, Thesis, Mu¨nster, 1993.
.