Epilepsy Research, 13 (1992) 89-92 0920-1211/92/SO5.00 0 1992 Elsevier Science Publishers B.V. All rights reserved
89
EPIRES 00502
An assessment of serum and red blood cell folate concentrations in patients with epilepsy on lamotrigine therapy
J.W.A.S. Sander and P.N. Patsalos Epilepsy Research Group, Chalfont Centre for Epilepsy,
Gerrarris Cross, Bucks. SL9 ORJ, UK and Institute of Neurology,
Queen Square, London WCIN 3BG, UK
(Received 14 February 1992; revision received 8 May 1992; accepted 10 May 1992) Key words: Lamotrigine; Serum folate; Red blood cell folate
Lamotrigine (LTG) is a new antiepileptic drug which is effective in refractory epilepsy and which has been shown to have weak antifolate properties in vitro. The effect of LTG on serum folate and red cell folate (RBC) concentrations was assessed in a series of 14 patients on short-term LTG treatment during a placebo-controlled double-blind study. A further 14 patients who had been treated with LTG for up to 5 years were also assessed. In the short-term double-blind study the baseline mean serum folate concentration was 2.7 ng/ ml and mean RBC folate concentration was 295 ng/ml. After 12 weeks of LTG therapy mean concentrations were 3.3 ng/ml and 339 ng/ ml respectively and corresponding levels after 12 weeks of placebo were 2.4 ng/ml and 288 ng/ml. Patients on chronic LTG therapy showed no significant difference in RBC folate concentrations compared to those prior to LTG therapy (346 compared to 407 ng/ml). Other biochemical and haematological parameters were unaltered by LTG therapy. Thus, neither short-term nor chronic LTG therapy appears to be associated with significant changes in serum or RBC folate concentrations.
Introduction
Lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,Ctriazine) is a new antiepileptic drug (AED) which is effective in refractory epilepsy12. It is a phenyltriazine derivative not related to any of the AEDs currently used and with a putative mode of action relating to the inhibition of glutamate release5. LTG was originally developed for its anti-folate properties based on the hypothesis that folates were potentially epileptogenic’. Although LTG has been shown to have weak anti-folate properties in vitro*, no such effects have been reported in Dr J.W.A.S. Sander, Chalfont Centre for Epilepsy, Gerrards Cross, Bucks. SL9 ORJ, UK. Correspondence
to:
vivo in man. Further, there are no data available in patients on long-term LTG therapy. We report on the effect of LTG on red blood cell (RBC) and serum folate concentrations in patients with epilepsy medicated with LTG for 12 weeks during a placebo-controlled double-blind study and on RBC folate concentrations in patients medicated for up to 5 years. Patients and methods
Two groups of patients were studied. Group
1
Twenty-one adult patients (18 male, 3 female) with chronic refractory epilepsy, in residential care at the Chalfont Centre for Epilepsy, were evalu-
90
ated during a double-blind placebo-controlled crossover study of the efficacy of LTG”. Eighteen patients were taking AED polytherapy, 2 patients carbamazepine (CBZ) and 1 patient phenytoin (PHT) monotherapy. Seven patients were on 2 AEDs and 11 were on 3 AEDs. Concomitant AEDs included (number of patients): CBZ (19), PHT (8), sodium valproate (13), primidone (3) clobazam (4) and nitrazepam (1). Haematological and biochemical screening showed no abnormalities other than those known to be due to AED medication. Patients were randomised to one of two treatment groups (A and B). Each group had an 8week baseline period. In group A this was followed by a 1Zweek LTG treatment period, a 6week washout period where LTG was withdrawn by week 2 and replaced by placebo, a second 12week placebo treatment period and a second 6week washout period. In group B, placebo was given through the first treatment period and the first washout period and LTG given during the second treatment period and reduced during the first 2 weeks of the second washout period. Placebo was given for the final 4 weeks of the second TABLE
Group 2
This group comprised 14 adults patients (6 male, 8 female) who had benefited from a previous trial of LTG and who had taken LTG continuously for more than 2 years (2.1-5 years)‘*. All patients had chronic refractory epilepsy and were evaluated either as in-patients or out-patients at the Chalfont Centre for Epilepsy, or as out-patients at the National Hospital for Neurology and Neurosurgery (Queen Square), London. Most patients were taking AED polytherapy at initiation of LTG treatment but 2 of these patients subsequently received LTG monotherapy. RBC folate and haematological screens were undertaken at baseline (i.e., before initiation of treatment with LTG) and at the last follow-up visit. Folate concentrations were determinated on a RA-XT Technicon Analyser (Basingstoke, Hampshire, UK) using manufacturer reagents and according to manufacturer instructions. The quoted
I
Patients on short-term Patient
washout period. Serum folate and RBC folate concentrations were determined at baseline and at 2week intervals during the first month of each treatment period, and monthly thereafter.
No.
lamotrigine
therapy
Concentration RBC folate
Placebo
Baseline period (ng/ml) Serum folate
period
Concentration RBC folate
Lamotrigine (ng/ml) Serum folate
Concentration RBC folate
period
_______.-
(ng/ml) Serum folate 3.1
468
1.8
528
2.0
324
2
380
2.5
183
1.7
212
3.4
3
245
1.7
178
2.5
213
2.3
4
136
3.9
355
2.6
427
4.6
5
439
3.3
552
3.9
399
3.8
6
3.0 1.5
110 219
2.0 2.7
166
I
128 193
2.9 1.9
8
268
2.3
208
3.1
332 232
2.0
420
1.2
287 151
3.1
9
3.7
380
1.6
397
4.6
239
3.8
390
3.8
595
4.8
3.6
439
3.7
429
5.3
13
338 471
3.8
367
3.1
5.4
14
167
3.1
195
2.0
465 187
288
2.4 2.Cb3.0
10 11 12
Geometric
mean
95% confidence interval
295 229-380
2.7 2.2-3.3
219-380
303
339 263436
2.4
1.6 3.3 2.6-3.3
91
reference values for serum folate and RBC folate concentrations are > 2 ng/ml and 12&860 ng/ml respectively.
Group 2
Data were analysed by paired t-test after logarithmic transformation.
RBC folate concentrations for the 14 patients in this group are shown in Table II. No significant difference was observed between baseline and LTG treatment periods. Haematological and biochemical parameters were unremarkable during the study period.
Results
Discussion
Group I
Folates, which function as co-enzymes in metabolic energy-related processes, are naturally found in a variety of foods. Consequently, serum folate concentrations fluctuate significantly with diet, and thus the measurement of RBC folate concentration is considered a better indicator of tissue folate stores’. In the present study we evaluated both serum and RBC folate concentrations in patients receiving short-term LTG therapy and in patients on chronic LTG therapy. In the double-blind placebo-controlled group, LTG treatment was not associated with any significant change in RBC or serum folate concentrations when compared to either placebo or baseline periods. Similarly, chronic LTG therapy was not associated with any significant change in RBC folate concentrations. As each patient acted as his/her own control concomitant AED medication (e.g., PHT, CBZ, primidone and phenobarbitonal, which have been associated with lower RBC and serum folate concentrations) is not a consideration”3,4,6977’o In conclusion, therefore, LTG therapy does not appear to have a significant effect on RBC or serum folate concentration and thus the routine monitoring of folate concentrations is probably not relevant in the use of this new AED in the management of epilepsy.
Statistical evaluation
Three patients did not complete the evaluation and 4 patients were excluded from the data analysis because they were subsequently determined to be on chronic folate supplementation (as 5 mg/ day folic acid). The RBC and serum folate concentrations of the 14 patients who completed the study are shown in Table I. Although the mean serum folate concentration increased during the LTG treatment period, no significant difference in RBC folate concentration was observed. LTG did not affect any other haematological or biochemical parameters studied.
TABLE
II
Patients on chronic lamotrigine Patient
Sex
No.
therapy
Duration
LTG
RBC folate
of therapy
daily
concentration
(years)
intake (mg)
Baseline
(ng/ml) LTG
1
M
5.1
500
468
512
2
F
4.4
300
332
596
3 4
F F
4.5
600
n/a
702
4.5
400
nla
243
5
F
4.3
400
488
423
6
M
4.2
500
332
386
7
M
4.2
400
450
322
8
F
4.1
150
232
460
9
M
3.4
850
296
390
10
F
3.3
200
nla
437
11 12
F F
283 346
338 277
3.3
400 500 400 300
13
F
3.0 2.5
14
M
2.1
Geometric
mean
95% confidence n/a, not available.
nia
540
nia
322
346 interval
295405
407 339479
Acknowledgements
We are grateful to the Wellcome Research Laboratories for the supply of lamotrigine and to Action Research, the Brain Research Trust and the National Society for Epilepsy -for financial support. We are also grateful to the patients who agreed to be evaluated.
92 References I Al-Mussed, mazepine
A.A., Zakrzewska,
J.M. and Bain, B.J., Carba-
and fohc acid in trigeminal
neuralgia
patients,
J.
2 Davis, R.E. and Nicol, D.J., Fohc acid, Inr. J. Biochem.,
20
T., Gough,
H., Bissessor,
M. and Callagham,
A., Crowly,
N., A comparative
effects of anticonvulsant
with epilepsy,
M., Baker,
study of the relative
drugs and dietary
folate status of patients
folate on red cell
Q. J. Med., 65 (1987)
H., Phenytoin:
Levy, R. Mattson, fuss (Eds.),
interactions
with other
B. Meldrum,
Antiepileptic
drugs.
In: R.
J.K. Penry and F.E. Drei-
Drugs,
Raven
Press,
New York,
5 Leach, M.J., Marden, ical studies
C.M. and Miller, A.A., Pharmacolog-
on lamotrigine,
II. Neurochemical
a novel potential studies
antiepileptic
on the mechanism
Levy, R. Mattson, fuss (Eds.),
Cloyd,
J.C.,
B. Meldrum,
Antiepileptic
Drugs,
NY, 1989, pp. 439-445. 7 Mattson, R.H. and Cramer,
J.K. Penry and F.E.
Drugs,
Raven
Press,
motrigine.
Primidone:
toxicity. Press,
B., Peck, A.W.,
D.N. and Morgan,
In: B.S. Meldrum
New
and
R.J. Porter
Drugs, John Libbey,
London,
Leach,
R.J., La-
(Eds.),
New
1986, pp. 165-
177. 9 Reynolds,
E.H., Milner, G., Matthews, therapy,
folic acid metabolism, 10 Reynolds,
E.H.,
son, B. Meldrum, Drugs,
D.M. and Chanarin,
megaloblastic
haemopoiesis
and
Q. J. Med., 35 (1966) 521-537.
Phenytoin:
toxicity.
In: R. Levy, R. Matt-
J.K. Penry and F.E. Dreifuss Raven
Press,
New York,
@is.),
NY,
Anfi-
1989, pp.
241-255.
11 Sander,
J.W.A.S.,
Patsalos,
P.N.,
Oxley,
J.R.,
double
controlled
in patients
In: R.
epilepsy, 12 Sander,
New York,
Patsalos,
toxicity.
epilepsy,
add-on
trial of lamotrigine
Hamilton,
blind placebowith severe
Epilepsy Res., 6 (1990) 221-226. J.W.A.S.,
Trevisoi-Bittencourt,
P.N. and Shorvon,
term tolerability J.A., Phenobarbitone:
Roth,
M.J. and Yuen, W.C., A randomised
J.K. Penry and F.E. DreiRaven
D.A.,
P.L., Parsons,
of ac-
tion, Epilepsia, 27 (1986) 49C497. I.E. and
B. Meldrum,
Antiepileptic
Sawyer,
Anticonvulsant
epileptic
NY, 1989, pp. 215-232.
6 Leppik,
A.A.,
I., Anticonvulsant
91 l-919.
drug.
8 Miller,
M.J., Wheatley,
(1988) 133-139.
4 Kutt,
(Eds.),
York, NY, 1989, pp. 341-355.
R. Sot. Med., 85 (1992) 19-22.
3 Goggin,
In: R. Levy, R. Mattson, Dreifuss
of lamotrigine
P.C.,
Hart,
Y.M.,
S.D., The efficacy
and long-
in the treatment
of severe
Epilepsy Res., 7 (1990) 226-229.
89
EPIRES 00502
An assessment of serum and red blood cell folate concentrations in patients with epilepsy on lamotrigine therapy
J.W.A.S. Sander and P.N. Patsalos Epilepsy Research Group, Chalfont Centre for Epilepsy,
Gerrarris Cross, Bucks. SL9 ORJ, UK and Institute of Neurology,
Queen Square, London WCIN 3BG, UK
(Received 14 February 1992; revision received 8 May 1992; accepted 10 May 1992) Key words: Lamotrigine; Serum folate; Red blood cell folate
Lamotrigine (LTG) is a new antiepileptic drug which is effective in refractory epilepsy and which has been shown to have weak antifolate properties in vitro. The effect of LTG on serum folate and red cell folate (RBC) concentrations was assessed in a series of 14 patients on short-term LTG treatment during a placebo-controlled double-blind study. A further 14 patients who had been treated with LTG for up to 5 years were also assessed. In the short-term double-blind study the baseline mean serum folate concentration was 2.7 ng/ ml and mean RBC folate concentration was 295 ng/ml. After 12 weeks of LTG therapy mean concentrations were 3.3 ng/ml and 339 ng/ ml respectively and corresponding levels after 12 weeks of placebo were 2.4 ng/ml and 288 ng/ml. Patients on chronic LTG therapy showed no significant difference in RBC folate concentrations compared to those prior to LTG therapy (346 compared to 407 ng/ml). Other biochemical and haematological parameters were unaltered by LTG therapy. Thus, neither short-term nor chronic LTG therapy appears to be associated with significant changes in serum or RBC folate concentrations.
Introduction
Lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,Ctriazine) is a new antiepileptic drug (AED) which is effective in refractory epilepsy12. It is a phenyltriazine derivative not related to any of the AEDs currently used and with a putative mode of action relating to the inhibition of glutamate release5. LTG was originally developed for its anti-folate properties based on the hypothesis that folates were potentially epileptogenic’. Although LTG has been shown to have weak anti-folate properties in vitro*, no such effects have been reported in Dr J.W.A.S. Sander, Chalfont Centre for Epilepsy, Gerrards Cross, Bucks. SL9 ORJ, UK. Correspondence
to:
vivo in man. Further, there are no data available in patients on long-term LTG therapy. We report on the effect of LTG on red blood cell (RBC) and serum folate concentrations in patients with epilepsy medicated with LTG for 12 weeks during a placebo-controlled double-blind study and on RBC folate concentrations in patients medicated for up to 5 years. Patients and methods
Two groups of patients were studied. Group
1
Twenty-one adult patients (18 male, 3 female) with chronic refractory epilepsy, in residential care at the Chalfont Centre for Epilepsy, were evalu-
90
ated during a double-blind placebo-controlled crossover study of the efficacy of LTG”. Eighteen patients were taking AED polytherapy, 2 patients carbamazepine (CBZ) and 1 patient phenytoin (PHT) monotherapy. Seven patients were on 2 AEDs and 11 were on 3 AEDs. Concomitant AEDs included (number of patients): CBZ (19), PHT (8), sodium valproate (13), primidone (3) clobazam (4) and nitrazepam (1). Haematological and biochemical screening showed no abnormalities other than those known to be due to AED medication. Patients were randomised to one of two treatment groups (A and B). Each group had an 8week baseline period. In group A this was followed by a 1Zweek LTG treatment period, a 6week washout period where LTG was withdrawn by week 2 and replaced by placebo, a second 12week placebo treatment period and a second 6week washout period. In group B, placebo was given through the first treatment period and the first washout period and LTG given during the second treatment period and reduced during the first 2 weeks of the second washout period. Placebo was given for the final 4 weeks of the second TABLE
Group 2
This group comprised 14 adults patients (6 male, 8 female) who had benefited from a previous trial of LTG and who had taken LTG continuously for more than 2 years (2.1-5 years)‘*. All patients had chronic refractory epilepsy and were evaluated either as in-patients or out-patients at the Chalfont Centre for Epilepsy, or as out-patients at the National Hospital for Neurology and Neurosurgery (Queen Square), London. Most patients were taking AED polytherapy at initiation of LTG treatment but 2 of these patients subsequently received LTG monotherapy. RBC folate and haematological screens were undertaken at baseline (i.e., before initiation of treatment with LTG) and at the last follow-up visit. Folate concentrations were determinated on a RA-XT Technicon Analyser (Basingstoke, Hampshire, UK) using manufacturer reagents and according to manufacturer instructions. The quoted
I
Patients on short-term Patient
washout period. Serum folate and RBC folate concentrations were determined at baseline and at 2week intervals during the first month of each treatment period, and monthly thereafter.
No.
lamotrigine
therapy
Concentration RBC folate
Placebo
Baseline period (ng/ml) Serum folate
period
Concentration RBC folate
Lamotrigine (ng/ml) Serum folate
Concentration RBC folate
period
_______.-
(ng/ml) Serum folate 3.1
468
1.8
528
2.0
324
2
380
2.5
183
1.7
212
3.4
3
245
1.7
178
2.5
213
2.3
4
136
3.9
355
2.6
427
4.6
5
439
3.3
552
3.9
399
3.8
6
3.0 1.5
110 219
2.0 2.7
166
I
128 193
2.9 1.9
8
268
2.3
208
3.1
332 232
2.0
420
1.2
287 151
3.1
9
3.7
380
1.6
397
4.6
239
3.8
390
3.8
595
4.8
3.6
439
3.7
429
5.3
13
338 471
3.8
367
3.1
5.4
14
167
3.1
195
2.0
465 187
288
2.4 2.Cb3.0
10 11 12
Geometric
mean
95% confidence interval
295 229-380
2.7 2.2-3.3
219-380
303
339 263436
2.4
1.6 3.3 2.6-3.3
91
reference values for serum folate and RBC folate concentrations are > 2 ng/ml and 12&860 ng/ml respectively.
Group 2
Data were analysed by paired t-test after logarithmic transformation.
RBC folate concentrations for the 14 patients in this group are shown in Table II. No significant difference was observed between baseline and LTG treatment periods. Haematological and biochemical parameters were unremarkable during the study period.
Results
Discussion
Group I
Folates, which function as co-enzymes in metabolic energy-related processes, are naturally found in a variety of foods. Consequently, serum folate concentrations fluctuate significantly with diet, and thus the measurement of RBC folate concentration is considered a better indicator of tissue folate stores’. In the present study we evaluated both serum and RBC folate concentrations in patients receiving short-term LTG therapy and in patients on chronic LTG therapy. In the double-blind placebo-controlled group, LTG treatment was not associated with any significant change in RBC or serum folate concentrations when compared to either placebo or baseline periods. Similarly, chronic LTG therapy was not associated with any significant change in RBC folate concentrations. As each patient acted as his/her own control concomitant AED medication (e.g., PHT, CBZ, primidone and phenobarbitonal, which have been associated with lower RBC and serum folate concentrations) is not a consideration”3,4,6977’o In conclusion, therefore, LTG therapy does not appear to have a significant effect on RBC or serum folate concentration and thus the routine monitoring of folate concentrations is probably not relevant in the use of this new AED in the management of epilepsy.
Statistical evaluation
Three patients did not complete the evaluation and 4 patients were excluded from the data analysis because they were subsequently determined to be on chronic folate supplementation (as 5 mg/ day folic acid). The RBC and serum folate concentrations of the 14 patients who completed the study are shown in Table I. Although the mean serum folate concentration increased during the LTG treatment period, no significant difference in RBC folate concentration was observed. LTG did not affect any other haematological or biochemical parameters studied.
TABLE
II
Patients on chronic lamotrigine Patient
Sex
No.
therapy
Duration
LTG
RBC folate
of therapy
daily
concentration
(years)
intake (mg)
Baseline
(ng/ml) LTG
1
M
5.1
500
468
512
2
F
4.4
300
332
596
3 4
F F
4.5
600
n/a
702
4.5
400
nla
243
5
F
4.3
400
488
423
6
M
4.2
500
332
386
7
M
4.2
400
450
322
8
F
4.1
150
232
460
9
M
3.4
850
296
390
10
F
3.3
200
nla
437
11 12
F F
283 346
338 277
3.3
400 500 400 300
13
F
3.0 2.5
14
M
2.1
Geometric
mean
95% confidence n/a, not available.
nia
540
nia
322
346 interval
295405
407 339479
Acknowledgements
We are grateful to the Wellcome Research Laboratories for the supply of lamotrigine and to Action Research, the Brain Research Trust and the National Society for Epilepsy -for financial support. We are also grateful to the patients who agreed to be evaluated.
92 References I Al-Mussed, mazepine
A.A., Zakrzewska,
J.M. and Bain, B.J., Carba-
and fohc acid in trigeminal
neuralgia
patients,
J.
2 Davis, R.E. and Nicol, D.J., Fohc acid, Inr. J. Biochem.,
20
T., Gough,
H., Bissessor,
M. and Callagham,
A., Crowly,
N., A comparative
effects of anticonvulsant
with epilepsy,
M., Baker,
study of the relative
drugs and dietary
folate status of patients
folate on red cell
Q. J. Med., 65 (1987)
H., Phenytoin:
Levy, R. Mattson, fuss (Eds.),
interactions
with other
B. Meldrum,
Antiepileptic
drugs.
In: R.
J.K. Penry and F.E. Drei-
Drugs,
Raven
Press,
New York,
5 Leach, M.J., Marden, ical studies
C.M. and Miller, A.A., Pharmacolog-
on lamotrigine,
II. Neurochemical
a novel potential studies
antiepileptic
on the mechanism
Levy, R. Mattson, fuss (Eds.),
Cloyd,
J.C.,
B. Meldrum,
Antiepileptic
Drugs,
NY, 1989, pp. 439-445. 7 Mattson, R.H. and Cramer,
J.K. Penry and F.E.
Drugs,
Raven
Press,
motrigine.
Primidone:
toxicity. Press,
B., Peck, A.W.,
D.N. and Morgan,
In: B.S. Meldrum
New
and
R.J. Porter
Drugs, John Libbey,
London,
Leach,
R.J., La-
(Eds.),
New
1986, pp. 165-
177. 9 Reynolds,
E.H., Milner, G., Matthews, therapy,
folic acid metabolism, 10 Reynolds,
E.H.,
son, B. Meldrum, Drugs,
D.M. and Chanarin,
megaloblastic
haemopoiesis
and
Q. J. Med., 35 (1966) 521-537.
Phenytoin:
toxicity.
In: R. Levy, R. Matt-
J.K. Penry and F.E. Dreifuss Raven
Press,
New York,
@is.),
NY,
Anfi-
1989, pp.
241-255.
11 Sander,
J.W.A.S.,
Patsalos,
P.N.,
Oxley,
J.R.,
double
controlled
in patients
In: R.
epilepsy, 12 Sander,
New York,
Patsalos,
toxicity.
epilepsy,
add-on
trial of lamotrigine
Hamilton,
blind placebowith severe
Epilepsy Res., 6 (1990) 221-226. J.W.A.S.,
Trevisoi-Bittencourt,
P.N. and Shorvon,
term tolerability J.A., Phenobarbitone:
Roth,
M.J. and Yuen, W.C., A randomised
J.K. Penry and F.E. DreiRaven
D.A.,
P.L., Parsons,
of ac-
tion, Epilepsia, 27 (1986) 49C497. I.E. and
B. Meldrum,
Antiepileptic
Sawyer,
Anticonvulsant
epileptic
NY, 1989, pp. 215-232.
6 Leppik,
A.A.,
I., Anticonvulsant
91 l-919.
drug.
8 Miller,
M.J., Wheatley,
(1988) 133-139.
4 Kutt,
(Eds.),
York, NY, 1989, pp. 341-355.
R. Sot. Med., 85 (1992) 19-22.
3 Goggin,
In: R. Levy, R. Mattson, Dreifuss
of lamotrigine
P.C.,
Hart,
Y.M.,
S.D., The efficacy
and long-
in the treatment
of severe
Epilepsy Res., 7 (1990) 226-229.
