147
Epilepsy Res., 11(1992) 147-150
Elsevier EPIRES 00463
Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-lO,ll-epoxide
T. Warner, P.N. Patsalos, M. Prevett, A.A. Elyas and J.S. Duncan Epilepsy Research Group, Chalfont Centre for Epilepsy and Institute of Neurology, Queen Square, London (UK)
(Received 15 November 1991; accepted 3 January 1992) Key worak Lamotrigine; Carbamazepine;
Carbamaxepine-lO,ll-epoxide;
Drug interaction
We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamaxepine (CBZ) and its primary metabolite CBZ-lO,ll-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P < 0.01) and the CBZE/CBZ ratio increased by 19% (P < 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.
INTRODUCTION Lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is a new antiepileptic drug (AED) which is thought to stabilise neuronal membranes and to inhibit excitatory neurotransmitter release, principally glutamate’. In experimental animal models LTG has been shown to have an antiepileptic profile similar to that of carbamazepine and phenytoin” and in add-on clinical trials to be effective against partial and generalised tonic-clonic seizuresg~‘3*‘4. In man, LTG is completely bioavailable, exhibits linear kinetics, is extensively metabolised Correspondence to: Dr. P.N. Patsalos, University Department of Clinical Neurology, Institute of Neurology, Queen Square, London WClN 3BG, UK.
and excreted in urine predominantly as a glucuronide conjugate lo. LTG metabolism is inducible so that the mean elimination half-life in patients taking enzyme-inducing AEDs is 15 h, compared to 24 h in normal volunteers4. Sodium valproate inhibits LTG metabolism and mean LTG half-life is increased to 59 h when co-medication consists of sodium valproate only lo. LTG has been observed to show neither marked inductive nor inhibitory properties and add-on studies of LTG have not demonstrated significant changes in serum concentration of concomitant AEDs, including carbamazepine (CBZ)2,gP’3,‘4. We report an interaction between LTG and CBZ and the primary metabolite of CBZ, carbamazepine-lO,ll-epoxide (CBZ-E), which is pharmacologically active3,i6 and has been implicated in contributing to CBZ toxicity’2,‘6.
0920-1211/92/$05.00 @ 1992 Elsevier Science Publishers B.V. All rights reserved
148 PATIENTS
AND METHODS
AEDs included (number of patients): phenytoin (2), sodium valproate (1) and clobazam (1). Patients were taking their AED maintenance therapy for at least 3 months prior to addition of LTG. Median daily intake of LTG was 200 mg (range 100-300 mg). Blood samples were obtained by venepuncture at 08.~ h after an overnight fast and prior to ingestion of morning AED medication before and 3-5 weeks after the introduction of LTG. In patient 1 and in an additional patient sampiing occurred after administration of 2 different LTG
Nine consecutive patients (5 male, 4 female) attending the Assessment Unit of the National Hospital-Chalfont Centre for Epilepsy were studied. They were aged 19-31 years (median = 26 years) and had no systemic, psychiatric or progressive neurological conditions. All patients had severe refractory epilepsy (Table I). All patients were taking CBZ, 6 were on CBZ monoth~rapy, 2 patients were on 2 AEDs and one patient was on 3 AEDs. Concomitant TABLE I Patient details Patient
Sex ._._._-
Age .-_-_____-
---_
Aetiology
____-
A ED medication Seizure type ._____ ___I___ ^_-
1
31
M
s
B,C
2
28
M
3 4 5 6 7 8 9
19 28 27 22 26 26 19
F M M F F M F
U S U S S S S S
D2 C A A
Daily intake (mg)
CBZ 1400 CBZ, SVP 1200,300O CBZ, PHT 1600,2so CBZ, PHT, CLB 1800,400,10 CBZ 1600 CBZ 1200 CBZ 1600 CBZ 2400 CBZ 2800 ___.__ .__~ .___ _,. -.___._---.
B,C B,C B B
.______..___ .___.- ._--__. Aetiology: U, unknown; S, symptomatic. Seizure type: A, simplepartial seizure; B, complex partial seizure; C, secondarily generalised seizure; D2, myoclonic seizure. Antiepileptic drugs (AEDs): CBZ, carbamazepine; CLB, clobazam; PHT, phenytoin; SVP, sodium valproate.
TABLE II Steady-stare serum concentrations -Patient
_~.----
----~
LTG
Serum L. TG
Serum CBZ concentration
Serum CBZ-E concentration
daily
concentration
intake
(,molll}
(~molll) ~-.
(WOW --___II
(m@
1
200
7.7
2
200
20.9
3
150
6.1
4
300
6.2
5
300
9.4
6
200
21.6
7
100
7.4
8
300
6.2
9
200
6.7
Before LTG ._--.31
21 21 24 36 23 32 35 28
During
%
Before
During
%
Before
During
LTG
change
LTG
LTG
change
LTG
LTG
28
-10 -10 +33 0 -11 +3.5 +69 ill +25
1.9 4.2 4.7 10.2 5.5 3.9 5.7 5.8 9.0
2.9 5.7 5.6 10.6 5.8 7.8 10.4 8.0 14.8
+ 53 + 36 + 19 + 4 + 5 +lOO + 82 + 38 +64
0.06 0.20 0.22 0.42 0.15 0.17 0.18 0.17 0.32
0.10 0.30 0.20 0.44 0.18 0.25 0.19 0.20 0.42
19 28 24 32 31 54 39 35
5.6-t2.5b 32+10 28-+6 _ -~~LTG, lamotrigine; CBZ, carbamazepine; CBZ-E, ca~amazepine-lO,ll-e~xide. a vs.b = P < 0.01: c vs. d = P < 0.02.
mean rt SD
CBZ-EICBZ ratio
7.9k3.Y
0.21+0.10d
._.-.I__ % change -_..-.~-
+61 +so -9 +5 +20 +47 +6 +l8 +31
o.25+o.11c __~
149 doses. After clot retraction, serum was separated by centrifugation and stored at -20°C until analysis. Measurements of serum CBZ were made by enzyme immunoassay (EMIT, Syva, UK), CBZ-E by high-performance liquid chromatography6 and LTG by radioimmunoassay’. Statistical analysis was by 2-tailed paired t-test. RESULTS Table II shows the steady-state serum concentrations of CBZ, CBZ-E and LTG in each of the 9 patients studied. Also shown are the calculated CBZ-EICBZ ratios. LTG administration (median daily dose, 200 mg; range 100-300 mg) was associated with an increase in trough steady-state CBZ-E serum concentration in all patients, mean rise of 45% (P < 0.01; Table II). There was a variable increase or decrease in concomitant serum CBZ concentration, mean rise of 16%. CBZE/CBZ ratio increased from a mean of 0.21 to 0.25 (19%, P < 0.02). In 4patients (patients 1,5,7 and 9) these changes were associated with clinical toxicity including dizziness, nausea and diplopia. Subsequent CBZ dose reduction was associated with a resolution of symptoms. In patient 1, a dose effect was observed. An increase in LTG from 200 to 400 mg was accompanied by an additional increase (17%) in CBZ-E. In one additional patient (a female taking CBZ monotherapy 1600 mglday) a LTG dose effect was also observed with serum CBZ-E increasing by 65% when LTG was increased from 100 mg/day to 300 mglday . Serum LTG con~ntrations were within the putative target range (4-12 pmol/l) in 7 patients. Two patients (2 and 6) had high serum LTG concentrations (Table II) but were not symptomatic. DISCUSSION LTG is a new AED which has been licensed in Ireland and will soon be available in the UK. In clinical practice, LTG will often be added to the therapy of a patient who is already taking the maximum tolerated dose of CBZ, and who will have little reserve for tolerating higher serum concen-
trations of CBZ or CBZ-E. It is important, therefore, to recognise any clinically significant drug interactions so that unwanted side-effects can be prevented. We report an interaction between LTG and CBZ in 9 consecutive patients; accepting the limitations of an unblinded study, in 4 patients these changes were associated with side-effects such as dizziness, nausea and diplopia which only resolved after a reduction in CBZ dosage. Our results show a significant increase in mean steadystate serum CBZ-E concentration on the introduction of LTG, in one patient by as much as 100%. A LTG dose-dependent interaction was observed in 2 patients. It was not thought likely that LTG was directly responsible for the side-effects since in all patients presenting with side-effects serum LTG concentrations were below 10 pmol/l and dose-related side-effects from LTG have generally been associated with serum concentrations in excess of 12 ~molll. It is possible that the symptoms were the result of the combination of LTG, CBZ and CBZ-E. CBZ-E, the primary metabolite of CBZ, is pharmacologically active3,16 and is considered to contribute to the development of CBZ-related sideeffects3*‘*. The administration of CBZ with other commonly prescribed AEDs such as phenytoin, phenobarbitone or valproic acid commonly results in an increase in CBZ-EICBZ ratio5,7,‘5. These interactions may occur by two mechanisms, Phenytoin and phenobarbitone, as potent enzyme inducers, induce the conversion of CBZ to CBZ-E while valproic acid inhibits epoxide hydrolase, the enzyme which converts CBZ-E to CBZ-lO,ll-dihydroxide. A marked increase in serum CBZ-E concentrations, and a minimal change in CBZ concentrations seen in the current study suggest that LTG interacts with CBZ by inhibiting epoxide hydrolase’. In vitro studies however are required to ascertain the exact mechanism of this interaction, In conclusion, we report a pharmacokinetic interaction between LTG and CBZ which would not be reliably detected by the routine monitoring of serum CBZ only. The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.
1.50
ACKNOWLEDGEMENTS We are grateful to the Wellcome Research Lab-
REFERENCES 1 Biddlecombe, R.A., Dean, K.L., Smith, CD. and Jeal, S.C., Validation of a radioimmunoassay for the determination of human plasma concentrations of lamotrigine, J. Pharm. Biomed. Anal., 8 (1990) 691-694. 2 Binnie, C.D., Debets, R.M.C. and Engelman, M., Double
blind crossover trial of lamotrigine as add-on therapy in intractable epilepsy, Epilepsy Res., 4 (1989) 222-229. Bourgeois, B.F.D. and Wad, N., Individual and combined epileptic and neurotoxic activity of carbamazepine and carbamazepine-lO,ll-epoxide in mice, 1. Pharmacol. Exp. ‘Z’her., 231(1984)411-415.
Cohen, A.F., Land, G.S., Breimer, D.D., Yuen, W.C., Winton, C. and Peck, A.W., Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans, Clin. Pharmacol. Ther., 42 (1987) 535-541. Duncan, J.S., Patsalos, P.N. and Shorvon, S.D., Effects of discontinuation of phenytoin, carbamazepine and valproate on concomitant antiepileptic medication, Epilepsia, 32 (1991) 101-116. Elyas, A.A., Patsalos, P.N., Agbato, O.A., Brett, E.M. and Lascelles, P.T., Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-lO,ll-epoxide in serum of children with epilepsy, Ther. Drug Monit., 8 (1986) 288-292. Hulsman, J. and Meijers, C., A quantitative approach to the influence of polypharmacy on the metabolism of carbamazepine, Epilepsia, 26 (1985) 544. Leach, M.J., Marsden, C.M. and Miller, A.A., Pharmacological studies on lamotrigine, a novel antiepileptic drug. II. Neurochemical studies on the mechanism of action, Epilepsia, 27 (1986) 490-497.
oratories for the supply of LTG and the LTG assays and to Ms. Carolyn Cowey for secretarial assistance.
9 Loiseau, P., Yuen, W.C., Duche, B., Menager, T. and Arne-Bes, M.C., A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures, Epilepsy Res., 7 (1986) 136-145.
10 Miller, A.A., Sawyer, D.A., Roth, B., Peck, A., Leach, M.J., Wheatley, P.L., Parsons, D.N. and Morgen, R.J.I., Lamotrigine, in: B.S. Meldrum and R.J. Porter (Eds.), New Anticonvulsant Drugs, John Libby, London, 1986, pp. 165-177. 11 Miller, A.A., Wheatley, P., Sawer, D.A., Baxter, M.G. and Roth, B., Pharmacological studies of lamotrigine, a novel antiepileptic drug. I. Anticonvulsant profile in mice and rats, Epilepsia, 27 (1986) 483-489. 12 Patsalos, P.N., Stephenson, T. J., Krishna, S., Elyas, A.A.. Lascelles, P.T. and Wiles, C.M., Side-effects induced by carbamazepine-lO,ll-epoxide, Lancer, ii, (1985) 496. 13 Sander, J. W.A.S., Patsalos, P.N., Oxley, J.R., Hamilton, M.J. and Yuen, W.C., A randomised double-blind placebo-controlled add-on trial of lamotrigine in patients with severe epilepsy, Epilepsy Res., 6 (1990) 221-226. 14 Sander, J.W.A.S., Trevisol-Bittencourt, P.C., Hart, Y.M. and Patsalos, P.N., The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy, Epilepsy Res., 7 (1990) 226-229.
15 Shoeman, J., Elyas, A.A., Brett, E.M. and Lascelles, P.T., Correlation between plasma carbamazepine-lO,ll-epoxide concentrations and drug side effects in children with epilepsy, Dev. Med. Child Neurol., 26 (1984) 757-764. 16 Tomsson, T. and Bertilsson, K., Potent clinical effect of carabamazepine-lO,ll-epoxide in trigeminal neuralgia, Arch. Neurol., 41 (1984) 598-601.
Epilepsy Res., 11(1992) 147-150
Elsevier EPIRES 00463
Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-lO,ll-epoxide
T. Warner, P.N. Patsalos, M. Prevett, A.A. Elyas and J.S. Duncan Epilepsy Research Group, Chalfont Centre for Epilepsy and Institute of Neurology, Queen Square, London (UK)
(Received 15 November 1991; accepted 3 January 1992) Key worak Lamotrigine; Carbamazepine;
Carbamaxepine-lO,ll-epoxide;
Drug interaction
We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamaxepine (CBZ) and its primary metabolite CBZ-lO,ll-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P < 0.01) and the CBZE/CBZ ratio increased by 19% (P < 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.
INTRODUCTION Lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is a new antiepileptic drug (AED) which is thought to stabilise neuronal membranes and to inhibit excitatory neurotransmitter release, principally glutamate’. In experimental animal models LTG has been shown to have an antiepileptic profile similar to that of carbamazepine and phenytoin” and in add-on clinical trials to be effective against partial and generalised tonic-clonic seizuresg~‘3*‘4. In man, LTG is completely bioavailable, exhibits linear kinetics, is extensively metabolised Correspondence to: Dr. P.N. Patsalos, University Department of Clinical Neurology, Institute of Neurology, Queen Square, London WClN 3BG, UK.
and excreted in urine predominantly as a glucuronide conjugate lo. LTG metabolism is inducible so that the mean elimination half-life in patients taking enzyme-inducing AEDs is 15 h, compared to 24 h in normal volunteers4. Sodium valproate inhibits LTG metabolism and mean LTG half-life is increased to 59 h when co-medication consists of sodium valproate only lo. LTG has been observed to show neither marked inductive nor inhibitory properties and add-on studies of LTG have not demonstrated significant changes in serum concentration of concomitant AEDs, including carbamazepine (CBZ)2,gP’3,‘4. We report an interaction between LTG and CBZ and the primary metabolite of CBZ, carbamazepine-lO,ll-epoxide (CBZ-E), which is pharmacologically active3,i6 and has been implicated in contributing to CBZ toxicity’2,‘6.
0920-1211/92/$05.00 @ 1992 Elsevier Science Publishers B.V. All rights reserved
148 PATIENTS
AND METHODS
AEDs included (number of patients): phenytoin (2), sodium valproate (1) and clobazam (1). Patients were taking their AED maintenance therapy for at least 3 months prior to addition of LTG. Median daily intake of LTG was 200 mg (range 100-300 mg). Blood samples were obtained by venepuncture at 08.~ h after an overnight fast and prior to ingestion of morning AED medication before and 3-5 weeks after the introduction of LTG. In patient 1 and in an additional patient sampiing occurred after administration of 2 different LTG
Nine consecutive patients (5 male, 4 female) attending the Assessment Unit of the National Hospital-Chalfont Centre for Epilepsy were studied. They were aged 19-31 years (median = 26 years) and had no systemic, psychiatric or progressive neurological conditions. All patients had severe refractory epilepsy (Table I). All patients were taking CBZ, 6 were on CBZ monoth~rapy, 2 patients were on 2 AEDs and one patient was on 3 AEDs. Concomitant TABLE I Patient details Patient
Sex ._._._-
Age .-_-_____-
---_
Aetiology
____-
A ED medication Seizure type ._____ ___I___ ^_-
1
31
M
s
B,C
2
28
M
3 4 5 6 7 8 9
19 28 27 22 26 26 19
F M M F F M F
U S U S S S S S
D2 C A A
Daily intake (mg)
CBZ 1400 CBZ, SVP 1200,300O CBZ, PHT 1600,2so CBZ, PHT, CLB 1800,400,10 CBZ 1600 CBZ 1200 CBZ 1600 CBZ 2400 CBZ 2800 ___.__ .__~ .___ _,. -.___._---.
B,C B,C B B
.______..___ .___.- ._--__. Aetiology: U, unknown; S, symptomatic. Seizure type: A, simplepartial seizure; B, complex partial seizure; C, secondarily generalised seizure; D2, myoclonic seizure. Antiepileptic drugs (AEDs): CBZ, carbamazepine; CLB, clobazam; PHT, phenytoin; SVP, sodium valproate.
TABLE II Steady-stare serum concentrations -Patient
_~.----
----~
LTG
Serum L. TG
Serum CBZ concentration
Serum CBZ-E concentration
daily
concentration
intake
(,molll}
(~molll) ~-.
(WOW --___II
(m@
1
200
7.7
2
200
20.9
3
150
6.1
4
300
6.2
5
300
9.4
6
200
21.6
7
100
7.4
8
300
6.2
9
200
6.7
Before LTG ._--.31
21 21 24 36 23 32 35 28
During
%
Before
During
%
Before
During
LTG
change
LTG
LTG
change
LTG
LTG
28
-10 -10 +33 0 -11 +3.5 +69 ill +25
1.9 4.2 4.7 10.2 5.5 3.9 5.7 5.8 9.0
2.9 5.7 5.6 10.6 5.8 7.8 10.4 8.0 14.8
+ 53 + 36 + 19 + 4 + 5 +lOO + 82 + 38 +64
0.06 0.20 0.22 0.42 0.15 0.17 0.18 0.17 0.32
0.10 0.30 0.20 0.44 0.18 0.25 0.19 0.20 0.42
19 28 24 32 31 54 39 35
5.6-t2.5b 32+10 28-+6 _ -~~LTG, lamotrigine; CBZ, carbamazepine; CBZ-E, ca~amazepine-lO,ll-e~xide. a vs.b = P < 0.01: c vs. d = P < 0.02.
mean rt SD
CBZ-EICBZ ratio
7.9k3.Y
0.21+0.10d
._.-.I__ % change -_..-.~-
+61 +so -9 +5 +20 +47 +6 +l8 +31
o.25+o.11c __~
149 doses. After clot retraction, serum was separated by centrifugation and stored at -20°C until analysis. Measurements of serum CBZ were made by enzyme immunoassay (EMIT, Syva, UK), CBZ-E by high-performance liquid chromatography6 and LTG by radioimmunoassay’. Statistical analysis was by 2-tailed paired t-test. RESULTS Table II shows the steady-state serum concentrations of CBZ, CBZ-E and LTG in each of the 9 patients studied. Also shown are the calculated CBZ-EICBZ ratios. LTG administration (median daily dose, 200 mg; range 100-300 mg) was associated with an increase in trough steady-state CBZ-E serum concentration in all patients, mean rise of 45% (P < 0.01; Table II). There was a variable increase or decrease in concomitant serum CBZ concentration, mean rise of 16%. CBZE/CBZ ratio increased from a mean of 0.21 to 0.25 (19%, P < 0.02). In 4patients (patients 1,5,7 and 9) these changes were associated with clinical toxicity including dizziness, nausea and diplopia. Subsequent CBZ dose reduction was associated with a resolution of symptoms. In patient 1, a dose effect was observed. An increase in LTG from 200 to 400 mg was accompanied by an additional increase (17%) in CBZ-E. In one additional patient (a female taking CBZ monotherapy 1600 mglday) a LTG dose effect was also observed with serum CBZ-E increasing by 65% when LTG was increased from 100 mg/day to 300 mglday . Serum LTG con~ntrations were within the putative target range (4-12 pmol/l) in 7 patients. Two patients (2 and 6) had high serum LTG concentrations (Table II) but were not symptomatic. DISCUSSION LTG is a new AED which has been licensed in Ireland and will soon be available in the UK. In clinical practice, LTG will often be added to the therapy of a patient who is already taking the maximum tolerated dose of CBZ, and who will have little reserve for tolerating higher serum concen-
trations of CBZ or CBZ-E. It is important, therefore, to recognise any clinically significant drug interactions so that unwanted side-effects can be prevented. We report an interaction between LTG and CBZ in 9 consecutive patients; accepting the limitations of an unblinded study, in 4 patients these changes were associated with side-effects such as dizziness, nausea and diplopia which only resolved after a reduction in CBZ dosage. Our results show a significant increase in mean steadystate serum CBZ-E concentration on the introduction of LTG, in one patient by as much as 100%. A LTG dose-dependent interaction was observed in 2 patients. It was not thought likely that LTG was directly responsible for the side-effects since in all patients presenting with side-effects serum LTG concentrations were below 10 pmol/l and dose-related side-effects from LTG have generally been associated with serum concentrations in excess of 12 ~molll. It is possible that the symptoms were the result of the combination of LTG, CBZ and CBZ-E. CBZ-E, the primary metabolite of CBZ, is pharmacologically active3,16 and is considered to contribute to the development of CBZ-related sideeffects3*‘*. The administration of CBZ with other commonly prescribed AEDs such as phenytoin, phenobarbitone or valproic acid commonly results in an increase in CBZ-EICBZ ratio5,7,‘5. These interactions may occur by two mechanisms, Phenytoin and phenobarbitone, as potent enzyme inducers, induce the conversion of CBZ to CBZ-E while valproic acid inhibits epoxide hydrolase, the enzyme which converts CBZ-E to CBZ-lO,ll-dihydroxide. A marked increase in serum CBZ-E concentrations, and a minimal change in CBZ concentrations seen in the current study suggest that LTG interacts with CBZ by inhibiting epoxide hydrolase’. In vitro studies however are required to ascertain the exact mechanism of this interaction, In conclusion, we report a pharmacokinetic interaction between LTG and CBZ which would not be reliably detected by the routine monitoring of serum CBZ only. The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.
1.50
ACKNOWLEDGEMENTS We are grateful to the Wellcome Research Lab-
REFERENCES 1 Biddlecombe, R.A., Dean, K.L., Smith, CD. and Jeal, S.C., Validation of a radioimmunoassay for the determination of human plasma concentrations of lamotrigine, J. Pharm. Biomed. Anal., 8 (1990) 691-694. 2 Binnie, C.D., Debets, R.M.C. and Engelman, M., Double
blind crossover trial of lamotrigine as add-on therapy in intractable epilepsy, Epilepsy Res., 4 (1989) 222-229. Bourgeois, B.F.D. and Wad, N., Individual and combined epileptic and neurotoxic activity of carbamazepine and carbamazepine-lO,ll-epoxide in mice, 1. Pharmacol. Exp. ‘Z’her., 231(1984)411-415.
Cohen, A.F., Land, G.S., Breimer, D.D., Yuen, W.C., Winton, C. and Peck, A.W., Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans, Clin. Pharmacol. Ther., 42 (1987) 535-541. Duncan, J.S., Patsalos, P.N. and Shorvon, S.D., Effects of discontinuation of phenytoin, carbamazepine and valproate on concomitant antiepileptic medication, Epilepsia, 32 (1991) 101-116. Elyas, A.A., Patsalos, P.N., Agbato, O.A., Brett, E.M. and Lascelles, P.T., Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-lO,ll-epoxide in serum of children with epilepsy, Ther. Drug Monit., 8 (1986) 288-292. Hulsman, J. and Meijers, C., A quantitative approach to the influence of polypharmacy on the metabolism of carbamazepine, Epilepsia, 26 (1985) 544. Leach, M.J., Marsden, C.M. and Miller, A.A., Pharmacological studies on lamotrigine, a novel antiepileptic drug. II. Neurochemical studies on the mechanism of action, Epilepsia, 27 (1986) 490-497.
oratories for the supply of LTG and the LTG assays and to Ms. Carolyn Cowey for secretarial assistance.
9 Loiseau, P., Yuen, W.C., Duche, B., Menager, T. and Arne-Bes, M.C., A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures, Epilepsy Res., 7 (1986) 136-145.
10 Miller, A.A., Sawyer, D.A., Roth, B., Peck, A., Leach, M.J., Wheatley, P.L., Parsons, D.N. and Morgen, R.J.I., Lamotrigine, in: B.S. Meldrum and R.J. Porter (Eds.), New Anticonvulsant Drugs, John Libby, London, 1986, pp. 165-177. 11 Miller, A.A., Wheatley, P., Sawer, D.A., Baxter, M.G. and Roth, B., Pharmacological studies of lamotrigine, a novel antiepileptic drug. I. Anticonvulsant profile in mice and rats, Epilepsia, 27 (1986) 483-489. 12 Patsalos, P.N., Stephenson, T. J., Krishna, S., Elyas, A.A.. Lascelles, P.T. and Wiles, C.M., Side-effects induced by carbamazepine-lO,ll-epoxide, Lancer, ii, (1985) 496. 13 Sander, J. W.A.S., Patsalos, P.N., Oxley, J.R., Hamilton, M.J. and Yuen, W.C., A randomised double-blind placebo-controlled add-on trial of lamotrigine in patients with severe epilepsy, Epilepsy Res., 6 (1990) 221-226. 14 Sander, J.W.A.S., Trevisol-Bittencourt, P.C., Hart, Y.M. and Patsalos, P.N., The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy, Epilepsy Res., 7 (1990) 226-229.
15 Shoeman, J., Elyas, A.A., Brett, E.M. and Lascelles, P.T., Correlation between plasma carbamazepine-lO,ll-epoxide concentrations and drug side effects in children with epilepsy, Dev. Med. Child Neurol., 26 (1984) 757-764. 16 Tomsson, T. and Bertilsson, K., Potent clinical effect of carabamazepine-lO,ll-epoxide in trigeminal neuralgia, Arch. Neurol., 41 (1984) 598-601.
