Alistair Ainslie Miller

Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action.

Summary: Lamotrigine (LTG) [3,5‐diamino‐6‐(2,3‐dichlorophenyl)‐1,2,4‐triazine] is a novel anticonvulsant chemically unrelated to current antiepileptic drugs and with a pharmacological profile similar to that of phenytoin. The effect of LTG has been compared with that of phenytoin, on the release of endogenous amino acids and radiolabelled acetylcholine evoked by veratrine or potassium, from slices of rat cerebral cortex in vitro. Both veratrine and potassium evoked a marked release of glutamate and γ‐aminobutyric acid (GABA), with a more moderate release of aspartate. LTG inhibited veratrine‐evoked release of glutamate and aspartate, with ED50 values of 21 μM for both amino acids, but LTG was less potent in the inhibition of GABA release (ED50= 44 μM). At concentrations up to 300 μM, LTG had no effect on potassium‐evoked amino acid release or on spontaneous release. Also, LTG was some five times less potent in the inhibition of veratrine‐evoked [3H]acetylcholine release (ED50= 100 μM) than in glutamate or aspartate release. The total lack of effect of LTG on potassium‐evoked release and the potent effect on veratrine‐evoked release (at concentrations found in rat brain after anticonvulsant doses) strongly suggest that LTG acts at voltage‐sensitive sodium channels to stabilise neuronal membranes and inhibit transmitter release, principally glutamate. The role of glutamate in the aetiology of epilepsy is discussed.

Pharmacological studies on lamotrigine, a novel potential antiepileptic drug. I: anticonvulsant profile in mice and rats

Summary: Lamotrigine (LTG), 3,5‐diamino‐6‐(2,3‐di‐chlorophenyl)‐1,2,4‐triazine, is a structurally novel anticonvulsant. The anticonvulsant profile of LTG following oral administration in two standard anticonvulsant tests, the maximal electroshock (MES) test in mice and rats and the pentylenetetrazol (PTZ) infusion test in mice, was studied in comparison with the known anticonvulsant drugs phenytoin (PHT), phenobarbitone, diazepam, carbamazepine (CBZ), sodium valproate, ethosuximide (ETH), and troxidone (TROX). ED50 values for the abolition of hindlimb extension (HLE) in the MES test and PTZ infusion tests and doses increasing the latency of PTZ‐evoked clonus were determined. The duration of action of LTG was examined in rats and mice in the MES test by determining ED50 values for the abolition of HLE at various drug intervals to shock administration. In the MES test, LTG was well absorbed in both species, with peak activity at 1 h and persistence at this level of potency for at least 8 h. Of the drugs examined, LTG was ranked the most potent and persistent in both species. LTG also abolished PTZ‐evoked HLE, while ETH and TROX were inactive. Clonus latency was not increased by LTG, PHT, or CBZ, but was significantly increased (p < 0.05) by the remaining anticonvulsants. Thus, LTG resembled PHT and CBZ in its ability to block HLE but not to increase PTZ‐induced clonus latency. Acute behavioural studies in mice and rats have suggested a wide separation between anticonvulsant doses and those producing behavioural impairment. These results suggest that LTG may be of value in the treatment of generalised tonic‐clonic and partial seizures.

Effects of lamotrigine on electrically induced afterdischarge duration in anaesthetised rat, dog, and marmoset.

Summary: The effects of lamotrigine (LTG), a novel potent anticonvulsant, following intravenous (i.v.) bolus injection were studied on the durations of electrically induced afterdischarges of the EEG in halothane‐anaesthetised dogs and marmosets, species used in toxicity studies. For comparison, the effect of LTG on hippocampal afterdischarge duration was also studied in halothane anaesthetised rats, a species in which the anticonvulsant action of LTG has been widely investigated. The known anticonvulsants phenytoin (PHT) and pheno‐barbital (PB) were included for comparison. LTG reduced afterdischarge duration in a dose‐dependent manner in rat and dog; it was approximately twofold more potent than PHT in the dog and three‐ to fourfold more potent than PB in both dog and rat (LTG ED50 values = 4.5 and 11.7 mg kg‐1 i.v. in dogs and rats, respectively). PHT was ineffective in the rat at sublethal doses (< 40 mg kg‐1 i.v.). In limited studies in marmosets, i.v. administration of both LTG and PHT (both 5–15 mg kg‐1) reduced or abolished afterdischarge. Thus, LTG was a potent anticonvulsant in rat, dog, and marmoset in after‐discharge models of partial (focal) seizures and may be of utility in the treatment of partial seizures in humans.