Lamotrigine (LTG), 3,5-diamino-6-(2,3-dichlorophenyl)-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 less than 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.

The effects of laudanosine, a metabolite of atracurium, on the behaviour of conscious mice, rats and dogs, and on cardiovascular function in conscious and anaesthetized dogs have been evaluated: EEG studies were performed in anaesthetized dogs. In mice and rats, i.v. bolus doses of laudanosine 10-20 mg kg-1, caused convulsions and hind limb extensions; these effects were prevented by pretreatment with diazepam. After the continuous infusion of laudanosine to conscious dogs, plasma concentrations in the order of 1.2 micrograms ml-1 did not cause behavioural disturbances. In anaesthetized dogs, laudanosine plasma concentrations of more than 6 micrograms ml-1 caused hypotension and bradycardia, laudanosine concentrations greater than 10 micrograms ml-1 induced epileptic EEG spiking and plasma concentrations greater than 17 micrograms ml-1 produced prolonged seizures. There is a wide difference between laudanosine plasma concentrations in patients given atracurium by bolus injection or by short-term infusion for surgical use and those required to induce epileptic activity in dogs. However, during the prolonged infusion of atracurium to patients this difference will be decreased. It is unlikely that the use of atracurium, in patients, would result in plasma concentrations of laudanosine capable of producing neurological or cardiovascular disturbances.

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 phenobarbital (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 (less than 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 afterdischarge models of partial (focal) seizures and may be of utility in the treatment of partial seizures in humans.

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