Pharmacological Studies on Lamotrigine, A Novel Potential Antiepileptic Drug

Abstract

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.

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

“…LTG is active against tonic extension seizures in the MES test but is ineffective against scPTZ-induced clonus (40).…”

Advances in pharmacotherapy: recent developments in the treatment of epilepsy

“…It is available in several European countries and is awaiting FDA approval in the United States. Its preclinicd profile appears to be most similar to phenytoin (84). There have been several published safety and efficacy studies on lamotrigine in patients with epilepsy.…”

“…In controlled clinical hids lamotrigine has demonstrated eflicacy in refractory patients with various seizures types (86) and refractory partial epilepsies (85,87). Chronic toxicity studies in rats and primates at doses of up to 20-125 mg/(kg day) have showed no toxic effects (84). The most frequently reported side-effects were diplopia, drowsiness, ataxia and headache (87).…”

“…These concentrations have not produced toxicity, yet it is unclear if higher concentrations will lead to increased efficacy. The therapeutic range for lamotrigine is as yet undefined (84)(85)(86)(87).…”

BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents

“…It is generally considered at present that the clinical success of a new antiarrhythmic agent would require a significant redress of the limitations of presently available therapy. During the course ofpharmacological studies at the Wellcome Research Laboratories, it was observed that certain phenyl diamino-1,2,4 triazines possessed anticonvulsant activity, a property attributable to the ability of these agents to modulate neuronal sodium transport (Miller et al, 1984;Leach et al, 1985). Preliminary evaluation demonstrated that some of these chemically novel triazines were also able to reduce, in a concentration-dependent fashion, the sodium-dependent rate of rise ofphase 0 of the cardiac action potential, an action ascribed as a class 1 antiarrhythmic action (Vaughan Williams, 1981).…”