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 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 gamma-aminobutyric acid (GABA), with a more moderate release of aspartate. LTG inhibited veratrine-evoked release of glutamate and aspartate, with ED50 values of 21 microM for both amino acids, but LTG was less potent in the inhibition of GABA release (ED50 = 44 microM). At concentrations up to 300 microM, 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 microM) 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.

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…214 Although lamotrigine has multiple cellular effects, inhibition of excessive presynaptic glutamate release appears to be important to its mechanism of action. [215][216][217] Supporting this idea, there is now preliminary evidence that riluzole, another drug that inhibits the release of glutamate, also has antidepressant properties both in MDD and BD. 218,219 Riluzole, approved by the FDA for the treatment of amyotrophic lateral sclerosis, exhibits neuroprotective properties in animal models of Parkinson's disease, NMDA receptor hypofunction neurotoxicity, ischemia and traumatic CNS injury.…”

Efficacy of lamotrigine in the management of chemotherapy‐induced peripheral neuropathy

“…[7][8][9][33][34][35][36][37] In addition, there are some clinical data (mostly from small uncontrolled clinical trials) suggesting a benefit to using lamotrigine for treating pain in normal volunteers or in patients with a variety of neuropathic syndromes. 10,[12][13][14][38][39][40][41][42][43][44][45][46] Conversely, several other studies have noted either a lack of benefit or an inconsistent benefit [47][48][49] when lamotrigine was tested for its benefit in neuropathy, a meta-analysis of all the placebo-controlled studies published concluding that there were no data to support the utility of lamotrigine as a therapy for pain syndromes.…”

“…[7][8][9] Lamotrigine has been suggested as a potentially useful agent for treating pain in neuropathic syndromes, based on the observation that increased activity of sodium channels appears to be the basis for hyperalgesia (eg, as suggested by the benefit of sodium channel inhibitors such as lidocaine on raising the pain threshold). In normal volunteers lamotrigine has been demonstrated to raise the threshold to cold-induced pain compared with placebo.…”

Choronic effects of Lamotrigine on liver function in adult male rats

“…It is effective in treating both partial and generalized seizure. LTG most probably exerts its antiepileptic activity by blocking the release of excitatory neurotransmitters, principally glutamate and aspartate in the central nervous system (1,2). At present it is one of the AEDS, which is frequently used in the medical world.…”

“…The most common sources of information on these drug toxicities are case reports and clinical trials which are better reflections of the prevalence and clinical implications of drug toxicity. A case of fatal progressive hepatotoxicity in a patient treated with LTG was reported (2,3). Liver, particularly, is vulnerable to drug -induced toxicity mainly because of its role as a primary organ of drug elimination and its subsequent exposure to potential toxins.…”