The New Antiepileptic Drugs: The Search for Synergy

Leach, John Paul (1996) The New Antiepileptic Drugs: The Search for Synergy. MD thesis, University of Glasgow.

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Many epileptologists believe that the new antiepileptic drugs as a group constitute a major advance in the treatment of epilepsy. Even their fiercest proponent, however, could not convincingly argue that they are the ideal treatment for all patients with epilepsy. It is widely accepted that if the 'magic bullet' for epilepsy exists, then we have still to find it. Given that the development of new antiepileptic compounds is an expensive, time-consuming gamble, then it may be more beneficial to expend our energies on a quest for better ways of using those compounds already available. Combination therapy is commonplace in other conditions such as hypertension, Parkinsons disease, cardiac failure, or infections such as tuberculosis, and there should be no reason why specific treatments should not be combined with particular efficacy in the treatment of epilepsy. Polypharmacy with antiepileptic drugs (AEDs) has fallen out of favour in recent times. For some years, the prevailing opinion has been that AED combinations merely maximise the incidence of drug-related adverse events while conferring little benefit in terms of seizure control. While this may have been true of the established drugs, phenytoin, carbamazepine, and valproate we should be open to the possibility that the newer AEDs are more suited to use as polypharmacy. We know that the newer AEDs have different mechanisms of action, have fewer pharmacokinetic interactions, and cause less sedation than their older counterparts, while pre-clinical trials would also suggest that they are more specific in their actions. These qualities may suggest that there will be a reduction in the frequency and / or severity of pharmacodynamic interactions when they are used simultaneously. Aside from chance observation, how else can we begin to plan our treatment combinations? The results of basic in-vitro research may suggest certain possibilities, but these will only be relevant in our clinics if we are aware of the key issues involving each new AED. Most importantly: What is/are the relevant mode(s) of action of each drug? To anticipate pharmacodynamic interactions and therapeutic synergy, we need to have a comprehensive view of the actions of each individual drug. For example, vigabatrin is known to inhibit GABA-transaminase, but what changes does it exert on the metabolism of glutamate? Does it have other important effects on GABA? Remacemide, another AED in development was known to be a non-competitive n-methyl-d-aspartate (NMDA) receptor antagonist, but recent evidence has proven its effect on sodium channel conductance. What effect will it have on the GABAergic system? Even once we have a fuller picture of each drug's neurochemical effects (and we cannot even do this convincingly for those drugs that are licensed in the UK!) then how do we proceed in planning the treatment of refractory epilepsy? Should we combine drugs which target the same system (e.g. two GABAergic drugs)? Or should we aim to manipulate two different systems (e.g. one drug acting on the GABAergic system, and one on the excitatory system)? Are there any pharmacodynamic or pharmacokinetic interactions between the two drugs? Are these effects beneficial or deleterious? The answer to this can only be gleaned from proper testing during preliminary clinical trials. Each new AED firstly has to undergo clinical trials as add-on therapy; pharmacokinetic interactions are usually picked up at this relatively early stage of investigation. During each trial, it may also be rational to carry out meta-analyses to investigate which co-therapies are particularly well or poorly tolerated. Despite the relative ease with which this might be accomplished in this age of computerisation, no such analyses have been carried out (or at least not been published!) for any of the emergent treatments, and possible reasons for this will be discussed later. Once both questions are satisfactorily answered, and we suspect that a particular combination of drugs may have some particular merit, then further testing against appropriate controls will be required. The difficulties involved in this will be addressed. The experiments described in this thesis investigate different aspects of some of the newer AEDs. Animal experiments are used to investigate the neurochemical actions of remacemide, gabapentin, tiagabine, and vigabatrin at varying doses with particular emphasis on the GABA shunt. Following the clinical observation of good additive effect with combined tiagabine and vigabatrin, the same parameters were used to look at this particular combination. Culture of rat astrocytes and neurones are used to delineate the dose-related effects of vigabatrin on GABA uptake, a phenomenon previously described in our laboratory. The specific combination of vigabatrin and tiagabine is also used to search for additive or synergistic effects on this system. One set of double-blind clinical studies attempts to investigate interactions between remacemide and the established AEDs, while another investigates the cognitive effects of add-on gabapentin. The issues faced by clinicians in the formation of a rational plan for AED polypharmacy are discussed, and the scope for further investigation is explored.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Martin Brodie
Keywords: Medicine, Pharmacology
Date of Award: 1996
Depositing User: Enlighten Team
Unique ID: glathesis:1996-75299
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 21:17
Last Modified: 19 Nov 2019 21:17

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