Preclinical Investigations With Remacemide Hydrochloride

Santangeli, Sarah (2001) Preclinical Investigations With Remacemide Hydrochloride. PhD thesis, University of Glasgow.

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Abstract

There is now convincing neurochemical and neurophysiological evidence to suggest that increased excitatory neurotransmission is involved in epilepsy. Antagonists of N-methyl-D-aspartate (NMDA)-type glutamate receptors are powerful anticonvulsants in many animal models of epilepsy. Early attempts to pharmacologically modulate glutamatergic transmission resulted in anticonvulsant compounds such as dizocilpine (MK801) and phencyclidine. Preclinical testing of these agents generally showed efficacy but also demonstrated severe side effects. A clinical application of pure glutamate antagonists has yet to be established. Remacemide hydrochloride (RMD) is an anticonvulsant compound which exhibits efficacy in a wide range of seizure models. Both RMD and its active metabolite, desglycinyl-remacemide (DGR), are said to have inhibitory actions on voltage-gated sodium channels and NMDA glutamate receptors with DGR possessing greater potency at both sites. The following studies were designed to further investigate the pharmacology of RMD and DGR in various neurochemical and epilepsy models. Clinical trial results reported while this project was in progress demonstrated that the drug did not perform well as monotherapy. It was initially believed that the additional action on NMDA receptors would result in RMD possessing an improved clinical profile compared to standard Na+ channel blockers such as carbamazepine (CBZ) and phenytoin (PHT). Further investigations as to why a drug with such a promising preclinical portfolio performed so poorly in the clinical environment were therefore conducted. Pharmacokinetic studies suggested that although some conversion of RMD to DGR does occur in the peripheral tissues the majority of DGR generation occurs at the blood/brain barrier, resulting in an accumulation of DGR in the brain. The pharmacokinetics of DGR were seen to outlast those of the parent compound both in serum and brain. The effects of hepatic enzyme induction on the pharmacokinetics and pharmacodynamics of RMD were investigated. Administration of phenobarbital (PB), a known hepatic enzyme inducer, resulted in a significant increase in both the content and activity of cytochrome P450 enzymes in the livers of mice. This increase in hepatic enzyme activity was shown to significantly decrease the brain concentrations of RMD and DGR although the effects on DGR concentrations were more pronounced. The efficacy of RMD against maximal electroshock (MES)-induced seizures was seen to decrease in induced animals when compared to saline-treated controls. In vitro investigations in the hippocampal slice permitted the effects of RMD and DGR to be studied separately. CBZ and ARR-15896, a putative NMD A antagonist, were employed for comparative purposes. RMD was found to have no effect on zero Mg2+/4-aminopyridine (4-AP) induced epileptiform burst firing in the rat hippocampal slice. In contrast, DGR, CBZ and ARR- 15896 all significantly reduced epileptiform activity. These results suggested that blockade of voltage-gated Na+ channels and the NMDA receptor protect against paroxysmal discharges in this model. The relatively low potency of RMD at these pharmacological targets may explain its lack of efficacy in this regard. A neurochemical study investigating the effects of RMD and DGR on sodium channel activity was conducted in rat brain synaptosomes. RMD and DGR were seen to reduce voltage-gated sodium channel activity in a concentration- related manner in agreement with previous electrophysiological investigations and confirmed the reported separation in potency at this site. Several antiepileptic drugs (AEDs) have effects on gamma-aminobutyric acid (GABA)/glutamate homeostasis. Previous studies have reported that DGR has effects on GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) following chronic administration to mice. The effects of RMD and DGR on the activity of glutamate dehydrogenase, one of the enzymes responsible for glutamate homeostasis, were analysed in rat brain mitochondria. RMD and DGR were shown to significantly reduce the formation of glutamate from alpha-ketoglutarate (alpha-KG) via an action on the enzyme glutamate dehydrogenase in rat brain mitchondria. It is possible that this action may contribute to the anticonvulsant properties of the compounds although further investigations are required. There is growing evidence to suggest that monoamines have an important role in epilepsy. The effects of RMD and DGR on the reuptake processes of serotonin (5-HT), norephinephrine (NE) and dopamine (DA) were investigated in rat brain synaptosomes. RMD was seen to significantly reduce the reuptake of DA at therapeutically relevant concentrations while DGR reduced the reuptake of 5-HT and NE at therapeutic concentrations. Further investigations are required to assess the mechanism and importance of the results obtained to RMD pharmacology in terms of epilepsy and possibly affective disorders. In conclusion, observations from the above studies indicate that there are differences in the pharmacology of RMD and DGR.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Graeme Milligan
Keywords: Pharmacology, Neurosciences
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-75793
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:10
Last Modified: 19 Nov 2019 18:10
URI: http://theses.gla.ac.uk/id/eprint/75793

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