Sarah Santangeli

Publications (3)6.91 Total impact

• Article: Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride.

  Graeme J Sills, Sarah Santangeli, Gerard Forrest, Martin J Brodie
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  ABSTRACT: Remacemide hydrochloride (RMD) is a putative anticonvulsant agent with an active metabolite, desglycinyl-remacemide (DGR) and a broad spectrum of activity in experimental seizure models. In clinical trials, however, the efficacy of RMD is questionable. In the case of add-on studies, the inconclusive findings may be related to pharmacokinetic interactions between RMD and established antiepileptic drugs. We have investigated the influence of cytochrome P450 (CYP(450)) induction following repeated treatment with phenobarbital (PB) on the pharmacokinetics and pharmacodynamics of RMD in mice. Pre-treatment with PB (80 mg/kg; once daily for 4 days) significantly increased CYP(450) content and activity in mouse liver. This was associated with a consistent reduction in the brain concentrations of both RMD and DGR and attenuation of the anticonvulsant effects of RMD in the maximal electroshock model. Pharmacokinetic analysis suggested that DGR was proportionately more susceptible to CYP(450) induction than the parent compound. As the principal active moiety, the selectively enhanced metabolism of DGR under induced conditions may underlie the debatable findings of add-on trials with RMD in refractory epilepsy. However, this hypothesis does not explain the similarly questionable efficacy of RMD monotherapy in newly diagnosed epilepsy, an observation that may have wider pharmacological implications.
  Epilepsy Research 06/2002; 49(3):247-54. · 2.29 Impact Factor
• Article: Differential effects of remacemide and desglycinyl-remacemide on epileptiform burst firing in the rat hippocampal slice.

  Sarah Santangeli, Graeme J Sills, Trevor W Stone, Martin J Brodie
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  ABSTRACT: Remacemide is a potential anticonvulsant drug with an active metabolite, desglycinyl-remacemide (DGR). Both moieties have been reported to block neuronal Na(+) channels and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The effects of remacemide and DGR on zero Mg(2+)/4-aminopyridine-induced epileptiform discharges were investigated in the rat hippocampal slice preparation and compared with carbamazepine (CBZ), a prototypic Na(+) channel blocker, and AR-R15896AR, a putative NMDA channel blocker. Remacemide (0-100 microM) was without significant effect, while DGR, CBZ and AR-R15896AR all decreased burst frequency in a concentration (0-100 microM) dependent manner. These findings suggest that remacemide is not sufficiently potent at the Na(+) channel or NMDA receptor to attenuate epileptiform activity in this model and that the anticonvulsant effects of the drug may be mediated by DGR.
  Neuroscience Letters 04/2002; 321(1-2):33-6. · 2.11 Impact Factor
• Article: Na(+) channel effects of remacemide and desglycinyl-remacemide in rat cortical synaptosomes.

  Sarah Santangeli, Graeme J Sills, George G Thompson, Martin J Brodie
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  ABSTRACT: The effects of the novel anticonvulsant, remacemide hydrochloride and its active metabolite, desglycinyl-remacemide, on veratridine-induced Na(+) influx in rat cortical synaptosomes were investigated and compared to established Na(+) channel blocking antiepileptic drugs. Remacemide and desglycinyl-remacemide reduced veratridine-stimulated Na(+) influx to 30.7% (IC(50)=160.6 microM) and 13.2% (IC(50)=85.1 microM) of control, respectively. Carbamazepine, phenytoin and lamotrigine similarly reduced Na(+) influx to 20.1% (IC(50)=325.9 microM), 79.8% and 27.9% (IC(50)=23.0 microM) of control, respectively. Resting internal Na(+) concentrations were significantly increased by desglycinyl-remacemide (1 and 10 microM) and, conversely, decreased by desglycinyl-remacemide and carbamazepine (both 1000 microM). These studies support previous electrophysiological investigations, which suggest that remacemide and desglycinyl-remacemide exert their antiepileptic effects, at least in part, by an inhibitory action on voltage-gated Na(+) channels. Desglycinyl-remacemide may have an additional action on Na(+) homeostasis that merits further exploration.
  European Journal of Pharmacology 04/2002; 438(1-2):63-8. · 2.52 Impact Factor