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Anne King - One of the best experts on this subject based on the ideXlab platform.

  • actions of the anticonvulsant Remacemide metabolite ar r12495aa on afferent evoked spinal synaptic transmission in vitro and on models of acute and chronic inflammation in the rat
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Aziz Asghar, Sibte S Hasan, Anne King
    Abstract:

    The effects of the anticonvulsant Remacemide [(±)-2-amino- N -(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its metabolite AR-R12495AA [(±)-1-methyl-1,2-diphenylethylamine-monohydrochloride] on primary afferent synaptic transmission were assessed in the young rat spinal cord in vitro. Stimulation of dorsal roots at A- and C-afferent intensity elicited a dorsal root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumulative ventral root depolarization (CVRD), a form of wind-up. Remacemide and AR-R12495AA antagonized the DR-VRP slow peak t 1/2 decay and slow phase total duration at drug concentration of ≥25 μM. AR-R12495AA was approximately 2-fold more potent than Remacemide. The most potent action was against the slow phase duration with IC50 values of 157 and 60 μM for Remacemide and AR-R12495AA, respectively. Both drugs at concentrations of ≥100 μM attenuated the DR-VRP fast peak amplitude (IC50 = 253 and 142 μM, respectively). The amplitude of CVRD was reduced by Remacemide and AR-R12495AA (IC50 = 195 and 111 μM, respectively). MK-801 reduced DR-VRP fast peak amplitude (IC50 = 58 μM), slow peak t 1/2 decay (IC50 = 60 μM), slow phase duration (IC50 = 50 μM), and CVRD amplitude (IC50 = 91 μM). In behavioral studies, AR-R12495AA (i.p.) reduced the mechanical hyperalgesia and paw swelling that followed hind paw injection of carrageenan or Freund's complete adjuvant. These electrophysiological and behavioral data indicate further studies should be conducted on the efficacy of Remacemide and AR-R12495AA as putative analgesics.

  • the anticonvulsant Remacemide and its metabolite ar r12495aa attenuate spinal synaptic transmission and carrageenan induced inflammation in the young rat
    European Journal of Pain, 2000
    Co-Authors: Aziz Asghar, Sibte S Hasan, Anne King
    Abstract:

    Abstract The effects of the anticonvulsants Remacemide [(±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its des -glycinated metabolite AR-R12495AA [(±)-1-methyl-1,2-diphenylethylamine- monohydrochloride] on primary afferent-induced synaptic transmission and frequency-dependent summation of synaptic potentials were assessed in the young rat spinal cord in vitro . Behavioural studies in the rat determined the effects of these anticonvulsant compounds in the carrageenan model of inflammation. Recordings of the extracellular dorsal root-evoked ventral root potential (DR-VRP) revealed a significant reduction of the duration and t 1 - 2 decay of the long latency, slow DR-VRP by Remacemide (50 and 100 μM) and AR-R12495AA (25, 50 and 100 mM). The short-latency, fast monosynaptic DR-VRP peak was reduced by only the highest concentration of AR-R12495AA (100 μM). In intracellular dorsal root-evoked excitatory postsynaptic potentials (DR-EPSPs) of single ventral horn neurons, AR-R12495AA (100 μM) attenuated the time course of the long-latency (slow) EPSP. Frequency-dependent (0.5–2.0 Hz) summation of dorsal root-evoked synaptic events (recorded extracellularly as the cumulative ventral root depolarization (CVRD), and intracellularly as wind-up) was attenuated by Remacemide (100 μM) and AR-R12495AA (50 and 100 μM). Pre-treatment with intra-peritoneal injection of 75 mg/kg of Remacemide or AR-R12495AA caused a significant reduction of carrageenan-induced mechanical hyperalgesia and oedema. These electrophysiological and behavioural data provide evidence that Remacemide and AR-R12495AA may also possess analgesic and anti-inflammatory activity. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain

  • electrophysiological effects of the anticonvulsant Remacemide hydrochloride and its metabolite arl 12495aa on rat ca1 hippocampal neurons in vitro
    Neuropharmacology, 1997
    Co-Authors: S K Norris, Anne King
    Abstract:

    The electrophysiological actions of the putative anticonvulsants Remacemide hydrochloride and its des-glycine metabolite ARL 12495AA were examined using whole-cell recordings from CA1 hippocampal neurons in adult rat brain in vitro. Remacemide hydrochloride (4-400 microM) and ARL 12495AA (4-400 microM) limited sustained high frequency repetitive firing (SRF) induced by application of long duration depolarizing current pulses (20-400 pA, 500 msec). This SRF limitation was concentration-dependent, and equipotent IC50 values of 66 and 60 microM were calculated for Remacemide hydrochloride and ARL 12495AA, respectively. Examination of the spike configuration revealed that, over the same concentration range, each compound caused a concentration-related reduction of: (a) the action potential amplitude; and (b) the rate-of-rise. Remacemide hydrochloride or ARL 12495AA increased spike duration and decreased or eliminated the spike after-hyperpolarization. Possible mechanisms for these electrophysiological actions including modulation of sodium and/or potassium channel activity are considered. It is suggested that such multiple mechanisms, including inhibition of SRF may be relevant to the anticonvulsant properties of Remacemide hydrochloride and its metabolite, ARL 12495AA. The activity of both compounds as modulators of neuronal excitability indicates that metabolic conversion of Remacemide hydrochloride to ARL 12495AA could enhance the therapeutic efficacy of the former.

John Paul Leach - One of the best experts on this subject based on the ideXlab platform.

  • Remacemide for drug resistant localization related epilepsy
    Cochrane Database of Systematic Reviews, 2002
    Co-Authors: John Paul Leach, Anthony G Marson, Jane L. Hutton
    Abstract:

    Background Epilepsy is a common neurological condition, affecting 0.5 to 1% of the population. Nearly 30 per cent of people with epilepsy have seizures that are refractory to currently available drugs. In response to this problem, potential new drugs are being developed. Remacemide is one of these. Objectives To evaluate the effects of add-on treatment with Remacemide upon seizures, adverse effects, cognition and quality of life for people with drug-resistant localization related epilepsy. Search strategy We searched the Cochrane Epilepsy Group trials register (4 July 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2002) and MEDLINE (28 May 2002). In addition, we contacted AstraZeneca (makers of Remacemide) and colleagues in the field to see if they were aware of any trials that we had missed. Selection criteria Randomized placebo controlled add-on trials of people of any age with localization related seizures, in which an adequate method of concealment of randomization was used. The studies could be blinded or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. Data collection and analysis Two reviewers independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50 per cent or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were by intention-to-treat. Dose response was evaluated in regression models. Main results Two parallel group trials were included representing 514 individuals. Daily doses of 300, 600, 800 and 1200mg of Remacemide were tested. The overall relative risk (RR) for Remacemide versus placebo with 95% confidence intervals(CI) for a 50 per cent or greater reduction in seizure frequency was 1.59(95% CI 0.91 to 2.79). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. Regression models did however suggest a significant effect for 800-1200mg Remacemide per day. Remacemide was more likely to be withdrawn than placebo, the RR for treatment withdrawal was 1.90(95% CI 1.00 to 3.60). The RR for dizziness indicates that it is significantly associated with Remacemide 3.08(99% CI 1.37 to 6.95). Effects on cognition and quality of life were not reported. Reviewer's conclusions Given the modest effect on seizure frequency and significant withdrawal rate it is unlikely that Remacemide will be further developed as an antiepileptic drug.

  • Levetiracetam, oxcarbazepine, Remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.
    Epilepsy research, 2001
    Co-Authors: Anthony G Marson, John Paul Leach, Jane L. Hutton, S Castillo, D Schmidt, S White, R Chaisewikul, Michael Privitera, David Chadwick
    Abstract:

    Abstract Objective: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, Remacemide and zonisamide for patients with drug resistant localization related epilepsy. Methods: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and Remacemide. Results: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of Remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62–5.44), 2.51 (1.88–3.33), 1.59 (0.91–2.97) and 2.46 (1.61–3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and Remacemide. The relative risks for treatment withdrawal were 1.21 (0.88–1.66), 1.72 (1.35–2.18), 1.90 (1.00–3.60) and 1.64 (1.02–2.62), respectively. Conclusions: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable ‘responder-withdrawal ratio’ followed by zonisamide and oxcarbazepine.

  • neurochemical actions of the desglycinyl metabolite of Remacemide hydrochloride arl 12495aa in mouse brain
    British Journal of Pharmacology, 1997
    Co-Authors: John Paul Leach, Graeme J Sills, G G Thompson, Elaine Butler, Gerard Forrest, Martin J. Brodie
    Abstract:

    Remacemide hydrochloride, a recently developed antiepileptic drug, is believed to exert its effects, at least in part, via its desglycinyl metabolite, ARL 12495AA. We have investigated the effects of ARL 12495AA on several neurochemical parameters in mouse brain. Adult male ICR mice were randomized into two groups and administered ARL 12495AA (0–75 mg kg−1) intraperitoneally, either as a single dose or once daily for 5 days. Six hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of γ-aminobutyric acid (GABA), glutamine and glutamate and for the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose ARL 12495AA was without effect on any of the parameters investigated. Repeated ARL 12495AA treatment did not alter brain concentrations of GABA and glutamine, but at a high dose there was a trend toward reduced brain glutamate concentrations (P=0.10). Repeated administration of ARL 12495AA at a high dose significantly increased GABA-T activity (P<0.05) and decreased that of GAD (P<0.05). 7 These findings may have relevance to the clinical use of Remacemide hydrochloride in human epilepsy.

  • lack of pharmacokinetic interaction between Remacemide hydrochloride and sodium valproate in epileptic patients
    Seizure-european Journal of Epilepsy, 1997
    Co-Authors: John Paul Leach, Virginia Jamieson, Tracey Jones, Jacqueline Girvan, A Richens, Martin J. Brodie
    Abstract:

    A randomized, double-blind, placebo-controlled cross-over study of adjuvant treatment with Remacemide hydrochloride was carried out in 17 patients taking sodium valproate (VPA) as monotherapy. Plasma concentration profiles of VPA, Remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single (300 mg) and multiple dosing (150 or 300 mg twice daily) of Remacemide hydrochloride for 14 days with a 300-mg final dose. Central nervous system side-effects were more common at the higher dose, which prompted dosage reduction to 150 mg twice daily for subsequent patients partway through the study. The mean area under the concentration-time curve, peak concentration and pre-dose concentration of VPA were unchanged by Remacemide hydrochloride in three patients on the higher and in 10 patients on the lower dose of Remacemide. The pharmacokinetic parameters of Remacemide and its active metabolite in the VPA-treated patients were similar to those described previously in healthy volunteers. Thus, Remacemide hydrochloride does not interfere with the pharmacokinetics of VPA and vice versa.

  • Mutual interaction between Remacemide hydrochloride and phenytoin
    Epilepsy research, 1997
    Co-Authors: John Paul Leach, Virginia Jamieson, Tracey Jones, Alan Richens, Jacqueline Girvan, Martin J. Brodie
    Abstract:

    Abstract A randomised, double-blind, placebo-controlled crossover study of add-on Remacemide hydrochloride was carried out in epilepsy patients being treated with phenytoin (PHT) monotherapy. Eleven patients were recruited, ten of whom completed the study. Plasma concentration profiles of PHT, Remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single and multiple dosing with Remacemide hydrochloride. Following 14 days' treatment with Remacemide hydrochloride 300 mg twice daily, the mean AUC of PHT was increased by 11.5% ( P =0.33), C max by 13.7% ( P =0.32) and C min by 22.2% ( P =0.12) over placebo. There was an increase in trough concentrations of PHT averaging 20% during active treatment compared with placebo ( P =0.01). No symptoms of PHT toxicity were reported by any patient. There was no evidence of autoinduction of Remacemide metabolism. However, average concentrations of Remacemide and its active metabolite in PHT-treated patients were around 40 and 30% lower, respectively than in healthy volunteers previously receiving the same dose of Remacemide hydrochloride. Thus, Remacemide hydrochloride has a small inhibitory effect on PHT metabolism, which itself induces that of Remacemide and its active metabolite. This mutual interaction is predictable and modest and should not present a barrier to their clinical use in combination.

Martin J. Brodie - One of the best experts on this subject based on the ideXlab platform.

  • influence of cytochrome p450 induction on the pharmacokinetics and pharmacodynamics of Remacemide hydrochloride
    Epilepsy Research, 2002
    Co-Authors: Graeme J Sills, Sarah Santangeli, Gerard Forrest, Martin J. Brodie
    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 (CYP450) 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 CYP450 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 CYP450 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.

  • efficacy and safety of Remacemide versus carbamazepine in newly diagnosed epilepsy comparison by sequential analysis
    Epilepsy & Behavior, 2002
    Co-Authors: Martin J. Brodie, Andrew Dean, Stephen Wroe, Thomas Holdich, John Whitehead, John Stevens
    Abstract:

    Abstract An international trial comparing Remacemide hydrochloride with carbamazepine was undertaken in newly diagnosed epilepsy using a novel double-blind, parallel group, double triangular sequential design. Patients with two or more partial or generalized tonic–clonic seizures in the previous year were randomized to 600 mg daily of Remacemide or carbamazepine. Subsequent dosage adjustments were allowed while maintaining the blind. The trial completed 20 months after initiation following the second interim analysis. Efficacy data on 449 patients showed carbamazepine to be significantly more effective than Remacemide in preventing seizure recurrence ( P = 0.003). Median time to first seizure after titration, the primary endpoint, was 112 days for Remacemide and 306 days with carbamazepine. Time to second, third, and fourth seizures after randomization all significantly favored carbamazepine. Remacemide was shown unequivocally to be inferior to carbamazepine in this patient population. This study also establishes carbamazepine as a proven treatment for use in subsequent active control comparative trials.

  • differential effects of Remacemide and desglycinyl Remacemide on epileptiform burst firing in the rat hippocampal slice
    Neuroscience Letters, 2002
    Co-Authors: Sarah Santangeli, Graeme J Sills, T W Stone, Martin J. Brodie
    Abstract:

    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 μM) was without significant effect, while DGR, CBZ and AR-R15896AR all decreased burst frequency in a concentration (0–100 μM) 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.

  • na channel effects of Remacemide and desglycinyl Remacemide in rat cortical synaptosomes
    European Journal of Pharmacology, 2002
    Co-Authors: Sarah Santangeli, Graeme J Sills, G G Thompson, Martin J. Brodie
    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% (IC50=160.6 μM) and 13.2% (IC50=85.1 μM) of control, respectively. Carbamazepine, phenytoin and lamotrigine similarly reduced Na+ influx to 20.1% (IC50=325.9 μM), 79.8% and 27.9% (IC50=23.0 μM) of control, respectively. Resting internal Na+ concentrations were significantly increased by desglycinyl-Remacemide (1 and 10 μM) and, conversely, decreased by desglycinyl-Remacemide and carbamazepine (both 1000 μM). 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.

  • simultaneous determination of Remacemide hydrochloride and desglycinylRemacemide ar r12495xx in brain tissue by high performance liquid chromatography
    Journal of Chromatography B: Biomedical Sciences and Applications, 2000
    Co-Authors: Sarah Santangeli, Graeme J Sills, Charles Mcneill, Martin J. Brodie
    Abstract:

    Remacemide hydrochloride, a novel anticonvulsant agent, and its major active metabolite, desglycinylRemacemide, were measured simultaneously in brain tissue by high-performance liquid chromatography with UV detection. Intra- and inter-assay variations for Remacemide (1, 5, 10 μg/ml) were 5.1, 10.5 and 3.1% and 3.1, 4.0 and 1.3%, respectively. Intra- and inter-assay variations for desglycinylRemacemide (1, 5, 10 μg/ml) were 4.2, 3.8 and 8.4% and 7.9, 8.8 and 3.1%, respectively. Limits of detection and quantification for both analytes were 4 and 31 ng/ml, respectively, with recovery consistently ≥85%. This reliable assay has applications in the pre-clinical neuropharmacokinetic and neuropharmacodynamic investigation of Remacemide hydrochloride.

Jane L. Hutton - One of the best experts on this subject based on the ideXlab platform.

  • Remacemide for drug resistant localization related epilepsy
    Cochrane Database of Systematic Reviews, 2002
    Co-Authors: John Paul Leach, Anthony G Marson, Jane L. Hutton
    Abstract:

    Background Epilepsy is a common neurological condition, affecting 0.5 to 1% of the population. Nearly 30 per cent of people with epilepsy have seizures that are refractory to currently available drugs. In response to this problem, potential new drugs are being developed. Remacemide is one of these. Objectives To evaluate the effects of add-on treatment with Remacemide upon seizures, adverse effects, cognition and quality of life for people with drug-resistant localization related epilepsy. Search strategy We searched the Cochrane Epilepsy Group trials register (4 July 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2002) and MEDLINE (28 May 2002). In addition, we contacted AstraZeneca (makers of Remacemide) and colleagues in the field to see if they were aware of any trials that we had missed. Selection criteria Randomized placebo controlled add-on trials of people of any age with localization related seizures, in which an adequate method of concealment of randomization was used. The studies could be blinded or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. Data collection and analysis Two reviewers independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50 per cent or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were by intention-to-treat. Dose response was evaluated in regression models. Main results Two parallel group trials were included representing 514 individuals. Daily doses of 300, 600, 800 and 1200mg of Remacemide were tested. The overall relative risk (RR) for Remacemide versus placebo with 95% confidence intervals(CI) for a 50 per cent or greater reduction in seizure frequency was 1.59(95% CI 0.91 to 2.79). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. Regression models did however suggest a significant effect for 800-1200mg Remacemide per day. Remacemide was more likely to be withdrawn than placebo, the RR for treatment withdrawal was 1.90(95% CI 1.00 to 3.60). The RR for dizziness indicates that it is significantly associated with Remacemide 3.08(99% CI 1.37 to 6.95). Effects on cognition and quality of life were not reported. Reviewer's conclusions Given the modest effect on seizure frequency and significant withdrawal rate it is unlikely that Remacemide will be further developed as an antiepileptic drug.

  • Levetiracetam, oxcarbazepine, Remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.
    Epilepsy research, 2001
    Co-Authors: Anthony G Marson, John Paul Leach, Jane L. Hutton, S Castillo, D Schmidt, S White, R Chaisewikul, Michael Privitera, David Chadwick
    Abstract:

    Abstract Objective: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, Remacemide and zonisamide for patients with drug resistant localization related epilepsy. Methods: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and Remacemide. Results: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of Remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62–5.44), 2.51 (1.88–3.33), 1.59 (0.91–2.97) and 2.46 (1.61–3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and Remacemide. The relative risks for treatment withdrawal were 1.21 (0.88–1.66), 1.72 (1.35–2.18), 1.90 (1.00–3.60) and 1.64 (1.02–2.62), respectively. Conclusions: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable ‘responder-withdrawal ratio’ followed by zonisamide and oxcarbazepine.

Aziz Asghar - One of the best experts on this subject based on the ideXlab platform.

  • actions of the anticonvulsant Remacemide metabolite ar r12495aa on afferent evoked spinal synaptic transmission in vitro and on models of acute and chronic inflammation in the rat
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Aziz Asghar, Sibte S Hasan, Anne King
    Abstract:

    The effects of the anticonvulsant Remacemide [(±)-2-amino- N -(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its metabolite AR-R12495AA [(±)-1-methyl-1,2-diphenylethylamine-monohydrochloride] on primary afferent synaptic transmission were assessed in the young rat spinal cord in vitro. Stimulation of dorsal roots at A- and C-afferent intensity elicited a dorsal root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumulative ventral root depolarization (CVRD), a form of wind-up. Remacemide and AR-R12495AA antagonized the DR-VRP slow peak t 1/2 decay and slow phase total duration at drug concentration of ≥25 μM. AR-R12495AA was approximately 2-fold more potent than Remacemide. The most potent action was against the slow phase duration with IC50 values of 157 and 60 μM for Remacemide and AR-R12495AA, respectively. Both drugs at concentrations of ≥100 μM attenuated the DR-VRP fast peak amplitude (IC50 = 253 and 142 μM, respectively). The amplitude of CVRD was reduced by Remacemide and AR-R12495AA (IC50 = 195 and 111 μM, respectively). MK-801 reduced DR-VRP fast peak amplitude (IC50 = 58 μM), slow peak t 1/2 decay (IC50 = 60 μM), slow phase duration (IC50 = 50 μM), and CVRD amplitude (IC50 = 91 μM). In behavioral studies, AR-R12495AA (i.p.) reduced the mechanical hyperalgesia and paw swelling that followed hind paw injection of carrageenan or Freund's complete adjuvant. These electrophysiological and behavioral data indicate further studies should be conducted on the efficacy of Remacemide and AR-R12495AA as putative analgesics.

  • the anticonvulsant Remacemide and its metabolite ar r12495aa attenuate spinal synaptic transmission and carrageenan induced inflammation in the young rat
    European Journal of Pain, 2000
    Co-Authors: Aziz Asghar, Sibte S Hasan, Anne King
    Abstract:

    Abstract The effects of the anticonvulsants Remacemide [(±)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its des -glycinated metabolite AR-R12495AA [(±)-1-methyl-1,2-diphenylethylamine- monohydrochloride] on primary afferent-induced synaptic transmission and frequency-dependent summation of synaptic potentials were assessed in the young rat spinal cord in vitro . Behavioural studies in the rat determined the effects of these anticonvulsant compounds in the carrageenan model of inflammation. Recordings of the extracellular dorsal root-evoked ventral root potential (DR-VRP) revealed a significant reduction of the duration and t 1 - 2 decay of the long latency, slow DR-VRP by Remacemide (50 and 100 μM) and AR-R12495AA (25, 50 and 100 mM). The short-latency, fast monosynaptic DR-VRP peak was reduced by only the highest concentration of AR-R12495AA (100 μM). In intracellular dorsal root-evoked excitatory postsynaptic potentials (DR-EPSPs) of single ventral horn neurons, AR-R12495AA (100 μM) attenuated the time course of the long-latency (slow) EPSP. Frequency-dependent (0.5–2.0 Hz) summation of dorsal root-evoked synaptic events (recorded extracellularly as the cumulative ventral root depolarization (CVRD), and intracellularly as wind-up) was attenuated by Remacemide (100 μM) and AR-R12495AA (50 and 100 μM). Pre-treatment with intra-peritoneal injection of 75 mg/kg of Remacemide or AR-R12495AA caused a significant reduction of carrageenan-induced mechanical hyperalgesia and oedema. These electrophysiological and behavioural data provide evidence that Remacemide and AR-R12495AA may also possess analgesic and anti-inflammatory activity. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain