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Anthony H Dickenson - One of the best experts on this subject based on the ideXlab platform.
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neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of Oxcarbazepine
European Journal of Pain, 2019Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H DickensonAbstract:BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic Oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, Oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, Oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic Oxcarbazepine, supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that Oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. SIGNIFICANCE: The inhibitory effects of lidocaine and Oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.
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neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of Oxcarbazepine
European Journal of Pain (2018) (In press)., 2018Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H DickensonAbstract:BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterised by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population but has clear efficacy in a sub-group with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitives with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic Oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, Oxcarbazepine markedly inhibited punctate mechanical, dynamic brush and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, Oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic Oxcarbazepine supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury, and that Oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. This article is protected by copyright. All rights reserved.
Zhihui Hao - One of the best experts on this subject based on the ideXlab platform.
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development of an online solid phase extraction liquid chromatography mass spectrometric analysis of Oxcarbazepine and its active metabolite licarbazepine from plasma with a direct injection step
Journal of Chromatography B, 2019Co-Authors: Lixuan Pan, Li Wang, Congmin Liu, Yanhong Tian, Zhihui HaoAbstract:Abstract We developed an online solid phase extraction procedure using a hydrophilic-lipophilic balance sorbent, with reversed-phase liquid chromatography-high-resolution mass spectroscopy for the determination of Oxcarbazepine and its active metabolite licarbazepine in plasma samples. The analytes were detected using a high-resolution Q Orbitrap mass spectrometer with targeted-selected ion monitoring (t-SIM) in positive scan mode. Under the optimized conditions, the method was linear with R2 values >0.99. The method was linear from 0.008 to 2.000 μg mL−1 and the lower limit of quantification was 0.008 μg mL−1 for both Oxcarbazepine and licarbazepine. Recoveries ranged from 92.34 to 104.27% and from matrix-matched samples from 94.26 to 104.19%. The intraday and interday precision RSD values were
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development of an online solid phase extraction liquid chromatography mass spectrometric analysis of Oxcarbazepine and its active metabolite licarbazepine from plasma with a direct injection step
Journal of Chromatography A, 2019Co-Authors: Lixuan Pan, Li Wang, Congmin Liu, Yanhong Tian, Zhihui HaoAbstract:We developed an online solid phase extraction procedure using a hydrophilic-lipophilic balance sorbent, with reversed-phase liquid chromatography-high-resolution mass spectroscopy for the determination of Oxcarbazepine and its active metabolite licarbazepine in plasma samples. The analytes were detected using a high-resolution Q Orbitrap mass spectrometer with targeted-selected ion monitoring (t-SIM) in positive scan mode. Under the optimized conditions, the method was linear with R2 values >0.99. The method was linear from 0.008 to 2.000 μg mL−1 and the lower limit of quantification was 0.008 μg mL−1 for both Oxcarbazepine and licarbazepine. Recoveries ranged from 92.34 to 104.27% and from matrix-matched samples from 94.26 to 104.19%. The intraday and interday precision RSD values were <9.13% with an associated accuracy of 92.71 to 104.06%. The total time for the one step online procedure was only 8 min. This method provides a direct and accurate measurement for therapeutic drug monitoring of Oxcarbazepine and its active metabolite licarbazepine.
Ying Wan - One of the best experts on this subject based on the ideXlab platform.
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a randomized placebo controlled study of Oxcarbazepine in painful diabetic neuropathy
Acta Neurologica Scandinavica, 2006Co-Authors: J Grosskopf, Jennifer Mazzola, Ying Wan, Margaret HopwoodAbstract:Objectives: To evaluate the efficacy and safety of Oxcarbazepine (1200 mg/day) in patients with painful diabetic neuropathy in a multicentre, double-blind, placebo-controlled, 16-week study. Methods: A total of 141 patients were randomized to Oxcarbazepine (1200 mg/day) (n = 71) or placebo (n = 70). The primary efficacy variable was the change in mean visual analogue scale (VAS) score from baseline to the last week the patient participated in the study. Results: The reduction in mean VAS score from baseline to the last study week was similar between the Oxcarbazepine and placebo groups. The majority of adverse events (most of which first occurred during titration) were mild to moderate in severity and resolved over the course of the study. Conclusions: In this study, no statistically significant difference in therapeutic effect was observed between Oxcarbazepine (1200 mg/day) and placebo. However, further studies are necessary to assess the effective dose range of Oxcarbazepine in the treatment of painful diabetic neuropathy.
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Oxcarbazepine in painful diabetic neuropathy results of a dose ranging study
Acta Neurologica Scandinavica, 2006Co-Authors: Ahmad Beydoun, Margaret Hopwood, Aziz Shaibani, Ying WanAbstract:Objectives To evaluate the efficacy and safety of Oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. Methods A total of 347 patients were randomized to Oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. Results No difference between any Oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the Oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. Conclusions Although the primary efficacy variable did not reach statistical significance, patients taking Oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.
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Oxcarbazepine in painful diabetic neuropathy a randomized placebo controlled study
European Journal of Pain, 2005Co-Authors: Sunil Dogra, Said R Beydoun, Jennifer Mazzola, Margaret Hopwood, Ying WanAbstract:In this multicentre, placebo-controlled, 16-week trial, the efficacy and safety of Oxcarbazepine monotherapy in patients with neuropathic pain of diabetic origin was evaluated. Eligible patients had a 6-month to 5-year history of neuropathic pain symptoms of diabetic origin and a pain rating of > or =50 units on the visual analogue scale (VAS). Oxcarbazepine was initiated at a dose of 300 mg/day and titrated to a maximum dose of 1800 mg/day. In total, 146 patients (Oxcarbazepine, n=69; placebo, n=77) were randomized. After 16 weeks, Oxcarbazepine-treated patients experienced a significantly larger decrease in the average change in VAS score from baseline compared with placebo (-24.3 vs. -14.7 units, respectively; p=0.01). The reduction from baseline in mean VAS score for Oxcarbazepine-treated patients was of a greater magnitude than placebo as early as week 2 (-8.0 vs. -4.7; p 50% reduction from baseline in VAS score at the end of treatment compared with placebo (35.2% vs. 18.4%, respectively; p=0.0156; number needed to treat=6.0). Global assessment of therapeutic effect rating was improved in more Oxcarbazepine patients than placebo patients (48% vs. 22%, respectively; p=0.0025). Patients on Oxcarbazepine were awakened less frequently due to pain than patients on placebo. Most adverse events were mild to moderate in severity, transient, and in line with the known tolerability profile of Oxcarbazepine. These observations suggest that Oxcarbazepine monotherapy, pending additional trials, may be efficacious and may provide clinically meaningful pain relief in patients with neuropathic pain of diabetic origin.
Margaret Hopwood - One of the best experts on this subject based on the ideXlab platform.
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a randomized placebo controlled study of Oxcarbazepine in painful diabetic neuropathy
Acta Neurologica Scandinavica, 2006Co-Authors: J Grosskopf, Jennifer Mazzola, Ying Wan, Margaret HopwoodAbstract:Objectives: To evaluate the efficacy and safety of Oxcarbazepine (1200 mg/day) in patients with painful diabetic neuropathy in a multicentre, double-blind, placebo-controlled, 16-week study. Methods: A total of 141 patients were randomized to Oxcarbazepine (1200 mg/day) (n = 71) or placebo (n = 70). The primary efficacy variable was the change in mean visual analogue scale (VAS) score from baseline to the last week the patient participated in the study. Results: The reduction in mean VAS score from baseline to the last study week was similar between the Oxcarbazepine and placebo groups. The majority of adverse events (most of which first occurred during titration) were mild to moderate in severity and resolved over the course of the study. Conclusions: In this study, no statistically significant difference in therapeutic effect was observed between Oxcarbazepine (1200 mg/day) and placebo. However, further studies are necessary to assess the effective dose range of Oxcarbazepine in the treatment of painful diabetic neuropathy.
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Oxcarbazepine in painful diabetic neuropathy results of a dose ranging study
Acta Neurologica Scandinavica, 2006Co-Authors: Ahmad Beydoun, Margaret Hopwood, Aziz Shaibani, Ying WanAbstract:Objectives To evaluate the efficacy and safety of Oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. Methods A total of 347 patients were randomized to Oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. Results No difference between any Oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the Oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. Conclusions Although the primary efficacy variable did not reach statistical significance, patients taking Oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.
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Oxcarbazepine in painful diabetic neuropathy a randomized placebo controlled study
European Journal of Pain, 2005Co-Authors: Sunil Dogra, Said R Beydoun, Jennifer Mazzola, Margaret Hopwood, Ying WanAbstract:In this multicentre, placebo-controlled, 16-week trial, the efficacy and safety of Oxcarbazepine monotherapy in patients with neuropathic pain of diabetic origin was evaluated. Eligible patients had a 6-month to 5-year history of neuropathic pain symptoms of diabetic origin and a pain rating of > or =50 units on the visual analogue scale (VAS). Oxcarbazepine was initiated at a dose of 300 mg/day and titrated to a maximum dose of 1800 mg/day. In total, 146 patients (Oxcarbazepine, n=69; placebo, n=77) were randomized. After 16 weeks, Oxcarbazepine-treated patients experienced a significantly larger decrease in the average change in VAS score from baseline compared with placebo (-24.3 vs. -14.7 units, respectively; p=0.01). The reduction from baseline in mean VAS score for Oxcarbazepine-treated patients was of a greater magnitude than placebo as early as week 2 (-8.0 vs. -4.7; p 50% reduction from baseline in VAS score at the end of treatment compared with placebo (35.2% vs. 18.4%, respectively; p=0.0156; number needed to treat=6.0). Global assessment of therapeutic effect rating was improved in more Oxcarbazepine patients than placebo patients (48% vs. 22%, respectively; p=0.0025). Patients on Oxcarbazepine were awakened less frequently due to pain than patients on placebo. Most adverse events were mild to moderate in severity, transient, and in line with the known tolerability profile of Oxcarbazepine. These observations suggest that Oxcarbazepine monotherapy, pending additional trials, may be efficacious and may provide clinically meaningful pain relief in patients with neuropathic pain of diabetic origin.
Ryan Patel - One of the best experts on this subject based on the ideXlab platform.
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neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of Oxcarbazepine
European Journal of Pain, 2019Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H DickensonAbstract:BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic Oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, Oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, Oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic Oxcarbazepine, supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that Oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. SIGNIFICANCE: The inhibitory effects of lidocaine and Oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.
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neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of Oxcarbazepine
European Journal of Pain (2018) (In press)., 2018Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H DickensonAbstract:BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterised by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population but has clear efficacy in a sub-group with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitives with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic Oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, Oxcarbazepine markedly inhibited punctate mechanical, dynamic brush and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, Oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic Oxcarbazepine supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury, and that Oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. This article is protected by copyright. All rights reserved.
