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Andrew Dilley - One of the best experts on this subject based on the ideXlab platform.
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Data for research paper: Neuritis and Vinblastine-induced axonal transport disruption lead to signs of altered dorsal horn excitability
2019Co-Authors: Ieva Satkeviciute, Andrew DilleyAbstract:Data for paper appearing in ‘Molecular Pain’ Dorsal horn electrophysiological, behavioural and immunohistochemical data following neuritis and Vinblastine-induced axonal transport disruption. Data set includes ongoing activity rates, wind-up and mechanical responses from wide dynamic range neurons, numbers of c-Fos positive cells and area of substance p labelling in the dorsal horn. Abstract from research paper: Background Many patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using Vinblastine, since neuritis disrupts such processes. Results At the peak of cutaneous hypersensitivities, recordings from wide dynamic range neurons revealed increases in wind-up following neuritis but not Vinblastine treatment. Ongoing activity from these neurons was unchanged. Vinblastine treatment caused a reduction in the responses of wide dynamic range neurons to noxious mechanical stimulation of the receptive field. The response of neurons to innocuous mechanical stimulation was also reduced in wide dynamic range neurons that were at a depth ≥550 µm following Vinblastine treatment. An examination of the superficial dorsal horn revealed an increase in c-Fos–positive neurons in both groups following electrical stimulation of the sciatic nerve. The area of dorsal horn expressing substance P was also decreased following Vinblastine treatment. Conclusion These findings indicate that a minor nerve insult, such as neuritis, can lead to changes within the dorsal horn that are consistent with a central neuropathic pain mechanism.
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neuritis and Vinblastine induced axonal transport disruption lead to signs of altered dorsal horn excitability
Molecular Pain, 2018Co-Authors: Ieva Satkeviciute, Andrew DilleyAbstract:Many patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using Vinblastine, since neuritis disrupts such processes. At the peak of cutaneous hypersensitivities, recordings from wide dynamic range (WDR) neurons revealed increases in wind-up following neuritis but not Vinblastine treatment. Ongoing activity from these neurons was unchanged. Vinblastine treatment caused a reduction in the responses of WDR neurons to noxious mechanical stimulation of the receptive field. The response of neurons to innocuous mechanical stimulation was also reduced in WDR neurons that were at a depth ≥550 μm following Vinblastine treatment. An examination of the superficial dorsal horn revealed an increase in c-Fos-positive neurons in both groups following electrical stimulation of the sciatic nerve. The area of dorsal horn expressing substance P was also decreased following Vinblastine treatment. These findings indicate that a minor nerve insult, such as neuritis, can lead to changes within the dorsal horn that are consistent with a central neuropathic pain mechanism.
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disruption of fast axonal transport in the rat induces behavioral changes consistent with neuropathic pain
The Journal of Pain, 2013Co-Authors: Andrew Dilley, Natalie Richards, Kim Pulman, Geoffrey M BoveAbstract:UNLABELLED Studies of peripheral nerve inflammation (neuritis) suggest that some symptoms of neuropathic pain can be generated from inflamed but otherwise uninjured axons. We have previously inferred a role for inflammation-induced axonal transport disruption in the underlying mechanisms. In the present study, we have investigated the development of sensory hypersensitivities following Vinblastine-induced axonal transport disruption. Similar to neuritis, locally applied .1 mM Vinblastine caused the rapid development of mechanical hypersensitivity within the first week postsurgery. The same animals did not develop heat hypersensitivity. Because aberrant firing from primary sensory neurons is considered necessary to drive spinal mechanisms that lead to hypersensitivities, the levels of ongoing activity and axonal mechanical sensitivity were examined. Recordings from A- and C-fiber neurons did not reveal differences in the levels of ongoing activity between Vinblastine-treated (<5.8%) and saline-treated control animals (<4.6%). However, 28% of C-fiber axons were mechanically sensitive at the Vinblastine treatment site. Using kinesin immunohistochemistry, we confirmed a reduction of anterograde axonal transport in Vinblastine-treated and neuritis animals. In summary, this study has revealed an alternative pain model, which may be relevant to conditions that are not accompanied by frank nerve injury. PERSPECTIVE In this study, we expand our previous reports and demonstrate that focal reduced axonal transport causes distal mechanical hypersensitivity considered consistent with neuropathic pain but in the absence of nerve injury. These findings may inform pain conditions that have a neural inflammatory component.
Yasufumi Sawada - One of the best experts on this subject based on the ideXlab platform.
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polymethoxylated flavones in orange juice are inhibitors of p glycoprotein but not cytochrome p450 3a4
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Hitomi Takanaga, Ayako Ohnishi, Shiho Yamada, Hirotami Matsuo, Satoshi Morimoto, Yukihiro Shoyama, Hisakazu Ohtani, Yasufumi SawadaAbstract:The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [ 3 H]Vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [ 3 H]Vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 μM), an inhibitor of P-gp. No significant effect on the uptake of 3- O -[ 3 H]methylglucose or [ 14 C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [ 3 H]Vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3′,4′,5,6,7,8-heptamethoxyflavone (HMF) and 4′,5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3′,4′,5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [ 3 H]Vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 μM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6β-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [ 3 H]Vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced Vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.
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polymethoxylated flavones in orange juice are inhibitors of p glycoprotein but not cytochrome p450 3a4
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Hitomi Takanaga, Ayako Ohnishi, Shiho Yamada, Hirotami Matsuo, Satoshi Morimoto, Yukihiro Shoyama, Hisakazu Ohtani, Yasufumi SawadaAbstract:The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [(3)H]Vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [(3)H]Vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [(3)H]Vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [(3)H]Vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 microM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6beta-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [(3)H]Vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced Vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.
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inhibition of Vinblastine efflux mediated by p glycoprotein by grapefruit juice components in caco 2 cells
Biological & Pharmaceutical Bulletin, 1998Co-Authors: Hitomi Takanaga, Ayako Ohnishi, Hirotami Matsuo, Yasufumi SawadaAbstract:We investigated the effect of components in grapefruit juice (GFJ) on the transport of Vinblastine, a substrate of P-glycoprotein (P-gp), across Caco-2 cells. The apical to basolateral flux of [3H]Vinblastine was increased in the presence of GFJ extracts. The steady-state uptake of [3H]Vinblastine from the apical side was significantly increased in the presence of GFJ in a dose-dependent manner within the range of 2.5 to 50% (v/v) of GFJ. Although naringin and naringenin reduced apical efflux of [3H]Vinblastine at the concentration present in GFJ and increased steady-state uptake from the apical side to 124 and 240%, respectively, the observed effect of naringin was not enough to account for the effect of GFJ and naringenin is not naturally present in GFJ. To investigate the effective components in GFJ, we examined the inhibitory effect of several organic solvent extracts of GFJ on the transport of [3H]Vinblastine in Caco-2 cells. Organic solvent extracts of GFJ enhanced the apical to basolateral transcellular transport and inhibited the apical efflux. The permeability coefficient of apical to basolateral transport of [3H]Vinblastine increased in the order of the ethyl acetate>diethyl ether>methylene chloride extracts of GFJ. Since the extracted amount of naringenin by ethyl acetate was less than that with the other organic solvents, the primary inhibitor in GFJ is suggested to be different from this flavonoid. The present study demonstrated the existence of inhibitory components in GFJ for the P-gp function in Caco-2 cells, which are distinct from known components such as naringin or naringenin.
Frederic Amant - One of the best experts on this subject based on the ideXlab platform.
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transplacental transfer of anthracyclines Vinblastine and 4 hydroxy cyclophosphamide in a baboon model
Gynecologic Oncology, 2010Co-Authors: K Van Calsteren, Rene Verbesselt, Jos H Beijnen, Roland Devlieger, L De Catte, Daniel Chai, R Van Bree, Liesbeth Heyns, J De Hoon, Frederic AmantAbstract:Abstract Objective The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. Methods Fluorouracil–epirubicin–cyclophosphamide (FEC) and doxorubicin–bleomycin–Vinblastine–dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for bioanalysis of doxorubicin, epirubicin, Vinblastine, and cyclophosphamide. Results In nine baboons, at a median gestational age of 139days (range, 93–169), FEC 100% ( n =2), FEC 200% ( n =1), ABVD 100% ( n =5), and ABVD 200% ( n =1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5±3.2% ( n =6) and 4.0±1.6% ( n =8) of maternal concentrations, respectively. Fetal tissues contained 6.3±7.9% and 8.7±8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5±15.5% ( n =9) of maternal concentrations. Anthracyclines and Vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1±6.3% ( n =3) and 63.0% ( n =1) of the maternal concentrations, respectively. Conclusion This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, Vinblastine, and 4-hydroxy-cyclophosphamide.
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transplacental transfer of anthracyclines Vinblastine and 4 hydroxy cyclophosphamide in a baboon model
Gynecologic Oncology, 2010Co-Authors: K Van Calsteren, Rene Verbesselt, Jos H Beijnen, Roland Devlieger, L De Catte, Daniel Chai, Liesbeth Heyns, J De Hoon, R Van Bree, Frederic AmantAbstract:Abstract Objective The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. Methods Fluorouracil–epirubicin–cyclophosphamide (FEC) and doxorubicin–bleomycin–Vinblastine–dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for bioanalysis of doxorubicin, epirubicin, Vinblastine, and cyclophosphamide. Results In nine baboons, at a median gestational age of 139days (range, 93–169), FEC 100% ( n =2), FEC 200% ( n =1), ABVD 100% ( n =5), and ABVD 200% ( n =1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5±3.2% ( n =6) and 4.0±1.6% ( n =8) of maternal concentrations, respectively. Fetal tissues contained 6.3±7.9% and 8.7±8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5±15.5% ( n =9) of maternal concentrations. Anthracyclines and Vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1±6.3% ( n =3) and 63.0% ( n =1) of the maternal concentrations, respectively. Conclusion This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, Vinblastine, and 4-hydroxy-cyclophosphamide.
Ieva Satkeviciute - One of the best experts on this subject based on the ideXlab platform.
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Data for research paper: Neuritis and Vinblastine-induced axonal transport disruption lead to signs of altered dorsal horn excitability
2019Co-Authors: Ieva Satkeviciute, Andrew DilleyAbstract:Data for paper appearing in ‘Molecular Pain’ Dorsal horn electrophysiological, behavioural and immunohistochemical data following neuritis and Vinblastine-induced axonal transport disruption. Data set includes ongoing activity rates, wind-up and mechanical responses from wide dynamic range neurons, numbers of c-Fos positive cells and area of substance p labelling in the dorsal horn. Abstract from research paper: Background Many patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using Vinblastine, since neuritis disrupts such processes. Results At the peak of cutaneous hypersensitivities, recordings from wide dynamic range neurons revealed increases in wind-up following neuritis but not Vinblastine treatment. Ongoing activity from these neurons was unchanged. Vinblastine treatment caused a reduction in the responses of wide dynamic range neurons to noxious mechanical stimulation of the receptive field. The response of neurons to innocuous mechanical stimulation was also reduced in wide dynamic range neurons that were at a depth ≥550 µm following Vinblastine treatment. An examination of the superficial dorsal horn revealed an increase in c-Fos–positive neurons in both groups following electrical stimulation of the sciatic nerve. The area of dorsal horn expressing substance P was also decreased following Vinblastine treatment. Conclusion These findings indicate that a minor nerve insult, such as neuritis, can lead to changes within the dorsal horn that are consistent with a central neuropathic pain mechanism.
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neuritis and Vinblastine induced axonal transport disruption lead to signs of altered dorsal horn excitability
Molecular Pain, 2018Co-Authors: Ieva Satkeviciute, Andrew DilleyAbstract:Many patients with neuropathic pain present without signs of nerve injury on routine clinical examination. Some of these patients may have inflamed peripheral nerves (neuritis). In this study, we have examined whether neuritis causes changes within the dorsal horn that may contribute to a central pain mechanism. Comparisons have been made to a model of axonal transport disruption induced using Vinblastine, since neuritis disrupts such processes. At the peak of cutaneous hypersensitivities, recordings from wide dynamic range (WDR) neurons revealed increases in wind-up following neuritis but not Vinblastine treatment. Ongoing activity from these neurons was unchanged. Vinblastine treatment caused a reduction in the responses of WDR neurons to noxious mechanical stimulation of the receptive field. The response of neurons to innocuous mechanical stimulation was also reduced in WDR neurons that were at a depth ≥550 μm following Vinblastine treatment. An examination of the superficial dorsal horn revealed an increase in c-Fos-positive neurons in both groups following electrical stimulation of the sciatic nerve. The area of dorsal horn expressing substance P was also decreased following Vinblastine treatment. These findings indicate that a minor nerve insult, such as neuritis, can lead to changes within the dorsal horn that are consistent with a central neuropathic pain mechanism.
Geoffrey M Bove - One of the best experts on this subject based on the ideXlab platform.
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disruption of fast axonal transport in the rat induces behavioral changes consistent with neuropathic pain
The Journal of Pain, 2013Co-Authors: Andrew Dilley, Natalie Richards, Kim Pulman, Geoffrey M BoveAbstract:UNLABELLED Studies of peripheral nerve inflammation (neuritis) suggest that some symptoms of neuropathic pain can be generated from inflamed but otherwise uninjured axons. We have previously inferred a role for inflammation-induced axonal transport disruption in the underlying mechanisms. In the present study, we have investigated the development of sensory hypersensitivities following Vinblastine-induced axonal transport disruption. Similar to neuritis, locally applied .1 mM Vinblastine caused the rapid development of mechanical hypersensitivity within the first week postsurgery. The same animals did not develop heat hypersensitivity. Because aberrant firing from primary sensory neurons is considered necessary to drive spinal mechanisms that lead to hypersensitivities, the levels of ongoing activity and axonal mechanical sensitivity were examined. Recordings from A- and C-fiber neurons did not reveal differences in the levels of ongoing activity between Vinblastine-treated (<5.8%) and saline-treated control animals (<4.6%). However, 28% of C-fiber axons were mechanically sensitive at the Vinblastine treatment site. Using kinesin immunohistochemistry, we confirmed a reduction of anterograde axonal transport in Vinblastine-treated and neuritis animals. In summary, this study has revealed an alternative pain model, which may be relevant to conditions that are not accompanied by frank nerve injury. PERSPECTIVE In this study, we expand our previous reports and demonstrate that focal reduced axonal transport causes distal mechanical hypersensitivity considered consistent with neuropathic pain but in the absence of nerve injury. These findings may inform pain conditions that have a neural inflammatory component.
