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Peter Jenner - One of the best experts on this subject based on the ideXlab platform.
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the effect of banisteriopsis caapi b caapi on the Motor deficits in the mptp treated common marmoset model of parkinson s disease
Phytotherapy Research, 2018Co-Authors: Ria Fisher, Louise Lincoln, Michael J Jackson, Robert C Hider, Peter Jenner, Vincenzo Abbate, Andrew J. Lees, Sarah RoseAbstract:: Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, Motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed Motor Disability, increased locoMotor activity, and induced moderate dyskinesia. B. caapi did not increase locoMotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved Motor Disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in Motor Disability without affecting locoMotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved Motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
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Motor performance and loss of dopaminergic innervation of the nigral-striatal pathway.
2017Co-Authors: Michel Modo, Michael J Jackson, Peter Jenner, Sarah Rose, William R. Crum, Madeline Gerwig, Anthony C. Vernon, Priya Patel, Mahmoud M. IravaniAbstract:A. Motor activity and Motor Disability in MPTP treated common marmoset treated with a single dose of 12.5mg/kg levodopa plus 12.5 mg/kg carbidopa. Administration of levodopa led a marked increased in Motor activity (left panel) and marked reduction in Motor Disability (right panel). Both Motor activity and Motor Disability peak at around 90 min of levodopa oral administration. Each data point is a mean ± s.e.m, n = 7. B. A denervation of tyrosine hydroxylase (TH) positive dopaminergic fibers is seen in the caudate and putamen after MPTP administration. C. A higher magnification of the caudate and putamen further highlights the dramatic loss of dopaminergic fibers in both structures with an even loss throughout the structure. D. A quantification of TH+ neurons in the substantia nigra further demonstrated a significant (p
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oral r 11 o valeryl n n propylnoraporphine reverses Motor deficits in mptp treated marmosets
Movement Disorders, 2016Co-Authors: Louise Lincoln, Ria Fisher, Michael J Jackson, Peter Jenner, Andrew J. Lees, John L Neumeyer, Anna W Sromek, Sarah RoseAbstract:Background The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from “off” periods, whereas continuous subcutaneous infusion is used to increase “on” periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of Motor Disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. Methods LocoMotor activity, Motor Disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). Results Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of Motor Disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of Motor Disability and increased locoMotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of Motor Disability reversal and increased locoMotor activity. Conclusion Oral administration of 11-OH-NPa valerate produced a rapid reversal of Motor Disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society
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The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets
European journal of pharmacology, 2014Co-Authors: Shinichi Uchida, Akihisa Mori, Kazuhiro Soshiroda, Eri Okita, Mika Kawai-uchida, Peter JennerAbstract:Abstract The adenosine A 2A receptor antagonist, istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged ‘OFF’ periods. In contrast, the effects of istradefylline on Motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01–0.1 mg/kg p.o.) and pergolide (0.003–0.1 mg/kg p.o.) administered alone produced dose dependent increases in locoMotor activity, a reduction in Motor Disability. Threshold doses of ropinirole (0.025–0.075 mg/kg p.o.) and pergolide (0.01–0.075 mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of istradefylline (10 mg/kg p.o.) alone resulted in a decrease in Motor Disability and increase in ‘ON’ time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with istradefylline resulted in an increase in the reversal of Motor Disability and increase in ‘ON’ time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that istradefylline is effective in improving Motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting.
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continuous administration of rotigotine to mptp treated common marmosets enhances anti parkinsonian activity and reduces dyskinesia induction
Experimental Neurology, 2009Co-Authors: K. Stockwell, Michael J Jackson, Sarah Rose, Dieter Scheller, Lance A. Smith, Mahmoud M. Iravani, Kayhan A Tayaranibinazir, C W Olanow, Peter JennerAbstract:Abstract Rotigotine is a novel, non-ergoline dopamine D 3 /D 2 /D 1 -receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of Motor Disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l -DOPA prevented l -DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l -DOPA was then co-administered for a further 28 days. Animals were assessed for locoMotor activity, Motor Disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved Motor deficits and normalized Motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l -DOPA alone. The addition of l -DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l -DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l -DOPA from inducing dyskinesia suggesting that l -DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Michael J Jackson - One of the best experts on this subject based on the ideXlab platform.
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antiparkinsonian effects of a metabotropic glutamate receptor 4 agonist in mptp treated marmosets
Journal of Parkinson's disease, 2020Co-Authors: Elizabeth Mann, Ria Fisher, Louise Lincoln, Michael J Jackson, Sarah Rose, Susan DutyAbstract:Background Increased firing across glutamatergic synapses may contribute to both the Motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both Motor dysfunction and dyskinesia in Parkinson's disease. Objective We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. Methods Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). LocoMotor activity was measured in automated test cages and animals were scored for dyskinesia and Disability. Results As expected, L-DOPA reversed Motor Disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the Motor Disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Conclusion Systemic administration of LSP1-2111 reduces Motor Disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.
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the effect of banisteriopsis caapi b caapi on the Motor deficits in the mptp treated common marmoset model of parkinson s disease
Phytotherapy Research, 2018Co-Authors: Ria Fisher, Louise Lincoln, Michael J Jackson, Robert C Hider, Peter Jenner, Vincenzo Abbate, Andrew J. Lees, Sarah RoseAbstract:: Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, Motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed Motor Disability, increased locoMotor activity, and induced moderate dyskinesia. B. caapi did not increase locoMotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved Motor Disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in Motor Disability without affecting locoMotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved Motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
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Motor performance and loss of dopaminergic innervation of the nigral-striatal pathway.
2017Co-Authors: Michel Modo, Michael J Jackson, Peter Jenner, Sarah Rose, William R. Crum, Madeline Gerwig, Anthony C. Vernon, Priya Patel, Mahmoud M. IravaniAbstract:A. Motor activity and Motor Disability in MPTP treated common marmoset treated with a single dose of 12.5mg/kg levodopa plus 12.5 mg/kg carbidopa. Administration of levodopa led a marked increased in Motor activity (left panel) and marked reduction in Motor Disability (right panel). Both Motor activity and Motor Disability peak at around 90 min of levodopa oral administration. Each data point is a mean ± s.e.m, n = 7. B. A denervation of tyrosine hydroxylase (TH) positive dopaminergic fibers is seen in the caudate and putamen after MPTP administration. C. A higher magnification of the caudate and putamen further highlights the dramatic loss of dopaminergic fibers in both structures with an even loss throughout the structure. D. A quantification of TH+ neurons in the substantia nigra further demonstrated a significant (p
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oral r 11 o valeryl n n propylnoraporphine reverses Motor deficits in mptp treated marmosets
Movement Disorders, 2016Co-Authors: Louise Lincoln, Ria Fisher, Michael J Jackson, Peter Jenner, Andrew J. Lees, John L Neumeyer, Anna W Sromek, Sarah RoseAbstract:Background The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from “off” periods, whereas continuous subcutaneous infusion is used to increase “on” periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of Motor Disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. Methods LocoMotor activity, Motor Disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). Results Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of Motor Disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of Motor Disability and increased locoMotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of Motor Disability reversal and increased locoMotor activity. Conclusion Oral administration of 11-OH-NPa valerate produced a rapid reversal of Motor Disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society
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continuous administration of rotigotine to mptp treated common marmosets enhances anti parkinsonian activity and reduces dyskinesia induction
Experimental Neurology, 2009Co-Authors: K. Stockwell, Michael J Jackson, Sarah Rose, Dieter Scheller, Lance A. Smith, Mahmoud M. Iravani, Kayhan A Tayaranibinazir, C W Olanow, Peter JennerAbstract:Abstract Rotigotine is a novel, non-ergoline dopamine D 3 /D 2 /D 1 -receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of Motor Disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l -DOPA prevented l -DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l -DOPA was then co-administered for a further 28 days. Animals were assessed for locoMotor activity, Motor Disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved Motor deficits and normalized Motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l -DOPA alone. The addition of l -DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l -DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l -DOPA from inducing dyskinesia suggesting that l -DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Sarah Rose - One of the best experts on this subject based on the ideXlab platform.
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antiparkinsonian effects of a metabotropic glutamate receptor 4 agonist in mptp treated marmosets
Journal of Parkinson's disease, 2020Co-Authors: Elizabeth Mann, Ria Fisher, Louise Lincoln, Michael J Jackson, Sarah Rose, Susan DutyAbstract:Background Increased firing across glutamatergic synapses may contribute to both the Motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both Motor dysfunction and dyskinesia in Parkinson's disease. Objective We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. Methods Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). LocoMotor activity was measured in automated test cages and animals were scored for dyskinesia and Disability. Results As expected, L-DOPA reversed Motor Disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the Motor Disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Conclusion Systemic administration of LSP1-2111 reduces Motor Disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.
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the effect of banisteriopsis caapi b caapi on the Motor deficits in the mptp treated common marmoset model of parkinson s disease
Phytotherapy Research, 2018Co-Authors: Ria Fisher, Louise Lincoln, Michael J Jackson, Robert C Hider, Peter Jenner, Vincenzo Abbate, Andrew J. Lees, Sarah RoseAbstract:: Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, Motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed Motor Disability, increased locoMotor activity, and induced moderate dyskinesia. B. caapi did not increase locoMotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved Motor Disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in Motor Disability without affecting locoMotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved Motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
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Motor performance and loss of dopaminergic innervation of the nigral-striatal pathway.
2017Co-Authors: Michel Modo, Michael J Jackson, Peter Jenner, Sarah Rose, William R. Crum, Madeline Gerwig, Anthony C. Vernon, Priya Patel, Mahmoud M. IravaniAbstract:A. Motor activity and Motor Disability in MPTP treated common marmoset treated with a single dose of 12.5mg/kg levodopa plus 12.5 mg/kg carbidopa. Administration of levodopa led a marked increased in Motor activity (left panel) and marked reduction in Motor Disability (right panel). Both Motor activity and Motor Disability peak at around 90 min of levodopa oral administration. Each data point is a mean ± s.e.m, n = 7. B. A denervation of tyrosine hydroxylase (TH) positive dopaminergic fibers is seen in the caudate and putamen after MPTP administration. C. A higher magnification of the caudate and putamen further highlights the dramatic loss of dopaminergic fibers in both structures with an even loss throughout the structure. D. A quantification of TH+ neurons in the substantia nigra further demonstrated a significant (p
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oral r 11 o valeryl n n propylnoraporphine reverses Motor deficits in mptp treated marmosets
Movement Disorders, 2016Co-Authors: Louise Lincoln, Ria Fisher, Michael J Jackson, Peter Jenner, Andrew J. Lees, John L Neumeyer, Anna W Sromek, Sarah RoseAbstract:Background The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from “off” periods, whereas continuous subcutaneous infusion is used to increase “on” periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of Motor Disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. Methods LocoMotor activity, Motor Disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). Results Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of Motor Disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of Motor Disability and increased locoMotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of Motor Disability reversal and increased locoMotor activity. Conclusion Oral administration of 11-OH-NPa valerate produced a rapid reversal of Motor Disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society
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continuous administration of rotigotine to mptp treated common marmosets enhances anti parkinsonian activity and reduces dyskinesia induction
Experimental Neurology, 2009Co-Authors: K. Stockwell, Michael J Jackson, Sarah Rose, Dieter Scheller, Lance A. Smith, Mahmoud M. Iravani, Kayhan A Tayaranibinazir, C W Olanow, Peter JennerAbstract:Abstract Rotigotine is a novel, non-ergoline dopamine D 3 /D 2 /D 1 -receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of Motor Disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l -DOPA prevented l -DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l -DOPA was then co-administered for a further 28 days. Animals were assessed for locoMotor activity, Motor Disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved Motor deficits and normalized Motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l -DOPA alone. The addition of l -DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l -DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l -DOPA from inducing dyskinesia suggesting that l -DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Lance A. Smith - One of the best experts on this subject based on the ideXlab platform.
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continuous administration of rotigotine to mptp treated common marmosets enhances anti parkinsonian activity and reduces dyskinesia induction
Experimental Neurology, 2009Co-Authors: K. Stockwell, Michael J Jackson, Sarah Rose, Dieter Scheller, Lance A. Smith, Mahmoud M. Iravani, Kayhan A Tayaranibinazir, C W Olanow, Peter JennerAbstract:Abstract Rotigotine is a novel, non-ergoline dopamine D 3 /D 2 /D 1 -receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of Motor Disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l -DOPA prevented l -DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l -DOPA was then co-administered for a further 28 days. Animals were assessed for locoMotor activity, Motor Disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved Motor deficits and normalized Motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l -DOPA alone. The addition of l -DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l -DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l -DOPA from inducing dyskinesia suggesting that l -DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
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the administration of entacapone prevents l dopa induced dyskinesia when added to dopamine agonist therapy in mptp treated primates
Experimental Neurology, 2007Co-Authors: Mohammed Zubair, Michael J Jackson, Sarah Rose, Lance A. Smith, K. Stockwell, Kayhan A Tayaranibinazir, Warren Olanow, Peter JennerAbstract:Abstract More continuous delivery of l -3,4-dihydroxyphenylalanine ( l -dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l -dopa regimens. We now investigate whether l -dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed Motor Disability and increased locoMotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l -dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of Motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l -dopa BID or QID without entacapone produced only a minor further reversal of Motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l -dopa BID or QID with entacapone also produced some further improvement in Motor function with the combination of entacapone and l -dopa BID significantly improving Motor Disability compared to l -dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l -dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.
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antiparkinsonian activity of l propyl l leucyl glycinamide or melanocyte inhibiting factor in mptp treated common marmosets
Movement Disorders, 2007Co-Authors: Regina Katzenschlager, Michael J Jackson, Peter Jenner, Sarah Rose, Lance A. Smith, K. Stockwell, Kayhan A Tayaranibinazir, Mohammed Zubair, Andrew J. LeesAbstract:The neuropeptide melanocyte-inhibiting factor (MIF) or L-propyl-L-leucyl-glycinamide (PLG) has been reported in some studies to improve the Motor signs of Parkinson's disease (PD) and in rodent models of PD. In this study of oral and intravenous MIF in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, a wide range of doses of MIF administered alone (0.25, 1, 2, 5, 10, 20 mg/kg orally) did not increase locoMotor activity, relieve Motor Disability, or induce dyskinesias. When MIF (1.0 and 5.0 mg/kg orally or 10 and 20 mg/kg intravenously) was administered concomitantly with levodopa/benserazide, no significant differences in Motor function or dyskinesias were observed compared with levodopa/henserazide alone. The results of this first study of MIF in the marmoset MPTP model provide no encouragement for the reinvestigation of MIF in the clinical management of the Motor signs of PD. (c) 2007 Movement Disorder Society.
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the novel adenosine a2a receptor antagonist st1535 potentiates the effects of a threshold dose of l dopa in mptp treated common marmosets
European Journal of Pharmacology, 2006Co-Authors: Sarah Rose, Michael J Jackson, Lance A. Smith, K. Stockwell, Louisa Johnson, Paolo Carminati, Peter JennerAbstract:Abstract Adenosine A 2a receptor antagonists may represent a novel non-dopaminergic approach to the treatment of Parkinson's disease. However, there is little information available on their ability to reverse Motor deficits in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-treated primates. We have studied the effects of the novel A 2a receptor antagonist 2-butyl-9-methyl-8-(2 H -1,2,3-triazol 2-yl)-9 H -purin-6-ylamine (ST1535) alone and in combination with l -3, 4-dihydroxyphenylalanine ( l -DOPA) in MPTP-treated common marmosets. ST1535 (10, 20 and 40 mg/kg, p.o.) when administered alone to MPTP-treated common marmosets produced a dose related increase in locoMotor Motor activity and tended to reverse Motor Disability. Treatment with a threshold dose of l -DOPA (2.5 mg/kg, p.o.) produced an increase in locoMotor activity and again tended to reverse Motor Disability. When l -DOPA (2.5 mg/kg, p.o.) was administered in combination with ST1535 (20 mg/kg, p.o.), there was an enhancement in the intensity and duration of the effect of l -DOPA (2.5 mg/kg, p.o.) in reversing Motor deficits as shown by both a further increase in locoMotor activity and reversal of Motor Disability. The combination of l -DOPA (2.5 mg/kg, p.o.) plus ST1535 (20 mg/kg, p.o.) significantly increased “on time” in these animals. These data substantiate the evidence that adenosine A 2a receptor antagonists are able to reverse Motor deficits in a highly predictive model of clinical efficacy in Parkinson's disease. The data suggests that ST1535 will be an effective anti-parkinsonian agent in combination with l -DOPA and allow a reduction in l -DOPA usage in the treatment of Parkinson's disease.
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combined use of the adenosine a2a antagonist kw 6002 with l dopa or with selective d1 or d2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in mptp treated monkeys
Experimental Neurology, 2000Co-Authors: Tomoyuki Kanda, Michael J Jackson, Lance A. Smith, R K B Pearce, Joji Nakamura, Hiroshi Kase, Yoshihisa Kuwana, Peter JennerAbstract:Abstract The novel selective adenosine A2A receptor antagonist KW-6002 improves Motor Disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l -DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in Motor Disability. Coadministration of KW-6002 with a low dose of l -DOPA also produced an additive improvement in Motor Disability, and increased locoMotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with l -DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate l -DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to l -DOPA. Selective adenosine A2A receptor antagonists, such as KW-6002, may be one means of reducing the dosage of l -DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.
K. Stockwell - One of the best experts on this subject based on the ideXlab platform.
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continuous administration of rotigotine to mptp treated common marmosets enhances anti parkinsonian activity and reduces dyskinesia induction
Experimental Neurology, 2009Co-Authors: K. Stockwell, Michael J Jackson, Sarah Rose, Dieter Scheller, Lance A. Smith, Mahmoud M. Iravani, Kayhan A Tayaranibinazir, C W Olanow, Peter JennerAbstract:Abstract Rotigotine is a novel, non-ergoline dopamine D 3 /D 2 /D 1 -receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of Motor Disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l -DOPA prevented l -DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l -DOPA was then co-administered for a further 28 days. Animals were assessed for locoMotor activity, Motor Disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved Motor deficits and normalized Motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l -DOPA alone. The addition of l -DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l -DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l -DOPA from inducing dyskinesia suggesting that l -DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
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the administration of entacapone prevents l dopa induced dyskinesia when added to dopamine agonist therapy in mptp treated primates
Experimental Neurology, 2007Co-Authors: Mohammed Zubair, Michael J Jackson, Sarah Rose, Lance A. Smith, K. Stockwell, Kayhan A Tayaranibinazir, Warren Olanow, Peter JennerAbstract:Abstract More continuous delivery of l -3,4-dihydroxyphenylalanine ( l -dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l -dopa regimens. We now investigate whether l -dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed Motor Disability and increased locoMotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l -dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of Motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l -dopa BID or QID without entacapone produced only a minor further reversal of Motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l -dopa BID or QID with entacapone also produced some further improvement in Motor function with the combination of entacapone and l -dopa BID significantly improving Motor Disability compared to l -dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l -dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.
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antiparkinsonian activity of l propyl l leucyl glycinamide or melanocyte inhibiting factor in mptp treated common marmosets
Movement Disorders, 2007Co-Authors: Regina Katzenschlager, Michael J Jackson, Peter Jenner, Sarah Rose, Lance A. Smith, K. Stockwell, Kayhan A Tayaranibinazir, Mohammed Zubair, Andrew J. LeesAbstract:The neuropeptide melanocyte-inhibiting factor (MIF) or L-propyl-L-leucyl-glycinamide (PLG) has been reported in some studies to improve the Motor signs of Parkinson's disease (PD) and in rodent models of PD. In this study of oral and intravenous MIF in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, a wide range of doses of MIF administered alone (0.25, 1, 2, 5, 10, 20 mg/kg orally) did not increase locoMotor activity, relieve Motor Disability, or induce dyskinesias. When MIF (1.0 and 5.0 mg/kg orally or 10 and 20 mg/kg intravenously) was administered concomitantly with levodopa/benserazide, no significant differences in Motor function or dyskinesias were observed compared with levodopa/henserazide alone. The results of this first study of MIF in the marmoset MPTP model provide no encouragement for the reinvestigation of MIF in the clinical management of the Motor signs of PD. (c) 2007 Movement Disorder Society.
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the novel adenosine a2a receptor antagonist st1535 potentiates the effects of a threshold dose of l dopa in mptp treated common marmosets
European Journal of Pharmacology, 2006Co-Authors: Sarah Rose, Michael J Jackson, Lance A. Smith, K. Stockwell, Louisa Johnson, Paolo Carminati, Peter JennerAbstract:Abstract Adenosine A 2a receptor antagonists may represent a novel non-dopaminergic approach to the treatment of Parkinson's disease. However, there is little information available on their ability to reverse Motor deficits in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-treated primates. We have studied the effects of the novel A 2a receptor antagonist 2-butyl-9-methyl-8-(2 H -1,2,3-triazol 2-yl)-9 H -purin-6-ylamine (ST1535) alone and in combination with l -3, 4-dihydroxyphenylalanine ( l -DOPA) in MPTP-treated common marmosets. ST1535 (10, 20 and 40 mg/kg, p.o.) when administered alone to MPTP-treated common marmosets produced a dose related increase in locoMotor Motor activity and tended to reverse Motor Disability. Treatment with a threshold dose of l -DOPA (2.5 mg/kg, p.o.) produced an increase in locoMotor activity and again tended to reverse Motor Disability. When l -DOPA (2.5 mg/kg, p.o.) was administered in combination with ST1535 (20 mg/kg, p.o.), there was an enhancement in the intensity and duration of the effect of l -DOPA (2.5 mg/kg, p.o.) in reversing Motor deficits as shown by both a further increase in locoMotor activity and reversal of Motor Disability. The combination of l -DOPA (2.5 mg/kg, p.o.) plus ST1535 (20 mg/kg, p.o.) significantly increased “on time” in these animals. These data substantiate the evidence that adenosine A 2a receptor antagonists are able to reverse Motor deficits in a highly predictive model of clinical efficacy in Parkinson's disease. The data suggests that ST1535 will be an effective anti-parkinsonian agent in combination with l -DOPA and allow a reduction in l -DOPA usage in the treatment of Parkinson's disease.