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Carlo Cattaneo - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy of Safinamide on symptoms severity and quality of life in fluctuating parkinson s disease patients
Journal of Parkinson's disease, 2020Co-Authors: Carlo Cattaneo, Wolfgang H Jost, Erminio BonizzoniAbstract:Background Parkinson's disease (PD) is characterized by a wide range of motor and non-motor symptoms. Levodopa is still the most effective drug; however, its long-term use is associated with motor complications which may deteriorate patient's quality of life. Safinamide is a unique treatment modulating both dopaminergic and glutamatergic systems. Previous results from two six months, double-blind, placebo-controlled studies demonstrated that Safinamide has positive effects on both motor functions and quality of life in PD patients. Objective To investigate the effects of Safinamide 100 mg/day over two-year treatment on PD symptoms severity and quality of life, using data from the study 018. Methods Data from 352 patients were analyzed to evaluate the effects of Safinamide on OFF time and ON time (with no or non-troublesome dyskinesia) in the overall population and in subgroups of patients (receiving levodopa monotherapy or with other anti-Parkinson therapies), and the effects of Safinamide on motor symptoms/clinical fluctuations (by means of UPDRS III and IV) and on health-related quality of life (using UPDRS II and PDQ-39 summary index score). Results Safinamide, administered as add-on to standard therapy in fluctuating PD patients, significantly improved motor symptoms and clinical fluctuations in the overall population and in some subgroups of patients. Additionally, Safinamide improved quality of life and activities of daily living, maintaining the efficacy in the long-term. Conclusions The findings of these analyses suggest that Safinamide may be considered an appropriate adjunct therapy in patient not sufficiently controlled. Further investigations are desirable to confirm these results in usual care setting.
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effects of Safinamide on pain in fluctuating parkinson s disease patients a post hoc analysis
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Paolo Barone, Erminio Bonizzoni, Marco SardinaAbstract:Background: Pain, a frequent non-motor symptom in Parkinson’s Disease (PD), significantly impacts on quality of life. Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients. Results from two 24-month, double-blind, placebo-controlled studies demonstrated that Safinamide has positive effects on both motor functions and quality of life in PD patients. Objective: To investigate the effects of Safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE. Methods: This post-hoc analysis evaluated the reduction of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39). A path analysis was performed in order to examine direct and indirect associations between Safinamide and PDQ-39 pain-related items assessed after 6-months of treatment. Results: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the Safinamide group compared to the placebo group. Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the “Bodily discomfort” domain. Path analysis showed that the direct effect of Safinamide on pain accounted for about 80% of the total effect. Conclusions: These results suggest that Safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms. Prospective studies are warranted to investigate this potential benefit.
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long term effects of Safinamide on mood fluctuations in parkinson s disease
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Thomas Müller, Erminio Bonizzoni, Gabriele Lazzeri, Ioannis Kottakis, Charlotte KeywoodAbstract:Background Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. Objective To investigate the effects of Safinamide on mood over two-year treatment in PD patients with motor fluctuations. Methods This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. Results Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the Safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). Conclusion The favorable effect of Safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.
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population pharmacokinetic and pharmacodynamic analyses of Safinamide in subjects with parkinson s disease
Pharmacology Research & Perspectives, 2016Co-Authors: Luca Loprete, Chiara Leuratti, Carlo Cattaneo, Mita Thapar, Colm Farrell, Marco SardinaAbstract:Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate Safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of Safinamide effect on the PD phase of normal functioning (ON-time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected-VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one-compartmental model with first-order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73–5.21) L/h, 166 (158–174) L, and 0.582 (0.335–0.829) h−1, respectively. CL/F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence Safinamide PK. The observed ON-time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON-time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON-time of 0.73 h (week 4), with further ON-time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or Safinamide exposure. The population models adequately describe the population PK of Safinamide and Safinamide effect on ON-time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested.
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Safinamide as add on therapy to levodopa in mid to late stage parkinson s disease fluctuating patients post hoc analysesof studies 016 and settle
Journal of Parkinson's disease, 2016Co-Authors: Carlo Cattaneo, Marco Sardina, Erminio BonizzoniAbstract:Background: Studies 016 and SETTLE showed that Safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of Safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms. Objective: To evaluate the clinical effects of Safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE. Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of Safinamide versus placebo on individual cardinal PD symptoms during ON time. Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, Safinamide improved bradykinesia, rigidity, tremor and gait. Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
Erminio Bonizzoni - One of the best experts on this subject based on the ideXlab platform.
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long term efficacy of Safinamide on symptoms severity and quality of life in fluctuating parkinson s disease patients
Journal of Parkinson's disease, 2020Co-Authors: Carlo Cattaneo, Wolfgang H Jost, Erminio BonizzoniAbstract:Background Parkinson's disease (PD) is characterized by a wide range of motor and non-motor symptoms. Levodopa is still the most effective drug; however, its long-term use is associated with motor complications which may deteriorate patient's quality of life. Safinamide is a unique treatment modulating both dopaminergic and glutamatergic systems. Previous results from two six months, double-blind, placebo-controlled studies demonstrated that Safinamide has positive effects on both motor functions and quality of life in PD patients. Objective To investigate the effects of Safinamide 100 mg/day over two-year treatment on PD symptoms severity and quality of life, using data from the study 018. Methods Data from 352 patients were analyzed to evaluate the effects of Safinamide on OFF time and ON time (with no or non-troublesome dyskinesia) in the overall population and in subgroups of patients (receiving levodopa monotherapy or with other anti-Parkinson therapies), and the effects of Safinamide on motor symptoms/clinical fluctuations (by means of UPDRS III and IV) and on health-related quality of life (using UPDRS II and PDQ-39 summary index score). Results Safinamide, administered as add-on to standard therapy in fluctuating PD patients, significantly improved motor symptoms and clinical fluctuations in the overall population and in some subgroups of patients. Additionally, Safinamide improved quality of life and activities of daily living, maintaining the efficacy in the long-term. Conclusions The findings of these analyses suggest that Safinamide may be considered an appropriate adjunct therapy in patient not sufficiently controlled. Further investigations are desirable to confirm these results in usual care setting.
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effects of Safinamide on pain in fluctuating parkinson s disease patients a post hoc analysis
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Paolo Barone, Erminio Bonizzoni, Marco SardinaAbstract:Background: Pain, a frequent non-motor symptom in Parkinson’s Disease (PD), significantly impacts on quality of life. Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients. Results from two 24-month, double-blind, placebo-controlled studies demonstrated that Safinamide has positive effects on both motor functions and quality of life in PD patients. Objective: To investigate the effects of Safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE. Methods: This post-hoc analysis evaluated the reduction of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39). A path analysis was performed in order to examine direct and indirect associations between Safinamide and PDQ-39 pain-related items assessed after 6-months of treatment. Results: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the Safinamide group compared to the placebo group. Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the “Bodily discomfort” domain. Path analysis showed that the direct effect of Safinamide on pain accounted for about 80% of the total effect. Conclusions: These results suggest that Safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms. Prospective studies are warranted to investigate this potential benefit.
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long term effects of Safinamide on mood fluctuations in parkinson s disease
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Thomas Müller, Erminio Bonizzoni, Gabriele Lazzeri, Ioannis Kottakis, Charlotte KeywoodAbstract:Background Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. Objective To investigate the effects of Safinamide on mood over two-year treatment in PD patients with motor fluctuations. Methods This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. Results Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the Safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). Conclusion The favorable effect of Safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.
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Safinamide as add on therapy to levodopa in mid to late stage parkinson s disease fluctuating patients post hoc analysesof studies 016 and settle
Journal of Parkinson's disease, 2016Co-Authors: Carlo Cattaneo, Marco Sardina, Erminio BonizzoniAbstract:Background: Studies 016 and SETTLE showed that Safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of Safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms. Objective: To evaluate the clinical effects of Safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE. Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of Safinamide versus placebo on individual cardinal PD symptoms during ON time. Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, Safinamide improved bradykinesia, rigidity, tremor and gait. Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
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long term effects of Safinamide on dyskinesia in mid to late stage parkinson s disease a post hoc analysis
Journal of Parkinson's disease, 2015Co-Authors: Carlo Cattaneo, Erminio Bonizzoni, R La Ferla, Marco SardinaAbstract:Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of Safinamide on dyskinesia may be related to severity of dyskinesia at baseline. Objective: This post-hoc analysis further characterized the effects of Safinamide on dyskinesia in mid- to late-stage PD patients. Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between Safinamide and placebo were evaluated using the Wilcoxon rank-sum test. Results: For the overall treated population (with or without baseline dyskinesia), Safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. Conclusions: While no statistically significant difference in mean DRS scores was seen between Safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of Safinamide on dyskinesia. These results may be related to Safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation.
Marco Sardina - One of the best experts on this subject based on the ideXlab platform.
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effects of Safinamide on pain in fluctuating parkinson s disease patients a post hoc analysis
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Paolo Barone, Erminio Bonizzoni, Marco SardinaAbstract:Background: Pain, a frequent non-motor symptom in Parkinson’s Disease (PD), significantly impacts on quality of life. Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients. Results from two 24-month, double-blind, placebo-controlled studies demonstrated that Safinamide has positive effects on both motor functions and quality of life in PD patients. Objective: To investigate the effects of Safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE. Methods: This post-hoc analysis evaluated the reduction of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39). A path analysis was performed in order to examine direct and indirect associations between Safinamide and PDQ-39 pain-related items assessed after 6-months of treatment. Results: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the Safinamide group compared to the placebo group. Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the “Bodily discomfort” domain. Path analysis showed that the direct effect of Safinamide on pain accounted for about 80% of the total effect. Conclusions: These results suggest that Safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms. Prospective studies are warranted to investigate this potential benefit.
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population pharmacokinetic and pharmacodynamic analyses of Safinamide in subjects with parkinson s disease
Pharmacology Research & Perspectives, 2016Co-Authors: Luca Loprete, Chiara Leuratti, Carlo Cattaneo, Mita Thapar, Colm Farrell, Marco SardinaAbstract:Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate Safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of Safinamide effect on the PD phase of normal functioning (ON-time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected-VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one-compartmental model with first-order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73–5.21) L/h, 166 (158–174) L, and 0.582 (0.335–0.829) h−1, respectively. CL/F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence Safinamide PK. The observed ON-time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON-time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON-time of 0.73 h (week 4), with further ON-time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or Safinamide exposure. The population models adequately describe the population PK of Safinamide and Safinamide effect on ON-time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested.
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Safinamide as add on therapy to levodopa in mid to late stage parkinson s disease fluctuating patients post hoc analysesof studies 016 and settle
Journal of Parkinson's disease, 2016Co-Authors: Carlo Cattaneo, Marco Sardina, Erminio BonizzoniAbstract:Background: Studies 016 and SETTLE showed that Safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of Safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms. Objective: To evaluate the clinical effects of Safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE. Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of Safinamide versus placebo on individual cardinal PD symptoms during ON time. Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, Safinamide improved bradykinesia, rigidity, tremor and gait. Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies.
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Safinamide and glutamate release new insights
Parkinsonism & Related Disorders, 2016Co-Authors: Elsa Melloni, Carla Caccia, Gloria Padoani, Alberto Brugnoli, Michele Morari, Silvia Vailati, Marco SardinaAbstract:s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e177 Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy; RD Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy Objectives: Safinamide (Xadago®) is a novel drug recently approved as add-on therapy to levodopa in midto late-stage Parkinson's disease. Xadago® shows a unique dual mechanism of action: it has both dopaminergic properties (highly selective, potent and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (state and usedependent sodium channel blockade causing inhibition of excessive glutamate release). The study aim was to evaluate the effect of Safinamide on stimulated glutamate release in rat hippocampus at doses giving free brain concentrations able to block sodium channels and to provide a PK/PD approach to support its clinical relevance on overactive glutamate release inhibition. Methods: Glutamate release, stimulated by veratridine in the hippocampus of rats, was measured by in vivo microdialysis. Results: Safinamide was able to significantly inhibit the glutamate release in a dose-dependent manner and the relative measured free brain concentrations (0.3-2.2 mM) support the inhibition of sodium channels (2050% Ki. A functional blockade of sodium channels suggests that pharmacodynamically active concentrations of Safinamide are available at the target sites in the brain: in rodents significant protection (50-70%) from convulsions was found when free brain concentration of 0.37-1.4 mM was reached. At the recommended clinical doses (50 and 100 mg) the estimated human free brain Safinamide concentrations (0.21-1.92 mM) overlap the range of measured free brain concentrations effective in inhibiting overactive glutamate release in animals. Conclusions: These results clearly support the non-dopaminergic aspects of Xadago® mode of action in rats, likely relevant also in humans. P 6.004. 4I (N-(3-CHLORO-2-METHYLPHENYL) QUINOXALIN-2-CARBOXAMIDE), A NOVEL 5-HT3 RECEPTOR ANTAGONIST ALLEVIATES DEPRESSIVE BEHAVIOR EVOKED IN STREPTOZOTOCIN-INDUCED DIABETIC MICE: ROLE OF OXIDATIVE STRESS Deepali Gupta, Mahesh Radhakrishnan. Department of Pharmacy, Pilani,
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long term effects of Safinamide on dyskinesia in mid to late stage parkinson s disease a post hoc analysis
Journal of Parkinson's disease, 2015Co-Authors: Carlo Cattaneo, Erminio Bonizzoni, R La Ferla, Marco SardinaAbstract:Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of Safinamide on dyskinesia may be related to severity of dyskinesia at baseline. Objective: This post-hoc analysis further characterized the effects of Safinamide on dyskinesia in mid- to late-stage PD patients. Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between Safinamide and placebo were evaluated using the Wilcoxon rank-sum test. Results: For the overall treated population (with or without baseline dyskinesia), Safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. Conclusions: While no statistically significant difference in mean DRS scores was seen between Safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of Safinamide on dyskinesia. These results may be related to Safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation.
Thomas Müller - One of the best experts on this subject based on the ideXlab platform.
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Safinamide in the treatment of Parkinson's disease
Future Medicine Ltd, 2020Co-Authors: Thomas MüllerAbstract:The deficiency pattern of neurotransmitters is heterogeneous in patients with Parkinson's disease. Consequence is an individual variable expression of motor and nonmotor features. They respond to agents with a broader spectrum of mode of actions, whereas dopamine substitution only targets impaired motor behavior. The pharmacological profile of Safinamide includes reversible monoamine oxidase B inhibition and modulation of voltage-dependent sodium- and calcium channels with consecutive decline of glutamate release. Safinamide improves motor and nonmotor symptoms. Combination of Safinamide with the catechol-O-methyltransferase inhibitor opicapone in one capsule is a promising future treatment alternative, which simplifies drug therapy in Parkinson's disease. Both agents complement each other in terms of application mode and efficacy on motor complications as adjuncts to levodopa therapy.
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Safinamide an add on treatment for managing parkinson s disease
Clinical Pharmacology: Advances and Applications, 2018Co-Authors: Thomas MüllerAbstract:Heterogeneous expression of neurotransmitter deficits results from onset and progression of Parkinson's disease. Intervals, characterized by reappearance of motor and associated certain nonmotor symptoms, determine the end of good tolerability and efficacy of oral levodopa therapy. These "OFF" states result from levodopa pharmacokinetics and disease progression-related deterioration of the central buffering capacity for fluctuations of dopamine levels. This review discusses Safinamide as an add-on therapeutic agent in orally levodopa-treated patients with "OFF" phenomena. Safinamide provided beneficial effects on "OFF" symptoms in pivotal trials with doses of 50 or 100 mg once daily. Safinamide reversibly inhibits mono-amine oxidase B and declines abnormal glutamate release by modulation of potassium- and sodium ion channels. An ideal candidate for combination with Safinamide is opicapone. This inhibitor of peripheral catechol-O-methyltransferase supports continuous brain delivery of levodopa and, thus, the continuous dopaminergic stimulation concept. Both compounds with their once-daily application and good tolerability may complement each other by reduction of necessary oral levodopa intakes and "OFF" times. Thus, a promising, future option will be combination of Safinamide and opicapone in one formulation. It will reduce adherence issues and may complement levodopa treatment. It will probably cause less nausea and edema than a dopamine agonist/levodopa regimen.
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determination of monoamine oxidase a and b activity in long term treated patients with parkinson disease
Clinical Neuropharmacology, 2017Co-Authors: Thomas Müller, Peter Riederer, Edna GrunblattAbstract:BACKGROUND Biogenic amines and monoamine oxidase inhibitors influence peripheral monoamine oxidase enzyme activity in chronic levodopa/dopa decarboxylase inhibitor-treated patients with Parkinson disease. Rasagiline is an irreversible inhibitor of monoamine oxidase B. Safinamide blocks this isoenzyme in a reversible fashion. OBJECTIVES The aim of this study was to determine monoamine oxidase A (plasma) and B (platelets) enzyme activity in long-term levodopa-treated patients without and with additional oral intake of 50- or 100-mg Safinamide or 1-mg rasagiline or first-time intake of rasagiline. RESULTS Monoamine oxidase A enzyme activity did not differ between all groups. Patients on rasagiline or Safinamide showed lower monoamine oxidase-B enzyme activity compared with patients without monoamine oxidase B inhibitor intake. No impact of the number of previous oral levodopa intakes was found. DISCUSSION Rasagiline and Safinamide did not essentially differ in terms of inhibition of monoamine oxidase B despite their different pharmacology regarding reversibility of monoamine oxidase B inhibition. In view of the observed, considerable heterogeneity of enzyme activities, we suggest to determine activities of monoamine oxidase A and B to reduce the risk for tyramine-induced hypertension and the serotonergic syndrome during chronic therapy with rasagiline or Safinamide.
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Clinical Pharmacokinetics and Pharmacodynamics of Safinamide
Clinical Pharmacokinetics, 2017Co-Authors: Thomas Müller, Paul FoleyAbstract:The symptoms of Parkinson’s disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of Safinamide includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent Na^+ channels, modulation of Ca^2+ channels, and inhibition of glutamate release. Safinamide is administered once daily at oral doses of 50–100 mg; it is well-tolerated and safe. Clinical trials have found that it ameliorates motor symptoms when added to established levodopa or single dopamine receptor agonist therapy. The future role of Safinamide in PD may be that it enables a reduction in the dosage of dopamine replacement therapies, thereby reducing the adverse effects associated with these treatments. The clinical convenience (once-daily administration), safety, and tolerability of Safinamide are better than those of dopamine receptor agonists. The introduction of Safinamide reflects a change of approach to drug development for anti-parkinsonian agents in that its broad spectrum of action corresponds to the multiple heterogeneous alterations of brain neurochemistry in PD, rather than being targeted at a single receptor type or neurochemical process. Safinamide is a promising new instrument for the effective symptomatic therapy of PD.
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long term effects of Safinamide on mood fluctuations in parkinson s disease
Journal of Parkinson's disease, 2017Co-Authors: Carlo Cattaneo, Thomas Müller, Erminio Bonizzoni, Gabriele Lazzeri, Ioannis Kottakis, Charlotte KeywoodAbstract:Background Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. Objective To investigate the effects of Safinamide on mood over two-year treatment in PD patients with motor fluctuations. Methods This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. Results Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the Safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). Conclusion The favorable effect of Safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.
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assessment of safety and efficacy of Safinamide as a levodopa adjunct in patients with parkinson disease and motor fluctuations a randomized clinical trial
JAMA Neurology, 2017Co-Authors: Anthony H V Schapira, Joseph Jankovic, Rajesh Pahwa, Robert A Hauser, Wolfgang H Jost, Christopher Kenney, Jaime Kulisevsky, R AnandAbstract:IMPORTANCE: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. OBJECTIVE: To investigate the efficacy and safety of Safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive Safinamide or placebo for 24 weeks. All patients had idiopathic PD with “off” time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient’s regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the Safinamide group and 10 individuals (3.6%) in the placebo group. INTERVENTIONS: Patients took Safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was each treatment group’s mean change from baseline to week 24 (or last “on” treatment value) in daily “on” time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. RESULTS: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to Safinamide and 275 to placebo. Among them, 245 (89.4%) receiving Safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for Safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). CONCLUSIONS AND RELEVANCE: The outcomes of this trial support Safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.
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long term efficacy and safety of Safinamide as add on therapy in early parkinson s disease
European Journal of Neurology, 2013Co-Authors: Anthony H V Schapira, Fabrizio Stocchi, Rupam Borgohain, Marco Onofrj, Mohit Bhatt, V Lucini, R Giuliani, P Lorenzana, R AnandAbstract:Background and purpose Safinamide is an α-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action in Phase III clinical development as a once-daily add-on to dopamine agonist (DA) therapy for early Parkinson's disease (PD). Methods Study 017 was a 12-month, randomized, double-blind, placebo-controlled pre-planned extension study to the previously reported Study 015. Patients received Safinamide 100 or 200 mg/day or placebo added to a single DA in early PD. The primary efficacy endpoint was the time from baseline (Study 015 randomization) to ‘intervention’, defined as increase in DA dose; addition of another DA, levodopa or other PD treatment; or discontinuation due to lack of efficacy. Safinamide groups were pooled for the primary efficacy endpoint analysis; post hoc analyses were performed on each separate dose group. Results Of the 269 patients randomized in Study 015, 227 (84%) enrolled in Study 017 and 187/227 (82%) patients completed the extension study. Median time to intervention was 559 and 466 days in the pooled Safinamide and placebo groups, respectively (log-rank test; P = 0.3342). In post hoc analyses, patients receiving Safinamide 100 mg/day experienced a significantly lower rate of intervention compared with placebo (25% vs. 51%, respectively) and a delay in median time to intervention of 9 days (P < 0.05; 240- to 540-day analysis). Conclusions The pooled data from the Safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that Safinamide 100 mg/day may be effective as add-on treatment to DA in PD.
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a randomized double blind placebo controlled trial of Safinamide as add on therapy in early parkinson s disease patients
Movement Disorders, 2012Co-Authors: Fabrizio Stocchi, Anthony H V Schapira, Rupam Borgohain, Marco Onofrj, Mohit Bhatt, V Lucini, R Giuliani, R AnandAbstract:Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily Safinamide 100 mg, Safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of Safinamide versus placebo was tested first; the success of Safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received Safinamide 100 mg (n = 90), Safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for Safinamide 200 mg, -6.0 for Safinamide 100 mg and -3.60 for placebo. The difference between Safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for Safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of Safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.
