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Moussa B. H. Youdim - One of the best experts on this subject based on the ideXlab platform.
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Rasagiline a novel anti parkinsonian monoamine oxidase b inhibitor with neuroprotective activity
Progress in Neurobiology, 2010Co-Authors: Orly Weinreb, Orit Baram, Tamar Amit, Moussa B. H. YoudimAbstract:Abstract Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to l -Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of Rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of Rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, Rasagiline. This paper will review the earlier and present studies in the development of Rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action.
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the neuroprotective mechanism of 1 r aminoindan the major metabolite of the anti parkinsonian drug Rasagiline
Journal of Neurochemistry, 2010Co-Authors: Orit Baram, Orly Weinreb, Tamar Amit, Moussa B. H. YoudimAbstract:J. Neurochem. (2010) 112, 1131–1137. Abstract The anti-parkinsonian drug, Rasagiline [N-propargyl-1-(R)-aminoindan; Azilect®], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B) inhibition and possesses neuroprotective and neurorestorative activities. A prospective clinical trial has shown that Rasagiline confers significant symptomatic improvement and demonstrated alterations in Parkinson’s disease progression. Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, 1-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound. Recent studies indicated the potential neuroprotective effect of 1-(R)-aminoindan, suggesting that it may contribute to the overall neuroprotective and antiapoptotic effects of its parent compound, Rasagiline. This review article briefly highlights the molecular mechanisms underlying the neuroprotective properties of the active metabolite of Rasagiline, 1-(R)-aminoindan, supporting the valuable potential of Rasagiline for disease modification.
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comparison of neuroprotective and neurorestorative capabilities of Rasagiline and selegiline against lactacystin induced nigrostriatal dopaminergic degeneration
Journal of Neurochemistry, 2008Co-Authors: Joseph Jankovic, Moussa B. H. Youdim, Jun Li, Weidong LeAbstract:Nigrostriatal neurodegeneration in Parkinson's disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of Rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 mug/side), into the medial forebrain bundle. Administration of Rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both Rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only Rasagiline managed to restore the nigrostriatal degeneration. Furthermore, Rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, Rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD.
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activation of tyrosine kinase receptor signaling pathway by Rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post mptp induced parkinsonism
Neurobiology of Disease, 2007Co-Authors: Yotam Sagi, Tamar Amit, Silvia Mandel, Moussa B. H. YoudimAbstract:Abstract The anti-Parkinson monoamine oxidase (MAO)-B inhibitor Rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that Rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway including ShcC, SOS, AF6, Rin1 and Ras and the increase in the Trk-downstream effector phosphatidylinositol 3 kinase (PI3K) protein. Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3β and Raf1. Thus, the activation of Ras-PI3K-Akt survival pathway may contribute to Rasagiline-mediated neurorescue effect. It is interesting to determine whether a similar effect is seen in parkinsonian patients after long-term treatment with Rasagiline.
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the anti parkinson drug Rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to mao inhibition in cell culture and in vivo
Annals of the New York Academy of Sciences, 2006Co-Authors: Moussa B. H. Youdim, A Wadia, W Tatton, Marta WeinstockAbstract:: The antiapoptotic and neuroprotective activity of irreversible monoamine oxidase (MAO) B inhibitor, Rasagiline [r(+)-N-propargyl-1-aminioindan], its S-isomer (TVP1022) and TV 3219, a novel anti-Alzheimer cholinesterase-MAO inhibitor drug derived from Rasagiline were examined in PC12 cells cultures and in vivo. We found that these drugs have potent antiapoptotic and neuroprotective activities in response to serum and NGF withdrawal in partially neuronally differentiated PC12 cells and prevent the fall in mitochondrial membrane potential, the first step in cell death. Closed head injury studies in mice have shown that both Rasagiline and TVP1022 are neuroprotective. All these compounds possess a propargyl moiety, which normally is responsible for irreversible inactivation of MAO, as is seen with Rasagiline. However, neither TVP1022 nor TV3219 are MAO inhibitors, both share the antiapoptotic and neuroprotective actions of Rasagiline, indicating that MAO inhibition is not a prerequisite for neuroprotection and that the propargyl moiety exhibits intrinsic neuroprotective pharmacological activity that requires identification.
Marta Weinstock - One of the best experts on this subject based on the ideXlab platform.
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the anti parkinson drug Rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to mao inhibition in cell culture and in vivo
Annals of the New York Academy of Sciences, 2006Co-Authors: Moussa B. H. Youdim, A Wadia, W Tatton, Marta WeinstockAbstract:: The antiapoptotic and neuroprotective activity of irreversible monoamine oxidase (MAO) B inhibitor, Rasagiline [r(+)-N-propargyl-1-aminioindan], its S-isomer (TVP1022) and TV 3219, a novel anti-Alzheimer cholinesterase-MAO inhibitor drug derived from Rasagiline were examined in PC12 cells cultures and in vivo. We found that these drugs have potent antiapoptotic and neuroprotective activities in response to serum and NGF withdrawal in partially neuronally differentiated PC12 cells and prevent the fall in mitochondrial membrane potential, the first step in cell death. Closed head injury studies in mice have shown that both Rasagiline and TVP1022 are neuroprotective. All these compounds possess a propargyl moiety, which normally is responsible for irreversible inactivation of MAO, as is seen with Rasagiline. However, neither TVP1022 nor TV3219 are MAO inhibitors, both share the antiapoptotic and neuroprotective actions of Rasagiline, indicating that MAO inhibition is not a prerequisite for neuroprotection and that the propargyl moiety exhibits intrinsic neuroprotective pharmacological activity that requires identification.
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Molecular Basis of Neuroprotective Activities of Rasagiline and the Anti-Alzheimer Drug TV3326 [lpar;N-Propargyl-(3R) Aminoindan-5-YL)-Ethyl Methyl Carbamate]
Cellular and Molecular Neurobiology, 2001Co-Authors: Moussa B. H. Youdim, Marta WeinstockAbstract:Rasagiline ( N -propargyl-1-( R )-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and antiapoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N -methyl-( R )-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the Rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [( N -Propargyl-(3 R )Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S -enantiomer TV3279 [( N -Propargyl-(3 S ) Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of Rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The antiapoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glycerlaldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PK11195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, Rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by Rasagiline and TV3326 is closely linked to the anti-apototic action of these drugs and their ability to process APP by activation of alpha-secretase.
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molecular basis of neuroprotective activities of Rasagiline and the anti alzheimer drug tv3326 n propargyl 3r aminoindan 5 yl ethyl methyl carbamate
Cellular and Molecular Neurobiology, 2001Co-Authors: Moussa B. H. Youdim, Marta WeinstockAbstract:Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and antiapoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the Rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S) Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of Rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The antiapoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glycerlaldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PK11195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, Rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by Rasagiline and TV3326 is closely linked to the anti-apototic action of these drugs and their ability to process APP by activation of alpha-secretase.
Robert A. Hauser - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and safety of Rasagiline in the treatment of Parkinson disease
Formulary, 2020Co-Authors: Robert A. HauserAbstract:Rasagiline was recently approved as monotherapy in early Parkinson disease (PD) and as an adjunct to levodopa in PD patients with motor fluctuations. Results of a 6-month, phase 3, monotherapy trial demonstrated significant benefits of Rasagiline 1 and 2 mg compared with placebo on Unified Parkinson's Disease Rating Scale scores, motor and activities of daily living subscales, and quality of life. Patients who started Rasagiline at the onset of the study and continued it for another 6 months derived significantly greater benefit than those who were switched from placebo to Rasagiline after 6 months, suggesting that Rasagiline may have a disease-modifying effect. Two phase 3, adjunctive-therapy studies found significant benefits of Rasagiline as add-on therapy for reducing off time in levodopa-treated patients. That benefit was accompanied by significant increases in on time and improvements in the ability to perform activities of daily living during off time. Rasagiline has been well tolerated in clinical trials. Reported adverse events have generally been similar in Rasagiline and placebo groups. Approximately 200 patients have been treated with Rasagiline for at least 3 years, with safety profiles similar to those observed during shorter exposure.
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Rasagiline for mild cognitive impairment in parkinson s disease a placebo controlled trial
Movement Disorders, 2016Co-Authors: Daniel Weintraub, Fernando Pagan, Robert A. Hauser, Matthew D Davis, Azhar ChoudhryAbstract:Background This study's aims were to determine the efficacy and tolerability of Rasagiline, a selective monoamine oxidase inhibitor B, for PD patients with mild cognitive impairment. Methods Patients on stable dopaminergic therapy were randomized to adjunct Rasagiline 1 mg/day or placebo in this 24-week, double-blind, placebo-controlled, multisite study. The primary endpoint was mean change from baseline to week 24 on the Scales for Outcomes of Parkinson's Disease-Cognition total score. Key secondary measures included changes in cognition, activities of daily living, motor scores, and Clinical Global Impression of Change, as well as safety and tolerability measures. Results Of the 170 patients randomized, 151 (88.2%) completed the study. Change in Scales for Outcomes of Parkinson's Disease-Cognition scores were not significantly different in the Rasagiline and placebo groups (adjusted mean: 1.6 [standard error {SE} = 0.5] vs. 0.8 [SE = 0.5] points; LS means difference = 0.8; 95% confidence interval: −0.48, 2.05; P = 0.22). There were no between-group differences in change in the MoCA (p=0.84) or Penn Daily Activities Questionnaire (P = 0.48) scores or in the distribution of Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change modified for mild cognitive impairment (P = 0.1). Changes in motor (UPDRS part III; P = 0.02) and activities of daily living (UPDRS part II; P < 0.001) scores favored Rasagiline. Rasagiline was well tolerated; the most common adverse events in both groups were falls and dizziness. Conclusions Rasagiline treatment in PD patients with mild cognitive impairment was not associated with cognitive improvement. Rasagiline did not worsen cognition, improved motor symptoms and activities of daily living, and was well tolerated in elderly cognitively impaired patients. © 2016 International Parkinson and Movement Disorder Society
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randomized controlled trial of Rasagiline as an add on to dopamine agonists in parkinson s disease
Movement Disorders, 2014Co-Authors: Robert A. Hauser, Eli Eyal, Azhar Choudhry, Dee Silver, Stuart IsaacsonAbstract:Dopamine agonists (DA) are often used as first-line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase-B (MAO-B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18-week, randomized, double-blind, placebo-controlled trial of Rasagiline 1 mg/d as an add-on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing Rasagiline and placebo groups. The modified intent-to-treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the Rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, −2.4 ± 0.95; 95% confidence interval [CI], −4.3, −0.5; P = 0.012). Mean improvement (LS mean ± SE) was −3.6 ± 0.68 in the Rasagiline group and −1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; Rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society
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a double blind delayed start trial of Rasagiline in parkinson s disease the adagio study prespecified and post hoc analyses of the need for additional therapies changes in updrs scores and non motor outcomes
Lancet Neurology, 2011Co-Authors: Olivier Rascol, Robert A. Hauser, Joseph Jankovic, Werner Poewe, Fabrizio Stocchi, Cheryl Fitzerattas, Anthony E Lang, William J Langston, Eldad Melamed, Eduardo TolosaAbstract:Summary Background The ADAGIO study investigated whether Rasagiline has disease-modifying effects in Parkinson's disease. Rasagiline 1 mg per day, but not 2 mg per day, was shown to be efficacious in the primary analysis. Here, we report additional secondary and post-hoc analyses of the ADAGIO study. Methods ADAGIO was a placebo-controlled, double-blind, multicentre, delayed-start study, in which 1176 patients with untreated early Parkinson's disease were randomly assigned to receive Rasagiline 1 mg or 2 mg per day for 72 weeks (early-start groups) or placebo for 36 weeks followed by Rasagiline 1 mg or 2 mg per day for 36 weeks (delayed-start groups). We assessed the need for additional antiparkinsonian therapy and changes in non-motor experiences of daily living and fatigue scales (prespecified outcomes) and changes in unified Parkinson's disease rating scale (UPDRS) scores and subscores in placebo and active groups (post-hoc outcomes). The ADAGIO study is registered with ClinicalTrials.gov, number NCT00256204. Findings The need for additional antiparkinsonian therapy was reduced with Rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg Rasagiline vs placebo 0·41, 95% CI 0·25–0·65, p=0·0002; 2 mg Rasagiline vs placebo 0·41, 0·26–0·64, p=0·0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg Rasagiline mean difference −1·88 [SE 0·35]; 2 mg Rasagiline −2·18 [0·35]; both p 25·5; n=145; mean difference −3·46 [SE 0·77]; p Interpretation These findings show that Rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the Rasagiline 1 mg per day early-start versus delayed-start group. The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. Understanding of the pattern of UPDRS deterioration is essential to assess disease modification. Funding Teva Pharmaceutical Industries and H Lundbeck A/S.
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long term efficacy of Rasagiline in early parkinson s disease
International Journal of Neuroscience, 2010Co-Authors: Robert A. Hauser, Tamar Goren, Howard I Hurtig, William G Ondo, Joanne Wojcieszek, Cheryl FitzerattasAbstract:ABSTRACTThis study was designed to follow the long-term efficacy, safety, and tolerability of Rasagiline for Parkinson's disease (PD) with data collected from all patients who had ever taken Rasagiline during the 12-month TEMPO monotherapy trial (N = 398) and subsequent open-label extension. Patients were followed for up to 6.5 years with a mean of 3.5 ± 2.1 years. After 12 months, additional PD medications were added as required. Of patients remaining in the trial at 2 years, 46% were maintained on Rasagiline monotherapy. The majority of patients received a dopamine agonist prior to levodopa as the first additional dopaminergic agent. Analysis using a Kaplan–Meier method indicated that by 5.4 years only 25% of patients progressed to Hoehn & Yahr stage III. Rasagiline was well tolerated, with 11.3% of patients (45/398) withdrawing because of an adverse event. Rasagiline therapy for PD was effective, well tolerated, and safe in this long-term trial.
Jack J. Chen - One of the best experts on this subject based on the ideXlab platform.
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the monoamine oxidase type b inhibitor Rasagiline in the treatment of parkinson disease is tyramine a challenge
The Journal of Clinical Pharmacology, 2012Co-Authors: Jack J. Chen, Jayne R. WilkinsonAbstract:Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize Rasagiline selectivity for the MAO-B enzyme and tyramine sensitivity, demonstrate that Rasagiline, when used at the recommended dose, is selective for MAO-B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical trials of Rasagiline in Parkinson disease involving 2066 Rasagiline-treated patients who did not require dietary tyramine restriction per protocol. In late 2009, US labeling for Rasagiline was modified to state that dietary tyramine restrictions are not ordinarily required when Rasagiline is administered at recommended doses. In addition, because Rasagiline has been demonstrated to be selective for MAO-B at the approved dose of up to 1 mg/d, contraindications regarding concomitant use with sympathomimetic amines, use of sympathomimetic vasopressors in conjunction with general or local anesthesia, and use in patients with pheochromocytoma also were removed.
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The monoamine oxidase type B inhibitor Rasagiline in the treatment of Parkinson disease: Is tyramine a challenge?
Journal of Clinical Pharmacology, 2012Co-Authors: Jack J. Chen, Jayne R. WilkinsonAbstract:Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize Rasagiline selectivity for the MAO-B enzyme and tyramine sensitivity, demonstrate that Rasagiline, when used at the recommended dose, is selective for MAO-B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical trials of Rasagiline in Parkinson disease involving 2066 Rasagiline-treated patients who did not require dietary tyramine restriction per protocol. In late 2009, US labeling for Rasagiline was modified to state that dietary tyramine restrictions are not ordinarily required when Rasagiline is administered at recommended doses. In addition, because Rasagiline has been demonstrated to be selective for MAO-B at the approved dose of up to 1 mg/d, contraindications regarding concomitant use with sympathomimetic amines, use of sympathomimetic vasopressors in conjunction with general or local anesthesia, and use in patients with pheochromocytoma also were removed. © 2012 The Author(s).
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comprehensive review of Rasagiline a second generation monoamine oxidase inhibitor for the treatment of parkinson s disease
Clinical Therapeutics, 2007Co-Authors: Jack J. Chen, David M Swope, Khashayar DashtipourAbstract:Background: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). Objective: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of Rasagiline in the treatment of PD. Methods: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, Rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of Rasagiline. Results: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that Rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, Rasagiline was found to be ≤10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, Rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was –4.20 (95% CI, -5.66 to -2.73) for Rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when Rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, Rasagiline and entacapone were associated with reductions of “off” time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P ≤ 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged ≥70 years) patients with early or advanced PD. Pharmacologically, Rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the “cheese reaction”). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, Rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. Conclusions: Based on this review, Rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether Rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.
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Rasagiline a second generation monoamine oxidase type b inhibitor for the treatment of parkinson s disease
American Journal of Health-system Pharmacy, 2006Co-Authors: Jack J. Chen, Anhvuong LyAbstract:Purpose. The pharmacology, pharmacokinetics, clinical efficacy, and safety of Rasagiline are reviewed. Summary. Rasagiline is a novel, investigational propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). Rasagiline demonstrates complete and selective inhibition of MAO-B and is at least five times more potent than selegiline. Unlike selegiline, which is metabolized to amphetamine derivatives, Rasagiline is biotransformed to the nonamphetamine compound aminoindan. Clinical studies have revealed that Rasagiline is associated with improved outcomes in patients with early Parkinson’s disease (PD) and also reduces “off” time in patients with moderate to advanced PD with motor fluctuations. Rasagiline is rapidly absorbed by the gastrointestinal tract and readily crosses the blood–brain barrier. The optimal therapeutic dosage is 0.5–1 mg administered orally once daily. Rasagiline appears to be well tolerated, although elderly patients may be more prone to treatment-emergent adverse cardiovascular and psychiatric effects. At the recommended therapeutic dosage of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, Rasagiline has demonstrated neuroprotective properties in experimental laboratory models. The mechanisms whereby Rasagiline exerts neuroprotective effects are multifactorial and include upregulation of cellular antioxidant activity and antiapoptotic factors. Conclusion. Rasagiline is an investigational selective and irreversible inhibitor of MAO-B that has demonstrated efficacy and safety for the treatment of PD. Whether Rasagiline is associated with clinically significant neuroprotection is the subject of ongoing clinical trials.
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clinical pharmacology of Rasagiline a novel second generation propargylamine for the treatment of parkinson disease
The Journal of Clinical Pharmacology, 2005Co-Authors: Jack J. Chen, David M SwopeAbstract:Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), Rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, Rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, Rasagiline offers the promise of clinically relevant neuroprotection.
Tamar Amit - One of the best experts on this subject based on the ideXlab platform.
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Rasagiline a novel anti parkinsonian monoamine oxidase b inhibitor with neuroprotective activity
Progress in Neurobiology, 2010Co-Authors: Orly Weinreb, Orit Baram, Tamar Amit, Moussa B. H. YoudimAbstract:Abstract Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to l -Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of Rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of Rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, Rasagiline. This paper will review the earlier and present studies in the development of Rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action.
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the neuroprotective mechanism of 1 r aminoindan the major metabolite of the anti parkinsonian drug Rasagiline
Journal of Neurochemistry, 2010Co-Authors: Orit Baram, Orly Weinreb, Tamar Amit, Moussa B. H. YoudimAbstract:J. Neurochem. (2010) 112, 1131–1137. Abstract The anti-parkinsonian drug, Rasagiline [N-propargyl-1-(R)-aminoindan; Azilect®], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B) inhibition and possesses neuroprotective and neurorestorative activities. A prospective clinical trial has shown that Rasagiline confers significant symptomatic improvement and demonstrated alterations in Parkinson’s disease progression. Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, 1-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound. Recent studies indicated the potential neuroprotective effect of 1-(R)-aminoindan, suggesting that it may contribute to the overall neuroprotective and antiapoptotic effects of its parent compound, Rasagiline. This review article briefly highlights the molecular mechanisms underlying the neuroprotective properties of the active metabolite of Rasagiline, 1-(R)-aminoindan, supporting the valuable potential of Rasagiline for disease modification.
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activation of tyrosine kinase receptor signaling pathway by Rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post mptp induced parkinsonism
Neurobiology of Disease, 2007Co-Authors: Yotam Sagi, Tamar Amit, Silvia Mandel, Moussa B. H. YoudimAbstract:Abstract The anti-Parkinson monoamine oxidase (MAO)-B inhibitor Rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that Rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway including ShcC, SOS, AF6, Rin1 and Ras and the increase in the Trk-downstream effector phosphatidylinositol 3 kinase (PI3K) protein. Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3β and Raf1. Thus, the activation of Ras-PI3K-Akt survival pathway may contribute to Rasagiline-mediated neurorescue effect. It is interesting to determine whether a similar effect is seen in parkinsonian patients after long-term treatment with Rasagiline.
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regulation of protein kinase c by the anti parkinson drug mao b inhibitor Rasagiline and its derivatives in vivo
Journal of Neurochemistry, 2004Co-Authors: Orit Baram, Tamar Amit, Merav Yogevfalach, Yotam Sagi, Moussa B. H. YoudimAbstract:We have recently shown that the anti-Parkinson-propargyl-containing monoamine oxidase B (MAO-B) inhibitor drug, Rasagiline [N-propargyl-(1R)-aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)-dependent mechanism in SH-SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of Rasagiline and its derivatives on the regulation of the PKC-dependent mechanism and APP processing under in vivo conditions. Administration of Rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane-bound holoprotein APP levels in the hippocampus. Additionally, we observed that Rasagiline up-regulated p-PKC levels and the expression of α and e PKC isozymes in the hippocampus, indicating that the mechanism by which Rasagiline affects APP processing may be related to PKC-associated signalling. The results also demonstrate that Rasagiline treatment significantly elevated the levels of phosphorylated myristoylated alanine-rich C kinase substrate (p-MARCKS), a major substrate for PKC, as well as the levels of receptors for activated C kinase 1 (RACK1). Similar effects on APP and PKC levels were also demonstrated for the two cholinesterase inhibitor derivatives of Rasagiline, TV3326 and TV3279. These results indicate that Rasagiline and its derivatives regulate PKC-dependent mechanisms and APP processing. The activation and induction of PKC and MARCKS by these drugs may have a crucial role not only in their neuroprotective activity, but also in their ability to affect neuronal plasticity and spatial learning processes.
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contrasting neuroprotective and neurotoxic actions of respective metabolites of anti parkinson drugs Rasagiline and selegiline
Neuroscience Letters, 2004Co-Authors: Moussa B. H. Youdim, Tamar Amit, Orit Bar AmAbstract:Abstract The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, Rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While Rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to l -methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either Rasagiline (1 μM) or selegiline (1 μM) is neuroprotective and anti-apoptotic as determined by Eliza and MTT tests. However, while aminoindan (1 μM), the major metabolite of Rasagiline does not interfere with the neuroprotective activities of Rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, l -methamphetamine (1 μM), inhibits them. In contrast to l -methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that Rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of Rasagiline is blocked by ERK inhibitor, PD98059 (20 μM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of Rasagiline in treatment of Parkinson's disease.
