2.217 1-Aminoindan, a main metabolite of rasagiline, enhances dopamine release and provides symptomatic benefit in an animal model of Parkinson's disease

Brotchie, Jonathan M.; Johnston, T.H.; Visanji, Naomi P.; Pires, Donna; Thiele, Sherri L.; Fitzer‐Attas, Cheryl; Montezinho, L.C.; Mørk, Arne; Thomsen, C.

doi:10.1016/s1353-8020(08)70628-x

Cited by 6 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The extended-release formulations of RAS may also have contributed to benefit because of prolonged exposure to rasagiline metabolites, which can potentially provide benefits through non-MAO-B-related mechanisms. [23][24][25] Indeed, preclinical studies in MPTP mouse model and 6-OHDA rat model demonstrated superior pharmacologic and motor benefits in comparison to the standard formulation of the drugs (data on file at Pharma Two B). The magnitude of benefit compared to placebo in untreated patients with PD previously observed with P2B001 in double-blind trials ($4.7 points) 14 is clinically meaningful, 21,26 and compares favorably with the benefit achieved with dopamine agonists and even the low doses of L-dopa that are typically used in early PD.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low‐Dose Extended‐Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended‐Release Pramipexole in Early Parkinson's Disease

Olanow,

Hauser,

Burdick

et al. 2023

Movement Disorders

View full text Add to dashboard Cite

BackgroundThere remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity.ObjectivesThe objective was to determine if P2B001 (a fixed, low‐dose, extended‐release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole‐ER.MethodsThis was a 12‐week, double‐blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole‐ER 0.6 mg or rasagiline‐ER 0.75 mg), or commercial doses of pramipexole‐ER titrated to optimal dose (1.5–4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole‐ER.ResultsP2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were −2.66 (95% CI, −4.33 to −1.00) versus pramipexole‐ER 0.6 mg (P = 0.0018) and − 3.30 (95% CI, −4.96 to −1.63) versus rasagiline‐ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole‐ER (mean, 3.2 mg), but significantly less worsening in daytime‐sleepiness (ESS treatment difference: −2.66 [95% CI, −3.50 to −1.81]; P < 0.0001). P2B001 was well‐tolerated with fewer sleep‐related and dopaminergic adverse events than titrated doses of pramipexole‐ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects.ConclusionsP2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole‐ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once‐daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society.

show abstract

Section: Discussionmentioning

confidence: 99%

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low‐Dose Extended‐Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended‐Release Pramipexole in Early Parkinson's Disease

Olanow,

Hauser,

Burdick

et al. 2023

Movement Disorders

View full text Add to dashboard Cite

show abstract

“…MAO-B inhibition with rasagiline also increases the availability of phenylethylamine, which can enhance striatal dopamine release [38]. Striatal dopamine release may also be enhanced by the rasagiline active metabolite, 1-aminoindan, an effect which is thought to be separate from MAO-B inhibition (although 1-aminoindan is also a weak MAO-B inhibitor) [39,40]. Both rasagiline and 1-aminoindan contain a propargylamine moiety which have been shown to inhibit apoptosis in both in vitro and in vivo models of PD [41].…”

Section: Rasagilinementioning

confidence: 99%

P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease

et al. 2022

View full text Add to dashboard Cite

Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

show abstract

“…An important component of the actions of rasagiline is the activity of its metabolite, 1‐amino‐indan (AI) 55. In rodent models of PD, AI enhances striatal dopamine transmission and improves motor function 56. These effects were independent of MAO inhibition (although AI is a weak inhibitor of MAO‐B57) and were dependent on the presence of dopaminergic terminals.…”

Section: Mitochondria and Rasagilinementioning

confidence: 99%

“…These effects were independent of MAO inhibition (although AI is a weak inhibitor of MAO‐B57) and were dependent on the presence of dopaminergic terminals. But so far, no interaction of AI was found with more than 100 potential neuronal and enzymatic targets 56. Interestingly, in in vivo microdialysis studies, AI increased synaptic concentrations of dopamine and serotonin but not noradrenaline 56.…”

Section: Mitochondria and Rasagilinementioning

confidence: 99%

“…But so far, no interaction of AI was found with more than 100 potential neuronal and enzymatic targets 56. Interestingly, in in vivo microdialysis studies, AI increased synaptic concentrations of dopamine and serotonin but not noradrenaline 56. However, in a cytotoxic human neuroblastoma SK‐N‐SH cell model of high‐density culture‐induced neuronal death, AI significantly reduced the S139 phosphorylation level of the apoptotic‐associated γ‐H2A.X protein, decreased the levels of cleaved caspases‐3 and ‐9, while increasing the levels of phosphorylated protein kinase C (PKC) as well as Bcl‐2 and Bcl‐xL 58.…”

Section: Mitochondria and Rasagilinementioning

confidence: 99%

See 1 more Smart Citation

Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline

Jenner

Langston

2011

Movement Disorders

View full text Add to dashboard Cite

The ADAGIO study demonstrated a symptomatic benefit for rasagiline in early Parkinson's disease (PD) and suggested a disease-modifying effect. Evidence indicates that mitochondrial dysfunction plays a role in the pathogenesis of PD and that this may be the site of effect for rasagiline. In this systematic review, evidence for the role of mitochondria in the pathogenesis of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and the actions of rasagiline and its component parts, namely propargylamine and the metabolite, aminoindan. Evidence for the role of mitochondria in the pathogenesis and treatment of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and clinical actions of rasagiline. Monoamine oxidase B (MAO-B) located in the outer mitochondrial membrane controls dopamine metabolism in early PD, and this is the likely location for the symptomatic action of rasagiline. Accumulating evidence indicates that mitochondrial impairment contributes to dopaminergic neuronal loss in PD, either directly or through other mechanisms such as oxidative stress or protein misfolding. Further rasagiline affects numerous mitochondrial mechanisms that prevent apoptotic cell death including prevention of opening of the mitochondrial transition pore, decreased release of cytochrome C, alterations in pro-antiapoptotic genes and proteins, and the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Thus, the functional neuroprotective actions of rasagiline may not be dependent on MAO-B inhibition, but rather may involve actions of the propargylamine moiety and the aminoindan metabolite. An accumulating body of literature indicates a mitochondrial site of action for rasagiline and highlights the neuroprotective action of the drug, providing strong biological plausibility for disease-modifying effects of the drug such as those observed in ADAGIO.

show abstract

2.217 1-Aminoindan, a main metabolite of rasagiline, enhances dopamine release and provides symptomatic benefit in an animal model of Parkinson's disease

Cited by 6 publications

References 0 publications

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low‐Dose Extended‐Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended‐Release Pramipexole in Early Parkinson's Disease

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low‐Dose Extended‐Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended‐Release Pramipexole in Early Parkinson's Disease

P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson’s Disease

Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline

Contact Info

Product

Resources

About